Collapsing focal segmental glomerulosclerosis (collapsing glomerulopathy)

INTRODUCTION — Collapsing focal segmental glomerulosclerosis (collapsing FSGS; also known as collapsing glomerulopathy) is a pattern of kidney injury characterized by segmentally or globally collapsed and sclerotic glomerular capillaries, with hyperplasia and hypertrophy of overlying glomerular epithelial cells. Patients typically present with the nephrotic syndrome. In the setting of active HIV infection, the kidney disease is also called "HIV-associated nephropathy" (HIVAN); however, collapsing FSGS is now increasingly described in patients without HIV, many of whom carry an underlying high-risk apolipoprotein L1 (APOL1) genotype. Collapsing FSGS is best considered as a histopathologic diagnosis associated with a heterogeneous group of disorders.

Collapsing FSGS not associated with HIV infection will be reviewed here. Collapsing FSGS and other kidney diseases that occur in association with HIV infection are discussed separately:

●(See "HIV-associated nephropathy (HIVAN)".)

●(See "Overview of kidney disease in patients with HIV".)

The epidemiology, classification, pathogenesis, clinical features, diagnosis, and treatment of other forms of FSGS are discussed elsewhere:

●(See "Focal segmental glomerulosclerosis: Clinical features and diagnosis".)

●(See "Focal segmental glomerulosclerosis: Pathogenesis".)

●(See "Focal segmental glomerulosclerosis: Genetic causes".)

●(See "Focal segmental glomerulosclerosis: Treatment and prognosis".)

EPIDEMIOLOGY — The prevalence of collapsing FSGS not associated with HIV infection is unclear and varies among different countries [1]. However, collapsing FSGS appears to comprise an increasing proportion of all cases of idiopathic FSGS (10 to 24 percent in some older series) [2]. In one report, collapsing FSGS represented 1.4 percent of all kidney biopsies performed at a single large center over a 15 year period [3]. Both sexes are equally affected, and most, but not all, reports have noted a predominance of Black patients [3,4].

PATHOGENESIS — The pathogenesis of collapsing FSGS in patients not infected with HIV is not clear [4]. As with HIV-associated nephropathy (HIVAN), the underlying pathogenic event appears to be a severe insult to the integrity and biology of the glomerular visceral (podocytes) and parietal epithelial cells [2,4]. The overlying hyperplastic epithelial cells lack normal podocyte markers, which has been attributed to podocyte dedifferentiation and proliferation; however, many of these cells express markers that are consistent with a parietal epithelial cell origin [5].

Genetic factors — Genetic susceptibility may contribute to the pathogenesis of collapsing FSGS.

APOL1 high-risk alleles — There is a predominance of Black patients noted in most reports of idiopathic collapsing FSGS [2-4]. Two high-risk allelic variants (G1, G2) in the gene encoding apolipoprotein L1 (APOL1) are common in individuals of West African ancestry and have been associated with protection from trypanosomal sleeping sickness. The presence of two high-risk alleles for APOL1 (G1G1, G1G2, or G2G2) is associated with an increased risk of nondiabetic kidney disease, hypertension in Black patients, and focal segmental glomerulosclerosis [6]. (See "Focal segmental glomerulosclerosis: Genetic causes", section on 'FSGS in Black patients'.)

In collapsing FSGS, these high-risk variants are strongly overrepresented in patients with HIVAN [7] as well as those with idiopathic collapsing FSGS [7,8] and collapsing FSGS associated with systemic lupus erythematosus [9], interferon therapy [10], membranous nephropathy [11], kidney transplantation [12], and coronavirus disease 2019 (COVID-19) infection [13-16] (see 'Infections' below). Mechanisms by which these high-risk variants lead to glomerular and podocyte injury are being actively investigated but include disruption of lysosomal or plasma membranes, insertion of pores or ion channels into podocyte cell membranes, and creation of a proinflammatory milieu leading to cell damage [17-20].

Other susceptibility genes — Genes that encode proteins directly involved in mitochondrial function have been associated with collapsing FSGS [4]. As an example, primary coenzyme Q10 deficiency secondary to genetic defects in the COQ2 gene or PDSS2 gene is a cause of collapsing FSGS [21,22]. This suggests that some disorders associated with collapsing FSGS may induce disease by affecting mitochondrial function, an important pathway leading to cell death, in kidney parenchyma. (See "Mitochondrial myopathies: Clinical features and diagnosis", section on 'Coenzyme Q10 deficiency'.)

Other genetic diseases associated with collapsing FSGS include action myoclonus-renal failure syndrome (SCARB2 defect) [23], Charcot-Marie-Tooth disease (INF2 defect) [24], Schimke dysplasia (SMARCAL1 defect) [25], mandibular dysplasia (ZMPSTE24 defect) [26], Galloway-Mowat syndrome (WDR73 defect) [27,28], and CDAP2 deficiency.

Several kindreds with familial collapsing FSGS have been described [29]. In one kindred, comprised of all White individuals, genetic defects in the TRPC6 gene were identified, which have also been linked to noncollapsing FSGS. This emphasizes that known genetic forms of FSGS can present with a collapsing pattern distinct from a mechanism related to APOL1.

