Version May 2024
INTRODUCTION — Focal segmental glomerulosclerosis (FSGS) is a morphologic pattern of glomerular injury primarily directed at the glomerular visceral epithelial cell (the podocyte) and defined by the presence of sclerosis in parts (segmental) of some (focal) glomeruli by light microscopy of a kidney biopsy specimen. The lesion of FSGS can be classified into primary, secondary, genetic, and undetermined forms using a clinicopathologic approach. This classification step is crucial for determining appropriate therapy; identification of an FSGS lesion solely by light microscopy is never sufficient for management decisions. The lesion of FSGS is distinct from focal and global glomerulosclerosis, which has a different prognosis and treatment.
This topic will review the genetic causes of FSGS. The epidemiology, classification, pathogenesis, clinical features, diagnosis, and treatment of FSGS and recurrent disease in the kidney transplant are discussed separately:
●(See "Focal segmental glomerulosclerosis: Clinical features and diagnosis".)
●(See "Focal segmental glomerulosclerosis: Pathogenesis".)
●(See "Focal segmental glomerulosclerosis: Treatment and prognosis".)
●(See "Kidney transplantation in adults: Focal segmental glomerulosclerosis in the transplanted kidney".)
EPIDEMIOLOGY OF GENETIC FSGS — The prevalence of genetic FSGS varies widely depending upon the population being studied [1-4]. In regions of the world where consanguinity is prevalent, for example, the prevalence of genetic FSGS among all patients with FSGS may be as high as 30 percent, whereas in the outbred population, the prevalence may be as low as <5 percent. The existence of founder mutations in a particular population may also affect prevalence rates. As an example, the prevalence of genetic FSGS in central Europe is generally higher than in the United States because of different founder mutations in the podocin (NPHS2) gene [3]. Overall, the prevalence of monogenic FSGS is estimated to be approximately 30 to 50 percent among patients with genetic/familial disease and 5 to 30 percent in sporadic FSGS.
The prevalence of genetic FSGS may also depend upon the age of onset of disease. In a European cohort study of 89 children from 80 families with the nephrotic syndrome manifesting in the first year of life, 85 percent of families with a disease onset before three months of age were found to have a known FSGS mutation, compared with 44 percent of families with a disease onset between 4 and 12 months of age [5].
Familial disease may account for a significant proportion of patients with glucocorticoid-resistant FSGS, particularly children [6,7]. In a large cohort study from the steroid-resistant nephrotic syndrome (SRNS) study group, 2016 patients from 1783 unrelated families were screened for mutations in 27 genes associated with glucocorticoid-resistant FSGS [2]. Mutations were found in 50 percent of infantile-onset cases (age 4 to 12 months), 25 percent of early childhood-onset cases (age 13 months to 6 years), 18 percent of late childhood-onset cases (age 6 to 12 years), and 11 percent of adolescent-onset cases (age 13 to 18 years). A monogenic form of FSGS accounted for 21 percent of the patients with SRNS with onset between 19 and 25 years of age.
The prevalence of genetic adult-onset FSGS is difficult to infer due to the paucity of large studies in this population [8]. Patients with adult-onset genetic FSGS without a known family history of kidney disease have been described, and the lack of family history may be due to the fact that many of the mutations associated with FSGS have an incomplete penetrance [9,10]. In one study of 193 adults with FSGS (43 with familial FSGS, 150 with sporadic FSGS), genetic testing by whole-exome sequencing yielded a diagnosis of genetic FSGS in 28 percent of patients with familial disease and 8 percent of those with sporadic disease, for an overall genetic diagnostic rate of 11 percent [10]. However, the prevalence of genetic FSGS in this cohort may be an underestimate of the actual prevalence among adults with FSGS. Among the 82 patients who were treated with immunosuppression and for whom treatment response was known, 45 and 29 percent achieved a partial or complete remission, respectively; none of the patients with a genetic mutation achieved complete remissions. These findings suggest that the study population may have included a significant proportion of patients with primary FSGS who would not be expected to have a genetic mutation. Another study in 24 adults with a high likelihood of having genetic FSGS identified a disease-causing variant in 7 (29 percent) [11].
