Chronic Kidney Disease: Clinical Guidelines

List of Abbreviations

BP – blood pressure

AH – arterial hypertension

AHS – antihypertensive drugs

aHUS – atypical hemolytic-uremic syndrome

ATC – Anatomical Therapeutic Chemical classification system

PEM – protein-energy malnutrition

CAKUT – congenital anomalies of the kidney and urinary tract

SHPT – secondary hyperparathyroidism

WHO – World Health Organization

HD – hemodialysis

HDF – hemodiafiltration

LVH – left ventricular hypertrophy

GH – growth hormone

HUS – hemolytic-uremic syndrome

GER – gastroesophageal reflux

DBP – diastolic blood pressure

LVDV – left ventricular diastolic function

RRT – renal replacement therapy

ACEI – angiotensin-converting enzyme inhibitors (ATC classification: "ACE inhibitors")

BI – burden index

iPTH – intact parathyroid hormone (name of the laboratory service for determining the blood parameter according to Order of the Russian Ministry of Health No. 804n dated October 13, 2017: "Determination of parathyroid hormone level in blood")

BMI – body mass index

IGF-1 – insulin-like growth factor 1

DD – developmental delay

CVD – cardiovascular disease

CT – computed tomography

LV – left ventricle

MBD – mineral and bone disorders

CKD-MBD – chronic kidney disease–mineral and bone disorder

BMD – bone mineral density

MRI – magnetic resonance imaging

NGT – nasogastric tube

CIR – circulatory insufficiency

AKI – acute kidney injury

BV – blood volume

PD – peritoneal dialysis

VUR – vesicoureteral reflux

PTA – post-transplant anemia

PTH – parathyroid hormone

PTX – parathyroidectomy

BMD – bone mineral density

RAAS – renin-angiotensin-aldosterone system

SBP – systolic blood pressure

GFR – glomerular filtration rate

ABPM – ambulatory blood pressure monitoring

HF – heart failure

RDI – recommended daily intake

CVS – cardiovascular system

US – ultrasound examination

TNF-α – tumor necrosis factor-α

FSGS – focal segmental glomerulosclerosis

CKD – chronic kidney disease

ECG – electrocardiography

EPO – erythropoietin

ESAs – erythropoiesis-stimulating agents (ATC classification: "Other antianemic preparations")

Echo-CG – echocardiography

Ca – calcium

CAKUT – Congenital Anomalies of the Kidneys and Urinary Tracts

CaSR – calcium-sensing receptor

CKiD – Chronic Kidney Disease in Children

DRI – Dietary Reference Intake

FGF-23 – fibroblast growth factor 23

IDMS – isotope dilution mass spectrometry

IL – interleukin

K – potassium (name of the laboratory service for determining the blood parameter according to Order of the Russian Ministry of Health No. 804n dated October 13, 2017: "Determination of potassium level in blood")

KDOQI – Kidney Disease Outcomes Quality Initiative

KDIGO – Kidney Disease: Improving Global Outcomes

Klotho – transmembrane protein required for activation of the FGF23 receptor

Na – sodium (name of the laboratory service for determining the blood parameter according to Order of the Russian Ministry of Health No. 804n dated October 13, 2017: "Determination of sodium level in blood")

NAPRTCS – North American Pediatric Renal Transplant Cooperative Study

NKF – National Kidney Foundation

P – phosphorus (phosphates) (name of the laboratory service for determining the blood parameter according to Order of the Russian Ministry of Health No. 804n dated October 13, 2017: "Determination of inorganic phosphorus level in blood")

Hb – hemoglobin (name of the laboratory service for determining the blood parameter according to Order of the Russian Ministry of Health No. 804n dated October 13, 2017: "Determination of total hemoglobin level in blood")

HIF-PHD – hypoxia-inducible factor - prolyl-4-hydroxylase domain

HL – High Level

RNI – recommended nutrient intake

SD – standard deviation

SDS – Standard Deviation Score

SDI – Suggested Dietary Intake

TSAT – transferrin saturation (name of the laboratory service for determining the parameter according to Order of the Russian Ministry of Health No. 804n dated October 13, 2017: "Determination of transferrin saturation")

VDR – vitamin D receptor

Terms and Definitions

Arterial hypertension – blood pressure exceeding the 95th percentile for a given sex and age across 3 doctor visits.

Adynamic bone disease – a condition characterized by a decrease in bone volume and mineralization coupled with a decrease in bone formation.

Protein-energy malnutrition – a deficiency of dietary energy and nutrients to meet the requirements of a child's physical development (referred to as malnutrition in English-language literature).

Extraosseous calcification – deposition of phosphates and calcium in the form of hydroxyapatite in the skin, muscles, vascular wall, internal organs, and periarticular tissues.

Secondary hyperparathyroidism – secondary hyperfunction and hyperplasia of the parathyroid glands developing against the background of a progressive decrease in functioning nephron mass in chronic kidney disease, due to hyperphosphatemia, elevated fibroblast growth factor 23, calcitriol deficiency, and hypocalcemia.

Hypertensive crisis – an acute blood pressure elevation > 30% above the baseline level, accompanied by clinical symptoms.

White-coat hypertension – blood pressure elevation when measured in a medical setting, with normal blood pressure levels at home in a calm environment (burden index on ABPM < 25%).

Developmental delay – a term used to describe children whose physical development, primarily height, is lower than expected (referred to as failure to thrive in English-language literature).

Renal replacement therapy – a set of specialized methods for replacing renal functions (hemodialysis, peritoneal dialysis, kidney transplantation). Kidney transplantation restores the full spectrum of lost renal functions.

Cardiovascular disease in CKD – progressive cardiovascular damage resulting from the combined effects of CKD-associated factors.

Masked hypertension – normal blood pressure levels when measured in a medical setting, but blood pressure spikes at home (according to ABPM or regular home blood pressure measurements).

Mineral and bone disorders in CKD – a systemic pathology syndrome including laboratory abnormalities in mineral and bone metabolism, bone abnormalities, and ectopic calcification associated with CKD.

Non-dipper – absence of a nighttime drop in mean SBP and DBP during sleep (normal is 10–20%).

Nutritional (trophological) status – a complex of clinical, anthropometric, and laboratory parameters characterizing the quantitative ratio of a patient's muscle and fat mass. The terms "nutritional status" or "nutrition state" are also used.

Acute kidney injury (AKI) – an acute, potentially reversible alteration in the renal parenchyma accompanied by varying degrees of renal function decline. This term is currently accepted internationally to replace the obsolete term "acute renal failure" (ARF). The latter statement is essentially incorrect, as the terms AKI and ARF are not synonymous. International consensus criteria for AKI are intended to describe three levels of renal impairment (risk, injury, failure) and two clinical outcomes (loss of kidney function and end-stage renal disease).

Parathyroidectomy – a surgical treatment method for hyperparathyroidism in CKD.

Peritoneal dialysis is a method of renal replacement therapy based on the principle of diffusion exchange, filtration, and convective transport of low- and middle-molecular-weight substances, including proteins, as well as fluid from the blood into the dialysate solution located in the peritoneal cavity, across the "peritoneal membrane" (peritoneum).

Automated peritoneal dialysis (APD) is a modality of peritoneal dialysis performed using special devices (peritoneal dialysis cyclers) that ensure the delivery and drainage of the dialysis solution without the patient's active participation. The cycler performs automatic cycles of solution exchanges in the abdominal cavity according to a program prescribed by the physician.

Continuous ambulatory peritoneal dialysis (CAPD) is a modality of peritoneal dialysis in which the exchange of the dialysis solution in the abdominal cavity (several times a day) is performed independently by the patient in an outpatient setting (at home).

Resistant hypertension – blood pressure levels above target values despite the use of 3 or more antihypertensive drugs (at optimal doses), one of which is a diuretic.

Heart failure – a syndrome developing as a result of structural or functional myocardial damage, leading to a decrease in the pumping function of the heart.

"Dry body weight" – the patient's body weight in a state of normohydration; in hemodialysis patients, it is the lowest body weight at which there are still no symptoms of hypovolemia (drop in blood pressure, muscle cramps in the extremities, abdominal pain).

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Chronic kidney disease (CKD) is persistent kidney dysfunction lasting for 3 months or more, defined as structural and/or functional changes with a varying degree of decline in clearance function [1].

Chronic kidney diseases, regardless of etiology, share common progression mechanisms and require specific therapeutic efforts aimed at delaying the onset of end-stage renal disease (ESRD).

Recommendations for the definition and classification of CKD were introduced by the National Kidney Foundation (NKF) and the Kidney Disease Outcomes Quality Initiative (KDOQI) in 2002 and were subsequently adopted with minor modifications by the Kidney Disease: Improving Global Outcomes (KDIGO) international guideline group, with adaptation in 2012 (see the "Diagnostics" section).

CKD can manifest with a variety of symptoms and syndromes. Maximizing the patient's life expectancy after the development of end-stage renal disease is determined not only by the availability of dialysis therapy, but also by the preservation of the child's overall physical and somatic status.

To denote nutritional status disorders, the term "protein-energy malnutrition" (PEM) is used, which refers to a deficiency of energy and dietary nutrients to meet the demands of a child's physical development (malnutrition in English literature) [2, 3].

Failure to thrive is a term used to describe children who are growing less than expected. The diagnosis of PEM (malnutrition) is based on anthropometric measurements, and undernutrition is defined as an imbalance between nutrient requirements and intake or delivery, which in turn leads to a deficiency of energy, protein, or micronutrients that can adversely affect growth and development [4].

The development of CKD in childhood has a negative effect on linear bone growth and frequently leads to pronounced final height deficit in patients. Growth retardation increases with the stage of CKD [5].

Anemia of CKD is the result of downstream signals arising from dysregulation of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) system, the consequences of which are a decrease in erythropoietin (EPO) production, altered iron (Fe) metabolism, and a reduction in hemoglobin (Hb). Renal anemia naturally complicates the course of CKD, being more commonly diagnosed when the GFR drops to 40–60 mL/min/1.73 m², although it can be detected at earlier stages of the disease [6, 7]. Anemia is associated with adverse outcomes, poor quality of life, and reduced neurocognitive abilities in CKD patients [8].

As CKD progresses with a decline in GFR to 50% of normal, metabolic acidosis leads to impaired growth and enhanced protein catabolism due to the reabsorption of filtered bicarbonate, decreased ammonia synthesis, reduced titratable acid excretion, and acidification of tubular fluid. Chronic metabolic acidosis results in alterations of ionic composition, bone resorption and deposition, and blunting of the effects of growth hormone. Acidosis suppresses the renal synthesis of 1,25(OH)₂D, which, combined with retained phosphate and hypocalcemia, ultimately leads to secondary hyperparathyroidism [9].

The KDIGO work group recommended in 2006 the term "chronic kidney disease–mineral and bone disorder (CKD-MBD)" to describe a systemic syndrome of mineral and bone metabolism disorder due to CKD manifested by either one or a combination of the following: abnormalities of calcium, phosphorus, parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), or vitamin D metabolism; bone abnormalities (short stature, reduced bone mineralization, and impaired bone turnover and strength); and vascular or other soft-tissue calcification. The previously used term "renal osteodystrophy" refers strictly to the description of bone pathology resulting as a complication of CKD and is based on bone biopsy assessment. Biopsy is currently not used to verify bone pathology in chronic renal failure.

Cardiovascular disease (CVD) in CKD is a progressive lesion of the cardiovascular system caused by the impact of a complex of CKD-related factors. CVD is the leading cause of shortened life expectancy in this patient cohort. Cardiovascular complications account for 25–32% of deaths in children and adolescents with stage 5 CKD [10, 11, 12].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Although the concept of CKD in children is similar to that in adults, pediatric CKD has certain specific features, less evidence, and numerous factors that are not yet fully understood.

In childhood, the primary cause of CKD is congenital kidney diseases. The causes of pediatric CKD also depend on age and country of residence. The most frequent etiological factors of neonatal CKD are renal hypoplasia/dysplasia, posterior urethral valves, and other congenital anomalies of the kidney and urinary tract (CAKUT). Other etiologies include polycystic kidney disease, cortical necrosis, and renal vascular thrombosis [13]. Antenatal determinants of CAKUT are diverse and include mutations in genes responsible for normal nephrogenesis. Large cohort studies show that copy number variants, genomic mutations, or de novo mutations can account for up to one-third of all CAKUT cases [108]. The impact of maternal and fetal environmental changes, as well as obstruction in normally developing urinary tracts, has been proven [318, 319, 320].

The kidneys and urinary outflow tracts begin to form at the 3rd week of intrauterine development and complete formation at the 36th week. Therefore, sensitivity to environmental risk factors that disrupt development throughout pregnancy is very high [320, 321].

According to the NAPRTCS (North American Pediatric Renal Transplant Cooperative Study) registry, the most frequent causes of CKD in Italy and North American countries are:

ᴑ Congenital anomalies of the kidney and urinary tract (CAKUT), which account for 60% of CKD cases in children. Glomerular causes account for 10–20% of children with CKD, depending on geographic location. Glomerular involvement is predominantly seen in children over 12 years of age, accounting for 45% of CKD patients in the United States, where focal segmental glomerulosclerosis (FSGS) remains the most common glomerular disease, occurring in 9% of Caucasian children and in 1/3 of adolescent African-American patients. Other causes of CKD in children can include hemolytic-uremic syndrome and secondary glomerular diseases (e.g., systemic lupus nephritis). Unlike in adults, diabetic nephropathy and hypertension are rare causes of CKD in children.

ᴑ Other diseases account for 20–30% of all pediatric CKD cases and include genetically determined disorders (cystinosis, oxalosis, hereditary nephritis) and interstitial nephritis [14, 15].

In some cases, the etiology of CKD remains unrecognized. Childhood obesity is a novel global problem. Recent studies have identified early renal function impairment and an increased risk of CKD in overweight children [16, 17]. Furthermore, infants with low birth weight and those small for gestational age have an increased risk of developing end-stage renal disease in adolescence [18, 19]. As the problems of childhood obesity and the aging population of individuals with low birth weight grow, the global community may face a potential shift in the epidemiology of pediatric CKD.

End-stage renal disease (ESRD). Glomerular disorders account for a large proportion of underlying causes in children with end-stage kidney disease (ESRD). This is due to the rapid rate of progression of CKD in patients with glomerular dysfunction compared to those with non-glomerular causes.

According to the 2017 US Renal Data System (USRDS) annual report, the leading causes of chronic renal failure in patients aged 0 to 21 years from 2011 to 2015—consistent with previous years—were congenital anomalies of the kidney and urinary tract (CAKUT, 22%), primary glomerular diseases (21.8%), cystic/hereditary/congenital disorders (12.5%), and secondary glomerular diseases/vasculitis (10.7%). The most frequent individual diagnoses associated with pediatric ESRD included focal segmental glomerulosclerosis (11.6%), renal hypoplasia/dysplasia (10%), congenital obstructive uropathies (9.7%), and systemic lupus erythematosus (6.3%) [20].

Inadequate nutrition is a well-known cause of poor growth in children with CKD. Protein-energy wasting (PEW) is associated with the progression of uremic symptoms, leading to protein-energy malnutrition and increased mortality in this patient population. A study by CS Wong et al. demonstrated that for each standard deviation decrease in height z-score in children with CKD compared to healthy children, the risk of death increases by 14% [21].

PEW is associated not only with an increased risk of hospitalization and mortality in children, but also with reduced arterial elasticity—carrying a potential risk of cardiovascular disease—and lower 25-OH vitamin D concentrations. Major guidelines, such as the Kidney Disease Outcomes Quality Initiative (KDOQI), recommend early, intensive nutritional support in children with CKD. Several studies in infants with CKD have shown a significant increase in growth velocity when adequate caloric intake is provided via nasogastric tube or gastrostomy feeding. Thus, ensuring adequate nutrition is one of the most critical aspects of managing a child with chronic kidney disease.

Disease-related PEW has several potential mechanisms: decreased food intake, increased nutrient requirements, increased nutrient losses, and impaired nutrient utilization by the body. Inflammation plays a major role in the development of disease-related PEW. Inflammation is viewed in a new light, as it can both cause PEW and act as one of the mechanisms contributing to its development. Inflammation can affect appetite and impair nutrient absorption; the net effect depends on whether the inflammation is acute (classic inflammation) or low-grade chronic (metainflammation) [22].

Causes of PEW in children with CKD:

• Poor appetite, which may be related to altered taste perception, polypharmacy, a preference for water in children with polyuria, and elevated circulating cytokines such as leptin, TNF-α (tumor necrosis factor alpha), IL-1 (interleukin-1), and IL-6, which act through the hypothalamus to affect appetite and satiety.

• Vomiting associated with gastroesophageal reflux and delayed gastric clearance due to reduced clearance of polypeptide hormones.

• Impaired absorption of dietary nutrients due to uremic injury to the intestinal epithelium and gut microbiome disruption.

• Onset of acute PEW associated with episodes of intercurrent infections, surgical interventions, etc.

• Associated comorbid conditions affecting nutrition [3, 23].

Anemia is a frequent complication in children with CKD, the incidence and severity of which increase as the disease progresses. Anemia is associated with the development of complications, including increased hospitalization and mortality rates, as well as the progression of cardiovascular disease risk factors such as left ventricular hypertrophy (LVH) [24, 25].

The primary cause of anemia is impaired erythropoietin (EPO) production by peritubular fibroblasts in the renal cortex [26].

Additional causes of anemia in pediatric CKD include:

1. Iron-deficiency erythropoiesis (absolute iron deficiency, functional iron deficiency, impaired iron metabolism).

2. Inflammation and hepcidin-mediated iron sequestration.

3. Chronic blood loss (frequent phlebotomy, losses in the hemodialysis circuit, gastrointestinal losses, menstrual losses).

4. Uremia and oxidative stress.

5. Hyperparathyroidism and myelofibrosis.

6. Deficiency states (vitamin B12, folic acid, carnitine, vitamin C).

7. Medications (angiotensin-converting enzyme (ACE) inhibitors, non-adherence to anemia therapy, drug toxicity, pure red cell aplasia).

Among the mechanisms of anemia in CKD, the hepcidin-mediated pathway is described, which blocks iron availability for erythropoiesis at various stages, from iron absorption by enterocytes to the release of stored iron from macrophages in the bone marrow [27].

Circulating EPO regulates erythroid progenitor proliferation and acts as a growth factor promoting erythrocyte maturation. The primary stimulus for EPO expression is hypoxia; EPO production is upregulated by hypoxia-inducible transcription factors that control the EPO gene. EPO production in CKD is impaired both due to the destruction of peritubular fibroblasts and impaired regulation of the renal oxygen-sensing mechanism, and due to impaired tubular sodium reabsorption in the distal tubules during a decline in GFR, which serves as a signal to suppress EPO production. EPO levels in CKD patients are usually normal or slightly elevated, whereas in patients with normal renal function and anemia, EPO levels increase 10- to 100-fold [28].

The onset of CKD in childhood can lead to pronounced final adult short stature. It has been established that 50% of children with stage 3b-5 CKD experience growth retardation. In untreated CKD caused by congenital pathology, growth retardation can be observed as early as the first two years of life, since infancy is characterized by the highest growth velocity. Healthy infants achieve 50% of their height potential by two years of age; therefore, early-onset CKD can have a major impact on final adult height. Between 3 and 10 years of age, healthy children maintain a relatively constant growth velocity of 5-7 cm/year, which is primarily dependent on growth hormone (GH) and thyroid hormones. Two to three years before puberty, growth velocity drops disproportionately in patients with CKD. The onset of the pubertal growth spurt is delayed, and its amplitude is reduced, leading to further loss of growth potential.

The causes of growth retardation can be diverse:

ᴑ genetic factors (parental height, sex, syndromes),

ᴑ prematurity,

ᴑ size for gestational age,

ᴑ need for intensive care at birth,

ᴑ comorbidities (systemic pathology, genetic syndromes: Schimke, Bardet-Biedl, and Galloway-Mowat),

ᴑ glucocorticoid therapy.

Other factors influencing growth processes include: protein-calorie malnutrition, water and electrolyte losses from polyuria and salt-wasting states, metabolic acidosis, anemia, CKD-MBD, and resistance to growth-mediating hormones [29, 30, 31, 32].

The tissue-level anabolic effect of GH is mediated via insulin-like growth factor 1 (IGF-1). CKD is a state of GH insensitivity characterized by a deficiency of functional IGF-1 due to downregulation of GH receptor expression in target organs, such as the liver, and impaired GH receptor signaling via Janus kinase 2, signal transducer and activator of transcription 5 pathway due to inflammation-induced suppressor of cytokine signaling expression and increased IGF-binding capacity in the setting of IGF excess [33]. The reduction in hypothalamic gonadotropin-releasing hormone release in uremia is attributed to inhibitory factors such as angiotensin II and glucocorticoid therapy, which may lead to decreased circulating bioactive luteinizing hormone, hypogonadism, and reduced pubertal growth. At the onset of puberty, the GH/IGF-1 axis is stimulated by an increase in sex hormone secretion—estrogens and testosterone in girls and boys, respectively. The onset of puberty is delayed in adolescents with CKD, and peak height velocity is postponed by approximately 2.5 years. The pubertal growth spurt is delayed and its magnitude reduced due to a shortened duration of the growth spurt. Pubertal height gain in children with CKD accounts for approximately 65% of that in healthy children [34]. Consequently, growth retardation in CKD is primarily driven by growth suppression during two critical periods: infancy (when growth depends mainly on nutritional factors) and puberty (which is sex hormone-dependent).

A key factor in the initiation and progression of CKD-MBD is the development of nephrosclerosis resulting from a reduced number of functioning nephrons. The consequences of these changes include decreased urinary phosphorus excretion, elevated phosphatemia, and increased production of fibroblast growth factor 23 (FGF23); decreased synthesis of the active form of vitamin D (calcitriol), reduced blood calcium levels, and elevated parathyroid hormone (PTH). Elevated phosphorus and decreased blood calcium are key triggering factors for alterations in bone tissue homeostasis in CKD. Parathyroid hormone plays a central and leading role in the mechanism regulating calcium levels in the body: normocalcemia is essential for normal vital functions (primarily the cardiovascular and central nervous systems). Prolonged hyperfunction of the parathyroid glands leads to their hypertrophy and hyperplasia with the formation of an adenoma. Continuous stimulation of bone turnover in the setting of hyperparathyroidism leads to impaired bone structure modeling and compromised bone strength, followed by deformities and fractures. In addition to pathological bone changes in secondary nephrogenic hyperparathyroidism, pathological conditions such as calcification of vascular walls, myocardial structures, and various soft tissue structures develop [35].

The modern concept of CKD-MBD pathogenesis also incorporates relatively novel biomarkers, regulators, and mechanisms, such as: fibroblast growth factor 23 (FGF23), one of the earliest biomarkers; a peptide secreted by osteoclasts and osteoblasts that regulates phosphate and vitamin D metabolism and directly inhibits PTH secretion; FGF23 receptors; Klotho (a transmembrane protein required for FGF23 receptor activation in target organs: the kidney and parathyroid gland); vitamin D receptor (VDR); calcium-sensing receptor (CaSR); sclerostin; undercarboxylated osteocalcin. Studies in children and adults have demonstrated elevated serum FGF23 levels and increased bone FGF23 expression in early stages of CKD, when phosphorus, calcium, and PTH levels are still within the normal range [36, 37, 38, 39, 40]. FGF23 can be considered a sensitive screening test for detecting CKD-MBD in the early stages. Calcitriol deficiency also stimulates PTH secretion via VDR activation in the parathyroid glands and indirectly contributes to the development of hypocalcemia, which is another potent stimulus for PTH secretion [41, 42]. Decreased serum calcium concentration is also a powerful stimulus for PTH secretion, which is associated with reduced CaSR expression in parathyroid cells [43]. Persistent VDR hyporeactivity and decreased CaSR expression lead to parathyroid gland hyperplasia and the development of tertiary hyperparathyroidism [44].

The pathophysiological aspects of CKD-MBD represent a complex cascade of events involving interactions between the kidney, parathyroid gland, bone, intestine, and cardiovascular system.

Specific aspects of bone metabolism in children include not only continuous bone remodeling, combining osteoblastic and resorptive processes, but also a continuous, highly dynamic process of longitudinal skeletal growth until growth plate closure, which significantly complicates the understanding of mineral and bone homeostasis in a child with CKD. Growth impairment is one of the main manifestations of CKD-MBD. Furthermore, achieving a normal final adult height is a major challenge for every patient with CKD.

