Epidemiology, classification, and pathogenesis of focal ...
Epidemiology, classification, and pathogenesis of focal segmental glomerulosclerosis
Author
Jochen Reiser, MD, PhD
Section Editors
Richard J Glassock, MD, MACP
Fernando C Fervenza, MD, PhD
Deputy Editor
John P Forman, MD, MSc
Literature review current through: May 2013. | This topic last updated: jun 13, 2013.
INTRODUCTION — Focal segmental glomerulosclerosis (FSGS) is a histologic lesion, rather than a disease, that is commonly found to underlie the nephrotic syndrome in adults and children, particularly in the United States, Brazil, and many other countries [1-6].
The focal nature of the glomerulosclerosis means that some mild cases of FSGS will be missed on renal biopsy due to sampling error and will be misclassified as minimal change disease.
The epidemiology, classification, and pathogenesis of FSGS will be reviewed in this topic. The treatment of both primary FSGS and recurrent disease in the renal transplant are discussed separately.
EPIDEMIOLOGY — A survey of renal biopsies performed in the United States from 1995 to 1997 for idiopathic nephrotic syndrome in adults found that focal segmental glomerulosclerosis (FSGS) was the most common lesion seen, accounting for 35 percent of all cases and over 50 percent of cases among blacks [1].
According to data from the United States Renal Data System (USRDS) collected over 21 years, FSGS is the most common pathology identified in patients with end-stage renal disease (ESRD) in the United States [3]. The prevalence of FSGS as a lesion associated with ESRD has risen. In 1980, FSGS was the cause of ESRD in only 0.2 percent of patients; by 2000, it was responsible for 2.3 percent of cases (excluding patients with HIV), an 11-fold increase. The risk of ESRD was fourfold higher in black patients compared with white and Asian patients and 1.5- to twofold higher in males compared with females.
By comparison, some other countries have found that FSGS is a less common lesion associated with the nephrotic syndrome. Among 2000 patients between 15 and 65 years of age with nephrotic syndrome noted in the glomerulonephritis registry of Spain, the most common histologic lesion was membranous nephropathy (24 percent), minimal change disease (16 percent), lupus (14 percent), and then FSGS (12 percent) [7].
CLASSIFICATION — The etiologic classification of focal segmental glomerulosclerosis (FSGS) is complicated and somewhat confusing, with some degree of overlap observed among the different categories [8,9]. One classification is based upon the known and/or postulated causes of this histologic pattern:
• Primary or idiopathic FSGS, which most often presents with the nephrotic syndrome.
• Secondary FSGS, which most often presents with non-nephrotic proteinuria and, commonly, some degree of renal insufficiency. This category most commonly refers to FSGS thought to represent an adaptive response to glomerular hypertrophy or hyperfiltration. This includes disorders associated with a reduced renal mass and/or renal vasodilation, such as unilateral renal agenesis. In addition, a nonspecific pattern of secondary FSGS can result from scarring produced by a previous injury (due to a variety of conditions, including active IgA nephropathy, vasculitis, and lupus nephritis).
• Other known causes of FSGS include infections (particularly HIV), toxins (including heroin, interferon, cyclosporine, and pamidronate), genetic abnormalities, and renal atheroembolic disease [10].
HISTOLOGIC VARIANTS — Several morphologic variants of focal segmental glomerulosclerosis (FSGS) as observed on light microscopy have been defined [11]. This schema assumes that renal scarring due to other primary glomerular diseases has been excluded as a diagnostic possibility.
Since this system is based upon sampling from a renal biopsy, the number of glomeruli that are available for accurate classification is often limited, resulting in some degree of uncertainty [9]. Expertise of the pathologist in reading renal biopsies is essential.
These histologic variants, which can be found with primary as well as some other forms of FSGS, include [8,12]:
• Classic FSGS, also called FSGS NOS (not otherwise specified), is the most common form
• Collapsing variant, although some argue that this should be considered a separate entity rather than a variant of FSGS
• Tip variant
• Perihilar variant
• Cellular variant
Although the appearance of the glomerulus on light microscopy, by definition, differs among these forms, they all share ultrastructural findings of podocyte alterations. The factors responsible for these different histologic variants are unknown, and the overall clinical value of this classification has not yet been validated in prospective studies.
Support for this classification is best provided by the observation that the histology of those with recurrent disease after kidney transplantation is most commonly the same as that observed prior to transplantation.
Classic FSGS — To make the histologic diagnosis of classic FSGS, the collapsing, tip, perihilar, and cellular variants must be excluded [8].
On light microscopy, classic FSGS (or FSGS NOS) is characterized by segmental areas of mesangial collapse and sclerosis in some, but not all, glomeruli (hence the name focal) (picture 1A-B) [8]. Sclerotic changes occur first in juxtamedullary glomeruli and therefore may be missed in superficial biopsies that only contain cortex. Mild mesangial hypercellularity and partial occlusion of the capillary lumens by hyaline deposits are commonly seen. The latter represent the insudation of plasma proteins into the abnormally permeable glomerular capillary wall [8,13].
Careful light microscopic examination is more compatible for the diffuse nature of the glomerular injury [14]. In one study, 32 percent of glomeruli had sclerotic lesions on single sections; when serial sections were evaluated, the number of affected glomeruli increased to 48 percent [15].
Immunofluorescence microscopy usually reveals no immune deposits, except for what may represent nonspecific binding of IgM and complement (C3 and variably C1) in sclerotic lesions (picture 2). Very weak mesangial deposition of IgM may also be observed [8].
Electron microscopy shows diffuse fusion of the epithelial cell foot processes, similar to that seen in minimal change disease (picture 3) [8]. By comparison, secondary FSGS is associated with lesser degrees of foot process effacement.
Collapsing variant — Collapsing FSGS, which can be induced by HIV infection or other disorders or may be idiopathic, is distinguished from classic FSGS by collapse and sclerosis of the entire glomerular tuft, rather than segmental injury (picture 4). Given its unique pathology, some investigators feel that this variant should be called collapsing glomerulopathy and not be considered a form of FSGS.
Collapsing FSGS often presents with more severe nephrotic syndrome than classic FSGS. Affected patients are frequently resistant to therapy and often have a rapid downhill course. Collapsing FSGS is most commonly seen in patients of African ancestry, which may contribute to the worse prognosis.
Tip variant — The tip variant is characterized by epithelial cell injury and foam cell accumulation that occur at the "tip" of the glomerulus near the origin of the proximal tubule (picture 5) [8]. Immunofluorescence microscopy may show positive staining for IgM and C3 in the sclerotic lesion and in the mesangium.
The tip lesion may identify a subset of patients who are more likely to present abruptly with the nephrotic syndrome and are more likely to respond to glucocorticoid therapy than patients with the other FSGS variants [16-19]. In a report of 47 patients with tip lesions, glucocorticoid therapy led to complete remission in 59 percent and partial remission in 14 percent [18].
Some patients with the tip variant undergo spontaneous remission without immunosuppressive therapy. In a series from Sweden of 20 patients with FSGS (13 of whom had the tip variant, most of whom received ACE inhibitor therapy), 70 percent had a partial remission within a median of ten months, and complete remission subsequently ensued in 11 patients (55 percent) [20].
Insight into the pathologic and clinical evolution of the glomerular tip lesion was reported in a retrospective study of two series of patients with FSGS who had more than one renal biopsy over time (sometimes including autopsy kidneys) [21]:
• Among 24 patients with an initial tip lesion who underwent a second biopsy for persistent or relapsing proteinuria, 17 subsequently had findings of classic FSGS, while seven continued to only have the tip lesion.
• Among patients with an original diagnosis of FSGS prior to transplantation, recurrent nephrotic syndrome was noted in seven renal allografts; six revealed the tip lesion.
• Patients with a tip lesion at initial presentation were more likely, compared with those with classic FSGS at initial biopsy, to have a complete response to glucocorticoids and to not progress to end-stage renal disease (ESRD). However, those patients who did not respond to glucocorticoids were more likely to progress to ESRD.
Given these findings, the authors speculated that, rather than being unique, the tip lesion may be an early form of classic FSGS in some cases and a variant of minimal change disease in others. Further study in larger numbers of patients is required to determine the histologic and prognostic significance of this lesion.
Perihilar variant — The perihilar variant consists of perihilar sclerosis and hyalinosis in more than 50 percent of segmentally sclerotic glomeruli [8]. Immunofluorescence and electron microscopic findings with the perihilar variant are similar to those observed with classic FSGS.
Although the perihilar form can occur with primary FSGS, it is frequently observed with secondary FSGS due to processes associated with increased glomerular capillary pressure, such as renal agenesis.
Cellular variant — The cellular variant is characterized by the presence of at least one glomerulus with segmental endocapillary hypercellularity that occludes the capillary lumen. Other glomeruli may exhibit findings consistent with classic FSGS. Diffuse foot process effacement is typically seen on electron microscopy. The tip and collapsing variants must be excluded histologically to make a diagnosis of the cellular variant [8].
Some claim that the cellular variant is characterized by severe proteinuria. At least some such cases may represent collapsing FSGS in which sampling limitations result in an inability to detect at least one glomerulus with collapsing changes. The combination of severe nephrotic syndrome and acute kidney injury (AKI) would strongly suggest collapsing FSGS. Some pathologists think that the cellular and collapsing variants are the same lesion.
