Glomerular diseases: immunoglobulin A nephropathy: clinical guidelines

List of Abbreviations

ARB – angiotensin-II receptor blockers (ATC classification: "Angiotensin II receptor blockers")

CI – confidence interval

RRT – renal replacement therapy

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

IC – immune complexes

IST – immunosuppressive therapy

MA – meta-analysis

ICD – International Classification of Diseases

AKI – acute kidney injury

WG – working group

РКИ – randomized controlled trial

GFR – glomerular filtration rate

eGFR – estimated glomerular filtration rate

ESRD – end-stage renal disease

CKD – chronic kidney disease

Gd-IgA – galactose-deficient immunoglobulin A1

IgA – immunoglobulin A

IgA1 – immunoglobulin A1

IgAN – immunoglobulin A nephropathy

IgG – immunoglobulin G

IgM – immunoglobulin M

MHC – major histocompatibility complex

Terms and Definitions

Rapidly progressive nephritic syndrome – a decrease in estimated glomerular filtration rate by ≥50% within 3 months or less in the presence of persistent proteinuria, hematuria, and active/necrotizing glomerular inflammation, with the exclusion of other causes of organ dysfunction development/progression.

Immunoglobulin A nephropathy – a chronic glomerular disease associated with inflammatory glomerular injury mediated by the deposition of immune complexes containing aberrant secretory immunoglobulin A, leading to irreversible fibroplastic changes in the organ.

Nephritic syndrome – a symptom complex characterized by urinary sediment abnormalities (hematuria and/or cylindruria) combined with moderate proteinuria (<3.5 g/day/1.73 m²) and extrarenal symptoms – edema (nephritic), arterial hypertension, renal dysfunction; its course may be acute, chronic, or subacute (rapidly progressive).

Nephrotic syndrome – a symptom complex caused by impairment of the glomerular basement membrane with the development of massive (nephrotic) proteinuria, the criteria for which are: proteinuria >3.5 g/day/1.73 m², hypoalbuminemia (blood albumin <30 g/L).

Glomerular filtration rate – the volume of blood plasma filtered in all renal glomeruli per minute; the glomerular filtration rate is expressed in mL/min, determined by renal plasma flow, filtration pressure, and filtration surface area, depends on the mass of functioning nephrons, is used as an integral indicator of the functional state of the kidneys, and is standardized to body surface area.

End-stage renal disease – a pathological condition characterized by a glomerular filtration rate of less than 15 mL/min/1.73 m², which corresponds to stage 5 chronic kidney disease.

Chronic kidney disease – organ damage persisting for three months or more due to various etiological factors, anatomically based on the replacement of normal anatomical structures with fibrosis, leading to organ dysfunction.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Immunoglobulin A nephropathy (IgAN) – a chronic glomerular disease associated with inflammatory glomerular injury mediated by the deposition of immune complexes containing aberrant secretory immunoglobulin A (IgA) and leading to irreversible fibroplastic changes in the organ [1,2].

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

IgAN is the most common immune glomerulopathy worldwide [3], which pathogenetically represents renal injury resulting from altered mucosal immune responses. A key event in the disease development is a minor molecular alteration in the hinge region of secretory immunoglobulin A1 (IgA1), manifesting as defective O-glycan galactosylation [4,5], which alters the molecular conformation and confers autoantigen properties [6]. A prerequisite for the hyperproduction of galactose-deficient IgA1 (Gd-IgA1) is the activation of mucosal immune responses and impaired secretory processes [7,8]. An increase in the circulating Gd-IgA1 pool leads to the formation of immune complexes (IC) based on IgG, IgA (immunoglobulin G and A, respectively) or IgM (immunoglobulin M) autoantibodies against Gd-IgA1, CD89 (FcαRI), and complement [9,10]. Due to their large molecular radius, Gd-IgA1-containing ICs cannot undergo natural clearance by hepatocytes [11]. As a result of Gd-IgA1 accumulation in the circulation, IgA-containing ICs are deposited in the mesangium and interact with CD71 (transferrin receptor), which induces mesangial cell proliferation followed by activation of the complement system, immune cells, and other resident cell populations, leading to organ damage and the formation of the typical morphological pattern of the disease [12,13]. Similar changes have been identified in children with IgAN or IgA vasculitis (Henoch-Schönlein purpura) and nephritis [100]. The prevalence, clinical and morphological manifestations, and prognosis of IgAN show significant geographical and racial variations [14-18]. Long-term clinical observations of IgAN cases suggest that the disease in the Russian population may have substantial features in terms of prevalence, clinical and morphological manifestations, and prognosis [19].

Although IgAN is considered a sporadic disease, rare familial cases have been described in the United States (eastern Kentucky) as well as in other regions. It is highly probable that IgAN is a genetically heterogeneous disease involving both major histocompatibility complex (MHC) defects and non-MHC alleles [101].

1.3 Epidemiology of the Disease or Condition

The prevalence of glomerular and interstitial renal diseases in Russia is approximately 1,500 cases per 100,000 population [20]. Separate official statistics and population-based studies on the prevalence, incidence, and mortality of glomerular diseases, including IgAN, are lacking. It is estimated that the proportion of immune glomerulopathies, which includes IgAN, among all glomerular and interstitial kidney diseases is 20-30%, with a prevalence of 300-450 per 100,000.

An analysis of population-based studies conducted using data from national European registries for the period from 1990 to 2020 showed that the overall incidence of IgAN ranges from 0.34 to 1.93 per 100,000 population. Among children and the elderly, the disease is recorded even less frequently: 0.2 and 0.3 cases per 100,000 of the respective population [102]. According to Japanese researchers, the incidence of IgAN is 4.5 cases per 100,000 children under 15 years old per year [103]. It should be noted that differences in disease prevalence may reflect regional approaches to kidney disease screening and indications for renal biopsy, including across different age populations.

The prevalence, clinical and morphological manifestations, and prognosis of IgAN show significant geographical and racial variations [14-18]. In Russia, IgAN in adults is detected in 41.5% of primary immune glomerulopathies, with an expected prevalence of 100-200 cases per 100,000. Available data [19] indicate that IgAN in Russia, as in other regions of the world, is the most frequent variant of immune glomerulopathies and the most common pathology identified during detailed clinical and morphological diagnostics, with a clear trend toward an increasing proportion of newly diagnosed disease cases, which has increased significantly within the study periods, reaching 41.5% among primary immune glomerulopathies and accounting for nearly every fourth case among renal biopsies performed for all indications. By this indicator, Russia significantly outpaces most countries in Asia, Europe, and America [3,18,21,22].

The obtained data allow us to draw preliminary conclusions about the potential incidence of IgAN. Taking into account that over the past five years, the Research Institute of Nephrology has annually detected about 45 cases of IgAN in residents of St. Petersburg, the incidence may be 8–10 cases per million population, which is comparable to European data [3,19]. At the same time, this estimate may be significantly underestimated, since far from all cases with characteristic manifestations of the disease undergo the necessary clinical and morphological diagnostics. This is evidenced by the duration of the period of persistence of IgAN symptoms before diagnosis establishment, the median of which was 41 months [19]. Based on our experience, the main explanations are the insufficient awareness of practicing nephrologists regarding this problem, and as a consequence, low activity in screening and detecting suspected cases, and persistence in confirming the diagnosis. A significant limitation in the management of patients with IgAN in domestic nephrology is also the widespread and unacceptable practice of empirical syndromic treatment and the low proportion of glomerulopathy cases undergoing clinical and morphological diagnostics due to the lack of appropriate resources. Given the high probability of significant regional differences in prevalence and incidence, the epidemiology of IgAN in Russia should become the subject of separate multicenter population-based studies. Such data can be critical for planning the development of modern nephrology within the framework of preventive approaches.

In Russia, epidemiological studies in children have not been conducted due to the low availability of clinical and morphological diagnostics in the regions.

Despite the relatively low prevalence, immune glomerulopathies in Russia are the most frequent cause of end-stage renal disease (ESRD) and the need for costly renal replacement therapy (RRT) using dialysis and kidney transplantation [23], consuming a significant share of the healthcare budget. Insufficient control of the autoimmune inflammatory process in the kidney is the main factor of progressive fibroplastic changes and loss of organ function.

1.4 Features of Coding the Disease or Condition

Given the variety of clinical and morphological manifestations of IgAN, its coding according to the International Classification of Diseases (ICD-10) should employ combinations of appropriate codes reflecting clinical syndromes and histology. Three-character categories (N00, N01, N02, N03, N04, N06) are based on clinical syndromes. They should be used with fourth characters classifying morphological changes (subcategories .1, .3, .4, .7, .8). The latter are indicated after a dot following the clinical syndrome code (e.g., N02.3). Subcategories should not be used if special studies (e.g., kidney biopsy or autopsy) have not been performed to identify lesions (Table 1).

Table 1. ICD-10 coding of IgAN

Cases of IgAN with Henoch-Schönlein purpura should be coded as N08.2 (Glomerular disorders in diseases classified elsewhere).

IgAN is, by definition, a chronic kidney damage, therefore all cases of this disease must be classified in accordance with the chronic kidney disease (CKD) guidelines [24,104].

To designate CKD stages, codes N18.1-N18.5 should be used (Table 2), and the glomerular filtration rate (GFR) must be calculated using the CKD-EPI formula in special calculators based on serum creatinine concentration, patient's sex, age, and race ("Appendix G1") [25,26].

Table 2. Classification of CKD stages by GFR level and correspondence to ICD-10 coding

Note: * – code N18.9 designates cases of CKD with unspecified stage.

