Acute Kidney Injury in Neonates: Clinical Guidelines

List of Abbreviations

AKIN – Acute Kidney Injury Network

KDIGO – Kidney Disease: Improving Global Outcomes

RIFLE criteria – acronym for risk, injury, failure, loss, and end-stage – standardized criteria for acute kidney injury and its stages

BP – blood pressure

ACE – angiotensin-converting enzyme

ATX – Anatomical Therapeutic Chemical (ATC) Classification System

CAKUT – congenital anomalies of the kidney and urinary tract

URT – upper respiratory tract

IVH – intraventricular hemorrhage

CHD – congenital heart disease

GI – gastrointestinal tract

RRT – renal replacement therapy

IMV – invasive mechanical ventilation

HC – healthcare organization

NEC – necrotizing enterocolitis

ARF – acute renal failure

AKI – acute kidney injury

NICU – neonatal intensive care unit

BV – blood volume

SCVHDF – sustained continuous veno-venous hemodiafiltration

SCVHF – sustained (extended) continuous veno-venous hemofiltration

PD – peritoneal dialysis

GFR – glomerular filtration rate

MODS – multiple organ dysfunction syndrome

US – ultrasound examination

CKD – chronic kidney disease

CNS – central nervous system

HR – heart rate

EchoCG – echocardiography

Terms and Definitions

Acute kidney injury (AKI) is a multi-etiology syndrome characterized by an acute decline in homeostatic renal functions, leading to the accumulation of nitrogen metabolism products, and fluid-electrolyte and acid-base balance disorders.

The term "AKI" is currently used universally, replacing the previously used term "acute renal failure (ARF)".

ARF is currently used to denote severe cases of AKI, which corresponds to stage 3 of the AKI Network (2007) and KDIGO (2016) classifications adapted for use in the neonatal period.

Renal replacement therapy (RRT) – a complex of specialized methods to replace excretory renal function. These include dialysis (hemodialysis and peritoneal dialysis) and kidney transplantation. The latter method restores the full spectrum of lost renal functions. Corresponds to the English term "Renal replacement therapy" (RRT). Depending on duration, renal replacement therapy methods are divided into intermittent, continuous, and extended. Intermittent RRT methods require an artificial kidney machine and a water treatment system capable of producing large volumes of dialysate (substitute); these techniques are extremely rarely used in neonatology. Continuous RRT methods are used in infants, characterized by a low blood and dialysate (filtrate removal) perfusion rate and long procedure duration (20–24 hours). Continuous RRT methods require special machines that do not require a water treatment system. Extended RRT methods (extended intermittent renal replacement therapy) occupy an intermediate position between intermittent and continuous. Their duration is usually 8–12 hours. They are often called "hybrid" methods.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Acute kidney injury (AKI) is a multi-etiology syndrome characterized by an acute decline in homeostatic renal functions, leading to the accumulation of nitrogen metabolism products, and fluid-electrolyte and acid-base balance disorders.

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

Traditionally, according to pathogenesis, three main variants of AKI are distinguished: prerenal, renal, and postrenal kidney injury; currently, there are also an increasing number of publications on phenotypes (hypoperfusion, obstructive, toxic, inflammatory/immune) and subphenotypes of AKI, which essentially replaced the old classification because they contribute to a better understanding of the mechanisms of development and progression of AKI, variants of the clinical course of the disease, treatment methods, and probable outcomes [1,2].

In 75–85% of cases, AKI in newborns is caused by prerenal causes (hypoxemia, hypovolemia, hypotension), in 10–15% by renal causes, while postrenal causes are quite rare.

The main causes of AKI in newborns are birth asphyxia (acute fetal hypoxia), arterial hypotension, severe infectious diseases (neonatal sepsis), the use of nephrotoxic drugs, and renal vascular thrombosis.

If congenital anomalies of the kidney and urinary tract (CAKUT) with a significant decrease in renal function (hypoplasia, renal tissue dysplasia) or its absence (renal agenesis, juvenile polycystic kidney disease) are detected, the term "congenital renal failure" should be used; if CAKUT is present along with a risk factor for AKI (sepsis, birth asphyxia, history of shock of any etiology) and partial recovery of renal function is planned, the term "AKI on the background of chronic kidney disease (CKD)" may be used.

Prerenal AKI may develop with a decrease in systemic blood flow due to fetofetal or fetoplacental transfusion, hemorrhage from placental abruption, massive hemorrhages into internal organs, congenital heart defects with a reduced systemic circulation, severe asphyxia, or surgeries [3–11].

The pathogenesis of hypotension in sepsis and asphyxia is quite complex: direct myocardial damage, changes in vascular tone regulation, impaired vascular permeability, etc. [12–14].

If reduced renal blood flow persists for a long time (more than 24 hours), prerenal AKI progresses to renal AKI, resulting in direct damage to the renal parenchyma [15–17].

Renal AKI implies the development of functional failure in the presence of renal parenchymal damage. Depending on pathogenesis, it may develop with prolonged persistence of prerenal (more frequently) or postrenal (rarely) AKI, or primarily due to exposure to nephrotoxic substances, both exogenous and endogenous [18].

Postrenal AKI develops in newborns, as a rule, against the background of congenital malformations of the urinary system, such as posterior urethral valves, urethral and ureteral strictures and stenoses, pronounced vesicoureteral reflux, urethral cyst, etc. [9,10,19–21].

With prolonged obstruction, hydrostatic pressure inside the nephrons increases, leading to damage to the tubular epithelium and a decrease in glomerular filtration, which results in damage to the renal parenchyma [22,23].

Regardless of the primary mechanism, two clinical variants of AKI are possible:

- oliguric (with decreased diuresis);

- non-oliguric (without decreased diuresis).

According to the time of onset in newborns, it is customary to distinguish:

- early AKI (first 7 days of life);

- late AKI (occurring at an age older than 7 days of life) [24,25].

According to the time of resolution [26]:

- Transient (resolves within 48 hours);

- Persistent (resolves within 48 hours – 7 days).

1.3 Epidemiology of the Disease or Condition

Approximately 8–15% of newborns require treatment in neonatal intensive care units (about 6–10% of term newborns and 40–50% of preterm newborns) [27–31]. The results of the completed multicenter AWAKEN study by J.G. Jetton et al. (2017) [24] showed that 605 out of 2022 newborns (30%) in NICUs had AKI status. AKI was diagnosed in 131 (48%) of 273 newborns born at 22 to 29 weeks of gestational age; in 168 (18%) of 916 newborns born at 29–36 weeks; and in 306 (37%) of 833 patients born after 36 weeks. AKI was diagnosed more frequently in preterm newborns with a low gestational age of 22–29 weeks. Newborns with AKI had a higher mortality rate of 10% (59 out of 605) than those without AKI at 1.4% (20 out of 1417) (p < 0.0001). The authors proved that AKI in newborns is a major and independent risk factor for mortality. According to meta-analysis data, the incidence of all stages of AKI is 30%, and severe AKI is 15%. Mortality associated with AKI is 30% [32].

