What is the treatment for a patient with significant proteinuria, predominantly albumin, and nephrotic syndrome?

Management of Significant Proteinuria with Predominantly Albumin

Start with maximally tolerated ACE inhibitor or ARB therapy combined with strict blood pressure control (target <120 mmHg systolic) and sodium restriction (<2.0 g/day), then determine if immunosuppressive therapy is warranted based on the underlying glomerular disease and response to conservative management. 1, 2

Initial Conservative Management

First-line pharmacologic approach:

• Initiate ACE inhibitor or ARB and uptitrate to the maximum tolerated dose (not just the dose that controls blood pressure) 1, 2
• Target systolic blood pressure <120 mmHg using standardized office measurements 1
• Do not discontinue ACE inhibitor/ARB if serum creatinine increases modestly and remains stable (up to 30% elevation), as this represents expected hemodynamic effects 1
• Stop ACE inhibitor/ARB only if kidney function continues to worsen or refractory hyperkalemia develops 1

Essential lifestyle modifications:

• Restrict dietary sodium to <2.0 g/day (<90 mmol/day) to enhance antiproteinuric effects 1, 2
• Normalize weight, stop smoking, and exercise regularly 1
• Treat metabolic acidosis if serum bicarbonate <22 mmol/L 1

Management of edema (if present):

• Loop diuretics (furosemide) as bolus or infusion for volume overload 1, 3
• Monitor for electrolyte depletion, particularly hypokalemia, which may develop with brisk diuresis 3
• Use potassium-wasting diuretics and/or potassium-binding agents to maintain normal potassium levels, allowing continuation of RAS blockade 1, 2

Critical Caveat for Abrupt-Onset Nephrotic Syndrome

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 minimal change disease. 1 It may be reasonable to delay initiation of ACE inhibitor/ARB in patients without hypertension who have podocytopathy (minimal change disease, steroid-sensitive nephrotic syndrome, focal segmental glomerulosclerosis) expected to be rapidly responsive to immunosuppression. 1

When to Consider Immunosuppressive Therapy

Criteria for initiating immunosuppression (after determining the specific glomerular disease by biopsy):

For membranous nephropathy, start immunosuppressive therapy when: 1, 4

• Urinary protein excretion persistently exceeds 4 g/day AND remains at >50% of baseline value despite 6 months of conservative therapy with ACE inhibitor/ARB, blood pressure control, and sodium restriction 1, 4
• OR presence of severe, disabling, or life-threatening symptoms related to nephrotic syndrome 1, 4
• OR serum creatinine has risen by ≥30% within 6-12 months (but eGFR remains >30 ml/min/1.73m²) 1, 4

For focal segmental glomerulosclerosis, consider immunosuppressive therapy only in idiopathic FSGS associated clinically with features of nephrotic syndrome. 1 However, first attempt conservative management with aggressive blood pressure control, weight loss, and RAS inhibition, especially if there are features suggesting secondary FSGS (obesity, relatively normal serum albumin, hilar histological variant). 1

Immunosuppressive Regimen Selection

For membranous nephropathy:

• First-line: 6-month course of alternating monthly cycles of oral and IV corticosteroids with oral cyclophosphamide (modified Ponticelli regimen) 1, 4
• Alternative (if contraindications to corticosteroids exist, such as uncontrolled diabetes, obesity with family history of diabetes, psychiatric conditions, or severe osteoporosis): Cyclosporine 3-4 mg/kg/day in divided doses for at least 6 months, targeting trough levels (C0) of 125-200 ng/ml 1
• Adjust cyclophosphamide dose according to patient age and eGFR to minimize toxicity 4

For focal segmental glomerulosclerosis:

• Prednisone or prednisolone at 1 mg/kg/day (maximum 80 mg) or alternate-day dose of 2 mg/kg (maximum 120 mg) 1
• Continue high-dose corticosteroids for minimum of 4 weeks, up to maximum of 16 weeks or until complete remission, whichever is earlier 1
• Taper corticosteroids slowly over 6 months after achieving complete remission 1
• Alternative first-line: Calcineurin inhibitors (cyclosporine preferred over tacrolimus in patients at risk for diabetes) for patients with relative contraindications to high-dose corticosteroids 1

Management of Refractory Proteinuria

If proteinuria fails to improve despite maximally tolerated ACE inhibitor/ARB:

• Intensify dietary sodium restriction further 1, 2
• Consider adding mineralocorticoid receptor antagonists (spironolactone or eplerenone), monitoring closely for hyperkalemia 1, 2
• Use potassium-wasting diuretics and/or potassium-binding agents to enable continuation of RAS blockade 1

Monitoring Strategy

Laboratory monitoring:

• Monitor serum electrolytes (particularly potassium), CO2, creatinine, and BUN frequently during the first few months of therapy and periodically thereafter 1
• Check serum and urine electrolytes particularly when patient is vomiting profusely or receiving parenteral fluids 3
• Monitor urine and blood glucose periodically in diabetics or those suspected of latent diabetes 3

Treatment response assessment:

• For membranous nephropathy: Monitor patients for at least 6 months following completion of immunosuppressive therapy before considering treatment failure 4
• Proteinuria goal is variable depending on primary disease process; typically <1 g/day 1
• Evidence of proteinuria improvement should be apparent by 3 months, with at least 50% reduction by 6 months 2

Important Counseling Points

Patient education:

• Counsel patients to hold ACE inhibitor/ARB and diuretics when at risk for volume depletion (sick days, vomiting, diarrhea) 1
• Advise patients they may experience symptoms from excessive fluid and/or electrolyte losses 3
• Warn about postural hypotension, which can usually be managed by getting up slowly 3
• Inform patients that potassium supplements and/or dietary measures may be needed to control or avoid hypokalemia 3