Q&A: Are You Sure the Diagnosis Is IgA Nephropathy?

The clinical presentation of immunoglobulin A nephropathy (IgAN) includes hematuria and proteinuria, often in a patient with a recent history of an upper respiratory tract infection. Kidney function is usually normal or mildly decreased, although patients occasionally have a rapidly progressive decline in estimated glomerular filtration rate (eGFR). Diagnostic confirmation is achieved by kidney biopsy showing dominant IgA mesangial staining in immunofluorescence microscopy, with C3 often present but not prominent compared with IgA. Medscape spoke with Arnold B. Alper, MD, an associate professor of medicine at Tulane University and at Tulane Medical Center, about the challenges in IgAN diagnosis.

Can you identify IgAN patients by their clinical presentation?

The hallmark of IgAN — hematuria and proteinuria — is not specific to IgA; it is seen in many glomerular diseases. There are signs and symptoms that could help clinicians to consider alternative diagnoses. I often see patients referred due to hematuria and proteinuria, usually subnephrotic range, and I ask them if they have a family history of kidney disease. In this scenario, I would consider Alport syndrome and look for vision and hearing impairment, mostly affecting males; or thin basement membrane nephropathy, a much more benign condition usually having microscopic hematuria only and no proteinuria. Skin rashes and joint pain should prompt investigation for IgA vasculitis, associated with lower limb petechiae, abdominal pain, and vomiting; or systemic lupus erythematosus (SLE), typically with the triad of fever, joint pain, and rash in a woman of childbearing age. As you mentioned infection, the timing between a throat infection — often Streptococcus — and kidney injury might suggest postinfectious glomerulonephritis (GN), when the kidney disease occurs after infection resolution (postpharyngitic). Patients with IgAN often develop gross hematuria concurrent with a respiratory infection (synpharyngitic). A patient presenting with oliguria, hypertension, and nephrotic syndrome should prompt suspicion of some type of membranoproliferative GN (MPGN).

What do you typically include in the initial investigation?

For all patients with proteinuria and hematuria, include a CBC, kidney function studies, urinalysis, quantification of proteinuria, and complement levels. Complement levels are typically normal in patients with IgAN but low in SLE, MPGN, IgA vasculitis, and poststreptococcal GN. A throat culture to rule out Streptococcus is useful. Poststreptococcal GN generally presents as a more acute and rapidly progressive kidney injury compared with IgAN. If systemic disease is suspected, I assess anti-DNA antibodies and antineutrophil cytoplasmic antibody (ANCA). A urine protein-to-creatinine ratio and eGFR are also indicated to assess the degree of kidney dysfunction and proteinuria. Nephrotic proteinuria is present in approximately 50% of MPGN patients.

At this point, would a kidney biopsy be recommended?

Yes, a kidney biopsy should be performed for definite diagnosis as there are no blood or urine tests that can confirm the diagnosis. IgAN biopsy usually shows mild mesangial expansion or diffuse proliferation with sclerosis and/or crescents in light microscopy, with predominant IgA deposits in the mesangium. Postinfectious GN, especially post-staph GN, can have a similar appearance on biopsy but also has much more significant C3 deposits. MPGN is characterized by enlarged glomeruli and increase in mesangial cellularity and matrix; immunofluorescent staining typically reveals intense peripheral, glomerular, capillary loop IgG deposition. SLE nephritis often has a "full-house appearance" with IgA, IgG, IgM, C3, and C1Q staining.

Are these kidney biopsy findings diagnostic of IgAN?

Yes. We have discussed idiopathic IgAN, and it is important to highlight other, secondary causes of IgAN, such as cirrhosis and celiac disease, where biopsy results would be similar. In clinical practice, this would be a patient known to have celiac disease or who might not have been diagnosed yet, but they would present with a lot of gastrointestinal complaints and hematuria or proteinuria. Similarly, a patient with liver disease who presents with episodes of hematuria — but in this case, you would identify that in their history.

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Cite this: Arnold B. Alper. Q&A: Are You Sure the Diagnosis Is IgA Nephropathy? - Medscape - Jan 22, 2025.