Role of immune activation — Collapsing FSGS has been associated with disorders that alter the activity of the immune system (table 1), suggesting that immune activation may play a role in the pathogenesis of this disease [4]. Proinflammatory cytokines (notably type 1 interferons) produced during immune responses upregulate the expression of mutant APOL1 in glomerular epithelial cells, causing direct injury to these cells [10]. Enhanced interferon signaling pathways and collapsing FSGS have also been described with viral infections (HIV, severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]), therapeutic interferon (interferon-alpha, -beta, or -gamma), systemic lupus erythematosus, natural killer cell leukemia [30], and rare genetic disorders associated with high interferon levels (eg, stimulator of interferon genes [STING]-associated vasculopathy [31]). Biopsies from these patients may demonstrate endothelial tubuloreticular inclusions as a hallmark of interferon upregulation. (See 'Infections' below and 'Bisphosphonates and other drugs' below and 'Autoimmune disorders' below.)

However, the finding of collapsing FSGS in patients with active HIV infection suggests that downregulation of certain parts of the immune system may also contribute to the development of this lesion.

ETIOLOGY — The majority of cases of collapsing FSGS are idiopathic. However, collapsing FSGS has been reported to occur in association with a growing list of disorders (table 1). In one series of 42 patients, for example, concurrent illnesses were present in 13 (31 percent); these included a systemic lupus erythematosus–like disorder, hepatitis C virus infection, and multiple myeloma [32].

Idiopathic — Most cases of collapsing FSGS not associated with HIV infection are idiopathic [2-4]. In one series of 88 patients with collapsing FSGS, 77 percent had idiopathic disease [3].

The etiology of idiopathic collapsing FSGS is, by definition, unknown. Circulating factors that may be toxic to the glomerular capillary wall or to glomerular visceral epithelial cells have been reported, but not conclusively identified, in patients with collapsing FSGS [4,33]. The recurrence of collapsing FSGS after kidney transplantation also supports the presence of a circulating factor in some of these patients [4,34,35]. However, many patients with collapsing FSGS who receive a kidney allograft do not have recurrence of their disease and the APOL1 risk alleles from the donor kidney, not the recipient, are associated with recurrence [18]. (See "Focal segmental glomerulosclerosis: Pathogenesis", section on 'Putative circulating permeability factors'.)

Infections — A number of infections other than HIV infection have been associated with collapsing FSGS. These include viral, bacterial, and parasitic diseases such as parvovirus B19 infection, pulmonary tuberculosis, cytomegalovirus infection, schistosomiasis, filariasis, falciparum malaria, and SARS-CoV-2 infection (table 1) [13,14,36-41]. Since most infections (excluding parvovirus and COVID-19) are only rarely associated with collapsing FSGS, and since the infections mentioned above have been found with other patterns of FSGS, further studies are needed to better understand these associations. (See 'Role of immune activation' above.)

Collapsing FSGS in patients infected with SARS-CoV-2 has been termed COVID-19-associated nephropathy (COVAN) to distinguish it from most cases of acute kidney injury in patients with COVID-19, which are characterized by acute tubular injury [14,42-44]. In one single center series of 23 patients with COVAN, 16 (70 percent) were male, 21 (91 percent) were Black, and most had only mild or moderate severity of COVID-19 infection [14]. Twenty-two of the 23 patients presented with acute kidney injury (approximately 60 percent required dialysis), 17 had nephrotic range proteinuria, and 6 had the nephrotic syndrome. Among the 17 patients who were genotyped, 16 (94 percent) had two high-risk alleles for APOL1. Despite treatment with supportive therapy, antiviral therapy (in 50 percent), or glucocorticoids (in 26 percent), overall outcomes were poor, with only 36 percent of patients achieving a partial remission of proteinuria, 32 percent having no remission, and 32 percent progressing to end-stage kidney disease or death. However, half of the patients who required dialysis were able to discontinue this treatment. Viral infection of the kidney by SARS-CoV-2 was not detected. Similar findings have been reported in other series [43,45]. (See "COVID-19: Issues related to acute kidney injury, glomerular disease, and hypertension", section on 'COVID-19 associated glomerular disease'.)

One proposed mechanism for COVAN involves infection-stimulated activation of the interferon-chemokine pathway, which upregulates expression of the APOL1 variant gene, leading to disruption of podocyte autophagy, mitochondrial injury, and promotion of glomerular epithelial cell death [44]. (See 'APOL1 high-risk alleles' above.)

Bisphosphonates and other drugs — An unexpected association has been noted between collapsing FSGS and therapy with the bisphosphonate pamidronate in patients with multiple myeloma or breast cancer (given to prevent skeletal complications) who are often treated with high doses [46-50]. A toxic effect on the glomerular epithelial cell is the presumed mechanism.

●(See "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors".)

●(See "Multiple myeloma: The use of osteoclast inhibitors".)