Both traditional risk factors and factors caused by decreased renal function play a role in the development of CVD in children with CKD. The former include arterial hypertension, physical inactivity, obesity, hyper- and dyslipidemia, and carbohydrate metabolism disorders; the latter include RAAS activation, phosphocalcium metabolism disorders, chronic inflammation, endothelial dysfunction, oxidative stress, hypervolemia due to sodium and water retention, and anemia [12, 45].

The primary factor in the progression of CKD and CVD is arterial hypertension. AH results from increased vascular tone (promoted by RAAS activation, oxidative stress, and pro-inflammatory cytokines triggering endothelial dysfunction) and increased circulating blood volume (caused by sodium and water retention due to kidney disease and/or RAAS activation).

Phosphocalcium metabolism disorders in CKD (hyperparathyroidism, hyperphosphatemia, elevated FGF23 and osteocalcin levels, as well as reduced activity of calcification inhibitors), in addition to disrupting bone tissue structure, contribute to vascular wall remodeling: intimal-medial thickening, fibrosis, and subsequent calcification of the muscular layer of arterial walls (including coronary arteries), along with left ventricular myocardial hypertrophy and calcification. As a result of remodeling, arterial elasticity and their ability to cushion pulse pressure waves are reduced, arterial stiffness increases, and pulse wave velocity rises [46]. Increased peripheral vascular resistance exacerbates AH, which in turn leads to further remodeling of the arterial muscular layer and progression of myocardial hypertrophy.

Myocardial hypertrophy is associated with decreased capillary density, which promotes ischemia. Ischemia provokes cardiomyocyte apoptosis, extracellular matrix accumulation, and myocardial fibrosis, which in turn exacerbates ischemia. Myocardial hypertrophy and fibrosis are also promoted by elevated levels of angiotensin II and aldosterone [47].

As CKD progresses, the aforementioned disorders worsen, reaching maximum severity at the dialysis stage. The prolonged, synergistic impact of risk factors leads to pronounced left ventricular hypertrophy and/or dilatation, followed by diastolic and subsequently systolic dysfunction. Circulatory failure ensues, and the risk of cardiac arrhythmias and ischemic attacks increases significantly, which may ultimately become the cause of death in a child with stage 5 CKD [12, 46].

1.3 Epidemiology of the Disease or Condition

Data on the prevalence of CKD among children in the literature are scarce. The true incidence of CKD in childhood is unknown, but it may reach 1% in the pediatric population [48]. Neonatal CKD occurs in approximately 1 in 10,000 live births, whereas the incidence of end-stage renal disease in this age group is about 7.1 per million age-related population [13]. Worldwide, CKD ranges from 2 to 16 per million children per year. The majority of children remain undiagnosed until adulthood. According to national registries, the incidence of children requiring RRT ranges from 9–10 new cases per million children per year (UK, Australia, and New Zealand) to 15 in the USA [15, 49, 50].

12,591 children adjusted for age, sex, and race/ethnicity. The mean age of children with CKD was 6 (1–13) years. The prevalence in children under 1 year of age was 20.2%, aged 1–3 years – 17.8%, 4–6 years – 12.0%, 7–10 years – 14.8%, 11–14 years – 15.2%, and 15–17 years – 19.9%. Furthermore, stage 1–2 CKD was diagnosed in 20.0% of patients, stage 3a and 3b CKD in 9.1% and 4.0%, stage 4 CKD in 1.5% of cases, and stage 5 CKD (non-dialysis) in 0.7%. In 64.7% of cases, CKD was diagnosed with an unspecified stage [51].

The prevalence of CKD in children in European Union countries ranges from 55–60 to 70–75 cases per million population in Spain and Italy, depending on the clinical definition of CKD used in each study [15]. Meanwhile, in the Middle East (Kuwait) and Southeast Asia (Brunei Darussalam), the prevalence of CKD is significantly higher, at 329 and 736 cases per million population [15, 52]. According to the Serbian Pediatric Registry, the prevalence of stage 2–5 CKD is 96.1 cases per million population [53]. The high prevalence of CKD in the Middle East and Southeast Asia can be explained by a high burden of hereditary disorders within families.

The development of end-stage renal disease (ESRD) in childhood has remained stable over the past 30 years worldwide, but the prevalence has increased alongside the frequency of dialysis cases and renal transplant recipients [8, 54].

The prevalence and incidence of stage 1–4 CKD in children in the Russian Federation have not been established. The prevalence of stage 5D CKD is 20.2 per 1,000,000 population. As of December 31, 2015, there were 626 children receiving renal replacement therapy (RRT) registered in the Russian Federation (peritoneal dialysis [PD], hemodialysis [HD], kidney transplantation [KT]): 6.06 patients/million pediatric population for HD, 5.0 patients/million for PD, and 9.13 patients/million for kidney transplantation [55].

Identifying and registering international data on the epidemiology of pediatric CKD is a challenging task. The reported number of children with CKD is likely underestimated because early stages of the disease are usually asymptomatic. In addition, underreporting may occur due to a shortage of healthcare services in resource-limited areas. As a result, it is difficult to compare pediatric CKD rates globally due to the variability in healthcare resources available for both caring for children with CKD and tracking and collecting accurate population data, as well as the use of varying definitions. Furthermore, published information is often based on reports from large reference centers, and it remains unclear whether these data truly reflect population-level risks.

Population-based estimates of moderate-to-severe CKD or end-stage renal disease in children requiring renal replacement therapy (RRT) were calculated based on the average annual incidence per million age-specific population and varied as follows:

• Europe – 11.9 cases.

• Latin America – from 2.8 to 15.8 cases.

• Sub-Saharan African countries, where healthcare resources are most limited, reported the lowest published CKD rates based on single-center studies, ranging from 1 to 3 cases.

The presented data on the prevalence of CKD requiring RRT vary due to differing levels of RRT accessibility for children in the reporting countries: New Zealand – 18 cases, USA – 15.5, Western Europe and Australia – 9.5, Russia – < 4 cases.

Summarizing studies investigating the prevalence of CKD in hospitalized children (from 0.3 to 1 case per 10,000 children), as well as the results of several population-based studies identifying a higher prevalence of CKD (from 1 to 10 cases per 1,000 children), the total number of children and adolescents worldwide suffering from stage 2–5 CKD currently exceeds 2 million cases out of a total pediatric population of 2 billion [322].

Racial, sex, and age differences. Data from the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) registry and the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) reported an increased risk of CKD among ethnic minorities.

In North America, the incidence of CKD in African American children is two to three times higher than in Caucasian children. In Australia and New Zealand, indigenous children (e.g., Aboriginals and Māori) have a higher risk of AKI and certain types of CKD. Rates of end-stage CKD among indigenous compared to non-indigenous populations are similar in children under 14 years of age, but increase significantly after 15 years.

In African Americans, the apolipoprotein L1 (APOL1) genotype may account for the increased risk of CKD. The high-risk genotype for APOL1 (homozygous for the "G1" or "G2" risk alleles, or compound heterozygous for G1G2) is associated with an increased risk of developing glomerular disease, particularly focal segmental glomerulosclerosis (FSGS), compared to those with a low-risk genotype (having 0 or 1 risk allele). In a pooled analysis of the Chronic Kidney Disease in Children (CKiD) and Nephrotic Syndrome Study Network (NEPTUNE) cohorts comprising 104 children with glomerular disease of African American ancestry, children with the high-risk genotype experienced a more rapid decline in kidney function over time compared to the low-risk genotype group.

The incidence and prevalence of CKD in children are higher in males. The increased risk of CKD in males is associated with a higher frequency of congenital anomalies of the kidney and urinary tract (CAKUT), including obstructive uropathy, renal dysplasia, renal hypoplasia, and prune-belly syndrome.

Patients with CKD present for care during childhood. In the NAPRTCS Chronic Renal Insufficiency (CRI) database, which contains records on over 7,000 patients with CKD, the age distribution at the time of CKD detection was as follows: < 12 months – 15%, 12 to 23 months – 5.2%, 2 to 6 years – 15.7%, 6 to 13 years – 32.1%, 13 to 18 years – 28.3%, 18 to 21 years – 3.7%.

CKD is the outcome of any renal or extrarenal disease, and its development occurs within the framework of the pathogenesis of the underlying condition.

The prevalence of protein-energy wasting (PEW) among children with stage 5 CKD is widespread and ranges from 20 to 80%. This pathological condition leads to the loss of muscle mass, fat mass, and growth retardation with a reduction in final adult height [56]. Approximately 40% of children with end-stage CKD achieve a shorter final height (below the 3rd percentile) compared to healthy individuals of the same age and sex in control groups [57, 58].

Data from multicenter studies show that anemia is diagnosed in 73% of children with stage 3 CKD, 87% with stage 4, and 93% with stage 5 (NAPRTCS) [59].

Growth impairment, occurring in 35% of children with stage 2–4 CKD, is the most difficult to treat and the most serious psychological problem [5]. According to J. Harambat et al., 43% of patients with end-stage renal disease (ESRD) in childhood fail to reach normal adult height [58]. Moreover, the actual prescription rate of somatotropin** to children with growth retardation and CKD remains low [60]. According to the CKiD registry, graft survival time following kidney transplantation is 40% shorter in children who had short stature prior to transplantation [61].

Arterial hypertension (AH) is registered in 40–80% of children with CKD, depending on the stage, with the highest prevalence among patients undergoing RRT. Cardiovascular disease markers such as left ventricular hypertrophy (up to 92%), carotid intima-media thickness (up to 89%), and coronary artery calcification (up to 20%) are most frequently detected in this same population [10, 12, 46].

According to the European Society for Paediatric Nephrology and the European Renal Association – European Dialysis and Transplant Association (ESPN / ERA-EDTA), the prevalence of pediatric renal replacement therapy (RRT) in Europe in 2012 was 27.9 cases per million population [62].

1.4 Features of Coding the Disease or Condition

Appropriate amendments have been made to the International Statistical Classification of Diseases (ICD-10) regarding the replacement of the outdated term "chronic renal failure" with "chronic kidney disease" (code N18.1), as well as the coding of CKD. Currently, codes N18.1 – N18.5 and N18.9 should be used to indicate CKD stages.

N18.1 – Chronic kidney disease, stage 1

N18.2 – Chronic kidney disease, stage 2

N18.3 – Chronic kidney disease, stage 3 (stages 3a and 3b)

N18.4 – Chronic kidney disease, stage 4

N18.5 – Chronic kidney disease, stage 5

N18.9 – Chronic kidney disease, unspecified stage

Codes for specifying the etiology of CKD:

N39.1 – Persistent proteinuria, unspecified

Q60.0 – Unilateral renal agenesis

Q60.3 – Unilateral renal hypoplasia

Q63.1 – Fused, lobulated, and horseshoe kidney

Q61.4 – Renal dysplasia

Q63.0 – Accessory kidney

1.5 Classification of the disease or condition

Diagnostic and staging criteria for CKD in children were adapted in 2012 by KDIGO [6]. CKD criteria are presented in Table 1.

Table 1. Criteria for defining CKD (if both persist for more than 3 months).

Reduced GFR can be detected using modern GFR estimation formulas based on serum creatinine and/or cystatin C.

It should be emphasized that the criterion "duration > 3 months" does not apply to newborns or infants aged ≤ 3 months, just as the criterion "GFR < 60 mL/min/1.73 m²" does not apply to children aged < 2 years, in whom age-appropriate values should be used. Total urinary protein / urinary albumin excretion above the upper limit of normal for age can be replaced by albuminuria ≥ 30 mg/24h. All electrolyte disorders in children should be evaluated in terms of age-specific norms.

The importance of the CKD classification lies in the following advantages: its correlation with outcomes such as disease progression, cardiovascular disease risk, and all-cause mortality; and the possibility of early therapeutic interventions to slow disease progression and improve quality of life and survival [6, 63, 64, 65]. Initially, it is necessary to assess the presence of markers of kidney damage, and subsequently determine the CKD stage based on GFR and the degree of albuminuria/proteinuria.

CKD progression is determined based on the GFR category (G stage) and the albuminuria category (A stage) (Table 2, Table 3). The GFR level is determined based on serum creatinine and/or cystatin C concentration. The level of albuminuria is determined based on the albumin-to-creatinine ratio in a single (spot) urine sample or 24-hour urinary albumin excretion. A complete CKD diagnosis includes the name of the kidney disease (the cause of CKD, if known) along with the assigned GFR and albuminuria categories.

Table 2. GFR categories (stages) in CKD [6].

Taking into account the results of large-scale evidence-based studies in adult patients, this staging classification of CKD is applicable to patients older than 2 years.

Table 3. Albuminuria categories (stages) in CKD [6].

Note: ACR – albumin-to-creatinine ratio.

¹ - _{Relative to the level characteristic of young adults.}

² - _{Including nephrotic syndrome (albumin excretion usually > 2200 mg/day [ACR > 2220 mg/g; > 220 mg/mmol]).}

The review by M. Murton et al. included ten observational studies involving 3,033 to 46,949 individuals conducted in the USA, China, France, Italy, and Spain. The most frequent outcome was the prevalence of stage 3–5 CKD, ranging from 2% to 17%. The majority of patients had normal albuminuria levels, while 0.4–3.2% had severely increased albuminuria. The vast majority of patients were classified into the low or moderate risk groups for CKD progression. According to KDIGO 2012 guidelines, 0.9–5.6% of study participants were classified into the high-risk group, and 0.3–4.8% into the very high-risk group [66].

2 SD – as markedly reduced GFR [6].

Table 4. ⁵¹Cr-EDTA clearance in healthy children under 2 years of age [67].

Transient albuminuria may occur due to high dietary protein intake, urinary tract infection, fever, strenuous physical activity in the preceding 24 hours, certain medications, menstruation, and other conditions [68].

The severity of protein-energy malnutrition (PEM) (mild, moderate, or severe) can be determined by plotting the z-score (standard deviation [SD] from the mean) for each of these anthropometric parameters (Table 5) [69].

Table 5. PEM indicators based on a single observation.

PEM is defined by duration (acute, < 3 months; chronic, > 3 months) and severity (mild, moderate, severe). A patient with a chronic disease and chronic PEM may develop acute PEM during an intercurrent infection, surgery, or disease "flare-up".

A general classification of cardiovascular disease in children has not been developed, but there is a classification for its individual manifestations (hypertension, heart failure) (Tables 6, 7, 8).

Table 6. Classification of hypertension [70].

Table 7. Classification of heart failure in children according to N.A. Belokon (1987) [71].

Table 8. Classification of functional classes of chronic heart failure according to R.D. Ross [71, 73].

1.6 Clinical presentation of the disease or condition

Clinical manifestations of CKD depend on the nature of the underlying condition (without glomerular involvement or in the setting of glomerular disease) and the presence or severity of renal failure. Patients may present with dysmorphic features or physical findings indicative of genetic disorders associated with renal anomalies and CKD (e.g., hereditary nephritis and cystinosis).

CKD should be suspected in any child with:

ᴑ a family history of CKD

ᴑ a history of prior AKI

ᴑ unexplained anemia

ᴑ serum creatinine above the age-adjusted normal range

ᴑ polyuria and nocturia

ᴑ low specific gravity of urine

ᴑ persistent proteinuria

ᴑ bilateral renal pathology on antenatal ultrasound / in UTI

ᴑ arterial hypertension

ᴑ bone deformities

ᴑ growth retardation

Risk factors for CKD may include:

ᴑ a history of acute pyelonephritis, HUS, VUR

ᴑ an episode of hemodynamic instability during extensive prior surgeries or burn disease

ᴑ low birth weight and prematurity

ᴑ born to a very young mother or of advanced maternal age, with accumulated somatic pathology in the mother

ᴑ myelodysplasia / lumbosacral spinal trauma (with impaired organ innervation)

Nonglomerular causes of CKD affect the tubulointerstitial space and mainly consist of CAKUT and cystic kidney diseases. Approximately 60% of pediatric CKD cases are caused by congenital anomalies. Typically, CKD in this population is associated with subtle signs of early renal dysfunction and is most often detected via imaging, including routine prenatal ultrasound revealing structural anomalies.

Polyuria may be an early finding, as many CAKUTs (e.g., obstructive uropathy, bilateral renal dysplasia), hereditary disorders (e.g., nephronophthisis), and tubulointerstitial disorders are associated with impaired concentrating ability (e.g., nephrogenic diabetes insipidus). In these settings, the impairment of renal concentrating capacity usually precedes a significant decline in GFR. Such patients are at high risk of AKI triggered by an acute episode of dehydration, which may occur during gastroenteritis.

Increase in serum creatinine concentration with age. It should be emphasized that patients with spina bifida, lower limb paralysis, or other conditions associated with reduced muscle mass may be at risk of underdiagnosis of CKD due to lower baseline creatinine levels, which overestimate GFR values.

Poor growth in CKD is associated with inadequate nutrition, electrolyte imbalances, tubular acidosis, and CKD-MBD.

Children with glomerular disease as the cause of CKD often have more pronounced signs and symptoms of kidney disease:

ᴑ tea-colored / "cola-colored" urine can be a leading symptom. The presence of erythrocytes in the urine may indicate glomerulonephritis. In other cases, microscopic hematuria may be an incidental finding.

ᴑ proteinuria is a closely associated biomarker of CKD and may be a sign of underlying glomerular disease or tubular dysfunction. Persistent (≥ 3 months) increased urinary protein excretion indicates CKD.

ᴑ edematous syndrome may be secondary to nephrotic-range proteinuria.

ᴑ progressive increase in serum creatinine concentration over time.

ᴑ arterial hypertension.

ᴑ symptom complexes of specific manifestations associated with secondary glomerulonephritis affecting renal function and leading to CKD, such as lupus nephritis or granulomatosis with polyangiitis. Clinical manifestations may include fever, arthralgias/arthritis, rash, and/or pulmonary symptoms, etc.

Clinical findings vary depending on the severity of renal dysfunction (see the section "Diagnosis of the Disease"):

In the early stages of CKD (C1 and C2), the disease is often asymptomatic unless there are signs and/or symptoms that are a direct result of underlying structural renal anomalies or systemic diseases with renal involvement. Asymptomatic patients may be identified by age-specific elevations in serum creatinine, urinalysis abnormalities (proteinuria, hematuria, or impaired renal concentrating ability), or the incidental detection of kidney disease on imaging studies, including prenatal ultrasound. Patients may show signs of anemia and vitamin D deficiency. During this period, there is an opportunity to treat any reversible cause of renal dysfunction and to prevent or slow the progression of chronic kidney disease. Educational efforts are initiated so that the child and family can understand and implement measures to prevent risk factors that may accelerate CKD progression (e.g., avoidance of nephrotoxic drugs, recurrent infections, dehydration, obesity, and adolescent smoking) and incorporate measures (e.g., strict blood pressure control and/or reduction of proteinuria) that can slow the process.

Mild to moderate CKD (C3a and C3b). Children who progress to stages G3a and G3b may begin to develop complications associated with CKD. These include: onset of edema, electrolyte disturbances, anemia, hypertension, dyslipidemia, endocrine disorders, growth impairment, mineral and bone disorders, and decreased clearance of substances normally excreted by the kidneys (uremia). In such patients, management focuses on the prevention and treatment of these complications. In addition, the risk factors described above should be avoided to slow CKD progression.

Severe CKD and End-Stage Renal Disease (C4 and C5). Patients with ongoing progressive disease must be identified well in advance of the need for renal replacement therapy (RRT) to ensure adequate preparation and education for both the patient and their family. Preparation for RRT typically begins in CKD stage 4, when the GFR drops below 30 mL/min per 1.73 m².

Complications of CKD

Clinical manifestations of protein-energy malnutrition (PEM) include: inadequate body weight for corrected age, a flat weight curve (inadequate rate of weight gain), inadequate linear growth rate, inadequate weight-to-height ratio, inadequate body mass index (BMI), and developmental delay.

Anemia presents with a range of symptoms that are difficult to differentiate from uremic symptoms. Often, a patient seeks medical attention for symptoms of anemia without being aware of their underlying kidney disease (pallor of the skin and mucous membranes). Clinical manifestations of anemia in CKD include: fatigue, somnolence, muscle weakness, dyspnea, cardiac pain, palpitations, tachycardia, increased cold sensitivity, loss of appetite, decreased libido, dysmenorrhea, and impaired memory and concentration.

The main clinical manifestations of CKD-MBD include: rickets-like skeletal deformities in children of various age groups; most commonly progressive varus or valgus curvature of the lower limbs; widening of the metaphyseal zones (resembling "rachitic rosary" / bracelets); gait abnormalities, particularly with hip joint involvement ("waddling gait"); bone pain with movement; recurrent fractures; bone epiphysiolysis in large and medium joints; impaired linear growth rate of the child; destruction of dental enamel and tooth loss, delayed or disordered tooth eruption; signs of trophic changes in other skin appendages (dry, brittle, poorly growing hair and nails); decreased muscle strength in the upper and lower extremities; calf muscle cramps; carpal spasm; afebrile tonic seizures; specific signs of soft tissue calcification (calcium crystal deposits), angular scleritis, and calcium crystal deposits in the sclera.

Clinical manifestations of cardiovascular disease in children with CKD are often subtle. Hypertension in gradual onset is usually asymptomatic and detected only by blood pressure measurement. In case of a sharp, sudden increase in blood pressure (hypertensive crisis), there may be headache, dizziness, nausea and vomiting, visual disturbances (mist, «floaters» before the eyes), a feeling of fear, convulsions, and impaired consciousness. There may be discomfort, palpitations, or irregular heartbeat due to cardiac arrhythmias accompanied by tachycardia and extrasystoles.

With the progression of CKD and cardiovascular disease, development of secondary cardiomyopathy, and decreased left ventricular myocardial contractility, symptoms of circulatory failure join in: lethargy, fatigue, reduced exercise tolerance, sweating, and dyspnoea. In infants, heart failure may manifest as anxiety, lethargy, feeding difficulties, anorexia, vomiting.

Chest pain in children with CKD is rare, but may occur as a manifestation of myocardial ischemia (e.g., in coronary artery calcification).

In children with stage 5 CKD receiving renal replacement therapy, a sudden deterioration in condition may occur, associated with cardiac overload and decompensation against the background of overt or occult fluid overload: anxiety, progressive dyspnoea, tachycardia, muffled heart sounds, a «gallop rhythm» on auscultation, and pulmonary crepitations. If treatment is not provided in a timely manner, fatal alveolar pulmonary oedema may develop.

At the same time, fluid overload in children with stage 5D CKD rarely manifests as obvious, generalized oedema. More often, puffiness of the eyelids, face, and shins is noted, along with weight gain, which is sometimes (especially in infants) interpreted as physiological weight gain.

On physical examination of a child, against the background of CKD symptoms (growth and physical developmental delay, pallor or specific skin pigmentation, bone deformities, etc.), symptoms caused by hypertension, cardiomyopathy, or circulatory failure can be detected: tachypnoea or dyspnoea with retraction of compliant chest areas, «cardiac hump»; percussion reveals enlargement of the relative cardiac dullness borders; auscultation reveals altered heart sound intensity (softening of the 1st sound, accentuation of the 2nd sound over the aorta), an accessory 3rd sound («gallop rhythm», indicating cardiac volume overload), functional heart murmurs, tachycardia, extrasystoles. Tonometry may reveal elevated blood pressure.

Children with stage 5 CKD are at risk for life-threatening cardiac arrhythmias (ventricular fibrillation, asystole), which manifest as sudden pallor, cyanosis, and loss of consciousness, requiring resuscitation measures.

Neurological disorders include various symptoms ranging from seizures and severe intellectual disability to more subtle impairments leading to poor school performance. Children with CKD have lower scores in executive function, verbal and visual memory, and greater fatigue compared to the general population.

Children on dialysis have lower cognitive function scores than children with milder CKD. This relationship can be partly explained by the impact of uremia on cognition and nervous system development. In addition, uremia is a complication of CKD, including manifestations such as anorexia, nausea, vomiting, and other symptoms. Platelet dysfunction, pericarditis, and uremic bleeding may occur against the background of uremia. Without adequate treatment, uremia can lead to seizures, coma, and death.

