INTRODUCTION — Focal segmental glomerulosclerosis (FSGS) is a histologic lesion, rather than a specific disease entity, that is commonly found to underlie the nephrotic syndrome in adults and children [1-7]. FSGS is characterized by the presence of sclerosis in parts (segmental) of at least one glomerulus (focal) in the entire kidney biopsy specimen, when examined by light microscopy (LM), immunofluorescence (IF), or electron microscopy (EM).

The term "FSGS" is somewhat misleading, however, since the lesions of FSGS are not as focal in distribution as the name suggests. In experimental models of FSGS, for example, nearly all glomeruli have sclerotic lesions on three-dimensional morphometric analysis, but LM examination reveals only a limited number of glomeruli with segmental sclerotic lesions. Since the average volume of a sclerotic lesion in FSGS is approximately 12.5 percent of the total glomerular volume, evaluation of kidney biopsies by conventional single sections largely underestimates the number of sclerotic glomeruli [8]. Thus, precise quantification of sclerotic glomeruli requires three-dimensional morphometric analysis of entire glomeruli and the examination of sufficient glomeruli. A biopsy specimen containing only cortical glomeruli may underestimate the frequency of FSGS lesion in the whole kidney. In order to maximize accuracy, the diagnostic set should be comprised of consecutive sections selected from 12 to 15 routinely cut serial sections and should contain a minimum of eight glomeruli [8-10]. Due to sampling error, some cases will be misclassified as minimal change disease. (See "Minimal change disease: Etiology, clinical features, and diagnosis in adults", section on 'Distinguishing MCD from primary FSGS'.)

The lesion of FSGS can be classified into primary, secondary, and genetic forms. FSGS arises as a consequence of multiple pathways either individually or collectively resulting in injury to the podocyte, hence the term "podocytopathy." In primary FSGS, a putative circulating factor that is toxic to the podocyte causes generalized podocyte dysfunction. Secondary FSGS generally occurs as an adaptive phenomenon that results from a reduction in nephron mass, or direct toxicity from drugs or viral infections. FSGS can also be caused by a number of genetic mutations in genes that code for proteins expressed in podocytes and at the slit diaphragm. The presence of an FSGS lesion in a kidney biopsy by itself does not establish a diagnosis but should initiate an evaluation to identify a specific etiology, since distinguishing between the different forms of FSGS has important implications for treatment and prognosis.

The lesion of FSGS must also be distinguished from the lesion of focal global glomerulosclerosis (FGGS), which is frequently a manifestation of normal aging and can be superimposed on a lesion of FSGS, particularly in older patients [11].

The pathogenesis of primary and secondary FSGS will be reviewed in this topic. Genetic forms of FSGS as well as the epidemiology, classification, clinical features, diagnosis, and treatment of FSGS and recurrent disease in the kidney transplant are discussed separately:

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

●(See "Focal segmental glomerulosclerosis: Epidemiology, classification, clinical features, and diagnosis".)

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

●(See "Kidney transplantation in adults: Focal segmental glomerulosclerosis in the transplanted kidney".)

PATHOGENESIS OF PRIMARY FSGS — In primary FSGS, a putative circulating factor that is toxic to the podocyte causes generalized podocyte dysfunction manifested by widespread foot process effacement [7,12-15]. However, involvement of parietal epithelial cells, independent of podocyte involvement, has also been described [16].

The identity of the circulating factor(s) has not yet been clearly established [17]. The existence of such factor(s) is supported by the following observations:

●Some patients with primary FSGS develop recurrent disease following kidney transplantation [18-20]. In such patients, diffuse foot process effacement can be observed by electron microscopy (EM) within minutes after reperfusion [18]; light microscopy (LM) at this early stage typically shows normal-appearing glomeruli. Marked proteinuria subsequently develops within hours to days posttransplant [21], and, with time, the characteristic FSGS lesion forms.

