ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Focal segmental glomerulosclerosis: Pathogenesis

Focal segmental glomerulosclerosis: Pathogenesis
Literature review current through: Jan 2024.
This topic last updated: Dec 16, 2022.

INTRODUCTION — Focal segmental glomerulosclerosis (FSGS) is a morphologic pattern of glomerular injury primarily directed at the glomerular visceral epithelial cell (the podocyte) and defined by the presence of sclerosis in parts (segmental) of some (focal) glomeruli by light microscopy of a kidney biopsy specimen. The lesion of FSGS can be classified into primary, secondary, genetic, and unknown forms using a clinicopathologic approach. This classification step is crucial for determining appropriate therapy; identification of an FSGS lesion solely by light microscopy is never sufficient for management decisions. The lesion of FSGS is distinct from focal and global glomerulosclerosis, which has a different prognosis and treatment.

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: 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 [1-5]. However, involvement of parietal epithelial cells, independent of podocyte involvement, has also been described [6].

The identity of the circulating factor(s) has not yet been clearly established [7]. The existence of such factor(s) is supported by the following observations:

Some patients with primary FSGS develop recurrent disease following kidney transplantation [8-10]. In such patients, diffuse foot process effacement can be observed by electron microscopy (EM) within minutes after reperfusion [8]; light microscopy (LM) at this early stage typically shows normal-appearing glomeruli. Marked proteinuria subsequently develops within hours to days posttransplant [11], and, with time, the characteristic FSGS lesion forms.

In patients who develop recurrent FSGS posttransplant, treatment with plasmapheresis, low-density lipoprotein apheresis, and/or immunoadsorption may reduce proteinuria [12,13]. (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 [14,15].

Transplacental transmission of permeability factors from mother to child causes transient neonatal proteinuria [16].

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 [17,18].

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 kidney allograft when a second biopsy, performed months or even years later, clearly demonstrates lesions of FSGS [19,20].

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. The nature and source of such factors also remain unclear. While it was previously thought that circulating factors are proteins, the potential contribution of lipids and nucleotides cannot be excluded. The contribution of immune cells to the pathogenesis of proteinuria in FSGS is also uncertain. Some of the most commonly discussed potential circulating 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 [21,22]. Elevated circulating levels of suPAR in kidney disease have been attributed to overproduction by immature myeloid cells of the bone marrow [23]. All forms of suPAR can induce sclerotic lesions in mice, but the timing and extent of injury vary based upon the suPAR substructure [23-26].

Support for a causal role of suPAR in primary FSGS was initially provided by the selective expression of suPAR variants in mice [24]. Mice exposed to some [24] but not all [26] 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 [27]. 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 [28].

Plasmapheresis, which is commonly used to treat recurrent FSGS following transplantation, has been shown to decrease serum suPAR levels and improve podocyte effacement in a subset of patients with recurrent FSGS [29]. (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 [30]. In patients with chronic kidney disease (CKD), for example, 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 [31,32]. Plasma suPAR levels cannot be used to accurately distinguish between primary and secondary forms of FSGS [33], and elevated suPAR levels have been reported in other glomerular diseases [33-35] as well as a number of diseases that do not involve proteinuria [36-40]. In one study, administration of two different, well-characterized forms of recombinant suPAR to wild-type mice produced deposition of the suPAR within glomeruli [26]. 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 [25] but may be required several months before the onset of glomerular injury [23].

Thus, there is evidence both in support of and against suPAR in the pathogenesis of FSGS. Overall, however, suPAR seems to represent a biomarker associated with CKD progression in CKD of any cause, and 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 [41]. 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 [42].

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 [43]; 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.

Other factors — A number of other molecules have also been proposed as factors involved in the pathogenesis of FSGS, such as plasminogen activator inhibitor type-1 (PAI-1), angiotensin II type 1 receptors (AT1R), dystroglycan (DG), metalloproteinases (MMPs), forkhead box P3 (FOXP3), and poly-ADP-ribose polymerase-1 (PARP1) [44].