The initial report described seven such patients who were HIV negative, six of whom had multiple myeloma and had undergone stem cell transplantation, and one of whom had breast cancer without transplantation [47]. A number of additional cases of pamidronate-associated collapsing FSGS have since been reported [48-50]. Almost all those with pamidronate-related collapsing FSGS have been White patients [4,47-49], and most have been older than 55 years of age.

Pamidronate has also been associated with nephrotic syndrome associated with other glomerular lesions, including noncollapsing FSGS and minimal change disease [46,49]. In some, but not all, reported cases, nephrotic syndrome was reversed when pamidronate was discontinued [51].

Other bisphosphonates, such as alendronate and zoledronate, have also been associated with collapsing FSGS in rare cases [46,52].

Anabolic steroids and other bodybuilding supplements [53] and the therapeutic use of interferon-alpha, beta, and gamma have all been associated with the development of collapsing FSGS [54].

●(See "Focal segmental glomerulosclerosis: Pathogenesis", section on 'Anabolic steroids'.)

●(See "Focal segmental glomerulosclerosis: Pathogenesis", section on 'Interferon'.)

Autoimmune disorders — Collapsing FSGS has been observed in patients with systemic lupus erythematosus [55-59]. As an example, a retrospective review of kidney biopsies performed in patients with SLE over a seven year period revealed 19 HIV-negative patients with collapsing FSGS [55]. Most of those identified were Black patients and were female (17 and 15 patients, respectively); 16 of the 19 patients had symptoms of an active lupus flare at the time of biopsy. All but one patient with available clinical data had nephrotic-range proteinuria (urine protein, 3 to 12 g/day), and all but one had a reduced glomerular filtration rate (GFR; serum creatinine, 1.6 to 26.5 mg/dL [141.4 to 2342.6 micromol/L]). Less than one-half of the patients had concurrent lupus nephritis identified histologically. Follow-up data were available on 13 patients, more than one-half of whom progressed to end-stage kidney disease within two years.

Importantly, the development of collapsing FSGS in Black patients with SLE is associated with risk polymorphisms in the APOL1 gene [9].

Collapsing FSGS has also been associated with other autoimmune conditions including adult-onset Still disease [60-62] and Behçet syndrome [63].

IgA nephropathy — Histopathologic and clinical features of collapsing FSGS have been described in patients with immunoglobulin A (IgA) nephropathy [64,65]. In one study, for example, collapsing FSGS (in the absence of HIV) was identified as an additional finding in the biopsies of 11 out of 128 adults with IgA nephropathy [64]. Compared with other patients in the series, those with histologic features of collapsing FSGS had significantly higher serum creatinine concentrations and significantly more proteinuria at the time of diagnosis, although proteinuria and hypoalbuminemia were less marked than in patients with idiopathic collapsing FSGS. Ten of these 11 patients were followed for a mean of 44 months; nine required dialysis.

Diabetic kidney disease — Typical histopathologic and clinical features of collapsing FSGS have also been noted in patients with diabetic kidney disease (DKD). In a study of 534 patients with DKD, 26 HIV-negative patients had collapsing FSGS superimposed on DKD (5 percent) [66]. Those with both lesions had more severe disease at the time of biopsy (the mean serum creatinine was 3.8 mg/dL and mean 24-hour proteinuria was 9.8 grams), and the development of end-stage kidney disease was more rapid than in patients with DKD but without collapsing FSGS.

Thrombotic microangiopathy/acute glomerular ischemia — A pathologic pattern consistent with collapsing FSGS has been described in patients with thrombotic microangiopathy (TMA) in native [67] and transplanted [2,34,68] kidneys. In a study of 53 patients with biopsy-proven TMA in the native kidney, collapsing FSGS lesions were identified in 19 (36 percent) [67]. In contrast with patients with idiopathic collapsing FSGS, most of these were White patients, nephrotic syndrome was rare (12 percent), and loss of podocyte immunohistochemical markers was less frequent. Glomerular ischemia and glomerular endothelial injury have been suggested as possible mechanisms. Similarly, glomerular ischemia has been proposed as the mechanism responsible for collapsing FSGS associated with other vaso-occlusive disorders including cholesterol emboli [69], sickle cell anemia [70], DKD [66], and renal infarction [71]. In older patients (age greater than 65 years), this pattern of collapsing FSGS associated with extensive vascular disease and glomerular ischemia is more common [72].

Hemophagocytic lymphohistiocytosis — Some patients with collapsing FSGS have hemophagocytic lymphohistiocytosis (also known as hemophagocytic syndrome), a nonmalignant activation of bone marrow histiocytes, which phagocytose blood cell precursors [73,74]. This syndrome, which is characterized by high levels of circulating proinflammatory cytokines (ie, cytokine "storm") and serum ferritin (often greater than 3000 mcg/L), can be seen in the setting of infections, autoimmune disease, or lymphoma. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)

Collapsing FSGS has also been described in adult-onset Still's disease [60].

