What is the diagnosis and treatment for a patient with pitting edema, elevated CRP, significant proteinuria, leukocytes, and casts in urinalysis, along with joint and lower back pain, and a history of hepatosplenomegaly?

Diagnosis: Nephrotic Syndrome with Suspected Glomerulonephritis

This patient requires urgent renal biopsy to establish the specific glomerular disease causing nephrotic syndrome, followed by immunosuppressive therapy guided by the biopsy findings, as the combination of significant proteinuria (3+), multiple cast types (hyaline, granular, and waxy), elevated inflammatory markers, systemic symptoms, and hepatosplenomegaly suggests an aggressive glomerular disease requiring prompt diagnosis and treatment. 1, 2, 3

Diagnostic Workup

Immediate Laboratory Studies Required

• Comprehensive metabolic panel including serum creatinine, BUN, electrolytes, and albumin to assess renal function and degree of hypoalbuminemia 1, 3
• Complement levels (C3, C4, CH50) to identify hypocomplementemic glomerulopathy, which is suggested by the systemic inflammatory presentation 3
• 24-hour urine protein quantification or spot urine protein-to-creatinine ratio, as 3+ proteinuria likely exceeds 3.5 g/day (nephrotic range) 1, 2
• Serologic testing including:
  • Antinuclear antibody (ANA) and anti-double stranded DNA for lupus nephritis 1
  • ANCA (anti-MPO and anti-PR3) for vasculitis 1
  • Serum and urine protein electrophoresis with immunofixation to exclude monoclonal gammopathy 1, 3
  • Hepatitis B and C serologies given hepatosplenomegaly 1, 3
• Blood cultures to exclude endocarditis as a cause of immune complex glomerulonephritis 3

Critical Diagnostic Procedure

Renal biopsy is mandatory and should include tissue for light microscopy, immunofluorescence, and electron microscopy 1, 3. The presence of waxy casts indicates chronic tubular damage and suggests advanced disease requiring urgent histologic diagnosis 4. If frozen tissue is inadequate, pronase digestion of paraffin-embedded tissue should be performed to unmask potential monoclonal deposits 3.

Differential Diagnosis Priority

Most Likely Diagnoses Based on Clinical Presentation

1. Lupus Nephritis - The combination of nephrotic-range proteinuria, elevated CRP, joint pain, and systemic symptoms strongly suggests this diagnosis 1

2. AA Amyloidosis - Hepatosplenomegaly with chronic inflammation (elevated CRP), joint pain, and nephrotic syndrome are classic features 5

3. Membranoproliferative Glomerulonephritis (MPGN) or C3 Glomerulopathy - Hypocomplementemia with nephrotic syndrome and systemic inflammation 3

4. IgA Nephropathy with nephrotic presentation - Can present with systemic symptoms and significant proteinuria, though less common 6

Treatment Algorithm

Immediate Supportive Management (Start Before Biopsy Results)

• Blood pressure control targeting <130/80 mmHg using ACE inhibitors or ARBs as first-line therapy 2
• Diuretics for edema management (loop diuretics for severe pitting edema) 7
• Thromboprophylaxis should be considered given nephrotic syndrome increases thrombotic risk 7
• Infection surveillance as nephrotic syndrome increases infection risk 7

Definitive Treatment Based on Biopsy Results

If Lupus Nephritis (Class III, IV, or V):

Initiate corticosteroids combined with either cyclophosphamide or mycophenolate mofetil as recommended for proliferative lupus nephritis 2, 8

If AA Amyloidosis:

Aggressive control of underlying inflammation with immunosuppressants plus strict blood pressure control, as remission of proteinuria is achievable with intensive therapy regardless of histological severity 5

If C3 Glomerulopathy or MPGN:

• For moderate disease: First-line treatment with limited course of glucocorticoids 3
• If glucocorticoid contraindications exist: Consider mycophenolate mofetil, rituximab, or cyclophosphamide 3
• Avoid calcineurin inhibitors for long-term use due to risk of immune complex-negative angiopathy 3

If Membranous Nephropathy:

Corticosteroids with cyclophosphamide or cyclosporine A for nephrotic syndrome with declining renal function 9, 10

Critical Pitfalls to Avoid

• Do not delay renal biopsy - The presence of waxy casts indicates chronicity, and delayed diagnosis worsens prognosis 4
• Rule out infection before immunosuppression - Tuberculosis can cause nephrotic syndrome with hepatosplenomegaly and must be excluded before starting immunosuppression 1, 6
• Do not miss monoclonal gammopathy - In patients over 50 years with nephrotic syndrome and hepatosplenomegaly, multiple myeloma or AL amyloidosis must be excluded 1, 3
• Ensure pronase digestion is performed if monoclonal protein is detected, as masked deposits can mimic C3 glomerulopathy 3
• Monitor for Clostridium difficile if patient has inflammatory bowel disease history, as this can elevate inflammatory markers 1

Monitoring Strategy

• Repeat urinalysis and proteinuria quantification every 3-6 months after treatment initiation 2
• Treatment goal is reduction of proteinuria to <0.5-1 g/day to improve long-term renal outcomes 2
• Serial complement levels if hypocomplementemic glomerulopathy is diagnosed 3
• Serum creatinine and eGFR monitoring to assess treatment response and disease progression 2