NephrologyTier 1Disease (DEADMAN)

Acute and chronic glomerulonephritis - rapidly progressive glomerulonephritis

Description

Loss of renal function over days to weeks (<3 months, often <6 weeks) with a nephritic sediment
Histological correlate: crescentic GN - crescents in >50% (some define >25%) of glomeruli
- Crescent = proliferating parietal epithelial cells, macrophages and fibrin in Bowman space, following rupture of the glomerular capillary wall
A renal emergency. Every day of delay costs nephrons that do not come back

The three immunopathological types - defined by immunofluorescence

Type	IF	Serology	Examples	%
I. Anti-GBM	Linear IgG	Anti-GBM	Goodpasture disease	~10-15
II. Immune complex	Granular	ANA/dsDNA, low C3/C4, ASOT, cryoglobulins	Lupus, post-infectious, IgA/HSP, MPGN, cryoglobulinaemia, endocarditis	~25-30
III. Pauci-immune	Negative or scant	ANCA (PR3 or MPO)	GPA, MPA, EGPA, renal-limited vasculitis	~60 - the commonest

*Type IV = double-positive (anti-GBM + ANCA), ~10-40% of anti-GBM cases* - acts like anti-GBM acutely, relapses like ANCA disease

Epidemiology

ANCA vasculitis is the commonest cause overall
Bimodal age peaks: 20-30 yrs and >55 yrs
- Young peak - anti-GBM, lupus
- Older peak - ANCA vasculitis (MPO/MPA more common in Australia and Asia; PR3/GPA more in northern Europe)
ANCA vasculitis incidence ~20 per million/year; renal involvement in ~70%

Aetiopathogenesis

Pauci-immune (ANCA)

ANCA binds primed neutrophils (TNF/complement-primed, surface PR3 or MPO)
- -> neutrophil degranulation, respiratory burst, NETosis at the capillary wall
- -> fibrinoid necrosis -> capillary wall rupture -> crescent formation
Alternative complement pathway amplification via C5a - the rationale for avacopan (C5a receptor antagonist)
Triggers: silica, hydrocarbons, infection; drugs - hydralazine, propylthiouracil, levamisole-adulterated cocaine, minocycline (usually MPO, high-titre, often ANA-positive)

Anti-GBM

IgG against the alpha-3(IV)NC1 domain; smoking/hydrocarbon exposure unmasks the alveolar epitope

Immune complex

Deposited or in-situ complexes -> classical/alternative complement -> leucocyte recruitment

Why crescents mean urgency

Cellular crescent (reversible) -> fibrocellular -> fibrous (irreversible) over ~2-4 weeks
Treatment converts cellular crescents; it cannot undo fibrous ones

Diagnosis

Presentation

Renal failure over <6 weeks + haematuria + proteinuria + oliguria + hypertension
Systemic: haemoptysis, arthralgia, myalgia, weight loss, fever, rash (palpable purpura), sinusitis, mononeuritis multiplex, scleritis
Often presents late because the systemic symptoms are attributed to something else

Urine

Dysmorphic RBCs, RBC casts, sub-nephrotic proteinuria - the nephritic sediment

Serology - send all of it, same day

ANCA (PR3 and MPO by ELISA, plus IIF), anti-GBM, ANA, anti-dsDNA, ENA, C3/C4
Cryoglobulins, hepatitis B/C, HIV, blood cultures (endocarditis mimics vasculitis exactly), ASOT/anti-DNase B
SPEP + serum free light chains
~10% of ANCA vasculitis is ANCA-negative - a negative ANCA does not exclude it

Renal biopsy - urgent, same admission

Crescents in >25-50% of glomeruli; report the proportion of normal glomeruli (the strongest prognostic variable)
ANCA: fibrinoid necrosis, pauci-immune (negative IF)
Anti-GBM: linear IgG, crescents all of the same age
Lupus: 'full house' IgG/IgA/IgM/C3/C1q, mixed-age crescents
Berden/Mayo classification (focal / crescentic / mixed / sclerotic) predicts renal outcome

Extrarenal assessment

CXR/HRCT chest, ENT review, nerve conduction, ophthalmology
DLCO if pulmonary haemorrhage suspected (raised)

