Level: Advanced — nephrology trainees and nephrologists
Educational disclaimer: This fictional case is for postgraduate education and does not replace clinical judgment, local protocols, multidisciplinary review, current prescribing information, or individual patient factors.
Learning objectives
After completing this case, learners should be able to diagnose and stage primary IgA nephropathy (IgAN), distinguish prognostic information from a treatment mandate, optimize kidney-protective care, and discuss an APRIL-directed treatment option using current evidence, regulatory limitations, infection precautions, and shared decision-making.
Stage 1 — Establishing the diagnosis and excluding secondary causes
A 34-year-old man is referred for persistent microscopic hematuria and proteinuria discovered during a routine occupational assessment. He reports no edema, purpura, arthralgia, chronic abdominal symptoms, or recurrent gross hematuria. He has treated hypertension and no known diabetes. His father developed kidney failure in his early sixties of an uncertain cause. He drinks alcohol infrequently and has no history of inflammatory bowel disease, chronic liver disease, hepatitis, HIV infection, or systemic autoimmune disease.
| Investigation | Result |
|---|---|
| Serum creatinine / eGFR | 1.70 mg/dL / 48 mL/min/1.73 m² |
| First-morning urine protein–creatinine ratio (UPCR) | 2.4 g/g on two measurements |
| Urine sediment | Dysmorphic erythrocytes; no red-cell casts |
| Serum albumin | 3.8 g/dL |
| Blood pressure | 142/88 mmHg |
| HbA1c | 5.4% |
| Hepatitis B, hepatitis C, HIV testing | Negative |
| Liver tests and abdominal ultrasonography | No evidence of chronic liver disease |
A kidney biopsy contains 18 glomeruli. Immunofluorescence shows dominant mesangial IgA deposition. Light microscopy and electron microscopy support IgAN. The revised Oxford score is M1 E0 S1 T1 C0, with mild interstitial fibrosis/tubular atrophy and no necrotizing lesion. There is no evidence of infection-related glomerulonephritis, monoclonal gammopathy-related disease, or a superimposed podocytopathy.
Decision point 1
Which interpretation is most appropriate?
| Option | Interpretation |
|---|---|
| A | Serum galactose-deficient IgA1 confirms primary IgAN, so a kidney biopsy is optional. |
| B | A biopsy is required to diagnose IgAN; after biopsy confirmation, secondary causes should be assessed and the MEST-C score documented for prognosis. |
| C | The S1 lesion proves that immediate systemic glucocorticoids are required in every patient. |
| D | The absence of edema excludes clinically meaningful risk of progressive kidney disease. |
Preferred decision: B. KDIGO states that IgAN can be diagnosed only by kidney biopsy, because there are no validated serum or urine biomarkers for diagnosis. Once IgAN is diagnosed, clinicians should assess for secondary causes and determine the MEST-C score. MEST-C, eGFR, proteinuria, blood pressure, and other biopsy-era clinical data contribute to risk assessment; no histologic component alone prescribes one universal treatment.[1]
Stage 2 — Quantifying risk and completing foundational care
The International IgAN Prediction Tool is reviewed with the patient using his biopsy-era data. The result supports a meaningful risk of progressive kidney-function loss over the next several years. The team emphasizes that the tool informs a discussion; it does not replace longitudinal assessment of eGFR slope, proteinuria, blood pressure, adverse effects, medication adherence, and the patient’s preferences.
Over the next six months, lisinopril is titrated to the maximally tolerated dose and dapagliflozin is added. Sodium intake, smoking avoidance, cardiovascular risk, vaccination history, body weight, and exercise are reviewed. His blood pressure becomes 126/76 mmHg. He tolerates both drugs without hyperkalemia, symptomatic hypotension, or recurrent genitourinary infection. Despite this optimized kidney-protective strategy, first-morning UPCR remains 2.1 g/g and eGFR is 47 mL/min/1.73 m².
Decision point 2
Which conclusion now best reflects current guidance?
| Option | Interpretation |
|---|---|
| A | Persistent proteinuria is not relevant once an ACE inhibitor and an SGLT2 inhibitor have been started. |
| B | A patient with proteinuria of at least 0.5 g/day or equivalent is at risk of progressive kidney-function loss; treatment or additional treatment should be considered while kidney-protective care continues. |
| C | The only meaningful goal is immediate normalization of the eGFR. |
| D | Sparsentan can be layered on top of the ACE inhibitor because both lower intraglomerular pressure. |
Preferred decision: B. KDIGO identifies proteinuria of at least 0.5 g/day or equivalent as a marker of risk for progressive kidney-function loss, whether the patient is on or off IgAN therapy. The broader treatment goal is to reduce the rate of kidney-function loss; urine protein is the validated early biomarker used to guide decisions and should be minimized, ideally below 0.3 g/day when achievable.[1] If sparsentan is selected, it replaces rather than accompanies ACE inhibitor or ARB therapy because it already incorporates angiotensin-receptor blockade.[1]
Stage 3 — Discussing a newer APRIL-directed option
The patient wants to avoid systemic glucocorticoids if a suitable disease-directed alternative is available. Targeted-release budesonide, sparsentan, and current U.S. options are reviewed in light of his disease features, tolerance of ACE inhibition, treatment burden, reproductive plans, local availability, insurance coverage, and the limits of direct comparative evidence. He has no active infection, has completed an age-appropriate vaccination review, and does not use systemic immunosuppressants.
