What is the likely diagnosis and appropriate management for a 25‑year‑old man presenting with recurrent painless gross hematuria after an upper‑respiratory infection and mild proteinuria?

IgA Nephropathy

The most likely diagnosis is IgA nephropathy, and the patient requires kidney biopsy for definitive diagnosis followed by ACE inhibitor or ARB therapy, with consideration of additional immunosuppressive treatment if proteinuria exceeds 1 g/day despite optimal supportive care. 1

Clinical Presentation Strongly Suggests IgA Nephropathy

The classic triad of recurrent painless gross hematuria triggered by upper respiratory infections (synpharyngitic hematuria), young adult age (25 years), and mild proteinuria is pathognomonic for IgA nephropathy. 1, 2 This presentation—where visible hematuria occurs within 1–2 days of a respiratory infection—distinguishes IgA nephropathy from post-infectious glomerulonephritis, which typically presents 1–3 weeks after infection. 3

• IgA nephropathy is the most common immune-mediated glomerular disease worldwide and the most frequent primary glomerulonephritis. 1, 2
• Approximately 30% of IgA nephropathy patients present with episodic visible hematuria concurrent with upper respiratory or gastrointestinal infections. 1
• The mean age at diagnosis is 34–45 years, making this 25-year-old patient's presentation typical. 1
• Another 60% of cases are detected incidentally with asymptomatic microscopic hematuria or proteinuria on routine urinalysis. 1

Immediate Diagnostic Workup Required

Confirm and Quantify Urinary Abnormalities

• Obtain a spot urine protein-to-creatinine ratio to quantify proteinuria; values ≥0.5 g/g warrant kidney biopsy. 1
• Perform urinalysis with microscopy to document persistent microscopic hematuria between episodes of gross hematuria and assess for dysmorphic RBCs (>80% suggests glomerular origin) or red cell casts (pathognomonic for glomerulonephritis). 4
• Measure serum creatinine and calculate eGFR to establish baseline renal function. 5

Exclude Secondary Causes of IgA Deposition

Before diagnosing primary IgA nephropathy, rule out conditions that cause secondary IgA deposition:

• Obtain complement levels (C3, C4) and antinuclear antibody (ANA) to exclude lupus nephritis. 6, 5
• Screen for hepatitis B and C serology, as viral hepatitis can cause secondary IgA nephropathy. 6
• Assess for inflammatory bowel disease, celiac disease, cirrhosis, and axial spondyloarthritis through targeted history and laboratory testing. 1
• Consider IgA vasculitis (Henoch-Schönlein purpura) if the patient has palpable purpura, abdominal pain, or arthralgias. 1

Kidney Biopsy Is Mandatory for Diagnosis

Adults with suspected IgA nephropathy and proteinuria ≥0.5 g/day should undergo kidney biopsy. 1

• The diagnosis requires demonstration of IgA-dominant immune deposits in the glomerular mesangium on immunofluorescence microscopy. 1, 3
• Biopsy also provides critical prognostic information through histopathologic scoring, identifying severe lesions such as crescents, glomerulosclerosis, or tubulointerstitial fibrosis that predict progression to end-stage renal disease. 2
• Serum IgA levels are elevated in only 50% of cases and cannot substitute for biopsy. 3

Prognosis and Risk Stratification

IgA nephropathy is not a benign condition—up to 50% of patients develop kidney failure within 10 years of diagnosis, and 20–39% progress to end-stage renal disease requiring dialysis or transplantation within 20 years. 1, 2

Three Major Independent Risk Factors for Progression

1. Arterial hypertension at presentation or during follow-up. 2
2. Proteinuria >1 g/day that persists despite treatment. 2
3. Severe histopathologic lesions on kidney biopsy, including glomerular crescents, segmental sclerosis, tubulointerstitial fibrosis, or high scores on validated histopathologic classification systems. 2

The presence of any of these risk factors mandates aggressive treatment to slow disease progression. 2

Evidence-Based Treatment Strategy

First-Line: Supportive Care for All Patients

Initiate ACE inhibitor or ARB therapy for all patients with proteinuria ≥0.5 g/day, regardless of blood pressure, to reduce proteinuria and slow progression. 7, 1

• Target blood pressure <120/70 mm Hg using ACE inhibitors or ARBs as first-line agents. 1
• Implement dietary sodium restriction to <2 g/day, which enhances the antiproteinuric effect of renin-angiotensin system blockade. 1
• Counsel on smoking cessation, weight control, and regular exercise. 1
• Consider adding a sodium-glucose cotransporter 2 (SGLT2) inhibitor to further reduce proteinuria and preserve kidney function. 1

Second-Line: Immunosuppressive Therapy for High-Risk Disease

For patients with proteinuria persistently >1 g/day despite 3–6 months of optimized supportive care, or those with severe histopathologic lesions on biopsy, add targeted-release budesonide or systemic glucocorticoids. 1, 2

• Targeted-release budesonide (16 mg/day for 9 months) reduces IgA-containing immune complex formation with fewer systemic corticosteroid side effects. 1
• Systemic glucocorticoids (e.g., prednisone 0.5–1 mg/kg/day tapered over 6 months) decrease immune complex-mediated glomerular injury but carry higher risk of adverse effects. 1, 2
• Iptacopan (a complement factor B inhibitor) is a newer agent that reduces glomerular injury in IgA nephropathy. 1
• Sparsentan (a dual endothelin angiotensin receptor antagonist) can be used alone or in combination with SGLT2 inhibitors for patients with IgAN-induced nephron loss. 1

Treatments to Avoid

• Tonsillectomy may reduce the frequency of gross hematuria episodes in patients with recurrent tonsillar infections but does not alter long-term renal outcomes. 3
• Fish oil showed conflicting results in clinical trials; the Mayo Clinic study suggested benefit, but other studies showed acceleration of renal function decline or no effect. 8
• Cyclosporine has not been shown to alter disease progression and is not recommended. 8

Monitoring Strategy

• Reassess proteinuria every 3–6 months using spot urine protein-to-creatinine ratio to evaluate treatment response. 5
• Monitor serum creatinine and eGFR every 3–6 months to detect progression. 5
• Measure blood pressure at every visit; hypertension is both a risk factor for progression and a consequence of worsening kidney disease. 2
• Treatment success is defined as complete remission (proteinuria <300 mg/day) or partial remission (≥50% reduction in proteinuria). 5
• Adjust therapy if proteinuria is not reduced by 50% after 6 months of treatment. 5

Critical Pitfall to Avoid

Do not dismiss this presentation as "benign hematuria" simply because the patient is young and asymptomatic between episodes. IgA nephropathy can progress insidiously over decades, and early intervention with ACE inhibitors or ARBs significantly improves long-term outcomes. 2, 3 The natural history is characterized by slow but relentless progression to glomerulosclerosis and end-stage renal disease in a substantial proportion of patients. 2, 8