What is the best treatment approach for a patient with nephrotic syndrome (excessive proteinuria) and hypertension (elevated blood pressure)?

Treatment of Nephrotic Syndrome with Hypertension

Start an ACE inhibitor or ARB immediately and uptitrate to the maximum tolerated dose as first-line therapy, targeting systolic blood pressure <120 mmHg, while restricting dietary sodium to <2.0 g/day. 1, 2

Blood Pressure Management

Target Blood Pressure

• Target systolic blood pressure <120 mmHg using standardized office BP measurement in most adult patients with nephrotic syndrome and hypertension 1, 2
• Practically, achieving SBP of 120-130 mmHg is realistic in most patients with glomerular disease 1
• For children, target 24-hour mean arterial pressure at the 50th percentile for age, sex, and height by ambulatory blood pressure monitoring 1

First-Line Pharmacotherapy

• Use ACE inhibitor or ARB as mandatory first-line therapy, uptitrating to the maximally tolerated or FDA-approved daily dose 1, 2
• This dual benefit addresses both hypertension control and proteinuria reduction simultaneously 1, 3
• Do not stop ACE inhibitor/ARB if serum creatinine increases modestly and remains stable (up to 30% elevation) 1, 3
• Stop ACE inhibitor/ARB only if kidney function continues to worsen or refractory hyperkalemia develops 1

Critical Caveat for ACE Inhibitor/ARB Initiation

• Do not start ACE inhibitor/ARB in patients presenting with abrupt onset of nephrotic syndrome, as these drugs can cause acute kidney injury, especially in patients with minimal change disease 1
• For patients without hypertension with podocytopathy (minimal change disease, steroid-sensitive nephrotic syndrome, focal segmental glomerulosclerosis) expected to be rapidly responsive to immunosuppression, it may be reasonable to delay ACE inhibitor/ARB initiation 1

Dietary and Lifestyle Modifications

Sodium Restriction

• Restrict dietary sodium to <2.0 g/day (<90 mmol/day) as this is synergistic with ACE inhibitor/ARB therapy and significantly enhances antiproteinuric effects 1, 2, 3
• For patients failing to achieve proteinuria reductions on maximally tolerated medical therapy, intensify dietary sodium restriction further 1, 2

Additional Lifestyle Interventions

• Normalize weight through caloric restriction and exercise 1, 2
• Stop smoking completely 1, 2
• Exercise regularly as part of comprehensive cardiovascular risk management 1, 2

Management of Edema

Diuretic Therapy

• Use loop diuretics (furosemide) for edema management in nephrotic syndrome 4
• Loop diuretics can be administered as bolus or continuous infusion 1
• Consider combination therapy with loop diuretics and intravenous albumin for diuretic-resistant patients 1

Strategies for Diuretic-Resistant Edema

• Add amiloride to reduce potassium loss and improve diuresis 1
• Consider acetazolamide to treat metabolic alkalosis, though it is a weak diuretic 1
• For severe refractory cases, consider ultrafiltration or hemodialysis 1

Management of Hyperkalemia to Enable RAS Blockade

• Use potassium-wasting diuretics and/or potassium-binding agents to reduce serum potassium to normal levels, allowing continued use of RAS blocking medications for blood pressure control and proteinuria reduction 1, 2
• Treat metabolic acidosis (serum bicarbonate <22 mmol/L) as this contributes to hyperkalemia 1

Refractory Hypertension and Proteinuria

Mineralocorticoid Receptor Antagonists

• Consider adding mineralocorticoid receptor antagonists (spironolactone or eplerenone) in refractory cases when proteinuria persists despite maximally tolerated ACE inhibitor/ARB therapy and optimal blood pressure control 1, 2, 3
• Monitor closely for hyperkalemia when using these agents 1, 2

Monitoring Strategy

Laboratory Monitoring

• Monitor labs frequently when on ACE inhibitor or ARB therapy, including serum creatinine, eGFR, potassium levels, and proteinuria 1, 2
• Check labs every 2-4 weeks initially after starting or uptitrating RAS blockade 2

Proteinuria Goals

• Proteinuria goal is variable depending on primary disease process, typically targeting reduction to <1 g/day 1
• Target proteinuria reduction of ≥25% by 3 months and ≥50% by 6 months 2, 3

Critical Patient Counseling

• Counsel patients to hold ACE inhibitor/ARB and diuretics when at risk for volume depletion, such as during intercurrent illnesses or "sick days" 1, 2
• This prevents acute kidney injury from volume depletion while on RAS blockade 1, 2
• Counsel patients according to their level of education in a culturally sensitive manner 1

Cardiovascular Risk Management

Lipid Management

• Consider statin therapy for persistent hyperlipidemia, particularly in patients with other cardiovascular risk factors including hypertension and diabetes 1
• Assess atherosclerotic cardiovascular disease (ASCVD) risk based on LDL-C, apolipoprotein B, triglyceride, and lipoprotein(a) levels 1
• Align statin dosage intensity to ASCVD risk 1
• For patients who cannot tolerate statins or fail to achieve lipid goals despite maximally tolerated statin dose, consider non-statin therapy including ezetimibe, PCSK9 inhibitors, fibrates, or bile acid sequestrants 1

Common Pitfalls to Avoid

• Never discontinue ACE inhibitor/ARB prematurely for modest creatinine elevations up to 30% if stable 1, 3
• Avoid starting ACE inhibitor/ARB in acute-onset nephrotic syndrome without first ruling out minimal change disease 1
• Do not undertitrate ACE inhibitor/ARB once blood pressure is controlled; continue uptitration to maximum tolerated dose for optimal antiproteinuric effect 1, 3
• Do not neglect sodium restriction, as pharmacotherapy alone without dietary sodium restriction significantly reduces treatment efficacy 1, 2, 3