A life­time of change: mak­ing decades of dif­fer­ence in IgAN dis­ease man­age­ment

Ten years can sound like a long time – but some­times we feel a decade goes by in the blink of an eye. Sud­den­ly we’re old­er and life has changed. For a per­son who has been di­ag­nosed with im­munoglob­u­lin A nephropa­thy, or IgAN, 10 years can feel both too short, and like a life­time. Be­cause that is how close they may be to kid­ney fail­ure.

The dev­as­tat­ing truth about IgAN, al­so known as Berg­er’s dis­ease, is that it im­pacts peo­ple in their 20s and 30s, and some­times even chil­dren. Pa­tients are in the prime of life, they are of­ten build­ing a ca­reer, they may be pur­su­ing their pas­sions, or they might be rais­ing chil­dren – what­ev­er they are do­ing, they have so much to look for­ward to. They want to see their kids go to col­lege, get mar­ried and have chil­dren, or go on a trip they’ve al­ways dreamed of. But if they can­not get treat­ment that can pre­vent the in­evitable kid­ney dam­age and loss of kid­ney func­tion that IgAN caus­es, all those oth­er plans are in jeop­ardy.

A life-lim­it­ing dis­ease with lim­it­ed op­tions

IgAN is char­ac­ter­ized by the de­po­si­tion of the an­ti­body im­munoglob­u­lin A (IgA) in the glomeruli, the fil­ter­ing units of the kid­neys. This de­po­si­tion leads to in­flam­ma­tion and scar­ring and can pro­gres­sive­ly dam­age the kid­neys caus­ing blood and pro­tein to leak in­to the urine even­tu­al­ly re­sult­ing in end-stage re­nal dis­ease, or kid­ney fail­ure, with­in 10 years of di­ag­no­sis in some peo­ple.¹ The ef­fects of kid­ney fail­ure go be­yond the phys­i­cal. The stress of liv­ing with this chron­ic con­di­tion can be as­so­ci­at­ed with men­tal health dis­or­ders like anx­i­ety and de­pres­sion.^2,3,4

Treat­ment op­tions for peo­ple liv­ing with IgAN have been lim­it­ed to over­all health man­age­ment: make sure you watch your di­et, ex­er­cise well, and con­trol your blood pres­sure.⁵ Ini­tial treat­ment ap­proach­es in­clude the off-la­bel use of an­ti­hy­per­ten­sive med­ica­tions like ACE in­hibitors and an­giotensin re­cep­tor block­ers (RAS in­hi­bi­tion), with bouts of im­muno­sup­pres­sive treat­ment dur­ing in­flam­ma­to­ry flare-ups.^5,6

Any pro­tein found in urine (known as pro­tein­uria) is not nor­mal; it is harm­ful and caus­es dam­age to the kid­neys. Ac­cord­ing to analy­ses of the UK Na­tion­al Reg­istry of Rare Kid­ney Dis­eases (RaDaR), a high pro­por­tion of in­di­vid­u­als re­main above tar­get pro­tein­uria lev­els de­spite RAS in­hi­bi­tion. As a re­sult, many strug­gle to man­age their dis­ease and progress more quick­ly to kid­ney fail­ure.¹

The lim­it­ed av­enues for in­ter­ven­tion left both pa­tients and nephrol­o­gists grap­pling with the un­cer­tain­ty of dis­ease pro­gres­sion and the need for dial­y­sis or kid­ney trans­plan­ta­tion and man­age­ment of side ef­fects.⁷

Build­ing a foun­da­tion for progress

Just a decade ago, there was not much hope for new treat­ments, as there was al­most no clin­i­cal de­vel­op­ment in rare kid­ney dis­eases (RKD). But 10 years can bring a life­time of change – and progress – when com­mit­ted re­searchers and the pa­tient com­mu­ni­ty work to­geth­er.

