What is the best course of treatment for a 44-year-old man with hyperlipidaemia (high cholesterol), who presents with nephrotic syndrome (NS) characterized by progressive bilateral lower limb oedema, frothy urine, and unintentional weight gain, and has a history of responding to corticosteroid therapy with intravenous methylprednisolone and oral prednisolone, but experienced a relapse after a few months?

Management of Relapsing Nephrotic Syndrome in Adults

For this 44-year-old man with steroid-responsive but relapsing nephrotic syndrome (likely minimal change disease based on biopsy findings), continue corticosteroid therapy with prednisolone at 1 mg/kg/day (maximum 80 mg) until complete remission is achieved, then transition to alternate-day dosing for at least 3 months, while simultaneously adding a steroid-sparing agent such as a calcineurin inhibitor (cyclosporine 3-5 mg/kg/day or tacrolimus 0.05-0.1 mg/kg/day) to prevent future relapses and minimize cumulative steroid toxicity. 1, 2

Immediate Management of Current Relapse

Corticosteroid Reinitiation

• Restart prednisolone at 1 mg/kg/day (approximately 60-80 mg daily for this patient) as a single morning dose until urine protein becomes trace/negative for at least 3 consecutive days 2, 3
• Given the severe edema described at relapse, consider intravenous methylprednisolone 30 mg/kg (approximately 2.5 grams for this patient) administered over at least 30 minutes for 3 consecutive days, followed by oral prednisolone, as this achieves faster remission in highly edematous patients (median 14 days vs 16 days, P=0.024) 4, 3
• After achieving remission (proteinuria <200 mg/g or trace on dipstick for 3 days), transition to alternate-day prednisolone at 40 mg/m² (approximately 60-70 mg) for a minimum of 3 months to reduce relapse risk 2, 5

Aggressive Edema Management

• Increase furosemide to 80-120 mg daily in divided doses (the patient was already on 40 mg, which proved insufficient) 6, 2
• Strictly restrict dietary sodium to <2.0 g/day (<90 mmol/day) 6, 2
• Restrict fluid intake to 800-1000 mL/day as already prescribed 6
• If diuretic response remains inadequate, add a thiazide diuretic (hydrochlorothiazide 25-50 mg daily) or metolazone 2.5-5 mg daily for synergistic effect 6, 1

Long-Term Management Strategy

Addition of Steroid-Sparing Agent (Critical for Relapsing Disease)

This patient has demonstrated steroid-dependent/frequently relapsing disease and requires a steroid-sparing agent to prevent future relapses and avoid cumulative steroid toxicity. 1, 2

• First-line steroid-sparing option: Calcineurin inhibitor (CNI)

  • Cyclosporine 3-5 mg/kg/day in two divided doses (preferred over tacrolimus due to lower risk of precipitating diabetes in this patient with hyperlipidemia and obesity) 1
  • Alternative: Tacrolimus 0.05-0.1 mg/kg/day in two divided doses 1, 2
  • CNIs are particularly appropriate for this 44-year-old adult given the increased risk of steroid-related complications (osteoporosis, diabetes, cardiovascular disease) compared to children 1
  • Monitor trough levels: cyclosporine target 100-175 ng/mL; tacrolimus target 5-10 ng/mL 1

• Alternative steroid-sparing options if CNI contraindicated or not tolerated:

  • Rituximab (375 mg/m² weekly for 4 doses or 1000 mg on days 1 and 15) 6
  • Mycophenolate mofetil 1-2 g/day in divided doses 7
  • Cyclophosphamide 2 mg/kg/day for 8 weeks (provides 70% remission at 2 years but carries significant toxicity concerns including infertility) 5

Optimization of Supportive Therapy

ACE Inhibitor/ARB Therapy:

• Up-titrate perindopril from current 2 mg to maximally tolerated dose (typically 8-16 mg daily) to reduce proteinuria and provide renoprotection 6
• Target blood pressure <120 mmHg systolic using standardized office measurement 6, 1
• Counsel patient to hold perindopril and diuretics during intercurrent illnesses to prevent volume depletion and acute kidney injury 6

Lipid Management:

• Continue simvastatin 40 mg nightly (already prescribed appropriately) 6
• Given this patient's severe hyperlipidemia (total cholesterol 16.26 mmol/L, triglycerides 7.79 mmol/L), obesity (BMI 32.6), and cardiovascular risk factors, consider adding ezetimibe 10 mg daily if lipid goals not achieved after 4-12 weeks 6
• Recheck fasting lipid panel 4-12 weeks after any medication adjustment 6

Thromboembolism Prophylaxis:

• This patient requires prophylactic anticoagulation given severe nephrotic syndrome (albumin 15 g/L, proteinuria 40 g/24h) and history of worsening leg swelling with tenderness 6
• Initiate prophylactic-dose low molecular weight heparin (enoxaparin 40 mg subcutaneously daily) or direct oral anticoagulant (rivaroxaban 10 mg daily or apixaban 2.5 mg twice daily) when albumin <2.5 g/dL and proteinuria >10 g/day 6
• Continue anticoagulation until sustained remission achieved (albumin >3.0 g/dL) 6

Infection Prophylaxis During Immunosuppression

Vaccinations (administer before intensifying immunosuppression if possible):

• Pneumococcal vaccine (23-valent PPSV23 or 13-valent PCV13) 6, 1, 2
• Annual influenza vaccine for patient and household contacts 6, 2
• Herpes zoster vaccine (recombinant preferred over live vaccine) 1

Screening:

• Screen for latent tuberculosis (tuberculin skin test or interferon-gamma release assay), hepatitis B, hepatitis C, and HIV before escalating immunosuppression 6, 1

Antimicrobial Prophylaxis:

• Trimethoprim-sulfamethoxazole 80/400 mg (single-strength) three times weekly during high-dose corticosteroid therapy (>20 mg prednisone daily) or when on cyclophosphamide/rituximab 6, 1

Monitoring Protocol

Short-Term (During Relapse Treatment)

• Daily urine dipstick or spot urine protein-to-creatinine ratio to assess response 2
• Complete remission defined as: urine protein <200 mg/g (<20 mg/mmol) or trace/negative on dipstick for 3 consecutive days 2
• Weekly serum creatinine, electrolytes, and albumin for first 4 weeks 6
• Monitor for steroid side effects: blood glucose, blood pressure, weight, mood changes 6

Long-Term (Maintenance Phase)

• Monthly urine protein-to-creatinine ratio and serum albumin for first 6 months, then every 3 months 6
• Serum creatinine and electrolytes every 3 months 6
• CNI trough levels every 2-4 weeks initially, then monthly once stable 1
• Fasting lipid panel every 3-12 months 6
• Monitor for CNI nephrotoxicity: rising creatinine, hypertension, hyperkalemia 1

Critical Pitfalls to Avoid

Do not declare treatment failure prematurely:

• Allow at least 8 weeks of adequate corticosteroid therapy before declaring steroid resistance 2
• Some patients show only partial response initially; continue therapy up to 16 weeks if gradual improvement occurring 2

Do not abruptly discontinue corticosteroids:

• After prolonged therapy (>3 weeks), taper gradually over several months to prevent adrenal insufficiency 6, 4
• Typical taper: reduce by 5-10 mg every 1-2 weeks once on <40 mg daily 5

Do not ignore the need for repeat biopsy in specific circumstances:

• While this patient declined repeat biopsy, strongly reconsider biopsy if: rapid deterioration in kidney function (doubling of creatinine over 1-2 months) without massive proteinuria (≥15 g/day), or if steroid resistance develops 6
• The initial biopsy showed mild mesangial proliferation with non-specific IgM staining, which could represent early focal segmental glomerulosclerosis (FSGS) that was missed due to sampling error 6

Do not use immunosuppression if contraindicated:

• Avoid immunosuppressive therapy if serum creatinine ≥3.5 mg/dL (eGFR ≤30 mL/min/1.73 m²) with small echogenic kidneys, or during active severe infections 6

Prognosis and Counseling

• Approximately 50% of adults with minimal change disease experience relapses, with this patient already demonstrating relapsing disease 5, 7
• Addition of a steroid-sparing agent (particularly CNI or rituximab) significantly reduces relapse frequency and allows steroid dose reduction 1, 7
• Cyclophosphamide provides approximately 70% sustained remission at 2 years but should be reserved for truly steroid-dependent disease given toxicity profile 5
• Counsel regarding fertility preservation if cyclophosphamide considered, particularly important for this 44-year-old man 6