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis of CKD is established in the presence of structural or functional kidney damage persisting for at least three months. According to KDIGO, diagnosing CKD requires meeting one of the following criteria [6]:

• GFR less than 60 ml/min/1.73m² for 3 months or more regardless of other markers of CKD; Presence of markers of renal damage, such as proteinuria/albuminuria (urine albumin/creatinine > 30 mg/g), persistent changes in the urinary sediment, kidney imaging abnormalities, and pathomorphological changes on kidney biopsy.

2.1 Complaints and Anamnesis

See section «Clinical Presentation». When collecting complaints and history, attention should be paid to changes in the child's activity, exercise tolerance, decreased appetite, changes in eating behavior, recurrent vomiting, episodes of headache, dizziness, muscle weakness, bone pain, chest pain, dyspnoea, loss of consciousness, or seizures. A detailed analysis of dietary, prenatal, and family history is necessary; assessment of the quantity, quality, and regularity of food intake; obtaining information regarding the onset of growth retardation. In all patients with stage 4-5 CKD (especially those receiving renal replacement therapy), information on fluid intake and output, including diuresis and ultrafiltration volume during dialysis procedures, as well as body weight dynamics, must be collected.

(CGR C; LOR 5)

Comment: for CKD risk factors, see subsection 1.2 «Etiology and pathogenesis of the disease or condition (groups of diseases or conditions)».

2.2 Physical Examination

During the physical examination of a child with CKD, attention should be paid to the following parameters:

- Child's physical development (body weight, body length/height, head circumference).

- Skinfold thickness.

- Mid-upper arm circumference.

- Skin colour (pallor, cyanosis, pigmentation).

- Presence of oedema.

- Presence of skeletal deformities.

- Visible abnormalities of the precordial area («cardiac hump», pulsations).

- Respiratory rate and rhythm, presence of dyspnoea involving accessory muscles and retractions of compliant chest areas.

- Borders of relative cardiac dullness (by percussion).

- Character of breathing upon lung auscultation.

- Intensity of heart sounds, presence of arrhythmia or «gallop rhythm», and murmurs upon heart auscultation.

2.3 Laboratory Diagnostics

(CGR C; LOR 4)

Comment: the frequency of dynamic testing is determined by the clinical situation. Blood acid-base imbalance manifests as metabolic acidosis, which progresses as GFR declines. Children in late stages of CKD develop high anion gap metabolic acidosis when the kidneys' ability to excrete organic acids becomes limited. When circulating buffers are depleted, bone begins to buffer excess hydrogen ions, leading to calcium release from the bone. If acidosis is uncorrected, osteopenia with growth retardation may develop, along with an increased risk of secondary hyperparathyroidism and CKD progression [75]. Metabolic acidosis in CKD can contribute to hyperkalaemia, promote protein catabolism, negatively affect muscle metabolism, stimulate inflammation, and increase insulin resistance [76]. Current KDOQI and KDIGO guidelines recommend maintaining serum bicarbonate levels in CKD patients at 22 mEq/L or higher (20 mEq/L for children under 2 years of age) [4, 6].

(CGR C; LOR 5)

Comment: the blood reticulocyte count test is performed in children with anaemia who are receiving treatment with drugs from the group «Other antianemic drugs» (erythropoietins) to monitor efficacy (see relevant clinical guidelines).

The frequency of dynamic testing is determined by the clinical situation. To diagnose anaemia in childhood, WHO age-specific haemoglobin thresholds are used (see Appendix A3.16). Anaemia in CKD is discussed in detail separately (see Clinical Guidelines «Anaemia in Chronic Kidney Disease») [79].

(CQR C; LE 5)

Comment: typically at least once every 3 months for those requiring dialysis. The frequency of Hb measurement may be determined by the clinical situation in patients with CKD.

(CGR C; LOR 5)

Comment: in children without a diagnosed condition of anemia, Hb levels should be measured at least once a year in patients with stage 3 CKD, at least twice a year in patients with stages 4–5 CKD, and at least once every 3 months in patients on RRT. Hb levels should be measured more frequently based on clinical indications and in children with diagnosed CKD-associated anemia. Anemia is diagnosed in children with CKD if the Hb concentration is below 110 g/L in children aged 6 months to 5 years, below 115 g/L in children aged 5–12 years, and below 120 g/L in children aged 12–15 years.

Hb levels should be monitored once a week during ESA dose titration and when switching from epoetin beta** to darbepoetin alfa**, then once every 2 weeks, but at least once a month.

In patients with pre-dialysis stages of CKD, Hb levels during maintenance ESA therapy should be monitored at least once every 3 months. In patients undergoing hemodialysis, Hb levels during maintenance ESA therapy should be monitored at least once a month.

(CQR C; LE 5)

Comment: anemia in children with CKD may be caused by factors other than EPO deficiency alone. Serum ferritin reflects body iron stores and should be maintained between 100 and 500 mcg/L. However, it is an acute-phase reactant, making results difficult to interpret in the presence of infection. It is recommended to simultaneously test serum C-reactive protein levels. Transferrin saturation reflects the amount of iron available for erythropoiesis and should be > 20 %. Absolute iron deficiency is a total reduction in body iron stores, defined by a serum ferritin level of < 100 mcg/L. Iron metabolism is impaired in patients with CKD, notably due to elevated levels of hepcidin (a liver hormone that prevents iron release from cells by binding to the iron exporter ferroportin) [81]. Excess hepcidin suppresses iron absorption and leads to iron sequestration in macrophages and hepatocytes, resulting in functional iron deficiency in CKD [82]. Functional iron deficiency entails a higher iron demand to sustain Hb synthesis than can be mobilized from stores. Functional iron deficiency is diagnosed based on serum ferritin levels (> 100 mcg/L), TSAT (< 15–20 %), and the percentage of hypochromic red blood cells (> 5–10 % with a normal value of < 2.5 %). These tests are essential for assessing iron status, diagnosing iron deficiency, and predicting the erythropoietic response to iron therapy.

When interpreting ferritin levels, it should be kept in mind that this parameter increases during inflammatory processes. Because ferritin is an acute-phase protein, its diagnostic value must be assessed differently than in patients without chronic kidney disease.

Transferrin saturation (TSAT) is calculated using the formula:

TSAT = Fe (mcmol/L) / 2 × transferrin (mcmol/L) (%)

Folate and vitamin B12 deficiencies are uncommon, yet important and treatable causes of anemia, usually associated with macrocytosis, in patients with CKD.

(CGR C; LOR 5)

Blood total protein test [88].

(CGR C; LOR 4)

Blood albumin test [87].

(LeveL of Evidence B; Grade of Recommendation 3)

Blood uric acid test [89, 325].

(CGR C; LOR 4)

Total bilirubin test. Blood conjugated (direct) bilirubin test, blood unconjugated (indirect) bilirubin test [86, 325, 326].

(Letal Level of Evidence B; Level of Reliability of Evidence 3)

Aspartate aminotransferase activity determination in blood, alanine aminotransferase activity determination in blood [83, 327, 328, 329].

(CGR C; LOR 5)

Blood chloride test [4, 330].

(CGR C; LOR 4)

Blood glucose test [89].

(CGR C; LOR 4)

Blood C-reactive protein test [84, 90].

(LeveL of Evidence B; Grade of Recommendation 2)

To assess the severity of azotemia, identify electrolyte disturbances, protein metabolism disorders, iron metabolism disorders, calcium-phosphorus metabolism disorders, and hyperlipidemia for the purpose of diagnosing the progression of renal disease and CKD complications, and for dynamic monitoring during treatment [4, 78, 83, 84, 85, 86, 87, 88, 89, 90].

(CGR C; LOR 5)

Comment: the frequency of follow-up tests is determined by the clinical situation. Serum urea and creatinine are commonly used as markers of renal dysfunction, but the accumulation of uremic toxins correlates only partially with GFR in children with CKD [91]. The term "azotemia" is used to denote the presence of "uremic toxins," whereas the term "uremia" generally refers to the clinical manifestations of azotemia. CKD is frequently associated with mineral and bone disorders, which may manifest as alterations in calcium and phosphorus metabolism [92]. Total protein and albumin levels may be reduced both as a manifestation of nutritional status alterations and due to the underlying chronic disease that led to CKD. Currently, albumin and prealbumin are no longer considered reliable biomarkers for diagnosing protein-energy wasting (PEW). Negative changes in acute-phase proteins, such as albumin, prealbumin, and transferrin, do not reflect nutritional status changes and depend on the severity of inflammation, fluid and electrolyte balance, and other factors. Due to nephron mass loss, CKD frequently leads to inadequate renal potassium excretion. Hyperkalemia is a well-established risk factor for arrhythmias and cardiac arrest, predictably leading to higher mortality [93, 94]. An elevated blood CRP concentration in CKD may indicate an ongoing infectious process or myocardial injury. However, it remains unknown whether dyslipidemia in children with CKD impacts cardiovascular morbidity and mortality. KDIGO recommends dietary measures and weight control as the first line of treatment for dyslipidemia in children. Due to very limited available data, the use of lipid-lowering agents (statins) is not recommended in children with CKD under 10 years of age [95].

(Letal Level of Evidence B; Level of Reliability of Evidence 3)

Comment: GFR is an indicator of renal function defined as the volume of plasma filtered by the kidneys per unit of time (usually one minute). Healthy children under 2 years of age have a physiologically lower GFR. GFR equals the sum of the filtration rates of all functioning nephrons and, therefore, correlates with the number of functioning nephrons. Healthy kidneys possess a significant reserve to maintain adequate GFR under various physiological conditions. While representing a tremendous biological advantage, this functional "excess" of nephrons complicates the clinical assessment of early-stage CKD. This is because unaffected nephrons are able to compensate for the damaged ones. Hypertrophy of the remaining nephrons may occur, leading to a partial restoration of GFR. Consequently, there is no linear correlation between nephron loss and GFR loss [103, 104]. Tubular creatinine secretion increases as GFR declines. Therefore, creatinine clearance may overestimate GFR in children with CKD. Other limitations of serum creatinine as a marker of renal function include its dependence on muscle mass and physical activity. Many physiological substances and medications interfere with creatinine assays [105].

The traditionally used Schwartz formula (1976) and Counahan-Barratt formula (1976), which were calculated using creatinine measured by the non-standardized Jaffe method, lead to an overestimation of eGFR values. The use of creatinine measured by isotope dilution mass spectrometry (IDMS) (isotope dilution mass spectrometry) in the original Schwartz formula (1976) leads to an overestimation of the true GFR by 20–40% [107].

To avoid inaccuracies in GFR assessment, the "Bedside" Schwartz formula should be used based on blood creatinine levels measured by an enzymatic method and standardized to IDMS [96, 97]:

eGFR = 36.5 × Ht / Scr (7),

where Ht is height (cm), and Scr is serum creatinine concentration (µmol/L).

In 2012, V. De Souza et al. modified the "Bedside" Schwartz formula, which became known as the Schwartz–Lyon formula (formula 10) [99].

eGFR = k × Ht / Scr,

where k is an age-specific conversion factor (for girls of all ages and boys < 13 years old – 32.5; for boys ≥ 13 years old – 36.5), Ht is height (cm), and Scr is serum creatinine concentration (µmol/L).

The "Bedside" Schwartz formula and the Schwartz–Lyon formula are validated in the pediatric population with stage 2–4 CKD, whereas the efficacy of these equations in healthy children is unknown.

It should be emphasized that laboratory measurement of the concentration of major endogenous GFR markers must be standardized for creatinine using IDMS [98, 108].

If blood creatinine is determined using a standardized Jaffe method, one must keep in mind pseudochromogens (glucose, bilirubin, a number of other beta-lactam antibacterial drugs (1st generation cephalosporins, 2nd generation cephalosporins, 3rd generation cephalosporins, 4th generation cephalosporins), etc.) that can distort its true values. Significant errors in creatinine measurement can occur in lipemic and hemolyzed serum; therefore, neither the enzymatic method nor the Jaffe reaction should be used in such situations [109].

The frequency of testing is determined by the clinical situation.

(CGR C; LOR 4)

Comment: Serum cystatin C is one of the most widely used alternative biomarkers for assessing GFR. Unlike creatinine, cystatin C is produced by all nucleated cells and does not depend on muscle mass. Cystatin C-based formulas are particularly useful for children with reduced muscle mass. To avoid inaccuracies in GFR assessment, it is recommended to use the CKiD formula, which includes cystatin C values (measured by turbidimetric assay) and blood urea nitrogen [95, 97]:

eGFR = 39.1 × [Ht/Scr]^0.516 × [1.8/Cys C]^0.294 × [30/BUN]^0.169 × [1.099]* × [Ht/1.4]^0.188,

where Ht is height (m), Scr is serum creatinine concentration (mg/dL), Cys C is cystatin C (mg/L), BUN is blood urea nitrogen (mg/dL), and * is used for boys only.

GJ Schwartz et al. (2012) also developed a single-variable GFR estimation equation based on cystatin C [101]. This formula has high accuracy:

eGFR = 70.69 × Cys C -0.931 (11),

where Cys C is cystatin C (mg/L).

It should be emphasized that laboratory measurement of the concentration of major endogenous GFR markers must be standardized: for cystatin C, according to the IFCC (International Federation of Clinical Chemistry – standardized calibrator ERM-DA471) [98, 108].

GJ Schwartz et al. established that cys-eGFR may be less accurate when using only a single variable, which accounts for anomalous outliers in estimated values at high body weight. Racial differences, high blood pressure, albumin levels, and glucocorticoid use do not affect cystatin C-based eGFR levels [101].

Conversion factors for units from the metric system to the International System of Units (SI) can be found in Appendix A3.14.

In 2021, C.B. Pierce et al., using the CKiD study patient database, calculated a new formula – CKiD U25 (CKiD under 25), which was presented in two versions: based on creatinine and cystatin C [331, 332].

Creatinine-based CKiD U25:

eGFR = k × (height (m) / Scr)

Constant coefficient for males: k = 41.8

Constant coefficient for females: k = 37.6

Age-dependent coefficient for males:

1 – < 12 years: k = 39.0 × 1.008^{(age – 12)}

12 – < 18 years: k = 39.0 × 1.045^{(age – 12)}

18 – < 25 years: k = 50.8

Age-dependent coefficient for females:

1 – < 12 years: k = 36.1 × 1.008^{(age – 12)}

12 – < 18 years: k = 36.1 × 1.023^{(age – 12)}

18 – < 25 years: k = 41.4

Scr – serum creatinine concentration (mg/dL)

For calculations, use the appropriate GFR calculator (https://qxmd.com/calculate/calculator_822/ckid-u25-egfr-calculator; https://kidney.wiki/gfr-calculator/), which allows entering creatinine values in mg/dL or µmol/L.

Cystatin C-based CKiD U25:

eGFR = k × (1 / CysC)

Constant coefficient for males: k = 81.9

Constant coefficient for females: k = 74.9

Age-dependent coefficient for males:

1 – < 15 years: k = 87.2 × 1.011^{(age – 15)}

15 – < 18 years: k = 87.2 × 0.960^{(age – 15)}

18 – < 25 years: k = 77.1

Age-dependent coefficient for females:

1 – < 12 years: k = 79.9 × 1.004^{(age – 12)}

12 – < 18 years: k = 79.9 × 0.974^{(age – 12)}

18 – < 25 years: k = 68.3

CysC – serum cystatin C concentration (mg/L)

For calculations, use the appropriate GFR calculator (see above).

The CKiD U25 formula is rationally used in children and adolescents with CKD (aged 1–25 years), as well as in young adults up to 25 years of age with onset of CKD before 18 years. However, the formula is not recommended for assessing GFR in healthy individuals [333].

Features of GFR assessment in young children

GFR in newborns increases with age, which is due to postnatal hemodynamic changes, ongoing nephrogenesis in preterm infants, and the maturation of renal filtration function by 2 years of age. Currently, the Smits formula (Smits eGFR) based on the Schwartz formula with a coefficient of 0.31 when assessing creatinine in mg/dL (27.4 in µmol/L [TA2]) is proposed as the most acceptable formula for full-term newborns [334].

(CGR C; LOR 5)

Comment: the analysis of the clinical situation includes data on intrauterine development, drug exposures to the fetus or mother, genetic disorders, organ malformations, physical examination findings, laboratory parameters in the prenatal and postnatal periods (including amniotic fluid analysis (amniotic fluid testing – most commonly performed: cytogenetic analysis of amniotic fluid, chromosomal microarray analysis of amniotic fluid, biochemical analysis of amniotic fluid)), results of pre- and postnatal imaging studies, as well as pathomorphological findings, including of the fetus and placenta.

(CGR C; LOR 5)

Comment: the frequency of testing during follow-up monitoring is determined by the clinical course of the disease.

(CGR C; LOR 5)

Comment: the albuminuria category serves as an important predictor of outcome. For all GFR categories, a stepwise increase in risk is demonstrated with increasing severity of albuminuria, while there is no single clearly established threshold value.

However, in children with CKD, upon detection of any pathological urinary protein excretion regardless of markers, it is necessary to take into account differences in parameters depending on age, sex, sexual maturation stage and/or body size (height, body weight, BMI), and the possibility of tubular rather than glomerular proteinuria predominating depending on the underlying disease. Proteinuria may also be used as a guide instead of albuminuria in children with CKD.

In newborns and infants, higher both glomerular and tubular proteinuria are acceptable due to the immaturity of the proximal tubules responsible for protein reabsorption. Approximate equivalents for urinary ACR and PCR in children are close to, but not identical with, the values cited for adults. Normal ranges vary. A.S. Brem (1981) proposed considering a proteinuria level within 6–8 mg/m²/h or > 240 mg/m²/day as acceptable. In children < 6 months of age, normal albuminuria values for this age are unknown [111].

Normal levels of daily protein excretion in children aged 6–24 months are < 4 mg/m²/h (< 150 mg/m²/day) when testing 24-hour urine, whereas in the first morning urine sample, a PCR level of < 500 mg/g (< 50 mg/mmol) is considered normal. In children older than 24 months, these values are < 4 mg/m²/h (< 150 mg/m²/day) in 24-hour urine, PCR < 200 mg/g (< 20 mg/mmol) in the first morning urine sample, or ACR < 30 mg/g (< 3 mg/mmol) in the first morning urine sample. In any age group, total urinary protein loss > 40 mg/m²/h (> 3 g/1.73 m²/day) is considered nephrotic-range proteinuria; values of 4–40 mg/m²/h reflect pathological but not "nephrotic" protein loss [112, 113, 319].

In children aged > 24 months, levels recommended in adult guidelines can be used to define the "proteinuria" category, with the exception of postural loss of glomerular proteins (albumin), i.e., orthostatic proteinuria observed in 2–5% of adolescents [114, 115].

The relationship between albuminuria and proteinuria categories is presented in Appendix A3.15.

(CGR C; LOR 5)

(CGR C; LOR 5)

Comment: CKD is recognized as a risk factor for AKI due to the epidemiological association between them [116, 117]. CKD is a powerful predictor of AKI upon exposure to contrast agents, major surgical interventions, and other medical conditions [118, 119, 120]. When managing patients with CKD and an increased risk of AKI in the setting of intercurrent illnesses or during examinations and procedures associated with an increased risk of AKI, it is necessary to follow the recommendations detailed in the KDIGO Clinical Practice Guidelines for AKI [6, 110].

(CQR C; LE 5)

Comment: in patients with CKD receiving treatment for CKD-MBD or in whom biochemical abnormalities are detected, it is advisable to increase the frequency of measurements to track trends, treatment efficacy, and side effects. The pathogenesis of CKD-MBD is still far from fully understood. It is known that subclinical changes in bone and mineral biomarkers can be detected at a very early stage of CKD development (stage G2), prior to a drop in calcitriol levels [123, 124]. One such early event is an increase in FGF23, a phosphatonin produced by osteocytes, which enhances renal phosphate excretion. The role of elevated FGF23 in early CKD stages may be protective, as it likely helps delay the onset of hyperphosphatemia. However, the gradual decrease in the number of functioning nephrons and the deficiency of Klotho, the FGF23 co-receptor, ultimately suppress the phosphaturic effect. Thus, FGF23 contributes to the early pathogenesis of secondary hyperparathyroidism prior to the development of serum mineral abnormalities [125]. Hyperphosphatemia typically develops in stage G4 CKD and stimulates parathyroid gland function, which contributes to secondary hyperparathyroidism. The net effect of these systemic changes, combined with current treatment modalities, can paradoxically lead to either excessive bone resorption or bone formation. However, in cases of overt bone mass increase, bone strength is still reduced because the deposited bone collagen fibers are immature [126].

(CGR C; LOR 5)

(CGR C; LOR 5)

Comment: FGF-23 exacerbates 1,25(OH)2-vitamin D deficiency by directly inhibiting 1α-hydroxylase gene expression via activation of the ERK1/2 signaling pathway [127]. Serum 25(OH)2-vitamin D concentration should be above 30 ng/mL at all stages of CKD [128].

(CGR C; LOR 5)

Comment: these indicators are more significant for determining the efficacy of therapy for mineral and bone disorders.

(CGR C; LOR 5)

Comments: the frequency of follow-up testing is determined by the clinical situation. Hypothyroidism and growth hormone deficiency can cause growth retardation in children, regardless of the underlying CKD.

2.4 Instrumental Diagnostics

(CGR C; LOR 5)

Comment: the frequency of follow-up testing is determined by the clinical situation. Renal ultrasound allows determining kidney size, position, structural features, assessing the state of the renal parenchyma and pelvicalyceal system, the severity of nephrosclerosis, as well as suspecting vascular anomalies that may cause renovascular hypertension (renal artery stenosis, thrombosis of major renal vessels). Renal artery duplex scanning evaluates renal blood flow. Prenatal ultrasound diagnostics can identify newborns at risk of developing CKD, especially if bilateral renal anomalies are present.

During ultrasound examination, the measured length of each kidney should be compared with age-appropriate normative values. A kidney size below normal indicates a reduction in renal mass due to CAKUT (e.g., renal hypoplasia), slow growth, or loss of renal parenchyma associated with the underlying disease or trauma.

Abnormalities such as unilateral renal agenesis, fused, lobulated and horseshoe kidney, renal dysplasia, and supernumerary kidney may also be detected.

Children with a solitary functioning kidney are at risk of GFR decline. Risk factors for GFR decline in a solitary kidney include additional congenital anomalies of the kidney and urinary tract (CAKUT) and kidney length that does not correspond to the expected compensatory hypertrophy.

(CGR C; LOR 5)

Comment: plain radiography of the kidneys has low informational value for detecting changes in the organ parenchyma. Contrast-enhanced studies, if necessary, should be performed after assessing renal function to implement measures for preventing complications of these procedures.

(CGR C; LOR 5)

Comment: in CKD patients undergoing diagnostics involving contrast agents, the risk of acute kidney injury must be carefully weighed against the diagnostic value of the procedure and its potential impact on management tactics to minimize the risks of adverse renal effects from such studies.

(CGR C; LOR 5)

Comment: detailed information on blood pressure measurement in children with hypertension is provided in the clinical guidelines for arterial hypertension in children.

(CGR C; LOR 5)

Comment: ABPM is difficult to perform in children under 5 years of age because they cannot calmly tolerate frequent automatic blood pressure measurements. ABPM allows the detection of masked hypertension, white-coat hypertension, circadian blood pressure rhythm abnormalities ("non-dipper"), as well as determining the severity of arterial hypertension and assessing the efficacy of antihypertensive therapy. When interpreting ABPM results, the average 24-hour, daytime, and nighttime SBP and DBP values are evaluated. Their values are assessed against gender, age, and height percentile tables developed from a sample of healthy children aged 5 to 16 years [70, 135].

In addition to average SBP and DBP values, ABPM evaluates maximum and minimum blood pressure values during different periods of the day, "blood pressure load" indices (hypertension time index), blood pressure variability, degree of nocturnal blood pressure dipping, magnitude and rate of the morning blood pressure surge, and duration of hypotensive episodes.

It should be noted that there are currently no reference data for children with a height of less than 120 cm, which complicates the interpretation of results. For data on the percentile distribution of blood pressure in children during office measurements and ABPM, see Appendix 1 [46].

See clinical guidelines for arterial hypertension in children.

(BOS C; LOC 3)

Comment: in children with stage 3 CKD, it is advisable to perform an ECG every 6 months; in children with stage 4–5 CKD, every 3 months; and more frequently if clinically indicated (presence of arrhythmia symptoms, extrasystoles, hypertension, circulatory failure). See clinical guidelines for arterial hypertension in children.

(CGR C; LOR 4)

Comment: the frequency of Holter ECG monitoring is determined by the clinical situation. See clinical guidelines for arterial hypertension in children.

