Lupus nephritis and systemic disease: SAQ

This girl has proliferative lupus nephritis. The combination of an active urinary sediment (haematuria with dysmorphic red cells and red cell casts), proteinuria, mild renal impairment, low complement (both C3 and C4), and strongly positive anti-dsDNA antibodies in an adolescent girl with systemic lupus features is diagnostic of lupus nephritis. The biopsy confirms Class IV diffuse proliferative disease, the most common and most severe paediatric pattern, defined by proliferative lesions affecting 50 percent or more of glomeruli with subendothelial deposits, wire-loop changes, and cellular crescents. The full-house immunofluorescence pattern is the histological hallmark. [1]

Question 1 (10 marks)

Outline your initial management of this child, including the choice of induction therapy, the role of glucocorticoids, and the specific counselling required before starting treatment. [2]

The overriding principle is prompt induction of the active proliferative inflammation to prevent irreversible glomerular scarring, because the cellular crescents and fibrinoid necrosis on her biopsy mark severe active disease that is reversible only if treated early. I would first stabilise her hypertension with amlodipine and manage her fluid status with salt restriction, because uncontrolled hypertension worsens the renal injury. I would involve a paediatric nephrologist and rheumatologist on the day of the biopsy result. [2]

For induction, my first-line choice is mycophenolate mofetil, because the pivotal trials established that it is non-inferior to cyclophosphamide for induction while avoiding gonadal toxicity, which is the critical consideration in a 13-year-old girl approaching reproductive age. I would target a dose of 2 to 3 g per day in two divided doses, starting lower and up-titrating to manage gastrointestinal side effects. This would be combined with intravenous methylprednisolone pulses (500 mg to 1 g daily for 3 days) followed by oral prednisolone (0.5 to 1 mg per kg per day, maximum 60 mg per day) tapered to the lowest effective dose. Low-dose Euro-Lupus cyclophosphamide (500 mg every 2 weeks for 6 doses) would be the alternative if she failed mycophenolate or had very severe disease with a high crescent burden. [2]

The specific counselling before starting treatment centres on the teratogenicity of mycophenolate, which demands reliable contraception and pregnancy avoidance in an adolescent girl. I would also counsel about the side effects of glucocorticoids (growth suppression, weight gain, glucose intolerance, osteoporosis, mood changes) and the need for bone protection with calcium and vitamin D. I would screen for latent tuberculosis, hepatitis, and HIV before immunosuppression, ensure her vaccinations (pneumococcal, influenza, hepatitis B, human papillomavirus) are up to date while avoiding live vaccines, and start hydroxychloroquine at 5 mg per kg per day for its proven benefit in reducing flares and improving renal outcomes. [2]

I would set a treat-to-target goal of a complete renal response: a urine protein-to-creatinine ratio below 0.5 with her creatinine at baseline, monitored at every clinic visit alongside the complement and anti-dsDNA titre. [2]

Question 2 (10 marks)

Describe how the diagnosis and management would differ if the same girl had presented with nephrotic-range proteinuria (protein-to-creatinine ratio of 4.5), a serum albumin of 18 g per litre, minimal haematuria, normal complement, and a biopsy showing diffuse subepithelial deposits with spike-and-dome changes and no endocapillary proliferation. [1]

This girl would have pure membranous Class V lupus nephritis rather than proliferative Class IV disease. The key differences are the histological pattern, the clinical syndrome, and the management emphasis. Class V is defined by global or segmental subepithelial immune deposits that injure the podocyte and produce nephrotic-range proteinuria with little or no haematuria and often preserved renal function, because the subepithelial deposits sit on the outer side of the basement membrane away from the endocapillary inflammation that causes bleeding and crescents. The spike-and-dome appearance on light microscopy and the subepithelial deposits on electron microscopy confirm the pattern. [1]

The management differs in two important ways. First, the immunosuppression for pure Class V is mycophenolate mofetil or a calcineurin inhibitor plus glucocorticoids, rather than the cyclophosphamide-containing regimens reserved for the most aggressive proliferative disease. Calcineurin inhibitors are particularly useful in membranous disease because they stabilise the podocyte cytoskeleton and reduce proteinuria independently of their immunosuppressive effect. Second, the management of the nephrotic state becomes the central focus, because the heavy proteinuria with a serum albumin of 18 g per litre carries a substantial thrombotic risk. [1]

I would address the nephrotic state with loop diuretics (furosemide 1 to 2 mg per kg per dose) and strict salt restriction for her oedema, lipid management for the hyperlipidaemia of nephrotic syndrome, and, critically, prophylactic anticoagulation, because a serum albumin below 25 g per litre in nephrotic-range proteinuria warrants thromboprophylaxis to prevent renal vein thrombosis and pulmonary embolism. This thrombotic risk is magnified if she has antiphospholipid antibodies, which I would test for. Hydroxychloroquine at 5 mg per kg per day would still be given for all the reasons that apply to any lupus nephritis patient. [1]

The treat-to-target goal would be the same (protein-to-creatinine ratio below 0.5 with creatinine at baseline), but I would counsel the family that the proteinuria in membranous disease often takes longer to resolve than in proliferative disease, and that Class V carries a higher long-term risk of progression to end-stage kidney disease if the proteinuria is not controlled. The long-term prognosis, with adherence to maintenance therapy (mycophenolate or azathioprine) and sustained proteinuria control, is generally good. [3]