CLINICAL PRESENTATION — Genetic forms of FSGS presenting in infancy or childhood typically present with full nephrotic syndrome and widespread foot process effacement on electron microscopy (EM). However, the clinical and histologic phenotype of adult-onset genetic FSGS is widely variable and rarely specific, with the same mutations showing different morphologic features on both light microscopy (LM) and EM [9]. These issues, as well as clinical features associated with specific FSGS gene mutations, are discussed in more detail elsewhere:
●(See "Focal segmental glomerulosclerosis: Clinical features and diagnosis", section on 'Pathology'.)
●(See 'Genes known to cause FSGS' below.)
●(See "Steroid-resistant nephrotic syndrome in children: Etiology", section on 'Genetic variants'.)
Findings suggestive, but not diagnostic, of familial FSGS include a family history of FSGS and disease onset in infancy or early childhood [12]. Thus, a detailed family history is of paramount importance in the evaluation of such patients.
Glucocorticoid resistance is a consistent finding in patients with genetic FSGS [13-16].
●(See "Steroid-resistant nephrotic syndrome in children: Etiology".)
GENETIC TESTING FOR FSGS
Indications for genetic testing — The decision to obtain genetic testing depends upon the clinical presentation of the patient and the genetic architecture of disease in the population where the clinician is practicing. Commercial tests are available to detect mutations in over 80 FSGS genes or to sequence the entire genome (whole-genome sequencing) or entire coding regions (whole-exome sequencing). The use of genetic testing in the evaluation of adult patients presenting with a documented FSGS lesion on kidney biopsy and pediatric patients with glucocorticoid-resistant idiopathic nephrotic syndrome is discussed separately. (See "Focal segmental glomerulosclerosis: Clinical features and diagnosis", section on 'Differentiating between primary, secondary, and genetic FSGS' and "Steroid-resistant nephrotic syndrome in children: Management", section on 'Genetic testing'.)
While one can make a case for more permissive testing in regions of the world where consanguinity is high or in regions of the world where there is a particular founder mutation, the same approach will not apply to the outbred population where the prevalence of mutation is likely to be low. In general, the likelihood of positive genetic testing is high in the following groups of patients:
●Pediatric patients with therapy-resistant FSGS.
●Adult and pediatric patients with a documented FSGS lesion and a family history of chronic kidney disease (especially with proteinuria and/or hematuria). The pattern of inheritance (eg, autosomal dominant, autosomal recessive, X-linked, matrilineal) may help to guide genetic testing.
●Patients with a documented FSGS lesion and a syndromic presentation (eg, skin lesions, deafness, neurologic abnormalities, ocular abnormalities, skeletal abnormalities, maturity onset diabetes of the young, hepatosplenomegaly, metabolic acidosis).
●Patients with FSGS of undetermined cause in whom the clinical presentation and pathologic features are discordant (eg, absence of nephrotic syndrome but widespread foot process effacement on electron microscopy [EM]) [17].
Proper selection of patients appears to increase the rate of positive genetic testing. In a study of 49 patients aged 18 years and older with an FSGS lesion on kidney biopsy, the overall rate of detection of a monogenic cause was 43 percent [17]. Individuals with FSGS of undetermined cause had the highest positive test rate (88 percent), followed by those with secondary FSGS without an identifiable cause (62 percent) and those with secondary FSGS with a known cause (33 percent). Univariate analysis showed that family history of kidney disease (odds ratio [OR] 13.8), absence of nephrotic syndrome (OR 8.2), and female sex (OR 5.1) were strong predictors of finding a causative genetic variant in the entire cohort. Most individuals with FSGS of undetermined cause in whom the clinical presentation and pathologic features were discordant (eg, absence of nephrotic syndrome but widespread foot process effacement on EM, or nephrotic syndrome with segmental foot process effacement) had a genetic diagnosis.
