Edema is the primary clinical symptom of NS and frequently prompts patients to seek medical attention. It results from sodium and water retention in the extravascular space and can range in severity from mild swelling to anasarca. Severe cases may be associated with transudative effusions including ascites, pleural effusions, or, more rarely, pericardial effusions. The mechanisms underlying edema formation have been debated and can be explained by two theories: the “overfill” and “underfill” hypotheses (for further details, see Chapter 29 ). Briefly, the overfill hypothesis, now recognized as the predominant mechanism in most cases, suggests that primary sodium retention occurs due to overactivation of epithelial sodium channels (ENaC) in the collecting duct. This sodium retention leads to water reabsorption, suppression of the renin-angiotensin-aldosterone (RAA) system and antidiuretic hormone (ADH), and increased release of natriuretic peptides. Blood volume generally remains normal or slightly elevated, though hypervolemia and hypertension can occur in some cases. In contrast, the underfill hypothesis attributes edema formation to hypoalbuminemia, which reduces plasma oncotic pressure and causes fluid to shift into the extravascular space, resulting in hypovolemia. This activates the sympathetic nervous system, the RAA system, and ADH, further promoting sodium and water retention and exacerbating edema. While the underfill mechanism lacks strong mechanistic support, ^, it may be relevant in severe cases, particularly in children. ^,

Hypovolemia needs to be excluded in all children presenting with NS, with or without edema, particularly in a setting of vomiting, diarrhea, reduced oral intake, or unsupervised diuretic use. ^, Clinical features include history of abdominal pain, vomiting, or postural hypotension; lethargy; prolonged capillary refill time; cold extremities; tachycardia; low-volume pulses; and hypotension. Biochemical parameters that indicate hypovolemia include elevated hematocrit, high blood urea (mg/dL)-to-creatinine (mg/dL) ratio, low fractional excretion of sodium (<0.5%), and high urinary potassium index (>0.6). ^, In children, dehydration and subsequent hypovolemia, often triggered by infectious complications, are major contributors to AKI. In adults, the mechanisms underlying AKI differ significantly. In MCD, AKI occurs in up to one-third of cases, and its leading cause is acute tubular necrosis (ATN), typically driven by tubular ischemia. In FSGS, AKI is less common but may occur in its collapsing variant, frequently linked to secondary causes such as viral infections or drug toxicity. MN rarely results in AKI; when it does, an alternative or overlapping etiology should be considered.

The severity of proteinuria in NS is closely linked to alterations in lipid metabolism, which involve both reduced clearance (the primary mechanism of hypercholesterolemia) and altered biosynthesis (the predominant mechanism of hypertriglyceridemia), as well as changes in lipid composition. This leads to markedly elevated levels of total cholesterol, low-density lipoprotein (LDL), triglycerides, and apolipoprotein B (ApoB)-containing lipoproteins (such as very low-density lipoprotein [VLDL], intermediate-density lipoprotein [IDL], and lipoprotein[a]). While high-density lipoprotein (HDL) levels typically remain unchanged, the lipoprotein itself undergoes impaired maturation and diminished cholesterol efflux function. For a detailed discussion, see Chapter 29 .

As a result, patients with NS exhibit a proatherogenic lipid profile, which accelerates the development of atherosclerosis. This leads to a 10-year cardiovascular event risk of 12.1% to 23.7%, approximately 2.5 times higher than in the general population, with the highest risk observed in FSGS, followed by MN. ^, The cardiovascular risk in NS mirrors that seen in individuals with ESKF and is associated with traditional risk factors, as well as the degree of proteinuria and renal function. ^, Studies on FSGS have shown that proteinuria >1.5 g/day increases the risk of adverse cardiovascular events and all-cause mortality by 2.11-fold, and a urine albumin-to-creatinine ratio (uACR) >0.7 g/g results in a 3.37-fold higher risk. Furthermore, hyperlipidemia contributes to the progression of chronic kidney disease (CKD) by exacerbating glomerular injury through lipid accumulation and oxidation, production of reactive oxygen species, recruitment of monocytes and macrophages, and subclinical inflammation. This leads to further glomerulosclerosis (the “lipid nephrotoxicity” hypothesis), in addition to promoting atherosclerosis of the renal vasculature. Lastly, elevated oxidized LDL levels increase the risk of thromboembolic events by enhancing platelet activation.

Venous thromboembolism (VTE) is a potentially life-threatening complication, resulting from hypercoagulable state in NS. Hypercoagulability is a consequence of both increased platelet activity (and in some cases also increased platelet count) and altered plasma hemostatic factors activity. In addition to albuminuria, patients with NS lose low-molecular-weight anticoagulants (e.g., antithrombin III and protein S) and fibrinolytics (e.g., plasminogen, tissue plasminogen activator [t-PA]) in their urine. Hepatic overproduction of proteins in response to hypoalbuminemia leads to increased levels of high-molecular-weight coagulation factors (e.g., factor V, factor VIII, fibrinogen, and von Willebrand factor) and inhibitors of fibrinolysis (plasminogen activator inhibitor-1 [PAI-1], α2-macroglobulin). This predisposes patients to VTE, occurring in both typical sites (deep vein thrombosis of lower limbs, pulmonary embolism) and atypical locations (e.g., renal vein ^, and dural sinuses ).

