Glomerulonephritis: Recognising the Patterns and the Emergencies

Introduction

Glomerulonephritis is not a single disease but a family of immune-mediated disorders of the glomerulus, unified by the finding of inflammation within the glomerular tuft and by a characteristic set of urinary abnormalities.¹ Collectively these conditions are the third commonest cause of end-stage renal disease in the UK, after diabetes and hypertension.

They can be approached in several ways - by clinical syndrome, by histological pattern, or by immunological mechanism - and confusion usually arises from mixing these up. The most clinically useful starting point is the clinical syndrome, because it is available at the bedside from a dipstick and a blood pressure, and it determines urgency.

The individual glomerulonephritides

IgA nephropathy (Berger disease)

• The commonest primary glomerulonephritis worldwide, with a peak incidence in the second and third decades and a male predominance
• Pathogenesis - abnormally glycosylated IgA1 forms immune complexes that deposit in the mesangium, triggering complement activation and mesangial proliferation
• Classic presentation: visible haematuria occurring 1 to 2 days after an upper respiratory tract infection (so-called synpharyngitic haematuria), often recurrent over years. Many patients instead present with asymptomatic non-visible haematuria and proteinuria found incidentally.
• Histology - mesangial proliferation with IgA and C3 deposition in the mesangium on immunofluorescence, which is the diagnostic finding. Complement C3 in the blood is typically normal.
• Associations - coeliac disease, chronic liver disease (impaired IgA clearance), HIV, and IgA vasculitis (Henoch-Schonlein purpura), which is essentially the same process with systemic features
• Management - ACE inhibitor or ARB with blood pressure control for all with proteinuria; corticosteroids are used selectively where proteinuria persists above 1 g/day despite optimal supportive care and there is a risk of progression, though the benefit is debated because of infection risk. Newer agents (targeted-release budesonide, sparsentan, SGLT2 inhibitors) are changing practice.
• Prognosis - very variable. Around 20 to 30% reach end-stage renal disease over 20 years; isolated haematuria with normal function and no proteinuria has an excellent outlook

Post-streptococcal glomerulonephritis

• Follows infection with a nephritogenic group A beta-haemolytic Streptococcus - typically 1 to 2 weeks after pharyngitis or 3 to 6 weeks after impetigo or another skin infection
• Mainly affects children aged 3 to 12
• Presents with a full nephritic syndrome - cola-coloured urine, periorbital oedema, hypertension and oliguria
• Investigations - low complement C3 with a normal C4, raised ASOT or anti-DNase B titres, and a positive throat swab if still culturable
• Histology (rarely needed) - diffuse proliferative GN with subepithelial 'humps' of immune complex on electron microscopy and starry sky granular C3 deposition on immunofluorescence
• Management is supportive - salt and fluid restriction, diuretics and antihypertensives; antibiotics treat the infection but do not alter the renal course
• Prognosis is excellent in children, with over 95% making a full recovery; adults do less well

Anti-GBM disease (Goodpasture disease)

• Autoantibodies against the alpha-3 chain of type IV collagen in the glomerular and alveolar basement membranes
• Presents as a pulmonary-renal syndrome - rapidly progressive glomerulonephritis with pulmonary haemorrhage, causing haemoptysis, breathlessness and anaemia. A bimodal age distribution (young men, and older women).
• Smoking and hydrocarbon exposure markedly increase the risk of alveolar involvement
• Diagnosis - circulating anti-GBM antibodies and, on biopsy, linear IgG deposition along the glomerular basement membrane (the classic 'ribbon' pattern) with crescents
• Treatment is urgent: plasma exchange to remove circulating antibody, plus corticosteroids and cyclophosphamide to stop its production. Plasma exchange is central here in a way it is not for most other glomerulonephritides.
• Prognosis depends entirely on the creatinine at presentation - patients who are already dialysis-dependent rarely recover renal function, which is why same-day recognition matters

ANCA-associated vasculitis

• The commonest cause of rapidly progressive glomerulonephritis in older adults, and pauci-immune on immunofluorescence (little or no immunoglobulin deposition)
• Granulomatosis with polyangiitis - c-ANCA / anti-PR3; upper and lower respiratory tract involvement with epistaxis, nasal crusting, saddle-nose deformity, sinusitis, pulmonary nodules and cavitation, plus glomerulonephritis
• Microscopic polyangiitis - p-ANCA / anti-MPO; glomerulonephritis with pulmonary haemorrhage but without granulomas
• Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) - p-ANCA, with asthma, eosinophilia and neuropathy; renal involvement is less common
• Systemic features are the clue - fever, weight loss, malaise, arthralgia, rash (purpura), mononeuritis multiplex, epistaxis and haemoptysis in a patient with an active urinary sediment⁵
• Treatment - corticosteroids with cyclophosphamide or rituximab for induction, then azathioprine, methotrexate or rituximab for maintenance; plasma exchange for severe renal disease or pulmonary haemorrhage
• See the vasculitis article for fuller detail

Lupus nephritis

• Occurs in around 40% of patients with SLE, and is a major determinant of prognosis
• Classified by the ISN/RPS system into six classes - class I and II (mesangial), class III (focal proliferative), class IV (diffuse proliferative - the commonest and most aggressive), class V (membranous - presents nephrotically) and class VI (advanced sclerosis). The class determines treatment, which is why biopsy is essential.
• Serology - positive ANA and anti-dsDNA, with low C3 AND low C4 (consumption of both classical and alternative pathways)
• Immunofluorescence shows a 'full house' - IgG, IgA, IgM, C3 and C1q all staining
• Treatment - mycophenolate or cyclophosphamide with corticosteroids for proliferative disease, increasingly combined with belimumab or voclosporin; hydroxychloroquine for all patients with lupus

Other patterns worth knowing

Rapidly progressive glomerulonephritis

Rapidly progressive glomerulonephritis is defined clinically - a decline in renal function over days to weeks accompanied by an active urinary sediment - and histologically by the presence of crescents in the glomeruli. A crescent is a proliferation of cells and fibrin filling Bowman's space, and it represents severe glomerular injury with rupture of the capillary wall.