●In patients who develop recurrent FSGS posttransplant, treatment with plasmapheresis and/or immunoadsorption may reduce proteinuria [22,23]. (See "Kidney transplantation in adults: Focal segmental glomerulosclerosis in the transplanted kidney", section on 'Pathogenesis'.)

●Administration of serum from patients with FSGS into rats induces proteinuria [24,25].

●Transplacental transmission of permeability factors from mother to child causes transient neonatal proteinuria [26].

●Proteinuria and histologic changes resolve when transplanted kidneys with recurrent FSGS are reimplanted in patients with end-stage kidney disease (ESKD) due to diseases other than FSGS [27,28].

Thus, damage to the podocyte is the key initial event in the pathogenic process, and diffuse foot process effacement is the earliest pathologic manifestation in the development of FSGS. This explains the absence of FSGS lesions by LM in an initial biopsy of the renal allograft when a second biopsy, performed months or even years later, clearly demonstrates lesions of FSGS [29,30].

However, as discussed above, the precise cause of primary FSGS is still unknown. Although the pathogenesis almost certainly involves one or more circulating factors that are likely to be heterogeneous in character, no single factor has been conclusively shown to underlay all forms of primary FSGS, and existing evidence remains incomplete. These potential factors are reviewed below.

Putative circulating permeability factors

suPAR — The soluble form of the urokinase plasminogen activator receptor (suPAR), a multi-domain signaling molecule, has been proposed as a circulating permeability factor in primary FSGS. The suPAR acts via activation of podocyte alpha v beta 3 integrin, which plays an important role both in the dynamic regulation of mature foot processes and the controlled adhesion to the glomerular basement membrane [31,32]. Elevated circulating levels of suPAR in kidney disease have been attributed to overproduction by immature myeloid cells of the bone marrow [33]. All forms of suPAR can induce sclerotic lesions in mice, but the timing and extent of injury vary based upon the suPAR substructure [33-36].

Support for a causal role of suPAR in primary FSGS was initially provided by the selective expression of suPAR variants in mice [34]. Mice exposed to some [34] but not all [36] forms of suPAR developed rapid-onset albuminuria and a progressive glomerulopathy characterized by effacement of foot processes, hypercellularity, mesangial expansion, mesangiolysis, and tuft adhesions. Infusion of full-length suPAR into mice downregulated expression of nephrin in podocytes and induced proteinuria [37]. In addition, coinjection of suPAR with anti-CD40 autoantibody, a potentially pathogenic antibody identified in the serum of patients with recurrent FSGS after kidney transplantation, elicited greater proteinuria in mice, suggesting that suPAR can also cooperate with other molecules to produce kidney injury [38].

Plasmapheresis, which is commonly used to treat recurrent FSGS following transplantation, has been shown to decrease serum suPAR levels and podocyte beta 3 integrin activity and improve podocyte effacement in a subset of patients with recurrent FSGS [39]. (See "Kidney transplantation in adults: Focal segmental glomerulosclerosis in the transplanted kidney", section on 'Pathogenesis'.)

Although the results from in vitro and animal studies are highly suggestive of a role for suPAR in the pathogenesis of FSGS, a number of studies have questioned the specific pathogenic role of suPAR in primary FSGS [40]. Serum levels of suPAR are inversely related to glomerular filtration rate (GFR) and, therefore, elevated suPAR levels can occur in patients with reduced GFR who do not have primary FSGS [41,42]. Plasma suPAR levels cannot be used to accurately distinguish between primary and secondary forms of FSGS [43], and elevated suPAR levels have been reported in other glomerular diseases [43-45] as well as a number of diseases that do not involve proteinuria [46-50]. In one study, administration of two different, well-characterized forms of recombinant suPAR to wild-type mice produced deposition of the suPAR within glomeruli [36]. However, deposition of either form of suPAR in the kidney did not result in increased glomerular proteinuria or altered podocyte architecture, suggesting that glomerular deposits of suPAR caused by elevated plasma levels of suPAR alone are not sufficient to cause albuminuria in the short term [35] but may be required several months before the onset of glomerular injury [33].