In 2020, a prospective study of 851 newborns from 20 neonatal intensive care units was conducted in the Russian Federation. Results: the incidence of AKI according to the modified KDIGO classification [33] was 22.7% (n = 193), of which early AKI accounted for 18.2% (n = 155). The maximum incidence of AKI was observed in children born before 29 weeks of gestation (44.9%), in children with extremely low birth weight (BW) (50% at BW less than 500 g), in patients with diaphragmatic hernias (83.3%), and intestinal obstruction (83.3%). Mortality was 6.2%. Among children who underwent surgery in the neonatal period, the incidence of AKI was 44.6% [34].

1.4 Features of Coding the Disease or Condition

P96.0 Congenital renal failure

N17.9 Acute kidney injury, unspecified

Comment: considering the irrationality of performing a kidney biopsy in newborns with AKI, it can be difficult to clinically establish the specific type of AKI; therefore, in the absence of exact data, the diagnosis "N17.9" is the most appropriate.

If the child has CAKUT with decreased renal function or congenital renal failure, the diagnosis "P96.0 Congenital renal failure" is established; in other cases, using this code is a major error.

1.5 Classification of the disease or condition

To date, several classifications of acute kidney injury (AKI) in newborns have been proposed, based on well-known pediatric classifications (AKIN, KDIGO) [33,35–38].

M. Zappitelli et al., AKI Workshop (2017) [33], propose a modification of the KDIGO AKI classification for newborns based on the criteria of serum creatinine elevation and decreased hourly urine output across stages 1, 2, and 3 over 24 hours.

Table 1. Proposed modifications to the definition of acute kidney injury in newborns from KDIGO (2017) [33]

This specific scale, converting blood creatinine values to µmol/L, is recommended for use in the clinical practice of neonatologists.

1.6 Clinical presentation of the disease or condition

Non-specific symptoms characteristic of critically ill newborns predominate (depressed consciousness, unstable hemodynamics, cardiac arrhythmias, metabolic disorders, etc.), which, in the absence of laboratory diagnostics, prevent the timely detection of decreased renal function.

In the oliguric form of AKI, the clinical picture is dominated by symptoms of fluid overload: peripheral edema, cerebral edema, pulmonary edema, ascites, hydropericardium, and hydrothorax.

When hyperkalemia develops – cardiac arrhythmias.

When metabolic acidosis develops – respiratory disorders, tachypnea/dyspnea.

In renal artery thrombosis, during the recovery phase of renal function, or in the acute period with marked fluid overload (rare) – arterial hypertension.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition:

The most important criteria for AKI are:

- increase in blood creatinine levels (not only the baseline level, but also the rate of its increase);

- decrease in hourly urine output (mL/kg/h).

A diagnosis of AKI can be established in the presence of the following signs [20]:

- increase in serum creatinine concentration by 26.5 µmol/L or more within 48 hours compared to baseline values;

- or increase in serum creatinine concentration by more than 1.5–1.9 times the baseline within the last 7 days;

- decrease in urine output rate to less than 1.0 mL/kg/h for 24 hours.

Comment: neonates more frequently present with a non-oliguric variant of AKI, which develops with preserved or moderately reduced hourly and daily urine output.

When urine output decreases without the development of azotemia, prerenal causes of impaired renal excretory function should be sought, such as decreased oncotic pressure, impaired central hemodynamics, etc. In addition, mechanical obstructions to urination must be ruled out.

2.1 Complaints and Anamnesis

• A newborn infant with AKI or suspected AKI is recommended to have a maternal and neonatal history taken to identify the cause of AKI [8,39–43].

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

Comment: presence of maternal and neonatal risk factors:

- complicated course of pregnancy in the mother (medication intake during pregnancy, past illnesses, presence of chronic pathology);

- complicated course of labor;

- use of adrenergic and dopaminergic agents (ATX code C01CA) in the first 7 days;

- grade 3 intraventricular hemorrhage (IVH);

- prematurity, birth weight less than 1500 g;

- cardiac surgery;

- neonatal sepsis;

- use of nephrotoxic drugs (aminoglycosides (ATX code J01G), glycopeptide antibiotics (ATX code J01XA), diuretics (ATX code C03), non-steroidal anti-inflammatory and antirheumatic drugs (ATX code M01A)).

2.2 Physical Examination

See Section 1.6 "Clinical picture of the disease or condition (groups of diseases or conditions)".

AKI has no specific clinical presentation and is generally masked by the manifestations of the underlying pathological condition (sepsis, neonatal asphyxia).

• A newborn infant is recommended to undergo a physical therapeutic examination to detect AKI [33,44–46].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: the physical therapeutic examination of a newborn with AKI includes:

- visual assessment of the degree of hydration (presence of pastosity, edema);

- examination of the skin and visible mucous membranes assessing the degree of pallor, jaundice, identification of skin rashes, hemorrhagic manifestations, and microcirculatory disorders;

- assessment of the central nervous system status;

- therapeutic percussion and auscultation of the lungs and heart, pulse examination;

- therapeutic palpation of the abdomen and kidneys (presence of the "palpable mass" syndrome – palpable kidneys).

With marked fluid overload, pulmonary edema may develop. With the development of acidosis – acidotic breathing, difficulty synchronizing with mechanical ventilation (MV);

With the development of hyperkalemia, arrhythmia and bradycardia may appear.

• A newborn infant with AKI or suspected AKI is recommended to have daily and hourly urine output determined in order to detect AKI and determine its stage [25,33,47,48].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

2.3 Laboratory Diagnostics

• A newborn infant with AKI is recommended to undergo a complete blood count (CBC) with differential leukocyte count (leukocyte formula) to diagnose infectious conditions and anemia as etiological factors in the development of AKI [8,39–41,49–53].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

• A newborn infant with AKI is recommended to have a serum C-reactive protein test to identify an infectious etiology of AKI [51,54].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

• A newborn infant with AKI is recommended to have acid-base balance and blood gas analysis performed to diagnose and treat metabolic acidosis [54–60].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: sodium bicarbonate**-refractory metabolic acidosis in AKI may be one of the indications for renal replacement therapy.

• A newborn infant with AKI is recommended to undergo a general biochemical blood test (levels of creatinine, urea, potassium, sodium, chlorides, total calcium, total protein, and albumin in the blood) to assess the functional state of renal excretory function and determine the stage of AKI [8,24,61].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: blood levels of creatinine, urea, potassium, sodium, chlorides, total calcium, total protein, and albumin are the main source of information on the functional state of renal excretory function.

To ensure the timely detection of AKI in high-risk newborns (severe neonatal asphyxia, congenital neonatal sepsis, shock of various etiologies), the following frequency of general biochemical blood tests for AKI markers and blood sodium, potassium, and chlorides is advisable: in the first hours after birth, at 48–72 hours of life, at 144–168 hours of life, and subsequently (with clinical and laboratory confirmation of AKI) every 7 days of life until the end of the neonatal period. Additional tests are prescribed if urine output declines over time during monitoring and delayed development of AKI is suspected.