The multidisciplinary team also discusses sibeprenlimab-szsi (Voyxact), a monoclonal antibody that inhibits APRIL. In the United States, it has accelerated approval to reduce proteinuria in adults with primary IgAN at risk for progression. This does not yet establish that it slows long-term kidney-function decline.[2]
In the VISIONARY phase 3 interim analysis, adults with biopsy-confirmed IgAN receiving sibeprenlimab 400 mg subcutaneously every four weeks had a 50.2% reduction in 24-hour UPCR at nine months, compared with a 2.1% increase with placebo; the placebo-adjusted relative difference was 51.2%.[3] The key eGFR-slope outcome is reported at trial completion, so the proteinuria signal must not be overstated as definitive long-term kidney protection.[3]
Decision point 3
Which counseling statement is most appropriate before starting sibeprenlimab in this patient?
| Option | Interpretation |
|---|---|
| A | Because it is approved for IgAN, sibeprenlimab should replace all supportive therapy. |
| B | It is a reasonable U.S. option to discuss after optimized supportive therapy, but accelerated approval is based on proteinuria reduction; assess active infection, review vaccines, avoid live vaccines shortly before and during treatment, and discuss the uncertainty about long-term eGFR benefit. |
| C | It can be combined indiscriminately with systemic immunosuppression because its safety is fully established in such combinations. |
| D | It is contraindicated when eGFR is below 90 mL/min/1.73 m². |
Preferred decision: B. Sibeprenlimab is an APRIL blocker, not a substitute for optimized kidney-protective care or individualized treatment selection. The U.S. label recommends assessment for active infection before treatment, monitoring for infection during treatment, and avoidance of live vaccines within 30 days before starting and during therapy. It also notes limited clinical data with concomitant systemic immunosuppressants.[2]
| Domain | Educational management plan |
|---|---|
| Foundational therapy | Maintain tolerated kidney-protective therapy, blood-pressure management, cardiovascular-risk assessment, and longitudinal surveillance. |
| New option | If selected in the relevant jurisdiction, sibeprenlimab is administered as 400 mg subcutaneously every four weeks according to current prescribing information.[2] |
| Infection and vaccination | Assess for active infection before initiation; monitor during therapy; revisit vaccination status and avoid live vaccines within 30 days before initiation or during treatment.[2] |
| Treatment framing | Explain accelerated-approval status, proteinuria-based evidence, the pending long-term eGFR outcome, administration burden, access, and the absence of head-to-head evidence proving universal superiority. |
| Alternatives | Compare targeted-release budesonide, sparsentan, and other locally available options using disease phenotype, contraindications, reproductive considerations, treatment burden, and patient values.[1] |
Stage 4 — Longitudinal response, intercurrent infection, and reassessment
After nine months of sibeprenlimab alongside continued kidney-protective therapy, the patient’s UPCR has fallen from 2.1 g/g to 0.92 g/g. eGFR is 46 mL/min/1.73 m². His blood pressure remains controlled and he has had no injection-site reaction. He now develops fever, productive cough, and focal crackles on examination one week before his next planned injection.
Decision point 4
Which response is most appropriate?
| Option | Interpretation |
|---|---|
| A | Administer the scheduled injection immediately because proteinuria has improved. |
| B | Treat the improved UPCR as a complete durable remission and discontinue kidney follow-up. |
| C | Evaluate the respiratory illness urgently and consider interrupting sibeprenlimab if infection is serious until the infection is controlled; continue a structured assessment of kidney trajectory, proteinuria, blood pressure, and treatment safety. |
| D | Add a live vaccine immediately to reduce future infection risk while continuing treatment. |
Preferred decision: C. New infection symptoms require timely clinical evaluation. The label advises consideration of treatment interruption if a serious infection develops until it is controlled.[2] The improvement in proteinuria is encouraging but remains above the ideal proteinuria target. It should prompt continued follow-up, rather than premature declaration of cure or indefinite continuation without reassessment.[1]
Expert synthesis
Primary IgAN requires diagnosis by kidney biopsy, active exclusion of secondary causes, structured risk assessment, and concurrent treatment of both immune-complex-mediated injury and chronic nephron-loss consequences. MEST-C contributes to prognosis and shared decision-making but should not be converted into an automatic drug-selection rule.
This patient has persistent high-risk proteinuria despite optimized kidney-protective therapy. Sibeprenlimab offers a newer APRIL-directed option in the United States, with an accelerated-approval indication based on proteinuria reduction. Its decision framework must explicitly include the unresolved long-term eGFR question, infection and immunization precautions, drug access, alternative disease-directed options, and the patient’s preferences. The result is a reasoned therapeutic discussion rather than a universal prescription.
References
[1] [inline_viewer url="https://kdigo.org/wp-content/uploads/2026/04/KDIGO-2025-IgAN-IgAV-Guideline.pdf"]
[2] [inline_viewer url="https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761434s000lbl.pdf"]
[4] FDA Drug Trials Snapshot: VANRAFIA (atrasentan)
Advanced self-assessment
Complete the 10-question Advanced self-assessment below. Detailed explanations are provided after submission.