CLINICAL FEATURES — Patients with idiopathic collapsing FSGS often present with a similar clinical picture as those with HIV-associated collapsing FSGS. This can include a preceding or ongoing febrile illness (in some patients), severe nephrotic syndrome, kidney function impairment at presentation, and rapid progression to end-stage kidney disease [2,4,32,75-78]. On urinalysis, the nephrotic sediment is associated with heavy proteinuria, lipiduria, and occasionally large granular casts. (See "HIV-associated nephropathy (HIVAN)", section on 'Clinical manifestations'.)

Compared with typical FSGS, collapsing FSGS presents with more severe kidney involvement, including higher levels of proteinuria (commonly over 10 g/day), profound hypoalbuminemia, and more severe kidney dysfunction [2,4,79]. In one series, for example, the average presenting serum creatinine concentrations of patients with collapsing FSGS were significantly higher than those observed among patients with typical FSGS (3.5 versus 1.3 mg/dL [309 versus 115 micromol/L]) [76]. Similar findings were noted in another report despite a shorter time from presentation to kidney biopsy in the patients with collapsing FSGS [77].

In general, kidney ultrasonography of patients with collapsing FSGS shows large echogenic kidneys (even in end-stage kidney disease) as opposed to typical FSGS where smaller, shrunken kidneys are common. (See "Focal segmental glomerulosclerosis: Clinical features and diagnosis".)

Clinical features in other secondary forms of collapsing FSGS may be more variable, including a milder phenotype (often sub-nephrotic proteinuria and less severe acute kidney injury [AKI]) in drug-induced and ischemia-associated forms of collapsing FSGS. (See 'Etiology' above.)

PATHOLOGY — By definition, collapsing FSGS is associated with segmental or global collapse and sclerosis of the glomerular tufts. Most often there is evidence of collapse and sclerosis of the entire glomerular tuft, rather than segmental collapse (picture 1). For many pathologists the finding of collapsing features of even one glomerulus on a kidney biopsy is sufficient for the diagnosis [80]. However, this finding needs to be interpreted within the clinical context of the patient, since a pathological diagnosis of collapsing FSGS from a single glomerulus, in the absence of characteristic clinical features of nephrotic syndrome, may lead to inappropriate treatment. (See 'Diagnosis' below.)

Compared with classic focal FSGS, the following features on kidney biopsy are particularly suggestive of collapsing FSGS:

●Marked hypertrophy and hyperplasia of overlying glomerular epithelial cells above the collapsed areas of the tuft [4,81]

●Often severe tubular injury with cystic dilatation of the tubules filled with proteinaceous casts (proliferative microcystic transformation) and tubular degeneration [4]

●The wrinkling and retraction of the glomerular basement membrane [2,4]

However, at an advanced stage of the disease, collapsing FSGS cannot always be distinguished histologically from typical FSGS (not otherwise specified).

Histologic features that may differ between collapsing FSGS due to HIV from that due to non-HIV infection include:

●The presence of tubuloreticular structures in glomerular endothelial cells on electron microscopy with HIV-associated disease (picture 2). However, such structures may also be seen in collapsing FSGS associated with other conditions in which interferon signaling pathways are upregulated (eg, viral infections, systemic lupus erythematosus, and interferon therapy). Tubuloreticular lesions may be absent in patients with HIV nephropathy who have been treated with antiretroviral therapy.

●A greater incidence of proliferative microcystic transformation with HIV nephropathy [32].

The proliferation of glomerular epithelial cells in collapsing FSGS may occasionally cause diagnostic confusion with the crescents seen in crescentic glomerulonephritis. The term "pseudocrescents" has often been used in the literature to refer to this finding. Proliferating glomerular epithelial cells are also known to be major constituents of classic crescents [82]. In this setting, an accurate diagnosis can be made only after careful interpretation of all clinical and histologic features, such as the clinical history, activity of the urine sediment (red cell casts seen only in crescentic glomerulonephritis), and findings with light microscopy, immunofluorescence, and electron microscopy. (See "Overview of the classification and treatment of rapidly progressive (crescentic) glomerulonephritis", section on 'Clinical presentation'.)

A separate issue is the possible presence of collapsing FSGS in patients in whom there is no evidence of glomerular collapse because of sampling error. Two factors would point toward the diagnosis of collapsing FSGS in such patients: a clinical history of marked proteinuria with acute kidney injury, which is not specific for collapsing FSGS but not often seen in idiopathic FSGS, and the characteristic microcystic tubular changes described above [2,4]. (See "Focal segmental glomerulosclerosis: Clinical features and diagnosis" and "Acute kidney injury (AKI) in minimal change disease and other forms of nephrotic syndrome".)

DIAGNOSIS

Establishing the diagnosis — The diagnosis of collapsing FSGS should be suspected in any patient presenting with nephrotic syndrome, especially if acute kidney injury is also present. A kidney biopsy is required to establish the diagnosis and exclude other possible causes of the nephrotic syndrome.

The general evaluation of a patient with an FSGS lesion on kidney biopsy is presented elsewhere. (See "Focal segmental glomerulosclerosis: Clinical features and diagnosis", section on 'Evaluation of the patient with an FSGS lesion'.)

