|
1
|
Praga M, Caravaca-Fontán F, Da Silva I, Fernández-Juárez G, Gutiérrez E, Sevillano AM, Trimarchi H. Tailored management strategies for IgA nephropathy based on clinical presentations. Nephrol Dial Transplant 2025; 40:874-883. [PMID: 39689916 DOI: 10.1093/ndt/gfae289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Indexed: 12/19/2024] Open
Abstract
The treatment landscape for immunoglobulin A nephropathy is rapidly evolving with the introduction of novel therapies targeting diverse disease pathways. Some have already been approved in different countries, while others are under investigation in randomized controlled trials (RCTs) with encouraging results. However, almost all performed RCTs have included only patients with refractory non-nephrotic proteinuria and preserved renal function. Other clinical presentations (rapidly progressive forms, malignant hypertension, thrombotic microangiopathy, nephrotic syndrome) have received less attention and are systematically excluded from RCTs. In contrast, certain aspects, such as the impact of haematuria or management in special populations (e.g. pregnant patients or transplant recipients), remain underexplored. This review proposes therapeutic algorithms to guide treatment decisions in different clinical scenarios while highlighting gaps in current research.
Collapse
Affiliation(s)
- Manuel Praga
- Department of Medicine, Universidad Complutense de Madrid, Madrid, Spain
| | | | - Iara Da Silva
- Department of Nephrology, Hospital Universitario Germans Trias i Pujol, Badalona, Barcelona, Spain
| | | | - Eduardo Gutiérrez
- Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Angel M Sevillano
- Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Hernan Trimarchi
- Department of Nephrology, Hospital Británico de Buenos Aires, Buenos Aires, Argentina
| |
Collapse
|
|
2
|
Floege J, Bernier-Jean A, Barratt J, Rovin B. Treatment of patients with IgA nephropathy: a call for a new paradigm. Kidney Int 2025; 107:640-651. [PMID: 39894081 DOI: 10.1016/j.kint.2025.01.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 01/15/2025] [Accepted: 01/22/2025] [Indexed: 02/04/2025]
Abstract
IgA nephropathy (IgAN), the world's most common primary glomerular disease, carries a significant lifetime risk for kidney failure as well as an enormous socioeconomic burden. In the past, studies in patients with IgAN largely focused on optimizing so-called supportive care, that is, blockade of the renin-angiotensin system, blood pressure control, and lifestyle modifications. The effectiveness of immunosuppressive measures, particularly high-dose corticosteroid therapy, has been reported variably, but there is considerable evidence for an increase in serious adverse effects with such therapies. This disappointing situation has changed dramatically with a better understanding of the pathogenesis of IgAN, and with regulatory agencies accepting changes in proteinuria and the estimated glomerular filtration rate loss or slope over 2 to 3 years as surrogate outcome markers. A multitude of new therapies are now being evaluated in IgAN, and several drugs, such as sodium-glucose transporter-2 inhibitors, sparsentan (a dual endothelin-1 and angiotensin II receptor blocker), nefecon (a targeted release formulation of budesonide), and iptacopan (a complement factor B inhibitor), have been approved, with more to come in the next few years. In this review, we propose a new treatment paradigm that combines therapies with different mechanisms of action to target the immune components and the chronic kidney disease components of IgAN in parallel to preserve long-term kidney survival.
Collapse
Affiliation(s)
- Jürgen Floege
- Department of Nephrology and Department of Cardiology, RWTH Aachen University Hospital, Aachen, Germany.
| | - Amelie Bernier-Jean
- Department of Medicine, University of Montreal, Montreal, Québec, Canada; Nephrology Service, CIUSSS du Nord-de-l'Île-de-Montreal, Montreal, Québec, Canada
| | - Jonathan Barratt
- Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
| | - Brad Rovin
- Nephrology Division, Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| |
Collapse
|
|
3
|
Salvadori M, Rosso G. What is new in the pathogenesis and treatment of IgA glomerulonephritis. World J Nephrol 2024; 13:98709. [PMID: 39723359 PMCID: PMC11572654 DOI: 10.5527/wjn.v13.i4.98709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 09/29/2024] [Accepted: 10/08/2024] [Indexed: 11/07/2024] Open
Abstract
Recently, new findings have been clarified concerning both pathogenesis and treatment of IgA nephritis. The four hits theory has been confirmed but several genetic wide association studies have allowed finding several genes connected with the pathogenesis of the disease. All these new genes apply to each of the four hits. Additionally, new discoveries concerning the microbiota and its connection with immune system and IgA generation have allowed finding out the role of the mucosa in IgA nephropathy pathogenesis. The IgA treatment is also changed included the future possibilities. The treatment of the chronic kidney disease, associated with the nephropathy, is mandatory, since the beginning of the disease. The classical immunosuppressive agents have poor effect. The corticosteroids remain an important cornerstone in any phase of the disease. More effect is related to the treatment of B cells and plasma cells. In particular, in very recent studies have been documented the efficacy of anti B cell-activating factor and anti A proliferation-inducing ligand agents. Most of these studies are to date in phase II/III. Finally, new agents targeting complement are arising. These agents also are still in randomized trials and act principally in hit 4 where the immunocomplexes in the mesangium activate the different pathways of the complement cascade.