Prognostic relevance — The prognostic and therapeutic decision-making value of the histologic variants of FSGS is debated, and further prospective controlled studies are necessary to resolve the controversy. In one study, there was no difference in response to therapy among patients with the different biopsy findings [22]. However, other studies suggest that the histologic classification can predict outcomes. This was illustrated in a retrospective analysis of 197 patients with biopsy-proven FSGS [19]. Three percent had the cellular variant, 11 percent collapsing, 17 percent tip lesion, 26 percent perihilar, and 42 percent classic. At a median follow-up of 1.8 years, 23 percent were on dialysis.
The following additional observations were reported:
• Patients with the collapsing and tip variants had more proteinuria.
• Patients with the tip lesion had the least tubulointerstitial injury and best renal function, and almost 50 percent achieved complete remission with glucocorticoid therapy.
• Patients with the collapsing variant had the worst outcomes, with lower rates of renal survival at both one year (74 versus 86 percent for the remaining patients) and three years (33 versus 67 percent).
This study supports a more favorable prognosis associated with the tip variant and a more unfavorable prognosis associated with the collapsing variant.
However, this study did not have a sufficient number of patients with the cellular variant to determine whether their outcomes differed significantly from the other types. A larger number of patients with the cellular variant were studied in separate review of 225 patients with biopsy-proven FSGS, in which 22 patients had the cellular lesion [23]. Follow-up was available on 18 of these patients. At a mean follow-up of 17 months, five (28 percent) progressed to ESRD, eight had a complete or partial remission following therapy, and five had persistent proteinuria or a progressive increase in the serum creatinine. The rates of remission and ESRD among these patients were similar to those who had the classic variant and were intermediate between the tip and collapsing variant. Thus, this study does not support the claim that the cellular and collapsing variants are the same.
PRIMARY FSGS — Some have theorized that primary focal segmental glomerulosclerosis (FSGS) and minimal change disease are related entities [12], demonstrating certain clinical and histologic similarities [24]. As an example of the former, occasional patients with FSGS follow a frequently relapsing, steroid-responsive course similar to that in minimal change disease [25]. This is particularly likely in patients with focal global (as opposed to segmental) sclerosis in whom steroid-resistance and progressive renal failure appear to be uncommon [26]; why focal global sclerosis has a more benign prognosis is unclear. In addition, some patients with biopsy-proven minimal change disease later progress to FSGS.
However, it is also possible that, due to the focal nature of FSGS, some patients who appear to "progress" from minimal change disease to FSGS had primary FSGS all along, but, possibly due to sampling error, characteristic sclerotic lesions were missed on the initial biopsy. If sampling error in a patient with FSGS produces a histologic specimen devoid of sclerotic lesions in the glomeruli, the only potential clue to the presence of FSGS would be regions of tubular atrophy and interstitial fibrosis. In addition, the pathogenesis of primary FSGS is increasingly seen as being distinct from that of minimal change disease.
Primary FSGS must also be distinguished from secondary FSGS, which can be clinically challenging.
Pathogenesis — Injury to the visceral epithelial cell or podocyte, which attaches to the glomerular basement membrane by discrete foot processes, appears to be the primary problem in most forms of FSGS as it is in minimal change disease [13,27,28]. However, involvement of parietal epithelial cells, independent of podocyte involvement, has also been described [29].
In the majority of patients with primary FSGS, injury to glomerular cells may occur as a consequence of a circulating factor. As an example, elevated circulating blood levels of the soluble urokinase plasminogen activator receptor (suPAR) are found in approximately 55 percent of pediatric patients with FSGS and in greater than two-thirds of adult patients with the disease [30,31]. Evidence supporting a pathogenic role for suPAR is discussed below.
Clinical observations that support a key role for a circulating factor such as suPAR in primary FSGS (and posttransplant FSGS) include the following:
• The rapidity and relatively high incidence of disease recurrence after renal transplantation in patients with primary FSGS within hours or months after transplantation. In addition, serum from some patients with recurrent FSGS after transplantation increases the permeability of isolated glomeruli to albumin.
• Transmission from a pregnant woman to the fetus. One woman, for example, developed the nephrotic syndrome in the thirteenth week of gestation that was found to be FSGS on renal biopsy [32]. At delivery, the child had proteinuria (935 mg/dL) and hypoalbuminemia that rapidly resolved within a few days. Serum suPAR levels were elevated in both the infant and mother at the time of birth, suggesting that transmission of suPAR from the mother to the child produced transient proteinuria in the otherwise healthy infant [33].
Expression of a microRNA (specifically, miR-193a) inside podocytes and subsequent downregulation of the Wilms tumor protein (WT1) may be an intracellular mechanism responsible for FSGS.
Soluble urokinase receptor — Increased circulating levels of soluble urokinase receptor (suPAR) may be a common causative factor of primary FSGS [34,35]. The following illustrate the range of findings:
• In a detailed analysis of 148 patients (78 with primary FSGS, 25 with minimal change disease, 7 with preeclampsia, 16 with membranous nephropathy, and 22 normal controls), suPAR was significantly elevated in sera from patients with FSGS compared with normal controls and patients with other proteinuric glomerular diseases [34]. The highest serum suPAR levels were in pretransplant sera of patients who developed recurrent FSGS after transplantation, suggesting an association of suPAR with recurrent FSGS.
• Serum suPAR using a commercially available assay was measured in a cohort comprised of 70 adult and 94 pediatric patients with biopsy-proven primary FSGS and an estimated glomerular filtration rate (eGFR) greater than 40 mL/min per 1.73 m2 [31]. Levels greater than 3000 pg/mL were found in 84 percent of adults and 55 percent of children. In contrast, elevated suPAR was detected in only 6 percent of healthy controls. Patients treated with immunosuppression had lower suPAR levels, and a reduction in suPAR with immunosuppressive therapy was associated with a reduction in proteinuria and a higher likelihood of achieving complete remission.
However, suPAR testing may not reliably identify primary FSGS in patients with end-stage renal disease (ESRD) because suPAR can accumulate due to lack of urinary excretion.
Support for a causal role of suPAR in primary FSGS was provided by the selective expression of suPAR in mice [34]. The mice developed albuminuria and a progressive glomerulopathy characterized by effacement of foot processes, hypercellularity, mesangial expansion, mesangiolysis, and tuft adhesions. suPAR acts via activation of podocyte alphaVbeta3 integrin, which plays an important role both in the dynamic regulation of mature foot processes and the controlled adhesion to the glomerular basement membrane [30,35]. Additional mechanisms are involved in the genetic diseases associated with the development of FSGS.
In the study cited above, serum from patients with recurrent FSGS, but not from those with nonrecurrent FSGS or normal controls, activated beta3 integrin activity in vitro, while inhibition of suPAR reduced beta3 integrin activity [34]. In addition, plasmapheresis, which is commonly used to treat recurrent FSGS following transplantation, induced clinical remission and decreased both serum suPAR levels and beta3 integrin activity in a subset of patients with recurrent FSGS. In animal studies, the expression of non-integrin-binding mutant forms of suPAR did not induce glomerular disease [34].
It appears that, with the commercially available test [34], roughly one-third of patients with primary FSGS do not have elevated serum suPAR concentrations [34]. This suggests that other circulating factors may contribute to the pathogenesis of primary FSGS, although fluctuations in suPAR concentrations, relative insensitivity of the assay, and individual variability in the response to the effects of suPAR may also play a role [35].
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 [36]; miR-193 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 'NPHS1 gene' below). 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, 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 not an intracellular mediator of circulating suPAR.
Clinical manifestations — Patients with primary FSGS may present with acute or insidious onset of proteinuria and can eventually exhibit features of the nephrotic syndrome, as manifested by peripheral edema, hypoalbuminemia, and nephrotic range proteinuria. However, some patients have non-nephrotic or nephrotic range proteinuria without overt clinical manifestations. Patients with FSGS also commonly have hypertension, and many have microscopic hematuria. The level of kidney function is variable.
The frequency of the following clinical features at either presentation or time of biopsy have been reported [22,37-40]:
• Nephrotic range proteinuria – 60 to 75 percent
• Microscopic hematuria with variable degrees of proteinuria – 30 to 50 percent
• Hypertension – 45 to 65 percent
• Renal insufficiency – 25 to 50 percent
SECONDARY FSGS — In addition to occurring in primary idiopathic focal segmental glomerulosclerosis (FSGS), FSGS can be observed in a variety of secondary settings [8,13]
In our view, the glomerulosclerosis of secondary FSGS usually results from an adaptive response to glomerular hypertrophy and hyperfiltration, from scarring due to previous injury (eg, healed lesions of lupus or vasculitis) or other glomerular abnormality such as thin basement membrane disease, or from direct toxic injury to podocytes. In the above context, 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 renal vasodilatation with an initially normal number of nephrons [8].
It is important clinically to distinguish secondary from primary FSGS since the treatment of secondary FSGS consists of angiotensin inhibition but not immunosuppressive therapy. How this distinction is made is discussed below.
Podocyte injury — The primary site of injury in secondary FSGS, as in primary FSGS, is the glomerular epithelial cell or podocyte [41-49]. A variety of factors have been postulated to cause injury to glomerular cells, including circulating cytokines (such as transforming growth factor-beta [TGF-beta]), angiotensin II, macrophage infiltration and other mediators of inflammation, direct effects of intraglomerular hypertension, toxins, and viral infection [44-46,50-52]. The renoprotective effects of angiotensin inhibition may be partly due to protecting podocytes from further injury.