Methods for genetic testing — The most common genetic testing methods used by clinicians and commercial laboratories are direct (Sanger) sequencing and targeted sequencing by NGS. As there are more than 80 known FSGS genes, targeted NGS is likely to be more practical and comprehensive. In areas where there is a founder effect for a particular mutation (eg, NPHS2 in Europe), some clinicians will screen for mutations in these particular genes first before screening for mutations in the entire panel. Some commercial entities are now offering clinical WES for the diagnosis of genetic FSGS. The exome is the coding region of the genome, and it accounts for only 1 percent of the entire human genome. The advantage of WES is that it is all inclusive and mutations may be detected in both candidate and novel genes. However, WES is more expensive than targeted sequencing, and it is more likely to identify multiple variants of unknown significance, especially in the absence of an informative pedigree.
CLINICAL IMPLICATIONS OF GENETIC FSGS — The identification of a causal mutation in a patient with FSGS will help to establish a firm diagnosis and should inform the approach to therapy and plans for future kidney transplantation. It should be noted, however, that a negative result on genetic testing (no mutation) does not completely rule out genetic FSGS, as the patient may have a mutation in a yet-to-be-discovered novel gene. In general, identification of a genetic cause of FSGS should lead to:
●Extensive discussion with the patient's family that immunosuppression is generally not indicated given the low likelihood of response to this therapy, and the use of such agents is not justified. Exceptions include cases with mutations in WT1, TRPC6, PLCE1, MAGIC2, TNS2, DLC1, CKD20, ITSN1, and ITSN2 genes that may respond to immunosuppression [18-20].
•(See "Focal segmental glomerulosclerosis: Treatment and prognosis".)
•(See "Treatment of idiopathic nephrotic syndrome in children", section on 'Initial therapy'.)
●Low threshold for discontinuing immunosuppression if the patient has already been started on immunosuppressive therapy and is not responding to treatment. As an example, therapy could be discontinued in an adult patient who has been unresponsive to treatment with glucocorticoids for six weeks. The same approach should be applied to calcineurin inhibitors and other immunosuppressive agents.
●Identification of targeted therapies based on the type of mutations. It is known, for example, that some patients with mutations in COQ6, COQ2, and COQ8B may respond to CoQ10 replacement therapy [21-23]. (See "Steroid-resistant nephrotic syndrome in children: Etiology", section on 'Specific gene variants'.)
●Prediction of posttransplant disease recurrence. As an example, the risk of FSGS recurrence in patients with primary FSGS is approximately 30 to 70 percent, depending upon how cases are selected, compared with 0 to 8 percent in patients with genetic FSGS [24-26]. The mechanisms underlying posttransplant recurrence of genetic FSGS are not well defined. Circulating anti-nephrin antibodies may play a pathogenic role in the development of recurrent FSGS in patients with mutations in NPHS1 but not NPHS2 [14,27-29]. (See "Kidney transplantation in adults: Focal segmental glomerulosclerosis in the transplanted kidney", section on 'Pathogenesis'.)
GENES KNOWN TO CAUSE FSGS — A number of genetic forms of FSGS have been described [10,12,30-38] and may account for a significant proportion of patients with glucocorticoid-resistant disease (table 1) [15,39]. In general, the genes involved encode for proteins that are integral for proper function of the components of the glomerular filtration barrier (podocytes, glomerular basement membrane [GBM], and the fenestrated capillary endothelium).
●(See "Biology of glomerular podocytes".)
●(See "Steroid-resistant nephrotic syndrome in children: Etiology".)
The majority of the genetic causes of FSGS in children follow an autosomal recessive pattern of inheritance and manifest in the first year of life, with mutations in the genes for nephrin (NPHS1), podocin (NPHS2), and phospholipase C epsilon 1 (PLCE1) being the most common. Autosomal recessive disease is usually completely penetrant with only very rare cases of asymptomatic individuals.
