Clinical and pathological phenotype of genetic causes of focal segmental glomerulosclerosis in adults

Abstract

Focal segmental glomerulosclerosis (FSGS) is a histologic lesion resulting from a variety of pathogenic processes that cause injury to the podocytes. Recently, mutations in more than 50 genes expressed in podocyte or glomerular basement membrane were identified as causing genetic forms of FSGS, the majority of which are characterized by onset in childhood. The prevalence of adult-onset genetic FSGS is likely to be underestimated and its clinical and histological features have not been clearly described. A small number of studies of adult-onset genetic FSGS showed that there is heterogeneity in clinical and histological findings, with a presentation ranging from sub-nephrotic proteinuria to full nephrotic syndrome. A careful evaluation of adult-onset FSGS that do not have typical features of primary or secondary FSGS (familial cases, resistance to immunosuppression and absence of evident cause of secondary FSGS) should include a genetic evaluation. Indeed, recognizing genetic forms of adult-onset FSGS is of the utmost importance, given that this diagnosis will have major implications on treatment strategies, selecting of living-related kidney donor and renal transplantation success.

Keywords: genetic FSGS; nephrotic syndrome; podocin; podocytopathies; steroid-resistant nephrotic syndrome.

Fig. 1.

(A, B) Focal segmental glomerulosclerosis; 22 year old Caucasian woman with a clinical picture of NS (24 h urine protein 5.8 g, serum albumin 3.3 g/dL) and impaired renal function (serum creatinine 1.5 mg/dL). Genetic analysis showed compound heterozygous mutation in the NPHS2 gene (see Table 3, patient 1). (A) Light microscopy showing segmental sclerosis (see black arrow). (B) EM showing diffuse foot process effacement; white thick arrows point to areas of foot process effacement. (A, periodic acid–Schiff ×40, B ×3500). (C, D) Focal segmental glomerulosclerosis; 25 year old Caucasian man with normal renal function (serum creatinine 1.0 mg/dL), sub-nephrotic proteinuria (2 g/24 h) and normal serum albumin (4 g/dL). Genetic analysis showed heterozygous mutation in the PLCE1 gene (see Table 3, patient 2). (C) Light microscopy showing segmental sclerosis (see black arrow). (D) EM showing only minimal foot process effacement; thick black arrows point to preserved foot processes (C, periodic acid–Schiff ×40, D, ×6000).

Fig. 2.

The figure shows EM from two siblings with genetic FSGS who share the same genotype (compound heterozygous R229Q + p.R286fs in the NPHS2 gene). (A, B) Focal segmental glomerulosclerosis; 58 year old Caucasian man with normal renal function (serum creatinine 1.1 mg/dL) and NS (urine protein 4.8 g/24 h, serum albumin 3.4 g/dL). EM shows diffuse foot process effacement, involving more than 80% of capillary loops; thin black arrows point to foot process effacement. See Table 3 for clinical information (patient 3) (A, ×6000 and B, ×5000). (C, D) Focal segmental glomerulosclerosis; 47 year old Caucasian woman with normal renal function (serum creatinine 0.8 mg/dL), sub-nephrotic proteinuria (2.7 g/24 h) and normal albumin (4.0 g/dL). EM shows segmental podocyte foot processes; thin black arrows point to foot process effacement and thick black arrow points to preserved foot processes. See Table 3 for clinical information (patient 4) (C, ×2900 and D, ×4800).

Fig. 3.

Focal global glomerulosclerosis; 32 year old Caucasian man with nephrotic-range proteinuria (7 g/day), normal serum albumin (4 g/dL) and normal renal function (creatinine clearance 90 mL/min). Genetic tests revealed heterozygous mutation R213H on exon 4 of the INF2 gene (see Table 3, patient 5). (A, B) Light microscopy showing mild focal global glomerulosclerosis (silver methenamine A, ×20, B, ×40). (C, D) EM showing segmental foot process effacement; black arrow points to segmental foot process effacement (C, ×3500 and D, ×6000).

Fig. 4.

Focal segmental glomerulosclerosis; 33 year old Caucasian man with impaired renal function (serum creatinine 1.8 mg/dL), nephrotic-range proteinuria (3.6 g/24 h) and normal albumin (4.3 g/dL). Genetic analysis showed heterozygosis in the COL4A3 gene for the variant c.4981C>T and heterozygous in the NPHS1 for a sequence variant designated c.133G>C. (A, B) Light microscopy showing segmental glomerulosclerosis sclerosis (thin black arrow: A, hematoxylin and eosin ×40 and B, periodic acid–Schiff ×40). (C, D) EM showing widespread foot process effacement; thick black arrow points to foot process effacement (C, D ×4500) (see Table 3, patient 6).