Glomerular diseases: focal segmental glomerulosclerosis: clinical guidelines

List of Abbreviations

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

CI – confidence interval

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

MA – meta-analysis

ICD – International Classification of Diseases

AKI – acute kidney injury

RR – relative risk

РКИ – randomized controlled trial

eGFR – estimated glomerular filtration rate

GFR – glomerular filtration rate

ESRD – end-stage renal disease

FSGS — focal segmental glomerulosclerosis

CKD – chronic kidney disease

EM — electron microscopy

Ig – immunoglobulin

Terms and Definitions

Calcineurin inhibitor dependency — recurrence of nephrotic syndrome or an increase in 24-hour proteinuria >50% after dose reduction or discontinuation of calcineurin inhibitors, provided that treatment has been administered for 12 months.

Nephrotic syndrome — a symptom complex caused by impairment of the glomerular barrier 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).

Infrequently relapsing focal segmental glomerulosclerosis — 1 relapse within 6 months after achieving remission or 1–3 relapses within 12 months.

Complete remission — reduction of proteinuria to values <300 mg/day/1.73 m², normalization of blood albumin levels, with no decrease in estimated glomerular filtration rate (eGFR) >20% from baseline.

Calcineurin inhibitor resistance — lack of reduction in 24-hour proteinuria or a reduction of <50% given a treatment duration of >6 months with achievement of target blood drug levels.

Relapse — increase in proteinuria to values ≥3.5 g/day/1.73 m² in patients who achieved complete remission, or an increase in 24-hour proteinuria by >50% with the return of nephrotic syndrome in patients after partial remission.

Steroid dependency — recurrence of the disease after dose reduction or discontinuation of glucocorticoids.

Steroid resistance — lack of remission after at least 4 weeks of glucocorticoid therapy.

Partial remission — reduction of 24-hour proteinuria by ≥50% from baseline (with regression of nephrotic syndrome), with no decrease in eGFR >20% from baseline.

Frequently relapsing focal segmental glomerulosclerosis — ≥2 relapses within 6 months after achieving remission or within 12 months.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Focal segmental glomerulosclerosis (FSGS) is a form of glomerulopathy that clinically manifests with proteinuria or nephrotic syndrome, and morphologically is characterized by focal (in individual glomeruli) and segmental (in individual capillary loops) sclerosis on light microscopy and effacement of podocyte foot processes on electron microscopy (EM) [1-6].

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

FSGS develops as a result of injury to the visceral epithelial cells of the renal glomeruli (podocytes) and belongs to the group of "podocytopathies." By pathogenetic mechanism, FSGS can be divided into primary, secondary (Table 1), and genetically determined. In primary FSGS, widespread podocyte injury is associated with circulating "permeability factors" in the blood. It is hypothesized that these factors cause structural and functional changes in podocytes, promote effacement of their foot processes, apoptosis, and detachment from the basement membrane, leading to disruption of the glomerular barrier and the development of proteinuria. Soluble urokinase-type plasminogen activator receptor, cardiotrophin-like cytokine factor-1, anti-CD40 antibodies, and others are considered potential permeability factors [7,8], although their exact significance is currently not fully defined.

Secondary FSGS usually occurs as an adaptive response with the development of intraglomerular hypertension and hyperfiltration in response to an absolute or relative reduction in functioning nephron mass, as well as due to the direct toxic effect of drugs, toxins, or viruses on podocytes, and as a consequence of hyperfiltration and hypertension in the remaining glomeruli in other glomerulopathies [6].

Under conditions of reduced nephron mass, intraglomerular hypertension and concomitant hypertrophy of the remaining glomeruli initially contribute to the compensatory maintenance of the required glomerular filtration rate (GFR). However, subsequently, "hypertensive" injury leads to gradual sclerosis of the remaining glomeruli. An absolute reduction in nephron number is observed in cases of a solitary kidney at birth (agenesis, renal hypoplasia, and other anomalies) or as a result of surgical removal of one kidney (nephrectomy, partial nephrectomy), prematurity, low birth weight, reflux nephropathy, hypertensive nephroangiosclerosis, as well as an outcome of chronic glomerulopathies (e.g., segmental glomerulosclerosis resulting from immune injury in glomerulonephritis) [9]. Relative oligonephronia occurs in individuals with morbid obesity, which is characterized by an increase in glomerular volume (glomerulomegaly), a perihilar variant of FSGS (see section 1.5) in only a small fraction of altered glomeruli, and focal smoothing of podocyte processes according to EM data [10]. Other examples of intraglomerular hypertension with a normal nephron number include diabetic nephropathy and rarer diseases such as sickle cell anemia, cyanotic congenital heart disease, and glycogen storage diseases associated with glucose-6-phosphatase deficiency (Von Gierke disease, type I glycogenosis).

The development of secondary FSGS (Table 1) can be caused by the intake of medications and toxic substances: pamidronic acid, interferons, systemic anabolic agents with a duration of use from 8 to 20 years [11-14]. Cases of FSGS have been described with long-term use of anthracyclines and related compounds (doxorubicin** et al.), lithium preparations, calcineurin inhibitors, and sirolimus [15-18]. Among viral infections, human immunodeficiency virus (HIV), parvovirus B19, cytomegalovirus, Epstein-Barr virus, SV40 virus, and hepatitis C virus are of pathogenetic importance for podocyte injury.

FSGS can also be caused by mutations in genes encoding structural proteins of podocytes and the slit diaphragm. In older children, adolescents, and adults with genetic FSGS, an autosomal dominant inheritance pattern is more frequently observed. Mutations in the type IV collagen α3, α4, and α5 genes are recognized as one of the most frequent genetic causes of FSGS in adults [19]. Formin (INF2) gene mutations (12–17% of all autosomal dominant FSGS cases), α-actinin-4 (ACTN4), TRPC6, WT1, and LMX1B mutations are also quite frequent [20,21].

Table 1. Potential causes for the development of secondary FSGS

A FSGS pattern unrelated to primary or genetic forms can result from any post-inflammatory, post-necrotic, or post-ischemic focal or segmental injury to the glomerular capillaries in the setting of any glomerulopathy or vascular disease. At the same time, a significant reduction in nephron number and capillary surface area resulting from any injury can subsequently lead to intraglomerular hypertension and hyperfiltration, inducing mechanisms of secondary FSGS.

1.3 Epidemiology of the Disease or Condition

Among patients with nephrotic syndrome, the prevalence of FSGS ranges from 12% to 35% [3, 22].

The incidence of FSGS is steadily increasing: while from 1994 to 2003 it was 1.4 per 100,000 person-years, in the period from 2004 to 2013 it increased to 3.2 per 100,000 person-years (a 41% increase), while the ratio of primary to secondary forms remains unchanged at approximately 1:3 [23]. Thus, FSGS is approaching the frequency of IgA nephropathy and diabetic nephropathy. The frequency of FSGS as a cause of end-stage renal disease (ESRD) is also rising. In 1980, FSGS was noted in 0.2% of patients with ESRD; whereas by 2000, it accounted for 2.3% of ESRD cases, representing an 11-fold increase. Internationally, the proportion of patients with ESRD resulting from FSGS is currently 2.3% [24], but in the Russian Federation, where glomerulopathies are the leading cause of ESRD, it may be significantly higher. The proportion of genetic FSGS among adult patients can reach up to 11% [25].