Collapse
Affiliation(s)
- Maurizio Salvadori
- Department of Renal Transplantation, Careggi University Hospital, Florence 50139, Tuscany, Italy
| | - Giuseppina Rosso
- Division of Nephrology, San Giovanni di Dio Hospital, Florence 50143, Toscana, Italy
| |
Collapse
|
|
4
|
Guo Y, Shi S, Zhao J, Wang C, Liu Z, Fu S, Chen N, Li G, Wang L, Ni Z, Zhang H, Lai L, Lv J, Zhang H. Prognosis of IgA nephropathy patient with proteinuria remission by supportive therapy: cohort from screening failed Chinese patients in TESTING study. Ren Fail 2024; 46:2398826. [PMID: 39248402 PMCID: PMC11385640 DOI: 10.1080/0886022x.2024.2398826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 08/22/2024] [Accepted: 08/26/2024] [Indexed: 09/10/2024] Open
Abstract
BACKGROUND During the run-in phase of the TESTING study, approximately half of patients with IgA nephropathy (IgAN) were excluded due to proteinuria below 1 g/24 h after intensive supportive therapy. The long-term prognosis of these patients needs further investigation. METHODS 112 screening failed patients in the TESTING study from 10 centers in China were enrolled in this retrospective study. The prognosis of 88 patients, who were excluded because of proteinuria below 1 g/24 h, was analyzed by Landmark Kaplan-Meier analysis. The composite kidney endpoint was defined by a ≥ 50% reduction in eGFR, ESKD (eGFR <15 mL/min per 1.73 m2), chronic dialysis for at least 6 months, or renal transplantation. RESULTS In total, 88 patients were excluded due to proteinuria less than 1 g/24 h. During the follow-up, 73/88 (83.0%) patients received renin-angiotensin system blocker. 72/88 (81.8%) had stable proteinuria remission and did not receive immunosuppressive therapy (IST), and 16/88 (18.2%) received IST because of a relapse of proteinuria. Landmark Kaplan-Meier analysis revealed that, the kidney survival from dialysis or composite kidney outcome of these excluded patients with IST was similar to those without IST during the early stages of follow-up (dialysis, before 60 months, p = 0.778; composite kidney outcome, before 48 months, p = 0.862); whereas the risk for dialysis of patients receiving IST was significantly higher than those without IST after 60 months (OR = 11.3, p = 0.03). Similarly, the risk for the composite kidney outcome of patients receiving IST was also significantly higher than those without IST after 48 months (OR = 5.92, p = 0.029). CONCLUSIONS IgAN patients who maintained a persistent remission of proteinuria after intensive supportive therapy had a much better long-term kidney outcome than those who experienced a relapse of proteinuria and needed IST.