Thus, there is evidence both in support of and against suPAR in the pathogenesis of FSGS. Further studies are needed to clarify its role in the pathogenesis of primary FSGS.

CLCF1 — Cardiotrophin-like cytokine factor 1 (CLCF1) is a 22 kDa member of the interleukin (IL)-6 family that has been detected in the plasma from patients with recurrent FSGS [51]. CLCF1 is believed to be secreted into the circulation as a heterodimeric cytokine with either cytokine receptor-like factor 1 (CRLF1) or soluble receptor alpha for ciliary neurotrophic factor (sCNTF R-alpha). Its role as a putative permeability factor in primary FSGS continues to be investigated [52].

MicroRNA — MicroRNAs are endogenous, small (18 to 24 nucleotides long), noncoding, single-stranded RNAs that regulate gene expression at the posttranscriptional level. Specifically, microRNAs bind to the messenger RNAs of various genes and lead to their degradation.

Expression of a specific microRNA called miR-193a produced FSGS in mice [53]; miR-193a inhibited the transcript for the Wilms tumor protein (WT1) in podocytes and therefore inhibited the expression of a variety of WT1-controlled genes that are important for podocyte function, such as nephrin (see "Focal segmental glomerulosclerosis: Genetic causes", section on 'NPHS1 gene'). In addition, elevated miR-193a expression was found in glomeruli from patients with acquired (nongenetic) FSGS but not in glomeruli from patients with minimal change disease, membranous nephropathy, or immunoglobulin A (IgA) nephropathy or from healthy controls. Expression of miR-193a in podocytes was not found in mouse models of suPAR-induced FSGS, suggesting that miR-193a is at least not directly downstream of circulating suPAR.

PATHOGENESIS OF SECONDARY FSGS — Secondary FSGS usually results from an adaptive response to glomerular hypertrophy and hyperfiltration, another glomerular abnormality (such as those involving the glomerular basement membrane), or direct toxic injury to podocytes (eg, drugs, virus) [7]. It is important, clinically, to distinguish secondary from primary FSGS since the treatment of secondary FSGS consists of conservative therapy aimed at a low-protein/low-salt diet and blood pressure control with inhibition of the renin-angiotensin system but not glucocorticoids or immunosuppressive therapy. How this distinction is made is discussed separately:

●(See "Focal segmental glomerulosclerosis: Epidemiology, classification, clinical features, and diagnosis", section on 'Clinical features'.)

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

Proteinuria in secondary FSGS, as in primary FSGS, is a manifestation of podocyte injury, but the mechanism is different. The visceral epithelial cells are unable to replicate. In the presence of the hypertrophic response to nephron loss or direct epithelial cell injury, it is postulated that the inability of these cells to replicate leads to decreased podocyte density and focal areas of denudation from the glomerular basement membrane. As a result, the barrier to filtration normally provided by the slit diaphragms between the foot processes is lost in these areas. The ensuing increase in flux of small solutes and water through these sites carries albumin along by solvent drag [13,15]. Larger macromolecules (such as immunoglobulin M [IgM] and fibrinogen and complement metabolites) are unable to cross the glomerular basement membrane but can form large subendothelial hyaline deposits.

Glomerular cell proliferation, macrophage infiltration, and the progressive accumulation of extracellular matrix components all may contribute to the development of the sclerotic lesion [54]. How these changes occur is not well understood, but cytokines, such as transforming growth factor (TGF)-beta, may be responsible for at least part of the matrix accumulation. TGF-beta accelerates podocyte damage by changing transcriptional activity to allow for expression of cytosolic cathepsin L [55]. Cytosolic cathepsin L in podocytes cleaves the large guanosine triphosphate hydrolase (GTPase) dynamin [56], synaptopodin [57], as well as CD2-associated protein (CD2AP), establishing the ultrastructural changes in podocytes seen in FSGS [55]. Allosteric activation of dynamin by a small molecule has been shown to reestablish podocyte architecture, decrease proteinuria, and extend survival of CD2AP-null mice [58]. (See "Focal segmental glomerulosclerosis: Genetic causes", section on 'Other genes'.)