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 [13,28]. Larger macromolecules (such as 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 [53]. How these changes occur is not well understood, but cytokines, such as transforming growth factor beta, may be responsible for at least part of the matrix accumulation. Transforming growth factor beta accelerates podocyte damage by changing transcriptional activity to allow for expression of cytosolic cathepsin L [54]. Cytosolic cathepsin L in podocytes cleaves the large GTPase dynamin [55], synaptopodin [56], as well as the as CD2AP establishing the ultrastructural changes in podocytes seen in FSGS [54].
Nephron loss — FSGS induced by the adaptive response to nephron loss occurs with many causes of chronic kidney disease (CKD), 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 [57]. (See
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.
Dose-dependence — 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 [58]. 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 renal failure. Clinically evident disease was usually delayed for at least five years after the surgery.
In 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 [59,60]. There was no evidence that nephrectomy was associated with an increased prevalence of renal 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) [60]. Similarly, long-term renal outcomes are generally excellent in kidney donors for renal transplantation.
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 [41,61]. However, proteinuria and renal insufficiency can occur in patients with an apparently normal solitary kidney [62], suggesting that loss of 50 percent of renal mass beginning at birth is sufficient to induce hemodynamically mediated glomerular injury.
Renal vasodilatation — Segmental areas of glomerulosclerosis can be induced by intraglomerular hypertension resulting from primary renal vasodilatation as occurs in diabetic nephropathy, sickle cell anemia, familial autonomic insufficiency, and type I glycogen storage disease [13,63,64].
Intraglomerular hypertension may also be responsible for FSGS associated with obesity, severe preeclampsia, anabolic steroid abuse, and treatment with interferon.
Severe obesity — FSGS has been described in occasional patients with severe (also called massive or extreme) obesity, a disorder that is increasingly common [65-69]. In one study, FSGS was present in 9 of 17 patients with severe obesity who underwent renal biopsy for marked proteinuria without an apparent systemic disease [67]. 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 [65].
The term "obesity-related glomerulopathy" has been used to refer to FSGS associated with obesity [65,70]. However, some obese patients with moderate to heavy proteinuria have little or no glomerulosclerosis and no epithelial cell injury or foot process fusion on renal biopsy; they do have significant mesangial expansion and glomerular capillary loop enlargement (glomerulomegaly) [65,70-73].
Hemodynamic factors appear to be pathogenetically important in the association between severe obesity and FSGS as evidenced by studies in animals and humans:
• Obese dogs acutely fed a high-fat diet developed a marked increase in GFR with expansion of Bowman's capsule [42].
• Caloric restriction in aging rats prevented the development of glomerular enlargement, proteinuria, and glomerulosclerosis [43].
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. After marked weight loss in the obese patients (32 percent reduction in body mass index), the mean GFR fell to 110 mL/min [74].These findings are compatible with a role for intraglomerular hypertension in the pathogenesis of the proteinuria and sclerotic lesions in obesity-related FSGS [65,67-69]. 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 [75].
The clinical and pathologic findings that distinguish obesity-related from primary FSGS are similar to those that distinguish other forms of secondary FSGS from primary FSGS. The data are presented below.
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 [65,67,76,77]. The best data come from a series of 95 patients with severe obesity and no clinical evidence of renal disease in whom intraoperative renal biopsy was performed during bariatric surgery [76]. 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 body mass index 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. Body mass index was independently associated with these glomerular lesions in the entire cohort. It is not known if these observations would also apply to the merely 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 [71,78]. 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 [79]. 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 [76], 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 [68,74,80,81]. The efficacy of weight loss was demonstrated in a study of 63 patients with biopsy-proven FSGS who participated in a weight loss program [81]. 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) body mass index. The findings were similar at 24 months.
Severe preeclampsia — FSGS is an occasional finding in pregnant women with severe preeclampsia [82,83]. Affected women tend to have both marked hypertension and larger glomeruli, suggesting that hemodynamic factors may be of primary importance. The typical although not uniform disappearance of proteinuria after delivery is compatible with the hypothesis that the FSGS was induced by pregnancy and preeclampsia rather than representing a preexisting or concurrent disease [82,83].
Anabolic steroid abuse — FSGS and proteinuria were associated with the long-term use of anabolic steroids in a cohort of ten patients identified from the archives of the Columbia Renal Pathology Laboratory [84]. 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:
• Six patients were hypertensive on presentation.
• Mean protein excretion was 10.1 g/day (range 1.3 to 26.3 g/day), eight patients had nephrotic range proteinuria even when corrected for the unusually large body surface area, and three patients had the nephrotic syndrome. 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.
• Nine patients had FSGS on biopsy, three with collapsing features. Four patients had glomerulomegaly in addition to FSGS, and one patient had glomerulomegaly without evidence of glomerulosclerosis.
Eight of the ten patients were followed for a mean of 2.2 years. Of these, one patient who had cortical scarring at the time of biopsy progressed to end-stage disease within one month. Seven patients were started on an angiotensin receptor blocker (ARB) and/or renin inhibitor and encouraged to discontinue anabolic steroids and supplements and to reduce their exercise regimen. All had improvement in or stabilization of the serum creatinine and a decrease in protein excretion. One patient who restarted steroids and dietary supplements had an increase in serum creatinine and urine protein within six weeks.
Renal hemodynamic factors and possibly a direct nephrotoxic effect of anabolic steroids probably underlie this association.
Treatment with interferon — The administration of interferon (IFN)-alpha has been associated with both FSGS [85,86] and minimal change disease [87]. In addition, 11 cases of collapsing FSGS associated with therapeutic doses of IFN-alpha (6), IFN beta (3) and IFN-gamma (2) were identified from the archives of the Columbia Renal Pathology Laboratory [88]. The following characteristics were noted:
• Ten of 11 patients were African-American, and one was Hispanic.
• The mean serum creatinine at the time of biopsy was 3.5 mg/dL and 10 of 11 patients had renal insufficiency. The mean 24-hour urine protein was 9.7 g/day, and 9 of 11 patients had nephrotic range proteinuria. Ten patients had hypoalbuminemia.
• Five patients had microhematuria, and one patient had leukocyturia, but no red cell casts were observed.
• Among ten patients for whom follow-up was available, 9 had a decrease in serum creatinine from a mean of 3.9 to 1.9 mg/dL following cessation of IFN therapy, and four patients returned to normal renal function. All seven patients for whom follow-up measurements of urinary protein excretion were obtained showed a decline in protein excretion from a mean of 9.9 to 3 g/day.
• Six patients were treated with glucocorticoids and one with cyclophosphamide plus glucocorticoids. Immunosuppressive therapy failed to provide any significant benefit.
Healing of prior inflammatory injury — FSGS can occur during the healing phase of any focal glomerular injury due, for example, to active IgA nephropathy, small vessel vasculitis, or lupus nephritis. In these settings and perhaps in other renal diseases as well, release of transforming growth factor-beta (TGF-beta) from platelets and glomerular cells may play a role in progressive renal injury [89].
TGF-beta stimulates extracellular matrix production, inhibits matrix degradation, and facilitates the adhesion of inflammatory cells to the matrix; each of these changes can promote the development of glomerulosclerosis [90]. TGF-beta expression and type 1 collagen are increased in animal models of chronic renal injury [91-93], while the administration of TGF-beta antibodies or inhibitors decreases matrix accumulation and the severity of glomerular scarring [92,94]. In addition, the suppressed expression of TGF-beta via the administration of other cytokines, such as hepatocyte growth factor, significantly limits renal fibrosis in mouse models of chronic renal disease [95].
The applicability of these findings to humans is unproven. A further discussion related to the wide variety of factors associated with progression of renal injury, including glomerulosclerosis, can be found elsewhere.
DISTINGUISHING BETWEEN PRIMARY AND SECONDARY FSGS — Differentiating primary and secondary focal segmental glomerulosclerosis (FSGS) clearly has important therapeutic implications but, as stated above, it remains controversial whether differentiation of the primary forms of FSGS into subcategories (eg, FSGS NOS [not otherwise specified] versus cellular variant) is useful in making treatment decisions.
About 50 to 60 percent of patients with primary FSGS respond to immunosuppressive agents such as glucocorticoids, while secondary FSGS is best treated with modalities aimed at lowering the intraglomerular pressure, such as angiotensin inhibitors. This distinction can usually be made from the history (such as one of the disorders associated with secondary disease) and from the clinical and histologic findings at diagnosis.
Clinical features — In contrast to patients with secondary FSGS who present with slowly increasing proteinuria and renal insufficiency over time, patients with primary FSGS most commonly present with the acute or subacute onset of the nephrotic syndrome and the associated features of peripheral edema, hypoalbuminemia, and usually high-grade (>3.5 g/d) proteinuria. By comparison, the proteinuria in patients with secondary FSGS is often in the non-nephrotic range, serum albumin levels are usually normal, and often, there is no peripheral edema, even when protein excretion exceeds 3 to 4 g/day [65,66,96,97].
The largest series evaluating the clinical differences between secondary and primary FSGS included 71 patients with obesity-related secondary FSGS and 50 patients with idiopathic FSGS [65]. The patients with obesity-related disease had the following significant differences: a lesser degree of proteinuria (4.1 versus 6.9 g/day), lower prevalence of the nephrotic syndrome (6 versus 54 percent), a higher serum albumin (3.9 versus 2.9 g/dL), a lower serum cholesterol (229 versus 335 mg/dL 5.9 versus 8.7 mmol/L), and a lower rate of edema (35 versus 68 percent).