1.5 Classification of the disease or condition

The classification of IgAN is based on assessing the severity of histological glomerular changes [27,28]: mesangial proliferation (M0 – in no more than 50% of glomeruli, M1 – 50% or more; more than three cells in the mesangial area), endocapillary proliferation (E0 – absent, E1 – indicates presence), segmental sclerosis or adhesion of capillary loops to the glomerular capsule (0 – no, S1 – indicates presence), tubular atrophy/interstitial fibrosis (T0 – less than 25% of the cortical zone, T1 – 26-50% of the cortical zone, T2 – more than 50% of the cortical zone; cellular or fibrocellular crescents (C0 – none, C1 – less than 25% of glomeruli, C2 – 25% or more of glomeruli).

1.6 Clinical presentation of the disease or condition

The main signs suggesting the presence of IgAN are presented in Table 3.

Table 3. Main signs suggesting the presence of IgAN

Clinical presentation at the time of diagnosis verification

IgAN predominates in young individuals of both sexes and is characterized by typical clinical manifestations of glomerular damage and progressive renal dysfunction. In most cases, it debuts with laboratory urine changes (proteinuria and microhematuria), chronic nephritic syndrome, and/or an episode of gross hematuria. Most patients at the time of kidney biopsy have significant erythrocyturia and proteinuria. The latter exceeds the nephrotic level in a third of cases, and the development of nephrotic syndrome is observed in every tenth case.

Disease progression is generally slow, but in Russia, the course of IgAN may be less favorable compared to other regions of the world [19]. A distinctive feature of the Russian population of patients with IgAN compared to cohorts from other regions of the world was a significantly more pronounced proteinuria, lower estimated GFR (eGFR) values, as well as the prevalence of renal dysfunction and hypertension. In the studied cohort, histological changes associated with active proliferative reactions were also more pronounced compared to European data. Immunomorphological features of IgAN in Russia were: IgA deposits in the glomerular capillary wall, detected in every sixth case, which may reflect the course of more severe forms of the disease with the formation of a membranoproliferative pattern and worsening prognosis; significant prevalence of extraglomerular changes; substantial detection frequency of interstitial inflammatory infiltration and peritubular capillary inflammation, closely associated with the main clinical manifestations – arterial hypertension, renal dysfunction, proteinuria, and hematuria. Peritubular capillaritis was identified as an independent factor associated with the risk of disease progression [19].

In general, renal survival in the Russian population is significantly lower than in Asian regions and compared to the European population due to significantly more pronounced histological changes associated with active proliferative reactions, which suggests a less favorable disease course and probably requires more aggressive therapy.

In a significant proportion of cases, clinical signs of mucosal immune activation were identified—chronic inflammatory diseases of the gastrointestinal tract, upper respiratory tract, including tonsillitis. Lower urinary tract and genital tract infections were less common.

In children with IgAN, gross hematuria is more common than in adults, recurring against the background of respiratory infections—"synpharyngitic" gross hematuria [105-107].

Unlike adults, who usually experience a linear decline in eGFR, children show an initial increase in eGFR that can last for up to several years, followed by the same linear decline as in adult patients [108].

Risk of IgAN progression

To calculate the risk of IgAN progression (a 50% decrease in eGFR or the development of ESRD), a calculator has been developed that includes a number of clinical parameters at the time of biopsy, as well as histological examination results ("Appendix G2") [29].

2. Diagnostics, medical indications and contraindications for diagnostic methods

General approaches to the diagnosis of IgAN (see Appendix B, cl. 1)

The diagnosis of IgAN should include two main directions for choosing the necessary treatment: 1) identifying specific immunological alterations and assessing their severity; 2) determining whether the disease is primary or secondary; and 3) identifying and assessing the severity of acute and/or chronic renal dysfunction. The basis of the first direction is a morphological study of the kidneys, without which a diagnosis of IgAN cannot be established. The second direction involves searching for extrarenal pathological processes that may be the cause of secondary IgAN, which differs in prognosis and therapeutic approaches. A diagnosis of primary IgAN should be established when causes of secondary variants of the disease are excluded (Table 4). The third direction is detailed in the relevant guidelines on acute kidney injury (AKI) and CKD, links to which will be provided below where necessary.

The diagnostic search tactics in pediatric patients with suspected IgAN and adults generally do not differ [111,112]. The features of IgAN diagnosis in children are given in the relevant subsections and in Appendix A3, cl. 2, 3.

• In patients with morphologically confirmed IgAN, we recommend performing clinical diagnostics in accordance with current guidelines and standards to identify extrarenal pathology that may be the cause of secondary IgAN (Table 4) and to determine the scope of necessary treatment [1,2,30].

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

Comments: In patients with known or suspected IgAN, we recommend standard diagnostic methods to detect chronic inflammatory processes within the mucosa and other pathological processes that may be causes of secondary forms of the disease (Table 4) [31].

Table 4. Main causes of secondary IgAN requiring diagnostic evaluation

Other causes of secondary IgAN may include: biliary atresia, disseminated tuberculosis, alpha-1 antitrypsin deficiency; cases of IgAN combined with Fabry disease have also been described [109,110].

• We recommend that nephrologists establish a diagnosis of primary IgAN after excluding all probable causes of secondary variants of the disease to assess the prognosis and subsequently select therapy [1,2,31].

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

• In patients with known or suspected IgAN, we recommend referring the patient for an appointment (examination, consultation) with an otolaryngologist to diagnose tonsil inflammation and determine the scope of necessary treatment, including tonsillectomy [32,33].

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

Comments: Tonsillectomy may be an effective therapeutic approach in IgAN (see section 3.2).

For the earliest possible detection of IgAN, we recommend that physicians of all specialties refer patients with persistent proteinuria and/or persistent hematuria and/or recurrent gross hematuria to a nephrologist for specialized nephrological diagnostics [24].

GRS CLOE 5Grade of Recommendation Strength C (Level of Evidence – 5)

Comments: The recommendation reflects standard approaches to the routing of patients with suspected IgAN and other immune glomerulopathies, which are a specific variant of CKD and generally require specialized medical care.

• We recommend that children with suspected IgAN undergo a family history review (to exclude hereditary diseases, e.g., Alport syndrome) and a history of the disease regarding renal and systemic manifestations, a detailed physical examination, confirmatory diagnostics, and differential diagnostics with diseases that may present with secondary IgAN [112].

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

Comments: the list of examinations is provided in Appendix A3, cl. 2 and 3.

IgA vasculitis and IgAN secondary to liver disease, viral illness, and inflammatory bowel disease, as well as systemic autoimmune diseases (or as part of them) and post-infectious glomerulonephritis, should be ruled out first before diagnosing primary IgAN [111].

When diagnosing primary IgAN (including ultrasound-guided renal biopsy followed by pathomorphological examination of the renal biopsy/surgical material), one should focus on the presence of hematuria (macroscopic and/or microscopic) persisting for 2-3 weeks in at least two urine samples with an interval of 1-2 weeks, while excluding other renal and urinary tract pathologies as the source of these changes (hypercalciuria, hypocitraturia, kidney stones and lower urinary tract stones, infections) with proteinuria (urine albumin/creatinine ratio ≥0.2 mg/mg or 20 mg/mmol) or signs of a systemic disease, with a normal serum C3 complement fraction level; this diagnosis should also be kept in mind in cases of persistent (>2-3 weeks) or recurrent (>2-3 times) gross hematuria occurring during an upper respiratory tract infection [112].

2.1 Complaints and Anamnesis

Clinical data obtained from the analysis of complaints and anamnesis that indicate the likely presence of IgAN are given in section 1.6.

2.2 Physical Examination

Physical examination data indicating the likely presence of IgAN are given in section 1.6.

2.3 Laboratory Diagnostics

2.3.1 Laboratory diagnostic tests in adult patients with IgAN

• To assess the severity of renal dysfunction, prognosis, and determine the scope of non-immunosuppressive therapy in patients with suspected IgAN, we recommend performing basic laboratory diagnostics provided for by CKD guidelines [24].

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

Comments: The clinical guidelines "Chronic Kidney Disease (CKD)" detail the approaches to diagnosing the presence and severity of renal dysfunction, which are fully applicable to patients with IgAN.

• To assess prognosis and select therapy in patients with IgAN during initial diagnosis, we recommend determining the 24-hour urine protein and performing microscopic examination of the urinary sediment [34,35,36].

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

• To assess prognosis and treatment efficacy in patients with IgAN, we recommend regular determination of 24-hour urine protein and microscopic examination of the urinary sediment at least twice a year [34,35,36].

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

Comments: According to a meta-analysis (MA) of randomized controlled trials (RCTs), mean 24-hour urine protein levels and their dynamics during treatment are reliable predictors of adverse outcomes in IgAN, regardless of the treatment administered. After initiating treatment, the 24-hour urine protein level should be determined at least every 2 months for the first 6 months, and subsequently twice a year. The frequency of examinations should be determined based on the CKD stage and the albuminuria/proteinuria grade. An alternative to determining the 24-hour urine protein level is measuring urinary albumin and urinary creatinine to calculate the albumin-to-creatinine ratio [24].

• In patients with suspected or established IgAN, for differential diagnosis purposes, we recommend that any urinalysis for hematuria include the identification of dysmorphic (altered) cells and red blood cell casts as part of the microscopic examination of the urine sediment [37].

