Primary and Secondary (Non-Genetic) Causes of Focal and Segmental Glomerulosclerosis

Chapter 18

Primary and Secondary (Non-Genetic) Causes of Focal and Segmental Glomerulosclerosis

Gerald B. Appel, Vivette D. D’Agati


Focal segmental glomerulosclerosis (FSGS), a histologic pattern of glomerular injury, defines a number of clinicopathologic syndromes that may be primary (idiopathic) or secondary to diverse etiologies15 (see also Chapter 19). Early in the disease process, the pattern of glomerulosclerosis is focal, involving a minority of glomeruli, and segmental, involving a portion of the glomerular tuft.4,5 Alterations of podocyte cytoarchitecture identified on electron microscopy are relatively diffuse, underscoring the pathogenetic importance of podocyte injury. As the disease progresses, more diffuse and global glomerulosclerosis evolves. Although it accounts for only a small percentage of cases of idiopathic nephrotic syndrome in young children, FSGS represents as many as 35% of cases in adults.1 It is a major cause of progressive renal disease and end-stage renal disease (ESRD) in certain populations.6

Diverse pathogenetic mechanisms have been identified and often manifest as particular histologic subtypes of disease. Through podocyte depletion and dysregulation, structural deterioration of the glomerular tuft leads to FSGS as a final common pathway.5 Although primary (idiopathic) FSGS is potentially treatable and curable in many patients, the optimal type and duration of immunosuppressive as well as adjunctive therapy remain controversial. For secondary FSGS, effective therapies exist to slow or to modify the disease course (see Chapter 80).

Etiology and Pathogenesis

Focal segmental glomerulosclerosis represents a common phenotypic expression of diverse clinicopathologic syndromes with distinct etiologies (Box 18-1). Causes include genetic mutations in podocyte components (see Chapter 19), circulating permeability factors, viral infections, drug toxicities, maladaptive responses to reduced number of functioning nephrons, and hemodynamic stress placed on an initially normal nephron population. In all these forms of FSGS, injury directed to or inherent within the podocyte is a central pathogenetic mediator.2,5,7,8 These injuries promote altered cell signaling, reorganization of the actin cytoskeleton, and resulting foot process effacement. Critical levels of injury cause podocyte depletion through detachment or apoptosis. Stress placed on the remaining podocytes may lead to local propagation of damage (see Chapter 79). Injury to podocytes may spread to adjacent podocytes by reduction in supportive factors such as nephrin signaling or increased toxic factors such as angiotensin II (Ang II) or mechanical strain on remnant podocytes.9 Cell-to-cell spread of podocyte injury until the entire glomerular lobule is captured could explain the characteristic segmental nature of the sclerosing lesions.10

Minimal Change Disease Versus Focal Segmental Glomerulosclerosis

By definition, the etiology of idiopathic or primary FSGS is unknown. Some clinical data support etiologic factors similar to those at work in minimal change disease (MCD; see Chapter 17).1 Certain corticosteroid-responsive FSGS patients who exhibit MCD on initial biopsy subsequently relapse and display FSGS on repeated biopsy. In some, this may simply represent a sampling error in the initial biopsy. In others with well-documented repeated relapses of nephrotic syndrome and multiple biopsies over years, FSGS truly appears to have evolved from an initial MCD pattern. The relatedness of these two diseases is further supported by the observation that pathologic changes in the nonsclerotic glomeruli of idiopathic FSGS resemble glomeruli of MCD.5 In addition, sequential biopsies of recurrent FSGS in the allograft show it passes through an early stage that mimics MCD.11 Thus, MCD and FSGS are often considered together under the rubric of “podocytopathies”.

Both MCD and primary FSGS are thought to be mediated by circulating permeability factors.12 Recent studies suggest that the permeability factors in FSGS and MCD differ and that the diseases can be distinguished using biomarkers. Elevated CD80, a costimulatory factor expressed on podocytes and B cells, is found in the urine of corticosteroid-sensitive MCD13 but not in FSGS. Angiopoietin-like-4, a podocyte-secreted glycoprotein, is upregulated in podocytes and is elevated in the serum of animal models and patients with MCD.14 In animal models, induction of urokinase plasminogen activator receptor (uPAR) in podocytes produces effacement, proteinuria, and FSGS by promoting a migratory podocyte phenotype through activation of β3 integrin.15,16 Patients with primary FSGS have higher levels of circulating soluble uPAR (suPAR) than equally proteinuric patients with MCD or membranous nephropathy.16 Elevated suPAR levels have been found in 55% of the European PodoNet cohort of FSGS patients and 84% of the American FSGS-CT cohort, and there was an association between treatment-induced reduction in proteinuria and reduction in suPAR levels.17 Patients with recurrent FSGS in the allograft also have high cir­culating suPAR levels, which are reduced by plasma exchange in parallel with reduction in proteinuria. However, some studies have found that patients with secondary FSGS and others with reduced GFR also have high circulating levels of suPAR.18 Thus the patho­genetic role of suPAR and its diagnostic value presently remain uncertain.

