Re: IgA nephropathy의 이해, 치료법 탐구

[문형철]

많은 사람들이 신장이 망가지며 투석하는 시대에 살고있다.

당뇨병으로 인한 신부전 

고혈압으로 인한 신부전

사구체 신염에 의한 신부전

신장 사구체에 염증이 생기고, 섬유화(굳어지는)되는 기전탐구를 위해!!!

왜 사구체에서 문제를 일으키는가? 

사구체에서는 단백질을 걸러서 재활용하죠.

정상 IgA(단백질구조)는 신장에서 걸러서 재활용.

그런데

변형된 IgA는 신장 사구체에서 걸러지지 못하고 축적되면서

염증 --> 염증만성화 --> 섬유화 이 과정을 거치는 것!!

Porto Biomed J

. 2024 Nov 14;9(6):264. doi: 10.1097/j.pbj.0000000000000264

Emerging perspectives in the management of IgA nephropathy: a comprehensive review

Ana Marta Gomes a,b,✉, Bruno Schau c, Ana Farinha d

• Author information
• Article notes
• Copyright and License information

PMCID: PMC11560120  PMID: 39544842

Abstract

IgA nephropathy (IgAN) is the most preval‎ent form of primary glomerulonephritis worldwide and a leading cause of chronic kidney disease and renal failure. This disorder is characterized by the deposition of immune complexes containing galactose-deficient forms of IgA and complement C3 in the glomeruli. Until now, disease management relied mainly on optimized supportive care. Systemic corticosteroid therapy is proposed for patients at high risk of disease progression, but the effectiveness and safety of this approach are under debate. A significant proportion of patients do not respond to current therapies and require kidney replacement therapy at a young age, with substantial costs and impact on quality of life. Recently, there have been multiple joint efforts to improve the understanding of IgAN pathophysiology. International collaborations resulted in multiple ongoing clinical trials that are providing new insights toward innovative therapeutic options such as SGLT2 inhibitors, dual endothelin and angiotensin receptor blockers, targeted-release budesonide, B-cell proliferation and differentiation inhibitors, and complement system blockers. Based on this new evidence, revision of the guidelines to manage IgAN is expected to occur in the near future. In addition to the novelty in therapeutic agents, there is also a growing interest in new noninvasive biomarkers for IgAN screening, risk stratification to monitor the course of the disease, and the response to treatment. In this review, we discuss current knowledge on the pathophysiology of IgAN, disease management, and emerging advances in clinical translation of IgAN research.

초록

IgA 신증(IgAN)은

전 세계적으로 가장 흔한 원발성 사구체신염 형태이며

만성 신장 질환 및 신부전의 주요 원인이다.

이 질환은

갈락토스 결핍형 IgA와 보체 C3를 포함한 면역 복합체가

사구체에 침착되는 것이 특징이다.

galactose-deficient forms of IgA and

complement C3

IgA1 : 혈액, 체액, 상부소화기 --> 바이러스, 독소 중화 --> 전신 방어

IgA2 : 소장, 대장 --> 병원체 박테리아 제거 --> 국소 점막 방어

Secretory IgA는 점막에서 특별한 보호막으로 둘러싸여 분비된 형태

그래서 IgA2가 많은 대장, 소장의 점막에는 Secretory IgA 비율이 높음. 

지금까지 질병 관리는

주로 최적화된 지지적 치료에 의존해 왔다.

질병 진행 위험이 높은 환자에게는

전신 코르티코스테로이드 치료가 제안되지만,

이 접근법의 효과와 안전성은 논란 중이다.

상당수 환자는

현재 치료에 반응하지 않아 젊은 나이에 신장 대체 요법이 필요하며,

이는 상당한 비용과 삶의 질에 영향을 미친다.

최근 IgAN 병리생리학에 대한 이해를 높이기 위한

다수의 공동 연구가 진행되었다.

국제적 협력을 통해 진행 중인 다수의 임상시험이

SGLT2 억제제,

이중 엔도텔린 및 안지오텐신 수용체 차단제,

표적 방출 부데소니드,

B세포 증식 및 분화 억제제, 보체 시스템 차단제 등

혁신적 치료 옵션에 대한 새로운 통찰력을 제공하고 있다.

SGLT2억제제 기전
1) 신장에서 포도당, 나트륨 재흡수 억제 --> 전신체액감소 --> 신장 사구체로 들어가는 혈류량 감소
2) 혈압 감소 --> 신장부담 감소
3) 항염증, 항섬유화 효과

황련, 황금 --> 항산화, 항염증, 항섬유화
단삼, 자황

이러한 새로운 증거를 바탕으로

IgAN 관리 지침의 개정이 가까운 시일 내에 이루어질 것으로 예상된다.

치료제의 혁신성 외에도,

IgAN 선별, 질병 경과 모니터링을 위한 위험 계층화,

치료 반응 평가를 위한 새로운 비침습적 바이오마커에 대한 관심도 증가하고 있다.

본 리뷰에서는

IgAN의 병리생리학, 질병 관리, 그리고

IgAN 연구의 임상 적용을 위한 최신 발전 동향에 대한 현재의 지식을 논의한다.

Key words: budesonide, complement system, ESKD, glomerular diseases, glucocorticoids, IgA nephropathy, proteinuria, RAAS inhibitors, SGLT2 inhibitors, sparsentan

Introduction

IgA nephropathy (IgAN) stands out as the most preval‎ent primary glomerular disease worldwide, accounting for a significant share of the global burden associated with end-stage kidney disease (ESKD).1,2 IgAN was first described more than 50 years ago. Its clinical heterogeneity presentation was recognized, but until recent years, treatment was not effective in delaying the progression of the disease. Currently, after years of stagnation, substantial several novel therapeutic approaches for the management of IgAN are emerging, mainly due to an increased recognition of the pathophysiologic mechanisms of the disease. In this review, we describe up-to-date information on the epidemiology, risk factors, clinical features, pathology, and innovative treatment strategies of IgAN.

서론

IgA 신병증(IgAN)은

전 세계적으로 가장 흔한 일차성 사구체 질환으로,

말기 신장 질환(ESKD)과 관련된 전 세계적 부담의 상당 부분을 차지한다.1,2

 IgAN은 50년 이상 전에 처음 기술되었다.

임상적 이질성이 인정되었으나,

최근까지도 질병 진행을 지연시키는 효과적인 치료법은 없었다.

현재, 수년간의 정체기를 거친 후,

주로 이 질환의 병리생리학적 기전에 대한 인식이 높아짐에 따라

IgAN 관리를 위한 상당한 수의 새로운 치료 접근법이 등장하고 있다.

본 리뷰에서는

IgAN의 역학, 위험 인자, 임상적 특징, 병리학 및 혁신적인 치료 전략에 관한 최신 정보를 설명한다.

Epidemiology

IgAN is most common in young adults and children. In Western populations, adults are commonly diagnosed around the age of 40–45 years.2 Nevertheless, in countries with proactive urine screening programs, such as Japan, diagnoses tend to occur at earlier ages.3

Data regarding the preval‎ence of IgAN have shown a remarkable variation across different geographical areas: of all kidney biopsy diagnoses, Asia has the highest preval‎ence (30–60%), Europe exhibits a moderate preval‎ence (20–30%), and Africa has the lowest preval‎ence with less than 5%.4,5 A recent systematic review of 16 international studies shows that IgAN incidence varies from 0.06 in South Africa to 4.2 cases per 100,000 per year in Japan.6 In Europe and North America, IgAN reportedly has a moderate annual incidence of 2.5 cases per 100,000.7 Another review focused on European studies of national kidney biopsy registry data estimated an annual IgAN incidence of 0.76 per 100,000 in patients of all ages and a point preval‎ence (the annual IgAN incidence multiplied by the estimated duration of disease) of 2.53 per 10,000.8

In Portugal, according to the national renal biopsy registry, IgAN was the most common diagnosis between 2018 and 2022 (13.4%).9 In 2022, there were 112 new IgAN diagnoses in a total of 411 renal biopsies performed.9 69% of these patients were male, and the mean age of diagnosis was 45.1 years.9 At the time of the renal biopsy/IgA nephropathy diagnosis, patients exhibited creatinine values of 2.24 mg/dl and proteinuria of 2.6 g/day.9 The main reason to undergo a renal biopsy was asymptomatic urinary abnormalities (27%).

It is important to consider, however, that these reports vary depending on the primary source of data. Data obtained from biopsy registries are prone to undervalue the incidence of IgAN because of the lack of inclusion of patients with mild disease, who often do not undergo biopsy. In fact, indications for kidney biopsy differ according to the country, leading to variations in definitive diagnosis of IgAN.1,10 For example, in Africa, only 0.8% of biopsy-proven primary glomerular disease has been reported, reflecting low accessibility to kidney biopsy and higher clinical thresholds to use costly examinations.11 In addition, geographical differences in the incidence and preval‎ence of IgAN could also be due to the fact that mass urine screening programs are systematically performed in several Asian countries, allowing detection of microscopic hematuria and/or mild proteinuria and early referral to a nephrologist.10

Despite these limitations in accessing the exact number of diagnosed patients across populations, diversity in the genetic background is also known to play a major role. Recently, a genome-wide association study (GWAS) with 17 international cohorts identified 16 new loci and defined 30 genome-wide significant risk loci that justify 11% of disease risk.12

역학

IgAN은

젊은 성인과 소아에서 가장 흔하다.