1.4 Features of Coding the Disease or Condition

N00.1 – Acute nephritic syndrome. Focal and segmental glomerular lesions

N01.1 – Rapidly progressive nephritic syndrome. Focal and segmental glomerular lesions

N02.1 – Recurrent and persistent hematuria. Focal and segmental glomerular lesions

N03.1 – Chronic nephritic syndrome. Focal and segmental glomerular lesions

N04.1 – Nephrotic syndrome. Focal and segmental glomerular lesions

N05.1 – Unspecified nephritic syndrome. Focal and segmental glomerular lesions

N06.1 – Isolated proteinuria with specified morphological diagnosis. Focal and segmental glomerular lesions

N07.1 – Hereditary nephropathy, not elsewhere classified. Focal and segmental glomerular lesions

FSGS is a specific variant of chronic kidney disease (CKD); therefore, the CKD stage must be indicated in all cases in accordance with the guidelines [26].

To designate the stage, codes N18.1–N18.5 should be used (Table 2) [26], and the eGFR must be calculated using the CKD-EPI formula via specialized calculators based on serum creatinine concentration, sex, age, and race ("Appendix G1–GN", cl. 1) [27, 28]. In addition to the CKD stage, the albuminuria grade must be indicated (Table 3) [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.

Table 3. Albuminuria grades (mg/day)

Note: * — corresponds to daily proteinuria ≥0.5 g; ** — corresponds to daily proteinuria ≥3.5 g.

1.5 Classification of the disease or condition

Based on the underlying cause, FSGS is classified as follows [29, 30]:

1) Primary FSGS – specific podocyte injury with no apparent cause, likely related to circulating serum factors; it most commonly presents with nephrotic syndrome. Electron microscopy (EM) reveals diffuse (≥80%) foot process effacement; it frequently recurs in the renal allograft (plasmapheresis is effective in this setting).

2) Secondary FSGS – caused by podocyte injury resulting from intraglomerular hyperfiltration/hypertension or direct exposure to toxins or viruses; characterized by marked proteinuria, often without nephrotic syndrome, and typically renal function impairment. This category of patients with FSGS exhibits adaptive changes, such as glomerular hypertrophy and hyperfiltration, with EM showing focal (<80%) podocyte foot process effacement.

3) Genetic FSGS – associated with mutations in genes encoding structural proteins of podocytes and the slit diaphragm; it may initially manifest as nephrotic syndrome in early childhood or debut with less pronounced proteinuria in adolescence or adulthood.

4) In some patients with FSGS, the cause or etiological factor cannot be identified despite thorough investigation, including genetic testing. Such patients should be classified as FSGS of unknown etiology.

Based on morphological features, FSGS is subdivided into [29]:

1) Classical variant – characterized by segmental areas of collapse and mesangial/capillary loop sclerosis (segmental lesions) in some, but not all, glomeruli (focal lesions). Injury initially localizes to juxtamedullary glomeruli and may therefore be missed on superficial biopsies containing only the cortex. Segmental hyaline deposits in glomeruli are also detected; proliferative changes are atypical. Immunofluorescence microscopy reveals no deposits of immunoglobulins (Ig) and complement, although some cases show IgM and complement C3 fraction (and possibly C1) deposits in areas of sclerosis and in the mesangium, the pathogenetic role of which remains unknown. Only 30% of patients with this variant respond to glucocorticoid therapy.

2) Tip lesion variant – characterized by podocyte injury and foam cell accumulation at the glomerular "tip" near the origin of the proximal tubule; immunofluorescence may reveal non-specific staining for IgM and C3 in sclerotic areas and the mesangium. The tip lesion variant of FSGS is thought to have a better response to glucocorticoid therapy compared to other variants.

3) Perihilar variant – sclerosis and hyalinosis develop in the perihilar region (around the vascular pole), frequently involving >50% of glomeruli. Non-specific deposition of IgM and C3 in sclerotic areas may also be observed. This form is most commonly identified in secondary FSGS as a consequence of injury related to intraglomerular hypertension and hyperfiltration, with a poor response to glucocorticoid therapy.

4) Cellular variant – diagnosed when the biopsy contains at least one glomerulus with segmental endocapillary hypercellularity occluding the lumen of individual capillaries. Other glomeruli exhibit features characteristic of the classical variant of FSGS. EM reveals diffuse foot process effacement. To diagnose the cellular variant of FSGS, tip and collapsing variants must be excluded. A therapeutic response is observed in approximately 20% of cases.

5) Collapsing variant – characterized by collapse and sclerosis of the entire glomerular tuft rather than segmental injury. Such injury is frequently caused by HIV infection, although other causes—such as parvovirus B19 infection, drugs, systemic lupus erythematosus, hemophagocytic syndrome, or COVID-19 infection—can also cause this form. Some researchers consider this variant a distinct form of renal injury unrelated to FSGS. It manifests with severe nephrotic syndrome, rapid decline in renal function, and resistance to glucocorticoids and calcineurin inhibitors. HIV-associated collapsing FSGS is characterized by cystic tubular dilatation and tubuloreticular inclusions in mesangial and endothelial cells [31, 32].

1.6 Clinical presentation of the disease or condition

In patients with primary FSGS, disease onset is acute or subacute in 70–100% of cases, with the development of nephrotic syndrome. Reduced renal function at disease onset is diagnosed in 25–50% of patients, hematuria in 50%, and arterial hypertension in 20% [33–37].

Patients with secondary FSGS typically present with a gradual increase in proteinuria (usually without nephrotic syndrome) and a steady decline in renal function. Exceptions include patients with drug-associated secondary FSGS (e.g., pamidronic acid) or virus-associated secondary FSGS (e.g., HIV infection), who typically develop severe nephrotic syndrome [38, 39]. The clinical picture is dominated by the features of the underlying diseases and conditions leading to secondary FSGS (see Section 1.2). In particular, renal injury in morbid obesity is characterized in its early stages by a subclinical course with mild proteinuria and a marked increase in GFR, followed by a slow decline in renal function [40].

Patients with genetic FSGS may present with a wide spectrum of clinical manifestations depending on the specific gene mutation. Adult-onset genetic FSGS is usually inherited in an autosomal dominant manner with variable penetrance, typically manifesting with proteinuria <5 g/day/1.73 m² and slowly progressive renal function decline [41, 42]. The predictive value of glucocorticoid resistance in genetic FSGS is low, as a proportion of patients with this variant respond to glucocorticoid therapy, although long-term complete remissions are rare [43].

2. Diagnostics, medical indications and contraindications for diagnostic methods

The criteria for the diagnosis of FSGS are: 1) morphological examination data of the renal tissue – detection of focal (in individual glomeruli) and segmental (in individual capillary loops) glomerulosclerosis (see Section 1.5); 2) proteinuria (<3.5 g/day/1.73 m²) with the absence or minimal hematuria, or nephrotic syndrome (proteinuria ≥3.5 g/day/1.73 m², hypoalbuminemia (blood albumin <30 g/L)) against the background of a known or suspected etiological factor (see Section 1.2).

• In patients with suspected or established FSGS, we recommend analyzing complaints, medical history, and physical examination data to assess the duration, severity, and clinical manifestations of the disease, and to identify associated conditions and diseases that may be important for treatment selection [1,2,30,44,45].

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

• We recommend that nephrologists establish the diagnosis of primary FSGS after excluding all probable causes of secondary variants of the disease to assess prognosis and subsequently select therapy [1,2,30,44,45].

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

Comments: The diagnosis of primary FSGS should be based on the exclusion of secondary causes of the disease (see Section 1.2).