The relationships among hypoalbuminemia, peripheral edema, and primary and secondary FSGS were also evaluated in a study of 37 patients with biopsy-proven FSGS and nephrotic range proteinuria (>3.5 g/day), of whom 19 had a serum albumin below 3 g/dL [97]. Primary FSGS was defined as idiopathic disease (rather than by histologic criteria), while secondary FSGS was thought to result from the presence of massive obesity, vesicoureteral reflux, or renal mass reduction. Only 2 of 18 patients with a normal serum albumin concentration compared with all with hypoalbuminemia had primary FSGS. In addition, all patients with, but none without, hypoalbuminemia had peripheral edema.
Pathologic features — The histologic findings are generally different in primary and secondary FSGS, although there is some overlap. Primary FSGS is associated with diffuse foot process fusion; in comparison, this abnormality tends to be focal in the secondary forms, being largely limited to the sclerotic areas [8,13,65]. In a systematic histologic study, the mean percentage of the glomerular surface area affected by foot process fusion was 65 percent in primary FSGS versus 25 percent in FSGS due to reflux nephropathy and 20 percent in obesity-related disease [8]. Foot process fusion was greatest (82 to 89 percent) in the most severe form, collapsing FSGS.
Similar findings were noted in the above report comparing obesity-related and idiopathic (primary) FSGS [65]. The following significant differences were noted in the patients with obesity-related disease: fewer glomeruli had segmental sclerotic lesions (10 versus 39 percent), glomerulomegaly was much more common (100 versus 10 percent), and foot process fusion was less extensive (40 versus 75 percent).
There are also pathologic findings that permit healed vasculitis to be distinguished from idiopathic FSGS or that are due to nephron loss. With healed vasculitis, the obsolescent segment of the capillary tuft is usually incorporated into scar tissue that is typically composed of collagens type I and III and that may fragment the tuft. On PAS stain, this scar tissue stains significantly less intensely than the strongly PAS-positive segment of collapsed capillary basement membrane material in primary FSGS.
GENETIC DISEASE
Overview — A number of genetic forms of focal segmental glomerulosclerosis (FSGS) have been described [78,98-106] and may account for a significant proportion of patients with steroid-resistant disease [107,108]. In some cases, the genetic forms of FSGS appear to be transmitted in an autosomal dominant pattern with variable penetrance, while autosomal recessive inheritance has been observed in other families.
As described in the following sections, suspect gene loci have been identified at multiple sites including chromosome 19q13 (coincidentally near the region that contains the nephrin gene [NPHS1] that is mutated in the congenital nephrotic syndrome of the Finnish type) [78,101,102], chromosome 11 (which harbors the gene for the canonical transient receptor potential 6 [TRPC6] ion channel), chromosome 1 (which harbors the NPHS2 gene and may harbor other suspect genes), and chromosome 14q (which harbors the INF2 gene that encodes the formin family of actin-regulatory proteins) [100,106,109-113].
In some series, chromosome 11 was the most frequently implicated genetic locus for familial disease. Among nine affected families in an Australian study, for example, FSGS segregated with loci on chromosomes 11 and 1 in four and two families, respectively, with no suspect genetic loci uncovered in three families [110]. Suspect genes in some of these loci have now been identified.
In general, the genes involved encode for proteins that are integral for proper glomerular basement membrane formation and/or glomerular podocyte differentiation and function. These include the gene(s) for podocin, nephrin, alpha-actinin-4, the TRPC6 ion channel, CD2AP (which interacts at the slit diaphragm with both podocin and nephrin), and the formin family of actin-regulatory proteins.
Podocin affects the expression and location of nephrin, a principal component of the slit diaphragm. Some mutant forms of these genes appear to result in intracellular retention of the abnormal proteins [114,115]. This suggests that drugs that ameliorate processing defects may provide therapeutic benefits in these disorders [114].
Commercial tests are available to detect NPHS1 and NPHS2 mutations but not the alpha-actinin-4, TRPC6, or CD2AP genes.
NPHS1 gene — Mutations in the gene for nephrin, called NPHS1, cause congenital nephrotic syndrome of Finnish type.
NPHS1 mutations have also been identified in older children with steroid-resistant nephrotic syndrome [116,117] and in at least one adult who presented with FSGS at age 27 years [117]. This patient was identified as part of study in which 97 patients from 89 unrelated families with steroid-resistant nephrotic syndrome and/or FSGS on biopsy were screened by direct DNA sequencing. Compound heterozygous or homozygous NPHS1 mutations were detected in five familial and seven sporadic cases of FSGS, including the adult patient described above and four children ages 8 months, 1 year, 6 years and 7 years; two of the children were from the same family. The detection rate of NPHS1 mutations among familial cases was 38 percent (5 of 13) and 10 percent (7 of 76) among sporadic cases. There were also two patients ages 27 and 29 years who had single NPHS1 variants of unknown effect.
NPHS2 gene — The causative gene for an autosomal recessive form of familial FSGS was cloned using a positional cloning technique directed at the chromosomal area 1q25-31 [103,118]. This gene, called NPHS2, encodes podocin, which is found exclusively in glomerular podocytes. Patients with FSGS due to mutations in NPHS2 usually present with early-onset nephrotic syndrome (age six years or less).
However, some affected patients have milder disease and present in adolescence or young adulthood. This was shown in a study of 30 families with apparent autosomal recessive late-onset FSGS (with an average age of onset of 21 years) and 91 individuals with non-familial or sporadic primary FSGS [119]. Mutations in NPHS2 cosegregated with the disease in nine families, while no likely disease-causing mutations were observed in 21. Affected individuals from six families were compound heterozygotes, and those from one family were homozygous for a specific nonconservative amino acid substitution in NPHS2. Allele frequency of this mutation, named R229Q, was 6 and 3.6 percent in those with non-familial disease and a non-disease control population, respectively, a difference that was not statistically significant. The presence of R229Q is associated with microalbuminuria in the non-disease general population [120].
The frequency of the R229Q variant has been assessed among various FSGS patient populations with discordant results [121-124].
• In one study, screening for known mutations in NPHS2 was performed in 87 adults with idiopathic FSGS identified through the Toronto Glomerulonephritis Registry database [121]. Of these, 15, 63, and 9 had steroid-sensitive (average age 41 years old), steroid-resistant (38 years old), and familial disease (23 years old), respectively [121]. No homozygous mutations were found, and only one patient had compound heterozygous mutations (R229Q and Q285fsX302).
• In a study of 377 biopsy-proven cases of FSGS and 919 controls, the role of NPHS2 polymorphisms was evaluated by sequencing exons and intron-exon junctions of the gene [122]. There was no increase in frequency of the R229Q mutation among patients with FSGS compared to the control population.
• By contrast, one large study suggested that compound heterozygosity for R229Q is associated with steroid-resistant adult-onset FSGS among patients from European or South America [123]. Among 546 patients from 455 ethnically diverse families with FSGS, 36 patients from 27 families were compound heterozygous for the R229Q variant and one pathogenic mutation [123]. Of the 27 families with compound heterozygosity, 11 were from Europe and 14 from South America. Furthermore, an analysis of the frequency of the R229Q allele in specific ethnic populations revealed highly significant differences in distribution among European and South American patients (mostly of Spanish descent) compared to controls of similar ethnic backgrounds, but no difference was observed among similarly controlled individuals from the Middle East or North Africa. Limitations in sample size prevented comparisons among other ethnic groups.
The presence of the mutation R138Q in only one NPHS2 allele is also associated with a markedly increased risk of FSGS. In the study cited above of 377 biopsy-proven cases of FSGS, carriers of the R138Q mutation were four- to fivefold more frequent among those with FSGS than among the control population. In addition, three carriers were steroid-resistant, suggesting an increased risk for this prognostic feature. No homozygote or compound heterozygotes were noted for any missense mutation.
In addition, mutations in both NPHS2 alleles have been described in approximately 10 to 25 percent of cases of apparently sporadic steroid-resistant FSGS in children from Europe and the Middle East.
Although one might expect that patients with NPHS2 mutations would not develop recurrent disease in the transplant, recurrence has been described.
Alpha-actinin-4 gene — Mutations in the alpha-actinin-4 gene on chromosome 19q13 are associated with an autosomal dominant form of the disease [101,125]. The mutant form of alpha-actinin-4 binds to actin more strongly than the wild type protein, suggesting that the disease might be due to an alteration in the actin cytoskeleton of the glomerular podocytes.
FSGS resulting from mutations in the alpha-actinin-4 gene may be associated with unique ultrastructural features on kidney biopsy. In one study of five patients with alpha-actinin-4 mutations, electron-dense podocyte aggregates were observed in all kidney biopsies, while a segmental and irregular immunofluorescent pattern for alpha-actinin-4 was noted in the four biopsies available for staining [126]. These observations were not found in the biopsies from patients with FSGS not due to an abnormal alpha-actinin-4 gene. Although intriguing, further study in a larger number of patients is required to better characterize these findings.
TRPC6 gene — As previously mentioned, chromosome 11 harbors a suspect genetic locus for FSGS, which is also the location for the gene for the canonical transient receptor potential 6 (TRPC6) ion channel. This receptor is expressed in podocytes and is a member of a family of calcium-permeable cation channels. TRPC6 also colocalizes to the slit diaphragm with nephrin, podocin, and CD2AP; in addition, alterations in TRPC6 calcium currents appear to underlie proper podocyte structure and function [112].
