Lupus nephritis and systemic disease: Viva

Branch 1: Classification and the biopsy

The candidate should identify this biopsy as Class IV diffuse proliferative lupus nephritis, the most common and most severe paediatric pattern. The defining feature is proliferative endocapillary and extracapillary change affecting 50 percent or more of glomeruli (65 percent in this case), with subendothelial deposits visible as wire-loop lesions and cellular crescents. A strong candidate should place this in the six-class ISN/RPS 2003 framework: Class I minimal mesangial and Class II mesangial proliferative are mild mesangial-only disease, Class III focal proliferative involves under 50 percent, Class IV diffuse proliferative involves 50 percent or more and is subdivided into IV-S segmental and IV-G global, Class V membranous shows subepithelial deposits with nephrotic-range proteinuria, and Class VI advanced sclerosing shows over 90 percent global sclerosis. The practical divide is proliferative (III, IV) versus non-proliferative. [1]

If the examiner presses on the full-house immunofluorescence, the candidate should explain that it means granular staining for all major immunoglobulins (IgG, IgA, IgM) and complement components (C3, C1q), which distinguishes lupus from other glomerulonephritides where the deposition is more restricted (IgA-dominant in IgA nephropathy). The candidate should also explain the activity-versus-chronicity indices: the activity index scores reversible inflammation (crescents, necrosis) and predicts response to immunosuppression, while the chronicity index scores irreversible damage (sclerosis, atrophy, fibrosis) and predicts the long-term outcome. [1]

Branch 2: Pathophysiology and serology

If asked about the mechanism, the candidate should describe the immune-complex cascade. Loss of tolerance to nuclear antigens releases double-stranded DNA from defective apoptotic clearance. Anti-dsDNA autoantibodies bind the DNA to form circulating immune complexes that deposit in the glomerulus. Subendothelial deposits, in contact with the bloodstream, trigger the aggressive proliferative pattern with endocapillary proliferation, wire-loop lesions, and crescents. The immune complexes activate the classical complement pathway (C1q, C3, C5b-9), which is why her C3 and C4 are low. A strong candidate should link the serology to the activity: the rising anti-dsDNA with falling complement is the signature of a flare, and these markers are used to monitor the response to treatment. [1]

Branch 3: The treatment plan

If asked about management, the candidate should structure the answer around the induction-maintenance paradigm. For induction, the first-line choice is mycophenolate mofetil (target 2 to 3 g per day) plus glucocorticoids, because the ALMS trial confirmed non-inferiority to cyclophosphamide while avoiding gonadal toxicity, which is critical in a 14-year-old girl. Low-dose Euro-Lupus cyclophosphamide (500 mg every 2 weeks for 6 doses) is the alternative for severe disease or mycophenolate failure. Induction lasts 3 to 6 months and is accompanied by methylprednisolone pulses and a prednisolone taper. [2]

The candidate should then describe maintenance: mycophenolate (1 to 2 g per day) or azathioprine (1 to 2 mg per kg per day) for years, with hydroxychloroquine (5 mg per kg per day) for every patient because it reduces flares and improves renal survival. The treat-to-target goal is a complete renal response with protein-to-creatinine ratio below 0.5 and creatinine at baseline, and achieving this in the first year predicts long-term renal survival. A strong candidate should address the reproductive counselling: mycophenolate and cyclophosphamide are teratogenic and demand reliable contraception, cyclophosphamide threatens ovarian reserve (the reason mycophenolate is preferred), and pregnancy should be planned during remission with a switch to azathioprine and hydroxychloroquine. [3]

If the examiner asks about refractory disease, the candidate should list the escalation options: switching between mycophenolate and cyclophosphamide, adding a calcineurin inhibitor as multi-target triple therapy, or using a biologic (rituximab, a B-cell-depleting anti-CD20 antibody, or belimumab, a B-cell-activating-factor antagonist). The candidate should note that the LUNAR trial was negative for rituximab as an add-on but that rituximab is widely used off-label in refractory disease, and that voclosporin, established by the AURORA trial, is approved in adults with paediatric experience emerging. [3]