Autosomal dominant causes of FSGS are more common in older children, adolescents, and adults. The most common single-gene cause of autosomal dominant FSGS is a mutation in the gene inverted formin, FH2 and WH2 domain containing (INF2), which is responsible for 12 to 17 percent of all cases of autosomal dominant FSGS [6,7,40,41]. Other major genes implicated in autosomal dominant FSGS include actinin alpha 4 (ACTN4), TRPC6, WT1, and LMX1B [5,42].
Unlike autosomal recessive disease, autosomal dominant disease may be incompletely penetrant, and it is not unusual to have family members with a mutation but no disease phenotype. Thus, kidney transplantation from family members should be handled cautiously, and there is a strong case for screening for the mutation found in the patient before accepting family members as kidney donors.
Although a matrilineal inheritance pattern of FSGS suggests a mitochondrial gene mutation (which will not be detected by genomic analysis), the trait can also be inherited from the maternal side in an X-linked or autosomal dominant fashion.
NPHS1 gene — Mutations in the gene for nephrin, called NPHS1, cause congenital nephrotic syndrome of Finnish type. (See "Congenital nephrotic syndrome", section on 'Congenital Nephrotic Syndrome of Finnish type'.)
NPHS1 mutations have also been identified in older children with steroid-resistant nephrotic syndrome (SRNS) [43,44] and in at least one adult who presented with FSGS at age 27 years [44]. This patient was identified as part of a study in which 97 patients from 89 unrelated families with SRNS 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 eight months, one year, six years, and seven years; two of the children were from the same family. The detection rate of NPHS1 mutations was 38 percent (5 of 13) among familial cases 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 [36,45]. 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). (See "Congenital nephrotic syndrome", section on 'Congenital Nephrotic Syndrome and NPHS2 variants'.)
However, some affected patients have milder disease and present in adolescence or young adulthood; this is found usually in patients with some hypomorphic mutations and also in the common R229Q variants inherited in combination with trans-associated mutation in the N-terminal region of the gene [46]. 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 nonfamilial or sporadic, primary FSGS [47]. Mutations in NPHS2 cosegregated with the disease in nine families, while no likely disease-causing mutations were observed in 21. In addition, mutations in both NPHS2 alleles have been described in approximately 10 to 25 percent of cases of apparently sporadic, glucocorticoid-resistant FSGS in children from Europe and the Middle East. (See "Treatment of idiopathic nephrotic syndrome in children".)
Although one might expect that patients with NPHS2 mutations would not develop recurrent disease in the transplant, recurrence has been described [14,28]. (See "Kidney transplantation in adults: Focal segmental glomerulosclerosis in the transplanted kidney".)
ACTN4 gene — Mutations in the actinin alpha 4 gene (ACTN4) on chromosome 19q13 are associated with an autosomal dominant form of the disease [34,48]. The mutant form of actinin alpha 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 actinin alpha 4 gene may be associated with unique ultrastructural features on kidney biopsy. In one study of five patients with actinin alpha 4 mutations, electron-dense podocyte aggregates were observed in all kidney biopsies, while a segmental and irregular immunofluorescent pattern for actinin alpha 4 was noted in the four biopsies available for staining [49]. These observations were not found in the biopsies from patients with FSGS not due to an abnormal actinin alpha 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 cation channel subfamily C member 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 [50].
These features pointed toward defects in the TRPC6 gene as a cause of familial FSGS. TRPC6 mutations have now been documented in individuals with both familial and nonfamilial FSGS [50-52]. In a study of 71 families with FSGS, mutations in the TRPC6 gene segregated with FSGS in five families with autosomal dominant disease [50]. Mutation analysis in 130 patients from 115 families identified TRPC6 mutations in two patients with nonfamilial FSGS and one with familial disease [52].