서양 인구에서는

성인이 주로 40~45세 경에 진단받는다.2

그러나

일본과 같이 적극적인 소변 검진 프로그램을 시행하는

국가에서는 더 이른 나이에 진단되는 경향이 있다.3

IgAN 유병률에 관한 데이터는

지역별로 현저한 차이를 보인다:

신장 생검 진단 전체에서

아시아가 가장 높은 유병률(30~60%)을 보이며,

유럽은 중간 수준(20~30%),

아프리카는 5% 미만으로 가장 낮은 유병률을 보입니다.4,5

최근 16개 국제 연구를 체계적으로 검토한 결과,

IgAN 발생률은 남아프리카공화국의 연간 10만 명당 0.06건에서

일본의 연간 10만 명당 4.2건까지 다양하게 나타났습니다.6

유럽과 북미에서는

IgAN의 연간 발생률은

10만 명당 2.5건으로 중간 수준으로 보고되었다.7

국가 신장 생검 등록 자료를 분석한 유럽 연구에 초점을 맞춘 또 다른 리뷰에서는

모든 연령대 환자의 연간 IgAN 발생률을 10만 명당 0.76건,

시점 유병률(연간 IgAN 발생률에 추정된 질병 지속 기간을 곱한 값)을 1만 명당 2.53건으로 추정하였다.8

포르투갈의 경우, 국가 신장 생검 등록부에 따르면 2018년부터 2022년 사이 IgAN이 가장 흔한 진단(13.4%)이었다.9 2022년에는 총 411건의 신장 생검 중 112건의 새로운 IgAN 진단이 있었다.9 이 환자들 중 69%는 남성이었으며, 진단 시 평균 연령은 45.1세였다. 9 신생검/IgA 신병증 진단 시 환자들의 크레아티닌 수치는 2.24 mg/dl, 단백뇨는 2.6 g/day를 나타냈다.9 신생검을 시행한 주된 이유는 무증상 요로 이상(27%)이었다.

그러나 이러한 보고는 데이터의 주요 출처에 따라 차이가 있음을 고려해야 한다. 생검 등록부에서 얻은 데이터는 경증 질환 환자를 포함하지 않아 IgAN 발생률을 과소평가하기 쉽다. 경증 환자들은 종종 생검을 받지 않기 때문이다. 실제로 신장 생검 적응증은 국가별로 달라 IgAN의 확정 진단률에도 차이가 발생한다.1,10 예를 들어 아프리카에서는 생검으로 확인된 원발성 사구체 질환이 전체의 0.8%에 불과한 것으로 보고되었는데, 이는 신장 생검 접근성 부족과 고비용 검사에 대한 임상적 사용 기준이 높기 때문이다. 11 또한, IgAN의 발생률과 유병률에 대한 지리적 차이는 여러 아시아 국가에서 체계적으로 시행되는 대량 소변 검진 프로그램으로 인해 미세 혈뇨 및/또는 경증 단백뇨를 발견하고 조기에 신장내과 전문의에게 의뢰할 수 있기 때문일 수도 있습니다.10

이러한 인구 집단 간 정확한 진단 환자 수 파악의 한계에도 불구하고, 유전적 배경의 다양성이 주요 역할을 한다는 점도 알려져 있다. 최근 17개 국제 코호트를 대상으로 한 전장유전체 연관 연구(GWAS)에서 16개의 새로운 유전좌위를 확인했으며, 질병 위험의 11%를 설명하는 30개의 전장유전체 유의 위험 유전좌위를 규명하였다.12

Clinical presentation and disease evolution

The clinical course of IgAN can present a broad range of manifestations. The 2 most common clinical presentations of IgAN are asymptomatic hematoproteinuria and chronic kidney disease (CKD) that are detected in routine urine and blood analysis.7 Other common presentations can be the appearance of macroscopic hematuria 1–2 days after the onset of a respiratory infectious synpharyngitic hematuria.4,10

Microscopic hematuria with minimal proteinuria was regarded as having a favorable prognosis.13 However, recent findings showed that the amount and progressive increase of proteinuria have a significant impact on long-term renal outcomes.13 CKD is also a common phenotype in multiple cohort studies,7 reflecting the late referral of many patients. In fact, most diagnoses are established in patients with proteinuria higher than 1–2 g/day and impaired renal function.10

Although less frequent, synpharyngitic hematuria is a classic clinical manifestation of IgAN, and due to the alarming nature of the symptom, it encourages patients to seek immediate medical care. It has been associated with a short-term favorable prognosis. Nevertheless, the development of persistent proteinuria is linked to the progression of the disease.14 There are also a few rare IgAN clinical manifestations that will not be covered within the scope of this review, such as rapidly progressive CKD and minimal change disease.

Despite the variable course of the disease, most patients undergo an inexorable decline in renal function and 10–60% reach ESKD 10–20 years after the diagnosis, mainly in younger patients.15,16 To prevent the progression of the disease to kidney failure, it is crucial that IgAN is detected and managed as early as possible. For this reason, the current approach to patient care needs to be re-eval‎uated through, for example, lowering the threshold for biopsy before irreversible damage occurs.16 Currently, proteinuria levels below 0.88 g/g (100 mg/mmol) have been indicated as a target to assess treatment response and inclusion of patients in clinical trials.16 In line with this, and owing to the asymptomatic onset of IgAN in many cases, routine urine analysis in young and active patients could be an interesting approach for early diagnosis and therapeutic decisions. Importantly, a significant number of patients who eventually require kidney replacement therapy are young adults (24–54 years old), with 22% of them younger than 30 years.17 This would have a key impact also from an economic perspective by reducing the need for this type of expensive therapy and the associated financial burden in health care.10

임상 증상 및 질환 진행

IgAN의 임상 경과는

광범위한 증상을 보일 수 있습니다.

IgAN의 가장 흔한 두 가지 임상 증상은

무증상 혈단백뇨와 만성 신장 질환(CKD)으로,

정기적인 소변 및 혈액 검사를 통해 발견됩니다.7

기타 흔한 증상으로는

호흡기 감염성 인두염성 혈뇨 발병 1~2일 후

육안적 혈뇨가 나타나는 경우가 있습니다.4,10

최소 단백뇨를 동반한 미세 혈뇨는

예후가 양호한 것으로 간주되었다.13

그러나 최근 연구 결과에 따르면

단백뇨의 양과 진행성 증가가 장기적인 신장 결과에

상당한 영향을 미치는 것으로 나타났다.13

CKD 역시 여러 코호트 연구에서 흔히 관찰되는 표현형으로,7

많은 환자들이 늦게 진료를 받는 현실을 반영한다.

실제로 대부분의 진단은

단백뇨가 1–2g/일 이상이고

신장 기능이 손상된 환자에서 이루어진다.10

비록 빈도는 낮지만,

인두염성 혈뇨는 IgAN의 전형적인 임상 증상으로,

증상의 심각성으로 인해 환자들이 즉각적인 의료 서비스를 찾도록 유도한다.

이는 단기적으로 양호한 예후와 연관되어 있다.

그럼에도 불구하고

지속적인 단백뇨의 발생은

질환 진행과 연관되어 있다.14

급속 진행성 만성 신장병(rapidly progressive CKD)이나

최소 변화 질환(minimal change disease)과 같이

본 리뷰 범위에서 다루지 않을 몇 가지 드문 IgAN 임상 증상도 존재한다.

질병 경과는 다양하지만,

대부분의 환자는 불가피한 신기능 저하를 겪으며,

주로 젊은 환자에서 진단 후 10~20년 내에

10~60%가 말기 신부전(ESKD)에 이릅니다.15,16

신부전으로의 진행을 방지하기 위해서는

IgAN을 가능한 한 조기에 발견하고 관리하는 것이 중요합니다.

이러한 이유로,

현재의 환자 관리 접근법은 예를 들어 돌이킬 수 없는 손상이 발생하기 전에

생검 기준을 낮추는 등의 방법을 통해 재평가될 필요가 있습니다.16

현재, 0.88g/g(100mg/mmol) 미만의 단백뇨 수치는

치료 반응 평가 및 임상 시험 환자 포함을 위한 목표로 제시되어 왔습니다. 16

이에 부합하고,

많은 경우 IgAN이 무증상으로 발병하기 때문에,

젊고 활동적인 환자에 대한 정기적인 소변 검사는

조기 진단 및 치료 결정에 흥미로운 접근법이 될 수 있습니다.

