Management of Diabetic Nephropathy with Nephrotic-Range Proteinuria
Start an ACE inhibitor or ARB immediately and uptitrate to the maximum tolerated dose, targeting systolic blood pressure <120 mmHg, while restricting dietary sodium to <2.0 g/day. 1, 2
First-Line Pharmacologic Therapy
ACE inhibitors or ARBs are mandatory first-line therapy for diabetic nephropathy with significant proteinuria, with aggressive uptitration to the maximum tolerated or FDA-approved daily dose for optimal antiproteinuric effect. 1, 3
For losartan specifically, the optimal antiproteinuric dose is 100 mg daily in patients with nephrotic-range proteinuria, as the 50 mg dose is less effective and 150 mg provides no additional benefit. 4
The RENAAL trial demonstrated that losartan (50-100 mg daily) in type 2 diabetic nephropathy patients reduced the composite endpoint of doubling serum creatinine, end-stage renal disease, or death by 16%, reduced ESRD by 28%, and decreased proteinuria by 35%. 5, 6
Target systolic blood pressure <120 mmHg using standardized office measurements, as validated in multiple guidelines. 1, 2
Critical Dietary Intervention
Restrict dietary sodium to <2.0 g/day (<90 mmol/day) as this is synergistic with ACE inhibitor/ARB therapy and significantly enhances the antiproteinuric effect. 1, 2
This sodium restriction is not optional—it is a mandatory component that amplifies the benefit of RAS blockade. 1
Management of Edema and Volume Overload
Use loop diuretics (furosemide) for edema management, which can be administered as bolus or continuous infusion depending on severity. 2
Add diuretics as the preferred second-line agent if blood pressure remains uncontrolled or volume overload is present. 1
Monitoring Strategy
Check labs every 2-4 weeks initially, including serum creatinine, eGFR, potassium, and urine protein-to-creatinine ratio. 1, 3
Continue ACE inhibitor/ARB therapy unless serum creatinine rises by more than 30% within 4 weeks of initiation or dose increase. 3
Target proteinuria reduction of ≥25% by 3 months and ≥50% by 6 months as markers of therapeutic success. 1
Management of Hyperkalemia
Use potassium-wasting diuretics and/or potassium-binding agents to reduce serum potassium to normal levels, allowing continued use of RAS blockade rather than discontinuing this critical therapy. 1, 2
Monitor serum potassium closely, as hyperkalemia is common with ACE inhibitors/ARBs, especially with reduced GFR. 3, 5
Refractory Proteinuria Management
If proteinuria persists despite maximized ACE inhibitor/ARB therapy and optimal blood pressure control, add a mineralocorticoid receptor antagonist (spironolactone 25-50 mg daily). 1, 2
Some evidence suggests combination therapy with ACE inhibitor plus ARB may provide greater antiproteinuric effect (51% reduction vs 33% with monotherapy), though this must be weighed against increased risks. 7
However, avoid dual RAS blockade in most patients as the VA NEPHRON-D trial showed no additional benefit for the combined endpoint but increased incidence of hyperkalemia and acute kidney injury compared to monotherapy. 5
Cardiovascular Risk Management
- Consider statin therapy for persistent dyslipidemia, particularly given the high cardiovascular risk in diabetic nephropathy patients. 1, 2
Critical Patient Counseling
- Counsel patients to hold ACE inhibitor/ARB and diuretics during intercurrent illnesses or when at risk for volume depletion (sick day rules) to prevent acute kidney injury. 1, 2
Common Pitfalls to Avoid
Do not stop ACE inhibitor/ARB for mild creatinine elevations (<30% increase)—this is an expected hemodynamic effect and the long-term renal benefits far outweigh this concern. 3
Do not use ACE inhibitor/ARB monotherapy without aggressive sodium restriction—you will miss substantial antiproteinuric benefit. 1
Do not coadminister aliskiren with losartan in diabetic patients, as this is contraindicated. 5
Monitor for NSAIDs use, as these can attenuate the antihypertensive and antiproteinuric effects of RAS blockade and worsen renal function. 5