FSGS-associated TRPC6 mutations have been shown to constitutively activate the calcineurin-nuclear factor of activated T cells (NFAT) pathway, and this effect can be blocked by calcineurin inhibitors [53]. Additional studies are needed to investigate the role of calcineurin inhibitors in the treatment of TRPC6-associated FSGS.
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 [40]. 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 kidney disease [ESKD], 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 [41].
Patients with INF2-associated FSGS present at a later age (adolescence or early adulthood) compared with those who have FSGS caused by NPHS1 and NPHS2 mutations, who typically present at a very early age. (See 'NPHS1 gene' above and 'NPHS2 gene' above.)
Collagen type IV alpha 3, 4, and 5 genes — Mutations in the type IV collagen genes known to cause Alport syndrome and thin basement membrane nephropathy (COL4A3, COL4A4, and COL4A5) may be common in patients with familial or sporadic FSGS. Studies have reported prevalence rates of up to 38 percent and 3 percent among cohorts of patients with familial and sporadic FSGS, respectively [54-56].
Several studies have found that patients with FSGS associated with COL4A mutations frequently do not have clinical or histological features of Alport syndrome [54-57]. As examples:
●In one study of 70 families with a diagnosis of hereditary FSGS, seven (10 percent) were found to have novel variants in COL4A3 or COL4A4 [54]. The predominant clinical finding at the time of diagnosis was proteinuria associated with hematuria. All seven families had individuals with nephrotic-range proteinuria and histologic features of FSGS on kidney biopsy. Electron microscopy (EM) data, which were available for five of the seven families, revealed thin GBMs in only one family; four other families had variable findings that were not consistent with Alport syndrome.
●In another study, 81 patients with FSGS (12 with familial FSGS) were screened for mutations in 39 genes implicated in FSGS; pathogenic mutations were identified in 10 (12 percent) [55]. Eight patients were found to have disease-causing mutations in COL4A3, COL4A4, or COL4A5; only one patient was suspected to have Alport syndrome. All patients had nephrotic-range proteinuria, and one presented with nephrotic syndrome. Although microscopic hematuria was present in the majority (63 percent) of patients, only one patient had hearing loss at presentation. EM showed GBM thickening, fraying, and lamellation characteristic of Alport syndrome in only one patient.
●In a study of 193 adult patients with FSGS (43 with familial FSGS, 150 with sporadic FSGS) who underwent genetic testing by whole-exome sequencing, pathogenic variants in COL4A3, COL4A4, or COL4A5 were identified in 11 of 20 (55 percent) patients with a genetic cause of FSGS [10]. Among those with COL4A pathogenic variants, the mean age of disease onset was 36 years (range 29 to 42 years), and nearly one-half of the patients (46 percent) developed ESKD at a mean age of 58 years. Of the nine patients who had an available kidney biopsy, five had evidence of GBM abnormalities and all had >50 percent foot process effacement on EM.
These data support the need to include COL4A3, COL4A4, and COL4A5 in genetic testing panels for FSGS. Patients with COL4A mutations associated with FSGS may not be clinically suspected of having Alport syndrome and, therefore, are unlikely to otherwise be screened for COL4A mutations. It is unclear if these cases represent phenocopy (ie, an individual displays features characteristic of a genotype other than its own that are produced by environmental rather than genetic factors) or true podocytopathy. One study found that FSGS was the most common misdiagnosis in female patients with X-linked Alport syndrome [58].
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 [59]. Although mutations in LMX1B are usually associated with nail-patella syndrome, some produce FSGS without any apparent extrarenal manifestations [60]. (See "Nail-patella syndrome", section on 'Pathogenesis and LMX1B gene mutations'.)
Other genetic disorders are also associated with FSGS on kidney biopsy as well as other renal and/or extrarenal lesions. These include Fabry disease, Alport syndrome, 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:
●(See "Fabry disease: Clinical features and diagnosis".)
