Nephrology
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1/23
IgA Nephropathy Treatment 2025
This interactive case study was supported by CSL Vifor.
Disclosure
Disclaimer
This interactive case study was developed with support from Claudia Seikrit, Division of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, Aachen, Germany
These are hypothetical patient cases and outcomes may not be reflective of clinical studies or real-life circumstances. The mention of these agents and their uses is intended solely for educational purposes and should not be considered an endorsement or recommendation for their use outside approved indications. Please always consult guidelines and local prescribing information in your country of practice, as information may vary.
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This material is intended for Healthcare Professionals only.
Patient History: Part 1
Symptoms:
For 4 weeks the patient experienced:
Medical History:
4 weeks prior, the patient had an upper respiratory tract infection and detected brownish urine on one day, which spontaneously resolved.
A 40-year-old, female, previously healthy patient presented to the Emergency Department.
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Glomerulonephritis
Feeling tired and exhausted
No fever or shortness of breath
Foamy urine, no symptoms of urinary tract infection
Body weight increase by 5 kg
Leg swelling
Hypertension
Proteinuria
Haematuria
Oedema
2/23
Send home to see if symptoms resolve by themselves
Conduct a biopsy
Refer to a nephrology unit
Prescribe antibiotics for a bacterial infection
A
B
C
D
What would be the immediate next steps for this patient?
Outcome: The patient was transferred to the local nephrology unit for further examination.
3/23
Proteinuria >3.5 g/day, oedema, and hypercholesterinaemia
Elevated blood pressure, microhaematuria, and proteinuria
Fever, back pain, and dysuria
Low blood pressure and macrohaematuria
What are the most common symptoms of nephritic syndrome?
4/23
MS Hashmi, Pandey J. Nephritic Syndrome [Internet] (2023) Treasure Island: StatPearls Publishing. Available at: https://www.ncbi.nlm.nih.gov- /books/NBK562240/. Last accessed: 14 November 2025.
5/23
Diagnostics
Examination:
Blood pressure was elevated at 140/80 mmHg. There were no signs of rash or skin lesions, no joint pain. BMI was 30 kg/m2
Laboratory Tests:
Laboratory values showed a normal red blood cell count, no signs of inflammation. Cholesterol was increased to 300 mg/dl. eGFR was 120 ml/min/1.73m², not decreased. Urine analysis was abnormal with relevant microhaematuria and proteinuria with 4.3 g/g creatinine in the spot urine. ANA and ANCA showed no abnormalities and complement in serum was not decreased.
ANA: antinuclear antibody; ANCA: antineutrophil cytoplasmic antibody; eGFR: estimated glomerular filtration rate; IgA: immunoglobulin A.
To confirm the diagnosis, a kidney biopsy was performed.
Kidney biopsy showed IgA Nephropathy with a MEST-C Score M0 E1 S1 T0 C0.
MEST-C Score: M: mesangial hypercellularity score; S: segmental glomerulosclerosis; E: endocapillary hypercellularity; T: tubular atrophy/interstitial fibrosis C: scoring of crescents
Taken from Ștefan, G et al. Systematic review of the Link between Oxford MEST-C classification and complement activation in IgA Nephropathy. Kidney International Reports. 2024 9(2), 356-369.
IgA Deposition, mesangial hypercellularity and C3 deposition
Macrohaematuria during acute mucosal triggered infections
Subepithelial PLA2R deposit
Occurrence of gd-IgA containing, circulating immune complexes
Which of these is not a diagnostic hallmark of IgA nephropathy?
C3: glomerular complement 3; gd-IgA: galactose-deficient immunoglobulin A; IgA: immunoglobulin A; PLA2R: Anti-phospholipase A2 receptor. Petrou D et al. IgA nephropathy: current treatment and new insights. Antibodies. 2023;12(2):40.
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7/23
IgAN Pathophysiology1,2
C3: glomerular complement 3; gd-IgA: galactose-deficient immunoglobulin A; IgA: immunoglobulin A. Adapted from, 1. Stamellou E et al. IgA nephropathy. Nat Rev Dis Primers. 2023;9(1):67. 2. Seikrit C et al. Precision medicine in immunoglobulin A nephropathy: still a journey ahead. Nephrol Dial Transplant. 2021;36(Suppl 2):24-30.
