FSGS of Undetermined Cause (FSGS-UC)
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
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
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
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
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.