What is the approach to managing a patient with proteinuria, particularly those with a history of diabetes or hypertension?

Approach to Proteinuria in Patients with Diabetes or Hypertension

Begin with spot urine albumin-to-creatinine ratio (ACR) on a first-morning specimen, and if elevated (>30 mg/g), confirm with 2 of 3 samples before initiating treatment—then immediately start an ACE inhibitor or ARB regardless of blood pressure, uptitrate to maximum tolerated dose, and restrict dietary sodium to <2.0 g/day. 1, 2

Initial Diagnostic Quantification

• Obtain spot urine albumin-to-creatinine ratio (ACR) rather than 24-hour collection, as it is more convenient and equally accurate 1
• Use first-morning specimens in all patients to avoid confounding from orthostatic proteinuria 1
• Normal is ≤30 mg albumin/g creatinine; microalbuminuria is 30-300 mg/g; macroalbuminuria is >300 mg/g 1
• For very high proteinuria (spot urine protein-to-creatinine ratio 500-1,000 mg/g or higher), measure total protein instead of albumin 1
• Confirm persistent proteinuria by repeating in 2 of 3 samples over several weeks before labeling as pathologic 1
• Measure baseline serum creatinine and calculate eGFR using Cockcroft-Gault equation for medication dosing 1
• Patients should refrain from vigorous exercise for 24 hours before sample collection 1

Risk Stratification and Screening Frequency

• Screen annually for microalbuminuria in all patients with diabetes, hypertension, or family history of CKD 1
• High-risk patients include: African Americans, those with CD4+ counts <200 cells/µL (if HIV-infected), diabetes, hypertension, or hepatitis C coinfection 1
• Patients with proteinuria ≥1+ by dipstick or eGFR <60 mL/min per 1.73 m² require nephrology referral 1

First-Line Pharmacologic Management

ACE inhibitors or ARBs are mandatory first-line therapy and should be started immediately, even in normotensive patients, as they provide blood pressure-independent antiproteinuric effects. 1, 2

• Uptitrate to maximum tolerated or FDA-approved dose (e.g., lisinopril 40 mg daily or losartan 100 mg daily) for optimal antiproteinuric effect, which provides approximately 30% reduction in proteinuria 2, 3
• Do not stop ACE inhibitor/ARB with modest and stable serum creatinine increase up to 30% 1
• Stop ACE inhibitor/ARB only if kidney function continues to worsen or refractory hyperkalemia develops 1
• Avoid starting ACE inhibitor/ARB in patients presenting with abrupt-onset nephrotic syndrome, as these drugs can cause acute kidney injury, especially in minimal change disease 1

Blood Pressure Target

• Target systolic blood pressure <120 mmHg using standardized office measurement in most adult patients with proteinuria 1, 2, 4
• This lower target provides additional renoprotection beyond proteinuria reduction alone 2, 4
• In children, target 24-hour mean arterial pressure at 50th percentile for age, sex, and height by ambulatory blood pressure monitoring 1

Essential Lifestyle Modifications (Mandatory, Not Optional)

Dietary sodium restriction to <2.0 g/day (<90 mmol/day) is mandatory and synergistic with ACE inhibitor/ARB therapy, significantly enhancing antiproteinuric effects. 1, 2, 4

• Normalize weight through diet and exercise if overweight 1, 2
• Stop smoking completely 1, 2
• Exercise regularly 1, 2

Second-Line Therapy for Uncontrolled Blood Pressure

• Add diuretics as preferred second-line agent if blood pressure remains uncontrolled or volume overload is present 4, 5
• Monitor for electrolyte depletion (hypokalemia, hyponatremia, hypochloremic alkalosis, hypomagnesemia) with diuretic use 5
• Check serum electrolytes, CO2, creatinine, and BUN frequently during first few months of diuretic therapy 5

Management of Hyperkalemia to Allow Continued RAS Blockade

Use potassium-wasting diuretics and/or potassium-binding agents to reduce serum potassium to normal, allowing continued use of ACE inhibitor/ARB for blood pressure control and proteinuria reduction. 1, 2, 4

• Treat metabolic acidosis if serum bicarbonate <22 mmol/L, as acidosis worsens hyperkalemia 1, 2
• Consider amiloride to reduce potassium loss if using loop diuretics 1

Management of Resistant Proteinuria

• Add mineralocorticoid receptor antagonist (spironolactone 25-50 mg daily or eplerenone) if proteinuria persists despite maximized ACE inhibitor/ARB and blood pressure control 1, 2, 4
• Monitor potassium carefully with mineralocorticoid receptor antagonist use 1, 2
• Intensify dietary sodium restriction further in refractory cases 1, 2
• Consider combination of ACE inhibitor plus ARB in young adults without diabetes or cardiovascular disease, but avoid in older patients due to increased risk of acute kidney injury and hyperkalemia 1, 3

Critical Monitoring Strategy

• Check labs every 2-4 weeks initially: serum creatinine, eGFR, potassium, and urine protein-to-creatinine ratio 2, 4
• Target proteinuria reduction of ≥25% by 3 months, ≥50% by 6 months, aiming for absolute proteinuria <1 g/day 2, 4
• If treatment results in significant reduction of microalbuminuria, switch to annual testing 1
• If no reduction in microalbuminuria occurs, evaluate whether blood pressure targets achieved and whether specific RAS-blocking drugs are part of therapy 1

Critical Patient Counseling to Prevent Acute Kidney Injury

Counsel patients to hold ACE inhibitor/ARB and diuretics during intercurrent illnesses (vomiting, diarrhea, fever) or when at risk for volume depletion to prevent acute kidney injury. 1, 4

• Educate patients in culturally sensitive manner according to level of education 1
• Consider transiently stopping RAS inhibitors during "sick days" 1

Cardiovascular Risk Management

• Consider statin therapy for persistent dyslipidemia, particularly in patients with other cardiovascular risk factors including hypertension and diabetes 1, 2, 4
• Target LDL-C <55 mg/dL with ≥50% reduction in type 2 diabetes at very high cardiovascular risk 2
• Consider GLP-1 receptor agonists (liraglutide, semaglutide, or dulaglutide) to reduce cardiovascular events and mortality in diabetic patients with cardiovascular disease or very high/high cardiovascular risk 2

Proteinuria Goals

• Target proteinuria <1 g/day, though this varies by primary disease process 1, 2
• In patients expected to be rapidly responsive to immunosuppression (minimal change disease, steroid-sensitive nephrotic syndrome, FSGS), it may be reasonable to delay ACE inhibitor/ARB initiation if no hypertension present 1

Common Pitfalls to Avoid

• Do not combine ACE inhibitor with ARB in patients with diabetes or cardiovascular disease, as benefits are uncertain and risks of hyperkalemia and acute kidney injury are increased 1
• Avoid calcium channel blockers (especially dihydropyridines) in patients receiving protease inhibitors due to drug interactions 1
• Do not discontinue ACE inhibitor/ARB prematurely for modest creatinine elevation (<30% increase), as this is expected and acceptable 1
• Refrigerate urine samples for assay same or next day; one freeze is acceptable but avoid repeated freeze-thaw cycles 1