A substantial (>50 percent) number of patients with clinical and histopathologic features suggestive of secondary FSGS are never definitively diagnosed with a specific etiology for their disease using the diagnostic tools available in clinical practice. These patients seldom respond to glucocorticoid treatment and have a low frequency of disease recurrence after kidney transplantation. Slow and indolent progression to end-stage kidney disease (ESKD) is common, although the rate of progression may be decreased by rigorous control of blood pressure and reduction of proteinuria. Many of these patients may have undiagnosed genetic forms of FSGS, and genetic analysis, which may include next-generation sequencing, should be considered [59]. Identifying a genetic cause is important since it would avoid exposing patients to the adverse effects of prolonged immunosuppression [12].

●(See "Focal segmental glomerulosclerosis: Epidemiology, classification, clinical features, and diagnosis", section on 'Approach to differentiating primary, secondary, and genetic FSGS'.)

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

Adaptive response to hyperfiltration — Hyperfiltration refers to an adaptive but abnormal increase in single-nephron glomerular filtration that increases the total glomerular filtration rate (GFR) above the level expected from the reduced number of glomeruli. The settings in which adaptive glomerular hypertrophy and hyperfiltration occur include the many diseases associated with either nephron loss and/or intraglomerular hypertension with an initially normal number of nephrons [60].

Reduced renal mass — FSGS induced by the adaptive response to nephron loss occurs with many causes of chronic kidney disease, including nonglomerular disorders such as reflux nephropathy and ischemia in benign hypertensive nephrosclerosis. It can also occur when there is a marked reduction in renal mass due to congenital absence or surgical removal [61]. (See "Clinical features, diagnosis, and treatment of hypertensive nephrosclerosis".)

In these settings, compensatory intraglomerular hypertension and hypertrophy in the remaining glomeruli will lead to an increase in the nephron filtration rate that will initially tend to maintain the total GFR. Over a period of years, however, "hypertensive" injury associated with intraglomerular hypertension can lead to FSGS and a decline in GFR. The protective effect of angiotensin inhibitors is mediated in part by the associated reduction in glomerular capillary pressure. (See "Secondary factors and progression of chronic kidney disease", section on 'Intraglomerular hypertension and glomerular hypertrophy' and "Antihypertensive therapy and progression of chronic kidney disease: Experimental studies", section on 'Preferential effect of RAS blockers on renal hemodynamics'.)

The risk of developing secondary FSGS after nephron loss is dose dependent or there may be a threshold effect, with surgical studies suggesting that loss of more than 50 percent of nephrons is required in adults. This was illustrated in a long-term follow-up of adults undergoing partial nephrectomy for renal cancer in a solitary kidney [62]. Patients who lost more than 75 percent of their total renal mass were at greatest risk for developing proteinuria, glomerulosclerosis, and, in some cases, progressive kidney failure. Clinically evident disease was usually delayed for at least five years after the surgery.

By comparison, long-term renal outcomes are generally excellent after loss of one kidney (50 percent nephron loss). As an example, a benign clinical course after 45 years was noted in 62 men who had one kidney removed (ie, 50 percent nephron loss) due to trauma during World War II and in a literature review of 3124 patients with reduced renal mass, almost all of whom had undergone unilateral nephrectomy [63,64]. There was no evidence that nephrectomy was associated with an increased prevalence of kidney dysfunction or hypertension, but there was a small increase in proteinuria and in the systolic blood pressure (2.4 mmHg initially and a further 1.1 mmHg per decade) [64]. Similarly, long-term renal outcomes are generally excellent in kidney donors for kidney transplantation. (See "Kidney transplantation in adults: Risk of living kidney donation".)

