Lupus nephritis and systemic disease: Case

This girl has systemic lupus erythematosus with active proliferative lupus nephritis. The diagnosis rests on the multisystem clinical picture (malar rash sparing the nasolabial folds, oral ulcers, symmetrical arthritis), the active urinary sediment (haematuria with dysmorphic red cells and red cell casts, proteinuria), mild renal impairment, and the serological signature of active lupus (positive antinuclear antibody, strongly positive anti-dsDNA, and low complement C3 and C4). The combination of an active sediment with falling complement and high-titre anti-dsDNA is the serological signature of proliferative Class III or IV disease, which a renal biopsy would confirm. [1]

Clinical findings

The pattern is unequivocally that of proliferative lupus nephritis. The systemic features of lupus (malar rash, oral ulcers, arthritis) accompany the renal presentation, which is the common adolescent scenario. The active urinary sediment with dysmorphic red cells and red cell casts reflects the endocapillary inflammation and basement membrane disruption of proliferative disease. The proteinuria (urinalysis 2 plus, confirmed quantitatively) reflects the loss of the filtration barrier integrity. The mild renal impairment (creatinine of 98, slightly elevated for a 13-year-old) reflects the reduction in glomerular filtration from the proliferative and crescentic lesions. The hypertension (140 over 90, above the 95th centile for age) is driven by the inflammatory and ischaemic injury to the glomerulus and the renin-mediated vasoconstriction that follows. [1]

The serology confirms active immune-complex disease. The low C3 (0.42) and low C4 (0.07) reflect consumption of both components through classical complement pathway activation by the glomerular immune complexes, which distinguishes lupus from post-infectious glomerulonephritis where only C3 falls. The strongly positive anti-dsDNA (350 IU per mL) is the antibody that forms the nephritogenic immune complexes and correlates with disease activity and nephritis. The homogeneous antinuclear antibody pattern is consistent with lupus. [1]

Investigations and diagnosis

A renal biopsy was performed and confirmed Class IV diffuse proliferative lupus nephritis. Light microscopy showed proliferative endocapillary and extracapillary changes affecting 68 percent of glomeruli, with subendothelial deposits visible as wire-loop changes, fibrinoid necrosis, and cellular crescents in 18 percent of glomeruli. Immunofluorescence showed the full-house pattern with granular staining for IgG, IgA, IgM, C3, and C1q. The activity index was high and the chronicity index was low, which is a favourable prognostic combination predicting responsiveness to immunosuppression. [1]

The differential diagnosis was considered. Post-infectious glomerulonephritis was excluded by the low C4 (which is normal in post-infectious disease), the strongly positive anti-dsDNA, the chronic multisystem presentation, and the full-house immunofluorescence. IgA nephropathy was excluded by the multisystem features, the hypocomplementaemia, and the full-house rather than IgA-dominant pattern. ANCA-associated vasculitis was excluded by the negative ANCA. The biopsy confirmed the diagnosis and provided the activity-versus-chronicity data needed to guide treatment. [1]

Management and outcome

Management began with blood pressure control using amlodipine and salt restriction for her hypertension and oedema. Induction therapy was started promptly given the active proliferative disease with crescents. She was commenced on mycophenolate mofetil (titrated to a target of 2 g per day in two divided doses), chosen over cyclophosphamide as first-line because of its non-inferior efficacy and the avoidance of gonadal toxicity in a girl approaching reproductive age, supported by the ALMS trial. This was combined with three daily pulses of intravenous methylprednisolone (500 mg) followed by oral prednisolone at 0.6 mg per kg per day, planned to taper. Hydroxychloroquine was started at 5 mg per kg per day. [2]

Before starting immunosuppression, she was screened for latent tuberculosis, hepatitis B and C, and HIV, all negative, and her pneumococcal, influenza, hepatitis B, and human papillomavirus vaccination status was confirmed. She and her family were counselled about the teratogenicity of mycophenolate and the need for reliable contraception, the side effects of glucocorticoids with bone protection (calcium and vitamin D), and the importance of adherence to long-term therapy. Ophthalmological baseline was arranged for hydroxychloroquine surveillance. [2]

Over the first three months of induction, her protein-to-creatinine ratio fell from 1.8 to 0.6, her creatinine normalised, her complement C3 rose to 0.75 and C4 to 0.14, and her anti-dsDNA titre fell. Her prednisolone was tapered. She was transitioned to maintenance therapy with mycophenolate (1.5 g per day) and continued hydroxychloroquine, with the treat-to-target goal of a complete renal response (protein-to-creatinine ratio below 0.5 and creatinine at baseline). The family was counselled that achieving this response within the first year predicts long-term renal survival, and that persistent proteinuria is the strongest predictor of progression to end-stage kidney disease. She will need long-term nephrology and rheumatology follow-up with a structured transition to adult care in late adolescence. [3]

The counterfactual: if the disease was refractory

If this girl had failed to achieve a partial response after six months of standard mycophenolate-based induction, she would be classified as having refractory lupus nephritis and the management would escalate. The options would be a switch to low-dose Euro-Lupus cyclophosphamide (500 mg every 2 weeks for 6 doses), the addition of a calcineurin inhibitor as multi-target triple therapy, or a biologic agent. Rituximab, a chimeric anti-CD20 monoclonal antibody that depletes B cells, is the most commonly used biologic in refractory disease, despite the LUNAR trial not meeting its primary endpoint as an add-on, because it is effective in clinical practice for patients who have failed standard therapy. Voclosporin, established by the AURORA trial, is an alternative calcineurin inhibitor approved in adults with paediatric experience emerging. This counterfactual illustrates why early adequate induction, sustained maintenance, and treat-to-target monitoring are essential to avoid the refractory state and the cumulative renal damage that drives progression to end-stage kidney disease. [3]