Collapse
Affiliation(s)
- Yingman Guo
- Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Sufang Shi
- Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Jinghong Zhao
- Department of Nephrology, The Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Caili Wang
- The First Affiliated Hospitals of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, China
| | - Zhangsuo Liu
- Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shuxia Fu
- Department of Nephrology, The Second Hospital, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Nan Chen
- Department of Nephrology, Institute of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guisen Li
- Renal Division and Institute of Nephrology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Sichuan, China
| | - Lihua Wang
- Division of Nephrology, Shanxi Medical University Second Hospital, Shanxi Kidney Disease Institute, Taiyuan, China
| | - Zhaohui Ni
- Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Haitao Zhang
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Lingyun Lai
- Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
| | - Jicheng Lv
- Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Hong Zhang
- Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| |
Collapse
|
|
5
|
Abdullah, Pushkar D, Kaul A, Behera MR, Khurana M, Prasad N, Bhadauria DS, Patel MR, Yachha M, Kushwaha RS. The Outcomes of IgA Nephropathy With Nephrotic Syndrome: A Clinicopathological Study From Northern India. Cureus 2024; 16:e76307. [PMID: 39867081 PMCID: PMC11761544 DOI: 10.7759/cureus.76307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/21/2024] [Indexed: 01/28/2025] Open
Abstract
Introduction Nephrotic syndrome, an unusual clinical presentation of IgA nephropathy (IgAN), occurs only in a few cases. The data regarding its clinical characteristics and treatment outcomes are lacking. Material and methods In this retrospective analysis, we reviewed kidney biopsies conducted between January 2007 and December 2018. All patients with biopsy-proven IgAN and clinical presentation of nephrotic syndrome were included. Results Sixty-seven (11.9%) out of 560 patients with primary IgAN had nephrotic syndrome as the first clinical presentation. On MEST-C scoring, the baseline estimated glomerular filtration rate (eGFR) was significantly lower in the presence of segmental sclerosis (S1) (p=0.04) and >25% tubular atrophy/interstitial fibrosis (T1/2) (p=0.004). With immunosuppression, complete remission (CR), partial remission (PR), and no response (NR) occurred in 28 (41.8%), 32 (47.8%), and 7 (10.4%) patients, respectively. During the median follow-up of 190 weeks, the median absolute change in eGFR was significant between CR and NR groups (p=0.002), and PR and NR groups (p=0.02); however, it was not significant between CR and PR groups (p=0.14). In the CR, PR, and NR groups, 9, 15, and 7 patients had eGFR losses of ≥15 ml/min (p=0.004). No patient in the CR group, one in the PR group, and three in the NR group progressed to end-stage kidney disease (ESKD) (p=0.003). Further, none of the MEST-C scores correlated with the clinical outcome parameters. Conclusion Immunosuppression in treating IgAN accompanied by nephrotic syndrome helps in proteinuria remission. Achieving remission, whether complete or partial, delays disease progression and improves renal survival. Moreover, the baseline eGFR was significantly lower when S1 and T1/2 lesions were present in kidney biopsies.
Collapse
Affiliation(s)
- Abdullah
- Nephrology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, IND
| | | | - Anupma Kaul
- Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, IND
| | - Manas R Behera
- Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, IND
| | - Mudit Khurana
- Nephrology, Sarojini Naidu Medical College, Agra, IND
| | - Narayan Prasad
- Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, IND
| | | | - Manas R Patel
- Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, IND
| | - Monika Yachha
- Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, IND
| | - Ravi S Kushwaha
- Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, IND
| |
Collapse
|
|
6
|
Gomes AM, Schau B, Farinha A. Emerging perspectives in the management of IgA nephropathy: a comprehensive review. Porto Biomed J 2024; 9:264. [PMID: 39544842 PMCID: PMC11560120 DOI: 10.1097/j.pbj.0000000000000264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 09/09/2024] [Accepted: 09/11/2024] [Indexed: 11/17/2024] Open
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.
Collapse
Affiliation(s)
- Ana Marta Gomes
- Nephrology Department, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal
- UMIB/ICBAS—Unit for Multidisciplinary Research in Biomedicine/Instituto de Ciências Biomédicas Abel Salazar, Porto, Portugal
| | | | - Ana Farinha
- Nephrology Department, Hospital de Vila Franca de Xira, Vila Franca de Xira, Portugal
| |
Collapse
|
|
7
|
Nagasawa H, Suzuki H, Ueda S, Suzuki Y. Dual blockade of endothelin A and angiotensin II type 1 receptors with sparsentan as a novel treatment strategy to alleviate IgA nephropathy. Expert Opin Investig Drugs 2024; 33:1143-1152. [PMID: 39425494 DOI: 10.1080/13543784.2024.2414902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 10/07/2024] [Indexed: 10/21/2024]
Abstract
INTRODUCTION Although immunoglobulin A nephropathy (IgAN) had been discovered more than 50 years ago, 30-40% of IgAN patients still have primary glomerular disease that progresses to end-stage renal disease. However, various treatment strategies for IgAN have rapidly expanded in recent years to include endothelin (ET) receptor antagonists. AREAS COVERED In this review, we discuss the role of the ET-1/ETA receptor axis in the development of IgAN, especially focusing on the potential of sparsentan, a dual ET and angiotensin receptor antagonist as a novel therapy for IgAN. EXPERT OPINION Evaluation of the MEST-C score at the time of renal biopsy in IgAN is important in determining treatment strategies. If lesions are mainly in the acute phase, such as crescents, steroid therapy should be continued. However, if lesions are mainly in the chronic phase, such as glomerulosclerosis, sparsentan rather than steroid or angiotensin II receptor blocker alone may improve renal outcomes. Although further clinical studies are needed to back up these assumptions, appropriate combination of new drugs containing sparsentan and conventional drugs for IgAN treatment at the appropriate disease stage is expected to further inhibit the progression of renal damage.