중요한 점은,

결국 신장 대체 요법이 필요한 상당수의 환자가 젊은 성인(24~54세)이며,

그중 22%는 30세 미만이라는 사실이다.17

이는 이러한 고비용 치료의 필요성과 의료비 부담을 줄임으로써

경제적 관점에서도 핵심적인 영향을 미칠 것이다.10

Pathogenesis

IgA is a class of immunoglobulins present in large amounts in mucosal secretions. They provide immunity against local infections, tolerance to environmental pathogens, and sustain the microbiome.

병인

IgA는 점막 분비물에

다량 존재하는 면역글로불린 계열이다.

이는 국소 감염에 대한 면역,

환경 병원체에 대한 내성,

미생물군집 유지 기능을 제공한다.

Multihit model of IgAN pathogenesis

Although the pathogenesis of IgAN is still incompletely understood, there is a widely accepted multihit model that gathers multiple factors that jointly trigger the development and progression of the disease (Fig. 1; Box 1). These include genetic predisposition, environmental triggers, and abnormal galactosylation of IgA1 and formation of IgA-containing immune complexes.18 According to this theoretical framework, the first event in the development of IgAN is the presence of elevated levels of circulatory galactose-deficient IgA1 (Gd-IgA1) (Hit 1), which leads to the production of autoantibodies of IgG, IgA, or IgM isotypes (Hit 2). The recognition of Gd-IgA1 by these antibodies leads to the formation of circulating immune complexes (Hit 3). These immune complexes eventually deposit in the glomerular mesangium, activate mesangial cells, and induce renal injury (Hit 4).7,19

IgAN 병인의 다중타격 모델

IgAN의 병인은 아직 완전히 규명되지 않았으나,

질병의 발병 및 진행을 공동으로 유발하는 다중 요인을 통합한

다중타격 모델이 널리 인정받고 있다(그림 1; 박스 1).

여기에는

유전적 소인, 환경적 유발인자,

IgA1의 비정상적인 갈락토실화 및 IgA를 포함하는

면역 복합체의 형성이 포함됩니다.18

이 이론적 틀에 따르면,

IgAN 발병의 첫 번째 사건은

순환계 내 갈락토스 결핍 IgA1(Gd-IgA1)의 증가된 수준 존재입니다

( (타격 1)의 존재로,

이는 IgG, IgA 또는 IgM 이소형 자가항체 생산으로 이어진다(타격 2).

이러한 항체에 의한 Gd-IgA1 인식은

순환 면역 복합체 형성을 유발한다(타격 3).

갈락토오스 결핍 IgA1(Gd-IgA1)의 사구간 공간 내 잔류는 IgA 신병증(IgAN)의 핵심 기전이지만, 그 세포 내 운명은 여전히 불분명하다. 여기서 우리는 트랜스페린 수용체 1(TfR1)이 Gd-IgA1을 사구간 세포의 리소좀으로 흡수시키는 매개체 역할을 하며, 이로 인해 소화 불가능한 응집체가 형성되고 리소좀 기능이 파괴되며 염증 반응이 유발된다는 사실을 보여줍니다. IgAN 환자의 신생검에서 IgA1 응집체는 리소좀 내 TfR1과 공위치를 보인다. 수컷 생쥐에서 TfR1 과발현은 Gd-IgA1의 리소좀 축적을 증가시킨 반면, TfR1 노크다운은 이를 감소시켰다. 기전적으로 산성 pH는 갈락토스 결핍 힌지 영역과 잔기 R276을 통해 TfR1-Gd-IgA1 결합을 강화한다. 환자 유래 IgA1에서 흔히 관찰되는 시알릴화가 TfR1 결합에 영향을 미칠 수 있으며 ASGPR과 같은 다른 수용체는 평가되지 않았음을 인정하지만, 본 연구 결과는 IgAN에서 리소좀 중심의 기전을 밝히고 Gd-IgA1의 수용체 매개 저류가 잠재적 치료 표적임을 시사한다.

갈락토스 결핍 IgA1(Gd-IgA1)은 IgA 신증(IgAN)의 병인에서 중요한 역할을 한다. Gd-IgA1 특이적 단일클론 항체(KM55)는 IgAN 및 신염을 동반한 IgA 혈관염(IgAV-N) 환자에서만 사구체 내 Gd-IgA1 침착을 확인하였다. 그러나 이러한 특이성은 논란의 여지가 있으며 소아 환자에서는 입증되지 않았다. 본 연구에서는 다양한 사구체 질환을 가진 소아 환자 60명을 대상으로 IgA와 Gd-IgA1에 대한 이중 면역형광염색을 시행하였다. 환자를 네 그룹으로 분류하였다: (1) IgAN 및 IgAV-N 환자(n=23); (2) 루푸스 신염, 막증식성 사구체신염, 막성 신병증을 포함한 IgA 침착을 동반한 면역복합체 매개 사구체신염 환자(n=14); (3) 특발성 신증후군(INS), 소변량증, 알포트 증후군, 고밀도 침착병, 초승달체 사구체신염 등 기타 IgA 침착을 동반한 사구체 질환 환자(n=11); (4) IgA 음성 질환 환자군: INS, 막증식성 사구체신염, 막성 신병증, 소변량증, 알포트 증후군, C3 사구체신염, 연쇄상구균 감염 후 급성 사구체신염, 용혈성 요독 증후군 포함 (n=12). KM55 염색 결과, 그룹 1의 23명 환자 모두와 그룹 2의 14명 환자 중 13명에서 Gd-IgA1 양성 소견이 관찰되었으나, 그룹 3 또는 4 환자에서는 관찰되지 않았다. 따라서 KM55는 소아 환자에서 우발적 IgA 침착을 검출할 수 있을 것이다. Gd-IgA1은 이러한 면역 관련 질환의 병인에 관여할 수 있으며, 또는 KM55가 비특이적 방식으로 IgA 관련 면역 복합체를 인식할 수도 있다.

이 면역 복합체는

결국 사구체 중간엽에 침착되어 중간엽 세포를 활성화하고

신장 손상을 유발한다(타격 4).7,19

https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1165394/full

Figure 1.

Open in a new tab

Pathogenetic multihit model of IgA nephropathy. Defective mucosal immune responses and antigen processing, among other upstream factors, exert a direct influence on 1 or more pathogenetic pathways in IgA nephropathy. Specifically, there is an increase in the circulation of IgA1 with galactose-deficient O-glycans (Gd-IgA1) in patients with IgA nephropathy (Hit 1). These Gd-IgA1 molecules are identified as autoantigens by antiglycan autoantibodies (anti-Gd-IgA1 autoantibodies; Hit 2), leading to the formation of nephritogenic immune complexes (Hit 3). Some of these complexes deposit in the kidney, triggering the activation of mesangial cells (Hit 4). Subsequently, mesangial cells undergo proliferation and excessive production of components in the extracellular matrix, cytokines, and chemokines. Some of these cytokines, in turn, contribute to podocyte injury, ultimately inducing proteinuria. The progression of these pathogenetic steps is likely influenced by various environmental and genetic factors.

IgA 신병증의 병인학적 다중 타격 모델.

점막 면역 반응 및 항원 처리 결함을 비롯한 상류 요인들은

IgA 신병증의 하나 이상의 병인 경로에 직접적인 영향을 미칩니다.

구체적으로,

IgA 신증 환자에서는 갈락토스 결핍 O-글리칸(Gd-IgA1)을 지닌

IgA1의 순환 증가가 관찰된다(1단계).

이러한 Gd-IgA1 분자는

항글리칸 자가항체(항-Gd-IgA1 자가항체; 타격 2)에 의해 자가항원으로 인식되어

신염 유발 면역 복합체(타격 3)를 형성합니다.

이 복합체 일부는

신장에 침착되어 사구간 세포의 활성화를 유발합니다(타격 4).

이후 사구간 세포는

증식하고 세포외 기질 성분, 사이토카인, 케모카인을 과도하게 생성합니다.

이러한 사이토카인 중 일부는

다시 포도세포 손상에 기여하여 궁극적으로 단백뇨를 유발합니다.

이러한 병리학적 단계의 진행은 다양한 환경적 및 유전적 요인의 영향을 받을 가능성이 있습니다.

Box 1. Multihit model of IgAN pathogenesis.