●(See "Genetics, pathogenesis, and pathology of Alport syndrome (hereditary nephritis)".)
●(See "Cystinosis".)
●(See "Nail-patella syndrome".)
●(See "Causes of differences of sex development", section on 'Global defects in testicular function'.)
FSGS IN BLACK PATIENTS — The relative frequency of the different causes of nephrotic proteinuria varies with race, with the largest difference between Black patients and White patients being the frequency of FSGS. (See "Glomerular disease: Evaluation and differential diagnosis in adults".)
Among patients with nephrotic proteinuria, two studies from the United States found that Black patients had a higher prevalence of FSGS than White patients, an effect that may be increasing over time. The following observations were noted:
●In a series of 358 adults who underwent kidney 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 patients compared with White patients in both time periods and increased to a similar degree in both Black patients and White patients from the earlier to the later time period [61]. 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 kidney biopsy (mean age 43 years) for nephrotic-range proteinuria over a 20-year period from 1975 to 1994, FSGS accounted for 57 percent of cases in Black patients and 23 percent in White patients [62]. Furthermore, the prevalence of FSGS in Black patients increased significantly from 39 percent in 1975 to 1984 to 64 percent in 1985 to 1994. The distribution did not vary with sex or age.
None of the above series described biopsy findings in Black patients who had proteinuria <3.5 g/24 hours or absence of nephrotic syndrome. Similarly, electron microscopy (EM) findings were not reported.
Black patients 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]) [63]. In addition, Black patients with this disorder have an increased incidence of a family history of end-stage kidney disease (ESKD). 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 kidney disease [64]. The patients with FSGS had a much higher percentage of first- and second-degree relatives with ESKD (24 versus 6 percent). (See "HIV-associated nephropathy (HIVAN)".)
The kidney disease in Black patients with nephrotic syndrome and FSGS is clinically and histologically distinct from the kidney disease in the great majority of hypertensive Black patients who have subnephrotic proteinuria and focal global glomerulosclerosis (FGGS) rather than focal segmental glomerulosclerosis (FSGS) [65,66]. In patients with FGGS, EM often reveals only segmental foot process effacement, in contrast with the widespread foot process effacement seen in Black patients with HIV-associated collapsing FSGS.
APOL1 — The increased susceptibility of Black patients 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 associated with an increased risk of developing FSGS [67-69].
Variants in the apolipoprotein L1 (APOL1) gene, which resides on chromosome 22, have been shown to be closely associated with nondiabetic nephropathy in Black patients [70,71]. Polymorphisms in APOL1 appear to be expressed almost exclusively in individuals of African descent but have been less commonly identified in other populations [70,72].
APOL1 polymorphisms are associated with FSGS in Black patients:
●An analysis that compared Black patients with nonfamilial biopsy-proven FSGS to Black patients without FSGS identified two APOL1 variants that are expressed more frequently in patients with FSGS [70]. The association of APOL1 variants with kidney disease was confirmed in a second, larger cohort of Black patients with hypertension-associated ESKD [70].
●APOL1 genotypes were compared among 271 cases of FSGS among Black patients, 168 cases of FSGS among European American patients, and 939 control subjects [73]. APOL1 variants conferred 17-fold higher odds (95% CI 11-26) for FSGS and 29-fold 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 ESKD but a similar sensitivity to glucocorticoids compared with other subjects [74]. Positive selective forces likely underlie this linkage disequilibrium, suggesting that a biological advantage is conferred by the inheritance of these variants [75]. 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 [70]. (See "Human African trypanosomiasis: Epidemiology, clinical manifestations, and diagnosis", section on 'Innate immunity'.)