2.1 Complaints and Anamnesis

A patient with FSGS may present with complaints of the onset and progression of peripheral edema, up to generalized edema. Typically, edema develops over several weeks, but the onset can also be acute with a weight gain of 5–10 kg. Patients note foamy urine. Weakness, fatigue, and loss of appetite are frequently observed.

The patient may be concerned about decreased urine output, dull lower back pain, increased or decreased blood pressure, palpitations (due to hypovolemia), and less commonly, the appearance of red urine (macrohematuria). Along with the main manifestations of nephrotic syndrome, its complications may come to the forefront in the clinical picture – infectious and thromboembolic (most commonly deep vein thrombosis of the lower extremities, renal vein thrombosis, pulmonary embolism), and acute kidney injury (AKI).

2.2 Physical Examination

Examination of patients with FSGS reveals the clinical picture of nephrotic syndrome, which often develops after a recently suffered upper respiratory tract infection. Pronounced edema can lead to skin cracks with leakage of serous fluid and infection of wound surfaces; blood pressure is elevated, and diastolic arterial hypertension can be severe (≥120 mm Hg).

Patients with acute-onset nephrotic syndrome are at risk for hypovolemia and the development of a nephrotic crisis as a consequence of hypoalbuminemia and decreased plasma oncotic pressure with excessive shifting of intravascular fluid into the interstitium. Symptoms of a nephrotic crisis include fever, vomiting, abdominal pain, diarrhea, cold extremities (due to slow capillary refill), oliguria, and tachycardia. Painful migrating erythema may appear on the skin of the thighs and abdomen. A clinical sign of hypovolemia can be a drop in blood pressure (orthostatic hypotension). Hypovolemia creates conditions for reduced renal perfusion and the development of prerenal AKI and tubular necrosis.

In rare cases, FSGS may occur without the development of nephrotic syndrome.

2.3 Laboratory Diagnostics

• We recommend performing a basic volume of laboratory diagnostics, as provided by the CKD guidelines, in all patients with a suspected or established diagnosis of FSGS in order to assess the severity of renal dysfunction, prognosis, identify factors that may affect treatment tactics, and determine the scope of therapy [26].

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

• To assess the risk of venous thrombosis and embolism, determine the scope of therapy, and adjust it in all patients with a suspected or established diagnosis of FSGS and nephrotic syndrome, we recommend determining the blood D-dimer concentration, prothrombin (thromboplastin) time in blood or plasma, international normalized ratio (INR), and activated partial thromboplastin time (aPTT), as well as testing the blood fibrinogen level [46-48].

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

Comments: According to the results of a meta-analysis (MA), the prevalence of thromboembolic complications in nephrotic syndrome is 8% (95% confidence interval (CI) 4–15%), which necessitates the diagnosis of hemostatic disorders and appropriate treatment, including prophylaxis. Among patients with an established diagnosis of FSGS, the incidence of thromboembolic complications averages 10%, increasing in cases of nephrotic syndrome relapse. An elevated blood D-dimer concentration is the most reliable predictor of thromboembolic complications in patients with FSGS and nephrotic syndrome.

• We recommend that patients with FSGS receiving treatment with cyclosporine** or #tacrolimus** undergo blood drug level testing weekly during the first month of dose titration or adjustment to ensure optimal treatment efficacy and reduce the toxicity of the therapy [49-55].

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

Comments: For information on the use of these drugs and target concentration ranges, see Section 3. The frequency of testing after 1 month depends on concentration stability and is determined individually.

2.4 Instrumental Diagnostics

• In patients with suspected or confirmed FSGS, we recommend performing instrumental diagnostics to the extent provided by the CKD guidelines to assess the severity of structural changes in the kidneys, as well as other organs and systems whose involvement is associated with decreased renal function and risks of other adverse events [26,56].

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

• In patients with suspected or confirmed FSGS and severe nephrotic syndrome (serum albumin <25 g/L) and suspected thromboembolic complications, we recommend performing duplex scanning of the inferior vena cava and renal veins, duplex scanning of the veins of the lower extremities, and, in the absence of contraindications, computed tomography (CT) of the chest organs with intravenous bolus contrast enhancement and/or CT of the abdominal organs with intravenous bolus contrast enhancement, and/or other necessary examinations to diagnose them [57-60,128].

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

Comments: The risks and incidence of thromboembolic complications were evaluated in a large retrospective study of 7,032 patients with nephrotic syndrome, regardless of its cause, including FSGS [57].

Regardless of the cause of nephrotic syndrome, the risk of thromboembolic complications increased 2.24-fold when nephrotic syndrome formed / serum albumin decreased below 3.0 g/dL (relative risk (RR) 2.24, 95% CI 1.24–4.05) and nearly 3-fold when albumin decreased below 2.5 g/dL (RR 2.79, 95% CI 1.45–5.37) [57].

In another study [58] examining 512 patients with nephrotic syndrome, a high incidence of thrombosis was demonstrated using chest and abdominal CT with intravenous bolus contrast enhancement (venous thrombosis of various locations in 35% of patients, in situ pulmonary embolism in 85% – of which 84% were asymptomatic, and renal vein thrombosis in 44%).

2.5 Other Procedures

• In patients with suspected FSGS in the absence of contraindications, we recommend performing an ultrasound-guided kidney biopsy followed by pathomorphological examination of the biopsy material to confirm the diagnosis and assess the severity of renal damage [24,36,61-69].

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

Comments: FSGS may be suspected based on the clinical picture in patients with nephrotic syndrome; however, the definitive diagnosis is established only by performing a kidney biopsy followed by pathomorphological examination of the biopsy material. Given the focal nature of glomerular involvement, especially in the early stages of the disease, the probability of detecting a segmental lesion critically depends on the number of glomeruli evaluated in the biopsy specimen. Furthermore, in the early stages of FSGS, glomerular changes predominantly occur in the juxtamedullary zone. Thus, an adequate tissue sample is required to identify focal segmental lesions. Ideally, 12–15 consecutive sections should be evaluated, each containing a minimum of 8 glomeruli [65,66]. Otherwise, it is not possible to reliably exclude the diagnosis of FSGS, and some cases will be erroneously classified as minimal change disease [29,65,73].

Glomerular morphological features on light microscopy are pathognomonic for various FSGS subtypes; however, light microscopy, as well as immunofluorescence microscopy, does not allow differentiating between a primary and secondary process. In some cases, immunofluorescence reveals granular deposits of IgM and C3 in areas of segmental sclerosis, the pathogenetic role of which remains incompletely understood. However, whatever the underlying molecular mechanism, staining for IgM and C3 is clearly a secondary phenomenon and does not help differentiate between various forms of FSGS.

Two consecutive meta-analyses clearly demonstrated that identifying specific microscopic glomerular changes is an integral part of diagnosing glomerular diseases (including detecting FSGS cases and their differential diagnosis with other glomerular diseases) [63,69]. They also form the basis for determining the histological variant of the disease and distinguishing between primary, secondary, and genetic FSGS. In addition, the choice and efficacy of treatment, renal outcomes, and mortality significantly depend on the clinicomorphological diagnosis, as confirmed in clinical studies [24,36,64-68].

• In patients diagnosed with FSGS, we recommend performing electron microscopy of kidney tissue sections to establish a differential diagnosis of the disease and distinguish between its primary and secondary forms [23,38,65,70-72].