Hit 1	Both IgA1 and Gd-IgA1 molecules are typically produced by mucosal IgA-committed B cells. Pathogenic alterations of IgA1 involve reduced galactosylation of O-linked N-acetylgalactosamine (GalNac) residues, with or without altered sialylation in the hinge region.18 Currently, it is thought that the gut microbiome or mucosal pathogens of the gastrointestinal tract can stimulate innate immune cells through Toll-like receptors, leading to overactivation of mucosal B cells. This originates an excessive production of Gd-IgA1 that enters circulation from mucosal sites or from systemic sources, due to the miss-homing of mucosal B cells4,18
Hit 2	The GalNac regions of Gd-IgA1, when exposed, can represent an epitope recognized by specific antiglycan antibodies (IgA, IgG, or IgM). Formation of cross-reacting antibodies as a trigger against GalNac is a well-known process since several bacteria and viruses express these same sequences on their surfaces18
Hit 3	Complex interactions lead to the formation of circulating macromolecular immune complexes. These complexes can be established between Gd-IgA1 and the specific antiglycan autoantibodies (Hit 2), but also between Gd-IgA1 and soluble CD89, which is generated after IgA-dependent shedding from the surface of myeloid cells.20 These complexes are prone to deposit in the mesangium in which they encounter mesangial cell receptors for IgA: transferrin receptor (CD71), integrins a1b1 and a2b2, transglutaminase 2, and b-1,4-galactosyltransferase4,20
Hit 4	The deposition of the circulating immune complexes in the glomerular mesangium triggers mesangial cell activation and proliferation, with overproduction of extracellular matrix, cytokines, and chemokines. This leads to podocyte injury and proteinuria, further fueling the recruitment of immune cells and inflammation and promoting glomerular and tubulointerstitial fibrosis19

타격 1

IgA1 및 Gd-IgA1 분자는 일반적으로 점막 IgA 특이적 B 세포에 의해 생성됩니다. IgA1의 병리학적 변형은 힌지 영역에서 시알릴화 변화 유무와 관계없이 O-결합 N-아세틸갈락토사민(GalNac) 잔기의 갈락토실화 감소와 관련이 있습니다.18 현재, 위장관의 장내 미생물군집 또는 점막 병원체가 Toll-like 수용체를 통해 선천성 면역 세포를 자극하여 점막 B 세포의 과활성화를 유발할 수 있다고 생각됩니다. 이로 인해 과도한 양의 Gd-IgA1이 생성되며, 이는 점막 부위 또는 전신적 기원에서 순환계로 유입됩니다. 이는 점막 B 세포의 잘못된 귀소(miss-homing) 때문입니다.4,18

Hit 2

노출된 Gd-IgA1의 GalNac 영역은 특정 항당단백질 항체(IgA, IgG 또는 IgM)가 인식하는 항원결정기(epitope)를 나타낼 수 있습니다. GalNac에 대한 교차 반응 항체의 형성은 여러 박테리아와 바이러스가 표면에 동일한 서열을 발현하기 때문에 잘 알려진 과정입니다18

Hit 3

복잡한 상호작용은 순환하는 거대분자 면역 복합체의 형성을 초래합니다. 이러한 복합체는 Gd-IgA1과 특정 항글리칸 자가항체(Hit 2) 사이뿐만 아니라, 골수계 세포 표면에서 IgA 의존적 탈락 후 생성되는 용해성 CD89와도 형성될 수 있다.20 이러한 복합체는 사구체간질에 침착되기 쉬우며, 여기서 IgA에 대한 사구체간질 세포 수용체( 트랜스페린 수용체(CD71), 인테그린 a1b1 및 a2b2, 트랜스글루타미나제 2, b-1,4-갈락토실트랜스퍼라제4,20

Hit 4

순환 면역 복합체의 사구체 중격부 침착은 중격 세포의 활성화 및 증식을 유발하여 세포외 기질, 사이토카인 및 케모카인의 과잉 생산을 초래합니다. 이는 사구세포 손상과 단백뇨를 유발하여 면역 세포의 추가 유입과 염증을 촉진하고 사구 및 세뇨관간질 섬유화를 촉진합니다19

Emerging perspectives in the management of IgA nephropathy: a comprehensive review - PMC

In addition, activation of the complement system by the immune complexes (Hits 3 and 4), especially the alternative and lectin pathways, plays an extremely important role in further triggering glomerular inflammation and kidney injury.20 This process is recognized as a key contributing factor to the pathogenesis of IgAN, as it will be further discussed.

또한 면역 복합체(Hits 3 및 4)에 의한 보체 시스템 활성화,

특히 대체 경로 및 렉틴 경로는

사구체 염증과 신장 손상을 추가로 유발하는 데 극히 중요한 역할을 합니다.20 

이 과정은

IgAN 병인에 기여하는 핵심 요인으로 인식되며,

이는 후속 논의에서 더 자세히 다룰 예정입니다.

Gd-IgA1-producing B cells

Extensive research has been conducted to explore the mechanisms behind the synthesis of Gd-IgA1, with a particular focus on understanding the involvement of the mucosal immune system and the dysregulated activation of mucosal IgA-committed B cells. Recent evidence has been gathering interest toward B-cell survival factors, specifically a proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF).21 These molecules are cytokines from the tumor necrosis factor (TNF) superfamily and generated by dendritic cells, myeloid cells, and mucosal epithelial cells exposed to antigens. Both cytokines function through receptors known as transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor (TACI) and B-cell maturation antigen (BCMA). In addition, BAFF also binds to the BAFF receptor (BAFF-R).21,22 Activation of these receptors is crucial for various B-cell-related processes, including survival, maturation, proliferation, and immunoglobulin class switching. At mucosal surfaces, APRIL, acting through TACI, facilitates the class switching of naïve B cells to IgA-producing B cells and is, therefore, a key mediator of IgA and Gd-IgA1.21,22 Interestingly, increased APRIL expression‎ in patients with IgAN correlates with high Gd-IgA1 levels and associates with more severe disease presentation and worse outcomes.21 Until now, observations have provided evidence that these cytokines contribute to the production of Gd-IgA1 in IgAN and point them as interesting therapeutic targets. However, further investigation is required to clarify the relative contribution of APRIL and BAFF in the pathogenesis of the disease and whether they have distinct roles depending on the stage of progression or subgroup of patients.21

Gd-IgA1 생성 B 세포

Gd-IgA1 합성 메커니즘을 규명하기 위한 광범위한 연구가 진행되어 왔으며,

특히 점막 면역 체계의 관여와

점막 IgA 특이적 B 세포의 조절되지 않은 활성화에 대한 이해에 중점을 두었습니다.

최근 증거는 B 세포 생존 인자,

특히 증식 유도 리간드(APRIL) 및 B 세포 활성화 인자(BAFF)에 대한

관심을 불러일으키고 있습니다.21

이 분자들은 종양 괴사 인자(TNF) 슈퍼 패밀리의 사이토카인으로,

항원에 노출된 수지상 세포, 골수성 세포 및 점막 상피 세포에 의해

생성됩니다.

두 사이토카인 모두

막 관통 활성화제 및 칼슘 조절제 및 사이클로필린 리간드(CAML) 상호작용제(TACI)와

B세포 성숙 항원(BCMA)으로 알려진 수용체를 통해 기능합니다.

또한 BAFF는

BAFF 수용체(BAFF-R)에도 결합합니다.21,22

이러한 수용체의 활성화는

생존, 성숙, 증식 및 면역글로불린 클래스 전환을 포함한

다양한 B 세포 관련 과정에 매우 중요합니다.

점막 표면에서 APRIL은 TACI를 통해 작용하여

미성숙 B 세포의 IgA 생성 B 세포로의 클래스 전환을 촉진하며,

따라서 IgA 및 Gd-IgA1의 핵심 매개체 역할을 합니다.21,22

흥미롭게도, IgAN 환자에서 증가된 APRIL 발현은 높은 Gd-IgA1 수치와 상관관계가 있으며, 더 심각한 질환 양상과 불량한 예후와 연관됩니다. 21 지금까지의 관찰 결과는 이들 사이토카인이 IgAN에서 Gd-IgA1 생성에 기여한다는 증거를 제공하며, 흥미로운 치료 표적으로 지목하고 있습니다. 그러나 이 질환의 병인에서 APRIL과 BAFF의 상대적 기여도와 진행 단계 또는 환자 하위군에 따라 서로 다른 역할을 하는지 여부를 명확히 하기 위해서는 추가 연구가 필요합니다.21

Role of the complement system

The complement system is a key modulator of the adaptive immune response, playing a crucial role in immunosurveillance and maintenance of tissue homeostasis. However, uncontrolled or prolonged activation of the complement cascade significantly contributes to kidney inflammation and glomerular injury.23 The formation of immune complexes between Gd-IgA1 and specific immunoglobulins and subsequent tissue deposition are known to trigger local complement activation, specifically the alternative and lectin pathways.24 Kidney biopsy samples from patients with IgAN exhibit mesangial deposits of C3, often in conjunction with properdin, which indicates activation of the alternative complement pathway.20,25 In a significant proportion of patients, mesangial deposition of C4, particularly C4d, and mannan-binding lectin also suggest the activation of the lectin pathway.20,24,26 Overall, glomerular deposits of complement system components have been shown to correlate with worse IgAN prognosis, namely lower estimated glomerular filtration rate (eGFR), higher proteinuria, and more severe histologic damage.24,27-30

Role of the endothelin pathway

Endothelin-1 (ET-1) is an endothelial-derived vasoconstrictor peptide. Nowadays, it is known that ET-1 is produced by practically all cell types in the kidney and acts in an autocrine and/or paracrine manner through the receptors ETAR and ETBR.31 Interestingly, transcriptional and immunostaining approaches performed in kidney biopsies have demonstrated that the endothelin pathway, namely ET-1 and ETAR, is activated in patients with IgAN and, moreover, is associated with worse clinical outcomes, such as increased proteinuria and decreased eGFR.31 These observations can be explained by the fact that ETAR activation induces a plethora of pathophysiological effects in the renal vasculature, glomerulus, and renal tubule. These include platelet aggregation and adhesion, immune cell migration and cytokine production, mesangial and vascular smooth muscle cell contraction, podocyte effacement, cell proliferation, extracellular matrix accumulation and fibrosis, induction of angiotensin II (AngII) and aldosterone, and others.31 In experimental models of IgAN, blockade of ETAR has been shown to exhibit renal protective effects and, more interestingly, reduce proteinuria in patients with IgAN.4,31 The endothelin pathway is, therefore, a major player in IgAN pathogenesis and, currently, one of the most attractive targets for therapeutic applications.

