Bring proteinuria to target

The unmet need for people living with IgA nephropathy

Professor Jonathan Barratt (University of Leicester, UK) gives his perspective on the existing unmet needs in immunoglobulin A nephropathy (IgAN). Professor Barratt discusses the epidemiology, current treatment methods, and key mechanisms and pathways involved in disease progression. 

IgAN, while rare, is a progressive disease and a major cause of kidney failure.^1–4 It is estimated to affect around 2.5/100,000 people per year worldwide, with most people diagnosed in their 30s and 40s.^1,5,6 The progressive nature of the disease also presents a significant physical and mental burden, with people commonly reporting experiencing pain and fatigue, as well as anxiety and depression.^2,7

A major unmet need is the lack of treatment options specifically indicated for IgAN. For treatment, the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend the use of renin–angiotensin system inhibitors (RASi) in people with proteinuria >0.5 g/day. RASi include angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB). They also recommend consideration of a 6-month course of glucocorticoid therapy in people with persistent proteinuria >0.75–1 g/day (despite at least 3 months of optimised supportive care) and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m².⁸ Additionally, the use of sodium–glucose cotransporter-2 inhibitors (SGLT2i) in clinical practice has increased.^9,10

The role of proteinuria in IgAN pathophysiology is a major focus, as it is known to be the strongest modifiable risk factor for disease progression.^5,11 By reducing proteinuria, it is possible to slow progression of IgAN and delay the time it takes to reach kidney failure.^5,11–13 In the KDIGO guidelines, reduction of proteinuria to below 1 g/day is a surrogate marker of improved kidney outcomes.⁸ However, Professor Barratt highlights that, despite current treatments, many people do not reach treatment targets and remain at risk of disease progression.^8,14

In IgAN, damage is caused by deposition of IgA-containing immune complexes in the mesangium (Figure 1), elevating levels of endothelin-1 (ET-1) and angiotensin II (ANG II), which also mutually upregulate each other.^2,15

Figure 1. IgAN is caused by deposition of galactose-deficient IgA-containing immune complexes.²

These pathways amplify disease damage and contribute to increased proteinuria levels in a positive feedback loop.^15–18 Overall, the endothelin and angiotensin pathways affect multiple pathophysiological processes involving the tubulointerstitial compartment, glomeruli, and haemodynamics (Figure 2).¹⁵

Figure 2. Dysregulation of endothelin-1 and angiotensin II pathways as part of the underlying pathophysiological effect on kidney damage in people with IgA nephropathy.¹⁵ ANG II, angiotensin II; ECM, extracellular matrix; ET-1, endothelin-1.

The amplification of damage caused by proteinuria and the dual ET-1/ANG II pathways accelerate progression to kidney failure, further highlighting that treatment of IgAN may require inhibition of both pathways.^15–17,19 To conclude, many people with IgAN are still at risk of disease progression despite the current standard of care, showing the need for treatments that are able to preserve kidney function and reduce proteinuria to target levels.^8,14

Visit https://www.targetproteinuria.com to find out more about the effects of proteinuria and the dual pathway in IgAN.

Jonathan Barratt

Professor Barratt leads the Renal Research Group at the University of Leicester College of Life Sciences, where his research focuses on improving understanding of IgAN pathogenesis. He is the Rare Disease Group lead for the National Registry for Rare Kidney Diseases (RaDaR) and member of the International IgAN Network steering committee.

Consulting and speaker fees from Alnylam Pharmaceuticals, argenx, Astellas, BioCryst, Calliditas, Chinook Therapeutics, Dimerix, Galapagos, Novartis, Osmeros, Travere Therapeutics, Vera Therapeutics, and Visterra. Grant support from argenx, Calliditas, Chinook Therapeutics, Galapagos, GlaxoSmithKline, Novartis, Omeros, Travere Therapeutics, and Visterra. Involvement in the following clinical trials: ADU-CL-19 & ALIGN (Chinook), APPLAUSE (Novartis), ARTEMIS-IGAN (Omeros), ENVISION (Visterra), NefIgARD (Calliditas), and ORIGIN (Vera Therapeutics). Involvement in research projects with argenx, Calliditas, Chinook Therapeutics, Galapagos, GlaxoSmithKline, Novartis, Omeros, Travere Therapeutics, and Visterra.

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References

1. McGrogan, 2011. The incidence of primary glomerulonephritis worldwide: a systematic review of the literature. https://doi.org/1093/ndt/gfq665
2. Lai, 2016. IgA nephropathy. https://doi.org/10.1038/nrdp.2016.1
3. Wyatt, 2013. IgA nephropathy. https://doi.org/10.1056/nejmra1206793
4. Yeo, 2018. Is immunoglobulin A different in different ethnic populations? https://doi.org/1111/nep.13592
5. Pitcher, Long-term outcomes in IgA nephropathy. https://doi.org/10.2215/CJN.0000000000000135
6. Nair, Is IgA nephropathy the commonest primary glomerulopathy among young adults in the USA? https://doi.org/10.1038/sj.ki.5000292
7. Kwon, A systematic literature review of the epidemiology, health-related quality of life impact, and economic burden of immunoglobulin A nephropathy. https://doi.org/10.36469/001c.26129
8. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. 2021. https://doi.org/10.1016/j.kint.2021.05.021
9. El Kharoui, 2024. Treatment of IgA nephropathy: A rapidly evolving field. https://doi.org/10.1681/asn.0000000000000242
10. Lim, 2024. An update on current therapeutic options in IgA nephropathy. https://doi.org/10.3390/jcm13040947
11. Reich, Remission of proteinuria improves prognosis in IgA nephropathy. https://doi.org/10.1681/ASN.2007050526
12. Thompson, Proteinuria reduction as a surrogate end point in trials of IgA nephropathy. https://doi.org/10.2215/CJN.08600718
13. Carroll, Estimating delay in time to ESKD for treatment effects on proteinuria in IgA nephropathy and FSGS. https://doi.org/10.1093/ndt/gfab104.004
14. Bagchi, Supportive management of IgA nephropathy with renin-angiotensin block, the AIIMS Primary IgA Nephropathy Cohort (APPROACH) study. https://doi.org/10.1016/j.ekir.2021.02.018
15. Komers, Dual inhibition of renin-angiotensin-aldosterone system and endothelin-1 in treatment of chronic kidney disease. https://doi.org/10.1152/ajpregu.00425.2015
16. Kohan, Endothelin and endothelin antagonists in chronic kidney disease. https://doi.org/10.1038/ki.2014.143
17. Sharma, From proteinuria to fibrosis: An update on pathophysiology and treatment options. https://doi.org/10.1159/000516911
18. Gorriz, Proteinuria: Detection and role in native renal disease progression. https://doi.org/10.1016/j.trre.2011.10.002
19. Raina, The role of endothelin and endothelin antagonists in chronic kidney disease. https://doi.org/10.1159/000504623

Visit https://www.targetproteinuria.com to find out more about the effects of proteinuria and the dual pathway in IgAN.