What is the best treatment approach for a patient with nephritic syndrome and significant proteinuria?

Management of Nephritic Syndrome with Significant Proteinuria

For nephritic syndrome with significant proteinuria, initiate maximally tolerated ACE inhibitor or ARB therapy combined with strict blood pressure control (target <120 mmHg systolic) and sodium restriction (<2.0 g/day), reserving immunosuppressive therapy for specific underlying glomerular diseases that fail to respond to conservative management after 6 months. 1, 2

Critical Initial Distinction

The term "nephritic syndrome" typically refers to glomerulonephritis with hematuria, hypertension, and variable proteinuria, which differs from "nephrotic syndrome" (proteinuria >3.5 g/day with hypoalbuminemia). However, many glomerular diseases present with overlapping features. The treatment approach depends critically on:

• Proteinuria severity: Nephrotic-range (>3.5 g/day) versus subnephrotic
• Underlying histology: Immune-mediated (lupus nephritis, IgA nephropathy) versus podocytopathies (minimal change disease, FSGS) versus membranous nephropathy
• Acuity of presentation: Abrupt onset versus chronic progressive disease

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First-Line Conservative Management (All Patients)

Renin-Angiotensin System Blockade

• Start with ACE inhibitor or ARB and uptitrate to maximally tolerated dose as the cornerstone of therapy for all patients with proteinuria, regardless of underlying etiology 1, 2
• Do not discontinue if serum creatinine increases modestly (up to 30% elevation) and remains stable, as this represents expected hemodynamic effects 1, 2
• Critical exception: Avoid initiating ACE inhibitor/ARB in patients with abrupt-onset nephrotic syndrome (particularly minimal change disease), as these drugs can precipitate acute kidney injury in this setting 1

Blood Pressure Targets

• Target systolic blood pressure <120 mmHg using standardized office measurements in most adult patients 1, 2
• For patients with proteinuria >1 g/day, aim for blood pressure ≤125/75 mmHg 2
• Strict blood pressure control is essential for reducing proteinuria and preventing progression to end-stage renal disease 3

Dietary Sodium Restriction

• Restrict dietary sodium to <2.0 g/day (<90 mmol/day) to enhance antiproteinuric effects of RAS blockade 1, 2
• Intensify sodium restriction further if proteinuria fails to improve despite maximally tolerated ACE inhibitor/ARB 1

Additional Supportive Measures

• Normalize weight, stop smoking, and exercise regularly 2
• Consider adding mineralocorticoid receptor antagonists (spironolactone or eplerenone) for refractory proteinuria, with careful monitoring for hyperkalemia 1, 2
• Use potassium-wasting diuretics and/or potassium-binding agents to maintain normal serum potassium and continue RAS blockade 2
• Treat metabolic acidosis (serum bicarbonate <22 mmol/L) to optimize therapy 2

Disease-Specific Immunosuppressive Therapy

When to Consider Immunosuppression

The decision to add immunosuppressive therapy depends on the underlying glomerular disease and response to conservative management:

Membranous Nephropathy

• Consider immunosuppression when urinary protein excretion persistently exceeds 4 g/day AND remains at >50% of baseline despite 6 months of conservative therapy with ACE inhibitor/ARB, blood pressure control, and sodium restriction 1
• First-line: 6-month course of alternating monthly cycles of oral and IV corticosteroids with oral cyclophosphamide (modified Ponticelli regimen) 1
• Alternative: Cyclosporine 3-4 mg/kg/day in divided doses for at least 6 months, targeting trough levels (C0) of 125-200 ng/ml 1

Lupus Nephritis (Class V or Mixed Lesions)