Polymeric gd-IgA1
Immune complexes containing IgA1, IgG and C3
Mesangial hypercellularity
Glomerular and endothelial damage
Mesangial deposits of IgA1-containing immune complexes
Mesangial inflammation & Complement activation
Haematuria and proteinuria
Kidney Failure
Podocyte
Endothelial cell
Mesangium
8/23
The Previous KDIGO 2021 treatment guidelines for IgAN
Recommend that in patients with proteinuria >1g/d despite at least 3 months of optimised supportive care, involving:
First line treatment with ACEi/ARB, irrespective of hypertension Lifestyle modification Addressing cardiovascular risk
Enrollment in clinical trials should be considered
If eGFR <30ml/min/1.73m2 , consider maximal supportive care
If eGFR≥30ml/min/1.73m2, consider toxicity risk stratification: advanced age, metabolic syndrome, obesity, latent infection (TB, HIV, HBV, HCV)
Risk/benefit of glucocorticoids should be discussed
Abbreviations
Rovin BH et al. Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4):753-79.
ACEi: angiotension-converting enzyme inhibitors; ARB: angiotension receptor blockers; BP: blood pressure; eGFR: estimated glomerular filtration rate; GN: glomerulonephritis; HBV: hepatitis B virus; HCV: hepatitis C virus; IgA: immunoglobulin A; IgAN: immunoglobulin A nephropathy.
According to the previous KDIGO 2021 Glomerular Disease and KDIGO 2024 CKD guidelines, which approach would be recommended for treating this patient?1,2
Starting treatment cyclophosphamide
Uptitrating RAS Blockade, SGLT2 inhibition, and lifestyle optimisation
Starting systemic steroids
Tonsillectomy
RAS: renin-angiotensin system; SGLT2: sodium-glucose co-transporter 2.
References
1. Rovin BH et al. Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4):753-79; 2. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. 2024;105(4S):S117-S314.
9/23
10/23
Patient History: Part 2
The treatment was followed by a nephrologist cabinet. Patient had regular follow-up visits.
Sequentially a thiazide diuretic, aldosterone inhibition, and a SGLT2 inhibitor have been added to the medication. Proteinuria was controlled to values under 1.0 g/d.
Over the years:
Blood pressure had been well controlled to values of 100/70 mmHg using the maximum allowed dose of RAS blockade with ramipril, SGLT-2 Inhibition with dapaglifozin, use of aldosterone antagonists and a diuretic. Cholesterol was well controlled with a statin. The patient had managed to lose body weight (BMI now 23).
11/23
Patient History: Part 3
eGFR: estimated glomerular filtration rate; IgA: immunoglobulin nephropathy. Pitcher D et al. Long-term outcomes in IgA Nephropathy. Clin J Am Soc Nephrol. 2023;18:727-38.
5 years later, the patient presented again to the university nephrologist consultant for a second opinion concerning persisting proteinuria of 2.0 g/g and an eGFR of 40mL/min/1.73m² (loss of 80 mL/min/1.73² in 5 years).
% of patients who will reach kidney failure based on eGFR at diagnosis
Kaplan–Meier survival curve of time to kidney failure/death event in a population of patients with IgAN
% of patients who will reach kidney failure based on eGFR at diagnosis*
A disease matrix based on an IgA nephropathy cohort (n=2439) showed that sustained eGFR decline of 3ml/min per 1.73m2 would result in 100% of patients younger than 40 years reaching kidney failure in their expected lifetime. A decline as little as 1ml/min per 1.73m2 per year would result in ~40% of adult patients younger than 50 at diagnosis reaching kidney failure within their expected lifetime
*Patients analysed (2299 adults and 140 children) had a biopsy-proven diagnosis of IgA nephropathy plus proteinuria >0.5 g/d or eGFR <60 mL/min per 1.73 m2. eGFR: estimated glomerular filtration rate; IgA: immunoglobulin nephropathy. Pitcher D et al. Long-term outcomes in IgA Nephropathy. Clin J Am Soc Nephrol. 2023;18:727-38.
Kaplan-Meier survival curve of time to kidney failure/death event in a population of patients with IgAN*
A Kaplan-Meier survival analysis in the same cohort evaluated the relationship between time-averaged proteinuria and kidney survival over 15 years
*Patients analysed (2299 adults and 140 children) had a biopsy-proven diagnosis of IgA nephropathy plus proteinuria >0.5 g/d or eGFR <60 mL/min per 1.73 m2. g/g: grams per gram, IgA: immunoglobulin nephropathy. Pitcher D et al. Long-term outcomes in IgA Nephropathy. Clin J Am Soc Nephrol. 2023;18:727-38.