Although loss of 50 percent of renal mass may be associated with a minor, long-term risk when it occurs in adults, unilateral renal agenesis is associated with an increased incidence of secondary FSGS. These patients often have structural disease (most often vesicoureteral reflux or partial urinary tract obstruction) in the solitary kidney, which may result in a greater degree of nephron loss [65,66]. However, proteinuria and renal insufficiency can occur in patients with an apparently normal solitary kidney [67], suggesting that loss of 50 percent of renal mass beginning at birth is sufficient to induce hemodynamically mediated glomerular injury. (See "Renal agenesis: Prenatal diagnosis".)

Low birth weight and premature birth, which are associated with reduced renal mass, may be risk factors for the development of FSGS. A retrospective study from Japan reviewed the birth weights and gestational age of all patients who underwent kidney biopsies at a single institution from 1995 to 2011 [68]. Among 16 patients who were diagnosed with FSGS, six (37.5 percent) had low birth weight, a rate that was significantly higher than the overall low birth weight rate in Japan (9.7 percent). All patients with FSGS and low birth weight also had premature birth (average gestational age 25.8 weeks).

Reflux nephropathy — Patients with reflux nephropathy are commonly hypertensive and have chronic kidney disease, and mild to moderate proteinuria is common due to a secondary FSGS lesion. However, development of nephrotic syndrome suggests other etiologies of proteinuria and warrants a kidney biopsy.

●(See "Clinical presentation, diagnosis, and course of primary vesicoureteral reflux".)

●(See "Focal segmental glomerulosclerosis: Epidemiology, classification, clinical features, and diagnosis", section on 'Patients with nephrotic syndrome'.)

Severe obesity — FSGS has been described in patients with severe (also called massive or extreme) obesity [69-74]. In one study, FSGS was present in 9 of 17 patients with severe obesity who underwent kidney biopsy for marked proteinuria without an apparent systemic disease [71]. The frequency of FSGS was much higher than in 34 normal body weight controls matched for age and sex with a similar renal presentation (53 versus 6 percent). Most patients also have glomerulomegaly, but some patients (14 of 71 [20 percent] in one series) have glomerulomegaly without evidence of glomerulosclerosis [69].

The term "obesity-related glomerulopathy" has been used to refer to FSGS associated with obesity [69,75]. However, some obese patients with moderate to heavy proteinuria have little or no glomerulosclerosis and no epithelial cell injury or foot process effacement on kidney biopsy; they do have significant mesangial expansion and glomerular capillary loop enlargement (glomerulomegaly) [69,75-78]. These findings suggest that obesity alone may not be sufficient to produce an FSGS lesion, and additional triggers may be required. Kidney biopsy findings suggestive of obesity-related glomerulopathy include fewer glomeruli showing an FSGS lesion (12 versus 39 percent in primary FSGS), a perihilar variant, glomerulomegaly, and <50 percent foot process effacement by electron microscopy (EM) [74].

Severe obesity in humans is associated with a marked increase in GFR. In one study, for example, the mean GFR in eight severely obese patients was 145 mL/min compared with 90 mL/min in nine healthy controls [79]. After marked weight loss in the obese patients (32 percent reduction in body mass index [BMI]), the mean GFR fell to 110 mL/min. These findings are consistent with a role for intraglomerular hypertension in the pathogenesis of the proteinuria and sclerotic lesions in obesity-related FSGS [69,71-73]. Decreased serum levels of an adipose-derived hormone, adiponectin, have been associated with proteinuria in obese patients and may play a pathogenetic role in the development of glomerulosclerosis [80].

