Focal Segmental Glomerulosclerosis
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Direct answer
Not one disease but a final common pathway of podocyte depletion: some glomeruli (focal), part of each tuft (segmental), scarred — hence focal segmental glomerulosclerosis. The Columbia classification splits it into five variants whose names carry prognosis directly: collapsing glomerulopathy is the worst, the tip lesion the best and the most steroid-responsive. The split that drives treatment, however, is primary versus secondary — a circulating permeability factor in primary disease answers to steroids and calcineurin inhibitors, while the maladaptive forms of obesity, reduced renal mass, reflux or sickle disease answer to none of them. Primary disease recurs in about a third of grafts, sometimes within hours of implantation, and that immediacy is the single most-tested fact in the whole chapter.
What you must remember
- Columbia variants: collapsing (worst prognosis, rapid function loss), cellular, tip (best prognosis, steroid-responsive like minimal change), perihilar (usually secondary maladaptive), and not otherwise specified.
- Collapsing associations: HIV-associated nephropathy, pamidronate, interferon and parvovirus — the variant that demands the infection and drug history.
- Secondary forms: obesity, reflux nephropathy, reduced renal mass, sickle cell disease, heroin and anabolic steroids; genetic disease — NPHS1, NPHS2 (podocin), TRPC6, INF2 — and APOL1 risk variants in African ancestry populations.
- Presentation contrast: unlike minimal change, expect hypertension, microscopic haematuria in a quarter to half, and a GFR already reduced at first visit.
- Primary disease therapy: a full sixteen-week steroid trial, then calcineurin inhibitors for resistant or dependent disease — response rates of roughly half, with relapse on withdrawal the rule rather than the exception.
- Natural history: untreated primary disease sends about half of patients to kidney failure within a decade; a partial or complete remission transforms that trajectory.
- Transplant recurrence: 30–40 per cent for primary disease, typically immediate proteinuria in the recovery room; plasmapheresis with or without rituximab is the rescue; genetic FSGS does not recur.
- suPAR: proposed circulating factor, unproven as a clinical test — quote it as history, not practice.
Reading the variant and the context together
Three patients, one biopsy phrase, three different conversations. A 28-year-old bodybuilder with anabolic steroid exposure and 6 g proteinuria: the first prescription is drug withdrawal, RAAS blockade and time, because secondary podocyte toxicities can remit when the trigger leaves. A 55-year-old with a body mass index of 36, a single kidney after a road accident decades ago, and 3.5 g proteinuria: this is maladaptive hyperfiltration disease — steroids are wasted, weight, blood pressure to below 130/80 and an SGLT2 inhibitor are the real therapy. A 24-year-old HIV-positive man with a creatinine of 3.8 and a biopsy showing collapsing lesions: the answer is antiretroviral therapy first, and the prognosis sentence must be honest. The fourth patient completes the set — a 40-year-old with primary FSGS, steroid-resistant after sixteen weeks, who goes on to ciclosporin, achieves partial remission, relapses off it, and finally receives a graft; nephrotic-range proteinuria on post-operative day two announces recurrence, plasma exchange begins that week, and the graft survives — the vignette that ties the whole topic together.
How the exam frames it
Two questions carry most of the marks. The immediate post-transplant proteinuria stem: nephrotic-range proteinuria within hours to days means recurrent FSGS until proven otherwise, and the answer is plasma exchange — the timing is the clue, since no other recurrent disease begins in the recovery room. The mislabelled adult stem: an obese patient with moderate proteinuria and a small biopsy sample labelled FSGS is plausibly secondary, and escalating immunosuppression is the wrong reflex. A quieter viva point distinguishes FSGS from minimal change on the presentation alone — hypertension, haematuria and impaired filtration at onset argue for segmental scarring before any biopsy is quoted — while the genetics question rewards knowing that podocin-related disease neither responds to steroids nor recurs after transplantation, because there is no circulating factor to transfer.
Frequently asked questions
Which Columbia variant carries the worst prognosis?
The collapsing variant — rapid progression, associations with HIV infection and specific drugs, and poor steroid responsiveness.
How long should a steroid trial run in primary FSGS?
Sixteen weeks at full dose in adults before declaring steroid resistance and moving to calcineurin inhibitors.
Why does genetic FSGS not recur after transplantation?
Recurrence implies a circulating permeability factor; inherited podocyte defects are intrinsic to the recipient's former kidneys and are not transferred with them.
How is recurrent FSGS in a graft treated?
Urgent plasma exchange, frequently combined with rituximab and intensification of immunosuppression — begun the moment early proteinuria appears.
What marks secondary rather than primary FSGS at the bedside?
Obesity, reduced renal mass, reflux, sickle disease, or drug exposure — with more gradual proteinuria and a response to treating the cause rather than immunosuppression.
What is the APOL1 connection?
Two APOL1 risk variants, common in African ancestry populations, strongly raise the risk of FSGS and of biopsy-proven non-diabetic kidney disease labelled "hypertensive nephrosclerosis".