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

Comments: The primary ultrastructural finding on EM is podocyte foot process effacement over the basement membrane associated with podocyte injury. The extent of podocyte foot process effacement or their total width can be used to differentiate between primary and secondary forms of FSGS.

In the cited studies with a reference method control (clinicomorphological differential diagnosis of primary and secondary FSGS), it was clearly shown that these parameters are approximately three times higher than normal and significantly greater than in other disease variants. Diffuse podocyte foot process effacement (involving ≥80% of the surface area) or their total width exceeding 1500–1600 nm on electron microscopy corresponds to primary FSGS (treatment-naïve). Potential exceptions include HIV-associated nephropathy and pamidronic acid-induced drug-related FSGS, in which foot process effacement reaches >80% and severe nephrotic syndrome develops [74].

The utility of EM in FSGS is not limited to podocyte assessment. Other ultrastructural findings (immune deposits, glomerular basement membrane alterations, etc.) can be of substantial value in accurate differential diagnosis of the disease.

• We recommend genetic testing in histologically confirmed FSGS combined with an absence of causes for a secondary disease variant, or disease onset in childhood, or a family history of the disease, or resistance to prednisolone** and/or calcineurin inhibitors, to identify genetic causes of the disease and adjust treatment [25,75-82].

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

Comments: The cited studies using a reference-method control (selection of the described FSGS case categories based on clinicomorphological diagnosis and assessment of treatment response) clearly showed that the prevalence of genetic causes in adult FSGS patients can be substantial (up to 40% of cases). Genetic testing can identify a molecular defect as the underlying cause of the disease and help avoid unnecessary immunosuppression and its complications.

Genetic FSGS may present in childhood or adulthood, depending on the mutation type. In some cases of genetic predisposition (e.g., APOL1 mutations), clinical manifestations appear only after exposure to a second hit, such as chemical toxicity, inflammation, or infection. Monogenic causes of genetic FSGS can be classified into kidney-limited and syndromic, with the latter associated with extrarenal manifestations such as hearing loss and visual impairment. Genes associated with non-syndromic FSGS and/or steroid-resistant nephrotic syndrome are expressed predominantly in podocytes and are involved in the organization of the slit diaphragm and actin cytoskeleton. Mutations in NPHS1, NPHS2, PLCε1, CD2AP, and MYO1E are inherited in an autosomal recessive manner, whereas mutations in TRPC6, ACTN4, and INF2 cause autosomal dominant FSGS.

A syndromic presentation of the disease—meaning its combination with extrarenal manifestations (e.g., deafness, skin, ocular, or skeletal lesions, neurological deficits, hepatosplenomegaly)—a clear family history of kidney disease (especially overt proteinuria or nephrotic syndrome), and resistance to prior calcineurin inhibitor therapy are the main indications for seeking gene mutations as the cause of FSGS. Syndromic FSGS results from mutations in genes encoding proteins expressed in tissues outside podocytes, such as WT1, LAMB2, ITGB4, CD151, SCARB, and LMX1b. In these cases, extrarenal manifestations aid clinicians in making the diagnosis.

In genetic FSGS, a response to immunosuppression is rare, and any such response is typically partial. There is an increasing number of reports of genetic FSGS variants resistant to glucocorticoids and calcineurin inhibitors in the absence of a family history of kidney disease in adults. The gene mutations responsible for the development of treatment-resistant FSGS are listed in Section 1.2. Exceptions include cases with mutations in the WT1, TRPC6, PLCE1, MAGIC2, TNS2, DLC1, CKD20, ITSN1, and ITSN2 genes, which may partially respond to immunosuppressive therapy [43]. Mutations in the podocin gene are the most common cause of monogenic FSGS [81].

Thus, a response to first-line glucocorticoid therapy can be considered confirmation of primary FSGS and eliminates the need for genetic testing. Currently, the most widespread genetic testing methods for patients with FSGS are direct (Sanger) sequencing and targeted next-generation sequencing. Whole exome sequencing is a more informative method for identifying mutations in candidate and novel genes, which is particularly important for identifying the genetic etiology of FSGS in the absence of a family history. Testing should be performed using targeted sequencing of a gene panel associated with genetic podocytopathies, and the choice of the optimal assay should be discussed with specialized diagnostic laboratories.

Genetic testing should definitely not be offered to patients with well-known conditions associated with secondary FSGS.

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

General approaches to the treatment of patients with FSGS are presented in "Appendix B", item 1.

3.1 Non-immunosuppressive therapy for FSGS

• In patients diagnosed with FSGS regardless of its etiology, we recommend administering non-immunosuppressive renoprotective therapy as indicated and in the scope specified by CKD clinical guidelines, to reduce proteinuria and the rate of disease progression, and to prevent and treat complications of renal dysfunction [26].

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

• In patients with FSGS and proteinuria, regardless of etiology and in the absence of contraindications, we recommend treatment with renin-angiotensin system inhibitors—angiotensin-converting enzyme inhibitors (ACE inhibitors) or angiotensin II receptor blockers (ARBs)—to reduce proteinuria, progression of renal dysfunction, cardiovascular events, and all-cause mortality [83-87].

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

Comments: ACE inhibitors or ARBs are a cornerstone of renoprotective therapy, as covered in detail in the 2021 Clinical Guidelines on Chronic Kidney Disease, Section 3.1 [26]. ACE inhibitors and ARBs should also be recommended for patients with secondary and confirmed genetic forms of FSGS. By acting on non-immune mechanisms of disease progression, ACE inhibitors and ARBs can also exert an antiproteinuric effect in genetic forms of FSGS [87,88].

• For the prevention of thromboembolic complications in hospitalized patients with nephrotic syndrome and serum albumin <25 g/L in the setting of suspected or confirmed FSGS, we recommend administering #enoxaparin sodium** or #dalteparin sodium (see comments) until resolution of severe hypoalbuminemia or initiation of alternative therapy [47,48,57,89-92].

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

Comments: In patients with nephrotic syndrome and blood albumin <25 g/L, a threefold increase in the risk of venous thromboembolic events was registered compared to patients without nephrotic syndrome. The highest risk of thromboembolic events was observed during the first 6 months of nephrotic syndrome [89].

In a study by Rostoker G et al. [90], patients with nephrotic syndrome, including FSGS, who had a high risk of thrombotic events, were treated with #enoxaparin sodium** 4,000 anti-Xa IU for 3 to 12 months for the prevention of venous thrombosis under the control of duplex scanning of the renal veins, lower limb veins, and lung perfusion scintigraphy, D-dimer levels, and fibrin degradation products.

As a result of treatment with #enoxaparin sodium**, no evidence of thrombosis was observed in any patient. In another study, the prophylactic use of #enoxaparin sodium** or #dalteparin sodium was evaluated in patients with nephrotic syndrome, including FSGS, with no cases of venous thrombosis registered [91].

Prophylactic doses of #enoxaparin sodium** range from 4,000 anti-Xa IU/0.4 mL [90, 91, 93] to 8,000 anti-Xa IU/0.8 mL [91] (administered once daily subcutaneously); #dalteparin sodium ranges from ≤5,000 (2,500–5,000) anti-Xa IU [91] to ≥5,000 in the study by Welander F et al. [92], reaching ≥7,500 anti-Xa IU in the study by Kelddal S et al. [91] (once daily, subcutaneously). The choice of dose should be personalized taking into account the risks of thromboembolic events and bleeding.

