What treatment is recommended for a patient with proteinuria and hypertension?

Management of Proteinuria and Hypertension

Start an ACE inhibitor or ARB immediately and uptitrate to the maximum tolerated dose, targeting systolic blood pressure <120 mmHg in most patients, with mandatory dietary sodium restriction to <2.0 g/day. 1, 2, 3

Initial Diagnostic Workup

Before initiating treatment, assess the following:

• Quantify proteinuria using urine protein-to-creatinine ratio or 24-hour urine collection to establish baseline severity 4, 1
• Measure baseline serum creatinine and eGFR to assess renal function 4, 3
• Check serum potassium as RAS blockade can cause hyperkalemia 3
• Evaluate for secondary causes of proteinuria if clinically indicated (e.g., diabetes, autoimmune disease) 4
• Assess cardiovascular risk factors including lipid panel, hemoglobin A1c if diabetic 4

Primary Pharmacologic Treatment

ACE Inhibitor or ARB Therapy

Initiate ACE inhibitor or ARB as first-line therapy regardless of current blood pressure status if proteinuria ≥1 g/day. 4, 1, 2

• For proteinuria 0.5-1 g/day, strongly consider starting ACE inhibitor or ARB even without hypertension 4, 1
• Uptitrate to maximum tolerated or FDA-approved dose, not just to blood pressure control—the goal is proteinuria reduction to <1 g/day 4, 1, 2
• Examples of maximum doses: lisinopril 40 mg daily, losartan 100 mg daily, ramipril 10 mg daily 5, 6

Blood Pressure Targets

Target systolic blood pressure <120 mmHg using standardized office measurements in most patients with proteinuria. 1, 2, 3

• In IgA nephropathy specifically: target <130/80 mmHg if proteinuria <1 g/day; <125/75 mmHg if proteinuria ≥1 g/day 4
• For patients with diabetes and hypertension: target systolic BP to 130 mmHg and <130 mmHg if tolerated, but not <120 mmHg 4
• Target diastolic BP <80 mmHg but not <70 mmHg 4

Essential Lifestyle Modifications

Restrict dietary sodium to <2.0 g/day (<90 mmol/day)—this is mandatory, not optional. 1, 2, 3

• Sodium restriction is synergistic with ACE inhibitor/ARB therapy and significantly enhances the antiproteinuric effect 1, 2, 3
• Achieve weight normalization through diet and exercise if overweight 4, 2
• Smoking cessation and regular physical activity (≥150 min/week moderate-to-vigorous exercise) 4, 3
• Limit alcohol consumption 4

Add-On Therapy for Inadequate Response

If blood pressure remains uncontrolled or proteinuria persists after 3-6 months of optimized ACE inhibitor/ARB:

Second-Line: Diuretic Therapy

Add a thiazide-like diuretic (chlorthalidone or indapamide preferred) or loop diuretic if volume overload present. 4, 2, 3

• Diuretics are the preferred second-line agent and enhance the antiproteinuric effect of RAS blockade 2, 7
• Uptitration of diuretic dosage on top of combined RAS blockade can further reduce proteinuria 7

Third-Line: Mineralocorticoid Receptor Antagonist

Add low-dose spironolactone (25-50 mg daily) or eplerenone for resistant proteinuria despite maximized ACE inhibitor/ARB and diuretic. 2, 3

• Requires careful potassium monitoring (check every 2-4 weeks initially) 3
• Consider potassium-binding agents if hyperkalemia develops to allow continued RAS blockade 3

For Diabetic Patients: SGLT2 Inhibitors

If the patient has diabetes with proteinuria >300 mg/g, add an SGLT2 inhibitor (empagliflozin, canagliflozin, or dapagliflozin) regardless of glycemic control. 4, 2

• SGLT2 inhibitors provide additive renoprotection to ARBs and reduce cardiovascular events 4
• Empagliflozin is specifically recommended to reduce risk of death in diabetic patients with CVD 4

Critical Monitoring Parameters

Expected Creatinine Changes

Accept up to 30% increase in serum creatinine after starting ACE inhibitor/ARB—this is hemodynamic and expected, not a reason to stop therapy. 1, 3

• Only discontinue if kidney function continues to worsen beyond 30% increase or refractory hyperkalemia develops 1
• This modest creatinine elevation represents beneficial hemodynamic changes and should not prompt premature discontinuation 1

Monitoring Schedule

Check labs every 2-4 weeks initially: serum creatinine, eGFR, potassium, and urine protein-to-creatinine ratio. 3

• Target proteinuria reduction of ≥25% by 3 months, ≥50% by 6 months 3
• Aim for absolute proteinuria <1 g/day or at least 30-50% reduction from baseline 2, 3
• Monitor blood pressure regularly with home measurements to detect hypotension 4

Common Pitfalls to Avoid

Do not discontinue ACE inhibitors prematurely due to modest creatinine elevation—this removes critical renoprotection. 1

• The up to 30% creatinine increase is an expected hemodynamic effect, not nephrotoxicity 1

Do not combine ACE inhibitor with ARB in most patients. 1

• Combination therapy increases adverse effects (hyperkalemia, acute kidney injury) without additional benefit in most patients 1
• The exception is carefully selected patients with severe resistant proteinuria under close monitoring 8, 6

Counsel patients to hold ACE inhibitor/ARB and diuretics during intercurrent illnesses with risk of volume depletion (gastroenteritis, fever, reduced oral intake). 1, 3

• This prevents acute kidney injury during volume-depleted states 1, 3

Do not use nondihydropyridine calcium channel blockers (diltiazem, verapamil) with calcineurin inhibitors if immunosuppression is being considered, as they can dramatically increase CNI levels. 4

Additional Cardiovascular Risk Management

Consider statin therapy for persistent dyslipidemia, particularly in patients with other cardiovascular risk factors. 4, 3

• In type 2 diabetes at very high CV risk: target LDL-C <1.4 mmol/L (<55 mg/dL) with ≥50% reduction 4
• Statins are first-choice lipid-lowering treatment; add ezetimibe if target not reached 4

Consider GLP-1 receptor agonists (liraglutide, semaglutide, or dulaglutide) in diabetic patients with CVD or very high/high CV risk to reduce cardiovascular events and mortality. 4

Timeline for Reassessment

Optimize ACE inhibitor/ARB therapy for 3-6 months before considering additional immunosuppressive therapy. 1

• If proteinuria remains >1 g/day after 3-6 months of optimized supportive care (maximum-dose RAS blockade, sodium restriction, blood pressure control), consider kidney biopsy if not already performed and evaluate for immunosuppression 1

Special Consideration: When to Delay ACE Inhibitor/ARB

Delay ACE inhibitor initiation in patients presenting with abrupt onset nephrotic syndrome, particularly if minimal change disease is suspected. 1

• ACE inhibitors can cause acute kidney injury in this specific setting 1
• Delay until after immunosuppression response in patients expected to be rapidly responsive without hypertension 1