Evaluation for associated conditions — In patients with the finding of collapsing FSGS on kidney biopsy, the following evaluation should be performed to evaluate for potential associated conditions (table 1):

●History and physical examination, including an assessment of the following:

•Exposure to drugs and/or toxins associated with collapsing FSGS (eg, bisphosphonates, anabolic steroids, interferon) (see 'Bisphosphonates and other drugs' above)

•History of infections (viruses [eg, HIV, parvovirus B19, SARS-COV-2, cytomegalovirus, Epstein-Barr virus (EBV)], tuberculosis, malaria, leishmaniasis) (see 'Infections' above)

•History of another glomerular disease (eg, lupus nephritis, IgA nephropathy, diabetic kidney disease) (see 'Autoimmune disorders' above and 'IgA nephropathy' above and 'Diabetic kidney disease' above)

●Complete blood count (CBC) with platelet count, to assess for anemia and thrombocytopenia.

●Examination of the peripheral blood smear for schistocytes.

●Tests for HIV, parvovirus B19, SARS-COV-2, cytomegalovirus, and EBV. (See "Screening and diagnostic testing for HIV infection" and "Clinical manifestations and diagnosis of parvovirus B19 infection", section on 'Diagnosis' and "Overview of diagnostic tests for cytomegalovirus infection".)

●Antinuclear antibody test. (See 'Autoimmune disorders' above.)

●Serum ferritin concentration. (See 'Hemophagocytic lymphohistiocytosis' above.)

●Genetic testing for APOL1 variants should be performed in all patients with collapsing FSGS in whom a positive result may influence clinical decision making (eg, prognostication, candidates for studies on the therapy of APOL1-positive patients, when deciding whether to evaluate relatives as potential donors for kidney transplantation for the patient). (See "Gene test interpretation: APOL1 (chronic kidney disease gene)".)

TREATMENT

General measures in all patients — General supportive measures in all patients with collapsing FSGS include dietary sodium and protein restriction, blood pressure control, minimization of proteinuria with renin-angiotensin system inhibition, treatment of dyslipidemia, and in selected patients, anticoagulation. Sodium-glucose cotransporter 2 (SGLT2) inhibitors may be of benefit, but data and experience are limited. Other aspects of therapy include diuretics to control edema and maintenance of adequate nutrition. This approach is consistent with the 2021 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Management of Glomerular Diseases [83]. These issues are discussed in greater detail elsewhere:

●Dietary sodium and protein restriction (see "Dietary recommendations for patients with nondialysis chronic kidney disease", section on 'Salt intake' and "Dietary recommendations for patients with nondialysis chronic kidney disease", section on 'Protein intake')

●Antihypertensive therapy (see "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults")

●Renin-angiotensin system inhibition (see "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Renin-angiotensin system inhibitors')

●SGLT2 inhibitors (see "Overview of the management of chronic kidney disease in adults", section on 'Patients with proteinuria')

●Lipid lowering (see "Lipid abnormalities in nephrotic syndrome", section on 'Management')

●Anticoagulation (see "Hypercoagulability in nephrotic syndrome", section on 'Patients with other causes of nephrotic syndrome')

●Treatment of edema (see "Overview of the management of chronic kidney disease in adults", section on 'Volume overload')

Patients with idiopathic collapsing FSGS — There are no clinical trials to guide the optimal therapy of idiopathic collapsing FSGS, and our approach is based primarily upon our clinical experience and data from retrospective studies.

Initial immunosuppressive therapy — In general, we treat most patients with idiopathic collapsing FSGS and nephrotic-range proteinuria with immunosuppressive therapy. Exceptions include patients who have contraindications to immunosuppression (eg, active infection) and those with more advanced kidney disease (ie, histologic evidence of extensive glomerulosclerosis and interstitial fibrosis on kidney biopsy) who are unlikely to respond to therapy.

●We suggest oral glucocorticoids as initial therapy. We typically give oral prednisone 100 to 120 mg every other day for the first two months, then subsequently taper the dose by 20 mg every two weeks until 40 mg every other day is reached, for a total of six months of therapy, at which time we discontinue the prednisone without further taper. Some clinicians prefer to start with daily dosing of glucocorticoids and then change to alternate-day therapy. Glucocorticoids should be used with caution, if at all, in patients at high risk for infection or in patients with diabetes.

Some but not all UpToDate contributors to this topic administer antimicrobial prophylaxis against Pneumocystis pneumonia (PCP) for the duration of glucocorticoid treatment. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)

●For patients who present with large amounts of proteinuria (>10 g/day), severe hypoalbuminemia (serum albumin of <2 g/dL), and preserved kidney function (estimated glomerular filtration rate [eGFR] ≥45 mL/min/1.73 m²), we prefer to add a calcineurin inhibitor (CNI; cyclosporine or tacrolimus) for the duration of glucocorticoid therapy to accelerate reversal of the proteinuria and hypoalbuminemia. The dosing of CNIs in patients with idiopathic collapsing FSGS is the same as for patients with primary (idiopathic) FSGS who are receiving CNIs as initial therapy. (See "Focal segmental glomerulosclerosis: Treatment and prognosis", section on 'Calcineurin inhibitors as alternative initial therapy'.)