Anti-nephrin autoantibodies were reported in a subset of adults and children with minimal change disease [45]. It is possible that some patients with presumed primary FSGS may have circulating anti-nephrin antibodies [46]. (See "Minimal change disease: Etiology, clinical features, and diagnosis in adults", section on 'Role of B cells'.)

Circulating CD40 has been found in patients with recurrent FSGS after transplantation [47], and anti-CD40 autoantibodies have been found in several cohorts of patients with FSGS [28].

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) [1]. 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 and use of sodium-glucose cotransporter 2 (SGLT2) inhibitors, but not glucocorticoids or immunosuppressive therapy. How this distinction is made is discussed separately:

(See "Focal segmental glomerulosclerosis: Clinical features and diagnosis", section on 'Classification and 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 [3,5]. 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. It is also possible that injury of the podocyte cytoskeleton and consequent flattening of the foot processes in the absence of podocyte loss allow for increased glomerular permeability due to a deficient compression of the glomerular basement membrane [48].

Glomerular cell proliferation, macrophage infiltration, lipid droplets accumulation, and the progressive accumulation of extracellular matrix components all may contribute to the development of the sclerotic lesion [49]. 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 [50]. Cytosolic cathepsin L in podocytes cleaves the large guanosine triphosphate hydrolase (GTPase) dynamin [51], synaptopodin [52], as well as CD2-associated protein (CD2AP), establishing the ultrastructural changes in podocytes seen in FSGS [50]. Allosteric activation of dynamin by a small molecule has been shown to reestablish podocyte architecture, decrease proteinuria, and extend survival of CD2AP-null mice [53]. The contribution of lipids accumulation in the cell body of podocytes has also gained interest, as genetic and pharmacologic induction of cholesterol efflux is sufficient to completely rescue mice with FSGS from disease progression [54,55]. (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 [56]. Among the most common genetic mutations associated with secondary glucocorticoid-resistant FSGS are those in the alpha-3, -4, and -5 chains of collagen IV, raising the possibility that many of these cases may represent underrecognized cases of Alport syndrome [57-59].

Identifying a genetic cause is important since it would avoid exposing patients to the adverse effects of prolonged immunosuppression [2].

(See "Focal segmental glomerulosclerosis: Clinical features and diagnosis", section on 'Differentiating between 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 kidney 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, ischemia in benign hypertensive nephrosclerosis, and sickle cell disease. It can also occur when there is a marked reduction in kidney 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. A similar mechanism of kidney protection is likely with the use of SGLT2 inhibitors [62]. (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 kidney cancer in a solitary kidney [63]. Patients who lost more than 75 percent of their total kidney 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 kidney 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 males 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 kidney mass, almost all of whom had undergone unilateral nephrectomy [64,65]. There was no evidence that nephrectomy was associated with an increased prevalence of kidney function impairment 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) [65]. Similarly, long-term kidney outcomes are generally excellent in kidney donors for kidney transplantation, with the limitation of donors carrying two apolipoprotein L1 (APOL1) risk alleles, in whom kidney donation may increase the probability to develop kidney failure [66]. (See "Kidney transplantation in adults: Risk of living kidney donation".)

Although loss of 50 percent of kidney 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 [67,68]. However, proteinuria and kidney function impairment can occur in patients with an apparently normal solitary kidney [69], suggesting that loss of 50 percent of kidney 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 kidney 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 [70]. 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: Clinical features and diagnosis", section on 'Patients with nephrotic syndrome'.)

Obesity — FSGS has been described in patients with class 3 (also referred to as severe, extreme, or massive) obesity [71-76]. In one study, FSGS was present in 9 of 17 patients with class 3 obesity who underwent kidney biopsy for marked proteinuria without an apparent systemic disease [73]. The frequency of FSGS was much higher than in 34 normal body weight controls matched for age and sex with a similar kidney 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 [71]. (See "Obesity in adults: Prevalence, screening, and evaluation", section on 'BMI-based classifications'.)