The most characteristic changes in AKI are azotemia and hyperkalemia.

When interpreting biochemical test results, it must be remembered that:

- urea – the increase in blood urea depends not only on renal factors: decreased glomerular filtration rate (GFR), oliguria, and anuria, but also on many extrarenal factors (primarily hypercatabolism developing with inadequate nutrition);

- hyponatremia is a sign of fluid overload, including that associated with tubular injury. Hyponatremia occurs in many critical conditions (loss of sodium via the gastrointestinal tract (GIT), through the skin, mineralocorticoid deficiency, pseudohypoaldosteronism, non-oliguric AKI, the polyuric phase of acute renal failure, use of furosemide** (ATX code C03CA01)) [47,62];

- hyperkalemia in AKI is associated with the loss of intracellular electrolytes, tissue damage, or hemolysis;

- hypocalcemia may be accompanied by hyperphosphatemia as a manifestation of vitamin D metabolism disorder (in renal impairment, the synthesis of the active vitamin D metabolite is reduced).

• A newborn infant with AKI is recommended to undergo a general (clinical) urinalysis to detect urinary syndrome [63–65].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: laboratory signs of urinary syndrome of any severity include: proteinuria, glucosuria (with normal or decreased blood glucose levels), leukocyturia, erythrocyturia, cylindruria, bacteriuria, presence of salt sediment, change in urine reaction from acidic to alkaline or neutral, and a decrease in the anti-crystallization capacity of urine [66].

The recommended timing for urinalysis monitoring is at 48–72 hours of life, 144–168 hours, and then weekly until the end of the neonatal period [204]. Additional tests are prescribed when the rate of diuresis decreases and AKI development is suspected.

• A newborn infant with AKI is not recommended routine determination of urine osmolarity, determination of urine specific gravity (relative density), urine creatinine level testing, urine sodium level testing, osmotic concentration index, nephron function testing via creatinine clearance (Reberg's test), and fractional excretion of sodium [47,62].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: these laboratory tests are not mandatory, but in complex cases, they help clarify the diagnosis and determine treatment tactics. When performing these tests, it must be borne in mind that therapy can affect measurement results: for example, the use of furosemide** (ATX code C03CA01) and several other drugs leads to an increase in sodium excretion.

Depends on the capabilities of a specific medical organization.

2.4 Instrumental Diagnostics

• A newborn infant with AKI is recommended to undergo echocardiography to rule out a prerenal component of AKI [67–70].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: the prerenal component of AKI develops as a result of heart failure, hypovolemia, congenital heart disease, imbalance between systemic and pulmonary blood flow, and hemodynamically significant communications with blood shunting leading to underperfusion of the systemic circulation.

• A newborn infant with AKI is recommended to undergo an ultrasound examination of the kidneys and adrenal glands and duplex scanning of the renal arteries to identify the etiology of renal injury [71–75].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: the complex of ultrasound examination of the kidneys must include: assessment of position, dimensions and, if possible, ultrasound-metric volume of the kidneys, parenchyma structure, width of the pelvicalyceal system, and the presence of echonegative "tracks". To rule out/confirm the vascular nature of AKI, it is advisable to perform duplex scanning of the renal arteries.

• A very preterm infant with non-oliguric hyperkalemia is recommended to have an electrocardiogram recorded to rule out arrhythmia and provide timely therapy [76–79].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comment: very preterm infants may experience so-called non-oliguric hyperkalemia associated with an increased shift of potassium from the intracellular space to the extracellular space during metabolic acidosis. This condition is hazardous for the infant as it leads to a change in transmembrane potential, which contributes to impaired functioning of the cardiac conduction system. Differential diagnosis with transient oliguria.

2.5 Other Procedures

Invasive methods of additional nephrological examination (cystography, intravenous urography, renal and urinary tract scintigraphy, renal biopsy) against the background of AKI in newborns are not used without extreme necessity, such as the impossibility to determine further treatment tactics without precise data. In most cases, the use of the aforementioned methods should be postponed until the resolution of AKI. The issue of using these methods after the resolution of AKI or the development of CKD is decided by a medical board (consilium), taking into account the ratio of diagnostic benefits and possible complications from the performed additional examination.

• A newborn infant with AKI is recommended to undergo serial body weight measurements to detect fluid retention [33,61].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

• A newborn infant with AKI is recommended to undergo general thermometry to identify the infectious etiology of AKI and assess tissue perfusion [54,60,80].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

• A newborn infant with AKI is recommended to undergo continuous bedside monitoring of vital functions and parameters (heart rate and blood pressure) for the timely detection of AKI complications (arterial hyper- or hypotension, cardiac rhythm disorders) and reduction of mortality [43,60,81–83].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

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

3.1 Conservative Treatment

3.1.1 Therapy Aimed at Eliminating Prerenal and Postrenal Causes of AKI

In newborns with diagnosed prerenal or postrenal causes of AKI, therapy is aimed at eliminating the causes of AKI.

3.1.1.1 Postrenal AKI

• Newborns with postrenal AKI are recommended to eliminate the causes of urinary tract obstruction and restore normal urodynamics [39,84,85].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

3.1.1.2 Prerenal AKI

• In newborns with shock or arterial hypotension in the presence of AKI or the risk of developing AKI, it is recommended to use adrenergic and dopaminergic agents (ATX code C01CA) (#dopamine**, dobutamine**, norepinephrine**, and epinephrine**) in combination with electrolyte solutions (ATX code B05XA) – sodium chloride** 0.9% for cardiotonic and vasopressor purposes [86-99]. Dosing regimen for #dopamine**: 2-20 mcg/kg/min intravenously, by drip infusion [92,203].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• A newborn with prerenal AKI or suspected prerenal AKI is recommended to administer electrolyte solutions (ATX code B05XA) (sodium chloride** 0.9%) (fluid challenge test) in a volume of 10–20 ml/kg over 30 minutes for differential diagnosis and treatment of hypovolemia [59,106].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comment: to restore the newborn's circulating blood volume (CBV), an infusion challenge with 0.9% sodium chloride** solution (ATX code B05XA03) is administered in a volume of 10–20 ml/kg over 30 minutes. Fluid challenge serves as both a diagnostic and therapeutic procedure; however, it must be performed with caution under heart rate and blood pressure monitoring, avoiding fluid overload. To clarify the current hemodynamic status, echocardiography (EchoCG) and duplex scanning of renal arteries must be performed, determining cardiac output, ejection fraction, myocardial contractility, blood flow velocity, and vascular resistance index in the renal arteries.

Upon an increase in diuresis (appearance of diuresis in patients with anuria or an increase in urine output rate of more than 1 ml/kg/h in patients with oliguria), consider the feasibility of continuing therapy aimed at correcting volume deficit. The goal of therapy is to normalize CBV without inducing hypo- or hypervolemia in the patient.