This treatment is more applicable in a hospital setting and should be continued until partial remission of the disease is achieved [93] or alternative therapy is prescribed (see the next statement).

• For the prevention and treatment of thromboembolic events, we recommend the use of direct factor Xa inhibitors (#apixaban**, #rivaroxaban**) [94–97] in patients with CKD G1–4 and nephrotic syndrome against the background of a suspected or established diagnosis of FSGS, regardless of its etiology, at eGFR >15 mL/min/1.73 m².

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

Comments: A systematic review and meta-analysis of 6 RCTs and 19 observational studies comparing the efficacy and safety of direct factor Xa inhibitors and warfarin** in patients with CKD showed that direct factor Xa inhibitors (#apixaban**, #rivaroxaban**) were associated with a significant reduction in the risk of thromboembolic events and stroke (22% risk reduction) and major bleeding (24% risk reduction) vs warfarin** [95]. In a single-center retrospective study by Keddal S et al., direct factor Xa inhibitors—#apixaban** orally at a dose of 5 mg twice daily and #rivaroxaban** orally at 20 mg daily for an average of 7 months—were used in patients with nephrotic syndrome with an albumin level of less than 25 g/L [94]. One retrospective cohort study demonstrated the safe and effective use of direct factor Xa inhibitors compared to warfarin** for the prevention of thromboembolic complications of nephrotic syndrome [96]. In the study by Van Meerhaeghe T et al., to prevent thromboembolic complications in patients with nephrotic syndrome, including FSGS with an albumin level below 20 g/L, #apixaban** was used at a standard dose of 5 mg twice daily, with a mean treatment duration of 153±132 days (average duration of about 5 months). A reduced dose of #apixaban** (2.5 mg twice daily) was used in patients older than 80 years, with a body weight ≤60 kg, or with an increase in serum creatinine ≥133 µmol/L (1.5 mg/dL) [97]. The use of #rivaroxaban** and #apixaban** when eGFR drops below 15 mL/min is contraindicated according to the prescribing information. In a randomized study by Zhang L et al., the efficacy and safety of #rivaroxaban** 30 mg daily for 3 weeks were compared with the efficacy and safety of heparin group drugs for the treatment of patients with nephrotic syndrome (including FSGS) who developed venous thrombosis. #Rivaroxaban** was superior to heparin group drugs in efficacy and had a favorable safety profile in this group of patients [96].

3.2 Treatment of primary FSGS

The algorithm for the treatment of primary FSGS is presented in Appendix B, section 2.

3.2.1 Treatment of the first episode of primary FSGS (initial therapy for primary FSGS)

A reliable indicator for assessing the subsequent prognosis of renal survival in FSGS remains the response to treatment. In 50% of non-responders, end-stage renal disease (ESRD) develops in less than 10 years, whereas the prognosis becomes favorable upon achieving partial or complete remission [98].

Before deciding on the prescription of glucocorticoids and calcineurin inhibitors, it is necessary to determine whether FSGS is primary or secondary. In the latter case, such treatment is not justified.

• For the induction of remission in patients with primary FSGS and nephrotic syndrome, we recommend high-dose prednisolone** monotherapy or calcineurin inhibitor therapy in combination with low-dose prednisolone** as first-line treatment [68, 98–102].

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

Comments: Treatment of the first episode of primary FSGS is also presented in Table 4.

Glucocorticoids are the traditional international approach to primary FSGS therapy, although in the absence of RCTs, the evidence base remains weak. The justification for this approach is determined by the likelihood of achieving a response (complete or partial remission) of about 50% according to several studies, as well as the fact that the evidence base for other immunosuppressive treatment options is built on steroid-resistant cases (or the development of glucocorticoid dependence or frequent relapses despite treatment). An alternative is a combination of cyclosporine** and glucocorticoids (the latter in low doses equivalent to 10–15 mg/day of prednisolone**), the efficacy of which regarding remissions and disease progression rates has been demonstrated in small retrospective [99, 102] and large cohort [100] studies. According to meta-analyses, the combination of cyclosporine** and glucocorticoids may be more effective than glucocorticoid monotherapy; however, the choice between these treatment options should be based on individual assessments of the benefits and risks of known complications. An exception may be the cellular variant of FSGS, in which preference should be given to glucocorticoid monotherapy [100]. Calcineurin inhibitor-based treatment should not be used in patients with significant vascular changes in the kidney or pronounced interstitial renal fibrosis based on histology, or with a decrease in eGFR <30 mL/min/1.73 m² due to the risk of nephrotoxic effects of these drugs.

Prednisolone** as monotherapy is used orally at a dose of 1 mg/kg/day, but not exceeding 80 mg/day for 8 weeks, then the dose is gradually tapered by 5–10 mg/day every 1–2 weeks to a maintenance dose of 10–15 mg/day (in individual cases, glucocorticoids in equivalent doses may be used instead of prednisolone**). An alternative option includes 3 intravenous #methylprednisolone** pulses of 1 g every 24 hours, followed by oral prednisolone** 0.5 mg/kg/day for 8 weeks, with a gradual taper to 10–15 mg/day [69]. The optimal duration of high-dose prednisolone** intake in adult patients with primary FSGS has not been precisely established. Data from individual retrospective studies indicate the achievement of a response in steroid-sensitive cases with a median treatment duration of 4 months [35, 69].

At the same time, some RCTs investigating the treatment of steroid-resistant FSGS cases defined them after 4–8 weeks of treatment [69, 103].

The duration of treatment should probably be determined individually based on dynamic assessments: treatment efficacy (a trend toward decreased proteinuria with stable GFR) and the development of known glucocorticoid complications (Appendix A3, item 1). When an early response to glucocorticoids is registered in the form of a decrease in proteinuria or remission, it is advisable to continue treatment in tapering doses for 6 months and transition to maintenance therapy (5 mg/day). Conversely, in the absence of an effect, especially combined with the development of treatment complications, the latter should be discontinued in a timely manner, classifying the case as steroid-resistant (see below).

In the study by Chávez-Mendoza CA et al. [102], a group of patients was treated with either cyclosporine** or #tacrolimus**, targeting serum drug levels of 100 to 180 ng/mL and 5 to 7 ng/mL, respectively, along with prednisolone** at a dose of 0.10 to 0.15 mg/kg per day. The comparison groups were prescribed prednisolone** at 0.8 to 1.0 mg/kg for 12 weeks, during which proteinuria was assessed, and if a reduction of <25% was observed, calcineurin inhibitors were added to the therapy in the specified doses in a third group. This treatment regimen led to a response in 72.7% of treated patients, with complete remission of FSGS achieved in 36.4% after 2 (1–4) months of treatment. The duration of calcineurin inhibitor therapy was 12 months. A response to treatment was achieved in all groups in 72.7%, 76.9%, and 87.5%, with complete remission in 36.4%, 48.7%, and 31.3%, respectively. There were no differences in post-treatment relapse rates (44.4%, 48.4%, and 46.7%) or in 5-year renal survival (81.8%, 87.2%, and 87.5%) [101].

Table 4. Some practical aspects of initial treatment of primary FSGS aimed at achieving remission [2]

3.2.2 Treatment of steroid-resistant primary FSGS

• To achieve remission in patients with steroid-resistant primary FSGS, we recommend treatment with cyclosporine** with or without low-dose prednisolone** (maximum 15 mg/day) for at least 6 months [61,62,69,105,106].

