NephrologyTier 2Disease (DEADMAN)

Renal manifestations of systemic and chronic disease

Description

The kidney is the commonest visceral target of systemic disease - and often the first clue
Four questions decide everything:
- 1. Which compartment? glomerulus / tubulointerstitium / vasculature
- 2. Nephritic or nephrotic?
- 3. Complement consumed?
- 4. Is the biopsy going to change treatment?

Pattern by systemic disease

Disease	Renal lesion
SLE	Immune-complex GN, ISN/RPS I-VI, full house IF
ANCA vasculitis	Pauci-immune crescentic GN
Anti-GBM / Goodpasture	Linear IgG, crescentic GN + pulmonary haemorrhage
IgA vasculitis (HSP)	Mesangial IgA, identical to IgAN
Cryoglobulinaemia (HCV)	MPGN, low C4 >> low C3
Myeloma	Cast nephropathy, AL amyloid, MIDD, Fanconi
Amyloid (AA/AL)	Nephrotic, Congo red apple-green birefringence
Diabetes	Nodular glomerulosclerosis (Kimmelstiel-Wilson)
Systemic sclerosis	Scleroderma renal crisis - onion-skin arterioles
Sarcoidosis	Granulomatous interstitial nephritis, hypercalcaemia
Sjogren	Distal (type 1) RTA, tubulointerstitial nephritis
Hepatitis B	Membranous, PAN
Infective endocarditis	Immune-complex GN, low C3
HIV	Collapsing FSGS (HIVAN)
Preeclampsia	Glomerular endotheliosis
TTP/HUS/aHUS	Thrombotic microangiopathy

Lupus nephritis: ~40-50% of SLE, higher and more severe in Asian, African and Aboriginal and Torres Strait Islander populations
Diabetes is the single commonest cause of ESKD in Australia (~35-40% of incident dialysis)
AL amyloid: renal involvement in ~70%

Lupus nephritis

Immune-complex mediated - anti-dsDNA and nucleosome complexes deposit or form in situ
- -> complement activation (classical pathway) -> glomerular inflammation
- Unchecked inflammation extends into the interstitium - interstitial fibrosis is the strongest histological predictor of ESKD
Deposit location determines phenotype:
- Mesangial -> class I/II, bland urine
- Subendothelial (accessible to circulation) -> proliferative, nephritic, class III/IV, low complement
- Subepithelial (podocyte side) -> membranous, nephrotic, class V, normal complement

Complement as a discriminator

Low C3 + low C4	Low C3, normal C4	Normal complement
SLE, cryoglobulinaemia (C4 disproportionately low), shunt nephritis	Post-infectious GN, C3 glomerulopathy	ANCA vasculitis, anti-GBM, IgAN, HSP

Screen every patient with systemic disease

Urinalysis (dipstick + microscopy for dysmorphic RBC and cellular casts) + UPCR/UACR + creatinine
- Proteinuria is the commonest urine abnormality in lupus nephritis
- Red cell casts = glomerulonephritis until proven otherwise

Serology panel

ANA, anti-dsDNA, anti-Sm, C3/C4
ANCA (PR3, MPO), anti-GBM
Cryoglobulins, hepatitis B/C, HIV
SPEP + serum free light chains + urine electrophoresis (any unexplained renal impairment over 40)
ASOT/anti-DNase B

When to biopsy in SLE

Biopsy if proteinuria >=500 mg/day, or active sediment, or unexplained creatinine rise
Not required if proteinuria <500 mg/day with a bland sediment

ISN/RPS lupus nephritis classification

Class	Histology	Clinical	Treatment
I Minimal mesangial	Deposits on IF/EM only, normal LM	Normal urine and Cr	Treat extrarenal SLE only
II Mesangial proliferative	Mesangial hypercellularity	Haematuria +/- proteinuria; good prognosis	Treat extrarenal SLE only
III Focal	<50% glomeruli	Haematuria, proteinuria, +/- HTN, dec GFR	Immunosuppress
IV Diffuse	>=50% glomeruli	Most severe; nephritic +/- nephrotic	Immunosuppress
V Membranous	Subepithelial deposits	Nephrotic, normal complement, thrombotic risk	Treat if nephrotic
VI Advanced sclerosis	>90% globally sclerosed	ESKD	Supportive / RRT

Class III/IV = proliferative = the ones that need immunosuppression; IF shows a 'full house' (IgG, IgA, IgM, C3, C1q)
Report activity index (reversible, treat) vs chronicity index (irreversible, do not)
Classes coexist (III+V, IV+V)

Class I / II

Class III / IV (proliferative) - induction

KDIGO 2024 moved to triple therapy as a first-line option

Glucocorticoids (reduced-dose regimens now standard) PLUS one of:
- MPAA (mycophenolate), or
- Low-dose IV cyclophosphamide (Euro-Lupus: 500 mg q2wk x 6) - fewer complications than daily oral or high-dose monthly IV
OR triple therapy: add belimumab, or use a CNI (voclosporin or tacrolimus) in place of the third agent - if eGFR >=30
- CNI-containing regimen preferred if preserved eGFR + nephrotic-range proteinuria (podocyte injury)
Hydroxychloroquine in everyone - reduces flares, thrombosis and damage accrual

Maintenance

Mycophenolate or azathioprine for >=3 years - both preferred over cyclophosphamide
- Azathioprine if pregnancy planned
Taper considered after 1-3 years of sustained remission; re-biopsy if proteinuria or eGFR worsens
Relapse -> repeat induction

Class V

Nephrotic-range proteinuria -> glucocorticoid + immunosuppression (MMF, CNI, cyclophosphamide or rituximab)
Sub-nephrotic -> antiproteinuric therapy alone

Refractory

Supportive - all classes

ACEi/ARB, BP <120 systolic, statin, SGLT2i for residual proteinuric CKD
PJP prophylaxis on high-dose steroid + cytotoxic; vaccination; bone protection
Pregnancy: azathioprine + prednisolone + aspirin; MMF and cyclophosphamide are teratogenic - stop 6 weeks (MMF) before conception

Monitoring

eGFR, UPCR, urine sediment, C3/C4 and anti-dsDNA (track disease activity), FBE

APS - overlaps with SLE; APS nephropathy is a TMA and is not steroid-responsive
Chronic HCV -> cryoglobulinaemia; treat with DAAs
Chronic HBV -> membranous nephropathy, PAN
Sarcoidosis -> hypercalcaemia, nephrocalcinosis, granulomatous interstitial nephritis
Systemic sclerosis -> scleroderma renal crisis (ACEi is treatment; steroids are a precipitant; ACEi does NOT prevent it)
Rheumatoid arthritis -> AA amyloid, gold/penicillamine membranous, NSAID injury
Multiple myeloma -> cast nephropathy is the commonest lesion; free light chains, not the paraprotein
Coeliac, IBD, ankylosing spondylitis -> IgA nephropathy

Lupus nephritis: 10-30% reach ESKD within 15 years; class IV worst untreated
- Complete renal response at 12 months (proteinuria <0.5-0.7 g/day with stable eGFR) is the best predictor of long-term renal survival
- Chronicity index and interstitial fibrosis predict irreversibility
Recurrence after transplant uncommon (<5%) - transplant outcomes good; wait until serologically quiescent
Excess mortality in SLE is bimodal: early from active disease and infection, late from cardiovascular disease
Amyloid and myeloma kidney: renal survival depends on haematological response, not renal therapy
Monitor for treatment toxicity: cyclophosphamide (infertility, haemorrhagic cystitis, bladder cancer, malignancy), steroids, CNI nephrotoxicity, hydroxychloroquine retinopathy

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