• To increase diuresis and differentiate between prerenal and renal AKI, a newborn with AKI is recommended a strictly single administration of sulfonamides (ATX code C03CA) – #furosemide** at a dose of 1–2 mg/kg [47,59,62,107,108].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comment: #furosemide** (ATX code C03CA01) is prescribed at a dose of 1–2 mg/kg to newborns after CBV restoration and complete stabilization of hemodynamic parameters (blood pressure, heart rate), in the absence of vasospasm and reduced blood flow in the renal arteries, but with persisting oliguria/anuria [59,83,107].

If diuresis increases after the administration of #furosemide** (ATX code C03CA01), it can be assumed that prerenal factors play a leading role in the pathogenesis of AKI, and in this case, it is advisable to continue therapy aimed at correcting hemodynamic disorders: infusion therapy, correction of life-threatening hypoproteinemia, cardiotonic and vasopressor support to normalize central hemodynamics, rather than repeated administration of the drug.

If there is no response to the administration of #furosemide** (ATX code C03CA01) (increase in diuresis) in the child, renal AKI may be suspected. In this case, the timely initiation of renal replacement therapy must be considered.

3.1.2 Infusion and diuretic therapy

• Newborns with AKI are recommended to undergo infusion therapy under serial echocardiography monitoring, allowing to rule out the occurrence of both hypervolemia and hypovolemia [109].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comment: if full-fledged infusion therapy is impossible due to a high risk of fluid overload, the consideration of renal replacement therapy is indicated.

• A newborn with the non-oliguric variant of AKI, in order to cover physiological losses, administer medications, and provide parenteral nutrition, is recommended to calculate the volume of administered fluid in accordance with physiological requirements, gestational age, and birth weight [61,110–113].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• It is not recommended to use diuretics (ATC code C03) for the prevention and treatment of AKI in newborns, except for the treatment of patients with fluid overload and hyperkalemia in the presence of diuresis (furosemide**) (ATC code C03CA01) [39,59,107,114].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: furosemide** (ATC code C03CA01) is the only recommended diuretic used in AKI in newborns[39].

Furosemide** (ATC code C03CA01) is pharmacologically inactive in hypovolemia and hypoalbuminemia, and its use is also irrational in the absence of adequate renal blood flow.

Furosemide** (ATC code C03CA01) is a drug with a known nephrotoxic effect; therefore, its combination with other nephrotoxic drugs (aminoglycosides (ATC code J01G), glycopeptide antibiotics (ATC code J01XA), non-steroidal anti-inflammatory and antirheumatic drugs (ATC code M01A)) is potentially hazardous [115,116].

An absolute contraindication to the use of furosemide** (ATC code C03CA01) is anuria for 12 hours or more. Furosemide** (ATC code C03CA01) must not be used in hypovolemia. Another clinical situation in which furosemide** (ATC code C03CA01) is used is hyperkalemia in the presence of diuresis (non-oliguric hyperkalemia): furosemide** (ATC code C03CA01) promotes renal potassium excretion [59]. The main complication of prolonged use of furosemide** (ATC code C03CA01) may be nephrolithiasis [18,117].

3.1.3 Antibacterial therapy in AKI

In more than 50% of cases, AKI develops against the background of a septic process or is complicated by secondary bacterial infections, making the issue of prescribing antibacterial therapy valid. At the same time, the vast majority of systemic antibacterial drugs used in neonatology (ATC code J01) are not metabolized in the liver and are excreted unchanged by the kidneys, making them potentially nephrotoxic [118].

With a decrease in diuresis, the concentration of systemic antibacterial drugs (ATC code J01) in the renal tubules increases, and nephrotoxic effects escalate. In addition, the presence of non-functioning nephrons, as observed in AKI, increases the load on functioning nephrons with a corresponding increase in their toxic effect.

Consequently, it is necessary to select the least nephrotoxic drugs, as well as to address the issue of reducing the administration frequency and dosage of systemic antibacterial drugs (ATC code J01).

• To reduce the damaging effect on renal function in a newborn with AKI, it is recommended to discontinue systemic antibacterial drugs (ATC code J01) with a proven nephrotoxic effect (aminoglycosides (ATC code J01G) - gentamicin**, amikacin**, netilmicin), (glycopeptide antibiotics (ATC code J01XA) - vancomycin**, except for situations where alternative, less nephrotoxic drugs are unavailable [57,59,119–121].

GCR CLoE 3Grade of Recommendation C (Level of Evidence – 3)

Comments: if discontinuation of the nephrotoxic drug is impossible, dose adjustment or modification of the administration frequency must be carried out in accordance with the drug's instructions.

Systemic antibacterial drugs (ATC code J01) with a potential nephrotoxic effect:

1. Aminoglycosides (ATC code J01G) rank first in terms of nephrotoxicity not only among systemic antibacterial drugs (ATC code J01), but also among potentially nephrotoxic agents in general. If the capabilities of a specific medical organization allow, it is advisable to monitor the concentration of aminoglycosides (ATC code J01G) in the blood plasma of patients when multiple doses are administered within 24 hours for a duration of more than one day [39].

2. Vancomycin** (ATC code J01XA01). Vancomycin** (glycopeptide antibiotics - ATC code J01XA) is generally considered the second most nephrotoxic drug. It should be borne in mind that in patients with normal renal function, the half-life of the drug is 4–6 hours. In renal impairment, this time increases to 7–10 days. Like first- (ATC code J01DB), second- (ATC code J01DC), third- (ATC code J01DD), and fourth-generation (ATC code J01DE) cephalosporins, vancomycin** (ATC code J01XA01) can cause an immunopathological process in the renal interstitium [39,41].

3.1.4 Therapy of metabolic and electrolyte disorders

• In a newborn with AKI, correction of identified homeostasis disorders is recommended [59,108,123–130]:

  In case of hyperkalemia, the following measures are recommended:

- 6.0–6.5 mmol/L — restriction of K⁺-containing drugs, intravenous administration of #sodium bicarbonate** at a dose of 1 mEq/kg over 10–30 min [108], calcium preparations (ATC code A12AA) — #calcium gluconate** 10% solution at a dose of 0.5–1 mL/kg [59, 108];

- 6.5–7.0 mmol/L — restriction of K⁺, intravenous administration of #sodium bicarbonate** at a dose of 1 mEq/kg over 10–30 min [108], calcium preparations (ATC code A12AA) — #calcium gluconate**, glucose-insulin mixture (0.2 IU of #insulin soluble [human genetically engineered]** (ATC code A10AB01) + 0.5 g/kg of #dextrose** (ATC code B05CX01) 10% solution, intravenous drip over 2 hours) [59, 108];

In case of hypocalcemia: #calcium gluconate** (ATC code A12AA03) 10% solution at a dose of 0.5–1 mL/kg.

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: if K⁺ > 7 mmol/L in 2 analyses taken within 6 hours during therapy aimed at correcting potassium excess, renal replacement therapy is indicated.

Non-oliguric hyperkalemia is a high (greater than 6.7 mEq/L) serum potassium level with a normal serum creatinine concentration and a normal urine output rate. Hyperkalemia can lead to cardiac arrhythmias and, consequently, to cerebral hemorrhage and/or sudden death.