The risk of VTE is highest during the early course of NS, with most cases occurring within the first 6 months of diagnosis and many detected simultaneously with the underlying glomerular disease. ^, Data from Danish National Registry have estimated an 18-fold higher incidence of VTE within the first 30 days post diagnosis and a more than 7-fold higher incidence in the first year, compared with the general population.

This risk correlates strongly with the severity of NS, with hypoalbuminemia below 2.5 g/dL being the most reliable predictor. ^{, ,} Among glomerular diseases, MN is associated with the highest VTE risk, including a predilection for renal vein thrombosis, though the mechanisms underlying this association remain unclear. The overall prevalence of VTE in MN is estimated at 7% to 8%, ^, rising to 22% to 37% in patients with NS. ^, Thromboembolic complications are also observed in MCD, occurring in 12% to 24% of adults ^, but only 3% of children. However, congenital NS (affecting children aged 0–3 months) carries an elevated VTE risk of up to 10%. Of note, VTE events occur more often in children developing severe infections during NS.

In the preantibiotic and preimmunosuppression era, infectious complications were the leading cause of death in children with NS, with mortality rates reaching up to 30% and infections accounting for 60% of these cases. Advances in medical care have nearly eliminated fatal infections, yet severe infections remain a significant burden, affecting approximately 40% of children and around 10% to 15% of adults with NS. ^{, ,} The mechanisms predisposing patients with NS to infections are multifaceted, involving impairments across all branches of the immune system. Notably, urinary losses of immunoglobulin G (IgG) and components of the alternative complement pathway (e.g., factors B and I) contribute to reduced humoral and innate immunity. Additionally, altered T-cell function exacerbates immune deficiencies. These immunologic changes align with the historically observed susceptibility to infections by encapsulated bacteria, which rely on complement-mediated opsonization for elimination. Streptococcus pneumoniae remains the most frequently implicated pathogen in these infections. Local factors also play a role in the development of infectious complications. These include fluid accumulation, which predisposes to peritonitis (the most commonly reported infection in children) and cellulitis. Other contributing factors are hypercatabolism, malnutrition, and the use of immunosuppressive medications, which further compromise immune defenses.

Malnutrition and muscle mass loss, although not systematically studied, may complicate the course of NS as a result of hypercatabolism. Similarly, disturbances in hormonal and microelement homeostasis may arise from the urinary loss of carrier proteins, along with bound fraction of hormones. Thyroid dysfunction is the most common hormonal abnormality in NS, with hypothyroidism predominating in children, while both hypothyroidism and sick euthyroid syndrome occur at similar frequencies in adults. Other potential disturbances include deficiencies in growth hormone, sex hormones, vitamin D, and iron, among others. The clinical implications of these hormonal and metabolic abnormalities remain uncertain, particularly in cases responding to therapy where they are transient. However, persistent NS warrants assessment and management of these derangements to mitigate potential long-term complications.

Supportive therapy plays an important role in management of patients with NS. It consists of lifestyle modification (diet, physical activity) aiming to reduce long-term cardiovascular risk and slow the progression of CKD; pharmacologic nephroprotective strategies (including therapy with angiotensin-converting enzyme inhibitors [ACEi] or angiotensin receptor blockers [ARB] and potentially sodium-glucose cotransporter-2 inhibitors [SGLT2i] as an add-on therapy); management of symptoms related to NS (e.g., lipid-lowering therapy for hyperlipidemia and diuretics for edema) and preventing its acute complications (thromboprophylaxis, vaccination); and proper and effective therapy of comorbid conditions (e.g., hypertension and diabetes).

Lifestyle recommendations for NS generally align with those for the healthy population. Sodium intake should be limited to 2 g/day (equivalent to 5 mg/day or 90 mmol of sodium chloride), while protein intake should be maintained at 0.8 to 1.0 g/kg/day, with additional protein equivalent to daily proteinuria (up to a maximum of 5 g/day) if kidney function is normal. In cases of impaired kidney function, protein intake should be reduced to 0.8 g/kg/day. High sodium and protein intake can lead to glomerular hyperfiltration, accelerating CKD progression and increasing proteinuria. Given that NS is a hypercatabolic state, energy intake should be increased to 35 kcal/kg/day. A heart-healthy diet is recommended, with total fat intake limited to <30%, saturated fat to <7% to 10%, and cholesterol to <200 mg/day. Patients should maintain a healthy body weight, engage in regular physical activity, and avoid smoking.