Management

Start treatment on clinical suspicion; do not wait for the biopsy

ANCA-associated vasculitis - induction

Glucocorticoid + (rituximab OR cyclophosphamide) - both are first-line
- Rituximab preferred: relapsing disease, younger patients, fertility concerns, PR3 disease
- Cyclophosphamide preferred: severe/dialysis-dependent renal disease (more experience), where rituximab is unavailable
Rapid glucocorticoid taper - the major change (PEXIVAS reduced-dose arm, LoVAS)
- Reduced-dose regimens give the same remission rate with significantly fewer severe infections
- Methylprednisolone 250-500 mg IV x1-3 (avoid the historical 1 g x3), then prednisolone ~1 mg/kg tapering to ~5 mg by 4-5 months
Avacopan (oral C5a receptor antagonist) - alternative to much of the glucocorticoid exposure, with rituximab or cyclophosphamide (ADVOCATE)
- Greatest benefit: high glucocorticoid-toxicity risk, and eGFR <20 - earlier albuminuria reduction and better eGFR recovery
- A KDIGO practice point, not a graded recommendation
Plasma exchange - no longer routine. Consider if:
- Creatinine >300 micromol/L, or dialysis-requiring, or rapidly rising creatinine
- Diffuse alveolar haemorrhage with hypoxaemia
- Double-positive (anti-GBM + ANCA) disease
- PEXIVAS: no overall benefit on death or ESKD, and more serious infection

ANCA - maintenance

Rituximab 500 mg 6-monthly (superior to azathioprine - MAINRITSAN) for >=18 months to 4 years
Alternatives: azathioprine, methotrexate (not if eGFR reduced), mycophenolate
Relapse risk higher with: PR3-ANCA, ENT involvement, persistent ANCA positivity

Anti-GBM disease

Plasma exchange (daily/alternate-day until antibody undetectable) + corticosteroid + cyclophosphamide - all three, urgently
Do not withhold because of dialysis dependence if there is pulmonary haemorrhage

Lupus nephritis (class III/IV)

Glucocorticoid + MPAA or low-dose IV cyclophosphamide (Euro-Lupus), or triple therapy adding belimumab or a CNI (voclosporin/tacrolimus)
Maintenance MMF or azathioprine >=3 years; hydroxychloroquine in everyone

Supportive - in all

PJP prophylaxis (trimethoprim-sulfamethoxazole), gastric and bone protection, vaccination
Fertility preservation counselling before cyclophosphamide
Check immunoglobulins before and during rituximab (hypogammaglobulinaemia)
Screen hepatitis B and TB before immunosuppression
Dialysis as required - many dialysis-dependent patients still recover independent function

Associations

ANCA vasculitis - GPA (ENT, cavitating lung nodules, saddle nose, subglottic stenosis), MPA, EGPA (asthma, eosinophilia, neuropathy)
SLE, IgA vasculitis (HSP), cryoglobulinaemia (hepatitis C), post-infectious GN, infective endocarditis, shunt nephritis
Anti-GBM disease - smoking, hydrocarbons, HLA-DRB1\*15:01
Drug-induced ANCA: hydralazine, propylthiouracil, levamisole-adulterated cocaine, minocycline, anti-TNF
Malignancy (paraneoplastic vasculitis), silica exposure
Alveolar haemorrhage - the differential of pulmonary-renal syndrome

Natural history & complications

Untreated: ESKD or death within weeks to months
Treated ANCA vasculitis: remission in ~80-90%; ~20-25% relapse within 5 years (higher with PR3)
~50% of RPGN overall progresses to ESKD
Mortality is from pulmonary haemorrhage early and sepsis later - treatment-related infection is the leading cause of death in the first year

Prognostic factors

Renal function at presentation - the strongest
Percentage of normal (non-crescentic, non-sclerosed) glomeruli on biopsy
Extent of interstitial fibrosis; dialysis dependence at diagnosis
Even dialysis-dependent ANCA patients recover independent function in ~50% - treat them
Anti-GBM with 100% crescents and dialysis dependence: renal recovery is very unlikely

Monitoring

eGFR, urine sediment, UACR, CRP
ANCA titre - rising titre predicts relapse but should not by itself trigger treatment
Anti-GBM titre until undetectable (transplant only after >=6 months negative)
Long-term: cardiovascular risk, malignancy surveillance (cyclophosphamide -> bladder cancer, haematological malignancy, infertility), infection

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