(CGR C; LOR 5)

Comment: EchoCG allows the detection of: myocardial hypertrophy (thickening of the interventricular septum, left ventricular posterior wall, increased left ventricular mass index), left ventricular diastolic dysfunction; impaired myocardial relaxation mechanics, left ventricular dilation, decreased myocardial contractility, aortic changes (dilation, wall hardening), pulmonary hypertension, coronary artery changes (wall hardening, coronary artery calcification), heart valve regurgitation/stenosis, hydropericardium. Global myocardial contractility impairment is diagnosed when the ejection fraction is less than 55% or fractional shortening is less than 35%. EchoCG can also reveal signs of vascular wall, heart valve, and myocardial papillary muscle calcification.

(CGR C; LOR 5)

Comment: the frequency of examinations, including during follow-up monitoring, depends on the clinical situation.

(CGR C; LOR 5)

Comment: Radiological signs of CKD-MBD include widening of Looser's zones (horizontal radiolucent bands in long tubular bones), structural abnormalities of the metaphyses of tubular bones; epiphysiolysis ("slipping" of the epiphysis from the diaphysis); fractures of various locations, recurrent and spontaneous fractures (often painless). In children with stage 5 CKD on dialysis for several years, calcification of the main arteries of the extremities can be detected. Calcified arteries are visualized on radiographs as radiopaque cords of uneven density.

(CGR C; LOR 5)

(Letal Level of Evidence B; Level of Reliability of Evidence 3)

Comment: modern bioimpedance meters (bioelectric body composition analyzers) allow for the determination of lean body mass, adipose tissue mass, extracellular and intracellular fluid volume, and extracellular fluid excess. The results of bioimpedance analysis should be interpreted taking into account clinical symptoms (dynamics of the child's body weight, blood pressure, condition of the subcutaneous adipose tissue, etc.). In the absence of other non-invasive methods for determining hypervolemia applicable in clinical practice, bioimpedance spectroscopy is a useful adjunct to the clinical examination of a patient with CKD. The limitations of the method are specified in the bioimpedance meter manual. A relative contraindication is the child's age under 2 years and a body weight of less than 10 kg [337].

(CQR C; LE 5)

Comment: children under 5 years of age generally require pharmacological sedation for these procedures, which somewhat limits their application. General anesthesia is performed according to indications.

(Letal Level of Evidence B; Level of Reliability of Evidence 3)

Comment: an appointment (examination, consultation) with an ophthalmologist should be performed at least once a year in children in a stable condition, as well as upon the development of a hypertensive crisis or visual disturbances. See clinical guidelines for arterial hypertension.

2.5 Other Procedures

Other diagnostic methods

(RRR C; LOE 5)

Comment: ensuring a balanced diet is one of the most important aspects of treating a child with CKD. PEW is associated with the progression of uremic symptoms, leads to protein-energy malnutrition, and increases mortality in this category of patients. In children under 2 years of age, body length is measured in the supine position; in children older than 2 years and adolescents, height is measured in the standing position. If the child cannot stand, measurement in the supine position is possible.

(RRR C; LOE 5)

Comment: these anthropometric parameters must be measured regularly and plotted on growth charts appropriate for the child's sex and age (with correction for preterm infants) [149]. Children with signs of growth retardation, comorbid conditions (CNS, cardiac, or hepatic impairment), altered health status, or changes in diet may require more frequent assessment [4, 150, 151]. SDS (standard deviation score) is an integral indicator used to assess how well a child's individual growth corresponds to reference data for the corresponding age and sex. The SDS demonstrates how many standard (sigma) deviations the difference is between the arithmetic mean and the measured value. SDS is calculated using the formula:

Height SDS = (x-X)/SD,

where x is height, X is the mean height for chronological age and sex, and SD is the standard deviation of height for the given chronological age and sex.

SDS = -2 corresponds to the 3rd percentile, SDS = 0 corresponds to the 50th percentile, and SDS = +2 corresponds to the 97th percentile.

Analysis of growth velocity allows for the early detection of deviation from the growth curve. To assess growth velocity, data from at least two accurate measurements must be available. To minimize calculation errors, it is preferable that the interval between measurements is at least 6 months. Growth velocity is calculated using the formula:

Growth velocity (cm/year) = (height 2 – height 1) / (chronological age 2 – chronological age 1)

Growth velocity and height should be compared with standardized growth charts [131].

(RRR C; LOE 5)

Comment: the calculation of target genetic height is performed using the Tanner formula for girls (equation 1) and for boys (equation 2):

Assessment of the degree of epiphyseal closure of the left wrist on a radiographic image is a standard approach for evaluating a child's growth potential [152].

(CGR C; LOR 5)

Comment: this recommendation should be followed if the child is on dialysis or has nephrotic syndrome. An important point in assessing the nutritional status of children with CKD, especially on dialysis, is the assessment of euvolemic or "dry" body weight, i.e., the child's true body weight. A large number of children with kidney diseases who have oliguria or anuria, or nephrotic syndrome, present with hypervolemia. At the same time, in children with polyuria and urinary sodium wasting, the actual body weight may be lower than the euvolemic weight. Recommendations on the frequency of measurements are presented in the appendix [153].

(CGR C; LOR 4)

Comment: a decrease in head circumference may indicate chronic inadequate nutrition in the absence of other diseases that can explain it. Conditions that cause macrocephaly (e.g., hydrocephalus) limit the significance of head circumference as a marker of nutritional status [153].

(CGR C; LOR 5)

Comment: when assessing height and body weight in children, comorbid conditions that impair linear growth (e.g., cerebral palsy) must be taken into account; for children with genetic or metabolic diseases, disease-specific physical development standards are used (e.g., Down syndrome). In children under 2 years of age, weight gain should be assessed in grams daily (see Appendix A3.3). Ideally, children with CKD should gain weight at a normal rate. However, in children with impaired linear growth, weight gain should be assessed proportionally to height [149].

(Level of Evidence C; Grade of Recommendation 4)

Comment: despite limiting factors, BMI or the weight-for-height ratio for children under 2 years remains the main indicator of PEW or obesity in children with CKD. In children on dialysis with both high and low BMI, the risk of mortality increases, although the mechanism is unclear [21].

BMI = body weight (kg) / height (m)²

(CGR C; LOR 5)

(CGR C; LOR 5)

(CGR C; LOR 5)

(CGR C; LOR 5)

(CGR C; LOR 4)

Comment: Data from the CKiD (Chronic Kidney Disease in Children) study showed that children with CKD consume a large amount of food high in "empty calories": fast food, chips, and other "snacks." Even if children consume macronutrients in sufficient quantities, trace elements are lacking in their diet [154].

(Letal Level of Evidence B; Level of Reliability of Evidence 3)

Comment: Performing a renal biopsy with morphological examination of the specimen is the standard diagnostic method for various diffuse organ lesions, including immune, vascular, and diabetic disorders. In vivo morphological data are also necessary to determine adequate etiotropic and pathogenetic therapy in order to suppress the activity of the pathological process, retard progression, and prevent adverse outcomes of CKD. Nephrobiopsy in patients with CKD, regardless of age and GFR, is safe and necessary to establish a correct diagnosis and initiate appropriate therapy.

• In patients with CKD, routine bone mineral density (BMD) testing (X-ray densitometry) is not recommended due to the lack of indications. If technically feasible, X-ray densitometry may be performed in patients with marked abnormalities in laboratory parameters (serum calcium, inorganic phosphate, parathyroid hormone levels) within the framework of osteopenia/osteoporosis guidelines to assess fracture risk [6, 110, 131].

(CGR C; LOR 5)

Comment: Timely diagnosis of bone pathology in CKD-MBD in children is of great importance. Identifying structural bone changes before the development of slipped capital femoral epiphysis/fracture and adjusting therapy is an important task for the nephrologist and the pediatric orthopedist-traumatologist specializing in metabolic bone disease. Renal osteodystrophy is defined as an alteration in bone morphology in patients with CKD, which is classified based on 3 histological features: bone turnover, mineralization, and volume. Currently, the invasive method for assessing bone mineral density can be successfully replaced by dual-energy X-ray absorptiometry (X-ray densitometry). This method has high accuracy and minimal radiation exposure, allowing repeated scans to assess the rate of bone loss and fracture risk or to evaluate the recovery of bone mass during therapy. Four prospective cohort studies have demonstrated that BMD measurement using X-ray densitometry can predict bone fracture risks in patients with CKD-MBD. The KDOQI Work Group (2017) also notes that this method cannot determine the type of bone turnover (high-turnover bone disease/osteitis fibrosa or adynamic bone disease) [6, 110]. To answer this question, it is necessary to correlate clinical and laboratory data with the results of X-ray densitometry.

X-ray densitometry is undergoing initial stages of research in pediatric practice. The KDIGO guidelines do not yet provide specific recommendations for children, acknowledging that there is an insufficient number of studies investigating the relationship between X-ray densitometry findings, bone mineral density characteristics, and fractures in children and adolescents with CKD-MBD.

One prospective study involving children with CKD stages 2–5D revealed that lower cortical bone mineral density is associated with a high risk of fractures.

(CGR C; LOR 5)

Comment: In this situation, bone biopsy data will influence the management process. Bone biopsy should also be considered in patients with unexplained fractures, refractory hypercalcemia, suspected osteomalacia, atypical response to standard treatments for elevated PTH, or progressive decline in bone mineral density despite standard therapy. R. Evenepoel et al. in 2017 presented updated information on the role of bone biopsy in the management of patients with CKD-MBD. Quantitative histomorphometric analysis of bone biopsy remains the gold standard for the diagnosis and specific classification of renal osteodystrophy. This study provides insight into bone metabolism and mineralization. Therefore, bone biopsy can assist in the prevention and treatment of osteodystrophy and its consequences [158, 159]. In other cases, bone biopsy is not required for diagnosing bone pathology in a patient with established CKD-MBD and a high risk of fractures. At the same time, the clinician must be confident in their ability to diagnose bone pathology non-invasively.

(CGR C; LOR 5)

Comment: An indirect sign of intracranial hypertension is papilledema according to fundus examination. Intracranial hypertension may progress during Somatropin** therapy.

(CGR C; LOR 5)

Comment: Pubertal staging should be performed in patients older than 10 years. Delayed puberty and blunted pubertal growth spurts are characteristic features of chronic CKD and are likely the result of decreased hypothalamic gonadotropin-releasing hormone release and reduced circulating levels of bioactive luteinizing hormone due to CKD-related inhibitory factors, such as angiotensin II [161]. Assessment of pubertal status (using Tanner staging) allows for the identification of delayed sexual development. Pubertal delay in the setting of growth retardation can be either constitutional (constitutional delay of growth and puberty) or pathological (hypogonadism), requiring further evaluation. Patients with delayed puberty should be referred to a pediatric endocrinologist for a comprehensive workup.

Other diagnostic examinations

(CGR C; LOR 5)

Comments: Initial and follow-up consultations (examinations) by a nephrologist, pediatrician / general practitioner (family physician), pediatric endocrinologist, pediatric cardiologist, and, if necessary, a pediatric surgeon (specializing in transplantology), medical psychologist, clinical pharmacologist, dietitian, and pediatric hematologist-oncologist.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1. Conservative management

Treatment of CKD includes treatment of the underlying primary kidney disease, which can prevent or slow disease progression, as well as management of known complications of CKD.

3.1.1. Nutrition in CKD

3.1.1.1 General provisions

The objectives of nutrition in a child with CKD are: symptom control and prevention of complications, particularly uraemia (fluid-electrolyte and acid-base balance) and mineral and bone disorders (thus delaying the need for RRT); ensuring optimal child growth (Appendix A3.1); and preserving residual renal function.

(CGR C; LOR 5)

Comment: Breast milk is a unique source of nutrition created for infants, including children with stages 2–5 CKD, as a low osmotic load is very important for their kidneys.

(CGR C; LOR 5)

Comment: Whey-predominant infant formulas have a protein and electrolyte profile closer to breast milk than casein-based formulas and are preferred in the 1st year of life. The use of soy-based formulas is not indicated up to 12 months of age due to the high phytoestrogen content.

(CGR C; LOR 5)

Comment: If it is necessary to restrict fluid volume, or when normal food volume causes vomiting or gastroesophageal reflux (GER), dry infant formula can be dissolved in a smaller volume of water. Most standard infant formulas have a concentration of 13%, i.e., 13 grams of dry formula per 100 ml of water, providing an energy density of about 67 kcal and 1.3 g of protein per 100 ml. The concentration of the formula can be increased by 1–3% per day, up to 20%, i.e., 20 g of dry formula per 100 ml of water, depending on the child's individual tolerance. Dry infant formula can be added to breast milk at a concentration of 3–6% (i.e., 3–6 g of dry formula per 100 ml of breast milk), thereby increasing the energy density up to 1 kcal/ml. Human milk fortifier may be used in premature infants.

(CGR C; LOR 5)

Comment: The concentration of the milk formula should be increased gradually to ensure tolerance to the increased osmolality, which may cause diarrhea, vomiting, or GER. Attention should be paid to the increased osmotic load on the kidneys, which can lead to an excess of phosphorus, potassium, and other minerals and electrolytes. An alternative to adding dry infant formula to breast milk can be the addition of a protein component and/or other energy sources (glucose polymers, fat emulsions) to provide a patient-oriented protein and energy profile, with the addition of vitamins and minerals if necessary.

(CGR C; LOR 5)

Comment: All children need to follow a healthy, balanced diet with a wide choice of foods, taking into account any possible dietary restrictions. Families should be educated on choosing healthier foods during the introduction of complementary foods in order to influence the development of eating preferences.

(CGR C; LOR 5)

Comment: Newborns and young children with stages 2–5D CKD may refuse oral feeding. At the same time, tube feeding contributes to the development of chewing and swallowing problems, food refusal, panic attacks, and poor oral motor development. Oral stimulation is desirable, even if oral intake is limited, to prevent the development of food aversion. Therefore, an important aspect of nutritional support is both the provision of nutrition proper and the shaping of eating behavior.

(CGR C; LOR 5)

(CGR C; LOR 5)

Comment: Oral nutritional correction should be carried out in children with inadequate dietary nutrient intake, after identifying the causes of reduced intake and potential medical correction. The fastest growth is observed in the first year of life, and failure to thrive is a signal for intervention. If weight gain is absent for just 2 weeks in the first 3 months of life, 1 percentile is lost. If over 4 weeks, 2 percentiles are lost. At 6 months of age, a 3-week lack of weight gain will lead to the loss of 1 percentile; at 9 months, 1 percentile is lost after 4 weeks of static weight.

In children in the 1st year of life with CKD, more sensitive markers are body weight and/or head circumference measurements, whereas length/height measurements are often inaccurate (physical development assessment is presented in Appendix A3.1; parameters and frequency of nutritional status assessment in children with stages 3B–5D CKD are presented in Appendix A3.2).

The first step in poor weight gain is to search for a potential cause of reduced food intake and correct it. For example, GER/vomiting issues (food thickeners, alginates, antacids, H2-receptor antagonists, proton pump inhibitors, gastrointestinal motility stimulants), acidosis, hypervolemia, hypertension, or inadequate dialysis. Children with CKD may have impaired taste and smell.

3.1.1.2 Energy

(CGR C; LOR 5)

Comment: Inadequate energy intake from non-protein sources leads to the utilization of dietary protein for energy production instead of growth, which also leads to hyperkalemia.

(CGR C; LOR 5)

Comment: Achieving optimal caloric intake may require oral or enteral nutritional support. Enteral nutrition is indicated for both infants and children when oral intake is inadequate to maintain growth and should be initiated as soon as the growth rate falls below normal (see Appendix A3.3).

(CGR C; LOR 5)

Comment: Children on peritoneal dialysis (PD) absorb glucose during the dwell time of the dialysis fluid, which provides an additional energy of 10 kcal/kg/day.

3.1.1.3 Protein

(CGR C; LOR 5)

Comment: A higher protein intake relative to the reference nutrient intake (RNI) is recommended (see Appendix A3.12, A3.13). The lower limit of the recommended protein intake is the safe minimum below which protein intake must not be reduced.

(Level of Consensus C; Level of Evidence 5)

(CGR C; LOR 5)

Comment: When the GFR drops < 25 ml/min/1.73 m², protein intake must be reduced to the RNI. KDOQI recommends 100–140% of protein intake in stage 3 CKD, and 100–120% in stages 4–5 CKD (see Appendix A3.12) [162, 325].

The target urea level should be < 20 mmol/L for infants and children under 10 years of age and < 30 mmol/L for children older than 10 years with normal serum albumin [23].

3.1.1.3 Potassium

Patients with CKD should have their potassium levels monitored, as the kidneys are responsible for excreting dietary potassium. Hyperkalemia is defined as a serum K+ level > 5 mmol/L for children and adolescents (> 5.5 mmol/L for newborns) and hypokalemia as < 3.5 mmol/L. Most patients with dyskalemia are asymptomatic, but severe hyperkalemia can lead to fatal cardiac arrhythmias. Hyperkalemia typically does not occur until the GFR drops to < 10% of normal.

Possible causes of hyperkalemia:

• inadequate energy intake;

• antihypertensive drugs and aldosterone antagonists, ACE inhibitors;

• high dietary potassium intake;

• acidosis;

• adequate control of plasma potassium levels is usually achieved by improving energy intake and restricting foods with a very high potassium content.

Furosemide** (parenteral form: no age restrictions; tablet form: approved by instructions for children aged 3 years and older) should be used with caution to correct hyperkalemia, as a decrease in circulating blood volume (CBV) can destabilize renal function and lead to AKI on top of CKD.

A small group of children with CKD may exhibit persistent hypokalemia, usually resulting from inherited or acquired renal tubular disorders.

The main sources of potassium for infants are breast milk or infant formula; for children and adolescents, they are milk, potatoes, vegetables, grains, fruits, and meat. Dietary supplements containing potassium salts contribute to increased potassium intake.

Traumatic blood collection and erythrocyte hemolysis are the most common causes of laboratory reports showing elevated potassium levels in children. The interpretation of serum potassium in children should be based on age-specific reference ranges. Younger children and infants have physiologically higher serum potassium levels.

(CGR C; LOR 5)

Comment: for children, KDOQI recommends restricting potassium intake to 40–120 mg/kg/day for infants and younger children, and 30–40 mg/kg/day for older children [4]. In addition, families should be educated on food preparation methods that can reduce the potassium content in meals, such as peeling, dicing, and pre-soaking potassium-rich vegetables, as well as avoiding broth [163].

Potassium is found in all types of food. Food preparation methods such as chopping, boiling, and microwave cooking can significantly reduce potassium concentration. According to studies, in children aged 18 months to 18 years, the main sources of potassium are milk and dairy products, starchy roots and tubers such as potatoes, grains, fruits, and meat. Most "ready-to-eat" foods contain K+ salt additives. Foods with added potassium salts may also contain phosphate-based additives, such as meat products, baked goods, and cheeses. The potassium content in foods is shown in Appendices A3.4, A3.5, A3.6.

(CGR C; LOR 5)

(CGR C; LOR 5)

Comment: hyperkalemia is a well-recognized risk factor for arrhythmias and cardiac arrest, and predictably leads to higher mortality [93, 94, 164].

Hyperkalemia is a potential side effect of certain medications used in CKD, including ACE inhibitors and angiotensin II receptor blockers, potassium-sparing diuretics, calcineurin inhibitors, and prostaglandins [165]. It should be taken into account that in children with CKD, discontinuing ACE inhibitors may be associated with an accelerated decline in renal function [339].

For the management of hyperkalemia, see Appendix A3.20. Dialysis is indicated when potassium levels are > 7.5 mmol/L.

(CGR C; LOR 5)

Comment: in pediatric practice, kayexalate is commonly used (active substance: sodium polystyrene sulfonate—an ion-exchange resin that releases sodium ions in exchange for potassium ions). Kayexalate (dietary supplement) is used in accordance with the dietary supplement instructions.

When potassium levels are < 5 mmol/L, the drugs should be discontinued. When potassium levels are > 5 mmol/L, they should be resumed.

If the drug cannot be administered orally, the dose may be given rectally in an amount equal to the oral dose diluted in the same proportions. However, special caution is required when administering rectally to children and newborns, as an excessive dose or inadequate dilution can lead to retention of the cation-exchange resin in the bowel. The risk of gastrointestinal bleeding or colonic necrosis means that special care must be taken when prescribing to premature infants or low-birth-weight newborns at risk for necrotizing enterocolitis [166].

(CQR C; LE 5)

(CGR C; LOR 5)

3.1.1.4 Calcium and phosphorus

Adequate intake of calcium (Ca) and phosphorus (P) is an important part of CKD management in children [167]. Low calcium or phosphorus intake leads to impaired bone mineralization and the development of chronic kidney disease-mineral and bone disorder (CKD-MBD). However, excessive intake of Ca and P is also dangerous and may contribute to the development of nephrocalcinosis and vascular calcification [168].

The main dietary sources of Ca for children are milk, dairy products, breast milk, and infant formulas. The main dietary sources of phosphorus for children are milk (including dairy products, breast milk, and ready-to-use infant formulas), grains and cereals, as well as meat and meat products (Appendix A3.7). Inorganic P added to certain processed foods can significantly increase phosphorus intake.

(CGR C; LOR 5)

(CGR C; LOR 5)

(CGR C; LOR 5)

Comment: in special cases, such as infants with CKD or children with severe osteoporosis, a higher calcium intake may be possible under close monitoring.

(CGR C; LOR 5)

Comment: treatment modifications should be based on serial results, integrating serum Ca, P, PTH, ALP, and 25(OH) vitamin D and its analogs.

(CGR C; LOR 5)

Comment: the contribution of phosphate from phosphate additives should be limited. The use of treatments for hyperkalemia and hyperphosphatemia is required for further control of P and PTH levels in addition to dietary restrictions.

(CGR C; LOR 5)

Comment: calcium can be provided via calcium supplements along with vitamin D and its analogs (typically in both native and active forms), as well as from other calcium sources such as high-calcium dialysate.

(CGR C; LOR 5)

Comment: some patients may require phosphorus supplements in cases of intensive dialysis or high urinary phosphorus losses.

(CGR C; LOR 5)

Comment: a temporary reduction in dietary calcium may be required without compromising adequate nutrition. Regular reassessment is required, especially when calcium intake is below the SDI.

A positive calcium balance exceeding the requirements of a growing child should be avoided (limiting the dose of calcium-based hyperkalemia and hyperphosphatemia treatments, timely administration of non-calcium hyperkalemia and hyperphosphatemia treatments, e.g., #sevelamer** (0.4–1.6 g) [169, 342]) to prevent vascular calcification [92].

3.1.1.5 Sodium and bicarbonate

Sodium (Na), water, and bicarbonate requirements depend on the underlying cause of CKD. Children with renal dysplasia and CAKUT usually require sodium, bicarbonate, and water supplementation. This is due to the severity of tubular disorders leading to decreased reabsorption of sodium, bicarbonate, and water. Such children are characterized by polyuria and polydipsia, and are prone to decompensation episodes with the development of hypovolemia and AKI if they do not receive sodium and bicarbonate supplementation and lack free access to water. Electrolyte losses are highest in children with tubulopathies, especially cystinosis; maintaining adequate sodium and bicarbonate levels can be difficult.

In stage 4–5 CKD, salt restriction is generally necessary. Sodium depletion leads to chronic hypovolemia and contributes to poor growth; hyponatremia is not a sign of sodium deficiency [170]. Excessive salt restriction carries the risk of stimulating the renin-angiotensin-aldosterone system, catecholamine production, and the development of dyslipidemia [171].

Young children on peritoneal dialysis (PD) may lose increased amounts of sodium in urine and dialysate and require sodium supplementation.

Children with CKD due to glomerulopathies generally retain sodium and water, contributing to the development of hypertension. Such children should follow a no-added-salt diet and avoid semi-finished products, fast food, and snacks [325].

(CGR C; LOR 5)

(CGR C; LOR 5)

Comment: it should be noted that the source of bicarbonate can also be HCO₃-based dialysis solutions or sodium lactate complex solution (potassium chloride + calcium chloride + sodium chloride + sodium lactate)**. If metabolic acidosis persists in a child on dialysis therapy, its cause should be individually evaluated (adequacy of dialysis dose, diet, high urinary bicarbonate losses).

