What is the recommended treatment for an adult with new‑onset nephrotic syndrome and diabetes?

Treatment of Adult-Onset Nephrotic Syndrome in Patients with Diabetes

In adults with diabetes presenting with new-onset nephrotic syndrome, the primary treatment is supportive care with RAS inhibition (ACE inhibitors or ARBs), sodium restriction, diuretics, and statins—immunosuppression should NOT be initiated until kidney biopsy confirms a primary glomerular disease rather than diabetic nephropathy. 1, 2, 3

Critical First Step: Establish the Underlying Cause

The most important initial consideration is that diabetes mellitus is the most common secondary cause of nephrotic syndrome in adults 3, 4. This distinction is critical because:

• Immunosuppression should NOT be used for secondary causes of nephrotic syndrome (including diabetic nephropathy), as risks outweigh benefits 1, 2
• Kidney biopsy remains the gold standard for distinguishing diabetic nephropathy from primary glomerular diseases that may benefit from immunosuppression 1
• In adults with steroid-resistant nephrotic syndrome and FSGS on biopsy, 11-24% will have genetic causes that also do not respond to immunosuppression 2

When to Suspect Primary Glomerular Disease vs. Diabetic Nephropathy

Consider kidney biopsy if any of the following are present:

• Short duration of diabetes (<5 years) or absent diabetic retinopathy 4, 5
• Rapid onset of proteinuria rather than gradual progression 4
• Active urinary sediment with dysmorphic RBCs or cellular casts 1
• Absence of other diabetic microvascular complications 5

Universal Supportive Care (All Patients Regardless of Cause)

Proteinuria and Blood Pressure Management

• Initiate ACE inhibitor or ARB therapy for all patients with proteinuria (UPCR >50 mg/mmol) or hypertension 1, 6, 3
• Losartan is specifically FDA-approved for diabetic nephropathy with elevated creatinine and proteinuria (albumin-to-creatinine ratio ≥300 mg/g) 6
• Maximize RAS inhibition before considering any immunosuppression 2, 7

Edema Management

• Sodium restriction (typically <2 g/day) and fluid restriction 1, 3, 4
• Loop diuretics (furosemide 0.5-2 mg/kg per dose, up to 6 times daily; maximum 10 mg/kg/day) 1, 3, 4
• If albumin infusions are given for severe hypovolemia, administer furosemide (0.5-2 mg/kg) at the end of each infusion 1
• Avoid routine prophylactic albumin infusions—reserve only for clinical signs of hypovolemia (hypotension, tachycardia) 7, 3

Cardiovascular Risk Reduction

• Statin therapy for persistent dyslipidemia (target LDL <100 mg/dL) 1, 3, 4
• Patients with nephrotic syndrome have 29% risk of renal vein thrombosis and 17-28% risk of pulmonary embolism 2
• Consider anticoagulation if serum albumin <2.0 g/dL, especially if persistent or with additional risk factors 1
• Routine prophylactic anticoagulation is NOT recommended without specific indications 3, 4

SGLT2 Inhibitors for CKD Protection

• For patients with eGFR ≥20 mL/min/1.73 m² and UACR ≥200 mg/g, add SGLT2 inhibitor (e.g., dapagliflozin) for kidney protection 2
• Use on top of maximally tolerated RAS inhibition, not as replacement 2
• Monitor for initial eGFR dip of 3-5 mL/min/1.73 m² in first 4 weeks (reversible, not indication to stop) 2
• Hold during acute illness with nausea/vomiting/diarrhea to prevent ketoacidosis 2

If Biopsy Confirms Primary Glomerular Disease

Minimal Change Disease (Rare in Diabetic Adults)

• Prednisone 1 mg/kg/day (maximum 80 mg) or 2 mg/kg every other day (maximum 120 mg) for at least 8 weeks 7
• Response rate in adults is 76% at 8 weeks (slower than children) 7
• Cyclosporine 3-5 mg/kg/day (target trough 125-175 ng/mL) is alternative for steroid contraindications, particularly relevant in diabetics 7

Focal Segmental Glomerulosclerosis (FSGS)

• Prednisone 1 mg/kg/day (maximum 80 mg) for minimum 4 weeks, up to 16 weeks as tolerated or until complete remission 1, 2, 7
• Taper slowly over 6 months after achieving complete remission 1, 2
• For steroid-resistant FSGS: Cyclosporine 3-5 mg/kg/day for at least 6 months (response rate ~70%, but 50% relapse rate) 1, 7
• Tacrolimus shows similar efficacy to cyclosporine 1
• Caution with CNIs in diabetics: must monitor for nephrotoxicity, especially with vascular disease on biopsy or decreased eGFR 1

Membranous Nephropathy

• Observe for 6 months with maximal supportive care before immunosuppression if proteinuria >4 g/day but stable renal function 1
• Initiate immunosuppression if: proteinuria persistently >4 g/day and remains >50% baseline after 6 months, OR severe/disabling symptoms, OR creatinine risen by 30% in 6-12 months with eGFR >25-30 mL/min/1.73 m² 1
• 6-month course of alternating monthly cycles of oral/IV corticosteroids and oral alkylating agents (cyclophosphamide or chlorambucil) 1
• Calcineurin inhibitors are alternative for CNI-based protocols 1

Common Pitfalls to Avoid

• Do NOT start immunosuppression without biopsy confirmation in diabetic patients—diabetic nephropathy is the most likely diagnosis and will not benefit 1, 2, 3
• Do NOT use insufficient treatment duration—adults require longer courses than children (minimum 4-8 weeks for initial response assessment) 7
• Do NOT ignore genetic testing in early-onset disease, family history, or steroid resistance—11-24% have genetic causes 2
• Steroid toxicity is significantly higher in diabetics—consider CNIs as first-line if diabetes is poorly controlled 1, 7
• Monitor for infections—increased susceptibility due to loss of immunoglobulins, compounded by diabetes and immunosuppression 2, 3

Monitoring During Treatment

• Proteinuria monitoring using spot protein-to-creatinine ratio or 24-hour urine collection 1, 7
• Complete remission defined as proteinuria <200 mg/g (<20 mg/mmol) or trace/negative on dipstick for 3 consecutive days 7
• Visits every 2-4 weeks for first 2-4 months, then every 3-6 months lifelong 1
• Screen for latent infections before immunosuppression initiation 1
• Monitor therapeutic drug levels for CNIs where indicated 1