Differentiating Primary, Genetic, and Secondary FSGS in Adults: A Clinicopathologic Approach

Abstract

FSGS describes a renal histologic lesion with diverse causes and pathogenicities that are linked by podocyte injury and depletion. Subclasses of FSGS include primary, genetic, and secondary forms, the latter comprising maladaptive, viral, and drug-induced FSGS. Despite sharing certain clinical and histologic features, these subclasses differ noticeably in management and prognosis. Without an accepted nongenetic biomarker that discriminates among these FSGS types, classification of patients is often challenging. This review summarizes the clinical and histologic features, including the onset and severity of proteinuria as well as the presence of nephrotic syndrome, that may aid in identifying the specific FSGS subtype. The FSGS lesion is characterized by segmental sclerosis and must be differentiated from nonspecific focal global glomerulosclerosis. No light microscopic features are pathognomonic for a particular FSGS subcategory. The characteristics of podocyte foot process effacement on electron microscopy, while helpful in discriminating between primary and maladaptive FSGS, may be of little utility in detecting genetic forms of FSGS. When FSGS cannot be classified by clinicopathologic assessment, genetic analysis should be offered. Next generation DNA sequencing enables cost-effective screening of multiple genes simultaneously, but determining the pathogenicity of a detected genetic variant may be challenging. A more systematic evaluation of patients, as suggested herein, will likely improve therapeutic outcomes and the design of future trials in FSGS.

Focal segmental glomerulosclerosis associated with acute cytomegalovirus infection in a renal transplant

“…A recent review has also listed parvovirus B19, EBV, and hepatitis C virus as “possible” causes of FSGS and CMV as a “probable” cause. Direct infection of podocytes by a virus leads to disruption of the cellular phenotype and subsequent apoptosis culminating in changes of FSGS …”

“…FSGS is well described to occur in the setting of reduced functioning nephron numbers, or when abnormal stress is placed on a normal nephron population; however, the resultant foot process effacement has been demonstrated to develop in a slow and heterogenous fashion. FSGS has also been reported to occur secondary to certain medications, such as the previously mentioned mTOR inhibitors, as well as some direct‐acting antiviral agents, lithium, interferon, calcineurin inhibitors, anthracyclines, and anabolic steroids, none of which were administered to our patient …”

“…FSGS has also been reported to occur secondary to certain medications, such as the previously mentioned mTOR inhibitors, as well as some direct-acting antiviral agents, lithium, interferon, calcineurin inhibitors, anthracyclines, and anabolic steroids, none of which were administered to our patient. 14…”

An audit of electron microscopy in the diagnosis of focal segmental glomerulosclerosis – are current pathological techniques missing important abnormalities in the glomerular basement membrane?

“…secondary, or genetic form. Primary FSGS is thought to be largely immunological in nature perhaps driven by an elusive permeability factor and secondary FSGS caused by compensatory hyperfilitration due to a previous glomerular injury (2). In recent years there has been a greater appreciation of the contribution of underlying genetic causes of this histological pattern.…”

Disease Progression and End-Stage Renal Disease in Diverse Glomerulopathies

“…5,6 FSGS is a histologic lesion that may reflect 1 of 3 main mechanisms: (1) primary FSGS that is caused by an immunologic/cytotoxic process that targets the podocyte and is commonly associated with the nephrotic syndrome and progressive loss of renal function; (2) secondary FSGS that is caused by assorted diseases (eg, obesity, druginduced, and reflux nephropathy) in which proteinuria is often subnephrotic and renal functional decline slower than in primary FSGS; and (3) FSGS that is secondary to genetic defects. 5,6 It would be of interest to determine what percentage of patients with FSGS were represented by each of these subtypes, in particular, by primary FSGS, in view of the higher risk of this subtype to progress to ESRD; notably, proteinuria in patients with FSGS studied by Sim et al 2 ranged from subnephrotic levels to massive proteinuria. As regards the issue of heterogeneity within a specific glomerulopathy, this is perhaps best illustrated by LN, 1 of the 5 glomerulopathies studied by Sim et al 2 ; there are 6 distinct classes of LN, 1 of which is MN, a glomerulopathy also numbering among the 5 analyzed in this study.…”