The term "obesity-related glomerulopathy" has been used to refer to FSGS associated with obesity [71,77]. 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) [71,77-80]. 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) [76].

Class 3 obesity in humans is associated with a marked increase in GFR. In one study, for example, the mean GFR in eight patients with class 3 obesity was 145 mL/min compared with 90 mL/min in nine healthy controls [81]. 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 [71,73-75]. 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 [82].

Some patients with class 3 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 [71,73,83,84]. The best data come from a series of 95 patients with class 3 obesity and no clinical evidence of kidney disease in whom intraoperative kidney biopsy was performed during bariatric surgery [83]. 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 [78,85]. 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 [86]. 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 [83], 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 [74,81,87,88]. The efficacy of weight loss was demonstrated in a study of 63 patients with biopsy-proven FSGS who participated in a weight loss program [88]. 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 kidney function impairment and ESKD may develop in 10 to 33 percent of patients [71,72,89].

Other causes — Segmental areas of glomerulosclerosis can be induced by intraglomerular hypertension occurring in patients with initially normal kidney mass, such as those with the following conditions [3]:

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

Sickle cell anemia [90] (see "Sickle cell disease effects on the kidney", section on 'Pathogenesis')

Cyanotic heart disease [91]

Glucose-6-phosphatase deficiency (glycogen storage disease I, von Gierke disease) [92]

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 [93], membranous nephropathy due to hepatitis B virus infection, and membranoproliferative glomerulonephritis due to hepatitis C virus infection [94].

Heroin-associated FSGS has a predilection for Black patients [93,95]. 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 [96]. 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 [97,98] and minimal change disease [99]. 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 [100].

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 (collapsing glomerulopathy)", 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 [101]. 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) [102]

Calcineurin inhibitors (among kidney transplant recipients) [103] (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 [104], cytomegalovirus [105], Epstein-Barr virus [106], simian virus 40 [107], hepatitis C virus [108], and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). (See "Collapsing focal segmental glomerulosclerosis (collapsing glomerulopathy)", section on 'Infections'.)

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

Overview – 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.)

Primary FSGS – 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.)

Secondary FSGS – 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. These patients are classified as FSGS of unknown cause. 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 earlier versions of this topic review.