The kidneys play an important role in maintaining acid-base balance through the excretion of hydrogen ions, reabsorption of filtered bicarbonate, and generation of new bicarbonate ions and other buffers. CKD can affect all components involved in renal regulation of acid-base balance, leading to metabolic acidosis. Symptoms of metabolic acidosis are non-specific. Stimulation of the respiratory center in the brainstem leads to hyperventilation to compensate for acidosis through CO₂ elimination. As a result, patients may exhibit varying degrees of dyspnea. In addition, patients may experience chest pain, tachycardia, headache, confusion, weakness, bone pain, decreased appetite, nausea, and vomiting [172]. In addition to urinary bicarbonate losses, an inability to acidify urine may be observed. Replacement therapy with sodium bicarbonate** is administered at a starting dose of 1 mmol/kg/day divided into two to four doses. A more precise calculation of the required amount of sodium bicarbonate** is made using the Mellemgaard-Astrup formula:

HCO3^- (mmol) = BE × 0.3 × m (patient body weight in kg), with 1 ml of 8.4% solution equaling 1 mmol.

The use of sodium bicarbonate** requires monitoring of the acid-base and general condition of the patient [173].

3.1.1.6 Vitamins

Patients with CKD are characterized by micronutrient deficiencies in their diet [174]. Data indicate deficiencies in ascorbic acid, thiamine (B1), pyridoxine (B6), and folic acid [343, 344].

(CGR C; LOR 5)

(CGR C; LOR 5)

(CGR C; LOR 5)

(CGR C; LOR 5)

Comment: folic acid is lost in the dialysate. Therefore, correction of hyperhomocysteinemia developing on this background requires the use of #folic acid**. Nevertheless, folic acid deficiency is also noted in children with CKD not on dialysis [378].

Correction may be performed depending on the blood homocysteine and/or folic acid levels (to maintain blood folic acid levels > 5 ng/mL, but not exceeding the upper limit of normal).

(CGR C; LOR 4)

(CGR C; LOR 5)

Comment: patients with impaired renal function exhibit high blood retinol levels, which may be associated with a combination of decreased glomerular filtration of the retinol-retinol-binding protein complex, decreased conversion of retinol to retinoic acid, and accumulation of retinol-binding protein. Elevated retinol levels are observed in children with stage 3–5D CKD and correlate with hypercalcemia [347].

3.1.1.7 Enteral nutrition

(CGR C; LOR 5)

Comments:

Enteral nutrition can be administered via a nasogastric tube (Nasogastric tube placement) or via a gastrostomy (Gastrostomy, Video-assisted endoscopic gastrostomy, Laparoscopic gastrostomy).

Although a nasogastric tube is placed for a short time, most families prefer it to a gastrostomy, which is not visible under clothing. Vomiting may be a decisive factor in preferring a gastrostomy.

Nasogastric tube (NGT)

Advantages:

Method of choice in children with body weight < 4 kg.

Tube placement is simple, and the family is easily trained.

There is no risk of peritonitis in children on peritoneal dialysis (PD).

Disadvantages:

Deterioration of the child's and family's quality of life due to the need for frequent tube replacements.

Impairs the development of oro-motor skills, leading to further speech development and swallowing problems.

The child's appearance is altered, and people around notice a "sick child".

Risk of esophageal or gastric perforation (rare).

Increased risk of gastroesophageal reflux, vomiting, and aspiration due to an open lower esophageal sphincter.

Transpyloric (nasojejunal) tube

The feeding tube can be advanced past the stomach into the duodenum or jejunum in an attempt to reduce vomiting. However: the tube dislodges easily and requires radiologic control as well as general anesthesia for repositioning; the tube cannot be used for bolus feeding, only for continuous long-term feeding.

Gastrostomy

Gastrostomy placement can be performed percutaneously via endoscopic, radiologic, or laparoscopic approaches, as well as by open surgery. Regardless of the placement technique, the exit site of the gastrostomy tube is restricted to the upper left quadrant of the abdomen or the midline due to gastric anatomy. Therefore, peritoneal dialysis catheters should not be placed in the upper left quadrant in children who will subsequently require gastrostomy placement [178].

NGT is preferred for short-term enteral nutrition.

Gastrostomy is preferred for long-term enteral nutrition.

The device for long-term enteral nutrition should be chosen in consultation with the parents/guardians.

The greatest effect in terms of improving physical development from aggressive nutritional support is expected under the age of 2 years, when growth depends entirely on nutrition [179]. Improved growth was observed in most studies in children under 2 years of age. In a large study of 153 infants on peritoneal dialysis, growth was better in children with a gastrostomy compared to those fed via NGT [180]. In a study of 40 children with stage 3-5D CKD with a gastrostomy (77.5% younger than 5 years; mean gastrostomy feeding duration was 5.32 years), the mean height SDS increased to the normal range (from -2.29 to -1.85), with statistically significant increases in body weight SDS, weight-for-height SDS, and BMI SDS. None of the children developed obesity [348].

3.1.2. Anemia in CKD

Treatment of anemia in CKD is associated with slower CKD progression, reduction of left ventricular hypertrophy, improved quality of life and reduced hospitalization rates, lower transfusion requirements, and consequently, a lower risk of infection and leukocyte antigen (HLA) sensitization [181].

The administration of iron supplements and other anti-anemic agents with erythropoiesis-stimulating properties (ESAs) helps increase Hb levels in the majority of patients with CKD. Treatment of anemia in CKD also includes correction of other reversible causes of decreased Hb, such as vitamin B12 and folic acid deficiency, and treatment of inflammation.

Anemia therapy in CKD is discussed in detail separately (see clinical guidelines "Anemia in Chronic Kidney Disease") [79].

Target hemoglobin levels in adults and children with CKD receiving maintenance ESA therapy are presented in Appendix A3.17.

3.1.3. Management of cardiovascular disease in CKD

Cardiovascular disease is the primary cause of high mortality and low life expectancy in patients with CKD. Therefore, CKD treatment is generally aimed at preventing and slowing the progression of CVD. Hypertension is the main driver of renal and cardiovascular disease progression in CKD. Blood pressure levels are associated with CVD markers such as intima-media thickness and pulse wave velocity [46, 182, 311, 335]. Achieving a blood pressure below the 90th percentile has been shown to be associated with slowed CKD progression in children with both glomerular and non-glomerular kidney diseases [182]. Maintaining office blood pressure below the 50th percentile prevents the development of left ventricular myocardial hypertrophy, thereby slowing CVD progression [349].

Given the complex pathogenesis of CVD in patients with CKD, adequate management of CKD manifestations such as anemia, PEM, and mineral and bone disorders is also crucial for CVD prevention. Accordingly, the principles of CVD management in CKD are:

Correction of arterial hypertension and hypervolemia.

Adequate management of calcium and phosphorus metabolism disorders. Avoid hypercalcemia, hyperphosphatemia, and prolonged use of high doses of active vitamin D and its analogs.

Achieving the target Hb level.

Adequate nutrition.

Adequate dialysis.

Earliest possible kidney transplantation.

3.1.3.1 Management of arterial hypertension in children with CKD

The goals of hypertension treatment in patients with CKD are to slow the progression of kidney damage, prevent target organ damage (heart, brain, eyes), prevent acute hypertension complications (hypertensive crisis, acute left ventricular failure, cerebrovascular accident), and ultimately improve patient survival and quality of life.

The objective of antihypertensive therapy is to reduce blood pressure below the 90th percentile for sex, age, and height. European guidelines for the management of hypertension in children [135] recommend a target blood pressure below the 75th percentile for children with CKD with non-proteinuric kidney diseases and below the 50th percentile for those with proteinuric diseases. The multicenter HOT-KID study (2023) demonstrated that children in the more intensive blood pressure control group (target office blood pressure < 40th percentile) had a lower left ventricular mass thickness index than those in the target blood pressure < 70th percentile group. Therefore, lowering blood pressure to < 50th percentile appears advisable to prevent CVD progression. However, in clinical practice, achieving this blood pressure level, especially in children with stage 5 CKD, may require multiple high-dose antihypertensive agents, which carries a risk of adverse effects from antihypertensive therapy. According to the 2024 KDIGO clinical practice guideline for the evaluation and management of CKD, the target systolic blood pressure for children and adolescents with CKD is the 50th–75th percentile [325].

For detailed information on hypertension therapy in children with CKD, see the clinical guidelines for arterial hypertension in children and adolescents.

Hyperhydration and vascular volume overload significantly contribute to the pathogenesis of hypertension in children with CKD, particularly in stages 4–5. Hyperhydration in CKD is caused by excessive sodium intake relative to physiological needs against the background of impaired renal excretion, leading to water retention. The primary measures for managing hypertension in children with CKD should include sodium and water intake control and achieving "dry weight" in dialysis patients. Sodium restriction measures are especially important for patients with edema (in nephrotic syndrome, glomerulonephritis) and for oliguric/anuric dialysis patients, whose fluid balance depends entirely on the ultrafiltration volume during hemodialysis or peritoneal dialysis procedures.

(CGR C; LOR 5)

Comment: in children with CKD without impaired natriuresis, sodium intake should not exceed the maximum for their age (see Appendix A3.10, A3.11) [294].

(CGR C; LOR 5)

Comment: the mass fraction of sodium in table salt is 40%, meaning daily sodium intake is 3000–4000 mg/day, in addition to that contained in food. Since the bulk of sodium enters the diet during food preparation (salting, use of flavoring additives, preservatives, etc.), sodium content in the diet can be reduced by the following measures:

- Completely exclude pickled foods, canned goods, smoked products, sausages, semi-finished foods, fast food, and snacks (chips, crackers, etc.). Limit bread consumption, especially rye bread.

- Food should be prepared without salt. Animal-derived products (meat, fish, milk, eggs) contain sufficient sodium to meet requirements. Food may be salted at the table, but the amount of table salt should not exceed 1-2 g/day.

Following a low-sodium diet reduces thirst and makes fluid restrictions easier for the patient to tolerate. A gradual reduction of sodium in the body leads to a decrease in extracellular fluid volume and circulating blood volume, facilitating hypertension control [186].

In children with salt-wasting states, dietary sodium restriction is contraindicated, as it can provoke hyponatremia, dehydration, and, with prolonged use, growth retardation [170].

(CGR B; LOR 2)

Comment: typically, diuresis is monitored daily in children with stage 5 CKD. However, assessing fluid balance based solely on fluid intake, diuresis, and ultrafiltration volume is not always feasible, as a significant amount of fluid is consumed with food (fruits, vegetables, porridges, soups, etc.), part of the water is lost via perspiration, etc. Daily weighing of a child with CKD helps suspect hyperhydration (in case of excessive daily weight gain). For children on peritoneal dialysis (PD), it is advisable to control body weight daily; for those on hemodialysis (HD), before each dialysis session, in order to properly adjust the dialysis regimen to ensure adequate ultrafiltration.

(CGR B; LOR 3)

Comment: regular bioimpedance analysis allows differentiation of physiological muscle and fat mass gain from weight gain associated with an increase in extracellular fluid volume. Methods for adapting the PD regimen and HD procedures to increase ultrafiltration are described in the relevant section.

(CGR C; LOR 5)

Comment: children and adolescents with stage 3–5 CKD should avoid reducing diets with severe calorie restriction leading to rapid weight loss. Unbalanced nutrition can provoke electrolyte disturbances and enhanced catabolism, increasing azotemia. At the same time, overweight in children is not in itself a reliably significant factor in CKD progression [61]. Studies in adult patients have shown better survival in obese dialysis patients compared to those with normal body weight, meaning that adequate fat and muscle mass is a prognostically favorable factor in dialysis patients [189]. According to our observations, dialysis patients with underweight and poorly developed subcutaneous tissue tolerate both dehydration and hyperhydration worse, likely due to a lack of reserves for extracellular fluid redistribution. Even minimal hyperhydration in them leads to elevated blood pressure due to increased circulating blood volume (CBV).

In children with CKD and hypertension, drug therapy is prescribed simultaneously with non-pharmacological methods of blood pressure correction in accordance with the clinical guidelines for arterial hypertension in children and adolescents. The drugs of choice for children with stages 1–3 and 5d CKD are ACE inhibitors / ARBs at the maximum tolerated dose due to their nephro- and cardioprotective effects [335]. They are prescribed under the control of blood pressure, kalemia, and GFR.

With an acute spike in blood pressure in children and adolescents, the risk of target organ damage increases sharply: cerebrovascular accidents, cerebral edema, white matter damage (posterior reversible encephalopathy syndrome, or PRES syndrome); retinal hemorrhages; coronary circulation disorders, acute left ventricular failure. In the case of a hypertensive crisis, therapy must be prescribed without delay. At the same time, in patients with long-standing hypertension, rapid (within several hours) normalization of blood pressure can also lead to impaired cerebral and coronary circulation.

The goal of treating a hypertensive crisis is a controlled reduction of blood pressure to a safe level to prevent complications.

For details on hypertension therapy in CKD in children, see the clinical guidelines for arterial hypertension in children and adolescents.

3.1.3.2 Management of heart failure in children with CKD

In the vast majority of cases, heart failure in children with CKD is a consequence of hyperhydration and uncontrolled hypertension. At the same time, both excess extracellular fluid and reduced myocardial contractility are initially compensated and practically asymptomatic. However, with increasing hyperhydration and/or hypertension, decompensation occurs with the development of acute left ventricular failure and pulmonary edema. Therefore, the main measure for the prevention and treatment of heart failure in children with CKD is the maintenance of normohydration and normotension. Controlled studies on heart failure therapy in children with CKD have not been conducted, and the evidence base is lacking. Recommendations for heart failure therapy in children with CKD are based on the extrapolation of studies conducted in adult patients with CKD and cardiovascular disease, and on expert opinion, and are mainly carried out according to the general principles of heart failure therapy in children [47, 71, 135].

(CGR C; LOR 5)

Comment: measures to restrict dietary sodium intake are outlined above.

(CQR C; LE 5)

Comment:

- For children on PD, perform round-the-clock exchanges of dialysis solution with an increased glucose concentration and shortened dwell time (1–2 hours). Intensive PD is carried out until normohydration is achieved and symptoms of pulmonary edema resolve. After condition stabilization, the child can be switched back to the previous PD regimen with daily control of body weight and ultrafiltration volume.

- For children on HD, ensure the gradual achievement of "dry body weight." Continuous methods (continuous venovenous HD or HDF) should be preferred because they have less pronounced hemodynamic effects than intermittent HD and provide gradual, prolonged ultrafiltration. If continuous procedures are not available, daily HD procedures with limited ultrafiltration are preferable. In patients with heart failure and hyperhydration, single high volumes of ultrafiltration (more than 3% of body weight) should be avoided, as a sharp decrease in circulating blood volume (CBV) can cause collapse, a drop in coronary blood flow, and acute myocardial ischemia.

To determine "dry body weight" and the target ultrafiltration volume in dialysis patients with heart failure, it is advisable to perform bioimpedance analysis (see above).

Antihypertensive therapy in patients with CKD and heart failure is carried out according to the principles outlined above.

Effective blood pressure control is extremely important for children with heart failure. The drugs of choice are ACE inhibitors / Angiotensin II Receptor Blockers (for details, see the Clinical Guidelines for Arterial Hypertension in Children and Adolescents). ACE inhibitors / Angiotensin II Receptor Blockers are contraindicated in stage 4 CKD (GFR < 30 ml/min), but can be used at the dialysis stage of CKD. The choice of ACE inhibitors / ARBs as the first-line antihypertensive therapy in CKD and heart failure is due to both their nephroprotective and cardioprotective properties (ACE inhibitors / ARBs slow down vascular remodeling and myocardial hypertrophy in CKD) [335, 350].

(CQR C; LE 5)

Comment: the prescription of diuretics varies depending on the stage of CKD. An aldosterone antagonist (spironolactone**) can be used in children with stages 1–3 CKD with careful monitoring of blood potassium levels (per instructions – contraindicated in children under 3 years of age). In stage 4–5 CKD, its use is not indicated due to the high risk of hyperkalemia. The combination of spironolactone** with ACE inhibitors / Angiotensin II Receptor Blockers is contraindicated.

Thiazide diuretics (hydrochlorothiazide**) are advisable to prescribe in heart failure for children with CKD stages 1–3, HF stage IIA, and moderate hypervolemia (approved by instructions for children aged 3 years and older). Thiazide diuretics can be used in combination with ACE inhibitors / angiotensin II receptor blockers. When GFR decreases < 30 mL/min, thiazide diuretics are ineffective.

"Loop diuretics" (furosemide**) (typically parenterally) are indicated for children with HF stages IIB–III, fluid retention, and edema at any stage of CKD. To rapidly relieve hypervolemia, furosemide** may be used at the dialysis stage of CKD in patients with residual renal function, in addition to intensive peritoneal dialysis or hemodialysis. Prolonged use of furosemide** can provoke hypokalemia, which is particularly undesirable when using digoxin**.

When using "loop" and thiazide diuretics in a patient with heart failure and CKD, the serum potassium and sodium levels should be monitored regularly (at least twice a week until the condition stabilizes). If hyponatremia or hypokalemia develops, correction of the diuretic dose and oral or intravenous potassium supplementation are indicated.

(CGR C; LOR 5)

Comment:

Treatment – see the clinical guidelines «Chronic heart failure in children».

Adrenergic and dopaminergic agents (non-glycoside fast-acting inotropic drugs, e.g., dobutamine**, etc.) are used for acute circulatory decompensation with a sharp decrease in cardiac output and a drop in blood pressure. They are prescribed by an anesthesiologist-resuscitologist and administered via continuous slow infusion in an intensive care unit under continuous blood pressure and ECG monitoring.

Dobutamine** stimulates myocardial beta₁-adrenergic receptors and produces a positive inotropic effect. It moderately increases heart rate, stroke volume, and cardiac output, and reduces systemic vascular resistance and pulmonary vascular resistance. Systemic blood pressure does not decrease significantly. It increases coronary blood flow, helps improve myocardial oxygen supply, and reduces ventricular filling pressure. The effect develops within 1–2 minutes and reaches a maximum in 10 minutes.

In acute HF, dobutamine** is prescribed at a dose of 5–10 mcg/kg/min. Dobutamine** is metabolized in the liver; dose reduction is not required in children with impaired renal function. It is prescribed to children with caution, under continuous monitoring of vital functions in the ICU.

3.1.4. Mineral and bone disorders in CKD

The goal of CKD-MBD therapy is both the prevention and treatment of secondary hyperparathyroidism (sHPT), which leads to bone structure abnormalities and severe cardiovascular complications. At the same time, one should keep in mind the possibility of developing adynamic bone disease resulting from incorrect and/or excessive treatment of hyperparathyroidism. Adequate therapy includes correction of elevated phosphorus levels while maintaining normal serum calcium levels, meeting vitamin D requirements, and correcting abnormal PTH levels.

(CGR C; LOR 5)

Comment: the recommendation is based on the results of large meta-analyses in the adult population, which indicate an increase in cardiovascular mortality when serum P concentrations exceed the upper limit of the reference range (> 1.48 mmol/L) [192]. It should be borne in mind that the normal serum phosphate level varies across different periods of childhood (see Appendix A3.18): it is highest in infants under three months of age, then gradually decreases as the child grows [193]. There are two main approaches to achieving the target serum phosphate level: dietary phosphorus restriction and the use of phosphate-binding agents—drugs for the treatment of hyperkalemia and hyperphosphatemia (phosphate binders). To determine the most effective strategy for lowering phosphorus levels, the following factors should be considered: renal functional capacity and P excretion ability; the amount of P ingested with food and medications; the presence of protein-energy malnutrition (PEM); the need for parenteral nutrition; the severity of metabolic acidosis; the efficacy of renal replacement therapy procedures and the possibility of intensifying dialysis therapy; the concentration (excess or deficiency) of vitamin D; compliance with medications for lowering P levels (drugs for the treatment of hyperkalemia and hyperphosphatemia); and the severity of clinical manifestations of SHPT and bone tissue sensitivity to intact PTH.

(CGR C; LOR 5)

Comment: dietary phosphorus requirements are in Appendices A3.8, A3.9, the reference range for serum phosphorus concentration is in Appendix A3.18, and the target ranges of PTH, phosphorus, and calcium for CKD stages are presented in Appendix A3.19.

In children with elevated levels of both PTH and serum phosphorus, dietary phosphorus should be further restricted to 80% of the DRI [194] while maintaining adequate protein intake (see Appendix A3.12, A3.13). During a low-phosphorus diet, monitoring of serum phosphorus levels is necessary at least once every 3 months in CKD stages 3–4 and monthly in CKD stage 5.

Dietary phosphorus restriction can lead to a decrease in phosphorus without the use of drugs for the treatment of hyperphosphatemia (drugs for the treatment of hyperkalemia and hyperphosphatemia). In addition to dietary organic phosphorus (plant and animal proteins – Table in Appendix A3.7), one should not forget to restrict the intake of inorganic phosphorus contained in food additives (antioxidants: E338-E343, E442, E450-E452, emulsifiers: E544-E545). Their intestinal absorption rate is 80–100%. The effectiveness of this approach is evidenced by data from several RCTs [195, 196, 197]. Plant-based organic phosphorus has a low bioavailability of 20–40%, while animal-based P has a bioavailability level of 40–70%.

Low-phosphorus food products help partially compensate for requirements and create a positive phosphorus balance in the body without a significant risk of PEM. When adjusting dietary phosphorus intake in CKD stages 3–4, the degree of reduction in renal phosphorus (P) excretion depending on GFR is taken into account: by 30 mg P/day for every 10 mL/min/1.73 m² at a GFR of 70–40 mL/min/1.73 m²; by 100 mg P/day for every 10 mL/min/1.73 m² at a GFR < 40 mL/min/1.73 m².

A decrease in serum phosphate levels below the recommended level should be avoided, as hypophosphatemia can have negative consequences for bone mineralization and the patient's linear growth, and leads to significant disorders of acid-base balance and basal metabolism [194, 195, 196, 197].

(CGR C; LOR 5)

Comment: the effectiveness of this approach has been confirmed by a meta-analysis of a randomized clinical trial (adult patients). A reliable positive effect is achieved when recommendations are followed for at least 4 months. A nephrologist, independently or in cooperation with a dietitian, provides the patient and their parents with the necessary knowledge and skills to ensure proper nutrition, prevention, and treatment of hyperphosphatemia [198, 199, 200, 201, 202].

(CQR C; LE 5)

Comment: considering that the function of drugs for the treatment of hyperkalemia and hyperphosphatemia (phosphate-binding agents / binders) is to prevent the intestinal absorption of dietary phosphorus, all drugs for the treatment of hyperphosphatemia should be taken 10–15 minutes before or during a meal (see Appendix A3.21). Since their capacity to bind phosphates is limited, it is also necessary to follow dietary restrictions regarding dietary phosphorus.

The most accessible drugs in this group are calcium preparations. Calcium carbonate and calcium acetate are used (registered in the Russian Federation as dietary supplements) [129].

When prescribing calcium preparations, it should be taken into account that the total intake of elemental calcium (including dietary calcium) should not exceed 200% of the DRI (daily requirement), and no more than 2500 mg/day for adolescents and young adults [194].

Calcium preparations (calcium-containing phosphate binders) should not be used as monotherapy in patients with hypercalcemia. For this group of patients, preferred are drugs for the treatment of hyperkalemia and hyperphosphatemia ("non-calcium-containing" binders), for example, sevelamer** (initial dose 121 ± 50 mg/kg/day up to 163 ± 46 mg/kg/day) (prescription in pediatric practice is permitted in the form of powder for the preparation of oral suspension from the age of 6 years, or if the body surface area is greater than 0.75 m²) [205, 342].

Aluminum preparations (aluminum-containing phosphate binders) should not be used in CKD due to aluminum toxicity, and also because calcium citrate increases aluminum absorption. Magnesium preparations (magnesium-based phosphate binders) also have limited use due to the risk of hypermagnesemia, hyperkalemia, and diarrhea [204]. Drugs for the treatment of hyperkalemia and hyperphosphatemia (phosphate binders containing lanthanum carbonate and iron preparations) have not been widely used in pediatric practice to date. Multicenter studies of these drugs are currently ongoing.

(CGR C; LOR 5)

Comment: vitamin D deficiency is detected in the majority of children with CKD and contributes to the further progression of CKD. Determination of vitamin D status (see Appendix A3.22) and therapy with native vitamin D and its analogues and/or active forms of vitamin D (see Appendix A3.23) in case of its deficiency play an important role in the success of CKD-MBD therapy.