30% of patients with 0.44-0.88 g/g time-averaged proteinuria progressed to kidney failure within 10 years 20% of patients with time-averaged proteinuria levels <0.44 g/g progressed to kidney failure within 10 years
These data highlight the need for monitoring in patients with proteinuria levels that may be traditionally deemed lower risk for kidney failure
Repeat kidney biopsy
Intensify treatment (CKD treatment and immunomodulation)
No changes are needed, this is the natural course of the disease
CKD: chronic kidney disease.
Continue treatment with intensified blood pressure control
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12/23
13/23
PROTECT study: % change from baseline protein/creatinine ratio by visit1,2
UP/C, urine protein-creatinine ratio.
In the PROTECT phase III study (n=404), patients with primary IgAN were randomised 1:1 to receive either 400mg sparsentan once daily or 300mg irbesartan once daily.
Primary Endpoint
1. Rovin BH et al. PROTECT: 2-year results from a randomised, active-controlled, phase 3 trial. Lancet 2023;402:2077-90. 2. CSL Vifor. Sparsentan. Summary of Product Characteristics. 2023. Available at: https://ec.europa.eu/health/docu-ments/community-regis-ter/2025/20250212165163/anx_165163_en.pdf. Last accessed 14 November 2025.
At 36 weeks, the geometric least squares mean percent change in UP/C from baseline was -49.8 % (95 % CI: -54.98, -43.95) in the sparsentan arm versus -15.1 % (95 % CI: -23.72, -5.39) in the irbesartan arm (p < 0.0001)
Improvement in proteinuria reduction was consistently observed with sparsentan as early as 4 weeks and sustained through week 110
14/23
eGFR: estimated glomerular filtration rate. 1. Rovin BH et al. PROTECT: 2-year results from a randomised, active-controlled, phase 3 trial. Lancet 2023;402:2077-90. 2. CSL Vifor. Sparsentan. Summary of Product Characteristics. 2023. Available at: https://ec.europa.eu/health/documents/community-register/2024/20240419162133/anx_162133_en.pdf. Last accessed 14 November 2025
PROTECT study: Change in eGFR from baseline up to week 1141,2
Secondary endpoints included rate of change of eGFR. Patients in the Spartensan group exhibited a slower rate of eGFR decline than those in the Irbesartan group.
From weeks 6-110, eGFR chronic 2-year slope in patients given Spartensan was -2.7mL/min per 1.73m2 per year vs -3.8mL/min per 1.73m2 per year in patients given Irbesartan. (Difference 1·1 mL/min per 1·73 m² per year, 95% CI 0·1 to 2·1; p=0·037)
This implies better preservation of kidney function when treating with sparsentan vs irbesartan
Treatment-emergent adverse events occuring more frequently with spartensan included dizziness and hypotension.
15/23
eGFR: estimated glomerular filtration rate, UPCR: urine protein-creatinine ratio.
NefIgArd study: Change in eGFR and UPCR from baseline when treated with modified release budesonide vs Placebo1,2
In the NefIgArd study, patients with primary IgAN (n=364) were randomised 1:1 to receive modified release budenoside 16mg/day or placebo for 9 months, with a 15-month follow-up.
Time-weighted eGFR average over 2 years showed significant treatment benefit with modified release budenoside vs placebo (difference 5·05 mL/min per 1·73 m² [95% CI 3·24 to 7·38], p<0·0001) The modified release budenoside group also recorded a reduction in UPCR, with a 40·9% (95% CI 31·9–48·7) reduction in time-averaged UPCR between 12 and 24 months compared with the placebo group (p<0·0001)
Treatment with modified release budenoside exhibited reduction in eGFR vs placebo, indicating a disease-modifiying effect in patients with IgA nepropathy
eGFR
UPCR
1. Lafayette R et al. NefIgArd trial investigators. Efficacy and safety of a targeted-release formulation of budesonide in patients with primary IgA nephropathy (NefIgArd): 2-year results from a randomised phase 3 trial. Lancet. 2023;402(10405):859-70. 2. Calliditas Therapeutics. Nefecon. Summary of Product Characteristics. 2024. Available at: https://www.medicines.org.uk/emc/product/15393/smpc/print. Last accessed 14 November 2025.
16/23
Treatment
With patient levels of proteinuria >1g/d, sparsentan was initiated at 200 mg (once daily) after completing RASi intake the day prior, and the aldosterone antagonist was stopped. SGLT2 inhibition was maintained. After 2 weeks sparsentan was increased to 400 mg/d. After 6 weeks of sparsentan 400 mg/d intake, proteinuria decreased by 50% to 1 g/d. The patient stopped smoking and improved lifestyle and diet measures. Finally, 3 months after initiation of sparsentan UPE was 0.25 g/d and remission was achieved.
