Glomerular Syndromes and Diagnostic Approach — Advanced

Low C3 with normal C4 most commonly reflects activation of the alternative complement pathway. This pattern is classically seen in post-infectious (post-streptococcal) glomerulonephritis and in complement-mediated diseases such as C3 glomerulopathy. Classical pathway activation (eg, lupus, cryoglobulinaemia with immune complexes) tends to reduce both C3 and C4. Isolated lectin pathway activation is uncommon and not characterised by this specific pattern. The option that complement levels do not help is incorrect: complement profiles provide useful diagnostic clues in glomerular disease.

Anti-GBM disease (Goodpasture syndrome) with pulmonary haemorrhage and rapidly progressive renal failure is a medical emergency; urgent plasma exchange (plasmapheresis) with concomitant immunosuppression (corticosteroids ± cyclophosphamide) is indicated to remove pathogenic antibodies and limit ongoing alveolar and glomerular damage. Waiting for a biopsy risks irreversible injury. Steroids and cyclophosphamide alone without plasma exchange are insufficient in the acute setting with alveolar haemorrhage. Conservative measures or steroid monotherapy are inappropriate for fulminant anti-GBM disease.

Minimal change disease is usually highly steroid-sensitive even in adults; first-line therapy is high-dose systemic corticosteroids to induce remission. Cyclophosphamide or calcineurin inhibitors are reserved for steroid-dependent, frequently relapsing, or steroid-resistant disease. Rituximab can be used in relapsing or steroid-dependent cases but is not first-line. Conservative therapy alone is inadequate for induction of remission in typical MCD presenting with nephrotic syndrome. Renal transplantation is irrelevant here.

Anti-PLA2R antibodies are implicated in primary membranous nephropathy; higher antibody titres correlate with disease activity and greater risk of persistent proteinuria and progression, and they can be used to monitor response to therapy. A positive anti-PLA2R supports primary rather than secondary membranous disease (though clinical correlation to exclude secondary causes is still required). Anti-PLA2R is not associated with MPGN or IgA nephropathy. It therefore has prognostic and monitoring value.

Membranous nephropathy is associated with the highest risk of venous thromboembolism among nephrotic disorders, including renal vein thrombosis and pulmonary embolism. The hypercoagulable state in nephrotic syndrome is multifactorial (loss of antithrombin III, increased fibrinogen, platelet hyperreactivity). While all causes of nephrotic syndrome increase thrombotic risk, membranous disease has the strongest association. Minimal change disease also increases risk but less so; IgA nephropathy, Alport and thin basement membrane disease are not typically associated with a high VTE risk.

C3 glomerulopathy is caused by dysregulation of the alternative complement pathway; terminal complement blockade with a C5 inhibitor such as eculizumab can be considered in selected, refractory cases to interrupt complement-mediated injury. Rituximab or conventional immunosuppressants are not specifically targeted at alternative pathway dysregulation and have variable efficacy. IVIG, mycophenolate and azathioprine are not mechanistically directed at complement activation; they may be used in other immune-mediated conditions but are not the primary targeted therapy for complement-mediated GN.

A family history of haematuria with sensorineural hearing loss and progressive renal disease is highly suggestive of Alport syndrome (collagen IV gene mutations). Genetic testing for COL4A3/COL4A4/COL4A5 is the most appropriate next step and may obviate the need for a diagnostic renal biopsy. The other tests listed are not directed at diagnosing inherited collagen IV disorders: ANCA/anti-GBM and complement tests investigate immune causes; urinary protein electrophoresis is for paraprotein-associated disease; skin biopsy is not a standard diagnostic test for Alport.

In nephrotic patients with severe hypoalbuminaemia, diuretic resistance may occur because loop diuretics are highly protein-bound and less effective. Administering intravenous albumin followed by a loop diuretic can transiently increase intravascular volume of distribution for the diuretic and enhance natriuresis and diuresis in diuretic-resistant oedema. Simply increasing oral diuretics may be ineffective; thiazide diuretics are sometimes used in combination with loop diuretics but are less appropriate alone in the hypoalbuminaemic, oliguric patient. Empiric anticoagulation and immediate dialysis are not first-line measures to overcome diuretic resistance.

Nephrotic patients (particularly with heavy proteinuria and those on immunosuppression) have increased susceptibility to infections with encapsulated organisms due to urinary losses of immunoglobulins and complement proteins. Pneumococcal vaccination (both conjugate and appropriate polysaccharide vaccines following local schedules) should be ensured before or during immunosuppression. Influenza vaccination is important but insufficient alone. Lifelong co-trimoxazole prophylaxis is not routinely indicated for nephrotic syndrome (it is used selectively to prevent Pneumocystis jirovecii in certain immunosuppressed regimens). Routine prophylactic antifungal therapy is not indicated.

Recent KDIGO and contemporary CKD guidance support the use of sodium–glucose cotransporter 2 (SGLT2) inhibitors to reduce progression of proteinuric CKD and to lower proteinuria when used in addition to maximally tolerated RAAS blockade, irrespective of diabetes status, provided eGFR is sufficient for their use. Switching to a beta-blocker does not reduce proteinuria. High-dose corticosteroids are not routinely indicated for IgA nephropathy unless specific histological or clinical features indicate steroid-responsive disease; they carry significant risks. Anticoagulation is not a treatment for proteinuria. A repeat biopsy is not routinely required before adding SGLT2 therapy.