RPGN, IgA nephropathy and Alport syndrome

Overview

Glomerulonephritis (GN) is immune-mediated inflammation of the glomeruli. It may show up as symptomless haematuria, as acute nephritic syndrome, or as rapidly progressive GN. These are a spectrum: the same disease (for example IgA nephropathy) can present in any of these ways.

This chapter covers the three TOS topics, RPGN, IgA nephropathy and Alport syndrome, and adds post-streptococcal GN because it is the classic comparison.

Rapidly progressive glomerulonephritis (RPGN)

Definition

A clinical syndrome of glomerular haematuria (red cell casts, dysmorphic red cells), with kidney function falling over days to weeks (to months), and focal necrosis with crescents on biopsy.

A crescent is a half-moon of proliferating parietal epithelial cells and macrophages (with fibrin) filling Bowman's space. It forms when glomerular capillaries rupture and blood products leak into the space. The name crescentic GN is used when many glomeruli (classically more than half) are affected.

Aetiology: the three immunofluorescence types

Anti-GBM disease

• About two-thirds have lung haemorrhage (Goodpasture syndrome): haemoptysis, iron-deficiency anaemia, diffuse shadowing. Young men (often smokers) are typical; a renal-only form occurs in older people of both sexes.
• Smoking and hydrocarbon exposure may unmask the hidden collagen epitope.
• It tends to be a single episode that does not relapse once treated.

ANCA vasculitis

• PR3-ANCA (cANCA) in most active GPA: upper airway (sinusitis, nasal crusting, saddle nose), lung nodules or cavities, kidney.
• MPO-ANCA (pANCA) in most MPA and renal-limited vasculitis.
• Drugs (propylthiouracil, hydralazine, minocycline, penicillamine) can induce MPO-ANCA vasculitis.
• Both ANCA and anti-GBM can be positive together; these patients behave like anti-GBM disease.

Clinical features

• Malaise, fever, weight loss, arthralgia, purpuric rash (vasculitis).
• Haematuria, oliguria, hypertension, oedema; creatinine rising week by week.
• Pulmonary–renal syndrome: haemoptysis with AKI suggests anti-GBM disease or ANCA vasculitis (also lupus).
• ENT and eye symptoms in GPA.

Confirmatory tests

• Urine: blood, red cell casts, proteinuria.
• Urgent serology: anti-GBM antibody, ANCA (PR3 and MPO by ELISA, with immunofluorescence pattern), ANA and anti-dsDNA, C3 and C4, ASO titre, cryoglobulins, hepatitis B and C, blood cultures.
• Renal biopsy (the confirmatory test): crescents and necrosis on light microscopy; immunofluorescence pattern gives the type; it also shows how much is reversible (cellular vs fibrous crescents).
• Chest X-ray or CT for lung haemorrhage; raised DLCO (carbon monoxide transfer) indicates fresh alveolar blood.

Management

Anti-GBM disease

• Plasma exchange to remove circulating antibody.
• Corticosteroids (high dose, e.g. pulsed IV methylprednisolone then oral prednisolone) to damp inflammation.
• Cyclophosphamide to stop new antibody production.
• Prognosis depends on damage at the start: if the patient is oliguric or creatinine is above about 600–700 µmol/L, the kidneys rarely recover (lung haemorrhage is still an indication to treat).

ANCA vasculitis (pauci-immune)

• Induction: high-dose steroids (pulsed methylprednisolone 1 g daily for 3 days in severe cases) plus IV cyclophosphamide or rituximab.
• Plasma exchange may be added for severe kidney failure or lung haemorrhage (recent large studies showed limited benefit).
• Maintenance: azathioprine or rituximab with low-dose steroid; relapses are common.
• Co-trimoxazole lowers relapse in GPA linked to nasal Staph. aureus carriage and protects against Pneumocystis.

Immune-complex RPGN: treat the cause (lupus, infection) plus immunosuppression as needed.

Supportive: dialysis for AKI, BP control, infection prophylaxis.

Post-streptococcal GN (for comparison)

• Children mostly; follows a nephritogenic group A β-haemolytic streptococcus infection of the throat or skin after 1–3 weeks (longer after skin infection).
• Acute nephritic syndrome: cola urine, periorbital oedema, hypertension, oliguria.
• Tests: raised ASO titre (anti-DNase B after skin infection), low C3 that returns to normal within weeks.
• Biopsy (rarely needed): diffuse proliferative GN with neutrophils, subepithelial "humps", granular IgG and C3.
• Treatment is supportive: salt and fluid restriction, diuretics, antihypertensives, dialysis if needed; penicillin to clear any persisting infection.
• Excellent prognosis in children; some adults later develop hypertension or CKD.

IgA nephropathy (Berger disease)

Aetiology and pathogenesis

• Now the commonest form of glomerulonephritis worldwide.
• Abnormal galactose-deficient IgA1 (poor O-glycosylation of the hinge region) triggers IgG autoantibodies. The resulting immune complexes lodge in the mesangium, activating mesangial cells.
• Exaggerated mucosal IgA response to infections explains the link with throat and gut infections. There is a genetic contribution.
• Serum IgA is raised in up to half of patients.