These features pointed toward defects in the TRPC6 gene as a cause of familial FSGS. FSGS mutations have now been documented in individuals with both familial and non-familial FSGS [112,113,127]. In a study of 71 families with FSGS, mutations in the TRPC6 gene segregated with FSGS in five families with autosomal dominant disease [112]. Mutation analysis in 130 patients from 115 families identified TRPC6 mutations in two patients with clinically non-familial FSGS and one with familial disease [127].
INF2 gene — Mutations of the INF2 gene, which encodes a member of the formin family of actin-regulating proteins, were initially identified in two large families with autosomal dominant FSGS [128]. Similar INF2 mutations were subsequently detected in nine additional probands with familial FSGS and shown to be present in affected family members (with biopsy-proven FSGS, end-stage renal disease (ESRD) or significant proteinuria without another cause); but not in control individuals who had no features of proteinuric kidney disease. In a subsequent study, INF2 mutations were identified in 28 of 78 patients (17 percent) with known autosomal dominant FSGS, but in only 1 of 84 patients with sporadic FSGS [129].
Based upon the phenotype of individuals with identified mutations, INF2-associated FSGS appears to present at a later age (adolescence or early adulthood) compared to FSGS caused by NPHS1 and NPHS2 mutations who typically present at a very early age.
Myo1e gene — A recent study identified two mutations in the Myo1e gene, which are linked to a childhood-onset and glucocorticoid-resistant form of FSGS [130]. Whole-genome linkage analysis was used to discover and sequence these mutations in 52 unrelated patients with FSGS. It was demonstrated that MYO1E is highly enriched in human podocytes, and the mutations A159P and Y695X were linked with decreased motile behavior of human podocytes and mislocalized expression of the MYO1E protein in vitro [130].
Other genes — CD2AP is a glomerular protein found at the slit diaphragm. Mutations in the gene for CD2AP have been described in two patients with primary FSGS [131]. Two mutations in the gene MY01E, which encodes a nonmuscle class I myosin, myosin 1E, have been closely associated with autosomal recessive FSGS [130].
Other genetic disorders are also associated with FSGS on kidney biopsy as well as other renal and/or extrarenal lesions. These include adult-onset cystinosis, nail-patella syndrome, Denys-Drash syndrome, Frasier syndrome, Charcot-Marie-Tooth disease, and glucose-6-phosphatase deficiency. These disorders are discussed in detail separately.
Distinguishing genetic from idiopathic FSGS — Distinguishing familial or genetic FSGS from idiopathic disease can be difficult, and familial disease may account for a significant proportion of patients with steroid-resistant FSGS, at least in children [107,108]. Genetic disorders can lead to a wide range of clinical disease, ranging from minimal change disease to adult-onset FSGS [106].
Findings suggestive, but not diagnostic, of familial FSGS include a family history of FSGS and disease onset in infancy or early childhood [106]. Thus, a detailed family history is of paramount importance in the evaluation of such patients.
Steroid resistance is a consistent finding that also may be seen in primary FSGS. Although steroid-resistant FSGS is due to familial disease in many children, its predictive value in adults is uncertain. In addition, some adults who have FSGS-associated mutations may respond to glucocorticoid therapy.
Morphologic characteristics seen on kidney biopsy cannot usually distinguish genetic and nongenetic forms of primary FSGS. Exceptions include the distinctive features associated with NPHS1 and alpha-actinin-4 gene mutations.
Genetic screening may identify patients who have familial disease. Among patients with congenital or infantile FSGS, genetic screening should be performed prior to initiating treatment.
FSGS IN AFRICAN AMERICANS — The relative frequency of the different causes of nephrotic proteinuria varies with race, with the largest difference between blacks and whites being the frequency of focal segmental glomerulosclerosis (FSGS).
Among patients with nephrotic proteinuria, two studies from the United States found that blacks had a higher prevalence of FSGS than whites, an effect that may be increasing over time. The following observations were noted:
• In a series of 358 adults who underwent renal biopsy for nephrotic syndrome between 1976 and 1979 and between 1995 and 1997, the frequency of FSGS as the cause was two to three times higher in black compared with white patients in both time periods and increased to a similar degree in both blacks and whites from the earlier to the later time period [1]. Between 1995 and 1997, FSGS accounted for more than 50 percent of cases of unexplained nephrotic syndrome in black adults and for more than 67 percent in black adults younger than 45 years. There were only seven cases of collapsing FSGS, making it unlikely that the increase in prevalence was due to HIV infection.
• In a report of 340 patients who underwent renal biopsy (mean age 43 years) for nephrotic proteinuria over a 20-year period from 1975 to 1994, FSGS accounted for 57 percent of cases in blacks and 23 percent in whites [6]. Furthermore, the prevalence of FSGS in blacks increased significantly from 39 percent in 1975 to 1984 to 64 percent in 1985 to 1994. The distribution did not vary with gender or age.
Blacks also account for the overwhelming majority of patients with HIV-associated FSGS (88 percent in a report from the United States Renal Data System [USRDS]) [132]. In addition, black patients with this disorder have an increased incidence of a family history of end-stage renal disease. This was illustrated in a study that compared 201 black patients with HIV-associated collapsing FSGS with a control group of 50 HIV-infected black patients without renal disease [133]. The patients with FSGS had a much higher percentage of first and second degree relatives with end-stage renal disease (ESRD) (24 versus 6 percent).
APOL1 — The increased susceptibility of blacks to FSGS may be explained, at least in part, by genetic factors, although socioeconomic and environmental factors may also play a role. Polymorphisms in a region of chromosome 22, which are strongly linked with African ancestry, are highly associated with an increased risk of developing FSGS [134,135]. The MYH9 gene that is located within this region encodes for kidney podocyte nonmuscle myosin IIA and contains multiple noncoding polymorphisms that were initially shown to be closely linked with both idiopathic and HIV-associated FSGS. The specific haplotype that confers the highest risk for FSGS is common in African-Americans but rare in European Americans (60 and 4 percent, respectively) [134,136].
Variants in the apolipoprotein L1 (APOL1) gene, which resides in close proximity to MYH9 on chromosome 22, have since been shown to be even more closely associated with nondiabetic nephropathy in African Americans [137,138]. In fact, a strong linkage disequilibrium (in which multiple loci are non-randomly associated) exists in this chromosomal region, such that the MYH9 haplotype that was initially implicated in kidney disease may simply reflect APOL1 variation [137]. It is possible that other variants in MYH9, APOL1, or other genes in this region of chromosome 22 are involved in kidney disease [139].
Polymorphisms in APOL1 appear to be expressed exclusively in individuals of African descent and have not been identified in any individuals from Europe, Japan, or China [137]. APOL1 polymorphisms are associated with FSGS in African Americans:
• An analysis that compared African Americans with non-familial biopsy-proven FSGS to African Americans without FSGS identified two APOL1 variants that are expressed more frequently in patients with FSGS [137]. The association of APOL1 variants with renal disease was confirmed in a second larger cohort of African American patients with hypertension-associated end-stage kidney disease [137].
• APOL1 genotypes were compared among 271 African American cases of FSGS, 168 European American cases of FSGS, and 939 control subjects [140]. APOL1 variants conferred a 17-fold higher odds (95% CI, 11-26) for FSGS and twenty-ninefold higher odds (95% CI, 13-68) for HIV-associated nephropathy (HIVAN). Individuals with two APOL1 risk alleles had an earlier age of onset and faster progression to ESRD but a similar sensitivity to steroids compared with other subjects. Positive selective forces likely underlie this linkage disequilibrium, suggesting that a biological advantage is conferred by the inheritance of these variants [139]. Although this hypothesis is speculative, in vitro studies suggest that the APOL1 gene variants that predispose to kidney disease may provide superior defense against a subspecies of Trypanosomes, which would provide a selective advantage to carriers of these variants against sleeping sickness [137].
HEROIN NEPHROPATHY — Heroin abuse may be associated with focal segmental glomerulosclerosis (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 [141], membranous nephropathy due to hepatitis B virus infection, and membranoproliferative glomerulonephritis due to hepatitis C virus infection [142].
Heroin-associated FSGS has a predilection for black patients [141,143]. Slow progression to renal failure can occur, usually over a period of several years rather than several months as in HIV-induced disease.
The pathogenesis of heroin nephropathy is uncertain. It has been proposed that glomerular epithelial cell injury may be induced by an exogenous toxin given with the heroin. 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 [144]. 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 renal disorders that are now recognized to be associated with other conditions (eg, hepatitis C).
OTHER CAUSES — Focal segmental glomerulosclerosis (FSGS) can be seen in a number of other disorders in which the pathogenesis is uncertain. Included in this group are chronic lithium therapy and malignancy, particularly Hodgkin and non-Hodgkin lymphomas [145,146]. The course of the glomerular disease parallels that of the malignancy. A discussion of the association between malignancy and nephrotic syndrome is presented separately.
SUMMARY
• Focal segmental glomerulosclerosis (FSGS) is a histologic lesion, rather than a disease, that is commonly found to underlie the nephrotic syndrome in adults and children. (
• In the United States, FSGS is one of the most common histologic lesions associated with the idiopathic nephrotic syndrome in adults, accounting for 35 percent of all cases and over 50 percent of cases among blacks. By comparison, FSGS is a less common cause of the nephrotic syndrome in many other countries.