Collapse
Affiliation(s)
- Hajime Nagasawa
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
- Division of Kidney Health and Aging, The Center for Integrated Kidney Research and Advance, Shimane University Faculty of Medicine, Shimane, Japan
| | - Hitoshi Suzuki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
- Department of Nephrology, Juntendo University Urayasu Hospital, Chiba, Japan
| | - Seiji Ueda
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
- Division of Kidney Health and Aging, The Center for Integrated Kidney Research and Advance, Shimane University Faculty of Medicine, Shimane, Japan
| | - Yusuke Suzuki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| |
Collapse
|
|
8
|
Filippone EJ, Gulati R, Farber JL. Contemporary review of IgA nephropathy. Front Immunol 2024; 15:1436923. [PMID: 39188719 PMCID: PMC11345586 DOI: 10.3389/fimmu.2024.1436923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 07/02/2024] [Indexed: 08/28/2024] Open
Abstract
IgA nephropathy (IgAN) is considered the most common primary glomerulonephritis worldwide with a predilection for Asian-Pacific populations and relative rarity in those of African descent. Perhaps 20%-50% of patients progress to kidney failure. The pathogenesis is incompletely understood. Mesangial deposition of immune complexes containing galactose-deficient IgA1 complexed with anti-glycan IgG or IgA antibodies results in mesangial cell activation and proliferation, inflammatory cell recruitment, complement activation, and podocyte damage. Diagnosis requires a biopsy interpreted by the Oxford criteria. Additional pathologic features include podocytopathy, thrombotic microangiopathy, and C4d staining. Biomarkers predicting adverse outcomes include proteinuria, reduced GFR, hypertension, and pathology. Acceptable surrogate endpoints for therapeutic trials include ongoing proteinuria and rate of eGFR decline. The significance of persisting hematuria remains uncertain. The mainstay of therapy is supportive, consisting of lifestyle modifications, renin-angiotensin inhibition (if hypertensive or proteinuric), sodium-glucose-transporter 2 inhibition (if GFR reduced or proteinuric), and endothelin-receptor antagonism (if proteinuric). Immunosuppression should be considered for those at high risk after maximal supportive care. Corticosteroids are controversial with the most positive results observed in Chinese. They carry a high risk of serious side effects. Similarly, mycophenolate may be most effective in Chinese. Other immunosuppressants are of uncertain benefit. Tonsillectomy appears efficacious in Japanese. Active areas of investigation include B-cell inhibition with agents targeting the survival factors BAFF and APRIL and complement inhibition with agents targeting the alternate pathway (Factors B and D), the lectin pathway (MASP-2), and the common pathway (C3 and C5). Hopefully soon, the who and the how of immunosuppression will be clarified, and kidney failure can be forestalled.