The cornerstone of conservative management is the initiation and titration of medications that block the renin-angiotensin-aldosterone system (RAAS), such as ACEi or ARB, to the maximum tolerated dose. The combination of these medications is generally not recommended. These drugs have demonstrated clear benefits in improving kidney outcomes by slowing the decline in estimated glomerular filtration rate (eGFR), reducing proteinuria, and enhancing the likelihood of spontaneous remission in MN. Their cardioprotective effects are also well established.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), known for improving renal and cardiovascular outcomes in CKD, ^, should be considered as an adjunctive therapy after reaching the maximum tolerated dose of ACEi/ARB. Robust data support the use of SGLT2i in nondiabetic patients with CKD, and emerging evidence from ancillary analyses of clinical trials in glomerular diseases shows similar benefits. However, patients on immunosuppressive therapy were excluded from these studies. ^, A retrospective study has demonstrated a positive effect of SGLT2i on proteinuria in patients with various glomerular diseases, although it was underpowered to detect effects on eGFR.

The metabolic effects of SGLT2i, such as modest reductions in body weight and blood pressure, lower serum glucose and uric acid, prevention of magnesium loss in urine, and increased natriuresis, offer potential benefits for patients receiving immunosuppressive therapies. For instance, glucocorticoids can cause weight gain, hypertension, hyperglycemia, and hyperuricemia, and calcineurin inhibitors (CNIs) can lead to hypomagnesemia, hyperuricemia, hyperglycemia, and hypertension, which may be mitigated by SGLT2i. Additionally, SGLT2i may help manage edema.

Nephrocardioprotective therapy is recommended for all patients except children with steroid-sensitive NS (SSNS) and adults with MCD who have preserved kidney function and normal blood pressure. ^{, ,} An important component of nephrocardioprotection includes optimal management of comorbidities, particularly blood pressure control, with a target systolic blood pressure of <120 mm Hg (or ≤50th percentile in children), if tolerated, or at least 120 to 130 mm Hg. ^,

Lipid-lowering therapy is also important. It is recommended to treat hyperlipidemia in steroid-resistant NS (SRNS) in children and nonremitting NS cases in adults following guidelines for general population regarding the assessment of cardiovascular risk, target LDL values, and therapeutic options. Of note, hyperlipidemia in NS is usually severe and achievement of target levels may be challenging, requiring combined therapy. Statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors may be particularly beneficial as they directly target lipoprotein metabolism pathways that are altered in NS. ^{, ,} Statins are considered the first-line medication, while the real-world evidence of efficacy and safety of PCSK9 inhibitors in NS is limited thus far. Patients with MN with hypoalbuminemia of 2.5 to 3.2 and high cardiovascular risk should be additionally offered acetylsalicylic acid (ASA).

Edema is the hallmark clinical feature of NS, and the most effective therapy is achievement of remission of the disease. Symptomatic treatment includes dietary salt restriction and diuretic use, except in cases of concomitant hypovolemia. NS, particularly severe, is considered related to “diuretic resistance”—a state requiring higher drug doses, switching to intravenous route of administration, and/or combination of drugs of different targets to achieve the adequate response. This is due to edema of the gut mucosa, resulting in altered drug bioavailability; hypoalbuminemia affecting volume of distribution and delivery to target ionic channels, as well as increased renal clearance secondary to podocyte injury; and increased permeability of the glomerular filtration barrier. ^, The rationale for using intravenous 20% albumin solution remains controversial. It has been shown that the natriuretic effect of albumin equals the sodium load provided as the drip solvent, arguing against any diuretic benefit. The accompanying significant albumin load is immediately leaked into the urine, aggravating proteinuria and its nephrotoxic effects. Intravenous albumin may therefore be considered only as a “salvage therapy” in cases of complete diuretic resistance before ultrafiltration (either isolated or during hemodialysis) may be required. In contrast to edema management, intravenous albumin administration is justifiable and recommended for hypovolemia in the course of NS, observed particularly in children ^, ( Fig. 30.3 ).

Management of edema and hypovolemia in nephrotic syndrome.

∗In children, edema severity is graded empirically as follows: mild (≤7% increase in body weight), moderate (7% to 15%), and severe (>15%). No grading system has been established for adult patients. (Adapted from Sinha A, Bagga A, Banerjee S, et al. Steroid sensitive nephrotic syndrome: revised guidelines. Indian Pediatr . 2021;58:461–481.)