Some patients with severe obesity have subclinical disease, which is defined as sclerotic lesions in a few glomeruli in patients with little or mild proteinuria and a normal GFR [69,71,81,82]. The best data come from a series of 95 patients with severe obesity and no clinical evidence of kidney disease in whom intraoperative kidney biopsy was performed during bariatric surgery [81]. Forty patients undergoing nephrectomy who were neither obese nor hypertensive served as controls. FSGS was observed in approximately 5 percent of the obese patients compared with none of the nonobese patients (median BMI 52 versus 25 kg/m²). Increased mesangial matrix, mesangial cell proliferation, and podocyte hypertrophy occurred in 73 and 5 percent of obese and nonobese patients, respectively. BMI was independently associated with these glomerular lesions in the entire cohort. It is not known if these observations would also apply to the moderately obese population (BMI = 30 to 45 kg/m²).

In some reports, obesity-related glomerulopathy has been attributed to coexistent sleep apnea, with its reversal leading to complete resolution of the proteinuria [76,83]. However, a subsequent, well-designed study of patients with varying degrees of sleep apnea found no correlation between proteinuria and the presence or severity of the sleep apnea [84]. Although the reasons for these discrepant findings are unclear, previous reports failed to exclude possible confounding factors, particularly decompensated heart failure. In the biopsy study cited above [81], sleep apnea was associated with glomerulomegaly (in the absence of proteinuria) in the extremely obese cohort.

Both weight loss and the administration of an angiotensin inhibitor can dramatically reduce protein excretion (up to 80 to 85 percent) in patients with obesity-related FSGS [72,79,85,86]. The efficacy of weight loss was demonstrated in a study of 63 patients with biopsy-proven FSGS who participated in a weight loss program [86]. Mean protein excretion was 1.5 g/day and mean baseline estimated GFR was 104 mL/min per 1.73 m². At six months, mean protein excretion decreased from 1.6 to 1.1 g/day in the 27 patients who lost weight in comparison with no reduction in proteinuria in patients who had a stable (n = 21) or increased (n = 8) BMI. The findings were similar at 24 months. It is important to recognize that proteinuria levels in this study were well below levels seen in patients with primary FSGS, and the trivial reduction in proteinuria may have been related to better blood pressure control in these patients.

In spite of the slowly progressive course of obesity-related FSGS, worsening renal impairment and ESKD may develop in 10 to 33 percent of patients [69,70,87].

Other causes — Segmental areas of glomerulosclerosis can be induced by intraglomerular hypertension occurring in patients with initially normal renal mass, such as those with the following conditions [13]:

●Diabetic nephropathy (see "Diabetic kidney disease: Pathogenesis and epidemiology", section on 'Glomerular hemodynamics')

●Sickle cell anemia [88] (see "Sickle cell disease effects on the kidney", section on 'Pathogenesis')

●Cyanotic heart disease [89]

●Glucose-6-phosphatase deficiency (glycogen storage disease I, von Gierke disease) [90]

●Familial dysautonomia

Drugs and toxins — A number of drugs and toxins have been associated with the development of FSGS.

Heroin — Heroin abuse may be associated with FSGS, including in patients who are HIV negative. Disorders other than FSGS also can occur in heroin abusers, including secondary amyloidosis due to chronic suppurative subcutaneous infections [91], membranous nephropathy due to hepatitis B virus infection, and membranoproliferative glomerulonephritis due to hepatitis C virus infection [92].

Heroin-associated FSGS has a predilection for Black patients [91,93]. Slow progression to kidney failure can occur, usually over a period of several years rather than several months, as in HIV-induced disease. (See "HIV-associated nephropathy (HIVAN)".)

The pathogenesis of heroin nephropathy is uncertain. It has been proposed that glomerular epithelial cell injury may be induced by a heroin adulterant. Compatible with this hypothesis is the observation that heroin nephropathy has largely disappeared in large urban centers at a time when the purity of street heroin has markedly increased [94]. An alternate explanation is that drug abusers have become HIV positive and either die earlier or develop HIV nephropathy or that heroin nephropathy represented a variety of kidney disorders that are now recognized to be associated with other conditions (eg, hepatitis C).

Interferon — The administration of interferon (IFN)-alpha has been associated with both FSGS [95,96] and minimal change disease [97]. In addition, 11 cases of collapsing FSGS associated with therapeutic doses of IFN-alpha (six), IFN-beta (three), and IFN-gamma (two) were identified from the archives of Columbia University's Renal Pathology Laboratory [98].