Secondary IgA deposition occurs with IgA vasculitis (Henoch–Schönlein purpura), chronic liver disease, coeliac disease, seronegative spondyloarthritis, psoriasis, HIV and some cancers.

Clinical features

• Typically children and young men.
• Recurrent visible haematuria within 1–2 days of an upper respiratory (or GI) infection ("synpharyngitic"), clearing over a few days.
• Or persistent microscopic haematuria found on routine testing.
• Proteinuria; about 5% are nephrotic. A few present with AKI or crescentic RPGN.
• Slowly progressive CKD in a proportion.

Confirmatory tests

• Urine: dysmorphic red cells, red cell casts, variable proteinuria; uPCR to measure risk.
• Serum IgA may be raised (not diagnostic). Complement is normal.
• Renal biopsy is the only confirmatory test: mesangial proliferation on light microscopy and dominant mesangial IgA deposits (with C3) on immunofluorescence. The Oxford (MEST) classification scores mesangial hypercellularity, endocapillary hypercellularity, segmental sclerosis and tubular atrophy/interstitial fibrosis to predict outcome.

Prognosis

Good outcome with normal BP, normal kidney function and little proteinuria. Poor prognostic factors: proteinuria >1 g/day, raised creatinine at diagnosis, hypertension, male sex, and tubular atrophy or interstitial fibrosis on biopsy. About a quarter of those with these features reach ESKD. Recurrent visible haematuria is, surprisingly, a good sign (it brings patients to attention early).

Management

• ACE inhibitor or ARB for all, to lower proteinuria and BP and protect kidney function (BP target below 130/80 mmHg).
• Persistent proteinuria above about 1 g/day despite this, with preserved function: a course of corticosteroids may be considered (weigh infection risk).
• Crescentic, rapidly progressive IgA disease: treat like RPGN (steroids plus cyclophosphamide).
• Tonsillectomy may reduce haematuria and proteinuria in patients with recurrent tonsillitis.
• Statin, salt restriction, smoking cessation; plan for RRT if CKD advances. Disease can recur in a transplant.

Alport syndrome (hereditary nephritis)

Aetiology

• Defect of type IV collagen, the main collagen of basement membranes in the kidney, cochlea and eye.
• About 85% X-linked: mutation in COL4A5 (α5 chain). Rarer autosomal recessive and dominant forms involve COL4A3/COL4A4.
• Males are severely affected and progress to ESKD, usually in early adult life. Female carriers usually have haematuria, with variable progression.

Associated symptoms

• Haematuria (microscopic, sometimes macroscopic) from childhood; proteinuria develops later and is usually modest.
• High-frequency sensorineural deafness (bilateral, progressive).
• Eye changes (about 15%): anterior lenticonus (conical bulge of the front of the lens; pathognomonic), perimacular and macular retinal flecks, cataract.
• Hypertension and progressive CKD.

Diagnosis

• Family history (males worse than females).
• Electron microscopy of kidney biopsy: irregular thickening, thinning and splitting (lamellation) of the GBM, giving a "basket-weave" appearance. Foam cells may be seen in the interstitium.
• Absent α5(IV) collagen on skin or kidney staining; genetic testing confirms.
• Audiometry and slit-lamp eye examination.

Management

• No cure. ACE inhibitors slow proteinuria and progression; control BP.
• Hearing aids; eye review.
• Dialysis and transplantation at ESKD. After transplant, the recipient's immune system sees the normal type IV collagen of the donor kidney as foreign and may make anti-GBM antibodies, causing anti-GBM disease in the graft (rare). Anti-GBM disease never occurs in the native Alport kidney.

Thin basement membrane disease (benign familial haematuria): autosomal dominant, persistent microscopic haematuria, uniformly thin GBM on EM, usually excellent prognosis. Some carriers of Alport genes look identical.

Quick revision

• RPGN: weeks; crescents (epithelial cells + macrophages in Bowman's space).
• Type I linear (anti-GBM), II granular (immune complex), III pauci-immune (ANCA).
• Goodpasture: anti-α3(IV) collagen; plasma exchange + steroids + cyclophosphamide.
• ANCA: steroids + cyclophosphamide or rituximab; maintenance azathioprine or rituximab.
• IgA: commonest GN; haematuria 1–2 days after infection; mesangial IgA; normal C3; ACE inhibitor/ARB.
• PSGN: 1–3 weeks after strep; low C3; ASO up; humps; supportive care.
• Alport: X-linked COL4A5; haematuria, sensorineural deafness, anterior lenticonus; split GBM.
• Thin GBM disease: autosomal dominant benign haematuria.

Written by The House Job from standard references (Kumar and Clark's Clinical Medicine; Fundamentals of Pathology).

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