• One FSGS classification scheme is based upon the known and/or postulated causes of the renal disease:
• Primary or idiopathic FSGS, which typically presents with the nephrotic syndrome.
• Secondary FSGS, which typically presents with non-nephrotic proteinuria and often renal insufficiency. This category most commonly refers to FSGS thought to represent an adaptive response to glomerular hypertrophy or hyperfiltration (eg, reduced renal mass) or a nonspecific pattern of scarring due to a previous injury.
• FSGS due to infections (particularly HIV), toxins (including heroin, interferon, cyclosporine, and pamidronate), genetic abnormalities, and renal atheroembolic disease.
Primary FSGS
• Several morphologic variants of primary (idiopathic) FSGS observed with light microscopy have been defined:
• Classic FSGS, also called FSGS NOS (not otherwise specified), is the most common form.
• Collapsing variant, although some experts argue that this should not be considered an FSGS variant.
• Tip variant.
• Perihilar variant.
• Cellular variant.
• The prognostic and therapeutic decision-making value of these histologic variants of FSGS is unclear.
• In the majority of patients with primary FSGS (and posttransplant FSGS), injury to glomerular cells may occur as a consequence of a circulating factor. Clinical observations support a key role for a circulating factor such as the soluble urokinase plasminogen activator receptor (suPAR). Expression of a microRNA (specifically, miR-193a) inside podocytes and subsequent downregulation of the Wilms tumor protein (WT1) may be another mechanism responsible for FSGS.
• Patients with primary FSGS may present with acute or insidious onset of the nephrotic syndrome, as manifested by peripheral edema, hypoalbuminemia, and nephrotic range proteinuria. The frequency of various clinical features at either presentation or time of biopsy have include:
• Nephrotic range proteinuria – 60 to 75 percent
• Microscopic hematuria with variable degrees of proteinuria – 30 to 50 percent
• Hypertension – 45 to 65 percent
• Renal insufficiency – 25 to 50 percent
Secondary FSGS
• In our view, the glomerulosclerosis of secondary FSGS usually results from an adaptive response to one or more of the following mechanisms:
• Podocyte injury, which may be due to, among other causes, inflammation, angiotensin II, toxins, and viral infection.
• Prior nephron loss due, for example, to reflux nephropathy, ischemia in benign hypertensive nephrosclerosis, and congenital absence or surgical removal of a kidney. In these settings, compensatory intraglomerular hypertension and hypertrophy in the remaining glomeruli can, over a period of years, lead to FSGS.
• Primary renal vasodilatation and glomerular hypertension as occurs in diabetic nephropathy, sickle cell anemia, familial autonomic insufficiency, type I glycogen storage disease, severe obesity, preeclampsia, anabolic steroid abuse, and treatment with interferon.
• Healing of a prior inflammatory injury due, for example, to IgA nephropathy, small vessel vasculitis, or lupus nephritis.
• Differentiating primary and secondary FSGS clearly has important therapeutic implications. About 50 to 60 percent of patients with primary FSGS respond to immunosuppressive agents such as glucocorticoids, while secondary FSGS is best treated with modalities aimed at lowering the intraglomerular pressure, such as angiotensin inhibitors. This distinction can usually be made from the history (such as one of the disorders associated with secondary disease) and from the clinical and histologic findings at diagnosis:
• Patients with secondary FSGS usually present with slowly increasing proteinuria and renal insufficiency over time; patients with primary FSGS typically present with the acute or subacute onset of the nephrotic syndrome. Primary FSGS is also associated with peripheral edema, hypoalbuminemia, and usually nephrotic range proteinuria. By comparison, the proteinuria in secondary FSGS is often non-nephrotic, and both low serum levels of albumin and edema are unusual even when protein excretion exceeds 3.5 g/day.
• The histologic findings are generally different in primary and secondary FSGS, although there is some overlap. Primary FSGS is associated with diffuse foot process fusion; in comparison, this abnormality tends to be focal in the secondary forms, being largely limited to the sclerotic areas.
Genetic disease
• A number of genetic forms of FSGS have been described and may account for a significant proportion of patients with steroid-resistant disease. In some cases, the genetic forms of FSGS appear to be transmitted in an autosomal dominant pattern with variable penetrance, while autosomal recessive inheritance has been observed in other families. In general, the involved genes encode proteins that are integral for proper glomerular basement membrane formation and/or glomerular podocyte differentiation and function. These include the gene(s) for NPHS1, NPHS2, alpha-actinin-4, the TRPC6 ion channel, CD2AP (which interacts at the slit diaphragm with both podocin and nephrin), and the formin family of actin-regulatory proteins.
• Commercial tests are available to detect NPHS1 and NPHS2 mutations, but not the alpha-actinin-4, TRPC6, or CD2AP genes.
• Distinguishing familial or genetic FSGS from idiopathic disease can be difficult, and familial disease may account for a significant proportion of patients with steroid-resistant FSGS, at least in children. Findings suggestive, but not diagnostic, of familial FSGS include a family history of FSGS and disease onset in infancy or early childhood. Morphologic characteristics seen on kidney biopsy cannot usually distinguish genetic and nongenetic forms of primary FSGS; exceptions include the distinctive features associated with NPHS1 and alpha-actinin-4 gene mutations. Genetic screening may identify some patients who have familial disease.
• The increased susceptibility of blacks to FSGS may be explained, at least in part, by genetic factors, although socioeconomic and environmental factors may also play a role. Variants in the apolipoprotein L1 (APOL1) gene have been shown to be closely associated with nondiabetic nephropathy in African Americans. Polymorphisms in APOL1 appear to be expressed exclusively in individuals of African descent and have not been identified in any individuals from Europe, Japan, or China.
REFERENCES
1. Haas M, Meehan SM, Karrison TG, Spargo BH. Changing etiologies of unexplained adult nephrotic syndrome: a comparison of renal biopsy findings from 1976-1979 and 1995-1997. Am J Kidney Dis 1997; 30:621.
2. Braden GL, Mulhern JG, O'Shea MH, et al. Changing incidence of glomerular diseases in adults. Am J Kidney Dis 2000; 35:878.
3. Kitiyakara C, Eggers P, Kopp JB. Twenty-one-year trend in ESRD due to focal segmental glomerulosclerosis in the United States. Am J Kidney Dis 2004; 44:815.
4. Bahiense-Oliveira M, Saldanha LB, Mota EL, et al. Primary glomerular diseases in Brazil (1979-1999): is the frequency of focal and segmental glomerulosclerosis increasing? Clin Nephrol 2004; 61:90.
5. Filler G, Young E, Geier P, et al. Is there really an increase in non-minimal change nephrotic syndrome in children? Am J Kidney Dis 2003; 42:1107.
6. Korbet SM, Genchi RM, Borok RZ, Schwartz MM. The racial prevalence of glomerular lesions in nephrotic adults. Am J Kidney Dis 1996; 27:647.
7. Rivera F, López-Gómez JM, Pérez-García R, Spanish Registry of Glomerulonephritis. Clinicopathologic correlations of renal pathology in Spain. Kidney Int 2004; 66:898.
8. D'Agati V. Pathologic classification of focal segmental glomerulosclerosis. Semin Nephrol 2003; 23:117.
9. Meyrier A. Nephrotic focal segmental glomerulosclerosis in 2004: an update. Nephrol Dial Transplant 2004; 19:2437.
10. Greenberg A, Bastacky SI, Iqbal A, et al. Focal segmental glomerulosclerosis associated with nephrotic syndrome in cholesterol atheroembolism: clinicopathological correlations. Am J Kidney Dis 1997; 29:334.
11. D'Agati VD, Kaskel FJ, Falk RJ. Focal segmental glomerulosclerosis. N Engl J Med 2011; 365:2398.
12. D'Agati VD, Fogo AB, Bruijn JA, Jennette JC. Pathologic classification of focal segmental glomerulosclerosis: a working proposal. Am J Kidney Dis 2004; 43:368.
13. Rennke HG, Klein PS. Pathogenesis and significance of nonprimary focal and segmental glomerulosclerosis. Am J Kidney Dis 1989; 13:443.
14. Remuzzi A, Mazerska M, Gephardt GN, et al. Three-dimensional analysis of glomerular morphology in patients with subtotal nephrectomy. Kidney Int 1995; 48:155.
15. Fogo A, Glick AD, Horn SL, Horn RG. Is focal segmental glomerulosclerosis really focal? Distribution of lesions in adults and children. Kidney Int 1995; 47:1690.
16. Beaman M, Howie AJ, Hardwicke J, et al. The glomerular tip lesion: a steroid responsive nephrotic syndrome. Clin Nephrol 1987; 27:217.
17. Haas M, Yousefzadeh N. Glomerular tip lesion in minimal change nephropathy: a study of autopsies before 1950. Am J Kidney Dis 2002; 39:1168.
18. Stokes MB, Markowitz GS, Lin J, et al. Glomerular tip lesion: a distinct entity within the minimal change disease/focal segmental glomerulosclerosis spectrum. Kidney Int 2004; 65:1690.
19. Thomas DB, Franceschini N, Hogan SL, et al. Clinical and pathologic characteristics of focal segmental glomerulosclerosis pathologic variants. Kidney Int 2006; 69:920.
20. Deegens JK, Assmann KJ, Steenbergen EJ, et al. Idiopathic focal segmental glomerulosclerosis: a favourable prognosis in untreated patients? Neth J Med 2005; 63:393.
21. 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.