Loss of the glomerular filtration barrier allows negatively charged albumin to leak into Bowman space. The alterations in glomerular capillary wall permeability may occur in response to circulating “humoral” substances that act on the podocyte to promote foot process effacement. Circulating permeability factors that enhance in vitro permeability of glomeruli to albumin have been found in the plasma of some FSGS patients. The presence of such permeability factors has been used to predict the recurrence of FSGS in transplanted FSGS patients.12 Some FSGS patients with recurrence of nephrotic syndrome after transplantation achieve remissions of nephrotic syndrome after plasma exchange or use of a protein A adsorption column, supporting the role of a circulating factor12,19,20 (see Chapter 108). As described above, one candidate is suPAR.16 Another candidate factor is cardiotrophin-like cytokine 1 (CLC1), a member of the IL-6 family of interleukins. Receptors for this cytokine are present on podocytes and are upregulated in human recurrent FSGS.21 The origin of the factor may be CD34+ stem cells.22 Induction of T regulatory cells attenuates the proteinuria in experimental FSGS, suggesting the capacity to block or to suppress the pathogenic cells.23

In contrast to MCD, the proteinuria in FSGS is usually nonselective, including albumin and higher-molecular-weight macromolecules. In human FSGS and toxin-induced animal models of FSGS, such as puromycin or doxorubicin (Adriamycin) nephrosis, nonselective proteinuria develops in conjunction with detachment of podocyte foot processes from the GBM, a finding not seen in MCD.5 The susceptibility gene to doxorubicin toxicity in Balb/c mice has been identified as PRKDC, required for double-stranded DNA break repair.24 Animals deficient in this DNA repair machinery develop mitochondrial DNA depletion following doxorubicin exposure, leading to podocyte cell death and FSGS. This mechanism illustrates how long-lived cells such as podocytes, which lack the ability to repair themselves by cell division, are especially vulnerable to genotoxic stress. In humans, repeated and diverse stresses to the podocyte could explain the development of FSGS pattern of injury in age-related nephrosclerosis and glomerular senescence.

Glomerular hypertrophy (or glomerulomegaly) may identify children with MCD at risk for development of FSGS. In early idiopathic FSGS and in many secondary forms of FSGS, such as obesity related, there is initially glomerular hypertrophy and a high glomerular filtration rate (GFR), supporting roles for hyperfiltration and increased intracapillary glomerular pressures (glomerular hypertension).25 Similarly, in secondary forms of FSGS with reduced nephron numbers, maladaptive hemodynamic alterations may be associated with glomerular hyperfiltration and increased intraglomerular capillary pressures. Other factors, such as intraglomerular coagulation and abnormalities of lipid metabolism, may contribute to glomerulosclerosis in these patients (see Chapter 79).

Genetic Variants of Focal Segmental Glomerulosclerosis

Genetic and familial forms of FSGS are covered in detail in Chapter 19. Many cases of apparently primary FSGS may harbor unidentified mutations or polymorphisms in podocyte genes that go unrecognized because of lack of genetic testing and the absence of a heralding presentation with young-onset corticosteroid-resistant disease or familial inheritance. In primary FSGS, a genetic predisposition may underlie the susceptibility to a “second hit,” whereby viral factors or other immune stimuli lead to the initiation of disease. Mutations in podocyte genes may also predispose to FSGS induced by such secondary causes as obesity, systemic hypertension, and infectious agents, allowing multifactorial podocyte stress. For example, mutations in myosin heavy chain 9 (MYH9) were initially identified as a major risk factor for FSGS in patients of African ancestry.26 Subsequent genetic mining of populations at risk for FSGS identified APOL1 gene, rather than MYH9, as the major risk gene for FSGS and chronic hypertensive arterionephrosclerosis among patients of African descent.27 APOL1 encodes for apolipoprotein L-1. The gene is located along the same stretch of chromosome 22 and is in linkage disequilibrium with MYH9. G1 and G2 mutations in APOL1 are protective against infection by Trypanosoma brucei, the parasite that causes African sleeping sickness. Similar to the gene for sickle cell disease, which confers selective advantage against malaria, this genetic mutation became prevalent in a population because it was protective against an infectious pathogen. Although APOL1 is present in preglomerular arterioles and podocytes,28 it remains unclear how sequence variations in APOL1 mechanistically cause glomerulosclerosis.

