What is the recommended treatment for a patient with hypertension and a high protein-to-creatinine ratio (proteinuria), despite having well-controlled blood pressures (hypertension)?

Management of Proteinuria in Hypertensive Patients with Well-Controlled Blood Pressure

Despite well-controlled blood pressure, you should intensify renin-angiotensin system (RAS) blockade therapy because proteinuria itself is an independent target requiring aggressive treatment beyond blood pressure control alone. 1

Primary Treatment Strategy: Optimize RAS Blockade

RAS blockers (ACE inhibitors or ARBs) are more effective at reducing albuminuria than other antihypertensive agents and are recommended as part of the treatment strategy in hypertensive patients with proteinuria, regardless of current blood pressure control. 1

Specific Medication Recommendations

• For patients with proteinuria ≥300 mg/g (or ≥300 mg/d), initiate or uptitrate an ACE inhibitor or ARB to maximum tolerated doses, as these agents provide blood pressure-independent antiproteinuric effects 1, 2, 3

• If already on an ARB or ACE inhibitor, uptitrate to maximum doses (e.g., losartan 100 mg daily, telmisartan 160 mg daily) before adding additional agents, as higher doses provide greater proteinuria reduction 4, 5

• Monitor serum creatinine and potassium within 7-14 days after initiation or dose changes, and accept up to 30% increase in creatinine as this does not warrant discontinuation 6, 7

Blood Pressure Targets Despite "Well-Controlled" Status

Target systolic BP to 120-129 mmHg (not just <140/90 mmHg) in patients with proteinuria and eGFR >30 mL/min/1.73 m², as lower targets provide additional renoprotection in proteinuric patients. 1

• The 2024 ESC guidelines recommend systolic BP range of 130-139 mmHg for most CKD patients, but 120-129 mmHg for those with moderate-to-severe CKD receiving BP-lowering drugs 1

• The 2017 ACC/AHA guidelines recommend BP <130/80 mmHg for all patients with CKD and proteinuria 1

• "Well-controlled" by traditional standards (140/90 mmHg) is insufficient for proteinuric patients—you need more aggressive BP lowering 3, 8

Add-On Therapy for Enhanced Proteinuria Reduction

First Add-On: Thiazide-Like Diuretic

Add a thiazide-like diuretic (chlorthalidone or indapamide preferred) to your RAS blocker if proteinuria persists despite maximum-dose RAS blockade. 1, 4

• The combination of losartan/hydrochlorothiazide reduces proteinuria more effectively than losartan alone, even when blood pressure is similar between groups, indicating blood pressure-independent renoprotective effects 4

• Use long-acting thiazide-like diuretics (chlorthalidone, indapamide) rather than hydrochlorothiazide when possible, as these have superior cardiovascular outcomes data 1

Second Add-On: Consider Mineralocorticoid Receptor Antagonist

For resistant proteinuria despite RAS blocker plus diuretic, add low-dose spironolactone (25-50 mg daily) or eplerenone, with careful potassium monitoring. 1

• Mineralocorticoid receptor antagonists provide additional antiproteinuric effects beyond conventional RAS blockade 9, 5

• Monitor potassium closely—check within 1 week of initiation and regularly thereafter, as hyperkalemia risk increases with dual RAAS effects 1, 6

SGLT2 Inhibitors for Diabetic Patients

If the patient has diabetes with proteinuria >300 mg/g, add an SGLT2 inhibitor (empagliflozin, canagliflozin, or dapagliflozin) regardless of glycemic control, as these provide additive renoprotection to ARBs. 6

• SGLT2 inhibitors reduce kidney disease progression and cardiovascular events in diabetic patients with albuminuria through mechanisms independent of glucose lowering 6

• Do not discontinue the ARB when adding an SGLT2 inhibitor—their combination provides complementary renoprotective mechanisms 6

Critical Monitoring Parameters

Monitor the following at each visit:

• Urine protein-to-creatinine ratio to assess treatment response—aim for reduction to <1 g/day or at least 30-50% reduction from baseline 6, 7, 3

• Serum creatinine/eGFR—accept up to 30% increase after RAS blocker initiation, but investigate if decline continues 6, 7

• Serum potassium—especially critical with RAS blockers plus MRAs or in patients with eGFR <45 mL/min/1.73 m² 1

• Blood pressure at every visit—continue targeting 120-129 mmHg systolic if tolerated 1

Common Pitfalls to Avoid

Do not stop RAS blockers for modest creatinine increases (<30%) or mild hyperkalemia (K+ <5.5 mEq/L), as the long-term renoprotective benefits outweigh these expected physiologic changes 6, 7

Do not combine ACE inhibitor with ARB—the ONTARGET trial showed increased adverse events (hyperkalemia, AKI, hypotension) without cardiovascular benefit, despite greater proteinuria reduction 9, 8

Counsel patients to temporarily hold RAS blockers and diuretics during acute illness with volume depletion (vomiting, diarrhea) to prevent acute kidney injury 6, 7

Do not assume "well-controlled BP" means optimal treatment—proteinuria requires specific antiproteinuric therapy beyond blood pressure control alone 3, 4

Lifestyle Modifications

Restrict dietary sodium to <2 g/day (<90 mmol/day), as sodium restriction enhances the antiproteinuric effects of RAS blockers 1, 7

Achieve weight normalization through diet and exercise, as obesity independently worsens proteinuria 7

Algorithm Summary

1. Maximize RAS blocker dose (ACE inhibitor or ARB to maximum tolerated) 1
2. Add thiazide-like diuretic if proteinuria persists 1, 4
3. Consider MRA (spironolactone/eplerenone) for resistant proteinuria with careful K+ monitoring 1
4. Add SGLT2 inhibitor if diabetic with proteinuria >300 mg/g 6
5. Target BP 120-129 mmHg systolic if eGFR >30 and tolerated 1
6. Monitor proteinuria, creatinine, and potassium regularly 6, 7