This is a hypothetical patient case and outcomes may not be reflective of clinical studies or real-life circumstances. SGLT2: sodium-glucose co-transporter 2; RASi: renin-angiotensin system inhibitor; UPE: urinary protein excretion.
Scenario A: Sparsentan in combination with SGLT2 inhibition
Proteinuria levels
Sparsentan initiated on top of SGLT2i (Proteinuria >1g/d)
6 weeks: -50%
3 months: -75%
Remission achieved
Discussion:
The treatment was successful, proteinuria remission was achieved. Generally, it is recommended that immunomodulatory treatment is initiated quickly. In this case, sparsentan is beneficial on top of SGLT2 Inhibition.
Sparsentan. Summary of Product Characteristics. 2023. Available at: https://ec.europa.eu/health/ documents/community-register/2025/20250212165163/anx_165163_en.pdf. Last accessed 14 November 2025.
17/23
Efficacy
Safety
SGLT2i: sodium-glucose cotransporter 2 inhibitor; UPCR: urine protein-creatinine ratio. Kooienga L, et al. ASN 2024; Poster #FR-PO851.
In a subset analysis of Phase III PROTECT OLE, sparsentan was well tolerated in combination with SGLT2 inhibitor therapy
18/23
With patient levels of proteinuria >1g/d, sparsentan was initiated. Six weeks after treatment with Sparsentan 400 mg/d, proteinuria decreased by 40% with a maximum decrease of 80% after 6 months. After 8- and 9-months proteinuria increased again to 1g/d, with an eGFR loss of 5 mL in 9 months. As patient proteinuria levels remained above >1g/d, modified release budesonide formulation was initiated.
This is a hypothetical patient case and outcomes may not be reflective of clinical studies or real-life circumstances. eGFR: estimated glomerular filtration rate.
Scenario B: Relapse during sparsentan treatment
Sparsentan initiated (Proteinuria >1g/d)
6 weeks: -40%
3 months: -80%
Relapse
+Modified release budesonide formulation
Discussion: Sparsentan showed benefit in combination with modified release budesonide formulation, which was well tolerated.
The patient was treated with modified release budesonide formulation. After 6 months of treatment, proteinuria decreased by 35% to approx. 1 g/d. eGFR remained stable.
Scenario C: Treatment with sparsentan on top of treatment with modified release budesonide formulation
Nefecon initiated
6 months: -35%
+Sparsentan (Proteinuria >1g/d)
+6 weeks: -60%
Disease progression could be prevented at an earlier timepoint.
Six weeks after treatment with sparsentan, proteinuria decreased by another 60% (to 0.4 g/d)
Sparsentan was added on top of modified release budesonide formulation treatment.
Discussion: In this case, sparsentan was associated with a reduction in proteinuria in a patient receiving MR budenoside.1,2
1. Calliditas Therapeutics. Nefecon. Summary of Product Characteristics. 2024. Available at: https://www.medicines. org.uk/emc/product/15393/smpc/print. Last accessed 14 November 2025. 2. Schanz M et al. First real-world evidence of sparsentan efficacy in patients with IgA nephropathy treated with SGLT2 inhibitors. Clin Kidney J. 2024;18(1):sfae394.
19/23
20/23
2025 Management Guidelines
Updated clinical practice guidelines have been published in 2025, streamlining an integrated parallel approach:
KDIGO 2025 Clinical Practice Guideline for the Management of Immunoglobulin A Nephropathy (IgAN) and Immunoglobulin A Vasculitis (IgAV). Kidney Int. 2025;108(4S):S1-71.
21/23
Focus on immunomodulatory treatment
Add an immunomodulatory treatment early
Only add immunomodulatory treatments after a long intensification of CKD Therapy
Which treatment approach is proposed by the current guideline draft?
CKD: chronic kidney disease; IgAN: immunoglobulin A nephropathy. Kidney Disease: Improving Global Outcomes (KDIGO) 2024 Clinical Practice Guideline for the Management of IgA Nephropathy (IgAN) and IgA Vasculitis (IgAV) (Draft). Available at:https://kdigo.org/igan-igav-public-review-draft/. Last accessed: 14 November 2025.
Address both causes and consequences of IgAN simultaneously
22/23
Conclusion
The new KDIGO 2025 Clinical Practice Guideline for the Management of IgAN and IgAV proposes an updated treatment strategy with parallel application of immunomodulatory and CKD drugs. Efforts need to be made to discover suitable biomarkers to aid patient selection and improve treatment.
23/23
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