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

Comments: Gross or microhematuria is directly related to the pathogenesis of IgAN, reflecting the severity of the inflammatory response in the glomeruli and interstitium, and is critical for assessing IgAN activity, its dynamics during therapy, and treatment selection. Dipstick testing can determine the presence or absence of microhematuria; however, microscopic identification of dysmorphic (altered) cells and red blood cell casts is essential for the differential diagnosis of hematuria. It should be noted that the morphological evaluation of hematuria is sensitive to the time elapsed between urine collection and analysis (requires a "fresh" sample), as well as to urine concentration, urine pH, sediment preparation, and the investigator's experience. In the cited MA, the mean values and 95% confidence intervals (CI) of sensitivity and specificity for the proportion of dysmorphic (altered) cells and red blood cell casts in glomerular pathology were 0.88 (0.86–0.90) and 0.95 (0.93–0.97), respectively, compared with the reference (kidney biopsy).

• In patients with morphologically confirmed IgAN, we recommend testing serum levels of complement component C3, complement component C4, and immunoglobulin A to assess the activity of the pathological process and the prognosis [38–42].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

2.3.2 Laboratory diagnostic tests in pediatric patients with IgAN

• For the diagnosis of IgAN in children, we recommend diagnostic laboratory tests similar to those for adult patients [104,111].

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

Comments: diagnostic interventions, including those for follow-up monitoring, do not conceptually differ in scope and content between adults and children.

Further details on the required tests for diagnosis and follow-up monitoring, as well as the list of nosologies and examinations for differential diagnosis in children with clinical signs of IgAN and an established diagnosis of IgAN, are provided in Appendix A3, sections 2 and 3.

GFR in children should be calculated using the Schwartz formula and its modifications (for details, see the clinical guidelines "Chronic Kidney Disease (age category: children)") [104].

2.4 Instrumental Diagnostics

2.4.1 Instrumental diagnostic tests in adult patients with IgAN

• In patients with suspected or confirmed IgAN, we recommend instrumental diagnostics to the extent provided by the CKD guidelines to assess the severity of structural changes in the kidneys and other organs and systems whose involvement is associated with decreased renal function and the risk of other adverse events [24].

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

2.4.2 Instrumental diagnostic tests in pediatric patients with IgAN

For the diagnosis of IgAN in children, we recommend instrumental diagnostic tests similar to those for adult patients [104,111,112].

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

Comments: diagnostic interventions, including those for follow-up monitoring, do not conceptually differ in scope and content between adults and children.

It should be noted that, overall, there are fewer clinical studies involving pediatric patients with IgAN than adults.

Further details on the required tests for diagnosis and follow-up monitoring, as well as the list of nosologies and examinations for differential diagnosis in children with clinical signs of IgAN and an established diagnosis of IgAN, are provided in Appendix A3, sections 2 and 3.

2.5 Other Procedures

2.5.1 Other diagnostic tests in adult patients with IgAN

• In patients with suspected IgAN in the absence of contraindications, we recommend ultrasound-guided renal biopsy followed by pathological examination of the renal biopsy (surgical) material to confirm the diagnosis, assess the severity of renal injury and prognosis, and select therapy [43,44].

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

• In cases of established IgAN where there is a need to revise the diagnosis and/or clarify the severity of histological changes and/or prognosis to decide on selecting or modifying therapy, we recommend, in the absence of contraindications, considering a repeat ultrasound-guided renal biopsy followed by pathological examination of the renal biopsy (surgical) material [45–48].

GCR BLEL 3Grade of Recommendation B (Level of Evidence – 3)

• In patients with suspected IgAN, we recommend that immunohistochemical methods be used during the pathological examination of the renal biopsy (surgical) material to determine glomerular deposits of IgA, IgM, IgG, complement fractions (C3, C1q), and Ig light chains (kappa, lambda) for use in diagnosis and disease prognostication [49–54].

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

• To standardize the diagnosis of IgAN, we recommend considering dominant or co-dominant glomerular IgA deposits as a reliable criterion for this diagnosis in all clinical cases [49,55].

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

• To assess prognosis and select therapy, we recommend that in patients diagnosed with IgAN, the pathological examination of the renal biopsy (surgical) material identifies and includes in the report at least the following classification criteria: severity of mesangial proliferation; severity of endocapillary hypercellularity; presence of segmental glomerulosclerosis or adhesion of capillary loops to the glomerular capsule; severity of tubular atrophy/interstitial fibrosis; presence of cellular, fibrous, or fibrocellular crescents (Table 5) [43,44].

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

Comments: The Oxford classification of IgAN, which should be used to describe the results of the pathological examination of the renal biopsy (surgical) material, is presented in Table 5.

Table 5. Oxford classification of IgAN

• In patients with primary IgAN, to assess the risk of progression and make treatment decisions, along with 24-hour proteinuria and the results of the pathological examination of the renal biopsy (surgical) material, we recommend using a dedicated risk calculator (see Appendix G2) [29].

GCR BLEL 3Grade of Recommendation B (Level of Evidence – 3)

Comments: When the calculated risk of progression over 5 years is >11%, the risk should be considered high, alongside proteinuria >1 g/day combined with hematuria and histological signs of active inflammation (M1, E1, C1–2 (see Table 5)). In such cases, immunosuppressive therapy is generally justified to improve the prognosis.

2.5.2 Other diagnostic tests in pediatric patients with IgAN

• For the diagnosis of IgAN in children, we recommend performing other diagnostic tests similarly to adult patients [104,111,112].

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

Comments: diagnostic interventions, including those for follow-up monitoring, do not conceptually differ in scope and content between adults and children.

It should be noted that, overall, there are fewer clinical studies involving pediatric patients with IgAN than adults.

Further details on the required tests for diagnosis and follow-up monitoring, as well as the list of nosologies and examinations for differential diagnosis in children with clinical signs of IgAN and an established diagnosis of IgAN, are provided in Appendix A3, sections 2 and 3.

• We recommend performing an ultrasound-guided renal biopsy followed by pathological examination of the renal biopsy material in children with suspected IgAN (acute nephritic syndrome alone or with proteinuria/nephrotic syndrome) after ruling out acute post-infectious GN [112].

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

Comments: the goal is to prevent unjustified invasive examinations in children.

Acute poststreptococcal glomerulonephritis is characterized by acute nephritic syndrome, a low serum C3 level, an elevated antistreptolysin-O titer, and the isolation of beta-hemolytic streptococcus from the throat or skin in streptoderma (for further details on testing, see Appendix A3, section 3).

• We recommend performing an ultrasound-guided renal biopsy followed by pathomorphological examination of the renal biopsy (surgical) material to confirm the diagnosis of IgAN, assess the nature and severity of renal parenchyma damage and prognosis, as well as select therapy according to the following indications: (1) immediately in children with persistent (>2-3 weeks) or recurrent hematuria and nephrotic-range proteinuria (urine albumin-to-creatinine ratio >2 mg/mg or 200 mg/mmol) and/or reduced GFR (<90 mL/min/1.73 m²); (2) on an elective basis in children with persistent (>2-3 weeks) or recurrent hematuria and a urine albumin-to-creatinine ratio >0.5 mg/mg (50 mg/mmol) in at least two urine samples taken 1-2 weeks apart; (3) on an elective basis in children with persistent (>2-3 weeks) or recurrent hematuria and a urine albumin-to-creatinine ratio of 0.2 to 0.5 mg/mg (20-50 mg/mmol) in at least three urine samples taken 1-2 weeks apart [112].

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

• We recommend evaluating the severity of morphological changes using the MEST-C criteria (Oxford classification of IgAN – see section 2.5, table 5) when predominant IgA deposits are detected in the renal biopsy of a child with nephritic syndrome, in order to plan the optimal therapeutic regimen [112].

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

• In children with suspected IgAN and a positive family history of hematuria and CKD, or in children diagnosed with IgAN who do not respond to adequate treatment, we recommend an initial consultation with a medical geneticist and molecular genetic testing for differential diagnosis purposes (including mandatory screening for mutations determining type IV collagen pathology) [112].

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

Comments: diagnostic interventions, including those for follow-up monitoring, do not conceptually differ in scope and content between adults and children.

It should be noted that, overall, there are fewer clinical studies involving pediatric patients with IgAN than adults.

Further details on the required tests for diagnosis and follow-up monitoring, as well as the list of nosologies and examinations for differential diagnosis in children with clinical signs of IgAN and an established diagnosis of IgAN, are provided in Appendix A3, sections 2 and 3.

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

3.1 General approaches to the treatment of IgAN in adults

• In patients diagnosed with IgAN, we recommend administering non-immunosuppressive renoprotective therapy as indicated and to the extent provided by CKD guidelines, in order to reduce proteinuria and the rate of disease progression, as well as to prevent and treat complications of renal dysfunction [24].

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

• In patients diagnosed with secondary IgAN, we recommend providing therapy for the pathology associated with renal involvement as indicated and to the extent provided by the relevant clinical guidelines, with the involvement of necessary specialists on an interdisciplinary basis to induce remission and reduce the rate of disease progression [1,2].

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

Comments: see Table 4.

• In patients with IgAN and proteinuria >0.5 g/day, we recommend treatment with angiotensin-converting enzyme inhibitors (ACE inhibitors) or angiotensin II receptor blockers (ARBs) to reduce proteinuria and the rate of disease progression [56-58].

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

• In patients with primary IgAN and proteinuria >1 g/day (despite ongoing and adequate non-immunosuppressive renoprotective therapy) in the absence of rapidly progressive nephritic syndrome and contraindications, we recommend considering treatment with #hydroxychloroquine** to reduce proteinuria and induce disease remission [59,60,150].

GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)

Comments: #Hydroxychloroquine** should be prescribed for 6 months in the following regimens: 200 mg orally twice daily for eGFR >60 mL/min/1.73 m², 100 mg orally 3 times daily for patients with eGFR from 45 to 60 mL/min/1.73 m² and 100 mg orally twice daily for patients with eGFR from 30 to 45 mL/min/1.73 m²[59,60,150,151,152]. The drug dose should be reduced to 100 mg daily for patients with an eGFR decrease of >25% or to <30 mL/min/1.73 m².

Apart from skin pigmentation, no significant increase in the risk of other adverse effects of the drug was identified in the recent MA, which does not override the need for an individualized approach to assessing potential adverse effects, including ophthalmological ones [61].

• In patients with primary IgAN, we recommend treating clinically significant infectious and/or autoimmune mucosal inflammation of any localization to reduce the activity of the pathological process in the glomeruli and induce disease remission [62-65].

GCR BLEL 3Grade of Recommendation B (Level of Evidence – 3)

Comments: IgAN is most frequently associated with chronic recurrent or progressive inflammation of the respiratory and gastrointestinal mucosa [66] (see Table 4). Impaired mucosal permeability upon exposure to microbes and/or allergens is a factor in the activation of the local immune system and increased production of pathological IgA1 [67-69]. Based on these concepts, we hypothesize that the identification and adequate control of mucosal inflammation may positively affect the course of IgAN and reduce the risk of infectious complications during glucocorticoid therapy (see also Section 3.3, recommendations on tonsillectomy).

3.2 General approaches to the treatment of IgAN in children

In children with IgAN and minimal changes (according to ultrasound-guided renal biopsy followed by pathomorphological examination of the renal biopsy/surgical specimen), spontaneous remission is possible in more than 50% of cases [113].

At the same time, children should continue to undergo regular dynamic status assessments (see Appendix A3, cl. 2), as a relapse may develop (the risk of relapse may change over time).

Treatment goals: to achieve remission or reduce disease activity to a degree that minimizes further renal damage. It should be noted that mild hematuria (microhematuria) may persist throughout life without leading to disease progression. Factors contributing to the progression of renal injury and, accordingly, the deterioration of renal function are proteinuria and arterial hypertension.

Target proteinuria: absent or ≤200 mg/day (≤400 mg/1.73 m²/day) or urine protein-to-creatinine ratio ≤200 mg/g (≤0.2 g/g [≤20 mg/mmol]).

Target systolic blood pressure is <90th percentile for age, sex, and height (in accordance with clinical guidelines for chronic kidney disease in children and arterial hypertension in children).

• In children with IgAN and proteinuria >0.2 g/day (or albumin-to-creatinine ratio 200 mg/g [0.2 mg/mg or 20 mg/mmol]), we recommend dietary optimization with the participation (consultation) of a clinical dietitian (if possible) and restriction of dietary sodium intake to below 3–5 g per day, in order to reduce renin-angiotensin system activation and blood pressure levels [112].

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

• We recommend that children with IgAN regularly perform therapeutic exercise for kidney and urinary tract diseases to maintain an optimal body weight [112].

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

Comments: Patients should also adhere to a healthy lifestyle, including smoking cessation.

• In children with IgAN and proteinuria >0.2 g/day (or albumin-to-creatinine ratio 200 mg/g [0.2 mg/mg or 20 mg/mmol]), we recommend treatment with ACE inhibitors or ARBs at the maximum tolerated doses to reduce proteinuria and the rate of disease progression [111,114–118].

GCR BLEL 3Grade of Recommendation B (Level of Evidence – 3)

Comments: There is compelling evidence demonstrating the benefits of renin-angiotensin system blockade in children. Doses of ACE inhibitors or ARBs are selected individually.

For example: #Enalapril** – children and adolescents: starting dose: 0.2 mg/kg/day; titrate to response at intervals of 4 to 12 weeks until the effect is achieved (on average, dose range: 0.2 to 0.6 mg/kg/day; maximum daily dose: 20 mg/day); a cross-comparison dose study showed that the effects on proteinuria are dose-dependent [119,149], or #losartan** – in children at a mean dose of 0.8 mg/kg/day, for an average of up to 2.8 years [115], or #losartan** – in children aged 6–9 years at a starting dose of 0.7 mg/kg once daily, with a gradual increase after 2 and 4 weeks—provided proteinuria persists and no adverse events occur—up to a maximum of 1.5 mg/kg/day or 100 mg/kg/day [sic: 100 mg/day]; in children under 6 years of age, doses of 0.1–0.7 mg/kg/day up to 1.4 mg/kg may be used [116], or #lisinopril** – in children aged 4–15 years at an initial single daily dose of 0.1–0.2 mg/kg body weight (maximum 10 mg/day) daily, and after the absence of adverse events for 1 week, an increase to a single daily dose of 0.4 mg/kg (maximum 20 mg/day) for a course of 24 months [117,118].

Dose adjustment for co-prescribed medications: potential significant drug interactions requiring dose/frequency adjustment or absolute contraindication of the medicinal product should be assessed in accordance with drug interaction databases for additional information. For example, concurrent administration of ACE inhibitors and ARBs should be avoided, and caution should be exercised with concurrent administration of ACE inhibitors and calcineurin inhibitors due to a higher risk of hyperkalemia and nephrotoxicity [116].

Blood pressure should be monitored (measurement of blood pressure on peripheral arteries).

In cases of nephrotic-range proteinuria, ACE inhibitors or ARBs are prescribed in combination with immunosuppressive therapy (see section 3.4).

When nephrotic syndrome develops in IgAN, children in general should be managed according to the relevant recommendations based on morphological changes from ultrasound-guided renal biopsy followed by pathomorphological examination of the renal biopsy (surgical) material [120,121].

3.3 Immunosuppressive and supportive therapy in adult patients with IgAN

• In patients with primary IgAN without rapidly progressive nephritic syndrome, but with initially high risks of progression based on clinical and/or histological signs of inflammation (persistent proteinuria >1 g/day combined with hematuria, a 50% decrease in eGFR or ESKD probability >11%, M1, E1, C1-2), or with persistent proteinuria >1 g/day combined with hematuria despite adequate non-immunosuppressive renoprotective therapy for 3 months, we recommend corticosteroid treatment to induce disease remission and reduce the rate of its progression [70,71-75].

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

Comments: Prednisolone** should be administered orally at a dose of 0.4-0.6 mg/kg body weight/day, not exceeding 40 mg, for 2-8 weeks, followed by a 20% monthly reduction in the daily dose over 4 months until discontinuation within 6 months. Other corticosteroids can be used in doses equivalent to prednisolone**. Initial doses, tapering rates, and duration of corticosteroid therapy may be individualized for a particular patient. In cases of high proteinuria/hematuria combined with active histological manifestations of the disease (M1, E1, C1-2), initiating corticosteroid treatment (methylprednisolone** or others in an equivalent dose) with intravenous administration at 250-1000 mg for 3 days may be considered on an individual basis [153-155].

The efficacy of corticosteroids for inducing remission and slowing disease progression is more evident at proteinuria levels above 2 g/day [19].

Corticosteroid use is associated with a significant increase in the likelihood of remission and a reduction in the development of ESKD, but also a 2-3 fold increase in the frequency of side effects (“Appendix A3”, cl. 1) — gastrointestinal, hematological, dermatological, and genitourinary infections, as well as impaired glucose tolerance or diabetes, which should be taken into account when prescribing therapy, informing the patient, and planning preventive measures. The risks of therapy-related complications increase substantially when eGFR is <50 mL/min/1.73 m². The efficacy of corticosteroids is enhanced in combination with ACE inhibitors or ARBs and/or tonsillectomy.

Approaches to the treatment of primary IgAN are presented in “Appendix B”, cl. 2.

• To reduce the likelihood of side effects, we recommend that the decision to treat with corticosteroids, with or without other immunosuppressive drugs (ATC classification: Antineoplastic and immunomodulating agents) in patients with IgAN, be made taking into account the risks of complications, including infectious ones, and after an individual discussion with the patient regarding the benefits and risks of this therapy [1].

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

Comments: Situations associated with an increased risk of severe complications from immunosuppressive therapy (IST) include (but are not limited to): diabetes mellitus, liver cirrhosis, latent infections, body mass index >30 kg/m², erosive or ulcerative gastrointestinal lesions, severe osteoporosis, and the likelihood of developing a psychiatric disorder.

• We recommend that treatment with corticosteroids, with or without other immunosuppressive drugs (ATC classification: Antineoplastic and immunomodulating agents) in patients with IgAN, be accompanied by supportive prophylactic therapy aimed at preventing Pneumocystis pneumonia and other infections, the development and progression of osteoporosis, and gastrointestinal lesions in accordance with current guidelines [1,76,77].

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

• In patients diagnosed with primary IgAN who are scheduled for IST, we recommend vaccination using inactivated pneumococcal and Haemophilus influenzae type b vaccines to reduce the risk of infectious complications [1].

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

• In patients diagnosed with primary IgAN who are scheduled for corticosteroid IST with or without other immunosuppressive drugs (ATC classification: Antineoplastic and immunomodulating agents), we recommend performing a tonsillectomy in the absence of contraindications to enhance treatment efficacy regarding remission induction, reduction of progression, and decreased risk of ESKD [32,33,56].

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

Comments: The evidence base for the efficacy of tonsillectomy is derived mainly from Asian studies. This issue has not been extensively studied in the European population of patients with IgAN. At the same time, the positive effect of tonsillectomy combined with corticosteroids for inducing remission and slowing disease progression was demonstrated in a large cohort study of patients with IgAN in Russia [78,79].

Tonsillectomy should be performed before or immediately after the completion of corticosteroid induction therapy to prevent the reconstitution of tonsillar germinal centers after treatment cessation [79].