An integral component of conservative therapy in severe cases of NS is prophylaxis of VTE events. The high-quality data on the optimal approach—indications, drug choice, and duration of thromboprophylaxis—are, however, lacking. Prophylaxis with warfarin or low-molecular-weight heparin (LMWH) is recommended in patients with MN, showing the most prominent association with the risk of VTE, with severe NS with serum albumin <2.5 g/dL and concomitant low risk of bleeding; otherwise, acetylsalicylic acid should be considered. ^, A potential benefit-risk ratio in MN may be calculated using the GN tools algorithm ( https://www.med.unc.edu/gntools/ ). In other glomerular diseases manifesting as NS, no direct guidelines are provided. The suggested indications for thromboprophylaxis include serum albumin of <2.0 to 2.5 g/dL and additional risk factors, such as massive proteinuria (>10 g/day), obesity (II–III degrees: body mass index >35 kg/m ² ), genetic mutations (or family history) predisposing to VTE, severe heart failure, recent surgery or prolonged immobilization, and the absence of contraindications to anticoagulation. Existing evidence has suggested clinical efficacy of vitamin K antagonists and LMWH ^, ; small studies have also reported efficacy and safety of direct oral anticoagulants (DOACs, such as apixaban, rivaroxaban, dabigatran). ^, However, it has been emphasized that DOACs’ effect may be diminished in hypoalbuminemia due to moderate-to-high albumin binding, while heparin effect may be affected by antithrombin deficiency (being the target for heparin). In-depth pharmacokinetic studies in this regard are not available for any of these groups, but small studies have reported reduced anti-Xa activity of LMWH with the need for doubled doses to achieve target levels. This, however, seems to not affect clinical efficacy of standard LMWH dosing, shown to be successful in preventing VTE in a cohort of 143 patients. Despite limited data, one survey conducted among nephrologists has revealed approximately half of them prescribing DOACs, presumably as the most convenient to use, and known to have the lowest risk of bleeding complications in the general population.

Morbidity due to severe infections, associated with disease relapses and immunosuppression, has declined with prompt diagnosis and immunization practices; however, they remain the chief cause of hospitalization. This underscores the importance of vaccination as a key preventive health measure. At disease onset, patients’ vaccination status should be reviewed and updated, ensuring completion of all vaccines according to national guidelines. Priority should be given to vaccines targeting encapsulated bacteria ( Streptococcus pneumoniae, Neisseria meningitidis , and Haemophilus influenzae ); hepatitis B; and varicella in children (live vaccine) or herpes zoster (recombinant vaccine) in adults. Annual influenza vaccination and repeating COVID-19 vaccination in line with national recommendations are also advised. The live-attenuated varicella vaccine is particularly important in children, as chickenpox can have a life-threatening course in immunocompromised young individuals. However, live vaccines (including those for varicella, measles, mumps, rubella, rotavirus, and yellow fever) are contraindicated during immunosuppressive therapy. Ideally, these vaccines should be administered at least one month before initiating immunosuppression. If this is not feasible, live vaccination should be deferred until at least 6 to 9 months after rituximab (RTX) dose, with confirmed B-cell reconstitution, and until other immunosuppressive agents have been discontinued for at least 1 to 3 months. This minimizes the risk of live vaccine-induced infections, which, however, is generally low according to current evidence. Inactivated vaccines can be administered safely during immunosuppressive therapy but may show reduced efficacy, particularly with prednisone doses >20 mg/day for more than 2 weeks or during RTX treatment. For optimal seroconversion, administration timing should follow the same guidelines as live vaccines where possible. Vaccination of household contacts is also recommended as part of a comprehensive preventive strategy. ^,

The immunosuppressive therapies used in treating NS target various mechanisms of the immune response, reflecting the complexity of the disease’s underlying pathophysiology.

Glucocorticoids act by binding to glucocorticoid receptors, which modulate gene expression and, to a lesser extent, post-translational pathways. This suppresses the production of proinflammatory cytokines, inhibits immune cell activation, and reduces T-cell proliferation, effectively dampening inflammation.

CNIs, including cyclosporine (which binds cyclophilin) and tacrolimus (which binds FK-binding proteins), inhibit calcineurin, a phosphatase necessary for activating nuclear factor of activated T cells (NFAT). This inhibition blocks T-cell activation and the production of interleukin-2 (IL-2), a critical mediator of T-cell proliferation. CNIs primarily target T-helper cells but also exhibit antiproteinuric effects. These include direct hemodynamic actions, such as afferent arteriole vasoconstriction, and cytoskeletal stabilization of podocytes. CNIs prevent the dephosphorylation of synaptopodin, an actin-binding protein essential for maintaining podocyte structure and preventing FPE.

Mycophenolate acid derivatives, such as mycophenolate mofetil (MMF) and mycophenolate sodium (MPS), inhibit inosine monophosphate dehydrogenase, a key enzyme in de novo purine synthesis. This action preferentially reduces the proliferation of T and B lymphocytes, which are dependent on this pathway for nucleotide synthesis.

Cyclophosphamide, an alkylating agent, induces DNA cross-linking, leading to apoptosis, particularly in rapidly dividing immune cells. This broadly suppresses both B and T-cell activity, contributing to its immunosuppressive effects.