Collapse
Affiliation(s)
- Edward J. Filippone
- Division of Nephrology, Department of Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States
| | - Rakesh Gulati
- Division of Nephrology, Department of Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States
| | - John L. Farber
- Department of Pathology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States
| |
Collapse
|
|
9
|
Sun H, Liu L, Wang G, Kong W, Zhong Y, Yi L, Zou Y. Comparison of different doses of Tripterygium glycosides treating in IgA vasculitis nephritis: A Bayesian network meta-analysis. Heliyon 2024; 10:e34329. [PMID: 39114002 PMCID: PMC11305250 DOI: 10.1016/j.heliyon.2024.e34329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 07/06/2024] [Accepted: 07/08/2024] [Indexed: 08/10/2024] Open
Abstract
Background Tripterygium glycosides (TG) is extracted from the roots of Tripterygium wilfordii Hook F (Lei gong teng, a traditional Chinese medicine). It is widely used in China to treat immunoglobulin A vasculitis nephritis (IgAVN), which is a common secondary glomerular disease. As there are no guidelines for the rational application of TG, we performed this study to evaluate the efficacy and safety of different doses of TG and to determine the optimal treatment for IgAVN. Methods Ten databases were searched from their inception to April 2023 for randomised controlled trials (RCTs) using TG, TG combined with glucocorticoids (GC), or TG combined with traditional Chinese medicine (TCM) to treat IgAVN. A network meta-analysis was performed following the protocol (CRD42023401645). Results Forty-four eligible RCTs involving 3402 patients were included. For effective rate, TG 1.5 mg/kg/d (TG1.5) + TCM was ranked as the best intervention, followed by TG 1.0 mg/kg/d (TG1.0) + TCM, TG1.5, TG1.0+GC, TG1.0, TCM, GC, and routine treatment (RT). TG1.0+TCM ranked best in reducing recurrence, followed by TG1.0+GC, GC, TG1.5, and RT. Compared with TG1.0, TG1.0+TCM and TG1.5+TCM effectively reduced liver injury events. Compared with TG1.5, TG1.5+TCM and TG1.0+TCM effectively reduced leukopenia events. No significant differences in the reduction of gastrointestinal events were observed between the interventions. Subgroup analyses explored the effects of the participants' age. The intervention rankings of the outcomes generally remained consistent. Only a small difference was observed in gastrointestinal events. TCM was the best treatment for reducing gastrointestinal events in paediatric patients. Conclusions The results showed a positive correlation between dose and efficacy, whereas no relationship was found between dose and adverse events. TCM can boost the efficacy and reduce adverse events when combined with TG. In conclusion, we consider TG1.5+TCM as the best treatment for IgAVN. However, further research is required to confirm these findings.
Collapse
Affiliation(s)
- Hui Sun
- Department of Nephrology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Lijia Liu
- Department of Nephrology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Gang Wang
- Zou's Nephrology Medicine Intangible Cultural Heritage Inheritance Studio, Nanjing Boda Nephrology Hospital, Nanjing, Jiangsu, China
| | - Wei Kong
- Department of Nephrology, Nanjing Hospital of Traditional Chinese Medicine, Nanjing, Jiangsu, China
| | - Yu Zhong
- Department of Nephrology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Lan Yi
- Department of Nephrology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yanqin Zou
- Department of Nephrology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- Zou's Nephrology Medicine Intangible Cultural Heritage Inheritance Studio, Nanjing Boda Nephrology Hospital, Nanjing, Jiangsu, China
| |
Collapse
|
|
10
|
Zhao B, Wang M, Cong Y, Song A, Lu J, Xie K, Dai H, Gu L. Urinary exosomal mRNAs as biomarkers for predicting the therapeutic effect of renin-angiotensin system inhibitors in IgA nephropathy patients. Clin Chim Acta 2024; 561:119750. [PMID: 38885756 DOI: 10.1016/j.cca.2024.119750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 02/08/2024] [Accepted: 05/22/2024] [Indexed: 06/20/2024]
Abstract
BACKGROUND Renin-angiotensin system inhibitors (RASi) treatment is the basic therapy for IgA nephropathy (IgAN) patients. However, there is few of biomarker that can predict the efficacy of RASi. This study aimed to find urinary exosomal mRNAs related to the therapeutic effect of RASi in the treatment of proteinuria in IgAN patients. METHODS We divided IgAN patients in screening cohort into A1 (proteinuria increase at 3 months), B1 (proteinuria decrease less than 50 % at 3 months), C1 (proteinuria decrease more than 50 % at 3 months) groups according to changes of proteinuria after treatment. The urinary exosomes were collected before biopsy, RNAs were extracted and analyzed with the microarray assay. The candidate genes were screened by differentially expressed genes (DEGs) analysis and then validated by quantitative real-time polymerase chain reaction (qPCR) in a validation cohort. A receiver operating characteristic (ROC) curve was used to evaluate gene performance in predicting therapeutic effect on RASi reducing proteinuria in IgAN patients. RESULTS ECE1 and PDE1A mRNAs were significantly different among the three groups, and were gradually decreased among A1, B1 and C1 groups. In the validation cohort, the level of urinary exosomal ECE1 and PDE1A mRNAs were also significantly lower in A2 group compared with C2 group(ECE1, P < 0.001;PDE1A, P < 0.01). Besides, the level of ECE1 mRNA was also lower in B2 group compared with C2 group (P < 0.01). The ROC curve verified that urinary exosomal ECE1 and PDE1A gene level predicted RASi efficacy in IgAN patients with area under curve (AUC) 0.68 and 0.63 respectively. CONCLUSION Urinary exosomal ECE1 and PDE1A mRNAs expression can serve as potential biomarkers for predicting the RASi efficacy to reduce proteinuria in IgAN patients.
