What is the treatment approach for nephrotic syndrome (NS) due to malignancy?

Treatment of Nephrotic Syndrome Due to Malignancy

The primary treatment for paraneoplastic nephrotic syndrome is definitive management of the underlying malignancy through surgical resection, chemotherapy, or appropriate oncologic therapy, as nephrotic syndrome typically resolves only after complete control of the cancer. 1, 2

Initial Diagnostic Approach

Exclude Secondary Causes and Identify Malignancy

• Perform age-appropriate cancer screening in all patients with new-onset nephrotic syndrome, particularly those over 60 years old, as malignancy-associated nephrotic syndrome occurs at a rate greater than chance alone 3, 2
• Limit malignancy workup to age-appropriate cancer screening unless specific risk factors or symptoms suggest the need for additional testing 3
• The most common solid tumors associated with nephrotic syndrome are lung, colorectal, breast, ovarian, and gastrointestinal stromal tumors 1, 2
• Consider testing for anti-PLA2R antibodies, as patients who are seronegative may represent secondary forms of disease and warrant further investigation for malignancy 3

Obtain Renal Biopsy for Histologic Diagnosis

• Membranous nephropathy (49%) is the most prevalent renal pathology in paraneoplastic nephrotic syndrome, particularly with lung, colorectal, or breast carcinoma 2
• Other less common histologic patterns include focal segmental glomerulosclerosis and minimal change disease 4
• Renal biopsy helps distinguish primary from secondary causes and guides prognosis 3, 2

Treatment Algorithm

Step 1: Treat the Underlying Malignancy

• Surgical resection of the tumor is the definitive treatment when feasible 1, 2
• Chemotherapy appropriate for the specific malignancy should be initiated if surgery is not possible or for metastatic disease 1, 2
• The likelihood of nephrotic syndrome remission is high regardless of whether treatment is for cancer alone or in combination with symptomatic NS management 2
• Complete remission of nephrotic syndrome typically occurs only after complete control of the underlying malignancy, with resolution of ascites and proteinuria 1

Step 2: Provide Supportive Management of Nephrotic Syndrome

While treating the malignancy, manage nephrotic syndrome complications:

Edema Management

• Loop diuretics are first-line agents, with twice daily dosing preferred over once daily dosing 5
• For resistant edema, add a thiazide diuretic (such as metolazone) for synergistic effect by blocking distal tubular sodium reabsorption 5
• Consider adding amiloride or spironolactone with careful potassium monitoring 5
• Restrict dietary sodium to <2 g/day (<90 mmol/day) to maximize diuretic effectiveness 5, 6

Blood Pressure Control

• ACE inhibitors or ARBs should be used as first-line therapy for hypertension in nephrotic syndrome to reduce proteinuria 5, 6
• Monitor serum creatinine after initiation, accepting increases up to 30% as this often reflects appropriate volume reduction 5, 6
• Discontinue if kidney function continues to worsen or refractory hyperkalemia develops 6

Thromboembolism Prevention

• Recognize that nephrotic syndrome carries high risk for venous thromboembolism 7
• Consider prophylactic anticoagulation in high-risk patients, though specific guidelines for paraneoplastic NS are limited 7

Step 3: Avoid Immunosuppressive Therapy

• Do not initiate immunosuppressive therapy for paraneoplastic nephrotic syndrome, as it will not resolve until the malignancy is controlled 1, 2
• Immunosuppression may be harmful by potentially promoting tumor growth and increasing infection risk 3
• The KDIGO guideline criteria for starting immunosuppression (persistent proteinuria >4 g/day for 6 months, etc.) apply only to idiopathic membranous nephropathy, not paraneoplastic cases 3

Monitoring and Follow-up

Track Both Renal and Oncologic Parameters

• Monitor proteinuria levels as a marker of disease activity, which should parallel tumor response 3, 2
• In anti-PLA2R positive cases, antibody titers may indicate immunologic activity and precede changes in proteinuria 3
• Relapse of proteinuria after initial remission suggests tumor recurrence and warrants oncologic re-evaluation 8
• Perform serial imaging and tumor markers appropriate for the specific malignancy 1

Renal Function Monitoring

• Monitor serum creatinine, estimated GFR, and urinalysis regularly 6
• Consider nephrology referral for patients with GFR <45 mL/min/1.73 m² or progressive CKD 3, 6

Critical Pitfalls to Avoid

• Do not misdiagnose paraneoplastic NS as idiopathic NS, which leads to inappropriate immunosuppression and delayed cancer diagnosis 2
• Do not attribute NS solely to chemotherapy toxicity without excluding paraneoplastic etiology, as manifestations of NS can occur before, during, or after cancer diagnosis (36%, 30%, and 34% of cases, respectively) 2
• Avoid nephrotoxic medications including NSAIDs, which can worsen renal function 6
• Do not delay cancer treatment while attempting to manage NS with immunosuppression alone 1, 2

Special Considerations

Chemotherapy-Induced Nephrotic Syndrome

• Tyrosine kinase inhibitors (such as sunitinib) can cause thrombotic microangiopathy manifested as nephrotic syndrome and difficult-to-control hypertension 4
• This complication requires stopping the offending drug for resolution 4
• Distinguish this from paraneoplastic NS by timing (occurs during treatment) and histology (thrombotic microangiopathy rather than membranous nephropathy) 4

Prognosis

• Prompt identification coupled with suitable cancer therapy has significant impact on outcome, with high likelihood of NS remission when malignancy is controlled 2
• The pathophysiologic link between malignancy and NS remains incompletely understood, though immune complex deposition is suspected 8