• In patients diagnosed with primary IgAN, proteinuria >1 g/day, and a high risk of progression (excluding rapidly progressive nephritic syndrome), we do not recommend the routine use of other immunosuppressive drugs (ATC classification: "Antineoplastic and immunomodulating agents") as first-line IST, other than glucocorticoids, for inducing disease remission and/or reducing its progression rate [70,71,73,75,80-82].

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

Comments: Most cited meta-analyses of randomized controlled trials have not convincingly shown the advantages of other immunosuppressive drugs (ATC classification: Antineoplastic and immunomodulating agents) (including in combination with corticosteroids) over corticosteroid monotherapy. However, we allow for the possibility of combination IST in individual cases of IgAN refractory to corticosteroid treatment as part of a personalized approach, discussing potential risks of adverse events [83-87].

• In selected patients with primary IgAN and a high risk of progression, but without signs of rapidly progressive nephritic syndrome, we recommend considering the combination of corticosteroids and #mycophenolate mofetil** to induce remission and reduce the risk of progression [84,88].

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

Comments: Meta-analyses of randomized controlled trials have demonstrated superior efficacy of this combination compared to supportive care without IST and other IST regimens regarding hard prognostic endpoints, with a comparable or lower incidence of treatment-related side effects. The approximate dosing regimen of #mycophenolate mofetil** used in several RCTs: induction therapy (duration up to 6 months) — oral administration, 1.5-2.0 g/day (750-1000 mg twice daily); maintenance therapy (duration up to 6-18 months) — oral administration, 0.75-1.0 g/day (total daily dose divided into 2 doses) [84,88,96,97,98]. Prednisolone** in combination with #mycophenolate mofetil** should be administered orally at 0.4-0.6 mg/kg body weight/day for 2 months, followed by 4 months with a 20% reduction in the daily dose each month [99]. Other corticosteroids can be used in doses equivalent to prednisolone**. Initial doses, tapering rates, and duration of corticosteroid therapy may be individualized for a particular patient. The combined use of corticosteroids and #mycophenolate mofetil** should not be regarded as a routine therapeutic approach. It requires careful patient selection, assessment of complication risks, and development of a prevention plan (typically in an expert center setting).

• In patients diagnosed with primary or secondary IgAN presenting with rapidly progressive nephritic syndrome against the background of marked proliferative activity and/or cellular crescents according to pathomorphological examination of the renal biopsy (surgical) material, we recommend combination IST with corticosteroids in combination with cyclophosphamide** to induce disease remission and slow its progression [89].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: The recommendation is based on RCT data [89], which are supported by other observational studies [84,90-93]. Treatment should expediently be initiated with intravenous glucocorticoids at a dose of 250-1000 mg (methylprednisolone** or equivalent dose) for 3 days [91,111] (the initial dose may be individualized for a specific patient).

• In patients with IgAN secondary to systemic IgA vasculitis, we recommend administering the same treatment as for primary IgAN to achieve disease remission and reduce the rate of its progression [1,2].

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

• In the absence of a response to ongoing therapy in patients with IgAN secondary to systemic IgA vasculitis, we recommend considering the use of #rituximab** to achieve disease remission [94].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comments: In the absence of RCTs, according to a systematic review with a meta-analysis of observational studies, #rituximab** may be a safe and useful agent for inducing disease remission and reducing the immunosuppressive burden in patients with IgA vasculitis who are resistant to glucocorticoids or other immunosuppressive drugs (ATC classification: Antineoplastic and immunomodulating agents), as well as in patients for whom these drugs are contraindicated. Dosing regimen: 375 mg/m² once weekly for 4 doses; or 1000 mg once every 2 weeks for 2 doses [94]. The preparation, storage, and administration guidelines for #rituximab** comply with the product insert.

• In patients with secondary IgAN without signs of rapidly progressive nephritic syndrome, nephrotic syndrome, marked proliferative activity, and/or cellular crescents, we recommend treating the underlying pathological process to achieve disease remission [31].

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

Comments: The treatment strategy for secondary IgAN is not defined by robust data. Most observational studies suggest treating the underlying disease combined with universal CKD management approaches. In cases of celiac disease and inflammatory bowel disease, their treatment can lead to the resolution of clinical and morphological manifestations of IgAN in some patients. In patients with other causes of secondary IgAN, the response to treatment is insufficiently documented.

3.4 Immunosuppressive and supportive therapy in pediatric patients with IgAN

• We do not recommend routine prescribing of steroid and/or immunosuppressive therapy to children with IgAN in the absence of progression risk, i.e., in isolated microhematuria, or resolution of macrohematuria triggered by an acute respiratory infection, provided there is regular follow-up for dynamic risk assessment [112].

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

Comments: The goal is to avoid unjustified drug prescription and adverse effects. Glucocorticoids are indicated in children with clinical risk of nephropathy progression:

1) with nephrotic-range proteinuria or nephrotic syndrome, taking into account morphological changes in the renal tissue;

2) with proteinuria (albumin-to-creatinine ratio of 0.5-1 mg/mg [50-100 mg/mmol]) persisting despite 3-6 months of renin-angiotensin system blockade;

3) with proteinuria (albumin-to-creatinine ratio >1 mg/mg [100 mg/mmol]) despite 4 months of ACE inhibitor therapy;

4) histopathological indicators of activity by MEST-C (1 or more of the following: M1, E1, S1 with podocyte changes, C1) and persistent proteinuria >1 mg/mg (100 mg/mmol) for 3 weeks or more.

• In children with IgAN, we recommend considering immunosuppression primarily with glucocorticoids to induce remission / reduce disease activity [106, 111, 112, 114].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

• We recommend considering a 4–6 month course of glucocorticoid therapy, for example, prednisolone** at a dose of 2 mg/kg per day (not exceeding 60 mg per day) (or an equivalent drug) for a duration of no more than 4 weeks, followed by an alternative-day regimen with a gradual dose reduction until complete discontinuation after 5–6 months, for children with primary IgAN and (1) persistent proteinuria despite adequate non-immunosuppressive renoprotective therapy, with an albumin/creatinine ratio >0.5–1 g/g (50–100 mg/mmol) for 3–6 months; (2) persistent proteinuria despite adequate non-immunosuppressive renoprotective therapy (with an albumin/creatinine ratio >1 g/g [100 mg/mmol]) for more than 4 weeks; (3) presence of MEST-C activity indicators (1 or more of the following scores: M1, E1, S1 with podocyte lesions, C1) and/or an albumin/creatinine ratio consistently (i.e., persisting for 2–3 weeks in at least two measurements with an interval of 1–2 weeks) >1 mg/mg (100 mg/mmol) – to induce remission / reduce disease activity (primarily reducing proteinuria and slowing its progression) [106, 111, 122].

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

Comments: Glucocorticoids have been shown to significantly reduce mesangial proliferation in children [106]. The duration of treatment is individualized, but typically consists of 4 weeks of oral prednisolone** at a dose of 1–2 mg/kg/day (or equivalent), followed by tapering every other day for 4–6 months. In rare cases, longer courses are used. Based on the extrapolation of adult studies, lower doses may be considered: prednisolone** 0.4 mg/kg/day for 2 months with gradual tapering over 6 months [112], or orally from 14 years of age with #methylprednisolone** 0.4 mg/kg/day for 2 months (maximum dose 32 mg/day for a duration of 2 months) followed by a dose reduction of 4 mg/day monthly for 6–9 months (with Pneumocystis jirovecii pneumonia prophylaxis during the first 12 weeks of the treatment period) [123, 124].

• We recommend considering a pulse therapy regimen with #methylprednisolone** (intravenous) in children with IgAN at high clinical and histopathological (pathomorphological) risk of progression, such as: (1) acute onset of IgAN with decreased renal function (GFR <90 mL/min/1.73 m²) and/or an albumin/creatinine ratio >1 mg/mg (100 mg/mmol) with active severe MEST-C scores (2 or more of the following scores: M1, E1, S1 with podocyte lesions, C1); (2) presence of IgAN with crescents (C2) – regardless of proteinuria [112].

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

Comments: #Methylprednisolone** is administered intravenously at a dose of 15 mg/kg/day (maximum dose 500 mg/day) for 3 consecutive days (pulse therapy) or every other day, followed by oral administration of prednisolone** according to the schedule and doses described above [112].

It should be noted that the use of glucocorticoids is associated with a significant increase in the probability of achieving remission and a reduced risk of developing CKD stage 4–5, but also a 2–3 fold increase in the frequency of side effects (Appendix A3, clause 1) – gastrointestinal, hematological, dermatological, and genitourinary infections, severe osteoporosis, the likelihood of psychiatric disorders, as well as impaired glucose tolerance or diabetes, which should be taken into account when prescribing therapy, informing the patient, and planning preventive measures.

In individual cases, the use of glucocorticoids can be considered concomitantly with ACE inhibitors, especially in the presence of nephrotic-range proteinuria, reduced GFR, and the presence of crescents or active inflammation according to histopathological examination.

The possibility of avoiding glucocorticoids should be considered when tubulointerstitial sclerosis exceeds 50% of the cortical layer (T2) in the absence of active lesions, due to the predictably high probability of ineffectiveness and unjustified risk of side effects for the patient.

• In children with primary IgAN and proteinuria >0.5 g/m² /day (or an albumin/creatinine ratio of 0.5 g/g) despite adequate non-immunosuppressive nephroprotective and/or steroid therapy in the absence of rapidly progressive nephritic syndrome and contraindications, we recommend treatment with #budesonide** (ATC classification, code A07EA06) to induce remission / reduce disease activity [125, 126].