Therapy with vitamin D and its analogues is divided into 2 stages: 1st — intensive restoration of vitamin D concentration (duration up to 3 months under the control of 25(OH)D); 2nd — maintenance phase. Treatment with vitamin D and its analogues should be discontinued or the dose reduced when the 25(OH)D concentration exceeds 48–50 ng/mL and/or in case of hypercalcemia.

(Letal Level of Evidence A; Level of Reliability of Evidence 2)

Comment: the physiological basis for the use of #cholecalciferol** at the first stage of SHPT correction (or in combination with active forms of vitamin D and its analogues) is its 1-alpha-hydroxylase activity in extrarenal cells, which enables the peripheral conversion of 25(OH)D into calcitriol. The use of #cholecalciferol** reduces the level of iPTH with a minor change in serum calcium and phosphorus levels.

Enteral vitamin D supplementation should be performed in children with CKD depending on the degree of serum 25(OH)D deficiency: in severe vitamin D deficiency (less than 5 ng/mL) — vitamin D dose of 8000 IU/day for 4 weeks, then 4000 IU/day for 2 months. In vitamin D deficiency of 5–15 pg/mL — vitamin D dose of 4000 IU/day for 3 months. With a serum 25(OH)D level of (16–30 ng/mL) — vitamin D dose of 2000 IU daily for at least 3 months. After determining the vitamin D concentration (dynamically) — determine the tactics for further correction of vitamin D deficiency (Appendix A3.22) [4].

To correct SHPT in vitamin D insufficiency (20–29 ng/mL) and deficiency (< 20 ng/mL), it is necessary to achieve a concentration of 30–50 ng/mL [209]. Treatment with cholecalciferol** should be discontinued if the serum 25(OH)D concentration exceeds > 50 ng/mL and/or when the serum total calcium level exceeds 10.5 mg/dL (2.62 mmol/L).

Conversion factors for units from the metric system to the International System of Units (SI) can be found in Appendix A3.14.

(CGR C; LOR 5)

or

• #paricalcitol**(off label up to 18 years as a solution for intravenous administration and up to 10 years in capsule dosage form). Capsules are prescribed to children from 10 years of age with CKD stage 3-4: - starting dose 1 mcg/day, 3 times a week, but not more often than once every 2 days). The dose is selected individually taking into account the iPTH level (target iPTH level for children with CKD stage 3 is 35-69 pg/mL, with CKD stage 4 is 70-110 pg/mL), serum calcium and phosphorus concentrations [210]. Intravenous #paricalcitol** is administered only to patients with CKD stage 5D after a hemodialysis session for vital indications (off label) at a starting dose of 0.04 mcg/kg if the baseline blood parathyroid hormone level is < 500 ng/L, or 0.08 mcg/kg if the baseline blood parathyroid hormone level is > 500 ng/L. The dose is increased by 0.04 mcg/kg every 2 weeks until the PTH level has decreased by 30% compared to baseline, or until a calcium level of more than 11 mg/dL (> 2.74 mmol/L) is reached, or a calcium-phosphorus product (Ca x P) of more than 75 mg²/dL² (> 6.04 mmol²/L²) [206].

(CGR C; LOR 5)

Comment: treatment with the indicated drugs in stage 3–5D CKD is associated with a reduction in fatal cardiovascular events [211, 212, 213, 214, 215]. Treatment with any of the indicated drugs is associated with the well-known risks of developing hypercalcemia, which should be taken into account when choosing these drugs (do not prescribe in hypercalcemia) and when monitoring the effect of therapy. In general, #paricalcitol** and #calcitriol** have no significant differences in their effect on Ca, P concentrations, ALP activity, or adverse events (studies were conducted in adult patients on dialysis [216, 217, 218].

Active forms of vitamin D and its analogues (#calcitriol** (in children with body weight < 10 kg — 0.05 mcg every other day, with body weight 10–20 kg — 0.1–0.15 mcg daily, with body weight > 20 kg — 0.25 mcg daily [129], alphacalcidol**) should be administered when the PTH level exceeds the target value and the serum 25(OH)D level exceeds 30 ng/mL, in the absence of hypercalcemia and hyperphosphatemia [206]. Active forms of vitamin D and its analogues have proven their efficacy in controlling PTH levels. There is no objective evidence supporting the choice of one over the others. There are indications that more selective preparations of vitamin D and its analogues (alphacalcidol**) as well as #paricalcitol** (contraindicated according to the instructions for children under 10 years of age in capsule dosage form and under 18 years of age as a solution for intravenous administration) are usually preferred for patients with hypercalcemia receiving #calcitriol**. The lowest dose should be used to achieve target iPTH concentrations and maintain normocalcemia. After initiating therapy, serum calcium and phosphorus levels should be measured at least once a month (for the first 3 months), and thereafter at least once every three months. Achieving the target serum iPTH value in children with CKD-MBD is one of the main goals in the conservative therapy of CKD.

The therapeutic algorithm described above (dietary phosphorus restriction, phosphate binders, calcium preparations as well as vitamin D and its analogues, #paricalcitol**) is not always effective in reducing serum iPTH levels. In individual patients with persistent hyperparathyroidism, the use of other iPTH-lowering agents should be considered. #Cinacalcet** (off-label in pediatric patients; a small number of studies demonstrate the efficacy of the drug in children; various studies have used the following doses of #cinacalcet**: initial 0.18–0.5 mg/kg/day, maximum 0.25–4.2 µg/kg/day). #Cinacalcet** increases the sensitivity of calcium-sensing receptors in the parathyroid gland, which leads to the suppression of PTH secretion. Although the experience of using the drug in children is still limited, existing data already indicate its efficacy in reducing PTH levels. However, the risk of hypocalcaemia during #cinacalcet** therapy requires further studies on the safety of the drug [219, 354].

(CGR C; LOR 5)

Comment: low serum iPTH levels (below the "target level") can lead to the development of adynamic bone disease, which occurs due to the suppression of osteoclasts and osteoblasts, and a decreased rate of osteoid formation. Adynamic bone disease can lead to diffuse mineralization defects, vascular calcification, marked growth retardation, and pathological fractures. In adynamic bone disease, the iPTH level is below target, alkaline phosphatase activity is normal, and Ca and P levels are normal or elevated. The main therapeutic measures are dose reduction or withdrawal of vitamin D and its analogues until the iPTH level normalizes. #Calcitriol** may be used at 35 ng/kg 2 times/week [222]. The initial dose of #calcitriol** during intermittent #calcitriol** therapy was 1.0 µg 3 times weekly, and the dose was increased by 0.5 µg if serum phosphorus and calcium levels were below 6.5 mg/dL (2.09 mmol/L) and 10 mg/dL (2.5 mmol/L), respectively [223].

(CGR C; LOR 5)

Comment: in patients with stage 5D CKD, dialysis is of primary importance in controlling serum phosphorus concentration (blood inorganic phosphorus testing). Following a standard 4-hour hemodialysis session, the amount of phosphorus removed from the body almost matches its daily dietary intake. Phosphorus elimination via renal replacement therapy methods is essential for normalizing blood phosphorus concentrations and controlling body phosphate overload. Increasing dialysis intensity (largely through its duration) is a major step in correcting hyperphosphatemia in renal replacement therapy-dependent patients [224, 225, 226].

(CGR C; LOR 5)

Comment: the widespread use of various groups of phosphate binders and potassium-lowering agents in patients with stage 3–5 CKD is impractical. The first step should be to utilize all non-pharmacological correction options (adequate diet, dosed physical activity, continuous monitoring of CKD progression). The restriction of calcium-containing phosphate binders and potassium-lowering agents is dictated by concerns regarding the adverse consequences of calcium overload on bone metabolism and the cardiovascular system, and the high risk of calciphylaxis [192]. The safety profile of phosphate binders and potassium-lowering agents in CKD-MBD remains somewhat uncertain, which precludes recommending the widespread use of phosphorus-lowering drugs in routine practice. In cases of high risk for progressive calcification and cardiovascular events, non-calcium-containing phosphate binders and potassium-lowering agents are more justified [228, 229].

(CGR C; LOR 5)

Comment: when phosphate-binding agents are used to treat hyperphosphatemia, intestinal P absorption is reduced by no more than 200–300 mg/day, which does not ensure a neutral phosphorus balance without dietary restriction and elimination via renal replacement therapy in patients with stage 5 CKD.

(CGR C; LOR 5)

Comment: a number of cohort studies have demonstrated that elevated iPTH levels above normal in patients with stage 3–5 CKD are associated with the risks of adverse events. With a continuous rise in iPTH > 2 times the upper limit of normal, it is advisable to initiate corrective metabolic therapy.

(CGR C; LOR 5)

Comment: the cited study demonstrated a trend toward an increased risk of fatal events when iPTH concentration increased within the range of 250–600 pg/mL. Across all analyzed studies, maximum mortality risks were observed at iPTH > 600 pg/mL. Thus, it is evident that treatment for SHPT should be initiated at a persistent iPTH elevation of > 250–300 pg/mL, aiming to prevent its rise to levels > 600 pg/mL.

A significant proportion of delayed therapy initiations when relying on a broader normal range (from 2 to 9 times the upper limit of normal according to KDIGO guidelines) is associated with more pronounced SHPT complications and increased mortality, as well as a reduced response to therapy due to irreversible changes in the parathyroid glands [237, 238].

(CGR C; LOR 5)

Comment: the necessity of correcting hypercalcemia is due to a substantial increase in the risks of fatal events.

(CGR C; LOR 5)

Comment: mild hypocalcemia in stage 3–5D CKD is most often asymptomatic, is not associated with an increased risk of fatal outcomes, and is associated with lower all-cause mortality [239]. Treatment aimed at correcting severe and symptomatic hypocalcemia should be performed to prevent adverse consequences (progression of SHPT and osteodystrophy, cardiac conduction disturbances / prolongation of the QTc interval).

(CGR C; LOR 4)

Comment: it should be noted that this clinical situation is extremely rare in pediatric practice. Observational studies (approximately 25,000 CKD patients with SHPT, adult cohort) have shown a significant reduction in mortality after parathyroidectomy (by 30%) compared with medical therapy, including other drugs regulating calcium-phosphorus metabolism [240, 241].

(CGR C; LOR 5)

Comment: in CKD patients, the continuation of CKD-MBD correction under the control of basic biochemical parameters (blood total calcium test, blood inorganic phosphorus test, blood alkaline phosphatase activity test, blood parathyroid hormone test, blood 25-OH vitamin D test) after kidney transplantation is necessary for at least 12 months. There is insufficient data to prescribe treatment beyond 12 months post-kidney transplantation. The safety of #denosumab** and bisphosphonates remains an area of research [243, 244].

(CGR C; LOR 5)

Comment: radical orthopedic correction should not be performed in the early post-transplantation period in children with a prolonged history of MBD (fractures, pseudarthrosis, consequences of slipped capital femoral epiphysis, significant deformity of the long tubular bones of the legs) in dialysis-dependent CKD.

Long-standing bone density impairments in a child with a functioning graft and uncompensated biochemical parameters of CKD-MBD lead to an unfavorable surgical treatment outcome.

(CGR C; LOR 5)

Comment: the following are used: exercise therapy, orthotic wear, therapeutic massage, swimming) and metabolic correction as indicated.

These measures are carried out, inter alia, for 2–3 years after kidney transplantation.

This ensures the normalization of bone mineral density and a favorable long-term result of surgical orthopedic correction. Additional multicenter studies on bone mineral density in children after kidney transplantation in the early and long-term periods are needed.

The KDIGO/2017 Basic Guidelines for nephrologists and specialists in other fields involved in the monitoring and treatment of patients with CKD-MBD provide a practical tool for objective clinical decision-making and the provision of high-quality care. Most of the guideline recommendations are at the "we suggest" level and are supported by a "low" level of evidence. This primarily highlights the presence of potential major issues and opportunities to find ways to address them.

3.1.5. Treatment of growth retardation in children with CKD

Therapy for growth retardation in CKD patients consists of correcting nutritional disorders, metabolic acidosis, anemia, mineral and bone disorders, ensuring an adequate dialysis dose, and treatment with somatropin**. Before considering somatropin** therapy, the role of all the growth-limiting factors listed above must be assessed, and they must be adequately controlled.

(CGR C; LOR 5)

(CGR C; LOR 5)

(CGR C; LOR 5)

Comment: randomized clinical trials have not been conducted among patients in this group; therefore, the efficacy and safety of somatropin** in patients with these conditions have not been evaluated. Concurrent or prior malignant neoplasms in anamnesis are also a contraindication to somatropin** therapy.

(CGR C; LOR 5)

Comment: severe secondary hyperparathyroidism (i.e., characterized by a serum intact PTH level > 500 pg/ml or an elevation of nine times the upper limit of normal) is associated with retarded longitudinal growth and an increased risk of slipped capital femoral epiphysis in children with CKD [247, 248].

(CGR C; LOR 5)

Comment: growth velocity below the 25th percentile for age and sex indicates progressive growth retardation in a short child (i.e., below the 3rd percentile or with a height standard deviation score (SDS) below -1.88). Any reduction in growth velocity during this phase can lead to severe short stature and potentially irreversible loss of growth potential [250]. KDOQI nutritional management guidelines for children with CKD recommend prompt initiation of somatropin** therapy if catch-up growth is not induced within 3 months of initiating nutritional optimization [251].

(CGR C; LOR 5)

Comment: the response to somatropin** treatment is significantly blunted in children on dialysis compared to children with earlier stages of CKD, regardless of the dialysis modality, most likely due to a higher degree of treatment resistance [252, 253].

(CGR C; LOR 5)

Comment: A meta-analysis of five randomized clinical trials on growth outcomes using systemic corticosteroid minimization protocols demonstrated a significant increase in height SDS in the group where steroid therapy was withdrawn (mean difference 0.38; 95% CI 0.07–0.68), particularly during the first year after withdrawal (mean difference 0.22; 95% CI 0.10–0.35), and in prepubertal patients (mean difference 0.60; 95% CI 0.21–0.98) []. According to the meta-analysis, patients receiving somatotropin** therapy had a significantly higher growth velocity 1 year after the initiation of therapy compared to the control group, with a mean height SDS difference of 0.68 (95% CI 0.25–1.11) [255]. The mean difference in height SDS change between the comparison groups was 0.52 (95% CI 0.37–0.68), and the growth response to somatotropin** therapy was better in children under 10 years of age than in older patients [256].

(CGR C; LOR 5)

Comment: a 2012 meta-analysis showed that compared with patients receiving 14 IU/m² per week, patients who received a somatropin** dose of 28 IU/m² per week increased their height velocity by 1.18 cm per year (95% CI 0.52–1.84). The height velocity was 1.48 higher (95% CI 0.03–2.93) in height velocity SDS after 1 year of treatment [257]. Evening injections are recommended to mimic the physiological circadian rhythm of endogenous GH secretion. The injection site should be rotated daily to avoid lipoatrophy.

In prepubertal children with severe end-stage CKD and after renal transplantation, a meta-analysis of 16 randomized controlled trials (809 patients) showed that after 1 year of therapy, patients receiving somatropin** were taller (+ 0.91 SDS) and grew faster (+ 3.88 cm/year) than untreated patients. The expected gain after 2–5 years of optimal treatment is 7.4 cm in boys and 7 cm in girls [355].

(CGR C; LOR 5)

Comment: consideration should be given to discontinuing somatropin** therapy in patients who do not respond adequately to treatment for at least 6 months. Non-adherence to daily subcutaneous injections or discrepancies between the somatropin** dosage and the patient's body weight must be ruled out. Growth-limiting factors associated with CKD (nutrition, metabolic acidosis, CKD-MBD) must also be adequately addressed in non-responders.

(CGR C; LOR 5)

Comment: in the presence of persistent headache or vomiting, it is important to discontinue therapy and rule out intracranial hypertension. In the presence of pain in the groin, inner thigh, or knee, as well as gait changes, therapy must be discontinued and an evaluation performed to rule out slipped capital femoral epiphysis. Stimulation of longitudinal growth can be performed in children prior to the closure of epiphyseal growth plates. During kidney transplantation, somatotropin** treatment must be discontinued in all patients. Somatotropin** therapy should be stopped when the patient reaches their genetic target height percentile. In a study by RN Fine et al. involving 22 patients whose somatotropin** therapy was discontinued due to reaching the target height percentile, discontinuation resulted in maintenance of height SDS in only 27% of cases, while 73% of cases showed a marked decrease in growth velocity, which subsequently required the resumption of somatotropin** therapy [258]. Alternatively, the dose of somatotropin** may be reduced when the patient reaches their genetic target height percentile, but outcomes associated with this approach have not been systematically studied [131, 355].

3.1.6 Renal replacement therapy

When the estimated GFR decreases below 30 mL/min per 1.73 m² (CKD stage 4), preparation for renal replacement therapy (RRT) is required [1]. The family and, if necessary, the child should be provided with information regarding kidney transplantation, peritoneal dialysis (PD), and hemodialysis (HD).

The frequency and prevalence of RRT in pediatric practice are significantly lower than in adults. Therefore, most studies have been conducted in adults, and these findings need to be adapted into pediatric guidelines.

(CGR C; LOR 5)

Comment: the balance between the benefits and risks of initiating RRT must be assessed based on dynamic clinical evaluation of not only uremic symptoms, but also other potentially life-threatening complications of CKD G5 (central nervous system (CNS) dysfunction (encephalopathy/cognitive impairment), serositis, decompensation of metabolic acidosis, hyperkalemia, uncontrolled fluid overload (anasarca, pulmonary edema) and hypertension, severe protein-energy wasting), as well as patient preferences expressed on the basis of the medical information received. Uremic symptoms are nonspecific and may not be clinically obvious, and some patients may adapt to low GFR levels without distinct complaints; therefore, when determining the timing of dialysis initiation in patients with CKD G5, the dynamics of GFR should obviously be monitored and evaluated. The decision to initiate RRT should not be based solely on the eGFR value, because in patients with CKD G5, blood creatinine levels are largely influenced by measurement accuracy regardless of the renal function assessment method, muscle mass, hydration status, and numerous other factors. Many patients with CKD G5 have muscle mass depletion due to age and comorbidities, are hyperhydrated, and consequently have a comparatively low blood creatinine level and higher eGFR values that do not correspond to the actual ones. The optimal eGFR level for RRT initiation remains unknown, but clear and progressive symptoms of uremic toxicity appear in most patients at an eGFR of 6–8 mL/min/1.73 m². Thus, clinical monitoring of the progression of potentially life-threatening complications of CKD G5 (noted above) and their comprehensive assessment by a nephrologist, taking into account eGFR values, are critically important to determine the optimal timing of dialysis initiation.

(CGR C; LOR 5)

Comment: each method has known advantages and limitations. An integrative approach to RRT involves personalizing the choice of a specific method (HD, HDF, PD) depending on clinical and social conditions and patient preferences. Consequently, all modalities of RRT—HD, HDF, and PD—must be available in the medical organization [167].

(CGR C; LOR 5)

Comment: a pre-planned initiation of HD or PD on an outpatient basis (or during hospitalization for other indications not related to stage 5 CKD complications) following at least 3 months of nephrologist follow-up and the presence of a permanent dialysis access should be considered criteria for optimal RRT initiation. An additional criterion may be the match between the dialysis modality at RRT initiation and that at 90 days of treatment. Suboptimal (emergency, unplanned) dialysis initiation should include all cases where RRT is initiated in a hospital setting due to the development of life-threatening stage 5 CKD complications in a patient with or without a permanent vascular access, typically in the absence of regular nephrologist follow-up. Available data suggest that applying the optimal start concept in determining the timing of RRT initiation is clinically more appropriate than the "late"/"early" approach based on higher or lower eGFR values. Lower treatment costs associated with the optimal start of RRT serve as an additional argument for this recommendation.

PD is the most common dialysis modality used to treat pediatric patients with end-stage renal disease, especially children under five years of age [1-3].

Chronic peritoneal dialysis has several advantages over hemodialysis for children:

- Less restricted diet, including fluid intake, because PD is performed daily. This is particularly beneficial for infants whose nutrition relies entirely or mostly on liquid diets.

- Therapy is performed at home, allowing regular school attendance and participation in other normal childhood activities.

- No need for vascular access and associated technical difficulties and risks (repeated venipunctures, bleeding, bacteremia, etc.).

The main disadvantages of the method are potential non-compliance with the treatment regimen by the patient/legal representative and the risk of PD-related infections, such as exit-site/tunnel infections and peritonitis [259, 260, 261, 262].

3.2 Surgical Treatment

3.2.1 Kidney transplantation

(CGR C; LOR 5)

(CGR C; LOR 4)

Comment: to date, kidney transplantation is considered the best renal replacement therapy in adults. However, for many years, outcomes of kidney transplantation in children differed significantly due to a high incidence of surgical and immunological complications, resulting in lower patient and graft survival rates. Over the past 15 years, there has been a tremendous breakthrough in improving pediatric kidney transplantation outcomes. Currently, the five-year graft survival rate in children is 83% and 71% for living and deceased donor kidney transplantation, respectively. Furthermore, it is well established that the outcomes of preemptive (pre-dialysis) kidney transplantation in children significantly outperform those of kidney transplantation after the initiation of dialysis. Therefore, kidney transplantation should be considered the preferred renal replacement therapy option in all possible cases.

(CGR C; LOR 5)

Comment: accumulated experience shows that over recent years, pediatric kidney transplantation outcomes have surpassed those in adult recipients. This is due to several reasons, including careful recipient preparation for transplantation, precise surgical technique, better donor organ quality, effective immunosuppressive therapy, and a good understanding of the pharmacokinetics of immunosuppressants in children. The use of modern immunosuppressive protocols has led to a significant decrease in acute rejection. In 1980, the incidence of acute rejection in the first year post-transplant was 55%, whereas in recent years it does not exceed 10-15%. These factors have a cumulative effect in centers performing more than 30-40 pediatric transplants annually and possessing all necessary infrastructure.

(CGR C; LOR 4)

Comment: the best option is pre-dialysis (preemptive) living-related kidney transplantation, given the elective nature of the surgery, good histocompatibility between donor and recipient, and minimal organ preservation time. According to studies, patients who received dialysis prior to transplantation had a higher risk of graft loss (hazard ratio 1.32; 95% confidence interval [CI]: 1.10-1.56) and a higher risk of death (hazard ratio 1.69; 95% CI: 1.22-2.33) compared to patients who underwent preemptive kidney transplantation. In children who were on dialysis for more than 1 year, the risk of graft loss was 52% higher, and in children on dialysis for more than 1.5 years, the risk of death was 89% higher compared to children who underwent preemptive transplantation, regardless of the donor organ source.

(CGR C; LOR 5)

Comment: allocating deceased donor organs with priority for pediatric recipients is standard global practice. According to Eurotransplant, establishing a separate waiting list for children along with priority allocation reduces the waiting time for a deceased donor organ in children by 2.5 times compared to adult recipients.

(CGR C; LOR 4)

Comment: outcomes of ABO-incompatible living-related kidney transplantation are comparable to and reliably superior to both deceased donor transplantation outcomes and other renal replacement therapy modalities.

Oncological diseases;

Infections;

Decompensated comorbid conditions;

Non-compliance with medical recommendations;

Mental disorders;

Diagnosed primary hyperoxaluria type 1 prior to liver or combined liver-fragment transplantation (kidney transplantation may be performed after liver or liver-fragment transplantation) due to a high likelihood of treatment failure or adverse outcomes [272].

(CGR C; LOR 5)

• Relative contraindications for kidney transplantation are recommended to include acute infectious diseases or exacerbation of chronic infections, a history of Wilms tumor, or other conditions (decompensated diabetes mellitus, high SLE activity, etc.) due to a high risk of complications [273, 274, 275, 276, 277, 278].

(CGR C; LOR 5)

Comments: relative contraindications to kidney transplantation are temporary, potentially treatable, or require a certain observation period.

Historically, ABO incompatibility and the presence of cytotoxic antilymphocyte antibodies against the donor were contraindications to transplantation; however, subsequent advances using special protocols have made such transplantation feasible in centers with extensive transplantation experience and specialized infrastructure.

Children with a history of malignancy may be considered as potential kidney transplant recipients only if there is compelling evidence of no risk of cancer recurrence at the time of transplantation.