There are no high-quality studies that have examined the efficacy of immunosuppressive therapy for idiopathic collapsing FSGS, and data primarily come from small retrospective studies [32,76,77,79]. Most, but not all, of these studies have shown a frequently poor response to immunosuppressive therapy. However, the largest series of 61 patients, 37 of whom were treated with immunosuppressive agents, found that those treated with immunosuppression had higher rates of complete or partial remission (70 versus 40 percent) and lower rates of end-stage kidney disease (35 versus 74 percent) compared with those who were treated with supportive therapy alone [79].

In most cases, glucocorticoids have been used, alone or in combination with a CNI (mostly cyclosporine) or a cytotoxic agent (such as cyclophosphamide). However, no prospective studies have directly compared the efficacy of different immunosuppressive regimens. Our practice is to use glucocorticoids as initial therapy in most patients. We do not use cytotoxic agents, such as cyclophosphamide or chlorambucil, given their poor efficacy and significant side effect profile [32,76,77].

Patients with severe nephrotic syndrome (eg, proteinuria >10 g/day and serum albumin <2 g/dL) generally have a poor prognosis, and early, more intensive therapy (eg, glucocorticoids plus a CNI) may be beneficial if kidney function is reasonably well preserved. There are no data to support this approach, and combination treatment with glucocorticoids and other immunosuppressive agents has not been proven to be superior to glucocorticoids alone. In a retrospective analysis of 275 patients who underwent immunosuppressive treatment for biopsy-proven primary FSGS (15 percent of whom had collapsing FSGS), there was no difference in the adjusted risk of end-stage kidney disease between patients treated with CNIs (with or without glucocorticoids) compared with those treated with glucocorticoids alone [84]. Nevertheless, a trial of more intensive immunosuppression is reasonable in patients with severe nephrotic syndrome given their otherwise poor prognosis.

Monitoring the response to therapy — There are no specific guidelines for monitoring the response to therapy. In patients receiving immunosuppressive therapy, we measure routine blood chemistries, including a plasma creatinine concentration for estimation of GFR, serum albumin concentration, and urine protein-to-creatinine ratio, every two to four weeks for the first two months and, if stable, monthly thereafter.

In patients receiving a CNI, we monitor whole blood trough concentrations on a monthly basis, aiming for cyclosporine trough levels of 125 to 225 ng/mL or tacrolimus trough levels of 5 to 10 ng/mL, although the lowest effective dose of CNI should be used to limit nephrotoxicity.

The response to therapy is assessed in terms of degree of reduction in proteinuria, using definitions that are the same as those used for patients with primary FSGS. (See "Focal segmental glomerulosclerosis: Treatment and prognosis", section on 'Monitoring the response to therapy'.)

Resistant disease — The optimal treatment for patients who do not respond to initial therapy with glucocorticoids with or without a CNI is not known. Collapsing FSGS often progresses quickly among patients who are resistant to initial immunosuppressive therapy, and the prognosis of such patients is typically poor. Our approach in patients with resistant disease is based upon personal experience and limited data from case reports:

●In patients who do not respond to initial therapy with glucocorticoids alone and who have an eGFR ≥30 mL/min/1.73 m², we discontinue glucocorticoids and treat with a CNI (cyclosporine or tacrolimus). Some experts switch to a CNI prior to the completion of six months of glucocorticoid monotherapy if the patient does not show any signs of response after 12 to 16 weeks. Other experts would treat with a CNI and continue low-dose glucocorticoids (eg, prednisone 5 to 10 mg/day). The dosing and duration of CNIs in patients with collapsing FSGS are the same as for patients receiving these drugs as initial therapy for primary FSGS. (See "Focal segmental glomerulosclerosis: Treatment and prognosis", section on 'Calcineurin inhibitors as alternative initial therapy'.)

In patients who have an eGFR <30 mL/min/1.73 m², we avoid using CNIs given the additional risk of nephrotoxicity in these patients. In such patients, rituximab (1 g initially followed 14 days later by another 1 g dose) is an alternative option, although the disease is often too advanced to consider further immunosuppression. Although there are no large studies to support this approach, case reports have described the successful use of rituximab in patients with resistant disease [85-87].

●In patients who do not respond to initial therapy with glucocorticoids plus a CNI, we discontinue these agents, since further treatment is unlikely to be of additional benefit. Some contributors to this topic would suggest a trial of rituximab (1 g initially followed 14 days later by another 1 g dose) based on limited data from case reports suggesting possible benefit [85-87].

Relapsing disease — Disease relapse (ie, a return of proteinuria to ≥3.5 g/day) following a good initial response to immunosuppressive therapy is uncommon among minimal change disease/patients with idiopathic collapsing FSGS. Treatment in this rare scenario would be similar to the therapy that achieved the initial remission. (See 'Initial immunosuppressive therapy' above.)