Genetic background

The pathogenesis of IgAN is deeply affected by genetic factors, and until now, several GWASs involving cohorts from different geographical areas have revealed risk loci associated with the development of this disease. The identified genes are mainly associated with mucosal immunity (ITGAM, ITGAX, DEFA, LIF, OSM, HORMAD2, MTMR3, and TNFSF13 (this latter encoding APRIL)), both innate and adaptive immunities (CARD9, VAV3, HLA-DQA1, HLA-DQB1, and HLA-DRB1), and complement activation (CFH, CFHR1, and CFHR3).32-34 In another study, VEGFA and PKD1L3 gene variants have also been associated with IgAN susceptibility.35 More recently, a GWAS with 17 international cohorts identified 16 new loci including TNFSF4/TNFSF18, REL, CD28, PF4V1, LY86, LYN, ANXA3, TNFSF8/TNFSF15, REEP3, ZMIZ1, OVOL1/RELA, ETS1, IGH, IRF8, TNFRSF13B, and FCAR.12 A specific GWAS brought to light 2 other significant loci encoding enzymes essential for the O-glycosylation of IgA1: C1GALT1 and C1GALT1C1.36

These genetic elements reside at the crossroads of various established pathways, indicating pivotal stages in the development of IgAN (preservation of the intestinal mucosal barrier, stimulation of mucosal IgA production, NF-κB signaling, protection against intracellular pathogens, and initiation of complement activation).36 Not surprisingly, a genetic risk score based on these loci is higher in Asian populations, moderate in Europeans, and lower in African and African American populations,2,37 consistent with reported IgAN preval‎ence. Specifically, mucosal immunity-related and complement-related genes were more strongly associated with Chinese than with Europeans.38

Histological classification

Histological classification systems are used to describe and categorize disease severity and features. There have been several attempts to classify the histological changes in IgAN to provide clinically relevant information. In the 1980s, Lee et al made the first attempt to predict the progression of renal disease in IgAN through the use of morphological markers.39 The study combined the severity of mesangial hypercellularity, glomerular sclerosis, crescents, and tubulointerstitial changes into 5 grades and correlated patients with diffuse proliferative lesions (grade IV) or chronic advanced lesions (grade V) with ESKD. Patients with normal histology or mild-to-moderate lesions (grades II and III) had a benign course without deterioration of renal function.39 Nevertheless, this classification was based in a small cohort of 13 patients followed for about 3 years, and subsequent studies led to the refinement of this system. Specifically, a study by Haas and colleagues more than 10 years later focused on a category of patients who did not fit into Lee's classification and who had focal segmental glomerulosclerosis (FSGS)-like lesions without crescents or interstitial chronic damage.40 Soon after, Haas established a new histologic grading schema to subclassify patients with IgAN, incorporating features from Lee's classification and of the World Health Organization classification system for lupus nephritis, but specifically recognizing FSGS-like lesions as part of the spectrum of IgAN. It also consisted of 5 classes that were, briefly, organized as follows: minimal histologic lesions (grade I), focal segmental glomerulosclerosis (grade II), proliferative glomerulonephritis in 50% of glomeruli and presence of possible crescents (grade III), proliferative glomerulonephritis in >50% of glomeruli and presence of possible crescents (grade IV), and >40% glomerular sclerosis and/or tubular atrophy (grade V).40

Despite these attempts to establish a reliable tool to be used for clinicopathological correlations in IgAN, the studies at the time lacked consistent inclusion criteria and end points and did not provide precise histopathological definitions. This prompted an international group of pathologists and nephrologists to develop a reproducible and clinically relevant IgAN classification system: the Oxford classification.41 This was based on a study with clinical data and renal biopsy material from 256 patients with IgAN from 8 countries and 4 continents, finding 4 reproducible histologic variables, independently associated with the clinical outcome.41

A large European cohort validation study investigating the utility of this classification system of IgAN (VALIGA) confirmed that M, S, and T lesions independently predicted the loss of eGFR and a lower renal survival.42 In patients with eGFR less than 30 ml/min/1.73 m2, the M and T lesions independently predicted a poor survival. In those with proteinuria under 0.5 g/day, both M and E lesions were associated with a rise in proteinuria to 1 or 2 g/day or more.42 A study involving 500 patients with IgAN showed that the predictive power of the Haas and Oxford classifications concerning renal outcomes were comparable43 but alerted for the fact that the relationship between pathological features and responsiveness to immunosuppression was limited because of the retrospective nature of the study.

A revision of the Oxford classification in 2016 led to the inclusion of crescent scores (C) as the fifth variable (MEST-C) (Box 2): C0 (absence of crescents), C1 (crescents in 1%–24% of glomeruli), and C2 (crescents in >25% of glomeruli).44 This was due to the observation that patients whose biopsy specimens showed crescents in more than 25% of glomeruli had a worse outcome irrespective of treatment.44 The prognostic value of the MEST-C criteria has since been the subject of validation studies, and one, in particular, concluded that there were significant differences in the scoring between local pathologists and a central reviewer, not showing uniform agreement regarding to which areas correlate with independent prognostic value.45 Overall, the Oxford MEST-C classification system provides valuable prognostic information at the time of diagnosis but its utility in selecting the management approach for IgAN remains unclear.

Box 2. MEST-C Score Oxford classification of IgAN.46.

Histological finding

Score

Open in a new tab

Diagnosis

The diagnosis of IgAN requires a kidney biopsy demonstrating the presence of dominant or co-dominant mesangial IgA deposits, generally by immunofluorescence or immunoperoxidase staining.4 In concomitance with these deposits, C3 and, more infrequently, IgG and IgM can also be found co-deposited in the mesangium and the capillary loops.4 Specific IgA1 O-glycoforms and IgA immune complexes may be elevated in the serum, but their use as diagnostic tests is not yet established.47

Modifiable risk factors of disease progression

Blood pressure

Hypertension is one of the most important factors of accelerated progression of IgAN. Given that hypertension is manageable, there is an obvious need to improve blood pressure in the clinical management of the disease.

The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines from 2021 suggest a systolic blood pressure target of <120 mmHg for adults with high blood pressure and CKD because of the cardiovascular and survival benefits rather than renal benefits.46 Given that IgAN is a main cause of CKD, several studies have then addressed the effect of lowering blood pressure during IgAN progression. In a study, Yu et al48 showed that systolic blood pressure was independently associated with composite kidney failure events in patients with IgAN, and that lowering it to <140–120 mmHg was renoprotective. Approaches to achieve lower blood pressure targets, such as the use of agents that block the renin-angiotensin-aldosterone (RAAS) system, are critical to properly manage IgAN and arrest its progression to ESKD.

Proteinuria

Sustained proteinuria is a strong predictor of the rate of renal disease progression and the development of renal failure in IgAN,16 and in this context, it has been considered the most promising surrogate end point in IgAN.49 A study with 542 patients with IgAN from Canada showed that the rate of eGFR decline was increased with the amount of proteinuria and the 121 patients who had sustained levels of 3 g/day lost renal function 25-fold faster than those with 1 g/day.50 This study also stressed the importance of remission or partial remission since the patients whose proteinuria levels decreased from 3 to 1 g/day later developed a similar course to patients who had 1 g/day throughout and managed far better than patients who never achieved remission.50 In this work, proteinuria exposure over time (as measured by time-average proteinuria or the average mean of every 6-month period measurements) was the strongest predictor of the rate of renal function decline.50 A recent retrospective study engaging a multiethnic cohort of adult patients with IgA nephropathy assessed the effect of the magnitude but also the duration of proteinuria remission in the progression of the disease.49 The authors defined proteinuria remission as a ≥25% reduction in proteinuria from the peak value after biopsy and an absolute reduction in proteinuria to <1 g/day. The results showed that among 1864 patients who underwent proteinuria remission, each 3-month period in remission was associated with an additional 9% reduction in the risk of ESKD or a 50% decline in eGFR over a median follow-up of 3.9 years.