22. Chun MJ, Korbet SM, Schwartz MM, Lewis EJ. Focal segmental glomerulosclerosis in nephrotic adults: presentation, prognosis, and response to therapy of the histologic variants. J Am Soc Nephrol 2004; 15:2169.
23. Stokes MB, Valeri AM, Markowitz GS, D'Agati VD. Cellular focal segmental glomerulosclerosis: Clinical and pathologic features. Kidney Int 2006; 70:1783.
24. Clement LC, Avila-Casado C, Macé C, et al. Podocyte-secreted angiopoietin-like-4 mediates proteinuria in glucocorticoid-sensitive nephrotic syndrome. Nat Med 2011; 17:117.
25. Siegel NJ, Gaudio KM, Krassner LS, et al. Steroid-dependent nephrotic syndrome in children: histopathology and relapses after cyclophosphamide treatment. Kidney Int 1981; 19:454.
26. Nash MA, Greifer I, Olbing H, et al. The significance of focal sclerotic lesions of glomeruli in children. J Pediatr 1976; 88:806.
27. 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.
28. Rennke HG. How does glomerular epithelial cell injury contribute to progressive glomerular damage? Kidney Int Suppl 1994; 45:S58.
29. 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.
30. Wei C, Möller CC, Altintas MM, et al. Modification of kidney barrier function by the urokinase receptor. Nat Med 2008; 14:55.
31. Wei C, Trachtman H, Li J, et al. Circulating suPAR in two cohorts of primary FSGS. J Am Soc Nephrol 2012; 23:2051.
32. 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.
33. Kemper MJ, Wei C, Reiser J. Transmission of glomerular permeability factor soluble urokinase plasminogen activator receptor (suPAR) from a mother to child. Am J Kidney Dis 2013; 61:352.
34. Wei C, El Hindi S, Li J, et al. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat Med 2011; 17:952.
35. Shankland SJ, Pollak MR. A suPAR circulating factor causes kidney disease. Nat Med 2011; 17:926.
36. 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.
37. Rydel JJ, Korbet SM, Borok RZ, Schwartz MM. Focal segmental glomerular sclerosis in adults: presentation, course, and response to treatment. Am J Kidney Dis 1995; 25:534.
38. Cattran DC, Rao P. Long-term outcome in children and adults with classic focal segmental glomerulosclerosis. Am J Kidney Dis 1998; 32:72.
39. Pokhariyal S, Gulati S, Prasad N, et al. Duration of optimal therapy for idiopathic focal segmental glomerulosclerosis. J Nephrol 2003; 16:691.
40. Crook ED, Habeeb D, Gowdy O, et al. Effects of steroids in focal segmental glomerulosclerosis in a predominantly African-American population. Am J Med Sci 2005; 330:19.
41. Cascio S, Paran S, Puri P. Associated urological anomalies in children with unilateral renal agenesis. J Urol 1999; 162:1081.
42. Henegar JR, Bigler SA, Henegar LK, et al. Functional and structural changes in the kidney in the early stages of obesity. J Am Soc Nephrol 2001; 12:1211.
43. Wiggins JE, Goyal M, Sanden SK, et al. Podocyte hypertrophy, "adaptation," and "decompensation" associated with glomerular enlargement and glomerulosclerosis in the aging rat: prevention by calorie restriction. J Am Soc Nephrol 2005; 16:2953.
44. Kriz W, Gretz N, Lemley KV. Progression of glomerular diseases: is the podocyte the culprit? Kidney Int 1998; 54:687.
45. Ding G, Reddy K, Kapasi AA, et al. Angiotensin II induces apoptosis in rat glomerular epithelial cells. Am J Physiol Renal Physiol 2002; 283:F173.
46. Durvasula RV, Petermann AT, Hiromura K, et al. Activation of a local tissue angiotensin system in podocytes by mechanical strain. Kidney Int 2004; 65:30.
47. Pagtalunan ME, Miller PL, Jumping-Eagle S, et al. Podocyte loss and progressive glomerular injury in type II diabetes. J Clin Invest 1997; 99:342.
48. Meyer TW, Bennett PH, Nelson RG. Podocyte number predicts long-term urinary albumin excretion in Pima Indians with Type II diabetes and microalbuminuria. Diabetologia 1999; 42:1341.
49. Lemley KV, Lafayette RA, Safai M, et al. Podocytopenia and disease severity in IgA nephropathy. Kidney Int 2002; 61:1475.
50. Wu DT, Bitzer M, Ju W, et al. TGF-beta concentration specifies differential signaling profiles of growth arrest/differentiation and apoptosis in podocytes. J Am Soc Nephrol 2005; 16:3211.
51. Yang HC, Ma LJ, Ma J, Fogo AB. Peroxisome proliferator-activated receptor-gamma agonist is protective in podocyte injury-associated sclerosis. Kidney Int 2006; 69:1756.
52. Peters I, Tossidou I, Achenbach J, et al. IGF-binding protein-3 modulates TGF-beta/BMP-signaling in glomerular podocytes. J Am Soc Nephrol 2006; 17:1644.
53. 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.
54. 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.
55. 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.
56. 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.
57. 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.
58. 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.
59. Narkun-Burgess DM, Nolan CR, Norman JE, et al. Forty-five year follow-up after uninephrectomy. Kidney Int 1993; 43:1110.
60. Kasiske BL, Ma JZ, Louis TA, Swan SK. Long-term effects of reduced renal mass in humans. Kidney Int 1995; 48:814.
61. Atiyeh B, Husmann D, Baum M. Contralateral renal abnormalities in patients with renal agenesis and noncystic renal dysplasia. Pediatrics 1993; 91:812.
62. Argueso LR, Ritchey ML, Boyle ET Jr, et al. Prognosis of patients with unilateral renal agenesis. Pediatr Nephrol 1992; 6:412.
63. Chen YT, Coleman RA, Scheinman JI, et al. Renal disease in type I glycogen storage disease. N Engl J Med 1988; 318:7.
64. Wesson DE. The initiation and progression of sickle cell nephropathy. Kidney Int 2002; 61:2277.
65. Kambham N, Markowitz GS, Valeri AM, et al. Obesity-related glomerulopathy: an emerging epidemic. Kidney Int 2001; 59:1498.
66. 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.
67. Kasiske BL, Crosson JT. Renal disease in patients with massive obesity. Arch Intern Med 1986; 146:1105.
68. 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.
69. Fletcher EC. Obstructive sleep apnea and the kidney. J Am Soc Nephrol 1993; 4:1111.
70. Chen HM, Liu ZH, Zeng CH, et al. Podocyte lesions in patients with obesity-related glomerulopathy. Am J Kidney Dis 2006; 48:772.
71. Sklar AH, Chaudhary BA. Reversible proteinuria in obstructive sleep apnea syndrome. Arch Intern Med 1988; 148:87.
72. Wesson DE, Kurtzman NA, Frommer JP. Massive obesity and nephrotic proteinuria with a normal renal biopsy. Nephron 1985; 40:235.
73. 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.
74. 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.
75. Sharma K, Ramachandrarao S, Qiu G, et al. Adiponectin regulates albuminuria and podocyte function in mice. J Clin Invest 2008; 118:1645.
76. Serra A, Romero R, Lopez D, et al. Renal injury in the extremely obese patients with normal renal function. Kidney Int 2008; 73:947.
77. D'Agati VD, Markowitz GS. Supersized kidneys: Lessons from the preclinical obese kidney. Kidney Int 2008; 73:909.
78. Mathis BJ, Kim SH, Calabrese K, et al. A locus for inherited focal segmental glomerulosclerosis maps to chromosome 19q13. Kidney Int 1998; 53:282.
79. Casserly LF, Chow N, Ali S, et al. Proteinuria in obstructive sleep apnea. Kidney Int 2001; 60:1484.
80. 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.
81. Shen WW, Chen HM, Chen H, et al. Obesity-related glomerulopathy: body mass index and proteinuria. Clin J Am Soc Nephrol 2010; 5:1401.
82. Nochy D, Heudes D, Glotz D, et al. Preeclampsia associated focal and segmental glomerulosclerosis and glomerular hypertrophy: a morphometric analysis. Clin Nephrol 1994; 42:9.
83. Nishimoto K, Shiiki H, Nishino T, et al. Glomerular hypertrophy in preeclamptic patients with focal segmental glomerulosclerosis. A morphometric analysis. Clin Nephrol 1999; 51:209.
84. Herlitz LC, Markowitz GS, Farris AB, et al. Development of focal segmental glomerulosclerosis after anabolic steroid abuse. J Am Soc Nephrol 2010; 21:163.
85. 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.
86. 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.
87. 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.
88. 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.
89. Yoshioka K, Takemura T, Murakami K, et al. Transforming growth factor-beta protein and mRNA in glomeruli in normal and diseased human kidneys. Lab Invest 1993; 68:154.
90. Sharma K, Ziyadeh FN. The emerging role of transforming growth factor-beta in kidney diseases. Am J Physiol 1994; 266:F829.
91. Wang W, Koka V, Lan HY. Transforming growth factor-beta and Smad signalling in kidney diseases. Nephrology (Carlton) 2005; 10:48.
92. Hou CC, Wang W, Huang XR, et al. Ultrasound-microbubble-mediated gene transfer of inducible Smad7 blocks transforming growth factor-beta signaling and fibrosis in rat remnant kidney. Am J Pathol 2005; 166:761.