Viral Induction of Focal Segmental Glomerulosclerosis

Although a number of studies have noted a relationship between prior viral infection with parvovirus or other viruses and FSGS, in particular collapsing FSGS, the data have been far from consistent.29 By contrast, the role of human immunodeficiency virus (HIV) infection in the pathogenesis is well established (see Chapter 58).

Drug-Induced Focal Segmental Glomerulosclerosis

A number of drugs and medications have been associated with the FSGS phenotype, including heroin, lithium, pamidronate, sirolimus, and interferons alpha, beta, and gamma30 (see Box 18-1). Heroin has been associated with the nephrotic syndrome and FSGS (heroin nephropathy), although its incidence is decreasing in the modern era.31 Pamidronate, a bisphosphonate used to prevent bone resorption in myeloma and metastatic tumors, has been associated with both collapsing FSGS and MCD.32 Stabilization of renal function and resolution of nephrotic syndrome may follow withdrawal of the offending medication (e.g., interferon, heroin, pamidronate). Long-term anabolic steroid abuse among bodybuilders has been associated with the development of FSGS. Many of these individuals also consume high-protein diets and potentially injurious supplements, including growth hormone. Mechanisms of glomerular injury include potential direct toxic effects of anabolic steroids on glomerular cells and adaptive responses to elevated lean body mass.33

Structural Maladaptation Leading to Focal Segmental Glomerulosclerosis

Many secondary forms of FSGS are mediated by adaptive structural-functional responses.1,5,7 These adaptive forms include patients with congenital reduction in the number of functioning nephrons and acquired reduction of nephron numbers, whereas other secondary forms are associated with hemodynamic stress placed on an initially normal nephron population (see Box 18-1). Obesity-related glomerulopathy (ORG) is increasingly common worldwide and may be associated with metabolic syndrome, including hypertension, diabetes, and hyperlipidemia. ORG usually lacks full nephrotic syndrome and has a low risk of progression to ESRD.25 Secondary FSGS resembling ORG has been reported in nonobese, highly muscular patients with elevated body mass index due to bodybuilding.34 Low birth weight associated with prematurity and reduced nephron endowment may also lead to glomerular hypertrophy, with secondary FSGS developing in adolescence or adulthood.35 Biopsy specimens with secondary adaptive FSGS typically show glomerulomegaly and perihilar lesions of segmental sclerosis and hyalinosis. These conditions resemble experimental models of renal ablation in which the surgical reduction in renal mass causes functional hypertrophy of remnant nephrons with increased glomerular plasma flows and pressures. Whereas these changes are initially “adaptive,” the resultant hyperfiltration and increased glomerular pressure become “maladaptive” and serve as mechanisms for progressive glomerular damage.7,8

Pathogenesis of Progressive Renal Failure in Focal Segmental Glomerulosclerosis

Although much attention has been focused on the pathogenetic basis for proteinuria in FSGS, the segmental and eventual global glo­merulosclerosis in association with interstitial fibrosis and tubular atrophy clearly underlie the progression to renal failure. The etiology of glomerulosclerosis and its progressive nature are discussed in Chapter 79. Podocytes in some forms of FSGS, such as the collapsing variant, display a dysregulated phenotype with dedifferentiation, proliferation, and apoptosis.36 Such biopsy samples have altered podocyte expression of cell cycle–related proteins.37 In renal biopsy specimens of patients with FSGS, the expression levels of transforming growth factor (TGF) β1, thrombospondin-1, and TGF-β2 receptor proteins and messenger RNAs are all increased, as are podocyte markers of the phosphorylated Smad2/Smad3 signaling pathway.38 Thus, pathways that promote podocyte depletion and overproduction of extracellular matrix converge to produce a sclerosing phenotype.


Studies of patients who have had a kidney biopsy show an increasing prevalence of FSGS in both adults and children in a number of countries on different continents.39 In some countries, such as Brazil, FSGS is currently the most common primary renal disease.40 An analysis of the prevalence of ESRD in the United States caused by FSGS during a 21-year period shows an increase from 0.2% in 1980 to 2.3% in 2000, and FSGS is the most common primary glomerular disease leading to ESRD.5,6 Although some of this change in prevalence may relate to changes in biopsy practice or disease classification, a real increase is likely in the frequency of FSGS.

