By Jula Inrig, M.D., Chief Medical Officer, Travere Therapeutics
When a specialized field of medicine has long been quiet, a buzz of breakthrough can seem like a sudden development. The reality is more nuanced.
The fact is, it can take years of focus, dedication, and investment to bring about a surprising advance like the wave of innovation we are seeing in rare kidney disease (RKD), and particularly in IgA nephropathy (IgAN). The recently proposed updates to the draft Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guideline, which were released for public comment in August, underscore the striking advances in treatment options for IgAN.1 Additionally, they reflect a deep understanding of the rapid progression of IgAN’s destructive mechanisms of disease.1 Not long ago, patients with IgAN were frequently told they had a slowly progressing kidney disease.
IgAN, also known as Berger’s disease, is often diagnosed in people during their 20s and 30s, and sometimes even children. This RKD is characterized by the deposition of the antibody immunoglobulin A (IgA) in the filtering units of the kidneys. The resulting inflammation can progressively damage the kidneys, eventually resulting in kidney failure.2
But the devastating truth is that the eventuality of kidney failure and the need for transplantation or dialysis was, in fact, happening much faster than expected.2
Clinical practice guideline evolution
The IgAN treatment target set in the 2012 published KDIGO guidelines was to achieve less than 1 gram per day in proteinuria, a measure of protein being lost in the urine due to damage in the kidneys’ ability to filter blood.3
Around the same time, the Kidney Health Initiative (KHI), a public-private partnership between the FDA and the American Society of Nephrology (ASN), was founded to catalyze innovation and the development of safe and effective patient-centered therapies for people with kidney diseases. One of its priorities was to identify more effective measures to forecast outcomes so that clinical trial protocols could be developed and completed within a reasonable time frame.
Proteinuria emerged as a valuable measure for progress in IgAN research and development.4 The KHI advanced key surrogate endpoints in IgAN clinical trials – proteinuria reduction and remission, both of which are measures of kidney health.5
Proteinuria is not normal; it is harmful and causes damage to the kidneys. Growing evidence that lower proteinuria levels are associated with better long-term outcomes saw a change nine years later in the next update to KDIGO for IgAN, incorporating and recommending risk stratification.6 Identifying patients at high risk of disease progression made it possible for clinicians to enroll appropriate candidates in clinical trials, advancing the development of potential new therapies.5
Assumptions of stability
While KHI continued to spur innovation, and clinical trial sites began to grow worldwide to test new approaches to halting kidney function decline, in the clinic, IgAN remained largely addressed through overall health management: watch your diet, exercise well, and control your blood pressure.7 Off-label use of antihypertensive medications like ACE inhibitors and angiotensin receptor blockers (RAS inhibition), with bouts of immunosuppressive treatment during inflammatory flare-ups was what there was; no FDA-approved treatment yet existed indicated for IgAN.7,8 This left many patients with proteinuria above the target.2
Patients were often told they were stable. They’re in the prime of life, building a career, pursuing their passions, raising children – whatever they are doing, their level of proteinuria indicates irreversible kidney damage and loss of kidney function. Not stability.
Changing the target
In 2023, a clear picture emerged in Clinical Journal of the American Society of Nephrology of the progression of IgAN and time to kidney failure.2 Using data from the UK National Registry of Rare Kidney Diseases (RaDaR) to analyze long-term outcomes in IgAN patients, researchers found that many patients, even those considered stable or low risk, had poor outcomes, with a significant number progressing to kidney failure or death within a median follow-up of 5.9 years.2
Accordingly, the recently updated draft 2024 KDIGO guidelines state that patients with proteinuria at or exceeding 0.5 grams per day are at risk for progressive loss of kidney function and should be biopsied and treated with a target of less than 0.5 grams per day; aiming to achieve near or complete remission reduces patients’ lifetime risk of kidney failure.1 With these guidelines along with new treatment options, we anticipate patients can find greater stability.
A better grasp of the disease means more treatment options
We have long known that IgAN involves overactivation of harmful cellular activity in both the kidney and the immune system. There has been tremendous progress in the development of treatments to address both disease processes, and the future will include using therapies in tandem in more effective ways.7 As outlined in KDIGO, the treatment landscape is evolving to a two-pronged approach: the use of complementary therapies addressing both the immune overactivation and the structural damage in the kidneys will be critical to protect kidney function in many with this complex RKD.1
Seeing the way forward
While the draft KDIGO updates reinforce the progress that has been made so far, the upcoming ASN Kidney Week in San Diego on October 23-27 should provide a glimpse of what is still to come.
The progress in understanding glomerular diseases such as IgAN could also be extended to other rare kidney diseases, such as focal segmental glomerulosclerosis (FSGS), a rare proteinuric disorder that is estimated to affect more than 40,000 people in the US.9
Pressing the pace
If the progress in RKD seems sudden, it’s worth noting that the nephrology community along with researchers, regulators, industry, patient advocacy organizations and families dedicated themselves for years to the progress we now see flourishing today. It is the kind of progress patients urgently deserve.
References
1 KDIGO 2024 Clinical practice guideline for the management of immunoglobulin A nephropathy (IgAN) and immunoglobulin A vasculitis (IgAV). Kidney Disease: Improving Global Outcomes (KDIGO). Accessed September 17, 2024. https://kdigo.org/wp-content/uploads/2024/08/KDIGO-2024-IgAN-IgAV-Guideline-Public-Review-Draft.pdf.
2 Pitcher D, Braddon F, Hendry B, et al. Long-term outcomes in IgA nephropathy. Clin J Am Soc Nephrol. 2023;18(6):727-738. doi: 10.2215/CJN.0000000000000135
3 KDIGO 2012 Clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Disease: Improving Global Outcomes (KDIGO). Accessed September 17, 2024. https://kdigo.org/wp-content/uploads/2017/02/KDIGO_2012_CKD_GL.pdf.
4 Mercer A, Barratt J. Proteinuria as a surrogate endpoint for disease progression in IgA nephropathy: predicting long-term treatment effects of sparsentan. Presented at the European Renal Association Congress. June 16, 2023. Milan, Italy.
5 Barratt J, Rovin B, Diva U, et al. Implementing the Kidney Health Initiative surrogate efficacy endpoint in patients with IgA nephropathy (the PROTECT trial). Kidney Int Rep. 2019;4(11):1633-1637. doi: 10.1016/j.ekir.2019.08.007.
6 Rovin BH, Adler SG, Barratt J, et al. Executive summary of the KDIGO 2021 guideline for the management of glomerular diseases. Kidney Int. 2021;100(4):753–779. doi: 10.1016/j.kint.2021.05.015.
7 Caster DJ, Lafayette RA. The treatment of primary IgA nephropathy: change, change, change. Am J Kidney Dis. 2024;83(2):229-240. doi: 10.1053/j.ajkd.2023.08.007.
8 Maixnerova D, Hartinger J, Tesar V. Expanding options of supportive care in IgA nephropathy. Clin Kidney J. 2023;16(Suppl 2):ii47-ii54. doi: 10.1093/ckj/sfad201.
9 Rheault MN, Alpers CE, Barratt J, et al. Sparsentan versus irbesartan in focal segmental glomerulosclerosis. N Engl J Med. 2023;389(26):2436-2445. doi: 10.1056/NEJMoa2308550.