Despite the growing body of knowledge regarding proteinuria as a modifiable risk and prognosis factor in IgAN, the fact is that information about disease progression in patients with traditionally considered benign clinical presentations is extremely scarce. This is largely explained by the fact that renal biopsies are generally not performed in this type of patient. Interestingly, a study involving a Caucasian cohort of patients with IgAN with normal renal function and minimal or negative proteinuria (<0.5 g/day) showed no progression of the disease for a median follow-up of 108 months.13

However, other investigations into IgAN have indicated that even lower levels of proteinuria can negatively influence the prognosis.50 This fact was confirmed recently with the study by Pitcher et al. This study gathered an IgAN cohort of 2299 adults and 140 children from UK National Registry of Rare Kidney Diseases and showed that even when proteinuria is <1 g/day, IgAN cannot be considered a benign condition.16 In fact, 30% of patients with a urinary protein-creatinine ratio (UPCR) of 0.44–0.88 g/g, who were traditionally considered at low risk, still had high rates of kidney failure in 10 years, independent of the age of diagnosis.16 Importantly, 20% of patients with UPCR <0.44 g/g were also shown to develop kidney failure within 10 years.16

Still, presently according to the KDIGO guidelines, a reduction of proteinuria to <1 g/day is considered as a reasonable treatment target in patients with IgA nephropathy.51 A certainty in the field is that reducing proteinuria is essential to improve prognosis in these patients. However, the optimal target for proteinuria reduction to attenuate progression of kidney disease is still under debate.

Another interesting aspect is that proteinuria can recur during the long-term course of IgAN. In a retrospective analysis of clinical records of patients with IgAN aged younger than 20 years, approximately 30% of those who had achieved proteinuria remission eventually had recurrence in the following 8 years, regardless of treatment.52 Significant factors associated with this recurrence were older onset age and the presence of hematuria after proteinuria remission.52 Overall, these data emphasize the need to maintain proteinuria remission to achieve a positive prognostic factor for kidney outcome.

Hematuria

As previously mentioned, hematuria, either macroscopic or microscopic, is a typical clinical feature of IgAN and is generally present at the time of diagnosis. Persistent microscopic hematuria, measured as time-average hematuria, has recently emerged as a biomarker of disease activity, either in the absence or most notably in the presence of proteinuria.53 It is also related to a higher loss of kidney function and progression to ESKD, independent of proteinuria and baseline kidney function.53 Moreover, hematuria remission had a significantly beneficial effect in the disease outcome.54 However, the value of this parameter is still a matter of debate and not fully supported by international recommendations.51 Microscopic hematuria has been frequently disregarded in clinical trials, largely because of technical difficulties. In fact, automated and sensitive systems are required to detect and quantify not only intact but also lysed red blood cells, and currently, flow cytometry particle analyzer systems have shown promise in replacing the laborious and operator-dependent manual microscopy.53 In conclusion, the current understanding is that hematuria should be included for enrollment in clinical trials as a readout for drug eval‎uation, particularly those targeting the immune and inflammatory pathways in IgAN.

Prognosis

Biomarkers that could predict IgAN course would be of great benefit, but until now, the prognosis of this disease largely depends on the extent of proteinuria, eGFR, and blood pressure.4 Histopathological eval‎uation of biopsies using the Oxford MEST-C classification is also useful to assess prognosis, as previously discussed. Fortunately, an international IgAN prediction tool has been developed, first to predict prognosis at the time of biopsy55 and later on to be used up to 2 years to eval‎uate the risk of a 50% decline in kidney function or kidney failure in 80 months (6.7 years).56 The model's formula includes parameters such as eGFR, blood pressure, proteinuria, age, information on treatment (RAAS inhibitors and immune suppression), race, and the scores of the MEST-C classification.55,56 This prediction tool has been externally validated and has been updated for use in children. It is also available for clinical use online and in a mobile app calculator.56 It has been recommended by the 2021 KDIGO guidelines to be used in risk stratification for IgAN.51,57 This tool provides a significant improvement in assisting the prognosis of the disease, but it has not been developed to guide treatment and caution should be advised in that matter.

TreatmentOptimized supportive and nonimmunosuppressive drug therapy

According to the latest KDIGO guidelines, optimized supportive care with lifestyle interventions and nonimmunomodulatory drugs remains the backbone of IgAN management51 (Fig. 2). Treatment outcome measures are essentially the reduction of proteinuria and the reduction in the slope of decline in eGFR.51

Figure 2.

Open in a new tab

Treatment approaches in patients with IgA nephropathy as proposed by El Karoui et al.58 CI, contraindication; MMF, mycophenolate mofetil; TRF, targeted-release formulation; SGLT2, sodium-glucose transporter 2. Adapted from El Karoui K, FC Fervenza, and AS De Vriese. Treatment of IgA nephropathy: A rapidly evolving field. J Am Soc Nephrol. 2024;35(1):103–116,58 under the Creative Commons Attribution License 4.0 (CC-BY).

Lifestyle modifications to be implemented include dietary modifications regarding protein and sodium restriction (<2.0 g/day), when appropriate, implementation of a regular physical activity, normalization of body mass, and smoking cessation.51 RAAS blockers such as angiotensin-converting enzyme inhibitors (ACEis) or angiotensin II receptor blockers (ARBs) are cornerstones of supportive therapy in patients with IgAN.51 These agents reduce intraglomerular pressure and proteinuria, key factors associated with disease progression.59 By mitigating glomerular injury and limiting the subsequent inflammatory response and fibrosis, RAAS blockers help preserve renal function and delay the progression of IgAN to ESKD.59–61 Clinical studies have demonstrated that RAAS blockade not only lowers proteinuria but also provides a renoprotective effect, underscoring their importance in the therapeutic regimen for patients with IgAN (Table 1).60–63

Table 1.

Overview of landmark clinical trials in the treatment of IgA nephropathy.

Praga et al62

Stop-IgAN64

TESTING65

NefIgArd66

DAPA-CKD67

EMPA-KIDNEY68

PROTECT69

Open in a new tab

ACEi/ARB, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; BP, blood pressure; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; N/A, not applicable; RAAS, renin-angiotensin-aldosterone system; sCR, serum creatinine; UACR, urine albumin-creatinine ratio.

Consequently, current guidelines dictate that ACEi or ARB should be used at maximally tolerated dose as first-line in treating patients with IgAN when proteinuria is >0.5 g/day, irrespective of hypertension.51,59

New therapies with potential to augment the supportive care approach are emerging, namely the sodium-glucose co-transporter-2 inhibitors (SGLT2is).70,71 In 2021, the DAPA-CKD trial investigated the effects of dapagliflozin, a SGLT2i, on the progression of CKD and other major adverse kidney and cardiovascular events in patients with IgAN (Table 1).67,72 Based on the results of this trial, dapagliflozin declines albuminuria by 26% and significantly reduced the risk of major adverse kidney events by 71% in patients with IgAN compared with the placebo group.67 However, DAPA-CKD enrolled patients who only received ACEi/ARB for 4 weeks, which is much shorter than the treatment course of 3 months recommended by the KDIGO guidelines.51 In addition, it was not considered whether the treatment with ACEi/ARB was performed considering the maximal well-tolerated dose, and thus, it might have led to overestimation of the dapagliflozin effect, as maximization of RAAS inhibition also decreases intraglomerular pressure and renoprotective effect.71 In addition, the study was not specifically designed to test the hypothesis in patients with IgAN. Patients were only followed for a median of 2.4 years,67,72 and long-term follow up studies are still necessary to prove the benefit of these type of drugs in the optimized supportive care of IgAN.71 Moreover, attention should be given to the fact that the primary composite end point (composite if a sustained decline in the eGFR of at least 50%, ESKD, or death due to renal or cardiovascular causes) occurred at an unexpected high frequency in the placebo control group.73 More recently, the EMPA-KIDNEY trial showed that empagliflozin, another SGLT2i, reduced the risk of kidney disease progression or death due to cardiovascular causes in a broad range of patients with CKD at risk of progression (Table 1).74

The endothelin pathway, as previously mentioned, has also emerged as a promising therapeutic target and the focus of new research in the area. Sparsentan is a novel, nonimmunosuppressive, dual ETAR and angiotensin II type 1 receptor antagonist, which has recently received US Food and Drug Administration (FDA) accelerated approval owing to its efficacy in reducing proteinuria in the PROTECT trial.4,69 In this study, 404 patients with IgAN with persistent proteinuria despite treatment with ACEis or ARBs were randomized 1:1 to receive daily oral doses of sparsentan or the active control irbesartan (ARB) (Table 1).75 Specifically, interim results of ongoing phase 3 of this study demonstrated 49.8% reduction of proteinuria from baseline after 36 weeks of treatment compared with the active control arm with irbesartan.69 Treatment-emergent adverse events with sparsentan were similar to irbesartan.69 The effects were maintained throughout 110 weeks, when proteinuria was 40% lower in the sparsentan group than in the irbesartan group.76 The composite kidney failure end point (confirmed 40% eGFR reduction, ESKD, or all-cause mortality) was reached by 9% of patients in the sparsentan group versus 13% of patients in the irbesartan group.76 Currently, sparsentan is indicated to reduce proteinuria in adults with primary immunoglobulin IgAN at risk of rapid disease progression, generally a UPCR ≥1.5 g/g. It has not been established whether sparsentan slows kidney function decline in patients with IgAN, and continued approval for this indication may be contingent on verification and description of clinical benefit in a confirm‎atory clinical trial.