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

Comments: The evidence base for this statement is grounded in data from four meta-analyses of randomized controlled trials on the use of cyclosporine** in patients with steroid-resistant FSGS compared to placebo or another treatment regimen. Cyclosporine** therapy is associated with an increased probability of remissions and a comparable rate of adverse events compared to other treatment regimens [62,69,105,106]. In individual cases, the use of low-dose glucocorticoids may be preceded by their intravenous administration at loading doses of 0.25–1.0 g once daily (for 1–3 days).

• In patients with steroid-resistant primary FSGS, as an alternative to cyclosporine** (in case of contraindications or intolerance), to achieve remission we recommend treatment with #tacrolimus** in combination with prednisolone** [104,107,108].

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

Comments: In the only randomized controlled trial for the induction of remission in steroid-resistant FSGS, #tacrolimus** was used at an initial dose of 0.1 mg/kg/day orally in 2 doses with subsequent dose adjustment until reaching the target serum drug concentration (5–10 ng/mL) within 6–12 months. In addition, patients received oral prednisolone** at a dose of 0.5 mg/kg; after 8 weeks of treatment, the prednisolone** dose was reduced by 5 mg every 2 weeks down to 15 mg/day and maintained at this dose for 8 weeks, followed by gradual discontinuation. The remission rate was 67% at 6 months (70% of which were complete) and 73% at 12 months [107]. These observations are, to one degree or another, confirmed in other cited studies, one of which demonstrated the efficacy of converting from cyclosporine** to #tacrolimus**.

The choice between cyclosporine** and #tacrolimus** may be based on their local cost, the availability of blood drug level monitoring, and known adverse effects, including renal toxicity [108].

• For patients with primary steroid-resistant FSGS receiving cyclosporine** treatment, we recommend adjusting the dosage individually based on blood drug concentrations in order to achieve remission and prevent complications of therapy [62,69,105,106,109-111].

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

Comments: Induction doses of cyclosporine** of 3.5–6 mg/kg/day were used in randomized controlled trials [62,115]. The use of higher doses [51] and higher concentrations is accompanied by an increased risk of nephrotoxicity. The hepatic metabolism of cyclosporine** is highly individual: high metabolism requires an increase in doses, and low metabolism requires a reduction, under the control of blood drug levels. For safety reasons, treatment should be initiated at a lower dose and gradually increased until the target blood drug level is reached. Monitoring of nephrotoxicity should be carried out through regular assessment of serum creatinine dynamics and eGFR, especially in the initial phase of treatment. In most randomized controlled trials (including those included in the cited meta-analyses [61,62,69,105,106,109-111]), the dose of the drug in FSGS patients was selected based on the target serum concentration of cyclosporine** 12 hours after the last dose (T0). It varied from 100 to 250 ng/mL [109-111]. Clinical practice shows that acute and chronic renal toxicity generally manifests at blood drug concentrations above 200 ng/mL. We believe that exceeding this level should be avoided, aiming for serum cyclosporine** levels of 125 to 200 ng/mL in the initial phase of treatment. As a response is achieved, doses and concentrations of the drug can be reduced by 25–50% to minimize toxicity.

• We recommend that patients with primary FSGS receiving #tacrolimus** treatment maintain blood concentrations of the drug in the range of 5–10 ng/mL in order to achieve remission and prevent complications of therapy [53,102,107,108].

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

Comments: The doses of #tacrolimus** should be adjusted according to the target blood concentration of the drug, which in the cited studies, including one randomized controlled trial, ranged from 5 to 11 ng/mL. The appearance of clinical signs of renal toxicity requires a reduction in the target blood level of the drug.

3.2.3 Treatment of patients with relapse, calcineurin inhibitor resistance, steroid-dependent and/or frequently relapsing primary FSGS

• In patients with a first relapse of primary FSGS after drug-induced remission and cessation of therapy, we recommend considering the re-administration of that variant of previous treatment which was effective previously to re-achieve remission [2].

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

• We recommend referring patients with primary FSGS who are resistant to glucocorticoids and resistant or intolerant to calcineurin inhibitors to specialized regional or federal centers for further diagnosis and determination of alternative treatment [2].

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

Comments: Further diagnosis specifically involves revising the diagnosis based on clinical and morphological analysis and performing molecular studies. Alternative therapy may include the use of #rituximab**, cyclophosphamide**, and #tacrolimus** (see corresponding statements below) individually or in combination, on a personalized basis, taking into account the balance of expected efficacy and the risk of side effects.

• We recommend the use of #rituximab** for induction of remission and/or reduction of relapse frequency in patients with primary FSGS resistant to glucocorticoids and calcineurin inhibitors [113].

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

Comments: According to a meta-analysis of 16 observational studies, the rate of complete remissions with #rituximab** in patients with primary FSGS was 42.9% (95% CI 10.8–82.3%), and partial remissions were 10.7% (95% CI 7.0–59.2%) with a mean follow-up of 18.7±9.0 months. The relapse rate in patients treated with #rituximab** was 47.3% (95% CI 25.4–70.2%). There was no significant difference in the rate of remissions and flares when using different doses: a total of 1500 mg/m² versus a total of ≥1500 mg/m2. Administration regimens, determined individually, may be as follows: 375 mg/m² once; 375 mg/m² once a week, 2 administrations; 375 mg/m² once a week, 4 administrations [113]. Rules for preparation, storage, and administration of #rituximab** comply with the instructions for medical use ("Appendix A3", cl. 2). #Rituximab** treatment can be administered as monotherapy or combined with other drugs, taking into account the known risks associated with B-cell depletion.

• We recommend considering the prescription of cyclophosphamide** for the induction of remission in patients with primary FSGS who show no response to high doses of glucocorticoids or calcineurin inhibitors, or when continuation of this therapy is not feasible [107,114].

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

Comments: The use of cyclophosphamide**, which showed no difference in efficacy compared to #tacrolimus** according to one RCT, can be considered as an alternative treatment in patients who failed standard therapy or in cases of high risk of complications from calcineurin inhibitors [114]. Cyclophosphamide** can be prescribed as monotherapy or in combination with low- or medium-dose glucocorticoids. Its prescription in combination with #tacrolimus** or #rituximab** is impractical given the significant B- and T-cell depletion.

• In patients with steroid-dependent or steroid-resistant primary FSGS, we recommend considering treatment with #tacrolimus** to achieve remission [2,54,107].

GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)

Comments: Such treatment can be an alternative to cyclophosphamide**, especially in cases of high risk and undesirability of the latter's known side effects. In individual cases, to increase treatment efficacy, #tacrolimus** can be used in some combination with glucocorticoids and/or #rituximab**.

In a randomized trial in patients with steroid-dependent and steroid-resistant FSGS, #tacrolimus** was used at a dose of 0.1 mg/kg/day combined with prednisolone** at an initial dose of 0.5 mg/kg per day in 2 divided doses. The dose of #tacrolimus** was adjusted according to serum drug concentration (C0 concentration from 5 to 10 ng/mL). After 8 weeks of treatment, the dose of prednisolone** was reduced by 5 mg every 2 weeks down to 15 mg/day. For patients with complete or partial remission, the dose of #tacrolimus** was reduced by 1 mg per day every 4 weeks after 6 months. Total therapy duration was 12 months. The relapse rate was comparable between the #tacrolimus** and cyclophosphamide** groups (26.7 vs 27.8%) [107]. In the study by Segarra A et al. [54], #tacrolimus** was prescribed at a dose of 0.15 mg/kg in two divided doses at 12-hour intervals. During subsequent follow-up, the dose was adjusted to achieve a 12-hour whole blood level of #tacrolimus** from 5 to 10 ng/mL. Treatment was continued for 6 months. Simultaneously with #tacrolimus**, prednisolone** was prescribed at a dose of 1 mg/kg/day (maximum daily dose 60 mg) orally for 4 weeks, and then 1 mg/kg every other day up to week 8. After week 8, the dose of prednisolone** was gradually tapered at a rate of 0.05 mg/kg/week until complete discontinuation by week 24. After discontinuation of #tacrolimus**, 76% of patients experienced a relapse. #Tacrolimus** was re-administered for 1 year. After 2 years of follow-up, 48% of patients achieved sustained remission. The main side effect was acute reversible nephrotoxicity (40%). The duration of treatment and dosages (target concentrations) of the drug may be modified depending on the obtained effect and its tolerability.