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

Comments: In two case reports, #budesonide** was successfully prescribed to children who showed no response to systemic glucocorticoid therapy: in one publication, a 12-year-old child with persistent nephrotic-range proteinuria received #budesonide** at a dose of 3 mg daily for 4 weeks, then 6 mg after normalization of blood creatinine levels, with gradual tapering to 3 mg every other day over 6 months [125]; in another report, a 13-year-old patient received a starting dose of 9 mg/day, and after 5 months due to decreased cortisol levels, the dose was reduced by 3 mg every 3 months with complete discontinuation after 1 year [126].

• We recommend administering additional immunosuppressive therapy (ATC classification: "Antineoplastic and immunomodulating agents") in cases of ACE inhibitor/ARB and glucocorticoid failure when there is a high risk of nephropathy progression, with the aim of inducing remission/reducing disease activity: (1) rapidly progressive nephritic syndrome with a GFR decline of more than 50% over a period of less than 3 months, presence of endocapillary proliferation and crescents in 25% or more of glomeruli (E1 and C2 according to MEST-C). In this situation, the use of #cyclophosphamide** or #mycophenolate mofetil** should be considered (for doses, see the commentary); (2) manifestations of nephrotic syndrome or nephrotic-range proteinuria (>2 mg/mg creatinine, 200 mg/mmol) resistant to prednisolone** therapy at a dose of 2 mg/kg/day for at least 4 weeks. In this situation, the prescription of calcineurin inhibitors or #mycophenolate mofetil** (for doses, see the commentary) is recommended [112].

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

Comments: Once proteinuria remission is achieved and renal function is restored/improved, immunosuppressive therapy should be continued for at least 6–12 months in the absence of severe adverse effects. After discontinuation, ACE inhibitor/ARB therapy must be maintained. In case of relapse, resumption of the previously effective therapy should be considered.

Immunosuppressive therapy is prescribed if glucocorticoids lack significant efficacy or if the proteinuria level exceeds >1 g/m²/day. Second-line immunosuppressive agents (in combination with glucocorticoids [e.g., prednisolone**] and, as a rule, with an ACE inhibitor or ARB [127]) may include, for example: (1) #azathioprine** at a dose of 2 mg/kg/day once daily for 24 months [112,127] or (2) #cyclophosphamide** – may be prescribed to patients with rapidly progressive nephritic syndrome presenting with prominent proliferative activity and/or crescents based on the pathomorphological examination of renal biopsy (or surgical) material (administered as pulse therapy in case of glucocorticoid failure: 3 or 6 intravenous pulses of 500 mg/1.73 m² [128] or 500 mg/m² per pulse monthly, for a 6-month course [127,129,130]) or (3) #mycophenolate mofetil** – in the presence of proliferative changes (mesangial proliferation and/or crescents) – therapy may be administered (orally) at 1.2 g/m²/day, but not exceeding 2 g/day in 2 divided doses for a course of 6–12 months, followed by a dose reduction by half for maintenance therapy lasting, on average, 6–12 months [133]; or #mycophenolate mofetil** 20–30 mg/kg/day for an average of 12 months, depending on the clinical response [112,127,131,132]; or a calcineurin inhibitor (prescribed primarily in the presence of signs of nephrotic syndrome and segmental glomerular sclerosis): (4) #cyclosporine** (#cyclosporine** doses are adjusted, where possible, under the control of cyclosporine A blood level monitoring: before the morning dose (C0) and two hours post-dose (C2), though C0 is frequently used – prior to the morning dose, i.e., 12 hours after the evening administration) (up to 100–150 [average 183.8±48.3 ng/mL] weekly at the start of treatment and then monthly, monitoring blood creatinine levels). On average, patients receive #cyclosporine** 4–5 mg/kg/day in 2 divided doses every 12 hours in equal doses, for an average of 9 months, combined with prednisolone** 0.4–0.6 mg/kg/day up to 2 mg/kg/day for 6–8 weeks. ACE inhibitors may be used concurrently (for doses, see above) [112,134,135]; or (5) #tacrolimus** (0.1–0.5 mg/kg/day in 2 divided doses every 12 hours in equal doses, under therapeutic drug monitoring of #tacrolimus** blood levels prior to the morning dose – 5–8 ng/mL) combined with prednisolone** 0.4–0.6 mg/kg/day for 6–8 weeks [135,136,137].

It should be borne in mind that both ACE inhibitors/ARBs and calcineurin inhibitors can cause hyperkalemia. Therefore, the combined use of these drugs increases the risk of hyperkalemia, requiring monitoring of blood potassium levels (blood potassium test).

Regular monitoring of drug toxicity should be performed in accordance with the respective Summary of Product Characteristics (SmPC).

• We recommend that glucocorticoid treatment, with or without other immunosuppressive medications (ATC classification: "Antineoplastic and immunomodulating agents") in children with IgAN, be accompanied by supportive prophylactic therapy aimed at preventing adverse treatment effects, including the development and progression of osteoporosis and gastrointestinal lesions, in accordance with current guidelines [111].

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

• In children diagnosed with primary IgAN, presenting with recurrent episodes of hematuria associated with relapses of acute tonsillitis or in the presence of surgical indications, we recommend considering tonsillectomy, in the absence of contraindications, to improve treatment efficacy regarding remission induction, reduction of renal injury progression, and the risk of end-stage renal disease [112].

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

Comments: The efficacy of tonsillectomy combined with pulsed #methylprednisolone** therapy has been demonstrated in steroid-resistant IgAN [138,139,140], as well as in combination with other variants of immunosuppressive therapy [141].

According to pediatric nephrologists from Japan, tonsillectomy may be considered as an adjunct to pulsed #methylprednisolone** therapy in children with newly diagnosed IgAN presenting with high disease activity, chronic tonsillitis, and gross hematuria following an upper respiratory tract infection [142].

In case of refractoriness to ACE inhibitors or ARBs, glucocorticoid therapy, or immunosuppressive therapy, the patient should be referred to a federal center to optimize the treatment approach or for inclusion in clinical trials.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Specific medical rehabilitation has not been developed for patients with IgAN.

• In adult patients with primary or secondary IgAN, we recommend providing medical rehabilitation as indicated and to the extent provided by the guidelines for CKD to improve disease outcomes [24].

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

• In children with primary or secondary IgAN, we recommend providing medical rehabilitation as indicated and to the extent provided by the guidelines for CKD to improve disease outcomes [104].

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

5. Prevention and Dispensary Observation

Methods and approaches to the primary prevention of IgAN have not been developed.

• In adult patients with primary or secondary IgAN, we recommend implementing preventive measures aimed at preventing complications of renal dysfunction and AKI, as well as routine clinical follow-up as stipulated by the CKD guidelines, to improve disease outcomes [24].

  Level of Recommendation C (Level of Evidence – 5)

We recommend following up children with IgAN even after achieving complete remission, as they may experience a relapse even many years later [112,113].

LoR BLoE 4Level of Recommendation B (Level of Evidence – 4)

Comments: patients are subject to clinical follow-up by a pediatrician/nephrologist and monitoring at a medical organization with experience in IgAN. Follow-up examinations are presented in Appendix A3, cl. 2.

Vaccine prophylaxis for children with IgAN

All patients with IgAN should undergo a vaccination status assessment (checking the completeness of immunization according to the national routine immunization schedule and clarifying whether the child received additional vaccines) at the time of diagnosis, followed by regular monitoring during subsequent consultations.

• We recommend immunization against infectious diseases using (inactivated) vaccines in children with IgAN to ensure protection against vaccine-preventable infections [111,143].

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

• We recommend annual influenza vaccination (using Inactivated Influenza Vaccine)** and pneumococcal vaccination (using Pneumococcal Conjugate Vaccine** and Pneumococcal Polysaccharide Vaccine**) for all children with IgAN for prophylactic purposes [111,143].

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

Comments: vaccination against pneumococcus using different vaccines is carried out observing the generally accepted intervals for these vaccines.

• We do not recommend using live vaccines in children with IgAN who are receiving immunosuppressive therapy, in order to prevent potential adverse events [111,143].

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

Comments: the immune response to vaccination in immunosuppressed patients may be reduced.

In patients receiving immunosuppressive therapy, inactivated vaccines are prescribed without restrictions.

The immunosuppressive dose of glucocorticoids for prednisolone** is 2 mg/kg/day administered for 14 days or longer; live vaccines may be administered to these patients 1 month or more after completing therapy [144]. Using such a dose for less than 2 weeks or lower doses for a longer period does not lead to significant immunosuppression.

Where possible, in addition to the live vaccines included in the National Immunization Schedule, children with IgAN should be vaccinated against varicella.

Currently, there is no consensus on the optimal interval between the potential use of live vaccines after the completion of immunosuppressive therapy. KDIGO 2021 clinical practice guidelines recommend immunization with live vaccines 1–3 months after discontinuing immunosuppressive therapy [111].

Family members and close contacts (in the absence of contraindications) of IgAN patients should be vaccinated, including annual influenza vaccination, which is an important strategy to protect patients from severe vaccine-preventable infections [111]. This approach is known as "cocooning vaccination".

Children with IgAN must avoid contact with secretions from individuals immunized with live vaccines for 3–6 weeks following vaccination [111].