  1. Rosenberg AZ, Kopp JB. Focal Segmental Glomerulosclerosis. Clin J Am Soc Nephrol 2017; 12:502.
  2. De Vriese AS, Sethi S, Nath KA, et al. Differentiating Primary, Genetic, and Secondary FSGS in Adults: A Clinicopathologic Approach. J Am Soc Nephrol 2018; 29:759.
  3. Rennke HG, Klein PS. Pathogenesis and significance of nonprimary focal and segmental glomerulosclerosis. Am J Kidney Dis 1989; 13:443.
  4. Laurens WE, Vanrenterghem YF, Steels PS, Van Damme BJ. A new single nephron model of focal and segmental glomerulosclerosis in the Munich-Wistar rat. Kidney Int 1994; 45:143.
  5. Rennke HG. How does glomerular epithelial cell injury contribute to progressive glomerular damage? Kidney Int Suppl 1994; 45:S58.
  6. Dijkman H, Smeets B, van der Laak J, et al. The parietal epithelial cell is crucially involved in human idiopathic focal segmental glomerulosclerosis. Kidney Int 2005; 68:1562.
  7. Savin VJ, Sharma R, Sharma M, et al. Circulating factor associated with increased glomerular permeability to albumin in recurrent focal segmental glomerulosclerosis. N Engl J Med 1996; 334:878.
  8. Chang JW, Pardo V, Sageshima J, et al. Podocyte foot process effacement in postreperfusion allograft biopsies correlates with early recurrence of proteinuria in focal segmental glomerulosclerosis. Transplantation 2012; 93:1238.
  9. Hoyer JR, Vernier RL, Najarian JS, et al. Recurrence of idiopathic nephrotic syndrome after renal transplantation. Lancet 1972; 2:343.
  10. Artero M, Biava C, Amend W, et al. Recurrent focal glomerulosclerosis: natural history and response to therapy. Am J Med 1992; 92:375.
  11. Cheong HI, Han HW, Park HW, et al. Early recurrent nephrotic syndrome after renal transplantation in children with focal segmental glomerulosclerosis. Nephrol Dial Transplant 2000; 15:78.
  12. Dantal J, Bigot E, Bogers W, et al. Effect of plasma protein adsorption on protein excretion in kidney-transplant recipients with recurrent nephrotic syndrome. N Engl J Med 1994; 330:7.
  13. Deegens JK, Andresdottir MB, Croockewit S, Wetzels JF. Plasma exchange improves graft survival in patients with recurrent focal glomerulosclerosis after renal transplant. Transpl Int 2004; 17:151.
  14. Le Berre L, Godfrin Y, Lafond-Puyet L, et al. Effect of plasma fractions from patients with focal and segmental glomerulosclerosis on rat proteinuria. Kidney Int 2000; 58:2502.
  15. Zimmerman SW. Increased urinary protein excretion in the rat produced by serum from a patient with recurrent focal glomerular sclerosis after renal transplantation. Clin Nephrol 1984; 22:32.
  16. Kemper MJ, Wolf G, Müller-Wiefel DE. Transmission of glomerular permeability factor from a mother to her child. N Engl J Med 2001; 344:386.
  17. Rea R, Smith C, Sandhu K, et al. Successful transplant of a kidney with focal segmental glomerulosclerosis. Nephrol Dial Transplant 2001; 16:416.
  18. Gallon L, Leventhal J, Skaro A, et al. Resolution of recurrent focal segmental glomerulosclerosis after retransplantation. N Engl J Med 2012; 366:1648.
  19. Howie AJ, Pankhurst T, Sarioglu S, et al. Evolution of nephrotic-associated focal segmental glomerulosclerosis and relation to the glomerular tip lesion. Kidney Int 2005; 67:987.
  20. Tejani A. Morphological transition in minimal change nephrotic syndrome. Nephron 1985; 39:157.
  21. Wei C, Möller CC, Altintas MM, et al. Modification of kidney barrier function by the urokinase receptor. Nat Med 2008; 14:55.
  22. Shankland SJ, Pollak MR. A suPAR circulating factor causes kidney disease. Nat Med 2011; 17:926.