In AKI, monitoring the level of ionized calcium is especially important. The level of total calcium depends on the severity of hyperphosphatemia, the ability of the kidneys to produce the active vitamin D metabolite, and the preservation of tubular reabsorption of calcium ions [124, 125].

Hyponatremia in AKI is attributed by most authors primarily to inadequate fluid load. When sodium levels drop below 120 mmol/L, correction of hyponatremia is indicated. The target concentration to achieve is 125 mmol/L. The calculation is performed using the formula (Appendix A3.2).

It should be remembered that hyponatremia, in most cases, is easier to prevent by timely restriction of the infusion volume than to correct.

With the development of severe AKI, metabolic acidosis occurs quite frequently and is one of the most formidable complications, which, combined with oliguria and hyponatremia, may be an indication for RRT. The difficulty of its correction is associated with the impossibility of administering high doses of #sodium bicarbonate** (in premature newborns, it is associated with a high risk of developing IVH).

- at pH below 7.2, #sodium bicarbonate** is prescribed by intravenous administration of medicinal products. The calculation formula is presented in Appendix A3.2.

The individual dose of #sodium bicarbonate** is selected under the control of acid-base balance studies and serial blood sodium, potassium, and chloride level tests [136, 137].

• Newborns with AKI are not recommended to use ion-exchange resin-based drugs (calcium polystyrene sulfonate**) (ATC code V03AE01) for the treatment of hyperkalemia [131–134].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: the use of ion-exchange resin-based drugs (calcium polystyrene sulfonate**) in newborns carries a high risk of complications (gastrointestinal lesions with the development of hemorrhagic, transmural, and ulceronecrotic colitis, hypernatremia) [131–134].

3.1.5 Therapy of arterial hypertension

Arterial hypertension in newborns with AKI is rare and, according to modern studies, accounts for 1.8% [141], in most cases being recorded only during the kidney function recovery stage. Therefore, all children require dynamic blood pressure monitoring. Reference values for the upper limit of blood pressure are presented in Appendix A3.3. Blood pressure-lowering drugs in the neonatal period are "off-label"; however, they are used in children of this age group for vital indications with informed consent obtained from the child's parents and by the decision of a medical board.

• For a newborn with AKI who develops arterial hypertension associated with renal pathology, it is recommended to prescribe antihypertensive drug therapy. The drugs of choice are: #nifedipine**(ATX code C08CA05) at a dose of 0.1-0.25 mg/kg/day per os every 4-6 hours; #propranolol**(ATX code C07AA05) at a dose of 0.75-2 mg/kg/day per os in 3 divided doses (if ineffective, the dose may be increased up to 5 mg/kg/day); #atenolol**(ATX code C07AV03) at a dose of 0.5-2 mg/kg/day once daily per os; #esmolol** (ATX code C07AV09) at a dose of 50–500 mcg/kg/min continuous intravenous infusion (for children with enteral feeding intolerance, on total parenteral nutrition) [19,59,142–149,202].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: the drug dose is selected individually under blood pressure monitoring.

#Nifedipine**(ATX code C08CA05) is a short-acting drug, and its use is advisable in patients with AKI in the recovery phase of renal function, when children may experience short-term spikes in blood pressure. After taking #nifedipine**(ATX code C08CA05), peripheral blood pressure measurement is performed after 40 minutes and 2 hours. Subsequently, if blood pressure spikes persist, the administration of the drug may be repeated.

3.1.6 Medicinal products not recommended for the prevention and treatment of AKI

The drugs listed below were previously used by foreign researchers in the treatment of AKI in adults and children, but their efficacy was extremely low.

• In a newborn, it is not recommended to use low doses of #dopamine**(ATX code C01CA) – 1-3 mcg/kg/min for the prevention or treatment of AKI [87,100–102].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

• In a newborn with thrombosis and AKI, it is not recommended to prescribe angiotensin-converting enzyme (ACE) inhibitors (captopril**) (ATX code C09AA01) and angiotensin II receptor antagonists (losartan**) (ATX code C09CA01) due to the risk of progression of already impaired renal functions [44].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: impaired renal functions include: oliguria/anuria, hyperkalemia, elevated creatinine.

3.2 Surgical Treatment

In neonatology, currently both intracorporeal renal replacement therapy (RRT) methods—peritoneal dialysis (PD)—and extracorporeal methods are used: continuous venovenous hemodialysis (CVVHD) (continuous hemodialysis) or continuous venovenous hemofiltration (CVVHDF) (continuous blood hemofiltration). The choice of method depends on the specific clinical situation and the equipment available at the medical facility.

If there are indications and capabilities, RRT should be initiated as early as possible [106,164–166].

Currently, there is no evidence of the superiority of one type of RRT over another [167,168].

Renal replacement therapy is a type of intensive care, and central nervous system damage in a child is not a contraindication to its performance.

Renal Replacement Therapy

• In a newborn with AKI in case of failure of ongoing conservative treatment, it is recommended to perform renal replacement therapy (RRT) for the treatment of AKI [22,62,120,150–154].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comment: indications for RRT in newborns [55,57,62,151,155–162]:

o anuria (less than 0.3 ml/kg/hour) for more than 24 hours against the background of adequate therapy (see above) in a child older than 48 hours of life

o anuria/oliguria combined with:

- multiple organ dysfunction syndrome (MODS) and weight gain of more than 15% over 48 hours;

- MODS and signs of volume overload and the development of cerebral edema/pulmonary edema/heart failure, circulatory failure;

- inability to provide adequate therapy and nutrition to the child due to the risk of fluid overload lasting more than 2 days;

- decompensated metabolic acidosis unresponsively corrected by conservative measures (pH 7.15 and below, HCO3 less than 12 mmol/l);

- hyponatremia, venous serum sodium concentration below 120 mEq/l;

- hyperkalemia in venous blood above 7 mmol/l in 2 analyses taken within 6 hours against the background of therapy aimed at correcting potassium excess;

- an increase in urea levels above 30 mmol/l against the background of enteral or parenteral nutrition (at least 2 g of protein per kg of body weight).

Also, RRT is the method of choice when hyperammonemia, rhabdomyolysis, or fluid overload is detected [163].

• In a newborn with AKI, if indicated, as the primary intracorporeal renal replacement therapy method, it is recommended to perform peritoneal dialysis (PD) for the treatment of AKI [55,57,120,150,162,169].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: performed if technically feasible. Appendix A3.4.

The only absolute contraindication to peritoneal dialysis in newborns is peritonitis requiring emergency surgery. Contraindications developed for adults (less than two days after laparotomy, inflammatory phenomena on the anterior abdominal wall, presence of drains in the abdominal cavity, and stomas) are relative for PD in newborns in the absence of technical feasibility for other RRT methods.

• As an alternative RRT method, in a newborn with AKI, it is recommended to perform an extracorporeal session of CVVHD (continuous hemodialysis) or CVVHDF (continuous blood hemofiltration) for the treatment of AKI [177–179].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comment: performed if technically feasible. Appendix A3.4.