Patients with associated conditions — In general, the treatment of collapsing FSGS with associated conditions is directed at the underlying condition responsible for the collapsing FSGS. Immunosuppressive therapy is not typically recommended, except in a few special circumstances, as discussed below. In addition, all patients with collapsing FSGS associated with secondary causes should receive general measures, such as blood pressure control, minimization of proteinuria with angiotensin inhibition, and treatment of dyslipidemia. (See 'General measures in all patients' above.)

It should be recognized that the high-risk APOL1 genotypes are susceptibility alleles, rather than secondary causes, and patients with these genotypes may still respond favorably to immunosuppression. (See 'APOL1 high-risk alleles' above.)

●Collapsing FSGS associated with infections – In patients with collapsing FSGS associated with infections (eg, parvovirus B19, cytomegalovirus, hepatitis C virus, hepatitis B virus, malaria, or tuberculosis) (see 'Infections' above), treatment of the underlying infection may improve kidney outcomes. As an example, in two case reports of collapsing FSGS associated with acute cytomegalovirus infection, treatment with antiviral agents (ganciclovir) and prolonged oral glucocorticoids resulted in an improvement in kidney function [88,89]. The role of glucocorticoids or other immunomodulatory agents in patients receiving anti-infective therapy is unclear. The risk of exacerbating the active infection must be recognized if glucocorticoids are being considered, and in most cases, this risk is likely to outweigh the potential benefit. The treatment of individual infections associated with collapsing FSGS is discussed separately:

•(See "Treatment and prevention of parvovirus B19 infection".)

•(See "Epidemiology, clinical manifestations, and treatment of cytomegalovirus infection in immunocompetent adults", section on 'Therapy'.)

•(See "Antituberculous drugs: An overview".)

●Collapsing FSGS associated with drugs – In patients with collapsing FSGS associated with drugs (see 'Bisphosphonates and other drugs' above), the primary approach to treatment is discontinuation of the offending agent. We do not routinely treat such patients with immunosuppressive therapy; however, the addition of glucocorticoids and/or a CNI may be considered depending upon the rapidity of deterioration in kidney function and the response to stopping the medication. Outcomes are variable, but both complete and partial remissions have been described after discontinuation of bisphosphonates without immunosuppression. The additional use of glucocorticoids has been reported, but it is unclear if the improvement in these cases was related to the immunosuppression or merely discontinuation of the drug [51,52,90-92]. Improvement after discontinuation of anabolic steroids has also been described [53].

●Collapsing FSGS associated with other disorders – Collapsing FSGS in patients with systemic lupus erythematosus typically presents in the setting of a lupus flare and may occur with or without the presence of concurrent lupus nephritis on kidney biopsy [55-59]. There are no clinical trials to guide therapy in this rare condition, but patients are often treated with immunosuppression similar to that used for class IV lupus nephritis. One study suggested a better response to therapy in patients who had concurrent lupus nephritis compared with those who only had collapsing FSGS on biopsy [55]. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis".)

When collapsing FSGS occurs in the setting of diabetic kidney disease or IgA nephropathy, it may be secondary to ischemia or vascular disease. Immunosuppressive therapy with glucocorticoids as discussed above (see 'Initial immunosuppressive therapy' above) may be reasonable in such patients who present with a more acute, severely nephrotic presentation. The use of glucocorticoids and other immunosuppressive medications must be weighed against the risk of infections and other complications.

PROGNOSIS — In general, the prognosis of idiopathic collapsing FSGS not associated with HIV infection is poor [4,76-79]. As examples:

●One retrospective study compared kidney outcomes between 61 patients with collapsing FSGS and 126 patients with noncollapsing FSGS [79]. At baseline, patients with collapsing FSGS had higher levels of proteinuria (12 versus 4 g/day) and lower estimated glomerular filtration rate (eGFR; 48 versus 60 mL/min/1.73 m²). At a median of 69 months, patients with collapsing FSGS were more likely to have end-stage kidney disease than those with noncollapsing FSGS (48 versus 26 percent). However, it should be noted in the 37 patients treated with immunosuppression, 70 percent achieved a complete or partial remission, suggesting that there may be a benefit to early immunosuppressive therapy. (See 'Initial immunosuppressive therapy' above.)

●Another large series compared 43 patients with collapsing FSGS with 50 matched controls with idiopathic FSGS [77]. The mean time from biopsy to end-stage kidney disease with collapsing FSGS was much shorter than in the patients with idiopathic FSGS (13 versus 63 months). However, most patients in this series had advanced kidney function impairment and marked interstitial fibrosis on kidney biopsy at the time of diagnosis.

Similar findings were noted in two other retrospective series. Patients with collapsing FSGS were more likely to be on dialysis within 15 months (5 of 14 compared with none of 25 with noncollapsing FSGS) [76] and at five years (40 versus 0 percent) [78]. The first prospective study of different FSGS variants confirmed the poor prognosis for collapsing FSGS [80].