Be­fore nov­el treat­ments could be ad­vanced, the un­der­stand­ing of RKD would have to evolve. For 50 years, end­points in nephrol­o­gy clin­i­cal tri­als were hard clin­i­cal out­comes – end-stage kid­ney fail­ure and death – which cre­at­ed bar­ri­ers for clin­i­cal tri­al de­sign and re­cruit­ment.^8,9 The Kid­ney Health Ini­tia­tive (KHI), a pub­lic-pri­vate part­ner­ship with the FDA and the Amer­i­can So­ci­ety of Nephrol­o­gy on which I served, was found­ed to cat­alyze in­no­va­tion and the de­vel­op­ment of safe and ef­fec­tive pa­tient-cen­tered ther­a­pies for peo­ple with kid­ney dis­eases. One of KHI’s pri­or­i­ties was to iden­ti­fy more ac­cu­rate ways of mea­sur­ing and fore­cast­ing out­comes so that bet­ter clin­i­cal tri­al pro­to­cols could be de­vel­oped.

Plan­ning more hope­ful fu­tures

Pro­tein­uria nat­u­ral­ly emerged as a valu­able mea­sure in IgAN re­search and de­vel­op­ment.¹⁰ Physi­cians had long seen that many pa­tients with IgAN had in­creas­ing pro­tein­uria. Based on Kid­ney Dis­ease: Im­prov­ing Glob­al Out­comes (KDI­GO) rec­om­men­da­tions, physi­cians en­rolled those at high risk of dis­ease pro­gres­sion in clin­i­cal tri­als, hope­ful to de­lay what seemed in­evitable.¹¹

RaDaR shed light on the in­dis­crim­i­nate speed of IgAN pro­gres­sion, high­light­ing the ur­gent need for ef­fec­tive in­ter­ven­tions, even in some pa­tients who were tra­di­tion­al­ly con­sid­ered low risk.¹

In­creased in­sights in­to the un­der­ly­ing dis­ease process­es have sparked the de­vel­op­ment of nov­el ther­a­pies tar­get­ing spe­cif­ic path­ways in­volved in IgAN patho­gen­e­sis. Im­por­tant­ly, the Kid­ney Health Ini­tia­tive ad­vanced key sur­ro­gate end­points in IgAN clin­i­cal tri­als – pro­tein­uria re­duc­tion and re­mis­sion, both of which are mea­sures of kid­ney health – ac­cel­er­at­ing the de­vel­op­ment of po­ten­tial new ther­a­pies.¹² To­day two treat­ments have re­cent­ly been ap­proved, there are dozens of on­go­ing tri­als in IgAN, and ad­vance­ments in re­search are chang­ing how clin­i­cians ap­proach this dev­as­tat­ing con­di­tion.⁵

Where we are to­day

Re­cent sci­en­tif­ic ad­vance­ments, achieved in part­ner­ship with the IgAN pa­tient com­mu­ni­ty, have be­gun to change the treat­ment par­a­digm.⁵ While the RaDaR da­ta were sober­ing, analy­ses al­so showed that the de­cline in kid­ney func­tion can be slowed, with RaDaR da­ta show­ing that a 50% re­duc­tion in pro­tein­uria can de­lay time to kid­ney fail­ure or death by 8.5 years, re­in­forc­ing the need for more ef­fec­tive treat­ment op­tions ad­min­is­tered ear­li­er.¹⁰

Re­cent­ly avail­able ther­a­py op­tions al­low nephrol­o­gists and pa­tients to aim for treat­ment goals that more close­ly mim­ic healthy hu­man phys­i­ol­o­gy. Fo­cus­ing on path­ways in­volved in the over­ac­ti­va­tion of harm­ful cel­lu­lar ac­tiv­i­ty in both the kid­ney and the im­mune sys­tem re­spon­si­ble for dis­ease pro­gres­sion of­fers new hope.