• We recommend cyclosporine** treatment in patients with steroid-dependent/frequently relapsing primary FSGS to achieve nephrotic syndrome remission and reduce relapse frequency [2,115,116].

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

Comments: In a non-randomized study, cyclosporine** therapy was started at an oral dose of 4 mg/kg per day at 12-hour intervals until a target serum level of 100–150 ng/mL was achieved in patients with nephrotic syndrome relapses [116]. Based on practical experience, the working group suggests that the dosing principles and target concentrations of the drug given in Section 3.2.2 apply to such cases. In individual cases, to increase treatment efficacy, cyclosporine** can be used in some combination with glucocorticoids and/or #rituximab**.

• We recommend the use of #rituximab** in patients with steroid-dependent and/or frequently relapsing primary FSGS to achieve/maintain remission and reduce relapse frequency [113,117].

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

Comments: In a meta-analysis of observational studies with good tolerability of #rituximab** treatment, the remission rate was >50% of cases (complete remissions >40%), and disease relapses were observed in 27% of cases. All patients received #rituximab** at a mean dose of 1500 mg/m² (ranging from 375 to 3375 mg). However, the #rituximab** therapy protocol varied from study to study depending on the B-cell count assessed by the level of CD19-positive cells. The most common regimens involving #rituximab** (in 6 RCTs) were infusions of the drug at a dose of 375 mg/m² four times at weekly intervals or 1 g twice at 2-3 week intervals [117]. In some studies, single and double infusion regimens of #rituximab** at a dose of 375 mg/m² were used [118-120].

• We recommend considering the use of cyclophosphamide**, 0.5–0.75 g/m¹, monthly, intravenously, for 6 months in patients with steroid-dependent primary FSGS to relieve flares and reduce relapse frequency [107,114].

GCR BLOE 2Grade of Recommendation B (Level of Evidence – 2)

Comments: In the RCT by Ren H et al. [107], with the use of cyclophosphamide** (0.5–0.75 g/m¹) monthly for 6 months in combination with glucocorticoids in adult patients with steroid-resistant or steroid-dependent FSGS, the remission rate at 6 and 12 months was 56% and 67%.

3.3 Treatment of secondary FSGS and FSGS of unknown etiology

• We do not recommend prescribing glucocorticoids and/or calcineurin inhibitors in patients with secondary FSGS, or with FSGS of undetermined cause, or with FSGS without nephrotic syndrome, due to their lack of efficacy and to prevent side effects [2,30,35,44,45,121].

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

Comments: Secondary FSGS and FSGS of unknown cause have similar clinical and laboratory manifestations—the absence of nephrotic syndrome and a slowly progressive decline in renal function. Since the development of secondary FSGS is based on pathogenetic mechanisms unrelated to immune processes (see Section 1.2), therapy with glucocorticoids and/or calcineurin inhibitors is not indicated in this case. According to a comparative study by Rydel JJ et al., patients with FSGS without nephrotic syndrome did not receive glucocorticoid treatment and had a more favorable prognosis than patients with nephrotic syndrome [35].

Nephroprotective therapy must be performed in accordance with CKD treatment guidelines. Immunomodulatory treatment should only be discussed if the diagnosis is revised in favor of the primary variant of the disease (see Section 3.2).

• We recommend targeting the underlying cause of secondary FSGS in patients to prevent disease progression [2,30,35,44,45,121].

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

4. Medical Rehabilitation and Sanatorium-Resort Treatment

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

• In patients with FSGS we recommend performing medical rehabilitation as indicated and to the extent provided by the CKD guidelines to improve disease outcomes [26].

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

5. Prevention and Dispensary Observation

Methods and approaches to primary prevention of FSGS have not been established.

• In patients with FSGS, we recommend carrying out preventive measures aimed at preventing complications of renal dysfunction and acute kidney injury, as well as clinical dispensary monitoring to the extent provided by the CKD guidelines to improve disease outcomes [26].

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

6. Organization of Medical Care

Main indications for emergency hospital admission of patients with FSGS:

1) Development or suspected development of 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 decrease in GFR and/or increase in blood creatinine level (by >50% over 3 months);

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

4) any of the following complications requiring emergency therapy, including 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;

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

6) newly detected decrease in GFR <30 ml/min/1.73 m².

Main indications for hospital discharge following emergency admission of patients with FSGS:

1) The diagnosis of AKI has been confirmed or excluded; 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) clinically significant complications of renal dysfunction have been treated: water-electrolyte disorders, blood acid-base balance disorders: hypovolemia, hyperkalemia, hypokalemia, hyponatremia, metabolic acidosis, metabolic alkalosis have been corrected or compensated (by conservative methods or dialysis methods);

5) blood pressure has been lowered, life-threatening manifestations of hypertension have been eliminated, and antihypertensive therapy has been optimized in patients with CKD G1-G5D;

6) in case of a newly detected decrease in GFR <30 ml/min/1.73 m² – diagnosis and treatment of the main complications of renal dysfunction have been performed.

Main indications for elective hospital admission:

1) Initial diagnosis when FSGS is suspected;

2) in patients with a known diagnosis of FSGS:

a. increasing proteinuria;

b. newly diagnosed nephrotic syndrome or a combination of hypoalbuminemia and proteinuria ≥3.5 g/day/1.73 m²;

c. need for diagnosis/differential diagnosis using renal biopsy or other diagnostic tests requiring hospitalization, including in a regional or federal center;

3) creation of vascular access for dialysis;

4) pregnancy;

5) administration of immunosuppressive treatment for FSGS and/or treatment of associated pathological processes;

6) preparation for surgical treatment for various indications.

Main indications for hospital discharge following elective admission:

1) The diagnosis of FSGS has been confirmed or refuted, treatment and initial diagnosis using renal biopsy or other diagnostic tests have been performed in accordance with the guidelines;

2) the diagnosis of relapse has been confirmed or refuted, treatment has been performed in accordance with the guidelines;

3) vascular access for dialysis has been established;

4) FSGS during pregnancy – renal prognosis has been determined, treatment and diagnostics have been performed in accordance with the guidelines;

5) administration of immunosuppressive treatment – a cycle or hospital phase of immunosuppressive therapy has been completed, diagnostics and treatment of its complications have been performed, the functional state of the kidneys has been monitored, diagnostics and treatment of complications of renal dysfunction (if identified) have been performed;

6) preparation for surgical treatment – necessary diagnostics and correction of CKD complications affecting the risks of surgical intervention have been carried out (conservatively or by dialysis methods).

Principles of outpatient care organization:

Outpatient management of patients with FSGS should be organized in accordance with the principles set out in the CKD guidelines [26].