Investigations

Bedside and urine

• Urine dipstick - the essential first test; blood and protein together is the signature of glomerular disease
• Urine microscopy - dysmorphic red cells and red cell casts confirm a glomerular origin of bleeding; white cell casts suggest interstitial disease or infection
• Urine protein:creatinine ratio or ACR - to quantify proteinuria, which is both a diagnostic and prognostic marker
• Blood pressure, which is frequently raised and needs treating in its own right
• Urine culture - to exclude infection as a cause of haematuria

Blood tests and immunology

• Also send U&Es, full blood count (anaemia, eosinophilia in EGPA), CRP and ESR, LFTs, clotting, and a chest X-ray (looking for infiltrates, nodules or haemorrhage)

Renal biopsy

• Biopsy is the definitive investigation and is indicated in almost all adults with unexplained glomerular disease, because the histological diagnosis determines treatment and prognosis
• The specimen is examined by light microscopy (pattern and distribution of injury, crescents, sclerosis, interstitial fibrosis), immunofluorescence (the pattern of immunoglobulin and complement deposition - linear, granular or pauci-immune) and electron microscopy (foot process effacement, deposit location)
• Check clotting, platelets and blood pressure beforehand, and confirm two kidneys are present; the principal complication is bleeding
• Biopsy is often deferred in children with typical steroid-responsive nephrotic syndrome and in classic post-streptococcal GN following a predictable recovery

Management

Measures applying to all patients

• Blood pressure control - the most important intervention for long-term renal survival, with tighter targets where there is proteinuria³
• ACE inhibitor or ARB - reduces intraglomerular pressure and proteinuria beyond its antihypertensive effect, and is indicated in essentially all patients with persistent proteinuria
• Sodium restriction, diuretics for oedema, and fluid management
• Statin therapy and cardiovascular risk reduction
• Avoid nephrotoxins, particularly NSAIDs
• Treat the trigger where there is one - antibiotics for infection, antivirals for hepatitis B or C, withdrawal of a culprit drug, treatment of an underlying malignancy
• Monitor renal function and proteinuria to detect progression

Immunosuppression

Immunosuppression is reserved for histologically confirmed disease that is active and likely to progress, because the risks are substantial. It is emphatically not given for isolated haematuria with normal function.²

Complications

• Acute kidney injury, sometimes requiring dialysis
• Progression to chronic kidney disease and end-stage renal disease
• Hypertension, often severe and requiring multiple agents, and accelerated cardiovascular risk
• Nephrotic complications where proteinuria is heavy - thromboembolism (including renal vein thrombosis), infection and hyperlipidaemia
• Pulmonary haemorrhage in anti-GBM disease and ANCA vasculitis - immediately life-threatening
• Hyperkalaemia, acidosis and fluid overload from renal failure
• Complications of immunosuppression - infection (including PCP and reactivated TB or hepatitis B), infertility from cyclophosphamide, malignancy, corticosteroid toxicity and bone marrow suppression
• Relapse - common in ANCA vasculitis and lupus nephritis, so long-term maintenance and monitoring are needed
• Recurrence in a transplanted kidney - particularly FSGS, IgA nephropathy and membranous nephropathy

Red flags

Prognosis

Outcomes range from complete spontaneous recovery to irreversible renal failure within weeks, and the histological diagnosis is the dominant determinant.

Post-streptococcal glomerulonephritis in children has an excellent prognosis, with over 95% recovering fully; the haematuria may persist for months and the low C3 normalises within 6 to 8 weeks, but permanent damage is unusual. Thin basement membrane disease is similarly benign and needs only reassurance and monitoring.

IgA nephropathy has a highly variable course. Patients with isolated haematuria, normal blood pressure and no proteinuria do very well, whereas roughly 20 to 30% of the overall cohort reach end-stage renal disease within 20 years. The predictors of progression are consistent across glomerular disease generally: the degree of proteinuria, the blood pressure, the creatinine at presentation, and the amount of interstitial fibrosis and tubular atrophy on biopsy.

Rapidly progressive glomerulonephritis was almost uniformly fatal before effective immunosuppression and remains the group in which prompt treatment makes the greatest difference. With modern induction regimens, remission is achieved in the large majority of ANCA-associated vasculitis, though relapse occurs in a substantial proportion and long-term maintenance is required. In anti-GBM disease the creatinine at presentation is decisive - patients who present before dialysis is needed often recover useful function, whereas those already dialysis-dependent seldom do, and that difference is frequently a matter of how quickly the diagnosis was considered.

Across all types, the treatment burden increasingly rivals the disease. Much of the morbidity in treated glomerulonephritis now arises from infection, corticosteroid toxicity, infertility and malignancy risk from cyclophosphamide - which is why the shift towards rituximab, targeted therapies and steroid-minimising regimens matters, and why immunosuppression is withheld in those whose disease is unlikely to progress.