  23. Hahm E, Wei C, Fernandez I, et al. Bone marrow-derived immature myeloid cells are a main source of circulating suPAR contributing to proteinuric kidney disease. Nat Med 2017; 23:100.
  24. Wei C, El Hindi S, Li J, et al. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat Med 2011; 17:952.
  25. Spinale JM, Mariani LH, Kapoor S, et al. A reassessment of soluble urokinase-type plasminogen activator receptor in glomerular disease. Kidney Int 2015; 87:564.
  26. Cathelin D, Placier S, Ploug M, et al. Administration of recombinant soluble urokinase receptor per se is not sufficient to induce podocyte alterations and proteinuria in mice. J Am Soc Nephrol 2014; 25:1662.
  27. Alfano M, Cinque P, Giusti G, et al. Full-length soluble urokinase plasminogen activator receptor down-modulates nephrin expression in podocytes. Sci Rep 2015; 5:13647.
  28. Delville M, Sigdel TK, Wei C, et al. A circulating antibody panel for pretransplant prediction of FSGS recurrence after kidney transplantation. Sci Transl Med 2014; 6:256ra136.
  29. Alachkar N, Wei C, Arend LJ, et al. Podocyte effacement closely links to suPAR levels at time of posttransplantation focal segmental glomerulosclerosis occurrence and improves with therapy. Transplantation 2013; 96:649.
  30. Maas RJ, Deegens JK, Wetzels JF. Serum suPAR in patients with FSGS: trash or treasure? Pediatr Nephrol 2013; 28:1041.
  31. Maas RJ, Wetzels JF, Deegens JK. Serum-soluble urokinase receptor concentration in primary FSGS. Kidney Int 2012; 81:1043.
  32. Meijers B, Maas RJ, Sprangers B, et al. The soluble urokinase receptor is not a clinical marker for focal segmental glomerulosclerosis. Kidney Int 2014; 85:636.
  33. Huang J, Liu G, Zhang YM, et al. Plasma soluble urokinase receptor levels are increased but do not distinguish primary from secondary focal segmental glomerulosclerosis. Kidney Int 2013; 84:366.
  34. Wada T, Nangaku M, Maruyama S, et al. A multicenter cross-sectional study of circulating soluble urokinase receptor in Japanese patients with glomerular disease. Kidney Int 2014; 85:641.
  35. Bock ME, Price HE, Gallon L, Langman CB. Serum soluble urokinase-type plasminogen activator receptor levels and idiopathic FSGS in children: a single-center report. Clin J Am Soc Nephrol 2013; 8:1304.
  36. Almasi CE, Christensen IJ, Høyer-Hansen G, et al. Urokinase receptor forms in serum from non-small cell lung cancer patients: relation to prognosis. Lung Cancer 2011; 74:510.
  37. Zimmermann HW, Koch A, Seidler S, et al. Circulating soluble urokinase plasminogen activator is elevated in patients with chronic liver disease, discriminates stage and aetiology of cirrhosis and predicts prognosis. Liver Int 2012; 32:500.
  38. Giamarellos-Bourboulis EJ, Norrby-Teglund A, Mylona V, et al. Risk assessment in sepsis: a new prognostication rule by APACHE II score and serum soluble urokinase plasminogen activator receptor. Crit Care 2012; 16:R149.
  39. Pawlak K, Buraczewska-Buczko A, Mysliwiec M, Pawlak D. Hyperfibrinolysis, uPA/suPAR system, kynurenines, and the prevalence of cardiovascular disease in patients with chronic renal failure on conservative treatment. Am J Med Sci 2010; 339:5.
  40. Lyngbæk S, Marott JL, Sehestedt T, et al. Cardiovascular risk prediction in the general population with use of suPAR, CRP, and Framingham Risk Score. Int J Cardiol 2013; 167:2904.
  41. Sharma M, Zhou J, Gauchat JF, et al. Janus kinase 2/signal transducer and activator of transcription 3 inhibitors attenuate the effect of cardiotrophin-like cytokine factor 1 and human focal segmental glomerulosclerosis serum on glomerular filtration barrier. Transl Res 2015; 166:384.