3.3 Other Treatment

Nutrition

• In a newborn infant with AKI, in the absence of gastrointestinal contraindications (NEC, intestinal malformations, postoperative period), it is recommended to preserve enteral nutrition to supply vital substances and energy provision [9,22,83,109,182].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: native maternal milk is the ideal nutritional substrate, as it contains the required amount of protein and phosphorus. Since the excretion of nitrogenous waste products in AKI is impaired, nutrition must provide basic energy requirements to prevent excessive catabolism:

Daily caloric intake should meet the recommended requirements for the given gestational and postnatal age.

• In a newborn with AKI, it is recommended to administer protein, fat, and carbohydrates to meet basic requirements [9,22,83,109,162,182].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: protein intake is required at least 1.5-2 g/kg/day, fats are prescribed individually under the control of triglyceride levels and visual assessment of serum chyle; the remaining caloric intake must be provided by carbohydrates.

Severe protein restriction should be avoided to prevent or delay the initiation of renal replacement therapy (RRT). It is more appropriate to perform RRT in a timely manner rather than drastically restrict protein intake [183].

Maintaining nutritional balance, both enteral and parenteral, is vital for the treatment of patients with AKI.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Not applicable.

5. Prevention and Dispensary Observation

5.1 Prevention

Specific preventive measures have not been developed. Main prevention strategies for AKI still include adequate hydration, maintenance of mean arterial pressure, and minimization of nephrotoxic drug exposure.

Newborns with a low Apgar score (Appendix G1), sepsis, shock, critical congenital heart defects, and newborns in the perioperative period are at risk for developing AKI [186–190].

5.2 Dispensary monitoring

• In a newborn who has undergone AKI, it is recommended to have follow-up appointments (examination, consultation) with a pediatric nephrologist to prevent the development of and ensure timely diagnosis of CKD [17,188].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

• In an infant under one year of age who has had AKI in the neonatal period, it is recommended to monitor physical development (body weight measurement, height measurement), blood pressure (peripheral blood pressure measurement), and urine volume dynamically for the timely diagnosis of chronic renal failure [17,188].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• In an infant under one year of age who has had AKI in the neonatal period, it is recommended to monitor a detailed complete blood count – 1 time every 1–3 months, urinalysis 1 time every 14–30 days, general clinical blood chemistry analysis (study of potassium, sodium, total calcium, inorganic phosphorus, total protein, urea, creatinine levels, determination of alkaline phosphatase activity in the blood) – 1 time every 1–3 months, calculation of the glomerular filtration rate – 1 time every 6-12 months for the timely diagnosis of chronic renal failure [17,188].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: in case of intercurrent diseases, an unscheduled examination is performed.

• For an infant in the first year of life who has suffered AKI in the neonatal period, it is recommended to perform an ultrasound of the kidneys and adrenal glands, and duplex scanning of the renal arteries every 6 months for the timely diagnosis of chronic kidney disease [17,188].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

6. Organization of Medical Care

Indications for hospitalization in a medical organization:

1) decrease in diuresis;

2) organ dysfunction;

3) detected azotemia.

Indications for patient discharge from a medical organization:

1) restoration of diuresis and reduction of azotemia;

2) relief of septic complications;

3) normalization of the function of organs and body systems.

7. Additional Information

Differential diagnosis of AKI should be carried out with the following conditions:

- Transient oliguria.

- AKI against the background of CKD. AKI in newborns can occur against the background of CAKUT. In such cases, it can be difficult to differentiate AKI against the background of CKD from congenital CKD [66].

- Syndrome of inappropriate antidiuretic hormone secretion.

In children who have undergone AKI with acute tubular necrosis, impaired renal function persists for the first year of life in approximately 40% of cases [132].

Poor prognostic factors: severity of the child's condition upon detection of AKI (sepsis, AKI after cardiac surgery, need for vasopressor therapy, mechanical ventilation, pronounced fluid overload) and late initiation of RRT [61,113,191–193].

With a favorable course of AKI, renal function is restored in most cases. The prognosis in AKI largely depends on the cause that led to the decline in renal function and on the adequacy and timeliness of initiating therapy.

Children who have suffered AKI subsequently have a higher risk of developing arterial hypertension, proteinuria, and CKD, requiring prolonged specialist follow-up [20,192,194,195].

AKI (ARF) is rarely the primary cause of death, but serves as one of the informative independent predictors of fatal outcome.

Mortality in multiple organ dysfunction syndrome, including AKI, reaches 80% [20,123,196–199], and the use of renal replacement therapy methods can significantly reduce mortality.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Balashova Ekaterina Nikolaevna – Candidate of Medical Sciences, Leading Researcher at the Prof. A.G. Antonov ICU of the Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health; Associate Professor at the Department of Neonatology of the Institute of Professional Education, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health; Associate Professor at the Department of Neonatology, Pediatric Faculty, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University), member of the Council of the Russian Society of Neonatologists.

2. Bokeria Ekaterina Leonidovna – Doctor of Medical Sciences, Leading Researcher at the Department of Pathology of Newborns and Premature Infants No. 2, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health; Professor at the Department of Neonatology, Pediatric Faculty, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University), member of the Council of the Russian Society of Neonatologists, member of the Association of Pediatric Cardiologists of Russia.

3. Volodin Nikolay Nikolaevich – Doctor of Medical Sciences, Academician of the Russian Academy of Sciences, Professor, President of the Association of Specialists in Perinatal Medicine, Providing Care to Pregnant Women and Fetuses, Newborns and Children Under 3 Years of Age (ASPM+), Head of the Pediatrics Department, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Ministry of Health of Russia.

4. Grebenkina Elizaveta Yurievna – Pediatrician at the 2nd Infectious Diseases Admission Department, Children's City Hospital No. 9 named after G.N. Speransky of the Moscow Healthcare Department.

5. Daminova Maria Anatolyevna – Candidate of Medical Sciences, Associate Professor at the Prof. E.M. Lepsky Department of Pediatrics and Neonatology, Kazan State Medical Academy – branch of the Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, member of the Interregional Public Organization “Creative Association of Pediatric Nephrologists”, Kazan.

6. Degtyarev Dmitry Nikolaevich – Doctor of Medical Sciences, Professor, Deputy Director for Research, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Head of the Department of Neonatology, Pediatric Faculty, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University), member of the Council of the Russian Society of Neonatologists.

7. Zverev Dmitry Vladimirovich – Candidate of Medical Sciences, Head of the Center for Gravitational Blood Surgery and Hemodialysis, St. Vladimir Children's City Clinical Hospital, Associate Professor at the Department of Pediatrics, MSMSU, board member of the Interregional Public Organization “Creative Association of Pediatric Nephrologists”.

8. Elena M. Kozlova – MD, DSc, Dean of the Pediatric Faculty, Professor at the Department of Faculty and Polyclinic Pediatrics, Privolzhsky Research Medical University of the Russian Ministry of Health, Chief Freelance Neonatologist of the Ministry of Health of the Nizhny Novgorod Region, member of the Russian Association of Perinatal Medicine Specialists (RASPM), Russian Society of Neonatologists (RSN), MARS, ADAR, and the Union of Pediatricians of Russia.