Rituximab, a monoclonal anti-CD20 antibody, targets B cells, causing their depletion. Beyond its effects on B-cell immunity, rituximab may stabilize the podocyte actin cytoskeleton by increasing the expression of sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b), a protein involved in cytoskeletal integrity. Notably, it is the only biologic routinely used for NS treatment.

This broad spectrum of immunosuppressive mechanisms reflects the multifaceted approach necessary for managing the diverse etiologies and pathophysiology of NS.

The final component of conservative management involves mitigating the side effects associated with immunosuppressive therapies. Key measures include gastrointestinal and bone protection during glucocorticoid therapy, gonadal protection when using cyclophosphamide, and, importantly, prevention of latent infections such as tuberculosis, Pneumocystis jiroveci, and hepatitis B reactivation during intensive immunosuppression, following local clinical guidelines.

Secondary forms of MCD are rare ( eBox 30.1 ). Among malignancies, MCD is commonly associated with lymphoid malignancies, particularly Hodgkin lymphoma (0.4% of patients ) and thymoma. It is most frequently observed in the nodular sclerosis subtype of Hodgkin lymphoma (71% of MCD cases secondary to this disease), typically coinciding with either the diagnosis or relapse of malignancy. In 38% of cases, glomerular disease precedes the diagnosis of lymphoma. Approximately half of MCD cases exhibit steroid resistance but often remit with effective lymphoma treatment.

MCD has also been reported as a late complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT), accounting for about 15% of glomerular diseases in this setting. MCD in these cases is usually seen in patients with prior chronic graft-versus-host disease and typically presents as abrupt-onset NS, responding favorably to immunosuppressive therapy. ^,

Drug-induced MCD is often linked to nonsteroidal anti-inflammatory drugs (especially fenoprofen, which has been withdrawn from the market), interferon, penicillins, lithium, and rifampicin. These cases may exhibit overlapping features of MCD and acute interstitial nephritis on biopsy, presenting clinically as NS accompanied by pyuria and renal insufficiency. Discontinuing the drug can lead to resolution of proteinuria; however, recovery of kidney function may take weeks to months and may be incomplete. ^,

Initial therapy consists of high-dose glucocorticoids, either based on body weight or on body surface area (see Fig. 30.7 )—both associated with similar outcomes. Therapy should be given for 8 to 12 weeks total at 60 mg/m ² /day (or 2 mg/kg/day; maximum 60 mg) until remission (protein trace/nil for 3 consecutive days) and continued for 4 to 6 weeks, followed by 40 mg/m ² (1.5 mg/kg, maximum 40 mg) on alternate days for 4 to 6 weeks. It has been shown that prolonged therapy, although it may delay the first relapse, does not affect the subsequent disease course (risk of subsequent or frequent relapses). ^,

Relapses, occurring in >70% of children, mostly within year from diagnosis, are precipitated by minor, usually upper respiratory tract, infections in almost half of cases. Proteinuria during infections may be transient, hence it is advisable to await resolution of infection, avoiding the need for corticosteroid therapy. However, 3+/4+ proteinuria that lasts for 3 days or longer is unlikely to resolve and is treated with prednisone at 60 mg/m ² /day (or 2 mg/kg/day; maximum 60 mg) until remission (protein trace/nil for 3 consecutive days), followed by 40 mg/m ² (1.5 mg/kg, maximum 40 mg) on alternate days for 4 weeks (see Fig. 30.7 ). Given the natural history of disease, relapses may continue to occur even while on immunosuppressive therapy; hence both sustained remission and infrequent relapses are considered acceptable and imply “stable remission.”

As mentioned earlier, almost half of pediatric patients with relapses show steroid dependency or frequently relapsing disease. ^, Prolonged therapy with high-dose prednisone is associated with significant steroid toxicity, as well as behavior problems, cataracts, glaucoma, hypertension, avascular hip necrosis, and diabetes. Relapses are associated with significant complications including infections, thrombosis, and dyslipidemia. Therefore children with frequent relapses or steroid dependence require expertise in management, with an aim to reduce the frequency of relapses, without impairing normal growth and scholastic and extracurricular activities, and avoiding adverse effects of immunosuppressive medications. In particular, the subgroup of patients that continues to show frequent relapses (or infrequent relapses in presence of significant steroid toxicity) despite use of two or more steroid-sparing agents (such as levamisole, cyclophosphamide, or mycophenolate mofetil), termed “difficult-to-treat” steroid-sensitive disease, might merit consideration for use of more potent medications (see Fig. 30.7 ). Table 30.2 summarizes recommendations on dose, duration and adverse effects, and precautions during therapy.

MCD treatment is recommended in all cases due to the low likelihood of spontaneous remission (unlike MN) and the significant morbidity associated with untreated nephrotic syndrome, such as infections and thromboembolic complications, among others. Treatment protocols for adults largely mirror those for children, with much of the evidence extrapolated from pediatric studies.