The association between APOL1 genotype and risk of kidney disease may be influenced by additional factors. As an example, the decline in kidney function attributed to APOL1 risk variants has been shown to be dependent upon plasma levels of the soluble urokinase plasminogen activator receptor (suPAR). In a study involving two independent cohorts of Black individuals (1094 patients), higher baseline suPAR levels were associated with a greater annual decline in estimated glomerular filtration rate (eGFR) among patients with two APOL1 risk alleles compared with those with one or no alleles [76]. This association may be explained by high-affinity protein-protein interactions between suPAR, ApoL1, and alpha v beta 3 integrin, whereby the ApoL1 protein variants G1 and G2 exhibit higher affinity for suPAR-activated alpha v beta 3 integrin than ApoL1 G0. In addition, ApoL1 G1 or G2 augment alpha v beta 3 integrin activation and cause proteinuria in mice in a suPAR-dependent manner. (See "Focal segmental glomerulosclerosis: Pathogenesis", section on 'suPAR'.)
Screening for APOL1 risk alleles in Black patients with FSGS lesions can confirm the association. Some experts advocate for universal screening of individuals of African ancestry with FSGS given that a clinical trial evaluating targeted therapy for APOL1-associated kidney disease is in progress [77,78]. (See "Focal segmental glomerulosclerosis: Treatment and prognosis", section on 'Investigational therapies'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults".)
SUMMARY AND RECOMMENDATIONS
●Overview – Focal segmental glomerulosclerosis (FSGS) can be caused by a number of genetic mutations in genes that encode for proteins expressed mainly in the podocytes and their slit diaphragm and also in other components of the glomerular filtration barrier such as the glomerular basement membrane (GBM). (See 'Introduction' above.)
●Epidemiology – The prevalence of genetic FSGS varies widely depending upon the population being studied. In regions of the world where consanguinity is prevalent, for example, the prevalence of genetic FSGS among all patients with FSGS may be as high as 30 percent, whereas in the outbred population, the prevalence may be as low as <5 percent. (See 'Epidemiology of genetic FSGS' above.)
●Clinical presentation – Genetic forms of FSGS presenting in infancy or childhood typically present with full nephrotic syndrome and widespread foot process effacement on electron microscopy (EM). However, the clinical and histologic phenotype of adult-onset genetic FSGS is widely variable and rarely specific, with the same mutations showing different morphologic features on both light microscopy (LM) and EM. (See 'Clinical presentation' above.)
●Indications for genetic testing – The decision to obtain genetic testing depends upon the clinical presentation of the patient and the genetic architecture of disease in the population where the clinician is practicing. The use of genetic testing in the evaluation of adult patients presenting with a documented FSGS lesion on kidney biopsy and pediatric patients with glucocorticoid-resistant idiopathic nephrotic syndrome is discussed separately. (See "Focal segmental glomerulosclerosis: Clinical features and diagnosis", section on 'Differentiating between primary, secondary, and genetic FSGS' and "Steroid-resistant nephrotic syndrome in children: Management", section on 'Genetic testing'.)
●Genes known to cause FSGS – The majority of the genetic causes of FSGS in children follow an autosomal recessive pattern of inheritance and manifest in the first year of life, with mutations in the genes for nephrin (NPHS1), podocin (NPHS2), and phospholipase C epsilon 1 (PLCE1) being the most common. Autosomal recessive disease is usually completely penetrant with only very rare cases of asymptomatic individuals.
Autosomal dominant causes of FSGS are more common in older children, adolescents, and adults. The most common single-gene cause of autosomal dominant FSGS is a mutation in the gene inverted formin, FH2 and WH2 domain containing (INF2). Other major genes implicated in autosomal dominant FSGS include actinin alpha 4 (ACTN4), TRPC6, WT1, and LMX1B.
Collagen type IV alpha 3, 4, and 5 gene mutations are increasingly recognized as the most common genetic causes of FSGS in adults. (See 'Genes known to cause FSGS' above.)
●FSGS in Black patients – The increased susceptibility of Black patients 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 Black patients. Polymorphisms in APOL1 appear to be expressed exclusively in individuals of African descent but have been less commonly identified in other populations. (See 'FSGS in Black patients' above.)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
