NephrologyTier 1Disease (DEADMAN)

Focal segmental glomerulosclerosis

Description

Histological pattern, not one disease - podocyte injury -> segmental sclerosis in some glomeruli
- Focal = some glomeruli; segmental = part of the tuft
Commonest primary cause of nephrotic syndrome in adults
Sampling error is intrinsic - deep juxtamedullary glomeruli affected first; a small biopsy reads as MCD

Columbia (histological) variants

Variant	Features	Prognosis
NOS (classic)	Commonest; segmental sclerosis, no defining feature	Intermediate
Tip	Lesion at proximal tubular pole	Best - steroid-responsive, MCD-like
Perihilar	At vascular pole; adaptive/secondary	Slow
Cellular	Endocapillary hypercellularity	Intermediate
Collapsing	Implosive tuft collapse + visceral epithelial hypertrophy/hyperplasia, severe foot process effacement	Worst - rapid ESKD

Collapsing: HIV, parvovirus B19, CMV, EBV, SARS-CoV-2; pamidronate, interferon, anabolic steroids; atheroembolism, CNI toxicity, chronic allograft nephropathy
**APOL1 high-risk genotype drives the collapsing phenotype in African ancestry**

The three-way split - determines whether to immunosuppress

A. Primary - circulating permeability factor, diffuse foot process effacement (>80%), abrupt full nephrotic syndrome
- Evidence for a circulating factor: recurrence within minutes to hours of transplantation; response to plasmapheresis and immunoadsorption
- suPAR proposed as the factor - still contested, do not use clinically
B. Genetic - podocyte structural genes
- NPHS1 (nephrin), NPHS2 (podocin), ACTN4, TRPC6, INF2, WT1, COL4A3-5
- Steroid-resistant nephrotic syndrome, familial, childhood onset, or FSGS + deafness/CMT -> gene panel
- Genetic disease does NOT recur post-transplant
C. Secondary / adaptive - hyperfiltration or direct toxicity
- Reduced nephron mass: reflux nephropathy, solitary/hypoplastic kidney, prior AKI, ageing
- Increased demand: obesity, sickle cell, cyanotic CHD, anabolic steroid use, high-protein states
- Viral: HIV (direct infection of glomerular and tubular epithelium; strong African-ancestry predilection), parvovirus B19, CMV, EBV, SARS-CoV-2
- Drugs: pamidronate, interferon, lithium, CNIs, heroin, anabolic steroids
- Scarring: any healed proliferative GN, hypertensive nephrosclerosis

Primary vs secondary is the whole management question - the histology often looks identical

Proteinuria is the defining feature; nephrotic syndrome (hypoalbuminaemia, hypercholesterolaemia, oedema) in most primary disease
HTN ~50%, microscopic haematuria ~50%, impaired eGFR at presentation ~25-50%

Primary vs secondary at the bedside

*Normal albumin + no oedema + heavy proteinuria = secondary. Do not immunosuppress.*

Biopsy

Work-up before treating

HIV, HBV, HCV, parvovirus B19
SPEP/serum free light chains, ANA
Drug and anabolic-steroid history, BMI, birth history (prematurity/low birth weight)
Genetic panel if steroid-resistant, familial, or age <25

HIVAN: collapsing FSGS + microcystic tubular dilatation + prominent interstitial inflammation, normal-to-large kidneys, rapid progression

Everyone - antiproteinuric and cardiorenal base

Maximally tolerated ACEi/ARB + Na restriction <2 g/day
SGLT2i - added for CKD with proteinuria irrespective of diabetes
Statin, BP target <120 systolic (standardised office), oedema managed with loop diuretic
This alone is the whole treatment of secondary and genetic FSGS

Primary FSGS with nephrotic syndrome - immunosuppression

Only for primary disease. No role in secondary; little evidence if not nephrotic.

1. Corticosteroids - prednisolone 1 mg/kg (max 80 mg) daily, or 2 mg/kg alternate-day
- Continue minimum 4 weeks, up to 16 weeks before declaring resistance, then taper over 3-6 months
- Complete remission in ~50% of responders; median time to remission 3-4 months - slower than MCD
2. Calcineurin inhibitor - ciclosporin or tacrolimus, for steroid resistance or steroid contraindication
- Continue 12 months minimum then taper - high relapse rate on withdrawal
- Also acts non-immunologically by stabilising the podocyte actin cytoskeleton (synaptopodin)
- Nephrotoxic - avoid if eGFR <40 or significant interstitial fibrosis
3. Others - MMF + high-dose dexamethasone, cyclophosphamide 1-2 mg/kg PO 8 weeks (30-50% response), rituximab, ACTH
- Rituximab far less effective in FSGS than in MCD or membranous
Sparsentan (dual endothelin A / AT1 antagonist) - approved for IgAN; FSGS data (DUPLEX) showed proteinuria reduction without an eGFR endpoint benefit

Definitions that drive the next step

	UPCR
Complete remission	<0.3 g/day
Partial remission	<3.5 g/day and >50% reduction
Steroid-resistant	Persistent nephrotic proteinuria after 16 weeks

Nephrotic complications

Thromboprophylaxis if albumin <20-25 g/L (especially membranous; lower risk in FSGS)
Pneumococcal + influenza vaccination; live vaccines contraindicated on immunosuppression
Loop diuretic +/- thiazide; IV albumin only if severe refractory oedema

HIV (HIVAN - collapsing), parvovirus B19, CMV, EBV, SARS-CoV-2
Obesity - obesity-related glomerulopathy (perihilar variant, glomerulomegaly)
Sickle cell disease, cyanotic congenital heart disease
Reflux nephropathy, solitary kidney, prematurity/low birth weight
Heroin, anabolic androgenic steroids, pamidronate, interferon, lithium, CNIs
**APOL1 G1/G2 high-risk genotype** - African ancestry; also drives hypertensive nephrosclerosis and HIVAN
Alport syndrome and other collagen IV disorders - FSGS on biopsy
Charcot-Marie-Tooth (INF2), Denys-Drash/WAGR (WT1)

Untreated nephrotic primary FSGS: ~50% ESKD at 5-10 years
Response to therapy is the strongest prognostic factor
- Complete remission -> <10% ESKD at 10 yrs
- Persistent nephrotic proteinuria -> >50% ESKD at 10 yrs
Other predictors: severity of proteinuria, eGFR at presentation, degree of interstitial fibrosis and tubular atrophy, collapsing variant
Variant hierarchy: tip > NOS/perihilar > cellular > collapsing

Transplantation

FSGS is the GN that most commonly recurs after transplant - ~15-55% (~40% typical)
- Recurrence risk: younger age, non-Black ancestry, rapid native ESKD (<3 yrs), heavy pre-transplant proteinuria, loss of a previous graft to recurrence (>80% in that group)
- Can recur within minutes to hours - proteinuria on day 1
- Treated with plasma exchange +/- rituximab
Genetic FSGS does not recur
Other GN that recur: IgA nephropathy, MPGN/C3 glomerulopathy, membranous

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