First-line therapy, as in pediatric INS, involves high-dose glucocorticoids (1 mg/kg/day, max. 80 mg/dose; or 2 mg/kg every other day, max. 120 mg/dose), which lead to CR within 16 weeks in more than 80% of adults (called steroid-sensitive MCD) (see Fig. 30.8 ). Glucocorticoid tapering is recommended starting 2 weeks after CR and continuing over 24 weeks. For individuals with relative contraindications to glucocorticoids, steroid-sparing drugs should be implemented, including CNIs, MPAA, and cyclophosphamide. Emerging evidence from small studies also supports rituximab monotherapy as an effective option.

Relapses are managed similarly to the initial episode, except for patients with frequent relapses or steroid dependence, accounting for approximately one-third of adult MCD cases. In these cases, steroid-sparing immunosuppressive agents are recommended to minimize glucocorticoid exposure and reduce the risk of side effects (see Fig. 30.8 ). These agents are typically initiated after achieving CR with high-dose glucocorticoids, and the glucocorticoids are tapered to discontinuation over 2 to 4 weeks. The Immunonephrology Working Group of the European Renal Association (IWG-ERA) recommends rituximab as the preferred option due to its long-lasting effect, convenient biannual administration, and favorable safety profile without metabolic side effects. However, given the comparable efficacy of available treatments, the choice of therapy should consider patient preferences, drug side effect profiles, availability, and cost.

Renal outcomes in MCD and INS are excellent, with <5% of patients progressing to ESKF. The incidence of ESKF is estimated at 1.34 to 2.22 per 100 patient-years. Long-term prognosis depends on the response to immunosuppressive therapy and worsens in patients with secondary steroid resistance or histologic progression to FSGS, where the 10-year risk of ESKF can reach 70%. Outcomes in steroid-resistant nephrotic syndrome in children and FSGS in adults are discussed in detail later.

Primary FSGS is estimated to account for 40% to 45% of all FSGS cases. Growing evidence supports the hypothesis that this immune-mediated podocytopathy shares a similar pathogenesis with MCD/INS and is considered a histologic progression, with a slower and poorer response to treatment compared with MCD, as well as a higher risk of progression to ESKF. However, the data regarding the prevalence of antinephrin antibodies are conflicting. Antibodies have been detected in only 9% of presumed primary FSGS cases in the landmark study, whereas a study of patients with post-transplant recurrence of presumed primary FSGS has found serum antinephrin antibodies and IgG deposits colocalizing with nephrin on graft biopsy in all cases. These findings suggest that further investigation is warranted.

Among genetic forms of FSGS, both inherited and sporadic cases can be distinguished, with presentations either restricted to the kidneys or syndromic (see also Chapter 44 ). Additionally, polymorphisms such as those in the APOL1 gene have been identified as contributors to the development of secondary FSGS (see later).

A hallmark of genetic nephrotic syndrome is its lack of response to immunosuppression (SRNS course). Genetic causes account for about 15% of SRNS in children, with mutations in podocyte-associated genes present in nearly 50% of patients with a family history of SRNS and in 10% to 30% of nonfamilial cases. ^, The likelihood of identifying a monogenic cause of SRNS decreases inversely with age. While two-thirds of those presenting before 1 year of age have monogenic disease, the chance of identifying a genetic cause for SRNS decreases substantially to 25% in children aged 1 to 6 years, 18% in those aged 7 to 12 years, 11% in adolescents aged 13 to 18 years, and 8% to 14% in adult-onset FSGS.

Rapid advances in next-generation sequencing have facilitated the identification of numerous novel causative genes. More than 80 genes are associated with monogenic SRNS, chiefly encoding structural elements of the podocyte slit-diaphragm or cytoskeleton (including NPHS1, NPHS2, CD2AP, TRCP6, and ACTN4 ); GBM proteins (LAMB2, COL4A5); mitochondrial genes (COQ2); or nuclear transcription factors (WT1, LMX1B) ( Table 30.4 ). ^{, ,} These genetic variations may be acquired in an autosomal recessive (NPHS1, NPHS2, PLCe1) or dominant (INF2, TRPC6, ACTN4) manner, or both (WT1). In addition, several monogenic mutations result in syndromic forms of SRNS ( Table 30.5 ). Reports have highlighted a high frequency of mutations in genes encoding type IV collagen (COL4A3, COL4A4, COL4A5), often as phenocopies of SRNS, with or without coexisting laminin alpha 5 (LAMA5) variants that act as potential effect modifiers. Of note, although the FSGS pattern predominates among genetic forms, MCD and diffuse mesangial sclerosis (DMS) are also seen. DMS is a histopathology observed in young children, characterized by progression to ESKF in early childhood. More than 80% of children with DMS have identifiable causal variants in NPHS2, WT1, PLCe1, or LAMB2.