9. Anastasia I. Makulova – PhD, Head of the Center for Neonatal Nephrology and Dialysis at Children's City Clinical Hospital No. 9 named after G.N. Speransky of the Moscow Healthcare Department, Associate Professor at the Department of Pediatrics of the Therapeutic Faculty named after Academician M.Ya. Studenikin, Pirogov Russian National Research Medical University of the Russian Ministry of Health, member of the Russian Society of Neonatologists, RDO, Federation of Anesthesiologists and Reanimatologists.

10. Yulia L. Podurovskaya – PhD, Head of the Department of Neonatal and Pediatric Surgery, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, member of the Russian Society of Neonatologists.

11. Nadezhda D. Savenkova – MD, DSc, Professor, Head of the Department of Faculty Pediatrics, Saint Petersburg State Pediatric Medical University of the Russian Ministry of Health, Chairman of the Board of the Interregional Public Organization "Association of Pediatric Nephrologists named after Prof. A.V. Papayan", Presidium member of the Interregional Public Organization "Creative Association of Pediatric Nephrologists", member of The European Society for Paediatric Nephrology (ESPN), The International Pediatric Nephrology Association (IPNA).

12. Asiya I. Safina – MD, DSc, Professor, Head of the Department of Pediatrics and Neonatology named after Professor E.M. Lepsky, Kazan State Medical Academy – branch of the Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, Honored Doctor of the Republic of Tatarstan, Honorary Member of RASPM, Presidium member of the Interregional Public Organization "Creative Association of Pediatric Nephrologists", member of the American Academy of Pediatrics, Honorary Member of the Emory University Global Collaborating Center in Reproductive Health (USA), Kazan.

13. Olga L. Chugunova – MD, DSc, Professor at the Department of Hospital Pediatrics named after Academician V.A. Tabolin of the pediatric faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health, member of RASPM, Chairman of the Nephrology Section of the Moscow Society of Pediatricians, Presidium member of the Interregional Public Organization "Creative Association of Pediatric Nephrologists", member of The European Society for Paediatric Nephrology (ESPN), The International Pediatric Nephrology Association (IPNA).

There is no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Methods used for collecting/selecting evidence: electronic database search.

Description of methods used for evidence collection/selection: the evidence base for the recommendations included publications from the Cochrane Library, PubMed, EMBASE and MEDLINE, Scopus, Web of Science, eLibrary, clinicaltrials.gov, electronic libraries, and clinical guidelines published by The National Institute for Health and Care Excellence, The European Association of Perinatal Medicine, The European Society for Pediatric Research, The European Foundation for the Care of Newborn Infants, and the European Society for Neonatology. The search depth was 37 years.

Methods used for assessing the quality and strength of evidence:

• expert consensus;

• assessment of significance in accordance with the rating scheme.

Scales for assessing the Levels of Evidence (LoE) (Appendix A2.1, A2.2) for diagnostic, preventive, therapeutic, and rehabilitation methods (interventions) with definitions, and the scale for assessing the Grades of Recommendation (GoR) (Appendix A2.3) for preventive, diagnostic, therapeutic, and rehabilitation methods (interventions).

Methods used for analyzing evidence:

• reviews of published meta-analyses;

• systematic reviews with evidence tables.

Description of methods used for analysis of evidence.

When selecting publications as potential sources of evidence, the methodology used in each study was reviewed to ensure its validity. Methodological evaluation was based on questions focused on study design features that significantly affect the validity of the results and conclusions.

To minimize potential subjective errors, each study was evaluated independently by at least two members of the working group. Any discrepancies in assessments were discussed by the full working group. If consensus could not be reached, an independent expert was involved.

Economic analysis:

Cost analysis was not performed, and pharmacoeconomic publications were not reviewed.

Method of guidelines validation:

• external expert review;

• internal expert review.

Description of the guidelines validation method:

The preliminary version of these guidelines was reviewed by independent experts who were asked to comment primarily on whether the interpretation of the evidence underlying the recommendations was accessible and understandable.

Comments were received from primary care physicians and district pediatricians regarding the clarity of the presentation of the guidelines and their assessment of the importance of the guidelines as a working tool in daily practice.

The draft version was also sent to a non-medically trained reviewer to obtain comments from a patient perspective.

Comments received from experts were carefully systematized and discussed by the chair and members of the working group. Each point was discussed, and resulting modifications to the guidelines were recorded. If no changes were made, the reasons for declining the changes were recorded.

Consultation and peer review:

Recent changes to these recommendations are presented for discussion in a preliminary version. An updated version for broad discussion was posted on the website of the Russian Society of Neonatologists (RSN) www.neonatology.pro and the Association of Specialists in Perinatal Medicine, Care for Pregnant Women and Fetuses, Newborns, and Children under 3 Years of Age (ASPM+) www.aspm.pro so that all interested parties have the opportunity to participate in the discussion and improvement of the recommendations.

The draft guidelines were reviewed by independent experts who were asked to comment primarily on the clarity and accuracy of the interpretation of the evidence base underlying the recommendations.

For the final revision and quality control, the recommendations were re-evaluated by the members of the working group, who concluded that all comments and feedback from the experts had been taken into account and the risk of bias in the development of the recommendations was minimized.

Target audience for these clinical guidelines:

1. neonatologists;

2. anesthesiologists-intensivists;

3. pediatricians;

4. nephrologists;

5. medical school students;

6. residents and interns.

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

Table 2. Levels of Evidence (LoE) grading scale for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitation interventions)

Table 3. Scale for assessing the grades of recommendation (GR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitation 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

Appendix A3.1 Related Documents

These clinical guidelines have been developed taking into account the following regulatory and legal documents:

1. Federal Law No. 323-FZ of November 21, 2011, "On the Fundamentals of Health Protection of Citizens in the Russian Federation."

2. Order of the Russian Ministry of Health No. 203n dated April 14, 2025, "On Approval of Criteria for Assessing the Quality of Medical Care."

3. International Classification of Diseases, Injuries and Causes of Death, 10th Revision (ICD-10) (World Health Organization), 2019 version.

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

5. Order of the Russian Ministry of Health No. 222n dated April 17, 2025, "On Approval of the Procedure for Providing Medical Care in the Profile 'Neonatology'."

6. Decree of the Government of the Russian Federation No. 3867-r dated December 18, 2025 "On Approval of the List of Vital and Essential Medicines, as well as Lists of Medicines for Medical Use and the Minimum Assortment of Medicines Required for Medical Care".

7. Methodological Letter of the Russian Ministry of Health No. 15-4/I/2-2570 dated March 4, 2020, "Resuscitation and Stabilization of Newborn Infants in the Delivery Room." Edited by E.N. Baybarina. Moscow: Ministry of Health of the Russian Federation; 2020.

8. State Register of Medicines: https://grls.rosminzdrav.ru

Appendix A3.2 Formulas for calculating sodium deficit and correction of acidosis

The calculation of administered sodium (mmol) for the correction of hyponatremia is performed using the formula:

Sodium deficit (mmol) = 0.6 × body weight × (125 – (minus) plasma/serum sodium level).