Tonsillectomy has been contemplated as a treatment of IgAN, with the rational of removing a source of pathogens, reducing mucosa-associated lymphoid tissue, and decreasing polymeric IgA synthesis. Nevertheless, its beneficial effect is not consensual and remains controversial in both Asian and Caucasian ethnicities.77 In the VALIGA cohort of European patients with IgAN, there was no significant correlation between tonsillectomy and renal function decline, namely in proteinuria, renal end point of 50% reduction in eGFR, and/or ESKD.78 A meta-analysis with mostly retrospective studies has suggested that tonsillectomy could be helpful in inducing clinical remission and inhibiting development of ESKD in patients with IgAN.77 However, this analysis lacked Caucasian study samples and could not provide any conclusions regarding potential differences between ethnicities.79 Thus, more evidence is needed to consider the addition of tonsillectomy to standard clinical treatment of IgAN.

Immunosuppressive therapy

Current guidelines for the management of IgAN recommend that patients with high risk of progressive loss of kidney function should be considered for immunosuppressive therapy with corticosteroids51 (Fig. 2). Systemic glucocorticoids exert anti-inflammatory and immunosuppressive actions and can further improve kidney outcomes. However, recent randomized controlled trials have raised concerns regarding serious infectious and metabolic toxicity.70,80 A systematic review gathering 9 randomized controlled trials of corticosteroid therapy for IgAN concluded that a relatively short course of immunosuppression with steroids in IgA nephropathy may reduce the risk of kidney failure by two-thirds compared with supportive therapy or ACEi alone.81 Unfortunately, the study also concluded that steroid therapy was associated with 55% higher risk of adverse events.81 This systematic review, however, had several limitations regarding the small and short-term studies included and the lack of consistency of data regarding adverse effects.81 The randomized controlled trial STOP-IgAN contributed to the controversy regarding the safety and efficacy of this treatment option (Table 1). This trial found no difference in the annual decline of eGFR between the supportive care group and the immunosuppression group over a median follow-up of 7.4 years.82,83 Although the addition of immunosuppressive therapy to supportive care was superior to supportive care alone in inducing remission of proteinuria in a proportion of patients, it did not translate into long-term beneficial effects on kidney outcomes, as there was no significant difference in the annual decline in eGFR between the 2 groups. Moreover, the corticosteroid group experienced a higher incidence of adverse events, including severe infections (including 1 death due to sepsis), impaired glucose tolerance, and weight gain.82 This study excluded patients with proteinuria >3.5 g/day and those who had a very rapid decrease in the eGFR during the run-in phase and, thus, cannot comment on the effectiveness of the immunosuppressive treatment in subgroups that could likely benefit from it. In addition, histological findings were not considered throughout the trial.

Meanwhile, the TESTING trial was a multicenter, randomized clinical trial that gathered 750 patients with IgAN with proteinuria >1 g/day and eGFR of 20–120 ml/min/1.73 m2 after at least 3 months of blood pressure control with RAAS blockade (Table 1).84 In this trial, patients were randomized 1:1 to oral corticosteroid (methylprednisolone) or placebo groups for 2 months, but after 2.1 years of median follow-up, the study was discontinued because of excess serious adverse events in the treatment groups, namely severe infections and 2 deaths.84 Nevertheless, until trial cessation, the results were consistent with a potential renal benefit, since the primary renal outcome (ESKD, death due to kidney failure, or a 40% decrease in eGFR) occurred in 5.9% in the methylprednisolone group vs 15.9% in the placebo group.84 A recent follow-up study of the TESTING trial investigated the effect of reduced-dose oral corticosteroid therapy with concomitant antibiotic prophylaxis on both the eGFR and proteinuria after a mean follow-up of 4.2 years.65 Results supported the renoprotective effects of the steroid treatment and the improved safety profile, but 1 infection-related death still occurred in the treatment group.65

Both the STOP-IgAN and the TESTING trials recognized the increased risk of serious infectious adverse effects associated with corticosteroid therapy. Nonetheless, while proteinuria was successfully decreased in both studies, the effect was transient in the STOP-IgAN trial. Interestingly, different outcomes in these studies could have been related to the fact that the STOP-IgAN trial only included Caucasian patients,82 whereas 95% of participants in the TESTING trial were of Asian ancestry, which is a population known to have more aggressive disease, higher baseline proteinuria levels, and a more rapid decline in kidney function.84

Current KDIGO guidelines regarding IgAN advocate that if after at least 90 days of optimized supportive care (including RAAS blockade), proteinuria stays >0.75 g/day and eGFR is >30 ml/min/1.73m2, patients should be considered for a 6-month course of steroid therapy (Grade 2B) or the enrollment in a therapeutic clinical trial.51 However, the guidelines stress that the clinical benefit of steroids in IgAN is still not established and that it should be avoided in patients with eGFR <30 ml/min/1.73 m2, diabetes, obesity, secondary disease, active peptic ulceration, uncontrolled psychiatric disease, or severe osteoporosis.51

Apart from glucocorticoids, other immunosuppressive therapies, such as azathioprine, cyclophosphamide, calcineurin inhibitors, and rituximab, are not currently recommended by the 2021 KDIGO guidelines,51 but other agents are currently under investigation.

Mycophenolate mofetil (MMF) is a potent immunosuppressive agent that is relatively selective for lymphocytes and strongly inhibits antibody production by B cells.85 It can be considered as an alternative to steroids or as a steroid-sparing agent in Chinese patients, since adverse events associated with MMF are lower than those observed with systemic glucocorticoids.85–88 Until now, only Chinese studies have showed that, in patients with IgAN with mild histologic lesions and persistent proteinuria despite maximal angiotensin blockade, MMF treatment may result in transient and partial remission of proteinuria in the short term and renoprotection in the long term (6 years of follow-up).88,89 A recent open-label 3-year trial with 170 Chinese patients with IgAN and persistent proteinuria were randomized to MMF therapy plus supportive care.85 Among patients with IgAN who were at high risk of progression, the trial found that the addition of MMF to standard care significantly reduced the risk of doubling of serum creatinine, ESKD, or death due to kidney or cardiovascular causes compared with standard care alone.85 It was concluded that addition of MMF to optimized standard care could be an alternative therapy for patients at risk of progressive disease and those not appropriate for steroid therapy.85 This trial excluded patients with proteinuria >3.5 g/day and, therefore, did not eval‎uate the efficacy of the treatment in this population.85 Contrary to these studies in the Chinese population, Belgian and North American trials that recruited patients with more advanced disease did not report any benefit from adding MMF to standard care.86,87,90 Owing to the lack of evidence regarding the effectiveness of MMF in the context of progressive IgAN, the 2021 KDIGO guidelines do not recommended its use in non-Chinese patients but suggests that it may be used as a glucocorticoid-sparing agent in Chinese patients.51

Hydroxychloroquine, a TLR9, TLR8, and TLR7 inhibitor, has been eval‎uated for the treatment of IgAN in a single-center Chinese study with patients with proteinuria of 0.75–3.5 g/day and eGFR >30 ml/min/1.73 m2 who were receiving optimized RAAS inhibitor therapy.91 Hydroxychloroquine in addition to optimized standard care effectively reduced proteinuria over 6 months without evidence of adverse events.91 Long-term data indicate that hydroxychloroquine with conventional RAAS inhibitor therapy can reduce proteinuria by 50% within 24 months, without significant decline in eGFR and major adverse events, underlining hydroxychloroquine as a potentially effective supportive treatment for Chinese patients in the long term.92

The intestinal mucosa immune system has been proposed as the main site of IgA production in the body, and a new targeted release formulation of the oral glucocorticoid budesonide (TRF-budesonide), which is preferentially released in the ileal gut-associated lymphoid system, has been shown to reduce the activity of IgAN,93,94 without the adverse effects related to systemic steroid therapy. The therapeutic potential of TRF-budesonide was assessed in an international, multicenter, double-blind phase III trial designated NefIgArd (Table 1).93 Patients with IgAN enrolled in the study had persistent proteinuria (>1 g/day), despite optimized supportive care, and an eGFR of 35–90 ml/min/1.73 m2 and had received the maximum tolerated dose of an RAAS inhibition therapy for at least 3 months before randomization.93 After 9 months, proteinuria was 27% lower in the TRF-budesonide-treated group compared with placebo, along with a benefit in eGFR preservation corresponding to a 3.87 ml/min/1.73 m2 difference versus placebo.93 Adverse events were mostly mild to moderate in severity and reversible.93 Follow-up data of 2 years recently concluded that the treatment with TRF-budesonide demonstrated a clinically relevant reduction in eGFR decline and a durable reduction in proteinuria versus placebo.94 In the treatment group, UPCR decrease reached a maximal effect 3 months after treatment discontinuation (−49.7% compared with placebo).94 However, after these 3 months until the end of the observational follow-up period (24 months), the percentage reduction in UPCR decreased from 49.7% to 30.1% (Nefecon versus placebo).94 TRF-budesonide was granted accelerated approval by the FDA, and it is the first approved treatment of IgAN.4

New therapeutic approaches in the management of IgAN

New milestones for the therapy of IgAN have been set in the past 2 years. We foresee that the guidelines for the management of IgAN will incorporate in the future the use of SGLT2 inhibitors and endothelin receptor antagonists, such as sparsentan, as options for the optimized supportive care approach and the inclusion of TRF-budesonide therapy for patients with high risk of progressive disease.58,80,95 It is also important to keep in mind that patients with IgAN with proteinuria levels <1 g/day remain at risk of kidney failure. This should be taken into consideration in future recommendations concerning the threshold for kidney biopsy, treatment options, and even enrollment in clinical trials.96,97

The increased recognition of proteinuria reduction as a surrogate marker of ESKD has greatly enhanced the viability of conducting clinical trials in IgAN. Presently, numerous trials are underway, focusing on various novel therapeutic targets. These are focused, essentially, on complement inhibition and interference with B-cell maturation and proliferation.