Evidence indicates that IgAN has been diagnosed more frequently since the onset of the novel coronavirus infection (COVID-19) pandemic, which may suggest a triggering role of this pathogen, alongside previously known respiratory infection agents [145]. At the same time, cases of clinical onset or exacerbation of IgAN have been described, including in children, following vaccination against the novel coronavirus infection (COVID-19) with foreign vaccines (mRNA and vector vaccines). These cases are exceptionally rare, outcomes in the majority of patients are favorable, and evidence of a causal relationship continues to be studied. Nevertheless, it is recognized that the potential benefit of vaccination outweighs potential adverse events [146,147,148]. Thus, vaccination against the novel coronavirus infection (COVID-19) should be performed in accordance with current guidelines and the instructions for the respective drugs. Symptoms should be monitored and, if necessary, laboratory diagnostic tests performed for the timely diagnosis and treatment of potential complications.

6. Organization of Medical Care

Patients with IgAN may be provided with any type, conditions, and form of medical care provided for by the legislation of the Russian Federation, as clinically indicated.

Main indications for emergency hospital admission of patients with IgAN:

1) Development of or suspected acute kidney injury (AKI) (decrease in urine output rate <0.5 ml/kg/h for >6 hours, or an increase in blood creatinine >50% from baseline over 7 days, or an increase in blood creatinine by >26 µmol/L over 48 hours;

2) rapidly progressive decline in GFR and/or increase in blood creatinine levels (>50% over 3 months) (for adults); newly detected GFR decline ≥50% (for children);

3) acute nephritic syndrome;

4) water-electrolyte disorders and acidosis (fluid loss and hypovolemia, hyperkalemia, hypokalemia, hyponatremia, metabolic acidosis, decompensated);

5) any of the following complications requiring emergency therapy, including the initiation of dialysis: central nervous system dysfunction; serositis; decompensation of metabolic acidosis; hyperkalemia; uncontrolled hypervolemia (anasarca, pulmonary edema) and arterial hypertension; severe protein-energy malnutrition;

6) arterial hypertension resistant to outpatient treatment (including hypertensive crisis);

7) newly detected GFR decline <30 ml/min/1.73 m².

Main indications for hospital discharge after emergency admission of patients with IgAN:

1) AKI diagnosis confirmed or ruled out; if confirmed, the etiology of AKI has been established;

2) full course of AKI treatment completed with an outcome (regression, CKD progression, ESRD);

3) the cause of the rapidly progressive GFR decline and/or increase in blood creatinine levels (>50% over 2–6 months) established and treatment completed with an outcome (regression, CKD progression, ESRD);

4) manifestations of acute nephritic syndrome resolved, and its cause established;

5) treatment of clinically significant complications of renal dysfunction completed: water-electrolyte disorders, acid-base balance disorders: hypovolemia, hyperkalemia, hypokalemia, hyponatremia, metabolic acidosis, metabolic alkalosis resolved or compensated (by conservative methods or dialysis);

6) blood pressure lowered, life-threatening manifestations of hypertension eliminated, and antihypertensive therapy optimized in patients with CKD G1–G5D;

7) in newly detected GFR decline <30 ml/min/1.73 m², diagnosis and treatment of major complications of renal dysfunction performed.

Main indications for elective hospital admission:

1) Initial diagnosis when IgAN is suspected;

2) in patients with a confirmed diagnosis of IgAN:

a. increase in proteinuria and/or hematuria;

b. newly detected nephrotic syndrome (combination of hypoalbuminemia and proteinuria >3.5 g/day/1.73 m²);

c. need for diagnosis/differential diagnosis using kidney biopsy or other diagnostic tests requiring hospitalization;

3) creation of vascular access for dialysis;

4) pregnancy;

5) administration of immunosuppressive therapy for IgAN and/or treatment of associated pathological conditions;

6) preparation for surgical treatment for various indications.

Main indications for hospital discharge after elective admission:

1) IgAN diagnosis confirmed or ruled out, initial diagnosis and treatment performed using kidney biopsy or other diagnostic tests in accordance with guidelines;

2) diagnosis of flare/relapse confirmed or ruled out, treatment administered in accordance with guidelines;

3) diagnosis of secondary IgAN causes performed in accordance with guidelines;

4) vascular access for dialysis created;

5) IgAN during pregnancy: renal prognosis determined, treatment and diagnosis performed in accordance with guidelines, teratogenic drugs excluded;

6) induction immunosuppressive therapy administered: a cycle or hospital phase of therapy completed, complications of therapy diagnosed and treated, functional renal status monitored, and complications of renal dysfunction diagnosed and treated (if identified);

7) preparation for surgical treatment: necessary diagnostics performed and CKD complications affecting surgical risks corrected (conservatively or via dialysis).

The organization of dietary nutrition for patients during inpatient treatment in medical organizations is carried out in accordance with Appendix 3 of the Order of the Russian Ministry of Health No. 1008n dated September 23, 2020, "On Approval of the Procedure for Providing Patients with Medical Nutrition".

Principles of organizing outpatient care:

Outpatient management of patients with IgAN should be organized in accordance with the principles outlined in the CKD guidelines [24].

7. Additional Information

The course and outcomes of IgAN are influenced by numerous factors associated with renal dysfunction. A multifactorial approach to improving patient-centered outcomes forms the basis of IgAN management, and approaches to correcting/modifying risk factors for progressive renal dysfunction are detailed in the guidelines "Chronic Kidney Disease" [24] and "Acute Kidney Injury" [95].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

From the National Association of Nephrologists (for adults):

Dobronravov V.A. (Working Group Head) – D.Sc. in Medicine, Prof., Director of the Research Institute of Nephrology, Professor of the Department of Propaedeutics of Internal Diseases with Clinic, Pavlov First Saint Petersburg State Medical University, Saint Petersburg. Vice President of the National Association of Nephrologists.

Bobkova I.N. – D.Sc. in Medicine, Prof., Professor of the Department of Internal, Occupational Diseases and Rheumatology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow. Board Member of the National Association of Nephrologists.

Vatazin A.V. – D.Sc. in Medicine, Prof., Head of the Surgical Department of Kidney Transplantation, Head of the Department of Transplantology, Nephrology and Artificial Organs, Moscow Regional Research and Clinical Institute (MONIKI), Moscow. Chief freelance nephrologist of the Russian Ministry of Health for the Central Federal District. President of the National Association of Nephrologists. Honored Doctor of the Russian Federation. Honored Scientist of the Russian Federation.

Zakharova E.V. – Ph.D. in Medicine, Associate Professor of the Department of Nephrology and Dialysis, Russian Medical Academy of Continuous Professional Education, Associate Professor of the Department of Nephrology, A.I. Evdokimov Moscow State University of Medicine and Dentistry, Head of the Nephrology Department, S.P. Botkin City Clinical Hospital, Moscow. Chairperson of the Russian Dialysis Society.

Karunnaya A.V. (Working Group Secretary) – Nephrologist, Head of the Chronic Hemodialysis Department of the Research Institute of Nephrology Clinic, Pavlov First Saint Petersburg State Medical University, Saint Petersburg. Member of the National Association of Nephrologists.

Kozlovskaya N.L. – D.Sc. in Medicine, Prof., Department of Internal Diseases with a Course of Functional Diagnostics and Cardiology named after Acad. V.S. Moiseev, Peoples' Friendship University of Russia, Head of the Center for Care of Pregnant Women with Renal Pathology, A.K. Eрамишанцев City Clinical Hospital, Moscow. Member of the National Association of Nephrologists.

From the Union of Pediatricians of Russia and the Creative Association of Pediatric Nephrologists (additions for children):

Baranov A.A. – Academician of the Russian Academy of Sciences, Professor, D.Sc. in Medicine; Honorary President of the Union of Pediatricians of Russia, Advisor to the Head of the Research Institute of Pediatrics and Child Health, National Medical Research Center for Children's Health and Pediatric Surgery named after Acad. B.V. Petrovsky, Professor of the Department of Pediatrics and Pediatric Rheumatology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Chief freelance pediatrician of the Russian Ministry of Health.

Namazova-Baranova L.S. – Academician of the Russian Academy of Sciences, Professor, D.Sc. in Medicine, President of the Union of Pediatricians of Russia; Past President of EPA/UNEPSA; Head of the Research Institute of Pediatrics and Child Health, National Medical Research Center for Children's Health and Pediatric Surgery named after Acad. B.V. Petrovsky, Head of the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University, Chief freelance pediatric specialist in preventive medicine of the Russian Ministry of Health.

Petrosyan E.K. – D.Sc. in Medicine, Professor of 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.

Margieva T.V. – Ph.D. in Medicine, Chief Specialist of the Methodological Center for Specialist Accreditation, I.M. Sechenov First Moscow State Medical University (Sechenov University), Nephrologist, Member of the Union of Pediatricians of Russia.

Vishnyova E.A. – D.Sc. in Medicine, Professor of the Russian Academy of Sciences, Deputy Head for Scientific Work of the Research Institute of Pediatrics and Child Health, National Medical Research Center for Children's Health and Pediatric Surgery named after Acad. B.V. Petrovsky, Professor of the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University, Member of the Union of Pediatricians of Russia.

Emirova Kh.M. – Ph.D. in Medicine, Professor of the Department of Pediatrics, A.I. Evdokimov Moscow State University of Medicine and Dentistry; Nephrologist at the Center for Gravitational Blood Surgery and Hemodialysis, St. Vladimir City Children's Clinical Hospital, Member of the Creative Association of Pediatric Nephrologists, Russian Dialysis Society.

Zokirov N.Z. – D.Sc. in Medicine, Head of the Department, Academy of Postgraduate Education, Federal Research and Clinical Center of the Federal Medical-Biological Agency of Russia, Federal Research and Clinical Center for Children and Adolescents of the FMBA of Russia, Member of the Union of Pediatricians of Russia.

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

Ananin P.V. – Ph.D. in Medicine, Nephrologist of the Nephrology Department, Senior Research Fellow, National Medical Research Center for Children's Health.