93. Huang Y, Border WA, Noble NA. Perspectives on blockade of TGFbeta overexpression. Kidney Int 2006; 69:1713.
94. Border WA, Noble NA, Yamamoto T, et al. Natural inhibitor of transforming growth factor-beta protects against scarring in experimental kidney disease. Nature 1992; 360:361.
95. Mizuno S, Kurosawa T, Matsumoto K, et al. Hepatocyte growth factor prevents renal fibrosis and dysfunction in a mouse model of chronic renal disease. J Clin Invest 1998; 101:1827.
96. Praga M, Borstein B, Andres A, et al. Nephrotic proteinuria without hypoalbuminemia: clinical characteristics and response to angiotensin-converting enzyme inhibition. Am J Kidney Dis 1991; 17:330.
97. Praga M, Morales E, Herrero JC, et al. Absence of hypoalbuminemia despite massive proteinuria in focal segmental glomerulosclerosis secondary to hyperfiltration. Am J Kidney Dis 1999; 33:52.
98. Faubert PF, Porush JG. Familial focal segmental glomerulosclerosis: nine cases in four families and review of the literature. Am J Kidney Dis 1997; 30:265.
99. Conlon PJ, Lynn K, Winn MP, et al. Spectrum of disease in familial focal and segmental glomerulosclerosis. Kidney Int 1999; 56:1863.
100. Winn MP, Conlon PJ, Lynn KL, et al. Linkage of a gene causing familial focal segmental glomerulosclerosis to chromosome 11 and further evidence of genetic heterogeneity. Genomics 1999; 58:113.
101. Kaplan JM, Kim SH, North KN, et al. Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet 2000; 24:251.
102. Vats A, Nayak A, Ellis D, et al. Familial nephrotic syndrome: clinical spectrum and linkage to chromosome 19q13. Kidney Int 2000; 57:875.
103. Boute N, Gribouval O, Roselli S, et al. NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet 2000; 24:349.
104. Vats AN, Ishwad C, Vats KR, et al. Steroid-resistant nephrotic syndrome and congenital anomalies of kidneys: evidence of locus on chromosome 13q. Kidney Int 2003; 64:17.
105. Kitamura A, Tsukaguchi H, Iijima K, et al. Genetics and clinical features of 15 Asian families with steroid-resistant nephrotic syndrome. Nephrol Dial Transplant 2006; 21:3133.
106. Pollak MR. The genetic basis of FSGS and steroid-resistant nephrosis. Semin Nephrol 2003; 23:141.
107. Caridi G, Bertelli R, Carrea A, et al. Prevalence, genetics, and clinical features of patients carrying podocin mutations in steroid-resistant nonfamilial focal segmental glomerulosclerosis. J Am Soc Nephrol 2001; 12:2742.
108. Ruf RG, Lichtenberger A, Karle SM, et al. Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome. J Am Soc Nephrol 2004; 15:722.
109. Tsukaguchi H, Yager H, Dawborn J, et al. A locus for adolescent and adult onset familial focal segmental glomerulosclerosis on chromosome 1q25-31. J Am Soc Nephrol 2000; 11:1674.
110. Rana K, Isbel N, Buzza M, et al. Clinical, histopathologic, and genetic studies in nine families with focal segmental glomerulosclerosis. Am J Kidney Dis 2003; 41:1170.
111. Prakash S, Chung KW, Sinha S, et al. Autosomal dominant progressive nephropathy with deafness: linkage to a new locus on chromosome 11q24. J Am Soc Nephrol 2003; 14:1794.
112. Reiser J, Polu KR, Möller CC, et al. TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat Genet 2005; 37:739.
113. Winn MP, Conlon PJ, Lynn KL, et al. A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science 2005; 308:1801.
114. Liu XL, Doné SC, Yan K, et al. Defective trafficking of nephrin missense mutants rescued by a chemical chaperone. J Am Soc Nephrol 2004; 15:1731.
115. Nishibori Y, Liu L, Hosoyamada M, et al. Disease-causing missense mutations in NPHS2 gene alter normal nephrin trafficking to the plasma membrane. Kidney Int 2004; 66:1755.
116. Philippe A, Nevo F, Esquivel EL, et al. Nephrin mutations can cause childhood-onset steroid-resistant nephrotic syndrome. J Am Soc Nephrol 2008; 19:1871.
117. Santín S, García-Maset R, Ruíz P, et al. Nephrin mutations cause childhood- and adult-onset focal segmental glomerulosclerosis. Kidney Int 2009; 76:1268.
118. Fuchshuber A, Mehls O. Familial steroid-resistant nephrotic syndromes: recent advances. Nephrol Dial Transplant 2000; 15:1897.
119. Tsukaguchi H, Sudhakar A, Le TC, et al. NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele. J Clin Invest 2002; 110:1659.
120. Pereira AC, Pereira AB, Mota GF, et al. NPHS2 R229Q functional variant is associated with microalbuminuria in the general population. Kidney Int 2004; 65:1026.
121. He N, Zahirieh A, Mei Y, et al. Recessive NPHS2 (Podocin) mutations are rare in adult-onset idiopathic focal segmental glomerulosclerosis. Clin J Am Soc Nephrol 2007; 2:31.
122. McKenzie LM, Hendrickson SL, Briggs WA, et al. NPHS2 variation in sporadic focal segmental glomerulosclerosis. J Am Soc Nephrol 2007; 18:2987.
123. Machuca E, Hummel A, Nevo F, et al. Clinical and epidemiological assessment of steroid-resistant nephrotic syndrome associated with the NPHS2 R229Q variant. Kidney Int 2009; 75:727.
124. Tonna SJ, Needham A, Polu K, et al. NPHS2 variation in focal and segmental glomerulosclerosis. BMC Nephrol 2008; 9:13.
125. Weins A, Kenlan P, Herbert S, et al. Mutational and Biological Analysis of alpha-actinin-4 in focal segmental glomerulosclerosis. J Am Soc Nephrol 2005; 16:3694.
126. Henderson JM, Alexander MP, Pollak MR. Patients with ACTN4 mutations demonstrate distinctive features of glomerular injury. J Am Soc Nephrol 2009; 20:961.
127. Santín S, Ars E, Rossetti S, et al. TRPC6 mutational analysis in a large cohort of patients with focal segmental glomerulosclerosis. Nephrol Dial Transplant 2009; 24:3089.
128. Brown EJ, Schlöndorff JS, Becker DJ, et al. Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis. Nat Genet 2010; 42:72.
129. Boyer O, Benoit G, Gribouval O, et al. Mutations in INF2 are a major cause of autosomal dominant focal segmental glomerulosclerosis. J Am Soc Nephrol 2011; 22:239.
130. Mele C, Iatropoulos P, Donadelli R, et al. MYO1E mutations and childhood familial focal segmental glomerulosclerosis. N Engl J Med 2011; 365:295.
131. Kim JM, Wu H, Green G, et al. CD2-associated protein haploinsufficiency is linked to glomerular disease susceptibility. Science 2003; 300:1298.
132. Abbott KC, Hypolite I, Welch PG, Agodoa LY. Human immunodeficiency virus/acquired immunodeficiency syndrome-associated nephropathy at end-stage renal disease in the United States: patient characteristics and survival in the pre highly active antiretroviral therapy era. J Nephrol 2001; 14:377.
133. Freedman BI, Soucie JM, Stone SM, Pegram S. Familial clustering of end-stage renal disease in blacks with HIV-associated nephropathy. Am J Kidney Dis 1999; 34:254.
134. Kopp JB, Smith MW, Nelson GW, et al. MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nat Genet 2008; 40:1175.
135. Pollak MR. Kidney disease and African ancestry. Nat Genet 2008; 40:1145.
136. Kao WH, Klag MJ, Meoni LA, et al. MYH9 is associated with nondiabetic end-stage renal disease in African Americans. Nat Genet 2008; 40:1185.
137. Genovese G, Friedman DJ, Ross MD, et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 2010; 329:841.
138. Genovese G, Tonna SJ, Knob AU, et al. A risk allele for focal segmental glomerulosclerosis in African Americans is located within a region containing APOL1 and MYH9. Kidney Int 2010; 78:698.
139. Freedman BI, Kopp JB, Langefeld CD, et al. The apolipoprotein L1 (APOL1) gene and nondiabetic nephropathy in African Americans. J Am Soc Nephrol 2010; 21:1422.
140. Kopp JB, Nelson GW, Sampath K, et al. APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol 2011; 22:2129.
141. Cunningham EE, Zielezny MA, Venuto RC. Heroin-associated nephropathy. A nationwide problem. JAMA 1983; 250:2935.
142. do Sameiro Faria M, Sampaio S, Faria V, Carvalho E. Nephropathy associated with heroin abuse in Caucasian patients. Nephrol Dial Transplant 2003; 18:2308.
143. Dubrow A, Mittman N, Ghali V, Flamenbaum W. The changing spectrum of heroin-associated nephropathy. Am J Kidney Dis 1985; 5:36.
144. Friedman EA, Tao TK. Disappearance of uremia due to heroin-associated nephropathy. Am J Kidney Dis 1995; 25:689.
145. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 15-1983. A 24-year-old man with cervical lymphadenopathy and the nephrotic syndrome. N Engl J Med 1983; 308:888.
146. Rault R, Holley JL, Banner BF, el-Shahawy M. Glomerulonephritis and non-Hodgkin's lymphoma: a report of two cases and review of the literature. Am J Kidney Dis 1992; 20:84.
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