Adaptive FSGS arises from glomerular maladaptation to reduced nephron numbers (e.g., due to low birth weight and solitary kidney) or excessive stress on a normal nephron population (e.g., obesity, high-protein diet, reflux nephropathy, and advanced stages of CKD of all causes) (see Table 30.3 ). These conditions disrupt the balance between glomerular load and capacity, leading to glomerular hypertension and hyperfiltration. The resulting compensatory glomerular hypertrophy increases the filtration surface area to counteract hypertension. However, this adaptation forces podocytes to stretch to cover the expanded surface, weakening their attachment to the GBM, ultimately causing detachment and loss. Hyperfiltration further exerts mechanical strain on podocytes, especially in the perihilar segments of the glomerular tuft, where blood flow is most disturbed. This mechanical stress initiates a loss of interdigitating foot processes appearance and ultimately leads to FPE, particularly in the perihilar region. ^, FPE occurs progressively and heterogeneously, involving only a part of glomerular surface (segmental FPE) (e.g., in 25% of reflux nephropathy-associated FSGS and 40% in obesity-associated FSGS). ^,

Additionally, individuals of African ancestry may carry sequence variants in the APOL1 gene, G1 and G2, that confer the risk of FSGS in a non-Mendelian fashion. Apolipoprotein L1, the gene product, is a protease that protects against Trypanosoma brucei, the parasite responsible for African sleeping sickness. These high-risk variants are found in approximately 35% of the African American population and 25% to 50% of the African population. Inheriting two such variants raises the risk for three distinct APOL1-mediated kidney diseases: hypertension-associated end ESKF with global glomerular sclerosis (a 7- to 10-fold increase), FSGS (around 17-fold), and HIV-associated nephropathy (29- to 89-fold) often manifesting as collapsing FSGS. ApoL1 disease is discussed in more detail in Chapter 43 , Chapter 74 .

Among viral infections, the pathogenesis of HIV-associated FSGS is the most extensively studied. HIV-associated nephropathy (HIVAN) predominantly affects individuals with high-risk APOL1 alleles, accounting for its disproportionately high prevalence among people of African and African American ancestry. ^, The pathogenesis involves direct podocyte infection by the virus, resulting in actin cytoskeleton disruption and FPE. This damage is further aggravated by cytokine release, including VEGF, which exacerbates podocyte injury. Histologic changes predominantly manifest as the collapsing variant of FSGS, accompanied clinically by nephrotic syndrome and severe AKI.

SARS-CoV-2-associated FSGS, termed COVID-associated nephropathy (COVAN), also presents histologically as collapsing FSGS and mirrors the pathogenesis of HIV-associated collapsing FSGS. This includes a combination of direct podocyte infection and cytokine-mediated injury, particularly among individuals with high-risk APOL1 gene polymorphisms. Other viral infections, such as cytomegalovirus, Epstein-Barr virus, parvovirus B19, and hepatitis C virus, have also been linked to FSGS. However, the pathogenesis of FSGS associated with these infections remains poorly understood. Infections are discussed in more detail in Chapter 34 , Chapter 58 .

The mechanisms underlying drug-associated FSGS remain controversial. This pattern of injury has been reported in association with several agents, including bisphosphonates (collapsing and other variants, as well as MCD lesions), interferon, lithium (also linked to MCD), and heroin abuse, among others.

First-line treatment for immune-mediated (primary) FSGS mirrors that for MCD, with high-dose glucocorticoids being recommended. However, FSGS patients generally show a slower and less frequent response to therapy, with remission rates of approximately 60% to 70%, often only partial (observed in one-third to half of patients). Optimal management for patients with delayed or absent response to glucocorticoids remains unclear. According to KDIGO guidelines, high-dose glucocorticoids should be continued for up to 16 weeks, and in cases of failure to achieve at least partial remission, a CNI should be added. Some studies suggest earlier initiation of additional immunosuppressive drug after 8 weeks in cases where proteinuria reduction is <20%, allowing to limit glucocorticoid exposure and increase the response rate.

CNIs are also recommended as an alternative to high-dose glucocorticoids in patients with relative contraindications to steroids, typically in combination with low-dose glucocorticoids. The therapeutic effect of CNIs may take 4 to 6 months to manifest; hence CNI resistance should not be diagnosed before a minimum of 6 months of therapy. CNIs are effective in 50% to 70% of steroid-resistant cases, ^{, , ,} and treatment should be maintained for at least 12 months. Discontinuation of CNIs, similar to that seen in MCD, is associated with a significant relapse rate, reported in up to 30% to 60% of patients. Moreover, transient, reversible declines in eGFR are observed in 16% to 40% of patients receiving CNI therapy. ^, Relapsing FSGS cases should be managed following MCD guidelines.

