Focal Segmental Glomerulosclerosis

Louis-Philippe Laurin

Laura H. Mariani

INTRODUCTION

Focal segmental glomerulosclerosis (FSGS) is a major cause of glomerular disease worldwide. It represents a histologic pattern of kidney injury rather than a pathophysiologic process.¹ FSGS is characterized by a segmental obliteration of glomerular capillaries by the extracellular matrix. Entrapment of plasma proteins as hyalinosis frequently accompanies sclerosis.² The presence of sclerosis is found in parts (segmental) of some (focal) glomeruli.

This histologic pattern of podocyte injury is nonspecific and can result from a number of underlying biologic processes. FSGS lesions on light microscopy can be categorized into four broad categories (Table 6.1).¹,³ Primary FSGS has been attributed to a yet unidentified circulating permeability factor. Genetic FSGS is the result of mutations that are often in specific podocyte genes coding for structural components of the glomerulus.⁴ FSGS can be secondary to an adaptative response to glomerular hypertension, as seen in conditions with reduced kidney mass.⁵ FSGS may also be secondary to drug exposures (eg, heroin, pamidronate, lithium), viral infections (eg, HIV, CMV), or various inflammatory processes (eg, Still disease, natural killer cell leukemia). In patients with no evidence of a secondary cause, segmental foot process effacement, and absence of nephrotic syndrome, FSGS can be classified as FSGS-UC (for undetermined cause) as suggested by the recently published Kidney Disease: Improving Global Outcomes (KDIGO) 2021 Clinical Practice Guideline for the Management of Glomerular Diseases.⁶

The estimated incidence of FSGS has been reported to vary from 1.4 to 21 cases per million population, denoting important geographical and racial differences.⁷ In the United States, the incidence of FSGS is approximately 5 times higher in patients of sub-Saharan African ancestry compared to White patients.⁸ There has been an increased number of patients with FSGS over the last decades, which makes FSGS the most frequent primary glomerulopathy reaching end-stage kidney disease (ESKD).⁹

PATHOGENESIS

FSGS comes from an injury to the podocyte from various etiology. Although the pathophysiology of primary FSGS remains poorly understood, this subgroup is believed to be an immunologically mediated disease. The additional sources of podocyte injury are diverse (ie, genetic abnormalities, viral infection, and medication), but the consequences on the podocytes are almost indistinguishable from a histopathologic standpoint. Podocyte depletion appears to have a central role in the initiation of glomerulosclerosis in many glomerular diseases, especially in

FSGS.¹⁰ Aside from genetic testing, no biomarkers are currently available to distinguish between these underlying causes of the FSGS lesion.

TABLE 6.1 Characteristics of the Main Forms of FSGS

			Secondary FSGS
	Primary FSGS	Genetic FSGS	Adaptative FSGS	Drug-Induced FSGS	Infection-Associated FSGS	FSGS of Undetermined Cause (FSGS-UC)
Mechanism	Yet unidentified circulating permeability factor	Mutations in genes encoding structural podocyte proteins.	Imbalance between glomerular load and capacity; glomerular hypertension	Direct injury to podocyte	Direct podocyte infection or by inflammatory cytokines	Undetermined
Clinical history	Acute-onset nephrotic syndrome	Possible family history of chronic kidney disease/FSGS. Consanguinity. Higher prevalence in patients of African Ancestry for APOL1 risk variants	Reduced nephron number: vesicoureteral reflux, low-birth weight, kidney dysplasia, sickle cell disease Normal nephron number: obesity, primary glomerular disease, systemic conditions (diabetic nephropathy, hypertensive nephrosclerosis)	Use of pamidronate, lithium, anabolic steroids, intravenous heroin, direct-acting antiviral therapy, mTOR inhibitors, CNIs, anthracyclines, interferon, NSAIDs	Positive serology for HIV, CMV, parvovirus B19, EBV, HCV Hemophagocytic syndrome SARS-CoV-2 (with APOL1 risk genotype)	No evidence of secondary cause
Clinical and laboratory findings	Nephrotic syndrome with high-degree proteinuria. Acute kidney injury (acute tubular necrosis) with severe proteinuria. Hematuria is common.	Severe nephrotic syndrome with childhood-onset genetic FSGS. Slowly progressive kidney disease with variable degree of proteinuria in adult-onset genetic FSGS	Variable degree of proteinuria, often slowly increasing. Albuminemia usually normal with no peripheral edema, even in patients with nephrotic-range proteinuria. Slowly decreasing kidney function over time	Variable degree of proteinuria. May present with nephrotic syndrome if associated with pamidronate	Variable degree of proteinuria. May present with nephrotic syndrome in collapsing HIV-associated nephropathy	Proteinuria without nephrotic syndrome
Kidney biopsy pathology	≥80% podocyte foot process effacement	Variable. Collapsing variant is common for APOL1 risk genotype.	<80% podocyte foot process effacement	Findings similar to adaptative FSGS	Collapsing variant is frequent in HIV	Segmental foot process effacement
Therapy	Immunosuppression	No response to immunosuppression. Decrease in proteinuria may be observed with CNIs.	Treat the underlying condition, eg, obesity. Blockers of the angiotensin II system	Stop causal drug	Treat the underlying infection	Supportive therapy
APOL1, apolipoprotein L1; CMV, cytomegalovirus; CNI, calcineurin inhibitor; EBV, Epstein-Barr virus; FSGS, focal segmental glomerulosclerosis; HCV, hepatitis C virus; HIV, human immunodeficiency virus; mTOR, mammalian target of rapamycin; NSAID, nonsteroidal anti-inflammatory drug; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Data from KDIGO 2021 Clinical Practice Guideline for the management of Glomerular Diseases.