  42. Königshausen E, Sellin L. Circulating Permeability Factors in Primary Focal Segmental Glomerulosclerosis: A Review of Proposed Candidates. Biomed Res Int 2016; 2016:3765608.
  43. Gebeshuber CA, Kornauth C, Dong L, et al. Focal segmental glomerulosclerosis is induced by microRNA-193a and its downregulation of WT1. Nat Med 2013; 19:481.
  44. Musiała A, Donizy P, Augustyniak-Bartosik H, et al. Biomarkers in Primary Focal Segmental Glomerulosclerosis in Optimal Diagnostic-Therapeutic Strategy. J Clin Med 2022; 11.
  45. Watts AJB, Keller KH, Lerner G, et al. Discovery of Autoantibodies Targeting Nephrin in Minimal Change Disease Supports a Novel Autoimmune Etiology. J Am Soc Nephrol 2022; 33:238.
  46. Takeuchi K, Naito S, Kawashima N, et al. New Anti-Nephrin Antibody Mediated Podocyte Injury Model Using a C57BL/6 Mouse Strain. Nephron 2018; 138:71.
  47. Doublier S, Zennaro C, Musante L, et al. Soluble CD40 ligand directly alters glomerular permeability and may act as a circulating permeability factor in FSGS. PLoS One 2017; 12:e0188045.
  48. Benzing T, Salant D. Insights into Glomerular Filtration and Albuminuria. N Engl J Med 2021; 384:1437.
  49. Floege J, Alpers CE, Burns MW, et al. Glomerular cells, extracellular matrix accumulation, and the development of glomerulosclerosis in the remnant kidney model. Lab Invest 1992; 66:485.
  50. Yaddanapudi S, Altintas MM, Kistler AD, et al. CD2AP in mouse and human podocytes controls a proteolytic program that regulates cytoskeletal structure and cellular survival. J Clin Invest 2011; 121:3965.
  51. Sever S, Altintas MM, Nankoe SR, et al. Proteolytic processing of dynamin by cytoplasmic cathepsin L is a mechanism for proteinuric kidney disease. J Clin Invest 2007; 117:2095.
  52. Faul C, Donnelly M, Merscher-Gomez S, et al. The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat Med 2008; 14:931.
  53. Schiffer M, Teng B, Gu C, et al. Pharmacological targeting of actin-dependent dynamin oligomerization ameliorates chronic kidney disease in diverse animal models. Nat Med 2015; 21:601.
  54. Wright MB, Varona Santos J, Kemmer C, et al. Compounds targeting OSBPL7 increase ABCA1-dependent cholesterol efflux preserving kidney function in two models of kidney disease. Nat Commun 2021; 12:4662.
  55. Pedigo CE, Ducasa GM, Leclercq F, et al. Local TNF causes NFATc1-dependent cholesterol-mediated podocyte injury. J Clin Invest 2016; 126:3336.
  56. Brown EJ, Pollak MR, Barua M. Genetic testing for nephrotic syndrome and FSGS in the era of next-generation sequencing. Kidney Int 2014; 85:1030.
  57. Gribouval O, Boyer O, Hummel A, et al. Identification of genetic causes for sporadic steroid-resistant nephrotic syndrome in adults. Kidney Int 2018; 94:1013.
  58. Gast C, Pengelly RJ, Lyon M, et al. Collagen (COL4A) mutations are the most frequent mutations underlying adult focal segmental glomerulosclerosis. Nephrol Dial Transplant 2016; 31:961.
  59. Miao J, Pinto E Vairo F, Hogan MC, et al. Identification of Genetic Causes of Focal Segmental Glomerulosclerosis Increases With Proper Patient Selection. Mayo Clin Proc 2021; 96:2342.
  60. D'Agati V. Pathologic classification of focal segmental glomerulosclerosis. Semin Nephrol 2003; 23:117.
  61. Abdi R, Dong VM, Rubel JR, et al. Correlation between glomerular size and long-term renal function in patients with substantial loss of renal mass. J Urol 2003; 170:42.