Patients with treatment-resistant FSGS should be referred to specialized centers and considered for enrollment in clinical trials. Current options for refractory cases include rituximab, MMF, and cyclophosphamide, though the use of the latter is limited by its unfavorable toxicity profile. Novel immunosuppressive agents under investigation for primary FSGS include obinutuzumab—a next-generation anti-CD20 antibody offering more potent and prolonged B-cell depletion (NCT04983888); adalimumab—an anti-TNF-α antibody (NCT04009668); SAR 442970—OX40 ligand and TNF-α inhibitor; frexalimab—anti-CD40L antibody; and rilzabrutinib—Bruton thyrosine kinase inhibitor (NCT06500702); among others. ^,

All FSGS patients including immune-mediated and non–immune-mediated forms (e.g., genetic, secondary, and undetermined) should receive comprehensive supportive care (as described above in the “Conservative Management” section of “Management of Patients with Nephrotic Syndrome” and summarized in Fig. 30.2 ) and targeted treatment of underlying causes where feasible (e.g., weight reduction in obesity-associated FSGS, urologic interventions in reflux nephropathy).

FSGS accounts for approximately 3% of all cases of ESKF. Kidney survival is closely linked to the etiology, degree of proteinuria, efficacy of therapy in reducing proteinuria, and kidney function at diagnosis. Registry data show that proteinuria >1.5 g/g increases the risk of kidney failure or death by approximately 2.3-fold (HR 2.34, 95% CI: 1.99–2.74). Additionally, a urine albumin-to-creatinine ratio (uACR) >0.7 g/g is associated with an unfavorable kidney outcome (defined as decline in eGFR >40%, eGFR <15 mL/min/1.73 m ² , or the initiation of kidney replacement therapy) by 5.27-fold in one study.

Primary FSGS, particularly in cases of refractory NS, is considered a high-risk factor for ESKF showing a rate of progression to kidney failure of 24% in 5 years, and 43% in 10 years of follow-up. In contrast, patients who achieve remission (either partial or complete) have a more favorable prognosis, with only 8% to 15% progressing to ESKF within 5 years and less than 8% to 25% within 10 years. ^{, ,} Similar findings are reported in pediatric studies on SRNS, where FSGS is the most common histologic diagnosis (55%–60% of cases). Among patients with undifferentiated or nongenetic SRNS, response to immunosuppression predicts kidney survival, with significantly higher risk of kidney failure in patients with persistent nonresponse. ^{, , , ,} The 10-year ESKF rate was 6% for those achieving CR, 28% for those achieving partial remission, and 57% for nonresponders.

In contrast, secondary FSGS, typically presenting as subnephrotic or nephrotic-range proteinuria without the full nephrotic syndrome, generally follows a slower course, with less than 15% progressing to ESKF over 10 years. ^, However, kidney failure eventually occurs in a significant proportion of patients including 10% to 33% of those with obesity-related FSGS. ^, On the other hand, APOL1-mediated FSGS, presenting as the collapsing variant, is characterized by rapid decline in kidney function and a 4-fold higher risk of progression to ESKF compared with other forms of FSGS, with a risk as high as 15% and peak occurrence of ESKF in individuals in their fifth decade.

Data on genetic forms of FSGS come mainly from pediatric studies on SRNS, showing a poor renal prognosis with a 2.9-fold higher odds of kidney failure compared with nongenetic cases. The progression to ESKF is 73% within 10 years and 83% within 15 years in these patients.

Immune-mediated FSGS is associated with a high recurrence rate after kidney transplantation, reaching 30% to 60%, and even 80% in cases of retransplantation due to graft loss resulting from FSGS recurrence. A similar frequency has been reported in children with SRNS. A systematic review and meta-analysis of 8 studies involving 581 children with SRNS estimated the overall risk of recurrence at 39% (95% CI: 34%–44%), with the risk increasing to 61% (95% CI: 53%–69%) in patients without an identified causative genetic mutation, particularly in those with secondary SRNS, where the recurrence risk can be as high as 60% to 80%. ^,

Proteinuria recurrence after renal transplantation in immune-mediated (primary) FSGS typically occurs within hours to weeks post transplant, with an average time to recurrence estimated at 1.5 months. This recurrence is associated with an increased risk of delayed graft function and both early and late graft loss, with rates reaching 40% to 50% over 5 years. ^, Data from a small study of 11 patients indicate punctate IgG deposits colocalizing with nephrin and the presence of antinephrin antibodies in the sera of these patients. Therapy usually comprises a combination of plasma exchange or immunoadsorption, high doses of CNI, and corticosteroids, with or without one to two doses of rituximab. Additional strategies that have been used successfully include addition of ACEI or ARB, high-dose corticosteroid pulses, and LDL apheresis. In contrast, maladaptive FSGS does not recur. Similarly, no recurrence is observed in grafts affected by FSGS associated with monogenic diseases.