Advanced Renal Clinic: Nephrotic Syndrome — When Should You Biopsy?

Correct answer: D. The combination of a substantial recent eGFR decline, dysmorphic haematuria, active urinary sediment, abrupt nephrotic-range proteinuria, and absent established diabetic retinopathy is atypical for uncomplicated diabetic kidney disease. These findings should prompt evaluation for a primary glomerular disease, secondary membranous nephropathy, or dual pathology. Oedema and dyslipidaemia are consequences of nephrotic syndrome rather than discriminating clues, while hypertension and SGLT2-inhibitor use do not establish the underlying diagnosis.

Correct answer: A. The correct approach is parallel assessment and stabilization. The patient needs quantification of proteinuria, urine-sediment review, kidney-function and electrolyte monitoring, secondary-cause testing, medication review, assessment for venous thromboembolism and infection, renal imaging, and biopsy planning. Supportive care can include sodium restriction, carefully monitored diuresis for symptomatic oedema, blood-pressure and proteinuria management, and avoidance of NSAIDs. Empiric immunosuppression before establishing the diagnosis can obscure pathology and expose the patient to avoidable harm. Anticoagulation is individualized according to thrombotic risk, albumin, histology, bleeding risk, and patient preference. Dual renin–angiotensin blockade and routine intravenous albumin are not appropriate default strategies.

Correct answer: C. A clearly positive anti-PLA2R result strongly supports PLA2R-associated primary membranous nephropathy and can provide useful prognostic and monitoring information. However, quantitative values are method-specific, there is no universally calibrated international standard across platforms, and a positive result is not an isolated command to biopsy or treat. High titres generally correlate with greater immunologic activity and lower likelihood of immediate spontaneous remission, but thresholds should not be transferred between assays without laboratory guidance. A positive result does not eliminate secondary-cause assessment or exclude coexisting diabetic or other renal pathology.

Correct answer: B. Although serology-led diagnosis may be reasonable in selected adults with typical nephrotic syndrome, preserved kidney function, and no atypical features, this patient has several reasons to obtain tissue. Dysmorphic haematuria, eGFR decline, diabetes without established retinopathy, and the possibility of dual or secondary disease reduce diagnostic certainty. Biopsy may alter prognosis, identify chronicity, reveal coexisting diabetic or inflammatory lesions, and redirect treatment or secondary-cause evaluation. A repeat assay may be useful for an unexpected or borderline result but does not replace assessment of biopsy value.

Correct answer: E. Secondary membranous nephropathy may be associated with autoimmune disease, infections, malignancy, medications or toxins, and monoclonal or other systemic disease. Assessment should be targeted to age, symptoms, epidemiology, pathology, exposure history, examination, and laboratory findings. No single test rules out all secondary causes, and a positive PLA2R result supports primary disease but does not negate clinical clues pointing elsewhere. Indiscriminate whole-body imaging is not a substitute for risk-based assessment.

Correct answer: D. Persistent severe nephrosis, albumin 17 g/L, reduced eGFR, high anti-PLA2R activity, and lack of early improvement indicate high-to-very-high risk of complications and progressive kidney-function loss. A specialist-led risk-based immunosuppressive discussion is therefore appropriate. Cyclical glucocorticoid–cyclophosphamide therapy has an important role in high- and very-high-risk disease, while rituximab is a key alternative when diabetes, fertility preservation, cumulative cyclophosphamide exposure, or steroid toxicity influence the decision. Calcineurin inhibitors may be used in selected patients but require careful nephrotoxicity monitoring. Unstructured multi-agent therapy is not a default strategy.

Correct answer: A. Rituximab requires pre-treatment safety assessment. Important elements include hepatitis B screening, review for active or latent infection according to local policy, vaccination planning, CBC, renal and liver function, immunoglobulin assessment when relevant, diabetes and cardiovascular-risk review, and discussion of infusion reactions and delayed infection. Pneumocystis prophylaxis should be considered according to the intensity of accompanying immunosuppression and local protocol. Live vaccines are generally avoided around significant immunosuppression, and dosing should not be repeated automatically based only on a positive antibody result.

Correct answer: C. The patient has a meaningful immunologic response and partial clinical remission. Anti-PLA2R commonly falls or becomes undetectable before proteinuria fully resolves, because repair of the glomerular filtration barrier and clearance of immune deposits take time. Treatment failure should not be diagnosed from residual proteinuria alone when proteinuria and albumin are improving, eGFR is stable, and antibody activity has resolved. Continue supportive care and monitor urine protein, albumin, eGFR, electrolytes, blood pressure, oedema, infection risk, and thromboembolic complications. Repeat biopsy is reserved for diagnostic uncertainty or an unexpected course.

Correct answer: E. The combination of recurrent nephrotic syndrome and a substantial rise in anti-PLA2R on the same assay strongly supports immunologic relapse. The clinician should confirm the change, repeat relevant safety tests, assess thrombosis and infection, review medication adherence and exposures, and reconsider secondary disease if new clues have appeared. A patient who previously responded to rituximab may respond to retreatment, but the decision depends on current disease risk, prior response, B-cell status where used, immunoglobulins, infection risk, and alternative regimen options. Diuretics address oedema but not immunologic relapse. Corticosteroid monotherapy, plasma exchange, and automatic repeat biopsy are not default responses.

Correct answer: D. Refractory disease requires a structured reassessment. The team should confirm that the clinical phenotype remains concordant with the original biopsy, reconsider secondary membranous nephropathy or a second renal process, verify dose and timing, review adherence and pharmacologic exposure, and assess B-cell depletion and immunoglobulin levels. Incomplete B-cell depletion, low drug exposure, anti-drug antibodies, urinary loss of rituximab, or irreversible glomerular damage may contribute to apparent resistance. If active immunologic disease and declining kidney function persist, an expert centre may discuss a different guideline-consistent regimen such as cyclical glucocorticoid–cyclophosphamide therapy or a selected CNI-containing strategy. Repeated dosing with hypogammaglobulinaemia or infection risk may be harmful.