  62. Rajasekeran H, Reich HN, Hladunewich MA, et al. Dapagliflozin in focal segmental glomerulosclerosis: a combined human-rodent pilot study. Am J Physiol Renal Physiol 2018; 314:F412.
  63. Novick AC, Gephardt G, Guz B, et al. Long-term follow-up after partial removal of a solitary kidney. N Engl J Med 1991; 325:1058.
  64. Narkun-Burgess DM, Nolan CR, Norman JE, et al. Forty-five year follow-up after uninephrectomy. Kidney Int 1993; 43:1110.
  65. Kasiske BL, Ma JZ, Louis TA, Swan SK. Long-term effects of reduced renal mass in humans. Kidney Int 1995; 48:814.
  66. Santoriello D, Husain SA, De Serres SA, et al. Donor APOL1 high-risk genotypes are associated with increased risk and inferior prognosis of de novo collapsing glomerulopathy in renal allografts. Kidney Int 2018; 94:1189.
  67. Cascio S, Paran S, Puri P. Associated urological anomalies in children with unilateral renal agenesis. J Urol 1999; 162:1081.
  68. Atiyeh B, Husmann D, Baum M. Contralateral renal abnormalities in patients with renal agenesis and noncystic renal dysplasia. Pediatrics 1993; 91:812.
  69. Argueso LR, Ritchey ML, Boyle ET Jr, et al. Prognosis of patients with unilateral renal agenesis. Pediatr Nephrol 1992; 6:412.
  70. Ikezumi Y, Suzuki T, Karasawa T, et al. Low birthweight and premature birth are risk factors for podocytopenia and focal segmental glomerulosclerosis. Am J Nephrol 2013; 38:149.
  71. Kambham N, Markowitz GS, Valeri AM, et al. Obesity-related glomerulopathy: an emerging epidemic. Kidney Int 2001; 59:1498.
  72. Praga M, Hernández E, Morales E, et al. Clinical features and long-term outcome of obesity-associated focal segmental glomerulosclerosis. Nephrol Dial Transplant 2001; 16:1790.
  73. Kasiske BL, Crosson JT. Renal disease in patients with massive obesity. Arch Intern Med 1986; 146:1105.
  74. Praga M, Hernández E, Andrés A, et al. Effects of body-weight loss and captopril treatment on proteinuria associated with obesity. Nephron 1995; 70:35.
  75. Fletcher EC. Obstructive sleep apnea and the kidney. J Am Soc Nephrol 1993; 4:1111.
  76. D'Agati VD, Chagnac A, de Vries AP, et al. Obesity-related glomerulopathy: clinical and pathologic characteristics and pathogenesis. Nat Rev Nephrol 2016; 12:453.
  77. Chen HM, Liu ZH, Zeng CH, et al. Podocyte lesions in patients with obesity-related glomerulopathy. Am J Kidney Dis 2006; 48:772.
  78. Sklar AH, Chaudhary BA. Reversible proteinuria in obstructive sleep apnea syndrome. Arch Intern Med 1988; 148:87.
  79. Wesson DE, Kurtzman NA, Frommer JP. Massive obesity and nephrotic proteinuria with a normal renal biopsy. Nephron 1985; 40:235.
  80. Chen HM, Li SJ, Chen HP, et al. Obesity-related glomerulopathy in China: a case series of 90 patients. Am J Kidney Dis 2008; 52:58.
  81. Chagnac A, Weinstein T, Herman M, et al. The effects of weight loss on renal function in patients with severe obesity. J Am Soc Nephrol 2003; 14:1480.
  82. Sharma K, Ramachandrarao S, Qiu G, et al. Adiponectin regulates albuminuria and podocyte function in mice. J Clin Invest 2008; 118:1645.
  83. Serra A, Romero R, Lopez D, et al. Renal injury in the extremely obese patients with normal renal function. Kidney Int 2008; 73:947.
  84. D'Agati VD, Markowitz GS. Supersized kidneys: Lessons from the preclinical obese kidney. Kidney Int 2008; 73:909.
  85. Mathis BJ, Kim SH, Calabrese K, et al. A locus for inherited focal segmental glomerulosclerosis maps to chromosome 19q13. Kidney Int 1998; 53:282.
  86. Casserly LF, Chow N, Ali S, et al. Proteinuria in obstructive sleep apnea. Kidney Int 2001; 60:1484.