Human immunodeficiency virus (HIV) infection has traditionally been considered an absolute contraindication to transplantation. However, the improvement in long-term prognosis for patients with HIV has prompted many transplant programs to revise their exclusion policies regarding HIV-infected patients. Several studies have demonstrated comparable patient and graft survival outcomes in HIV-infected and HIV-uninfected patients undergoing kidney transplantation following the initiation of potent antiretroviral therapy (ART).

One- and three-year patient survival rates were 95% and 88%, respectively; graft survival rates were 90% and 74%, respectively. Patient and graft survival remained stable at four years, at 89% and 69%, respectively.

Certain systemic diseases are relative contraindications to kidney transplantation. These include systemic conditions that may have caused renal failure (e.g., antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis or systemic lupus erythematosus). Transplantation is feasible during a period of disease remission (at least 6 months).

In patients with lupus nephritis, kidney transplantation is the preferred modality of renal replacement therapy.

Severe hyperparathyroidism (with a parathyroid hormone level greater than 1000 pg/mL) is a relative contraindication requiring comprehensive treatment. Once the target parathyroid hormone level (less than 700 pg/mL) is achieved, kidney transplantation may be performed.

(CGR C; LOR 5)

Comment: the introduction of routine childhood immunizations has dramatically reduced the incidence and mortality of infection.

However, vaccines may be ineffective when administered to immunocompromised patients. Therefore, efforts to fully immunize children prior to transplantation are critical. Because children with end-stage renal disease often have a suboptimal immune response and reduced duration of immunity, higher initial doses, additional doses, and antibody titer monitoring with booster vaccine doses may be required. Live vaccines are not recommended in the post-transplant period, making it crucial to ensure that all appropriate vaccinations are administered prior to transplant surgery.

Regarding (live attenuated) vaccines, a minimum interval of 4 weeks between vaccine administration and transplantation is recommended, given the theoretical risk of vaccine-strain disease [280].

Inactivated vaccine immunizations can be administered after immunosuppressive therapy reaches low maintenance doses, usually 6 to 12 months post-transplantation.

(CGR C; LOR 5)

Comment: congenital anomalies of the urinary tract are the most common cause of renal failure in children. Until recently, children with congenital lower urinary tract anomalies or bladder dysfunction were excluded from kidney transplant programs because they were considered to be at very high risk for infectious complications and graft loss. Over the past few decades, it has been demonstrated that augmentation cystoplasty with the creation of a low-pressure reservoir improves long-term renal graft survival. Studies show that the rate of urological complications following urological reconstructions does not differ from that in the general population with normal urinary tract function.

Patients with posterior urethral valves may require vesicostomy at an early age to decompress a dysfunctional bladder. The vesicostomy may be maintained for many months post-transplantation. Children with a small bladder capacity may require bladder augmentation using an ileal segment conduit. In addition, the appendix is frequently used to create a continent stoma allowing clean intermittent catheterization.

The most common complications of augmentation cystoplasty and continent urinary diversion are bacteriuria and urinary tract infections, which typically do not lead to graft loss with appropriate antibiotic management.

(CGR C; LOR 4)

Comment: in the long term, a significant number of graft losses occur due to non-adherence to medical recommendations. There are a number of preventive measures that can improve adherence to medical recommendations by children and their parents: continuous education, personalized medical information, and psychological support. The transition of growing adolescents to adult care facilities is associated with a theoretically high risk of graft loss due to treatment non-adherence. A set of simple and effective measures aimed at improving treatment adherence is recommended: early preparation for transition and alternating outpatient visits between pediatric and adult nephrology departments.

In the past, clinical studies regarding treatment adherence focused solely on medication regimen adherence. However, it is now recognized that adherence (compliance) is a broader concept encompassing more than just taking prescribed medications.

(CGR C; LOR 4)

Comment: there are several arguments in favor of individualizing pharmacokinetic profiles in children. This is due to the increased volume of distribution of drugs in young children, as well as altered drug metabolism in the gut, liver, and renal graft. This circumstance is often accompanied by instability of immunosuppressant concentrations and requires more frequent laboratory monitoring compared to the adult population.

(CGR C; LOR 4)

Comment: Kidney transplant recipients require lifelong immunosuppressive therapy to maintain stable graft function. However, long-term use of immunosuppressants can be accompanied by specific side effects associated with immune system suppression, such as an increased risk of infections and malignancies.

In 5-15% of cases, recurrence of the primary disease is the cause of renal graft dysfunction in pediatric kidney transplant recipients [291].

Among glomerular diseases that can recur in the graft, focal segmental glomerulosclerosis (FSGS) is the most common. The overall risk of nephrotic syndrome recurrence after transplantation is estimated at approximately 30%. FSGS is the most frequent cause of graft loss due to disease recurrence. The risk of recurrence in FSGS is higher in children than in adults. FSGS recurrence most commonly occurs within the first few days after transplantation. In patients whose first graft was lost due to disease recurrence, the recurrence rate in a subsequent graft is approximately 80% [292].

3.3 Other Treatment

Not applicable.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Renal rehabilitation (RR) comprises coordinated actions aimed at optimizing the physical, psychological, and social functioning of children with CKD, thereby reducing disability and mortality. RR includes five core components: physical exercise, diet and fluid balance control, drug therapy, patient education, and psychological counseling [356].

Children with CKD more frequently demonstrate physical inactivity, reduced physical performance, and a lower quality of life [357, 358, 359].

(CGR B; LOR 2)

Comment 1. Children with CKD are physically less active compared to their healthy peers. It should be emphasized that physical inactivity appears already in the early stages of the disease and gradually worsens as CKD progresses. There is a significant decrease in muscle strength, physical performance, and cardiorespiratory endurance in pediatric patients with CKD. Physical activity should be adapted and individualized according to the needs and capabilities of children suffering from CKD [376].

Comment 2. In children with CKD, low physical activity is caused not only by deconditioning, but also by skeletal muscle wasting associated with the effects of uremic acidosis, protein-energy malnutrition, and glucocorticosteroid therapy [377].

Increased physical activity is associated with an improved ability and capacity to perform daily activities, as well as an improved health-related quality of life and increased life expectancy in patients with CKD. Therefore, regular physical exercise is recommended for all patients with CKD.

(CGR B; LOR 2)

Comment 1. Patients with pre-dialysis stages of CKD are advised to engage in moderate-load physical exercise (moderate-intensity aerobic exercise, strength training and balance training, therapeutic physical culture complexes) for 30 minutes on most days of the week or for 45 minutes 3 times a week [361, 362, 363].

Comment 2. Children receiving maintenance hemodialysis are advised to engage in moderate-load physical exercise (muscle stretching and isometric exercises) for 40 minutes at least 3 times a week, which can increase physical endurance and significantly improve quality of life. It is worth noting that children on hemodialysis need well-organized programs covering all physical and psychological aspects, with reasonable time allocation and increased attention from medical staff [364]. The necessity of a family-centered approach and seamless cooperation between the child, parents, and medical staff to ensure the maximum positive effect should be emphasized [359].

(CGR C; LOR 5)

Comment 1. Spa-and-resort treatment for children with stage 1-3 CKD is carried out in marine and desert climate health resorts, climate-balneological and mud-bath sanatoriums [365]. It is advisable to conduct spa-and-resort treatment in the warm season for 3–5 months, from May to September inclusive [366]. The choice of physical factor, localization, dose, and duration of procedures makes it possible to purposefully influence the state of the immune system, renal hemodynamics, and the functional state of the upper and lower urinary tract, thereby preventing the progression of CKD.

Comment 2. Climatotherapy includes aero-, helio-, and thalassotherapy and is aimed at improving the neurohumoral regulation of the body and the urinary system, normalizing body resistance, and increasing its tolerance to adverse environmental factors [367].

Comment 3. Among balneological factors in the treatment of patients with stage 1-3 CKD resulting from chronic pyelonephritis, carbon dioxide, sodium chloride, iodine-bromine, and radon baths are used, which helps normalize blood circulation, especially venous circulation, in the pelvic area and reduces the progression of the inflammatory process in the urinary tract. Balneotherapy is prescribed in the remission stage no earlier than three months after an exacerbation. Drinking mineral waters of low and medium mineralization is also used. Their therapeutic effect is associated with a change in urine pH, which creates unfavorable conditions for the development of pathogenic microflora. The complex of spa-and-resort measures must include therapeutic physical culture and terrain cures [366].

Comment 4. The rehabilitation of patients with CKD associated with chronic glomerulonephritis is based on climatotherapy. For CKD resulting from nephrotic syndrome, desert climate resorts, as well as marine resorts without sharp fluctuations in daily temperature, are most suitable. The dry and hot air of these resorts helps enhance sweating, excrete intermediate products of nitrogen metabolism, and normalize water balance [365]. It is possible to take sitting or general sodium chloride baths (with a concentration of 20 g/L), pearl baths, or sea-salt baths with a water temperature of 37–38 °C, every other day, for a total of 8–10 baths [374]. Spa-and-resort treatment is contraindicated in the presence of severe proteinuria (over 4 g/day) and marked hypoproteinemia (below 60 g/L) combined with multiple edema. Summer heat is contraindicated in patients with CKD resulting from the hematuric variant of glomerulonephritis. They are suited for resorts in the steppe zone of central Russia [365].

Comment 5. Starting from stage 3 CKD, the goal of spa-and-resort treatment becomes reducing the risk of complications, as well as improving the quality and duration of life. Such patients require a strictly individual approach and selection of optimal spa-and-resort treatment conditions. Thermotherapy may be used in patients with advanced stages of CKD. Thermotherapy is a treatment using metered aero-hyperthermic baths in a climatron environment, where the main parameters of a dry and hot desert climate are modeled.

Comment 6. Patients with the dialysis stage of CKD or after kidney transplantation are referred to resorts equipped with dialysis centers.

5. Prevention and Dispensary Observation

5.1 Prevention

5.1.1 Vaccination of children with CKD

One of the components of prevention is protection against infectious diseases, which can lead to the progression of CKD and are life-threatening in patients undergoing dialysis or those who have undergone a kidney transplant.

All vaccines should be administered to children with CKD in accordance with the national immunization schedule, while live attenuated vaccines (vaccines) should not be administered to children with an immunodeficient state [6, 110, 297].

(CGR C; LOR 5)

(CGR C; LOR 5)

(CGR C; LOR 5)

(CGR C; LOR 5)

(CGR C; LOR 5)

Comment: ideally, the vaccine is administered as a two-dose schedule when the child is receiving low doses of systemic corticosteroids (e.g., less than 2 mg/kg body weight on alternate days) or when corticosteroid therapy is not being administered.

(CGR C; LOR 5)

5.1.2 Methods for preventing or slowing the progression of CKD

(CGR C; LOR 5)

(CGR C; LOR 5)

Comments: in children with CKD, renal replacement therapy (RRT) is usually necessary when the glomerular filtration rate (GFR) drops below 15 mL/min/1.73 m² (CKD stage G5, kidney failure) and in some cases even earlier. Therefore, as soon as the estimated GFR drops to < 30 mL/min/1.73 m² (stage G4), preparation of the child and family for renal replacement therapy (RRT) should begin [3]. The family and patient must receive information on the timing and choice of RRT (kidney transplantation, peritoneal dialysis, or hemodialysis).

(CGR C; LOR 5)

Comments: pediatricians and neonatologists caring for premature infants should remain vigilant regarding potential renal dysfunction in this patient population.

(CGR C; LOR 5)

Comments: decreased renal perfusion and the administration of nephrotoxic agents are two common conditions that can lead to further kidney damage in children with CKD.

(CGR C; LOR 5)

Comments: a subset of children with CKD have impaired tubular sodium reabsorption (salt wasting) and urinary concentrating ability, which increases the risk of hypovolemia and hypoperfusion during minor illnesses. At-risk patients should be identified early in an intercurrent illness associated with hypovolemia or hypotension to ensure fluid replacement before renal blood flow decreases significantly.

Renal hypoperfusion is caused by hypotension (e.g., septic shock), the use of drugs that reduce renal perfusion (such as nonsteroidal anti-inflammatory and antirheumatic drugs, ACE inhibitors, and angiotensin II receptor blockers), and a decrease in circulating blood volume due to vomiting, diarrhea, diuretic use, burns, major surgeries (e.g., cardiac surgery performed with cardiopulmonary bypass, major spinal orthopedic surgery), and/or bleeding.

(CGR C; LOR 5)

Comments: such medications include many nonsteroidal anti-inflammatory and antirheumatic drugs, diagnostic agents (e.g., radiocontrast agents), aminoglycosides, amphotericin B**, cyclosporine**, and tacrolimus**. The use of such drugs should be avoided or applied with caution in patients with chronic kidney disease, under therapeutic drug monitoring (blood drug level testing, blood drug level testing using tandem mass spectrometry).

Certain drugs or their components, such as Co-trimoxazole [Sulfamethoxazole + Trimethoprim]** and ciprofloxacin**, lead to an increase in blood creatinine levels without raising blood urea nitrogen (BUN) levels, as they affect either tubular creatinine secretion or the laboratory assay for creatinine (they do not directly impair renal function).

(CGR C; LOR 5)

Comments:

Indications are considered to be:

- high blood pressure (> = 90th percentile)

and/or

- significant proteinuria/albuminuria

ᴑ urine protein-to-creatinine ratio ≥ 0.5 mg/mg or 50 mg/mmol,

ᴑ albumin-to-creatinine ratio ≥ 0.3 mg/mg or 30 mg/mmol.

Prescription depending on CKD stage:

- In CKD stages 1–3: prescribe as early as possible, use long-term.

- In CKD stages 4 and 5:

ᴑ patients already taking ACE inhibitors or angiotensin II receptor blockers – continue treatment, provided it is well tolerated,

ᴑ patients not taking ACE inhibitors or angiotensin II receptor blockers: consider initiating therapy with careful monitoring.

Practical aspects:

- initiation of treatment using the maximum approved dose tolerated by the patient,

- monitoring of peripheral blood pressure measurements, blood creatinine levels, and blood potassium levels within 2–4 weeks after initiation or dose increase of ACE inhibitors or angiotensin II receptor blockers, depending on GFR and blood potassium levels,

- hyperkalemia associated with the use of ACE inhibitors or angiotensin II receptor blockers can generally be managed by measures to lower blood potassium levels rather than by reducing the dose or discontinuing these drugs,

- therapy with ACE inhibitors or angiotensin II receptor blockers should be continued if blood creatinine levels do not increase by more than 30% within 4 weeks of treatment initiation or dose increase,

- consider reducing the dose or discontinuing ACE inhibitors or angiotensin II receptor blockers in the setting of symptomatic hypotension or uncontrolled hyperkalemia despite medical treatment, or to reduce uremic symptoms during the management of renal failure (estimated glomerular filtration rate [eGFR] < 15 mL/min per 1.73 m²),

- ACE inhibitors and angiotensin II receptor blockers should not be combined [325, 368].

Therapy is more frequently initiated with an ACE inhibitor, as there are more data on the safety and efficacy of this drug class in children compared to ARBs: For example, #enalapril** 0.08 mg/kg per day (maximum 5 mg/day), titrated up to a maximum dose of 0.6 mg/kg per day (maximum 40 mg/day) based on the patient's blood pressure and laboratory test results (e.g., serum potassium levels).

In patients with intolerance to ACE inhibitors (e.g., cough), ARBs may be used, for example, #losartan** at an initial dose of 0.7 mg/kg per day (maximum 50 mg/day), titrated up to a maximum dose of 1.4 mg/kg per day (maximum 100 mg/day) [138, 325, 368].

The teratogenic potential of these drugs in women of childbearing potential should also be discussed with adolescent girls of pubertal age when considering the prescription of an ACE inhibitor or ARB [138].

(CGR C; LOR 5)

Comments: the most effective method contributing to the slowdown of renal function decline is blood pressure control and the use of antihypertensive therapy when necessary in children with CKD, based on evidence that strict blood pressure control reduces the rate of CKD progression in children.

See Clinical guidelines for arterial hypertension in children and adolescents.

• For children requiring antihypertensive therapy, it is recommended to prioritize the use of ACE inhibitors or angiotensin II receptor blockers in accordance with the clinical guidelines for the management of children with arterial hypertension [297, 335].

(CGR C; LOR 5)

Comments: there is compelling evidence that these agents possess greater renoprotective capacity than antihypertensive drugs in combination with diuretics in slowing CKD progression (by controlling blood pressure and also reducing proteinuria even in children with stage 3-5 CKD).

Angiotensin blockade using ACE inhibitors or angiotensin II receptor blockers can also slow the progression of CKD in patients with hereditary nephritis without elevated blood pressure by reducing proteinuria.

(CGR C; LOR 5)

Comments: currently in pediatric practice, children with CKD are prescribed a daily protein intake appropriate for their age.

It has been hypothesized that hyperuricemia, resulting from decreased urinary urate excretion, contributes to the progression of CKD, partly by decreasing renal perfusion and partly by stimulating the proliferation of afferent arteriolar smooth muscle cells. However, there are no recommendations for monitoring serum uric acid in children with CKD.

5.2 Clinical follow-up is lifelong and includes:

(CGR C; LOR 5)

Comments:

Specialist appointments (examinations, consultations):

ᴑ Pediatrician / general practitioner (family physician) once a month.

ᴑ Nephrologist once every 2-3 months.

ᴑ Pediatric dentist once every 6 months.

ᴑ Ophthalmologist once a year.

ᴑ Otorhinolaryngologist once a year.

ᴑ Geneticist as indicated (for tubulopathies and glomerulonephritides as part of a genetic syndrome).

Laboratory tests:

ᴑ routine urinalysis (once a month and as clinically indicated);

ᴑ complete blood count with differential (frequency as clinically indicated);

ᴑ routine biochemical blood test (once every 3 months and as clinically indicated);

ᴑ acid-base balance and blood gas analysis (once every 3 months and as clinically indicated);

ᴑ blood parathyroid hormone level test (once every 3 months and as clinically indicated);

ᴑ blood 25-OH vitamin D level test (once every 3-6 months);

ᴑ thyroid function hormones (blood thyroid-stimulating hormone (TSH) level test, blood free triiodothyronine (FT3) level test) (once every 3-6 months and as clinically indicated);

ᴑ blood insulin-like growth factor I level test (in case of growth retardation and therapy with somatropin** (recombinant growth hormone));

Instrumental diagnostic methods:

ᴑ ultrasound examination of the urinary system (renal ultrasound, ureter ultrasound, bladder ultrasound) once every 6 months and as clinically indicated.

6. Organization of Medical Care

Patients with CKD may be provided with any type, conditions, and form of medical care stipulated by the legislation of the Russian Federation, as needed.

Patients must be registered for dispensary observation, receiving primary health care in outpatient settings. The primary condition for providing care to a patient with CKD must be ensuring continuous monitoring, receiving relapse-prevention treatment, and timely hospitalization.

The child is monitored by a pediatrician / general practitioner (family physician), a nephrologist, and in the presence of urological pathology, by a urologist (specializing in pediatric urology-andrology) / pediatric urologist-andrologist, with the participation, when necessary, of a dietician, geneticist, pediatric oncohematologist, trauma surgeon / orthopedist, pediatric cardiologist, ophthalmologist, dentist, pediatric surgeon, otorhinolaryngologist, and other specialists as needed.

Indications for hospitalization in a medical organization for children with stage 3-5 CKD

1. Anorexia, nausea, vomiting (not related to an intercurrent infection).

2. Anemia (Hb less than 80 g/L).

3. Presence of symptoms and signs of anemic hypoxia even at higher Hb concentrations.

4. Crisis course of arterial hypertension.

5. Arrhythmias, cardiac pain.

6. Decreased exercise tolerance, fatigue, shortness of breath (in the absence of symptoms of bronchospastic syndrome).

7. Excessive weight gain, progressive edema.

8. Pain in the extremities, spine (spontaneous and upon exertion).

Indications for patient discharge from a medical organization

1. Stable condition, good general well-being.

2. Absence of fluid overload.

3. Satisfactory blood pressure control (< 90th percentile).

4. Compensation of anemia and mineral and bone disorders.

The organization of dietary nutrition for patients during inpatient treatment in medical organizations is carried out in accordance with Appendix 3 of Order No. 1008n of the Russian Ministry of Health dated September 23, 2020, "On approval of the procedure for providing patients with therapeutic nutrition".

Preparing the patient for transition to the adult nephrology service is a matter of their safety and compliance with patient rights, which prevents potential complications during their transfer to the adult world.

Educational programs for the patient (taking into account their age) and family members, interaction between pediatric and adult nephrologists during the transfer process of the growing patient, and family support are important components of a successful transition.

Structuring the transition stages helps maintain stability in the course of CKD.

The following multi-stage transition model has been adapted (similar to the transition protocol by Raina R. et al. (2022) [372]).

Stage I: pediatric (the longest in duration). Age 13-17 years.

1. Educate the patient with the active participation of family members to understand the disease and develop self-monitoring and self-management skills.

2. Foster adherence to treatment, regimen, diet, and medication intake (prevention of adolescent risks).

3. Maintain social function - continue education.

4. Help patients acquire skills for independent communication with medical staff.

Stage II: pre-transition (the shortest in duration). Age 17-18 years.

1. Prepare a transfer epicrisis specifying the activity of the inflammatory process in the patient with CKD, presence of complications, and comorbid conditions. Prepare short-term treatment recommendations. Ensure consultations with subspecialists.

Stage III: actual transfer of the patient to the adult nephrology healthcare service. Age 18 years.

1. Ensure continuity of treatment and adaptation of the adolescent with CKD to the new social environment without the active participation of family members.

2. Joint planning of the adolescent's management tactics by the pediatric and adult services for 1 year, if necessary.

After the adolescent transitions to the adult healthcare system, parents are excluded from key team players. However, situations related to the disease course and the patient's psychosocial characteristics may arise when parental support remains necessary even after the transition [373].

7. Additional Information

In a retrospective cohort study of patients with stage 2–4 CKD, it was found that children with glomerular disease progress to end-stage renal disease faster than those with congenital anomalies of the kidney and urinary tract (CAKUT) [299].

According to the NAPRTCS report, the youngest pediatric patients have the worst survival rates at 12, 24, and 36 months after starting dialysis [14]. The 5-year survival probability is 89% for patients starting treatment for end-stage CKD, and the mortality rate is 30 times higher than that of healthy children. The most common cause of death among children is cardiopulmonary death, followed by infection [15, 300].

Hypertension and proteinuria are independent risk factors for CKD progression. It has been established that a 10% decrease in eGFR is inversely proportional to a 14% increase in the urine protein-to-creatinine ratio, regardless of the cause of CKD [301].

Other factors affecting CKD progression include the primary disease, age, sex, racial/genetic factors, urological problems, low birth weight, and social background. Premature newborns are at high risk for neonatal AKI, which can further reduce nephron endowment and enhance CKD progression [302]. Thus, according to a multicenter retrospective cohort study, the incidence of neonatal AKI is 48% in those born before 29 weeks of gestation [303]. According to a Norwegian registry study conducted from 1967 to 2004, the relative risk of developing end-stage CKD for children with a birth weight < 10th percentile is 1.7 [18]. A large national registry-based study involving more than 20,000 individuals born between 1924 and 1944 and followed until death showed that both prematurity and low birth weight were associated with an increased risk of CKD, with infants born before 34 weeks of gestation having a 2.6-fold higher risk of developing CKD [304]. Among a group of adolescents born prematurely, infants with low birth weight were 1.4 times more likely to have microalbuminuria and decreased GFR, and those who also had intrauterine growth restriction had a 2.4-fold increase in albuminuria [305, 306].

According to the results of the CKiD study, cohort analysis revealed an annual GFR decline of -4.2%; the median GFR decline was -1.8 mL/min/1.73 m² (interquartile range from -6.6 to 1.6); this can be expressed as a median absolute GFR decline of -4.3 mL/min/1.73 m² (interquartile range from -11.9 to 1.1) and -1.5 mL/min/1.73 m² (interquartile range from -5.0 to 1.8) [74].

According to studies based on registry data, risk factors for mortality among children with renal failure receiving renal replacement therapy (RRT) include young age, female sex, non-white race, non-CAKUT etiology of kidney disease, anemia, hypoalbuminemia, and glomerular filtration rate values at the initiation of dialysis [307].

In the non-glomerular disease group, factors affecting CKD progression include a urine protein-to-creatinine ratio > 2 mg/mg, hypoalbuminemia, elevated blood pressure, dyslipidemia, male sex, and anemia [87, 301].