Conflict of interest: none.

Appendix A2. Methodology for Developing Clinical Guidelines

The guideline development process consisted of the following stages: selection of the working group (WG) lead, members, and secretariat; identification during discussions of the areas most critical to routine clinical practice that the guidelines should cover; definition of specific research questions and formulation of recommendations; development of evidence-retrieval strategies; and finalization of the list of recommendations and its structure. The directives presented in these guidelines are based on an analysis by the group members of studies in nephrology and related medical fields, along with systematic reviews and meta-analyses published up to June 2024. The original 2021 draft of the clinical guidelines addressed only the adult population (as stated by the Russian Association of Nephrologists). In 2024, at the insistence of the Russian Ministry of Health, it was supplemented with provisions for children, prepared by pediatric nephrologists and presented in separate subsections.

The WG members sought to ensure that each recommendation was based on the highest possible levels of evidence and grades of recommendation. Nevertheless, the WG deemed it necessary to retain a number of recommendations that formally have a low level of evidence or are based on expert consensus, taking into account many years of experience in managing patients of the relevant profile and the fact that these recommendations may be of substantial importance for practical work.

To assess the quality and strength of the recommendations, levels of evidence and grades of recommendation were used (Tables 1–3).

Target audience for these clinical guidelines:

1. Nephrologist.

2. Physician / General Internist.

3. District General Practitioner.

4. General Practitioner (Family Physician).

5. Urologist.

6. Otorhinolaryngologist.

7. Pediatrician.

Table 1.Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2.Levels of Evidence (LoE) grading scale for prevention, treatment and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3.Grades of Recommendation (GoR) for prevention, diagnostic, treatment and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The update mechanism for clinical guidelines provides for their systematic revision—at least once every three years, as well as upon the emergence of new evidence-based data regarding the diagnosis, treatment, prevention, and rehabilitation of specific conditions, 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

1. Adverse effects of glucocorticoids.

The frequency and severity of adverse effects depend on the duration of administration, the dose used, and adherence to the circadian rhythm of drug administration.

The following adverse effects may occur during treatment:

- endocrine system: decreased glucose tolerance, steroid-induced diabetes mellitus or manifestation of latent diabetes mellitus, adrenal suppression, Cushing's syndrome;

- digestive system: nausea, vomiting, steroid-induced gastric and duodenal ulcer, erosive esophagitis, gastrointestinal bleeding, increased or decreased appetite;

- skin and mucous membranes: delayed wound healing, petechiae, hyper- or hypopigmentation of the skin, acne, striae, susceptibility to pyoderma and candidiasis;

- musculoskeletal system: osteoporosis, steroid myopathy, reduced muscle mass;

- mineralocorticoid-mediated: fluid and sodium retention, hypernatremia, hypokalemic syndrome.

The full list is provided in the package leaflet (see the State Register of Medicinal Products, http://grls.rosminzdrav.ru).

2. Initial evaluation and subsequent follow-up of children with IgA nephropathy

Approximate scope of initial evaluation and subsequent follow-up for children with IgA nephropathy (modified from IPNA clinical practice recommendations for children with steroid-resistant nephrotic syndrome) [112] with modifications

¹ Indications for an unscheduled visit: signs of exacerbation, clinical deterioration, new symptoms, increasing proteinuria, decline in renal function, etc.

3. Main nosologies for differential diagnosis of IgAN and required evaluations

Main nosologies for differential diagnosis of IgAN in children and required evaluations for their exclusion/confirmation, modified from [112]

Appendix B. Physician Action Algorithms

1. General approaches to the diagnosis of immunoglobulin A nephropathy

2. Approaches to the treatment of primary immunoglobulin A nephropathy in adults

Note: RPN – rapidly progressive nephritic syndrome; GCS – glucocorticoids; CY – cyclophosphamide**; MMF – #mycophenolate mofetil**; TE – tonsillectomy (may be performed before or after IST).

Appendix C. Patient Information

Immunoglobulin A nephropathy (IgAN) is a chronic kidney disease caused by the deposition of "faulty" immunoglobulins, leading to irreversible organ damage and decreased renal function.

In a significant proportion of cases, the disease occurs after infections (tonsillitis, cold, gastrointestinal infections, etc.), during which the body increases the production of immunoglobulins designed to fight the pathogen. The main problem is that the immunoglobulins produced in the mucous membranes are "faulty" and, instead of being secreted onto the mucosal surface, enter the bloodstream and then the kidneys, causing inflammation.

IgAN can also develop against the background of other autoimmune disorders (e.g., sarcoidosis, psoriasis, etc.) – in which case the disease is secondary.

Failure to treat the disease can lead to complete loss of renal function, the timing of which is determined by the specific disease course in each individual case. As renal function declines, a number of changes develop in other organs and systems, affecting the quality and duration of life, and requiring monitoring and appropriate treatment, including dialysis. According to V.A. Dobronravov et al. [19], in Russia 16% and 25% of patients with IgA require dialysis at 5 and 10 years after diagnosis, respectively.

Diagnosis should include a range of interventions aimed at: a) confirming the disease diagnosis; b) clarifying the degree of kidney damage; c) identifying inflammatory mucosal changes and other conditions that contribute to the development and progression of IgAN (see above).

The only way to confirm the diagnosis of IgAN, assess the disease prognosis, and choose optimal treatment is to perform a renal biopsy and special microscopic examinations of the kidney sample.

A kidney biopsy is a routine diagnostic procedure without which the disease diagnosis cannot be established. It is performed with a special needle through the skin in the lumbar region to take 2-3 small samples of kidney tissue (5-10 mm long, less than 1 mm wide) for subsequent microscope examination.

The procedure is performed under local anesthesia with the patient lying in the prone position. Under ultrasound guidance, a special needle is inserted through a skin puncture to the kidney, and a renal puncture is performed to obtain the necessary tissue samples.

After the procedure, bed rest must be observed for 24 hours so that a blood clot forms at the puncture sites.

The risks of the procedure are mainly related to the possibility of renal bleeding and the formation of a perirenal hematoma (blood accumulation). In the overwhelming majority of cases, such hematomas do not pose a significant threat and resolve on their own. In rare cases (approximately 1 per 500-1000 procedures), a blood transfusion or surgery may be required to stop the bleeding.

To minimize bleeding risks, blood coagulation tests are performed before the procedure and must be normal at the time of the intervention.

In the vast majority of cases, the benefits of obtaining crucial information about the kidney disease—which determines the prognosis and scope of treatment—significantly outweigh the potential risks of biopsy complications.

Treatment of IgAN should be carried out under the supervision of a nephrologist. Before starting treatment, the nephrologist and the patient should discuss the proposed treatment to clearly understand the expected benefits and be aware of potential side effects. IgAN is a specific variant of the so-called "chronic kidney disease," therefore general approaches to kidney pathology management also apply to patients with IgAN. In cases of unfavorable IgAN progression, treatment may require specific approaches, including the administration of drugs that suppress abnormal immune reactions, as well as tonsillectomy (a surgical procedure to remove the palatine tonsils).

The use of medications that suppress abnormal immune reactions has positive effects, such as significantly reducing disease activity and slowing the decline in renal function, but it also has a number of side effects (see Appendix A3). The benefit-risk balance when prescribing treatment must be determined by the nephrologist individually in each case, and the patient must receive complete information about this before consenting to treatment.

One of the aspects of IgAN treatment is performing a tonsillectomy (see above). The presence of inflammatory foci in the tonsils can negatively affect disease progression; conversely, their removal along with other treatments can halt the progression of IgAN. Tonsillectomy is performed in a hospital setting by an otorhinolaryngologist under local or general anesthesia. Rehabilitation after the procedure generally involves a minimal number of complications.

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

Appendix G1. Russian title: Formula for estimating GFR proposed by the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) [25,26]

Original title: CKD-EPI equation to estimate the glomerular filtration rate (CKD-EPI formula)

Source (official developer website, validation publication):

https://pubmed.ncbi.nlm.nih.gov/19414839/

Type (underline):

— rating scale

— index

— questionnaire

— other (specify): formula

Purpose: determination of GFR value

Content (template):

GFR = 141 * min (Serum creatinine / kappa, 1)^alpha * max (Serum creatinine / kappa, 1)^1.209 * 0.993^Age * Sex * Race,

for females, the following values are used:

sex = 1.018; alpha = - 0.329; kappa = 0.7;

for males, the following values are used: sex = 1; alpha = - 0.411;

kappa = 0.9;

for individuals of Black race: "race" coefficient = 1.159.

Key (interpretation): staging of CKD based on GFR level (Table 2, Section 1.4)

Notes: for calculation convenience, an online calculator has been created:

https://www.kidney.org/professionals/KDOQI/gfr_calculator 

Appendix G2. Russian title: Calculator for IgAN progression risk assessment [29]

Original title: International IgAN Prediction Tool at biopsy - Adults

Source (official developer website, validation publication): https://pubmed.ncbi.nlm.nih.gov/30980653/

Type (underline):

— rating scale

— index

— questionnaire

— other (specify): calculator

Purpose: calculation of IgAN progression risk

Content (template):

To use the calculator, the following data are required: at the time of biopsy – patient age, eGFR, blood pressure (systolic and diastolic), 24-hour urine protein quantification, information on ACEi/ARB use and IST performance (before or during biopsy); histological data – MEST (see Section 1.5); patient race. To calculate the risk, it is also necessary to enter the number of months post-biopsy (maximum – 80).

Note: For convenience, an online calculator has been created:

https://qxmd.com/calculate/calculator_499/international-igan-prediction-tool-adults