Bisphosphonates — Bisphosphonate therapy, particularly with pamidronate, has been associated with the development of the collapsing variant of FSGS. This is discussed in more detail elsewhere. (See "Collapsing focal segmental glomerulosclerosis not associated with HIV infection", section on 'Bisphosphonates and other drugs'.)

Anabolic steroids — FSGS and proteinuria were associated with the long-term use of anabolic steroids in a cohort of 10 patients identified from the archives of Columbia University's Renal Pathology Laboratory [99]. All patients engaged in weightlifting for the purpose of bodybuilding or strength competitions and used at least one anabolic androgenic steroid for a number of years (range 8 to 20 years). Most patients also used dietary supplements such as creatine monohydrate and a high-protein diet. The following characteristics were noted:

●Mean protein excretion was 10.1 g/day (range 1.3 to 26.3 g/day), and the average creatinine clearance was 96 mL/min (range 17 mL/min to 196 mL/min). The mean serum creatinine was much higher (3 mg/dL [265 micromol/L]) than usually expected from the near-normal mean creatinine clearance, which presumably reflects the marked increase in muscle mass and therefore creatinine production.

●Discontinuation of the anabolic steroids and supplements resulted in improvement in or stabilization of the serum creatinine and a decrease in protein excretion.

Renal hemodynamic factors and possibly a direct nephrotoxic effect of anabolic steroids probably underlie this association.

Other drugs — Other medications that have been associated with FSGS include the following:

●Anthracyclines (eg, doxorubicin, daunorubicin) [100]

●Calcineurin inhibitors (among kidney transplant recipients) [101] (see "Kidney transplantation in adults: Focal segmental glomerulosclerosis in the transplanted kidney", section on 'De novo FSGS')

●Lithium (see "Renal toxicity of lithium", section on 'Nephrotic syndrome')

●Sirolimus (particularly at high plasma drug levels) (see "Pharmacology of mammalian (mechanistic) target of rapamycin (mTOR) inhibitors", section on 'Proteinuria')

Viruses — FSGS has been associated with a number of viral infections, particularly infection with HIV, which can cause the collapsing variant of FSGS. (See "HIV-associated nephropathy (HIVAN)".)

In addition, FSGS lesions have been reported among patients infected with parvovirus B19 [102], cytomegalovirus [103], Epstein-Barr virus [104], simian virus 40 [105], and hepatitis C virus [106].

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

●Focal segmental glomerulosclerosis (FSGS) is a histologic lesion, rather than a specific disease entity, that is commonly found to underlie the nephrotic syndrome in adults and children. FSGS is characterized by the presence of sclerosis in parts (segmental) of at least one glomerulus (focal) in the entire kidney biopsy specimen, when examined by light microscopy (LM), immunofluorescence (IF), or electron microscopy (EM). The lesion of FSGS can be classified into primary, secondary, and genetic forms. (See 'Introduction' above.)

●In patients with primary FSGS, injury to glomerular visceral epithelial cells (podocytes) occurs likely as a consequence of a circulating permeability factor or factors, the identity of which has not yet been clearly established. (See 'Pathogenesis of primary FSGS' above.)

●The glomerulosclerosis of secondary FSGS usually results from an adaptive response to glomerular hypertrophy and hyperfiltration or other glomerular abnormality (such as those involving the glomerular basement membrane) or from direct toxic injury to podocytes. However, in a substantial (>50 percent) number of patients with clinical and histopathological features suggestive of secondary FSGS, a specific etiology cannot be identified with the diagnostic tools available in clinical practice. It is possible that many of these patients have undiagnosed genetic forms of FSGS, and genetic analysis, which may include next-generation sequencing, should be considered. (See 'Pathogenesis of secondary FSGS' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Jochen Reiser, MD, PhD, who contributed to an earlier version of this topic review.