To calculate the requirement of #sodium bicarbonate** for correcting metabolic acidosis in a newborn, the following formula is used:

M (mmol) = 0.3 × BW × BE,

where BE is base excess (mmol/L); BW is body weight (kg) [136,137].

1 ml of 5% sodium bicarbonate** solution contains 0.6 mmol of bicarbonate ions.

1 ml of 4.2% sodium bicarbonate** solution contains 0.5 mmol of bicarbonate ions.

1 ml of 8.4% sodium bicarbonate** solution contains 1 mmol of bicarbonate ions.

Appendix A3.3 Blood pressure (mm Hg) in term and preterm newborns after 14 days of life [146,200]

Appendix A3.4 Technique of renal replacement therapy

Peritoneal dialysis

A peritoneal catheter is placed into the abdominal cavity [58,170–173], after which peritoneal dialysis solution (ATX code B05D) is infused via a tubing system. While the peritoneal dialysis solution (ATX code B05D) remains in the abdominal cavity, an exchange takes place between the blood and the peritoneal dialysis solution (ATX code B05D). The main physicochemical mechanisms of this process are diffusion, ultrafiltration, and convection. After the required time (dwell time) elapses, the peritoneal dialysis solution (ATX code B05D) is drained by gravity into a collection bag, and the next fill is initiated immediately. The volume of the infused peritoneal dialysis solution (ATX code B05D) depends on the child's body weight. Most guidelines recommend starting with a volume of 10 ml/kg, gradually increasing it to 30–40 ml/kg over several days. The recommended dwell time ranges from 30 minutes to several hours, depending on the clinical situation and the characteristics of the infant's peritoneum (high or low transporter). Cases of continuous-flow peritoneal dialysis have also been described [174,175].

Advantages of PD: feasibility in infants of any body weight; simplicity of the procedure; no need for vascular access; no heparinization required; no significant impact on hemodynamics; lower procedure cost compared to other RRT modalities. This type of dialysis can be performed even in extremely low birth weight infants.

Disadvantages: low clearance, unpredictability, and lower ultrafiltration rate compared to CVVH or CVVHDF.

Complications of peritoneal dialysis in newborns:

- dialysate leakage around the catheter;

- dialysis-related peritonitis;

- catheter exit-site infection;

- dialysate leakage into the subcutaneous fat layer or hernia sacs;

- development of hyperglycemia;

- hypothermia due to inadequate warming of the dialysate solution;

- hypovolemia.

CVVHD (continuous venovenous hemodialysis) or CVVHDF (continuous venovenous hemodiafiltration)

Performing CVVHD or CVVHDF requires vascular access, which can be challenging in small infants.

During the procedure, the patient's blood is pumped via a roller pump through a silicone tubing system, passes through the dialyzer, and returns to the bloodstream. In clinical practice in Russia, hemodialysis and hemofiltration machines are currently used for RRT.

Advantages: high procedure efficiency; no significant impact on hemodynamics; no need for a water treatment system unlike conventional hemodialysis;

Disadvantages: need for central vascular access; use of heparin group drugs (ATX code B01AB); high cost. Technical impossibility of performing these procedures in low-weight newborns.

Contraindications: hemostatic disorders (active bleeding, hemorrhages); inability to establish central vascular access.

Complications: coagulation disorders leading to bleeding of various locations with the development of post-hemorrhagic anemia, or thrombosis of CVVHD or CVVHDF circuits during the procedure;

in the absence of adequate warming, the extracorporeal circuit cools the blood and the child's body, which can lead to hypothermia; if blood flows, replacement fluid, and hemodialysis/hemofiltration solutions (ATX code B05Z) are incorrectly set, disequilibrium syndrome may develop due to a rapid drop in urea levels [168,180,181].

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Acute kidney injury (AKI) is a formidable, life-threatening condition with a high mortality rate. It can occur as a result of prior asphyxia, severe neonatal infection, renal vascular thrombosis, decreased blood pressure, and uncontrolled use of nephrotoxic drugs. A separate cause of acute renal injury and congenital renal failure can be malformations of the urinary system, such as hypoplasia, dysplasia, renal agenesis, polycystic kidney disease, hydronephrosis, as well as impaired urine outflow due to urinary tract malformations (ureteral strictures, urethral strictures, etc.). Clinically, AKI manifests as progressive edema, unstable blood pressure, decreased urine output, and the accumulation of nitrogen in the blood that is not excreted by the damaged kidneys. With worsening edema syndrome, blood electrolyte disturbances occur, leading to cardiac dysfunction. Pronounced edema syndrome can spread to internal organs, causing pulmonary and cerebral edema, which can be fatal. Treatment of acute kidney injury primarily involves correction of infusion therapy, discontinuation of nephrotoxic drugs, therapy aimed at improving renal blood flow, stabilization of blood pressure, and, in certain cases, the prescription of diuretics. In congenital renal failure caused by malformations, the child may receive surgical care. When conservative therapy is ineffective, the only life-saving method is renal replacement therapy. There are several methods of renal replacement therapy: peritoneal dialysis, continuous or prolonged venovenous hemodialysis, or venovenous hemofiltration. Renal replacement therapy is performed depending on the capabilities of the hospital where the newborn is located. Peritoneal dialysis is most commonly used due to the possibility of performing it in newborns of any body weight. The main contraindication to peritoneal dialysis is peritonitis requiring emergency surgical care. The method of peritoneal dialysis involves placing two drains into the abdominal cavity of the child and introducing special dialysis solutions through one drain to remove excess nitrogen from the blood, while the used dialysis fluid is drained through the second drain into a special reservoir. This procedure is performed several times a day until edema begins to subside and intrinsic renal function begins to recover. After recovering from AKI, the child requires long-term follow-up by a nephrologist due to the high risk of developing chronic kidney disease progressing to end-stage renal disease and the need for chronic dialysis and transplantation."

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

Appendix G1. Apgar score assessment in newborns 1

Russian name: Assessment of the newborn using the Apgar score.

Original name: The Apgar Score.

Source (official developer website, validation publication):

Apgar V, Holaday DA, James LS, Weisbrot IM, Berrien C. Evaluation of the newborn infant-second report. JAMA. 1958; 168 (15): 1985–1988.[201].

Type: rating scale.

Purpose: assessment of the newborn's condition at birth.

Content (template):

¹ Methodological letter "Resuscitation and stabilization of newborns in the delivery room". Ed. Baybarina E.N. Moscow: Ministry of Health of the Russian Federation; 2020.

Key (interpretation) of the Apgar score.

A score of 4–7 points at 1 min after birth corresponds to mild-to-moderate birth asphyxia (P21.1), and 0–3 points at 1 min after birth corresponds to severe asphyxia (P21.0). Although according to ICD-10 a total of 7 points at 1 min after birth corresponds to moderate-to-severe asphyxia, it is inappropriate to assign this diagnosis, since an Apgar score of 7 points by the end of the 1st minute is not clinically and/or prognostically significant.