About targeting B cells, and consequently production of Gd-IgA1 and anti-Gd-IgA1 antibodies, numerous studies are on the way. Although the chimeric monoclonal anti-CD20 antibody rituximab reduced circulating B cells, it did not demonstrate any benefit in IgAN, as it failed to lower serum Gd-IgA1 and anti-Gd-IgA1 levels.98 These results led to the hypothesis that CD20+ cells might not be the exclusive producers of Gd-IgA1. In fact, a current clinical trial is investigating felzartamab as a targeting agent of CD38+ cells (NCT05065970). There are also ongoing strategies involving the inhibition of BAFF and APRIL, through either monoclonal antibodies such as sibeprenlimab (NCT04287985), zigakibart (NCT04287985), and blisibimod (NCT02062684) or inhibitors such as atacicept (NCT04716231), telitacicept (NCT05799287), and fostamatinib (NCT02112838). In fact, a recent randomized, double-blind placebo-controlled, phase 2 trial reported that 12 months of treatment with sibeprenlimab (a humanized IgG2 monoclonal antibody that binds to and neutralizes APRIL) resulted in a significantly greater decrease in proteinuria and lower eGFR decline in patients with IgAN than in placebo.99

Considering complement system-directed therapies, there are numerous ongoing phase II/III trials but those with the most promising results concern narsoplimab, an IgG4 monoclonal antibody that inhibits MBL-associated serine protease 2 which is the key effector enzyme of the lectin pathway, and iptacopan, an oral selective inhibitor of factor B of the alternative pathway. Narsoplimab showed substantial reduction of proteinuria in a phase II clinical trial (NCT02682407), but the interim analysis of the phase III trial yielded unfavorable results, leading to the discontinuation of the trial (NCT03608033). In the phase II trial, iptacopan led to continuous decrease in proteinuria and strong inhibition of alternative pathway activity over 6 months,100 and a phase III study (APPLAUSE-IgAN) is currently ongoing (NCT04578834). The results of these and other ongoing trials hold the potential to significantly alter the future of the treatment paradigm for IgAN.

Future perspectives

Imperative tasks for the future are to identify the best treatment combinations and biomarkers to guide therapeutic choices and allow personalized and tailored management of IgAN. While we anticipate the development of future strategies that target the upstream production of Gd-IgA, specific antibodies, and/or the immune complexes, multidrug approaches that target the various pathogenic processes of the disease may be needed in the treatment of IgAN in the foreseeable future. At the moment, the treatment paradigm is guided by levels of proteinuria and eGFR, which are nonspecific and frequent markers of kidney damage. Advances in reliable, noninvasive biomarkers of disease activity and remission will be crucial to shape clinical practice. The availability of such markers, for example, assessing the levels of Gd-IgA1 or IgG/IgA autoantibodies, could help define an appropriate treatment strategy, monitor disease activity during follow-up, and predict the need for retreatment.19,80 Patients with IgAN have relapsing episodes, and unfortunately, there are still very limited data on second-line therapy, retreatment for these situations, or need to perform a second renal biopsy.101

Conclusions

New and exciting advances in IgA management are expected in the near future. The growing body of knowledge on the pathophysiology of this heterogeneous and progressive disease is leading to a plethora of clinically relevant groundbreaking approaches. Novel treatments, biomarkers, and other integrative tools will soon be available to prevent disease progression and increase the life expectancy of patients with IgAN.

Acknowledgements

The authors thank CSL Vifor for financial support to this work and Evidenze Portugal, Lda. for medical writing assistance.

Author contributions: Conceptualization: A.M.G., A.F., B.S. Writing - original draft preparation: A.M.G., A.F., B.S. Writing - review and editing: A.M.G., A.F., B.S. All authors have read and agreed to the published version of the manuscript.

Footnotes

A.A. and A.M.G. have no conflicts of interest to declare. B.S. is an employee of CSL Vifor at the moment of draft preparation and submission.

References

• [1].McGrogan A, Franssen CF, de Vries CS. The incidence of primary glomerulonephritis worldwide: a systematic review of the literature. Nephrol Dial Transpl. 2011;26:414–30. [DOI] [PubMed] [Google Scholar]
• [2].Lee M, Suzuki H, Nihei Y, Matsuzaki K, Suzuki Y. Ethnicity and IgA nephropathy: worldwide differences in epidemiology, timing of diagnosis, clinical manifestations, management and prognosis. Clin Kidney J. 2023;16(Suppl 2):ii1–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
• [3].Lai KN, Tang SCW, Schena FP, et al. IgA nephropathy. Nat Rev Dis Primers. 2016;2:16001. [DOI] [PubMed] [Google Scholar]
• [4].Stamellou E, Seikrit C, Tang SCW, et al. IgA nephropathy. Nat Rev Dis Primers. 2023;9:67. [DOI] [PubMed] [Google Scholar]
• [5].Zhang H, Barratt J. Is IgA nephropathy the same disease in different parts of the world? Semin Immunopathol. 2021;43:707–15. [DOI] [PubMed] [Google Scholar]
• [6].Kiryluk K, Freedberg DE, Radhakrishnan J, et al. Global incidence of IgA nephropathy by race and ethnicity: a systematic review. Kidney360. 2023;4:1112–22. [DOI] [PMC free article] [PubMed] [Google Scholar]
• [7].Rodrigues JC, Haas M, Reich HN. IgA nephropathy. Clin J Am Soc Nephrol. 2017;12:677–86. [DOI] [PMC free article] [PubMed] [Google Scholar]
• [8].Willey CJ, Coppo R, Schaefer F, Mizerska-Wasiak M, Mathur M, Schultz MJ. The incidence and preval‎ence of IgA nephropathy in Europe. Nephrol Dial Transpl. 2023;38:2340–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
• [9].Gabinete de Registo de Biópsias Renais, Registo Nacional de Biópsias Renais. Lisbon, Portugal: Sociedade Portuguesa de Nefrologia; 2022. [Google Scholar]
• [10].Schena FP, Nistor I. Epidemiology of IgA nephropathy: a global perspective. Semin Nephrol. 2018;38:435–42. [DOI] [PubMed] [Google Scholar]
• [11].Okpechi IG, Ameh OI, Bello AK, Ronco P, Swanepoel CR, Kengne AP. Epidemiology of histologically proven glomerulonephritis in Africa: a systematic review and meta-analysis. PLoS One. 2016;11:e0152203. [DOI] [PMC free article] [PubMed] [Google Scholar]
• [12].Kiryluk K, Sanchez-Rodriguez E, Zhou XJ, et al. Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy. Nat Genet. 2023;55:1091–105. [DOI] [PMC free article] [PubMed] [Google Scholar]
• [13].Gutierrez E, Zamora I, Ballarín JA, et al. Long-term outcomes of IgA nephropathy presenting with minimal or no proteinuria. J Am Soc Nephrol. 2012;23:1753–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
• [14].Le W, Liang S, Chen H, et al. Long-term outcome of IgA nephropathy patients with recurrent macroscopic hematuria. Am J Nephrol. 2014;40:43–50. [DOI] [PubMed] [Google Scholar]
• [15].Coppo R. Treatment of IgA nephropathy: recent advances and prospects. Nephrol Ther. 2018;14(Suppl 1):S13–21. [DOI] [PubMed] [Google Scholar]
• [16].Pitcher D, Braddon F, Hendry B, et al. Long-term outcomes in IgA nephropathy. Clin J Am Soc Nephrol. 2023;18:727–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
• [17].Fassbinder W, Brunner FP, Brynger H, et al. Combined report on regular dialysis and transplantation in Europe, XX, 1989 . Nephrol Dial Transplant. 1991;6(Suppl 1):5–35. [PubMed] [Google Scholar]