It is also known that puberty is associated with worsening renal function in patients with CKD. Data from the ItalKid project demonstrated that the probability of RRT was 9.4% during the first decade of life and 51.8% during the second decade. The renal survival curve showed a distinct inflection point during puberty, followed by a post-pubertal decline in both males and females [308].

Life expectancy for a child < 14 years old with stage 5 CKD (in the US) is 21.7 years on dialysis and 57.8 years with a kidney transplant, given a general population average life expectancy of 72.4 years. First-year mortality post-transplantation is 15 times higher than in the normal population for individuals aged 16–21 years and 130 times higher for children aged 0–4 years at the time of transplantation. Twenty-year survival for children on RRT is 83%, for children < 1 year old it is 76%, for 2–5 years old it is 81%, and for 6–18 years old it is 85%. The main causes of death on RRT are cardiovascular disease (30%) and infections (20%). Malignant neoplasms account for 14% of deaths in post-transplant patients, the majority occurring more than 10 years later [50, 309].

Criteria for Evaluating the Quality of Medical Care

Quality of care criteria for primary health care in children with chronic kidney disease

Quality of care criteria for specialized medical care in children with chronic kidney disease

References

Appendix A1. Working Group Composition

Emirova Kh.M. – Doctor of Medical Sciences, Professor at the Department of Pediatrics, Russian University of Medicine of the Russian Ministry of Health; Nephrologist at the Center for Blood Gravitational Surgery and Hemodialysis, St. Vladimir Children's City Clinical Hospital of the Moscow Healthcare Department, member of the Russian Dialysis Society.

Abaseeva T.Yu. – Candidate of Medical Sciences, Associate Professor at the Department of Pediatrics, Russian University of Medicine of the Russian Ministry of Health; Nephrologist at the Center for Blood Gravitational Surgery and Hemodialysis, St. Vladimir Children's City Clinical Hospital of the Moscow Healthcare Department, member of the Russian Dialysis Society.

Apkhanova T.V. – Chief Researcher at the Department of Physiotherapy and Reflexology, National Medical Research Center for Rehabilitation and Balneology of the Russian Ministry of Health, Doctor of Medical Sciences, member of the National Association of Experts in Sanatorium-Resort Treatment.

Baranov A.A. – Academician of the Russian Academy of Sciences, Professor, Doctor of Medical Sciences; Honorary President of the Union of Pediatricians of Russia, Advisor to the Head of the Research Institute of Pediatrics and Child Health in NSC № 2 of the Petrovsky National Research Centre of Surgery, Professor at the Department of Pediatrics and Pediatric Rheumatology, Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), Chief freelance pediatric specialist of the Russian Ministry of Health.

Vishnyova E.A. – Doctor of Medical Sciences, Professor of the Russian Academy of Sciences, Deputy Head of the Research Institute of Pediatrics and Child Health in NSC № 2 of the Petrovsky National Research Centre of Surgery, Professor at the Department of Faculty Pediatrics, Institute of Motherhood and Childhood, Pirogov Russian National Research Medical University (Pirogov University) of the Russian Ministry of Health, member of the Union of Pediatricians of Russia.

Gadzhieva P.M. – Candidate of Medical Sciences, Pediatrician, Nephrologist, Immunologist at the Pediatric Transplantation Department, V.I. Shumakov National Medical Research Center of Transplantology and Artificial Organs of the Russian Ministry of Health.

Generalova G.A. – PhD in Medical Sciences, Associate Professor at the G.N. Speransky Department of Pediatrics, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health; Nephrologist at the Center for Blood Gravitational Surgery and Hemodialysis, Saint Vladimir Children's City Clinical Hospital of the Moscow Healthcare Department; member of the Creative Association of Pediatric Nephrologists (TODN).

Zharikov A.A. – Surgeon, Academician V.I. Shumakov National Medical Research Center of Transplantology and Artificial Organs of the Russian Ministry of Health.

Kalyuzhnaya T.A. – PhD in Medical Sciences, Leading Researcher at the Department for the Development of Scientific Approaches to Immunization of Patients with Health Deviations and Chronic Diseases, Pediatrician at the Research Institute of Pediatrics and Child Health, Academician B.V. Petrovsky National Research Center of Surgery, Center No. 2; Associate Professor at the Department of Faculty Pediatrics, Institute of Motherhood and Childhood, Pirogov Russian National Research Medical University (Pirogov University) of the Russian Ministry of Health; member of the Union of Pediatrists of Russia.

Karatseva M.S. – Pediatrician, member of the Union of Pediatrists of Russia.

Karapityan A.R. – Surgeon, Academician V.I. Shumakov National Medical Research Center of Transplantology and Artificial Organs of the Russian Ministry of Health.

Konchugova T.V. – Chief Researcher at the Department of Physiotherapy and Reflexology, National Medical Research Center for Rehabilitation and Balneology of the Russian Ministry of Health; Doctor of Medical Sciences, Professor; member of the National Association of Experts in Sanatorium and Resort Treatment.

Lupan I.N. – PhD in Medical Sciences, Associate Professor at the Department of Pediatrics and Neonatology, Institute of Additional Professional Education, South Ural State Medical University; Chief Visiting Pediatric Nephrologist of the Ministry of Health of the Chelyabinsk Region; member of TODN, member of the Union of Pediatrists of Russia.

Margieva T.V. – PhD in Medical Sciences, Chief Specialist at the Methodological Center for Accreditation of Specialists, I.M. Sechenov First Moscow State Medical University (Sechenov University) of the Russian Ministry of Health; Nephrologist, member of the Union of Pediatrists of Russia.

Makarova T.P. – Doctor of Medical Sciences, Professor at the Department of Hospital Pediatrics, Kazan State Medical University of the Russian Ministry of Health; member of TODN, member of the Union of Pediatrists of Russia.

Kvaratskhelia M.V. – Associate Professor at the Department, Russian University of Medicine of the Russian Ministry of Health; Nephrologist, Saint Vladimir Children's City Clinical Hospital.

Shilova M.M. – PhD in Medical Sciences, Associate Professor at the Department of Propaedeutics of Children's Diseases, Pirogov Russian National Research Medical University (Pirogov University) of the Russian Ministry of Health.

Mstislavskaya S.A. – PhD in Medical Sciences, Associate Professor at the Department of Pediatrics, Russian University of Medicine of the Russian Ministry of Health; Nephrologist at the Center for Blood Gravitational Surgery and Hemodialysis, Saint Vladimir Children's City Clinical Hospital of the Moscow Healthcare Department.

Muzurov A.L. – PhD in Medical Sciences, Associate Professor at the Department of Pediatric Anesthesiology, Intensive Care and Toxicology, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health; Anesthesiologist-Intensivist, Head of the Center for Blood Gravitational Surgery and Hemodialysis, Saint Vladimir Children's City Clinical Hospital of the Moscow Healthcare Department; member of TODN.

Pankratenko T.E. – PhD in Medical Sciences, Associate Professor at the Department of Transplantology, Nephrology and Artificial Organs, Moscow Regional Research Clinical Institute (MONIKI) named after M.F. Vladimirsky; Nephrologist at the Center for Blood Gravitational Surgery and Hemodialysis, Saint Vladimir Children's City Clinical Hospital of the Moscow Healthcare Department; member of the Russian Dialysis Society (RDO).

Orlova O.M. – PhD in Medical Sciences, Assistant at the Department of Pediatrics, Russian University of Medicine of the Russian Ministry of Health; Nephrologist at the Center for Blood Gravitational Surgery and Hemodialysis, Saint Vladimir Children's City Clinical Hospital of the Moscow Healthcare Department.

Petrosyan E.K. – Doctor of Medical Sciences, Professor at the Department of Hospital Pediatrics named after Academician V.A. Tabolin, Pediatric Faculty, Pirogov Russian National Research Medical University; Head of the Nephrology Department, Russian Children's Clinical Hospital.

Popa A.V. – Associate Professor at the Department, Russian University of Medicine of the Russian Ministry of Health.

Prikhodina L.S. – Doctor of Medical Sciences, Head of the Department of Hereditary and Acquired Kidney Diseases named after Professor M.S. Ignatova, Research Institute of Pediatrics and Child Surgery named after Academician Yu.E. Veltishchev, Pirogov Russian National Research Medical University (Pirogov University) of the Russian Ministry of Health; Professor at the Department of Pediatrics named after Academician G.N. Speransky, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health; President of the Creative Association of Pediatric Nephrologists.

Rumyantsev A.L. – PhD in Medical Sciences, Head of the Dialysis Department, N.F. Filatova Children's City Clinical Hospital of the Moscow Healthcare Department; member of RDO, ITPA, IPNA, ESPN, AST, ERA.

Namazova-Baranova L.S. – Academician of the Russian Academy of Sciences, Professor, Doctor of Medical Sciences, President of the Union of Pediatrists of Russia; Past-President of EPA/UNEPSA; Head of the Research Institute of Pediatrics and Child Health, Academician B.V. Petrovsky National Research Center of Surgery, Center No. 2; Head of the Department of Faculty Pediatrics, Institute of Motherhood and Childhood, Pirogov Russian National Research Medical University (Pirogov University) of the Russian Ministry of Health; Chief Visiting Pediatric Specialist in Preventive Medicine of the Russian Ministry of Health.

Saydulaev D.A. – PhD in Medical Sciences, Head of Surgical Department No. 1, Academician V.I. Shumakov National Medical Research Center of Transplantology and Artificial Organs of the Russian Ministry of Health.

Selimzyanova L.R. – PhD in Medical Sciences, Head of the Department of Standardization and Study of Evidence-Based Medicine Fundamentals, Research Institute of Pediatrics and Child Health, Academician B.V. Petrovsky National Research Center of Surgery, Center No. 2; Associate Professor at the Department of Pediatrics and Pediatric Rheumatology, I.M. Sechenov First Moscow State Medical University (Sechenov University) of the Russian Ministry of Health; Associate Professor at the Department of Faculty Pediatrics, Institute of Motherhood and Childhood, Pirogov Russian National Research Medical University (Pirogov University) of the Russian Ministry of Health; member of the Union of Pediatrists of Russia.

Sedashkina O.A. – PhD in Medical Sciences, Associate Professor at the Department of Faculty Pediatrics, Samara State Medical University of the Ministry of Health of the Russian Federation; Nephrologist, Samara Regional Clinical Hospital named after V.D. Seredavin; recipient of the Governor's Prize in Science and Technology; member of the Union of Pediatrists of Russia, member of TODN, member of RDO.

Fedoseenko M.V. – PhD in Medical Sciences, Head of the Department for the Development of Scientific Approaches to Immunization of Patients with Health Deviations and Chronic Diseases, Leading Researcher, Pediatrician at the Research Institute of Pediatrics and Child Health, Academician B.V. Petrovsky National Research Center of Surgery, Center No. 2; Associate Professor at the Department of Faculty Pediatrics, Institute of Motherhood and Childhood, Pirogov Russian National Research Medical University (Pirogov University) of the Russian Ministry of Health; member of the Union of Pediatrists of Russia.

Tsygin A.N. – Doctor of Medical Sciences, Professor, Head of the Nephrology Department, National Medical Research Center for Children's Health; Professor at the Department of Nephrology, N.A. Semashko Scientific and Educational Institute of Clinical Medicine, Russian University of Medicine; Interregional Public Organization "Creative Association of Pediatric Nephrologists".

Vyalkova A.A. – Doctor of Medical Sciences, Professor, Head of the Scientific and Advisory Center for Childhood Nephrology, Federal Expert in the Scientific and Technical Sphere at the Research Institute of the Republican Research Center for Science and Technical Information (RIMC); Head of the Department of Faculty Pediatrics, Orenburg State Medical University of the Russian Ministry of Health; Pediatrician, Nephrologist of the highest qualification category; Chief Visiting Pediatric Nephrologist of the Ministry of Health of the Orenburg Region; President of the Orenburg Regional Branch of the Union of Pediatrists of Russia; Head of the Interregional Public Scientific Organization "Association of Nephrourologists"; Honored Scientist of the Russian Federation; Honored Physician of the Russian Federation.

Chesnokova S.A. – PhD in Medical Sciences, Associate Professor at the Department of Faculty Pediatrics, Orenburg State Medical University of the Russian Ministry of Health; Pediatrician, Nephrologist.

Conflict of interest: The authors confirm that there is no financial support or conflict of interest that needs to be disclosed.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Nephrologists;

2. Pediatricians;

3. General practitioners (family physicians);

4. Dietitians;

5. Anesthesiologists-intensivists;

6. Cardiologists;

7. Pediatric cardiologists;

8. Pediatric surgeons;

9. Urologists;

10. Pediatric urologists-andrologists;

11. Pathologists;

12. Clinical pharmacologists;

13. Medical students;

14. Residents and postgraduate students.

Methods used for evidence collection/selection:

- search in electronic databases.

Methods used for analyzing evidence:

- reviews of published meta-analyses;

- systematic reviews with evidence tables.

Methods used to formulate the recommendations:

- Expert consensus.

- Significance assessment according to the rating scheme.

The strength and quality of the recommendations according to the evidence analysis (Tables P1, P2) are provided in the text.

Table 1. Scale for assessing the levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing the levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for assessing the grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Care delivery pathways:

1. Order of the Ministry of Health and Social Development of the Russian Federation No. 366n dated April 16, 2012, "On Approval of the Procedure for Providing Pediatric Care".

2. Information on medicinal products: State Register of Medicines: https://grls.rosminzdrav.ru

3. Federal Law No. 323-FZ of November 21, 2011, "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation" (Collected Legislation of the Russian Federation, 2011, No. 48, Art. 6724).

4. International Statistical Classification of Diseases and Related Health Problems (ICD-10).

5. Order of the Ministry of Health of the Russian Federation No. 205n of May 2, 2023, "On Approval of the Nomenclature of Positions of Medical and Pharmaceutical Workers."

6. Order of the Ministry of Health of the Russian Federation No. 541n dated July 23, 2010, "Unified Qualification Reference Book of Positions of Managers, Specialists and Employees", section "Qualification Characteristics of Healthcare Sector Employee Positions".

7. Federal Law No. 489-FZ dated December 25, 2018, "On Amendments to Article 40 of the Federal Law 'On Compulsory Medical Insurance in the Russian Federation' and the Federal Law 'The Fundamentals of Healthcare Legislation in the Russian Federation' Regarding Clinical Practice Guidelines."

8. Order of the Russian Ministry of Health No. 103n dated February 28, 2019, "On approval of the procedure and timelines for the development of clinical guidelines, their revision, the standard template of clinical guidelines, and requirements for their structure, composition, and scientific validity of the information included in the clinical guidelines."

9. Order of the Ministry of Health of the Russian Federation No. 804n dated October 13, 2017, "On Approval of the Nomenclature of Medical Services."

10. Order of the Ministry of Health of the Russian Federation No. 4n dated January 14, 2019, "On Approval of the Procedure for Prescribing Medicinal Products, Prescription Form Templates, Procedure for Issuing Said Forms, Their Accounting and Storage."

11. Medical contraindications to preventive vaccination with vaccines of the national immunization schedule: Guidelines.—M.: Federal Center for State Sanitary and Epidemiological Surveillance of the Russian Ministry of Health, 2002.— 16 p.

12. "Methodological Recommendations on the Detection, Investigation and Prevention of Adverse Events Following Immunization".

Key regulatory legal acts governing the provision of palliative medical care:

1. Federal Law "On Amendments to the Federal Law 'The Fundamentals of Healthcare Legislation in the Russian Federation' Regarding the Provision of Palliative Medical Care" No. 18-FZ dated March 6, 2019.

2. Order of the Ministry of Health of the Russian Federation No. 345n, Ministry of Labor of the Russian Federation No. 372n dated May 31, 2019, "On Approval of the Regulations on the Organization of Palliative Medical Care, Including the Procedure for Interaction between Medical Organizations, Social Welfare Organizations and Public Associations, Other Non-Profit Organizations Operating in the Sphere of Health Protection".

3. Order of the Russian Ministry of Health No. 348n dated May 31, 2019, "On approval of the list of medical devices intended to maintain human organs and body systems, provided for home use."

4. Order of the Russian Ministry of Health No. 505n dated July 10, 2019, "On approval of the Procedure for the transfer by a medical organization to a patient (their legal representative) of medical devices intended to maintain the functions of human organs and body systems for home use in the provision of palliative medical care."

5. Order of the Ministry of Health of the Russian Federation No. 831 dated October 3, 2019, "On Approval of the Departmental Target Program 'Development of the Palliative Medical Care Delivery System'".

To code the etiological factor (the disease that led to the development of CKD) or conditions associated with CKD with the designation "Background condition" or "Complication", the corresponding ICD-10 codes should be used.

In cases of preparation for renal replacement therapy (RRT), codes Z49.0–Z49.2 must be used.

Z49.0 – Preparatory procedures for dialysis (vascular access for hemodialysis, peritoneal catheter) in

CKD: N18 (N18.4; 18.5)

Z49.1 – Extracorporeal dialysis (hemodialysis, hemodialfiltration)

Z49.2 – Other dialysis (peritoneal dialysis)

Z99.2 – Dependence on renal dialysis (this code is used for patients on long-term renal replacement therapy). The corresponding ICD-10 codes are used to code CKD complications and associated conditions:

D63.8 – Anaemia in other chronic diseases classified elsewhere

E21.1 – Secondary hyperparathyroidism not elsewhere classified

E43 – Severe protein-energy malnutrition

E44.0 – Moderate protein-energy malnutrition

E44.1 – Mild protein-energy malnutrition

E45 – Retarded development following protein-energy malnutrition.

Alimentary: short stature (dwarfism), growth retardation.

Physical developmental delay due to malnutrition.

E46 – Unspecified protein-energy malnutrition

E83.3 – Disorders of phosphorus metabolism

E83.5 – Disorders of calcium metabolism

E83.8 – Other disorders of mineral metabolism

E87.2 – Acidosis

E87.5 – Hyperkalaemia

E89.2 – Postprocedural hypoparathyroidism

I15.1 – Hypertension in other kidney diseases

I43.8 – Cardiomyopathy in diseases classified elsewhere

N25.0 – Renal osteodystrophy

N39.1 – Persistent proteinuria, unspecified

Q60.0 – Unilateral renal agenesis

Q60.3 – Unilateral renal hypoplasia

Q63.1 – Fused, lobulated, and horseshoe kidney

Q61.4 – Renal dysplasia

Q63.0 – Accessory kidney

Examples of diagnoses:

Examples of diagnosis formulation in CKD patients aged 3 months to 2 years:

• Autosomal recessive polycystic kidney disease: polycystic kidney and liver disease. CKD with moderately decreased GFR. Secondary arterial hypertension, stage 2.

• Congenital anomaly of the kidney and urinary tract (CAKUT): left renal hypoplasia. CKD with normal GFR.

• CAKUT: proximal tubular dysgenesis. Congenital CKD, terminal stage.

• Congenital nephrotic syndrome of the Finnish type. CKD with severely decreased GFR.

aged over 2 years:

• Right renal cyst. CKD G1.

• CAKUT: left vesicoureteral reflux, stage 3. CKD G1A1. Post-endoscopic correction status (12.02.2018).

• Chronic glomerulonephritis (morphology: focal segmental glomerulosclerosis), nephrotic syndrome. CKD G3aA3.

• Chronic glomerulonephritis (morphology: IgA nephropathy), recurrent synpharyngitic haematuria. CKD G1A1. CAKUT: hypoplastic dysplasia of both kidneys. CKD G5D (maintenance hemodialysis since 14.02.2010).

• Chronic glomerulonephritis (morphology: focal segmental glomerulosclerosis). CKD G5. Living-donor kidney allotransplantation dated 15.06.2011. CKD G3aA3T. STEC-HUS, severe grade B (2012). CKD G3bA2. Secondary arterial hypertension, stage 2.

Appendix A3.1 Assessment of physical development in children

[Peterkova V.A., Nagaeva E.V., Shiryaeva E.Yu. Guidelines "Assessment of physical development of children and adolescents", National Medical Research Center for Endocrinology, 2017, Moscow, 98 p.].

Appendix A3.2 Parameters and frequency of nutritional status assessment in children with stage 3b-5D CKD. Anthropometric measurements [293]

Appendix A3.3 Expected daily weight gain by age (g) [293]

Appendix A3.4 Potassium content in fruits

Appendix A3.5 Potassium content in vegetables and legumes

Appendix A3.6 Potassium content in other food groups

Appendix A3.7 Phosphorus content in basic food products

Appendix A3.8 Recommended Dietary Intakes (RDI) of calcium and phosphate in children with stage 2-5D CKD [221]

Appendix A3.9 Recommended phosphorus intake for children with CKD [178]

Appendix A3.10 Sodium intake recommendations for children by age (KDIGO, 2024)

Appendix A3.11 Recommended daily potassium intake for children with CKD [178]

Appendix A3.12 Protein requirements in children with CKD (DRI) [4]

* RNI + 0.1 g/kg/day to compensate for HD (hemodialysis) losses

** RNI + 0.15 + 0.3 g/kg/day to compensate for PD (peritoneal dialysis) losses

Appendix A3.13 Energy and protein requirements for infants, children, and adolescents aged 0 to 18 years with stage 2-5D CKD [162]

Appendix A3.14 Conversion factors from the metric system to the International System of Units (SI) [6]

Note: unit of measurement × conversion factor = SI unit

Appendix A3.15 Correlation between albuminuria and proteinuria categories [6, 110]

¹ – 24-hour albumin excretion

² – 24-hour protein excretion

³ – albumin-to-creatinine ratio

⁴ – total protein-to-creatinine ratio

Appendix A3.16 Haemoglobin thresholds for the diagnosis of anaemia according to the World Health Organization (WHO)

Appendix A3.17 Target haemoglobin levels in adults and children with CKD receiving maintenance therapy with "Other antianemic preparations" (erythropoietins) [295, 296]

¹ haemoglobin

Appendix A3.18 Reference ranges for inorganic phosphorus and total calcium blood levels in children

Appendix A3.19 Target serum levels of PTH, total calcium, and inorganic phosphorus by CKD stage

Corrected Ca (mmol/L) = Total Ca + 0.02 mmol × (40 – A [g/L]);

Corrected Ca (mg/dL) = Total Ca + 0.8 mmol × (4 – A [g/dL])

Appendix A3.20 Conservative management of hyperkalaemia [138, 315, 341]

Appendix A3.21 Phosphate-binding agents [4, 129, 162]

Appendix A3.22 Status of vitamin D and its analogues [4, 129, 310]

Appendix A3.23 Forms of vitamin D and its analogues, and other anti-parathyroid drugs used in children with CKD [129, 206, 210, 223, 310, 352, 353]

Appendix A3.24 Explanation of notes

** – a medicinal product included in the Decree of the Government of the Russian Federation No. 2406-r dated October 12, 2019 (as amended) "On approval of the list of vital and essential medicinal products, as well as lists of medicinal products for medical use and the minimum assortment of medicinal products required for medical care";

# – off-label use of a medicinal product in accordance with indications (characteristics) not specified in its instructions for use is carried out in accordance with Federal Law No. 323-FZ dated November 21, 2011 (as amended), subject to signed informed consent and, if necessary, by decision of the medical commission.

Appendix B. Physician Action Algorithms

Appendix B1. Algorithm for diagnosing CKD in children

Appendix C. Patient Information

Chronic kidney disease is a condition in which the kidneys fail to fully perform their functions. Normally, the kidneys filter the blood and remove waste products, excess salts, and water from it.

In chronic kidney disease, the kidneys gradually lose this filtering capacity. Over time, the kidneys may completely stop functioning.

Therefore, it is extremely important to implement measures to slow down the progression of chronic kidney disease.

Chronic kidney disease may initially be asymptomatic. As the disease progresses, symptoms may include leg edema, fatigue, hypertension, and bone tissue disorders.

A nephrologist will tell you what needs to be done. It is essential to strictly follow their recommendations, for example:

Take antihypertensive medications, if prescribed, at the dose and schedule specified by the doctor.

If adverse reactions occur, be sure to inform your doctor.

Avoid taking certain medications, including some analgesics and antipyretics (e.g., ibuprofen**). Always consult your attending physician if you plan to use any medications.

In cases where the kidneys completely stop working, there are several treatment approaches:

- hemodialysis;

- peritoneal dialysis;

- kidney transplantation.

Each method has its advantages and disadvantages. Before making a decision, consult your attending physician to choose the optimal treatment option.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Not applicable.