7. Additional Information

The following factors are distinguished that influence renal survival in patients with FSGS:

Magnitude of proteinuria. In patients with nephrotic syndrome, 5-year renal survival is 60-90%, and 10-year renal survival is 30-55%. In cases of treatment resistance, massive proteinuria exceeding 10 g/day/1.73 m² is associated with disease progression to ESRD within 5 years. The highest renal survival (over 85% at 10 years) is observed in patients without nephrotic syndrome who have preserved renal function [5,9,74,122].

Clinical data. Higher risks of developing ESRD are associated with cases of FSGS with baseline marked renal dysfunction [33,98,123], against the background of more widespread glomerulosclerosis and interstitial fibrosis, as well as severe, long-standing persistent nephrotic syndrome without response to therapy and progressive decline in renal function. In addition, patients with impaired renal function are more likely to have a poor response to treatment.

Morphological data. The severity of interstitial fibrosis and tubular atrophy [36,68,123], and the collapsing variant of FSGS are unfavorable predictors for the development of ESRD [67]. Patients with the tip lesion variant of FSGS have a better response to glucocorticoid treatment, although its presence does not guarantee the achievement of remission [36,124,125].

Response to therapy. The strongest prognostic indicator of renal survival in FSGS is the initial response to therapy, regardless of the morphological picture [35,49,69,98]. Patients who achieve partial or complete remission have a much higher chance of preserving renal function at 10 years (approximately 80% vs <50% in non-responders or untreated patients) [34,35,98,126,127].

Disease progression. Despite the achievement of partial remission, disease progression with worsening renal function may be observed, which always indicates ongoing disease activity or secondary hemodynamic injury: repeat biopsy shows an increase in the percentage of sclerotic glomeruli. Genetic factors may contribute to progression.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Bobkova I.N. – MD, PhD, Professor, Department of Internal, Occupational Diseases and Rheumatology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow. Member of the National Association of Nephrologists.

2. Vatazin A.V. – MD, Professor, Head of the Surgical Department of Renal Transplantation, Head of the Department of Transplantology, Nephrology and Artificial Organs, Moscow Regional Research Clinical Institute named after M.F. Vladimirsky, Moscow. President of the National Nephrology Association. Honored Doctor of the Russian Federation. Honored Scientist of the Russian Federation.

3. Dobronravov V.A. (Head of the Working Group) – MD, Professor, Director of the Research Institute of Nephrology, Professor of the Department of Propaedeutics of Internal Diseases with Clinic, First Saint Petersburg State Medical University named after Acad. I.P. Pavlov, Saint Petersburg. Board Member of the National Nephrology Association.

4. 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.

5. Chebotareva N.V. – MD, PhD, Department of Internal, Occupational Diseases and Rheumatology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow. Center for Excellence in Medical Care in Nephrology, V.I. Shumakov National Medical Research Center of Transplantology and Artificial Organs, Chief Specialist. Member of the National Association of Nephrologists.

Conflict of interest: none.

Appendix A2. Methodology for Developing Clinical Guidelines

The 2013 clinical guidelines "Focal Segmental Glomerulosclerosis" and international guidelines on the subject served as the basis for the development of these clinical guidelines for FSGS. The preparation process consisted of the following stages: selection of the lead, working group members, and secretariat; identification during discussions of the most critical areas for clinical practice that the guidelines should cover; definition of specific research questions and formulation of recommendations; development of evidence retrieval methods; and formation of the final list of recommendations and its structure.

Following the initial submission of the draft guidelines in 2021, it was revised based on reviews by the Center for Expertise and Quality of Medical Care (in August 2022, December 2023, and July 2024). The instructions presented in these guidelines are based on the analysis of studies in nephrology and related medical fields, their systematic reviews and meta-analyses conducted by group members and published up to May 2024.

The working group members sought to ensure that each recommendation was based on the highest possible levels of evidence and recommendation grades. Nevertheless, the working group 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 with this profile and the fact that these recommendations may be of substantial importance for practical work.

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

Target audience for these clinical guidelines:

1. Nephrologist.

2. General practitioner / Physician.

3. General practitioner / district physician.

4. General practitioner (family physician).

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

Table 2. Scale for grading levels of evidence certainty (LEC) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

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

Procedure for updating clinical guidelines.

The clinical guidelines update mechanism 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 diseases, or 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;

- gastrointestinal 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, decreased muscle mass;

- related to mineralocorticoid activity: fluid and sodium retention in the body, hypernatremia, hypokalemic syndrome.

The complete list is provided in the instructions for medical use of the medicinal product (see State Register of Medicinal Products, http://grls.rosminzdrav.ru).

2. Preparation and storage rules for the medicinal product #rituximab**

The required amount of the drug is withdrawn under aseptic conditions and diluted to the calculated concentration (1-4 mg/mL) in an infusion bottle (bag) with 0.9% sodium chloride** solution for infusion or 5% dextrose** solution (solutions must be sterile and pyrogen-free). To mix, gently invert the bottle (bag) to avoid foaming. Prior to administration, visually inspect the solution for particulate matter or discoloration.

The prepared infusion solution is physically and chemically stable for 12 hours at room temperature or for 24 hours at 2 to 8 °C.

The drug must be administered strictly as an intravenous infusion via a separate catheter! Intravenous push or bolus administration is prohibited!

The recommended initial rate of the first infusion is 50 mg/h; after the first 30 minutes, the rate may be increased by 50 mg/h every 30 minutes, up to a maximum rate of 400 mg/h.

Subsequent infusions can be started at a rate of 100 mg/h and increased by 100 mg/h every 30 minutes up to a maximum rate of 400 mg/h.

Detailed information is provided in the instructions for medical use of the drug (see State Register of Medicines, http://grls.rosminzdrav.ru).

Appendix B. Physician Action Algorithms

1. General approaches to the treatment of FSGS

2. Treatment algorithm for primary FSGS

Note: CsA** – cyclosporine**.

Appendix C. Patient Information

Focal segmental glomerulosclerosis (FSGS) is one of the causes of nephrotic syndrome. The cause of primary FSGS is unknown. FSGS can be secondary (e.g., associated with certain other diseases, specific medications, etc. (Table 1, Section 1.2)), or develop as a result of a genetic defect.

The main symptom of nephrotic syndrome that prompts patients to seek medical care is typically edema. Increased urinary protein loss may lead to "foamy" urine. The disease is accompanied by a gradual decline in renal function.

Diagnosis should include a range of interventions aimed at: a) confirming the diagnosis of the disease; b) determining the severity of kidney damage; c) identifying other diseases that contribute to the development and progression of FSGS.

The only way to confirm the diagnosis of FSGS, assess disease prognosis, and select optimal treatment is to perform a kidney biopsy and conduct specialized microscopic examinations of the renal tissue sample.

Patients with low urinary protein loss and preserved renal function generally have a more favorable prognosis; therefore, achieving disease remission with treatment is critical.

The treatment of FSGS must be managed under the supervision of a nephrologist. Before starting treatment, the nephrologist and the patient should discuss the proposed therapy to clearly understand the expected benefits, potential side effects, and principles of their prevention.

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

1. Russian title: Formula for GFR calculation proposed by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) research group [27,28]

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):

eGFR = 141 * min(Serum creatinine / kappa, 1)^alpha * max(Serum creatinine / kappa, 1)^(-1.209) * 0.993^Age * [1.018 if female] * [1.159 if Black],

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