• Initiate immunosuppression universally for nephrotic-range proteinuria in lupus nephritis 3
• Induction: Low-dose IV cyclophosphamide (500 mg every 2 weeks for 6 doses) OR mycophenolate mofetil, combined with glucocorticoids 4
• Initial IV methylprednisolone pulses: 500-750 mg for 3 consecutive days 4
• Oral prednisone: 0.3-0.5 mg/kg/day for 4 weeks, then taper to ≤7.5 mg/day by 3-6 months 4
• Maintenance: Azathioprine 2 mg/kg/day or mycophenolate mofetil 1-2 g/day for minimum 3-5 years 4
• Add hydroxychloroquine ≤5 mg/kg/day for all lupus nephritis patients 4

IgA Nephropathy

• For persistent proteinuria >1 g/day despite 3-6 months of optimized supportive care and GFR >50 ml/min/1.73 m², consider a 6-month course of corticosteroid therapy 2

Focal Segmental Glomerulosclerosis (FSGS)

• Consider immunosuppression only in idiopathic FSGS with nephrotic syndrome features, after attempting conservative management with aggressive blood pressure control, weight loss, and RAS inhibition 1

Monitoring Strategy and Treatment Goals

Laboratory Monitoring

• Monitor serum electrolytes (particularly potassium), CO2, creatinine, and BUN frequently during the first few months of therapy and periodically thereafter 1
• For lupus nephritis: Monitor body weight, blood pressure, serum creatinine, eGFR, serum albumin, proteinuria, urinary sediment, C3/C4, anti-dsDNA, and complete blood count at each visit 4

Treatment Response Timeline

• Evidence of proteinuria improvement should be apparent by 3 months 1, 2
• At least 50% reduction in proteinuria by 6 months 1, 2
• For membranous nephropathy: Monitor for at least 6 months following completion of immunosuppressive therapy before considering treatment failure 1
• For lupus nephritis: Target proteinuria <0.5-0.7 g/24 hours with near-normal GFR at 12 months 4

Proteinuria Goals

• General target: <1 g/day, though this varies by primary disease process 1
• More relaxed goal of 0.7-0.8 g/day may be acceptable based on long-term outcome data 3

Critical Prognostic Considerations

Risk Stratification by Proteinuria Level

• Proteinuria >3.8 g/day carries a 35% risk of end-stage renal disease within 2 years, compared to only 4% risk for proteinuria <2.0 g/day 3
• Prolonged nephrotic proteinuria leads to renal scarring and eventual renal failure through mechanisms that remain incompletely understood 3

Extrarenal Complications Requiring Attention

• Thromboembolic risk: Prevalence of 29% for renal vein thrombosis, 17-28% for pulmonary embolism, and 11% for deep vein thrombosis in nephrotic syndrome 3
• Cardiovascular disease: Four times greater risk than age- and sex-matched controls due to hypercholesterolemia, hypertension, hypercoagulability, and steroid exposure 3
• Infection risk: Particularly cellulitis and spontaneous bacterial peritonitis in children 3
• Hypoalbuminemia: Each 1.0 g/dL decrease increases odds of morbidity by 89% and mortality by 137% 3

Adjunctive Therapies for Nephrotic Syndrome

• Consider anticoagulation for high-risk patients (albumin <20 g/L) 5
• Pneumococcal vaccination 5
• Lipid-lowering therapy with statins (target LDL <100 mg/dL for lupus nephritis) 4
• Loop diuretics in fractionated increasing doses for edema management 6

Common Pitfalls to Avoid

• Do not delay ACE inhibitor/ARB initiation in chronic proteinuric disease, but recognize the exception for abrupt-onset nephrotic syndrome 1
• Do not stop RAS blockade prematurely for modest creatinine increases up to 30% 1, 2
• Counsel patients to hold ACE inhibitor/ARB and diuretics during volume depletion (sick days) 2
• Do not use cyclosporine without recognizing its nephrotoxic potential and the need for drug level monitoring 3
• Recognize that proteinuria reduction does not always indicate histologic quiescence, particularly with calcineurin inhibitors; repeat biopsies may be needed 3
• For lupus nephritis, do not treat subnephrotic proteinuria (<3.5 g/day) the same as nephrotic-range proteinuria; treatment should be guided by extrarenal manifestations when proteinuria is low-level 3