  87. Morales E, Valero MA, León M, et al. Beneficial effects of weight loss in overweight patients with chronic proteinuric nephropathies. Am J Kidney Dis 2003; 41:319.
  88. Shen WW, Chen HM, Chen H, et al. Obesity-related glomerulopathy: body mass index and proteinuria. Clin J Am Soc Nephrol 2010; 5:1401.
  89. Tsuboi N, Koike K, Hirano K, et al. Clinical features and long-term renal outcomes of Japanese patients with obesity-related glomerulopathy. Clin Exp Nephrol 2013; 17:379.
  90. Aygun B, Mortier NA, Smeltzer MP, et al. Glomerular hyperfiltration and albuminuria in children with sickle cell anemia. Pediatr Nephrol 2011; 26:1285.
  91. Morgan C, Al-Aklabi M, Garcia Guerra G. Chronic kidney disease in congenital heart disease patients: a narrative review of evidence. Can J Kidney Health Dis 2015; 2:27.
  92. Chen YT, Coleman RA, Scheinman JI, et al. Renal disease in type I glycogen storage disease. N Engl J Med 1988; 318:7.
  93. Cunningham EE, Zielezny MA, Venuto RC. Heroin-associated nephropathy. A nationwide problem. JAMA 1983; 250:2935.
  94. do Sameiro Faria M, Sampaio S, Faria V, Carvalho E. Nephropathy associated with heroin abuse in Caucasian patients. Nephrol Dial Transplant 2003; 18:2308.
  95. Dubrow A, Mittman N, Ghali V, Flamenbaum W. The changing spectrum of heroin-associated nephropathy. Am J Kidney Dis 1985; 5:36.
  96. Friedman EA, Tao TK. Disappearance of uremia due to heroin-associated nephropathy. Am J Kidney Dis 1995; 25:689.
  97. Dressler D, Wright JR, Houghton JB, Kalra PA. Another case of focal segmental glomerulosclerosis in an acutely uraemic patient following interferon therapy. Nephrol Dial Transplant 1999; 14:2049.
  98. Coroneos E, Petrusevska G, Varghese F, Truong LD. Focal segmental glomerulosclerosis with acute renal failure associated with alpha-interferon therapy. Am J Kidney Dis 1996; 28:888.
  99. Tovar JL, Buti M, Segarra A, et al. De novo nephrotic syndrome following pegylated interferon alfa 2b/ribavirin therapy for chronic hepatitis C infection. Int Urol Nephrol 2008; 40:539.
  100. Markowitz GS, Nasr SH, Stokes MB, D'Agati VD. Treatment with IFN-{alpha}, -{beta}, or -{gamma} is associated with collapsing focal segmental glomerulosclerosis. Clin J Am Soc Nephrol 2010; 5:607.
  101. Herlitz LC, Markowitz GS, Farris AB, et al. Development of focal segmental glomerulosclerosis after anabolic steroid abuse. J Am Soc Nephrol 2010; 21:163.
  102. Mohamed N, Goldstein J, Schiff J, John R. Collapsing glomerulopathy following anthracycline therapy. Am J Kidney Dis 2013; 61:778.
  103. Meehan SM, Pascual M, Williams WW, et al. De novo collapsing glomerulopathy in renal allografts. Transplantation 1998; 65:1192.
  104. Moudgil A, Nast CC, Bagga A, et al. Association of parvovirus B19 infection with idiopathic collapsing glomerulopathy. Kidney Int 2001; 59:2126.
  105. Tomlinson L, Boriskin Y, McPhee I, et al. Acute cytomegalovirus infection complicated by collapsing glomerulopathy. Nephrol Dial Transplant 2003; 18:187.
  106. Joshi A, Arora A, Cimbaluk D, et al. Acute Epstein-Barr virus infection-associated collapsing glomerulopathy. Clin Kidney J 2012; 5:320.
  107. Li RM, Branton MH, Tanawattanacharoen S, et al. Molecular identification of SV40 infection in human subjects and possible association with kidney disease. J Am Soc Nephrol 2002; 13:2320.
  108. Stehman-Breen C, Alpers CE, Fleet WP, Johnson RJ. Focal segmental glomerular sclerosis among patients infected with hepatitis C virus. Nephron 1999; 81:37.
Topic 117558 Version 10.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