Primary FSGS is slightly more common in males than in females, and the incidence of ESRD due to FSGS in males of all races is 1.5 to 2 times higher than in females. The incidence in both children and adults is higher in blacks than in Caucasians.1 In the United States, FSGS is the most common cause of idiopathic nephrotic syndrome in adult African Americans.6 African Americans had a fourfold greater risk of ESRD from FSGS than Caucasians did. Even in an almost entirely Caucasian U.S. population, a clear major increase in the incidence of FSGS has been documented over a 30-year period,41 whereas this has not been the case in some Caucasian populations in Europe.42

Clinical Manifestations

Patients with primary FSGS present with asymptomatic proteinuria or full nephrotic syndrome.13 In children, 10% to 30% of patients with asymptomatic proteinuria are detected on routine checkups and sports physical examinations; in adults, asymptomatic detection occurs at military induction examinations, obstetric checkups, and insurance or employment physical examinations. The incidence of nephrotic-range proteinuria at onset in children is 70% to 90%, whereas only 50% to 70% of adults with FSGS present with nephrotic syndrome. Secondary forms of FSGS associated with hyperfiltration, such as remnant kidney and ORG, typically have lower levels of proteinuria, and many such patients have subnephrotic proteinuria and a normal serum albumin concentration.25,34

Hypertension is found in 30% to 50% of children and adults with FSGS at diagnosis. Microhematuria is found in 25% to 75% of these patients, and a decreased GFR is noted at presentation in 20% to 30%.13 Daily urinary protein excretion ranges from less than 1 to more than 30 g/day. Proteinuria is typically nonselective. Complement levels and other serologic test results are normal. Occasional patients will have glycosuria, aminoaciduria, phosphaturia, or a concentrating defect indicating functional tubular damage as well as glomerular injury.

Different histologic patterns of FSGS may display different clinical features. When patients with the tip variant of FSGS were compared to those with MCD or FSGS not otherwise specified (NOS), their clinical features were more similar to those of MCD.43 Those with tip variant typically manifested abrupt clinical onset of full nephrotic syndrome (almost 90%), shorter time course from onset to renal biopsy, more severe proteinuria, and less chronic tubulointerstitial disease than in FSGS NOS. The cellular variant also typically presents with greater proteinuria and higher incidence of nephrotic syndrome than FSGS NOS. Compared with FSGS NOS, the collapsing variant usually presents with greater proteinuria, more full-blown nephrotic syndrome, and lower GFR.44,45

Diagnosis and Differential Diagnosis

Before biopsy, patients with FSGS may be confused with any patient who has glomerular disease or nephrotic syndrome with negative serologic test results. Tests for permeability factors are not available in routine clinical practice. In children with FSGS, most of whom present with nephrotic syndrome, the major differential will be between MCD and other variants of corticosteroid-resistant nephrotic syndrome. In adults with subnephrotic proteinuria, the differential includes almost all glomerular diseases without positive serologic results. In adults with nephrotic syndrome, membranous nephropathy (MN) and MCD may present in an identical manner, and only a renal biopsy will clarify the diagnosis. Focal sclerosing lesions caused by other glomerulopathies (e.g., segmental scarring from chronic glomerulonephritis) must be excluded pathologically. Moreover, because the defining glomerular lesion of FSGS is focal and may be confined to deeper juxtamedullary glomeruli early in the disease, it may not be sampled on renal biopsy. A large glomerular sample of more than 20 glomeruli for light microscopy increases the likelihood of identifying the diagnostic segmental lesions.

Even after the diagnosis of FSGS is established, the primary (idiopathic) form must be distinguished from secondary forms by careful clinicopathologic correlation (see Box 18-1). In general, many forms of adaptive FSGS have lower levels of proteinuria than primary FSGS, a lower incidence of hypoalbuminemia, and on biopsy, lesser degrees of foot process effacement. In patients younger than 25 years and in those with a family history of FSGS, genetic screening for mutations in podocin, nephrin, or other podocyte genes may be useful (see Chapter 19).


The pathologic manifestations of FSGS are heterogeneous, both qualitatively and with respect to the location of lesions within the glomerular tuft. A classification of FSGS by histologic variants (Box 18-2)46 can be applied to both primary and secondary forms of FSGS (Box 18-1). Subtypes include classic, or NOS; perihilar variant, in which more than 50% of glomeruli with segmental lesions display hyalinosis and sclerosis involving the vascular pole region; cellular variant, manifesting endocapillary hypercellularity; collapsing variant, in which at least one glomerulus has global collapse and overlying visceral cell hypertrophy and hyperplasia; and tip variant, with segmental lesions involving the tubular pole. This working classification has been applied successfully to retrospective and prospective series of renal biopsies. Other, more controversial histologic variants of FSGS include FSGS with diffuse mesangial hypercellularity and C1q nephropathy (see Chapter 28). Some believe that these are distinct disease entities with unique clinicopathologic features; others believe these are merely subgroups of FSGS.47,48

Jun 4, 2016 | Posted by in NEPHROLOGY | Comments Off on Primary and Secondary (Non-Genetic) Causes of Focal and Segmental Glomerulosclerosis

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