That means the next few years in RKD re­search and de­vel­op­ment have the po­ten­tial to build on re­cent suc­cess­es even more. Can we pre­serve kid­ney func­tion and re­duce pro­tein­uria across oth­er RKDs, such as fo­cal seg­men­tal glomeru­loscle­ro­sis (FS­GS)?¹³ And can we do more for pa­tients who are in ear­li­er stages of dis­ease, who have less pro­tein­uria?

The dy­nam­ic na­ture of IgAN treat­ment, and new un­der­stand­ing of the speed of pro­gres­sion of the dis­ease ne­ces­si­tates a part­ner­ship be­tween pa­tients and physi­cians to ad­dress IgAN as ear­ly as pos­si­ble, and to mon­i­tor dis­ease pro­gres­sion, pro­tein­uria, and re­mis­sion. The RKD com­mu­ni­ty – from re­searchers and health­care providers to bio­phar­ma com­pa­nies and pa­tient ad­vo­ca­cy groups – must re­main vig­i­lant, con­tin­u­ing to push the bound­aries of sci­en­tif­ic re­search, while pro­vid­ing re­sources and sup­port for peo­ple liv­ing with this dis­ease.

A life­time of progress

Af­ter 20 years car­ing for pa­tients with kid­ney dis­ease and run­ning nephrol­o­gy clin­i­cal stud­ies, I’m en­er­gized to be part of a much-need­ed era of crit­i­cal change and progress in nephrol­o­gy. The emer­gence of treat­ment op­tions is dri­ving a surge in ac­tiv­i­ty in re­search in­to RKD. With ad­vance­ments in our un­der­stand­ing of dis­ease patho­gen­e­sis and the avail­abil­i­ty of kid­ney tar­get­ed ther­a­pies, we could see a life­time of change in the years to come.

 Ref­er­ences

¹ 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.

² Goh ZS, Gri­va K. Anx­i­ety and de­pres­sion in pa­tients with end-stage re­nal dis­ease: im­pact and man­age­ment chal­lenges – a nar­ra­tive re­view. Int J Nephrol Ren­o­vasc Dis. 2018;11:93-102. doi: 10.2147/IJN­RD.S126615.

³ Ab­del-Kad­er K, Un­ruh ML, Weis­bord SD. Symp­tom bur­den, de­pres­sion, and qual­i­ty of life in chron­ic and end-stage kid­ney dis­ease. Clin J Am Soc Nephrol. 2009;4(6):1057-1064. doi: 10.2215/CJN.00430109.

⁴ Fer­oze U, Mar­tin D, Reina-Pat­ton A, et al. Men­tal health, de­pres­sion, and anx­i­ety in pa­tients on main­te­nance dial­y­sis. Iran J Kid­ney Dis. 2010;4(3):173-80. PMID: 20622304.

⁵ 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.

⁶Maixnero­va 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.

⁷ In­sani WN, Whit­tle­sea C, Ju C, et al. Im­pact of ACEIs and ARBs-re­lat­ed ad­verse drug re­ac­tion on pa­tients’ clin­i­cal out­comes: a co­hort study in UK pri­ma­ry care. Br J Gen Pract. 2023;73(736):e832-e842. doi: 10.3399/BJGP.2023.0153.

⁸Thomp­son A, Car­roll K, Inker LA, et al. Pro­tein­uria re­duc­tion as a sur­ro­gate end point in tri­als of IgA nephropa­thy. Clin J Am Soc Nephrol. 2019;14(3):469-481. doi: 10.2215/CJN.08600718.

⁹Inker LA, Mon­dal H, Greene T, et al. Ear­ly change in urine pro­tein as a sur­ro­gate end­point in stud­ies of IgA nephropa­thy: an in­di­vid­ual pa­tient meta-analy­sis. Am J Kid­ney Dis. 2016;68(3):392-401. doi: 10.1053/j.ajkd.2016.02.042.

¹⁰ 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.

¹¹ 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.

¹² 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.

¹³Rheault 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.