The prognosis for collapsing FSGS associated with other diseases is more variable. The numbers of patients with collapsing FSGS associated with entities such as systemic lupus erythematosus or bisphosphonates are too small to draw firm conclusions about whether the course of such patients differs significantly from that of patients with idiopathic collapsing FSGS. In general, collapsing FSGS associated with SLE has a more rapidly progressive course, whereas some medication-induced (eg, pamidronate) or familial forms of collapsing FSGS may have a better prognosis. (See 'Etiology' above.)

TRANSPLANTATION — Kidney transplantation has been performed in patients with idiopathic collapsing FSGS. Recurrent disease can occur, supporting the presence of a pathogenic circulating factor, with a recurrence rate similar to that of other patterns of FSGS [4,34,35]. De novo collapsing FSGS in the kidney allograft has also been described and may occur in the setting of inflammation (acute rejection or viral infections [especially cytomegalovirus]), or secondary to glomerular ischemia from acute vascular occlusion (due to thrombotic microangiopathy [TMA], atheroembolism, or cortical necrosis) [68]. (See "Kidney transplantation in adults: Focal segmental glomerulosclerosis in the transplanted kidney".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults".)

SUMMARY AND RECOMMENDATIONS

●Overview – Collapsing focal segmental glomerulosclerosis (collapsing FSGS; also known as collapsing glomerulopathy) is a cause of the nephrotic syndrome that is characterized histologically by segmentally or globally collapsed glomerular capillaries and severe tubulointerstitial disease. In the past, collapsing FSGS was most often seen in association with HIV infection but is increasingly recognized in patients without HIV. (See 'Introduction' above.)

●Pathogenesis – The underlying pathogenic event appears to be a severe insult to the integrity and biology of the glomerular visceral epithelial (podocytes) and parietal epithelial cells. This is accompanied by a profound loss of function of the glomerular filtration barrier. There may be a genetic predisposition toward collapsing FSGS. Black patients with risk polymorphisms in the APOL1 gene are at increased susceptibility to develop collapsing glomerulopathy. (See 'Pathogenesis' above.)

●Etiology – The majority of cases of collapsing FSGS are idiopathic. However, collapsing FSGS has been reported to occur in association with a growing list of disorders (table 1). (See 'Etiology' above.)

●Clinical features – Patients with idiopathic collapsing FSGS present with a similar clinical picture as those with HIV-associated collapsing FSGS. This can include a preceding or ongoing febrile illness, severe nephrotic syndrome, kidney function impairment at presentation, and rapid progression to end-stage kidney disease. On urinalysis, the nephrotic sediment is associated with heavy proteinuria, lipiduria, and occasionally large granular casts. Compared with typical FSGS, collapsing FSGS presents with more severe kidney involvement, including higher levels of proteinuria (commonly over 10 g/day) and more severe kidney dysfunction. (See 'Clinical features' above.)

●Diagnosis – The diagnosis of non-HIV collapsing FSGS should be suspected in any patient presenting with nephrotic syndrome, especially if acute kidney injury is also present. A kidney biopsy is required to confirm the diagnosis and to exclude other possible causes of the nephrotic syndrome. In patients with the finding of collapsing FSGS on kidney biopsy, an evaluation should be performed to exclude potential secondary causes. (See 'Diagnosis' above.)

●Treatment

•Supportive measures in all patients – General supportive measures in all patients with collapsing FSGS include dietary sodium and protein restriction, blood pressure control, minimization of proteinuria with renin-angiotensin system inhibition, treatment of dyslipidemia, and in selected patients, anticoagulation. Sodium-glucose cotransporter 2 (SGLT2) inhibitors may be of benefit, but data and experience are limited. (See 'General measures in all patients' above.)

•Idiopathic collapsing FSGS – There are no high-quality studies to guide the optimal treatment of idiopathic collapsing FSGS, and our approach is based upon the clinical expertise of the authors and editors:

-For patients with idiopathic collapsing FSGS who do not have a contraindication to immunosuppression, we suggest initial therapy with glucocorticoids plus supportive measures rather than supportive measures alone or combined with alternative immunosuppressive therapy (Grade 2C).

-For patients with large amounts of proteinuria (>10 g/day), severe hypoalbuminemia (serum albumin of <2 g/dL), and preserved kidney function (estimated glomerular filtration rate [eGFR] ≥45 mL/min), we prefer to add a calcineurin inhibitor to the glucocorticoid regimen to accelerate reversal of the hypoalbuminemia and proteinuria. Although there are no data to support this approach, a trial of more intensive immunosuppression is reasonable in patients with severe nephrotic syndrome given their otherwise poor prognosis. (See 'Initial immunosuppressive therapy' above.)

•Patients with associated conditions – The treatment of non-HIV collapsing FSGS with associated conditions is directed at the underlying condition responsible for the collapsing FSGS. Immunosuppressive therapy is not typically recommended, except in a few special circumstances, as discussed above. (See 'Patients with associated conditions' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Peter J Nelson, MD, who contributed to earlier versions of this topic review.