The pathogenesis of FSGS is complex and implies genetic and epigenetic factors as well as the effect of presumed circulating factors and other insults.¹¹ The hypothesis postulating that primary FSGS is caused by a circulating factor comes from its rapid recurrence after kidney transplantation in 30% to 40% of patients.¹² In fact, the only form of FSGS that can be linked to a circulating permeability factor is FSGS which recurs rapidly after kidney transplantation and responds to plasmapheresis. Several candidates have been proposed as the putative factor, but none have been proved to cause FSGS in humans yet.¹¹ It has also been suggested that the local microenvironment may influence the FSGS progression, and a crosstalk between the podocytes and parietal epithelial cells, and between glomerular endothelial cells and tubular epithelial cells is involved.¹¹

Histopathology

Although the hallmark of this diagnosis is the segmental lesion, there is considerable variability in the appearance of the individual lesions across the biopsy and between patients, again highlighting the likely biologic heterogeneity underlying FSGS. Five histologic subtypes of the FSGS lesion (Figure 6.1) have traditionally been described by the Columbia classification of FSGS: collapsing variant, tip lesion, cellular variant, perihilar variant, and not-otherwise-specified (NOS).⁵ These variants may differ in their demographic and epidemiologic characteristics, clinical presentation, clinical course, and prognosis, especially when comparing tip lesion, which is thought to be more responsive to therapy, to the collapsing variant.¹³ There is evidence of heterogeneity in glomerular epithelial cell phenotype between different FSGS variants. Certain variants have been associated with a secondary form of FSGS. However, evidence supporting the predictive value of histopathologic classification to distinguish between the primary and secondary forms of FSGS has been conflicting.¹³,¹⁴,¹⁵

The collapsing variant is characterized by segmental global mesangial consolidation and loss of endocapillary patency in association with extracapillary epithelial hypertrophy and/or proliferation.

The tip lesion variant is characterized by at least one segmental lesion involving the tip domain, the portion of the glomerular tuft juxtaposed to the tubular pole, with adhesion or confluence of podocytes with parietal of tubular cells at the tubular lumen or neck.

The cellular lesion shows podocyte hyperplasia, endocapillary proliferation occluding lumens with or without foam cells and karyorrhexis. This FSGS subtype is the least common variant.

The perihilar variant shows segmental sclerosis and segmental obliteration of capillary loops with matrix increase near the hilum. Perihilar FSGS is a typical injury associated with obesity and reduced kidney mass.

The NOS variant is also determined by segmental sclerosis not meeting the definition of other variants. It is the most common FSGS subtype and can be seen in both primary and secondary FSGS.

CLINICAL FINDINGS

The natural course of disease progression in patients with FSGS varies with the underlying etiology. The severity of proteinuria (determined by urine protein-to-creatinine ratio or 24-hour urine collection) and hypoalbuminemia
can provide insights into the presumed cause (Figure 6.2). High-grade proteinuria and severe hypoalbuminemia are typically associated with primary FSGS. Other causes of FSGS can present with variable levels of proteinuria, usually slowly increasing over time.

FIGURE 6.1: Light microscopy findings of FSGS lesion: A, Collapsing variant (periodic acid-Schiff, original magnification × 400). B, Tip variant (periodic acid-Schiff, original magnification × 400). C, Perihilar variant (periodic acid-Schiff, original magnification × 400). D, NOS (periodic acid-Schiff, original magnification × 200). FSGS, focal segmental glomerulosclerosis; NOS, not-otherwise-specified. (Images courtesy of Dr. Virginie Royal, Department of Pathology, Hôpital Maisonneuve-Rosemont, Université de Montréal, Montréal, Québec, Canada.)

Primary FSGS is characterized by sudden-onset nephrotic syndrome with heavy proteinuria. It is the most common cause of nephrotic syndrome in adults, representing 40% of cases, and the second most common cause in children.¹⁶ Its kidney pathology shows widespread foot process effacement.

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