What is the most likely diagnosis in a patient with low complement C3, positive antinuclear antibody, elevated anti‑double‑stranded DNA IgG, hypoalbuminemia, hypercholesterolemia, and normal creatinine?

Systemic Lupus Erythematosus with Nephrotic Syndrome

The most likely diagnosis is systemic lupus erythematosus (SLE) with active lupus nephritis presenting as nephrotic syndrome. The constellation of low C3, positive ANA, elevated anti-dsDNA IgG, hypoalbuminemia, and hypercholesterolemia with preserved renal function (normal creatinine) is pathognomonic for active SLE with renal involvement manifesting as nephrotic-range proteinuria. 1

Diagnostic Rationale

Serologic Profile Interpretation

• Positive ANA with elevated anti-dsDNA IgG confirms the diagnosis of SLE, as anti-dsDNA antibodies are highly specific (98.23%) for SLE and are particularly associated with renal involvement. 2

• Low C3 complement indicates classical complement pathway activation and is strongly associated with active lupus nephritis—92.3% of patients with active renal lupus demonstrate low C3 levels. 3

• The combination of low C3 and elevated anti-dsDNA has a 95.36% sensitivity and 96.90% specificity for diagnosing SLE, and this pattern is particularly predictive of renal flares. 3, 2

Nephrotic Syndrome Without Azotemia

• Hypoalbuminemia with hypercholesterolemia represents classic nephrotic syndrome, indicating significant proteinuria (typically >3.5 g/day). 1

• Normal creatinine despite active nephritis suggests early-stage lupus nephritis or membranous lupus nephritis (Class V), which can present with preserved GFR while manifesting heavy proteinuria. 1

• The absence of elevated creatinine does not exclude significant renal involvement—lupus nephritis frequently presents with nephrotic-range proteinuria before GFR decline occurs. 1

Essential Immediate Workup

Mandatory Laboratory Studies

• Quantitative 24-hour urine protein or spot urine protein-to-creatinine ratio to confirm nephrotic-range proteinuria (>3.5 g/day or UPCR >3.5 mg/mg). 1

• Complete urinalysis with microscopy to evaluate for dysmorphic red blood cells, cellular casts (particularly RBC casts), and active urinary sediment. 1, 4

• Serum C4 level should be measured alongside C3, as combined low C3 and C4 strongly suggests lupus nephritis or cryoglobulinemia; isolated low C3 with normal C4 would suggest alternative pathway activation. 4, 5

• Complete blood count to assess for cytopenias (thrombocytopenia, leukopenia, hemolytic anemia) which support SLE diagnosis. 1

• Serum albumin and lipid panel to fully characterize nephrotic syndrome. 1

Additional Autoantibody Testing

• Anti-Sm, anti-RNP, anti-Ro, and anti-La antibodies should be checked at baseline as recommended for all SLE patients, though they do not change immediate management. 1

• Antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein I) must be checked given the thrombotic risk in nephrotic syndrome and potential antiphospholipid syndrome overlap. 1

Critical Diagnostic Procedure

Kidney Biopsy Indication

• Renal biopsy is mandatory in this patient to establish the histologic class of lupus nephritis, guide immunosuppressive therapy selection, and assess chronicity. 1

• Biopsy should be performed urgently (within days to 1-2 weeks) given active serologic disease and nephrotic syndrome, as the histologic class determines treatment intensity. 1

• Immunofluorescence pattern will show "full house" staining (IgG, IgM, IgA, C3, C1q) typical of lupus nephritis, distinguishing it from other causes of nephrotic syndrome. 5

Differential Considerations and Pitfalls

Alternative Diagnoses to Exclude

• Protein-losing enteropathy can rarely present with hypoalbuminemia, hypercholesterolemia, and positive ANA in SLE patients, but this is uncommon and typically shows negative anti-dsDNA. 6

• Membranous nephropathy from other causes (idiopathic, malignancy, hepatitis B) could present similarly, but the combination of low C3 and high anti-dsDNA makes lupus nephritis far more likely. 1, 5

• Monoclonal gammopathy-related nephropathy should be considered in patients >50 years, requiring serum and urine protein electrophoresis with immunofixation, though the positive anti-dsDNA argues against this. 1, 4

Common Diagnostic Errors

• Do not delay biopsy waiting for creatinine elevation—normal creatinine does not exclude severe lupus nephritis requiring aggressive immunosuppression. 1

• Do not assume inactive disease based on normal creatinine alone; patients can have "serologically active, clinically quiescent" lupus or membranous lupus nephritis with preserved GFR. 1

• Repeat ANA testing is not indicated for monitoring—only anti-dsDNA and complement levels should be followed serially. 1

Immediate Management Priorities

Pre-Biopsy Supportive Care

• ACE inhibitor or ARB therapy should be initiated immediately for antiproteinuric and renoprotective effects, titrated to maximum tolerated dose while monitoring blood pressure (target <130/80 mmHg), potassium, and GFR. 1

• Hydroxychloroquine 400 mg daily (or 6.5 mg/kg/day, whichever is lower) should be started immediately, as it reduces renal flares and improves long-term renal outcomes in lupus nephritis. 1

• Avoid nephrotoxic agents including NSAIDs, which can worsen proteinuria and precipitate acute kidney injury. 1

Post-Biopsy Treatment Algorithm

• Class III or IV proliferative lupus nephritis requires induction therapy with either mycophenolate mofetil (2-3 g/day) or cyclophosphamide plus high-dose corticosteroids (methylprednisolone 500-1000 mg IV for 3 days, then prednisone 0.5-1 mg/kg/day). 1

• Class V membranous lupus nephritis with nephrotic syndrome typically requires immunosuppression with mycophenolate mofetil or calcineurin inhibitors plus moderate-dose corticosteroids. 1

• Mixed class III/IV + V should be treated as proliferative disease with aggressive induction immunosuppression. 1

Monitoring Strategy

Serial Laboratory Assessment

• Anti-dsDNA and complement (C3, C4) levels should be monitored monthly during active treatment, as rising anti-dsDNA or falling complement predicts renal flares 20-25 weeks before clinical manifestations. 1, 7

• Urine protein-to-creatinine ratio should be checked monthly to assess treatment response; failure to show improvement by 3-4 months indicates unsatisfactory response requiring treatment modification. 1

• Serum creatinine and estimated GFR should be monitored at least every 3 months during the first 2-3 years after diagnosis. 1

Response Definitions

• Complete renal response requires UPCR <0.5 mg/mg with stable or improved GFR. 1

• Partial renal response requires ≥50% reduction in proteinuria with stable GFR. 1

• No improvement or worsening after 3-4 weeks warrants immediate reassessment for nonadherence, inadequate immunosuppression, or alternative diagnoses. 1