Collapse
Affiliation(s)
- Bingru Zhao
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Renji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University, School of Medicine, China
| | - Minzhou Wang
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Renji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University, School of Medicine, China
| | - Yue Cong
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Renji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University, School of Medicine, China; Department of Emergency Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ahui Song
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Renji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University, School of Medicine, China
| | - Jiayue Lu
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Renji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University, School of Medicine, China
| | - Kewei Xie
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Renji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University, School of Medicine, China
| | - Huili Dai
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Renji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University, School of Medicine, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, China; Central Laboratory, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, China.
| | - Leyi Gu
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Renji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University, School of Medicine, China.
| |
Collapse
|
|
11
|
Chiu AW, Bredenkamp N. Sparsentan: A First-in-Class Dual Endothelin and Angiotensin II Receptor Antagonist. Ann Pharmacother 2024; 58:645-656. [PMID: 37706310 DOI: 10.1177/10600280231198925] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/15/2023] Open
Abstract
OBJECTIVE To provide an overview of the guidelines on the management of immunoglobulin A nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS), review the evidence for sparsentan, and discuss its place in therapy. DATA SOURCES A literature search was conducted using MEDLINE, EMBASE, and clinicaltrials.gov using the search terms "sparsentan" and "RE-021" up to the end of Jun 2023. STUDY SELECTION AND DATA EXTRACTION English studies were included if they evaluated the pharmacology, pharmacokinetics, efficacy, and safety of sparsentan in human subjects. Information from the Food and Drug Administration (FDA) and manufacturer's monograph were also extracted. DATA SYNTHESIS In comparison with irbesartan, sparsentan reduced urine protein-to-creatinine ratio (UPCR) in both IgAN (-49.8% vs -15.1% at interim 36 weeks) and FSGS (-44.8% vs -18.5% at 8 weeks). Hypotension and edema were the most common adverse events in the sparsentan groups. Hepatotoxicity appears to be comparable between sparsentan and irbesartan in short-term results. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON WITH EXISTING DRUGS Sparsentan provides a new option for patients with IgAN who are otherwise at high risk of progressive kidney disease. Continued FDA approval is dependent on long-term study results on renal function decline and safety. CONCLUSION Sparsentan reduces proteinuria in IgAN and FSGS, and has expedited approval by the FDA for IgAN in patients at risk of rapid disease progression, generally at urine protein-to-creatinine ratio (UPCR) ≥1.5 g/g. Interim results from PROTECT and results from DUET showed promise for improving proteinuria in IgAN and FSGS. Long-term renal function benefit and safety data are pending.
Collapse
Affiliation(s)
- Ada W Chiu
- Renal Program, Fraser Health Authority, Surrey, BC, Canada
| | | |
Collapse
|
|
12
|
Zhang Q, Zhang Q, Duan Z, Chen P, Chen JJ, Li MX, Zhang JJ, Huo YH, Zhang WX, Yang C, Zhang Y, Chen X, Cai G. External Validation of the International IgA Nephropathy Prediction Tool in Older Adult Patients. Clin Interv Aging 2024; 19:911-922. [PMID: 38799377 PMCID: PMC11127691 DOI: 10.2147/cia.s455115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 04/30/2024] [Indexed: 05/29/2024] Open
Abstract
Purpose The International IgA Nephropathy Prediction Tool (IIgAN-PT) can predict the risk of End-stage renal disease (ESRD) or estimated glomerular filtration rate (eGFR) decline ≥ 50% for adult IgAN patients. Considering the differential progression between older adult and adult patients, this study aims to externally validate its performance in the older adult cohort. Patients and Methods We analyzed 165 IgAN patients aged 60 and above from six medical centers, categorizing them by their predicted risk. The primary outcome was a ≥50% reduction in estimated glomerular filtration rate (eGFR) or kidney failure. Evaluation of both models involved concordance statistics (C-statistics), time-dependent receiver operating characteristic (ROC) curves, Kaplan-Meier survival curves, and calibration plots. Comparative reclassification was conducted using net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Results The study included 165 Chinese patients (median age 64, 60% male), with a median follow-up of 5.1 years. Of these, 21% reached the primary outcome. Both models with or without race demonstrated good discrimination (C-statistics 0.788 and 0.790, respectively). Survival curves for risk groups were well-separated. The full model without race more accurately predicted 5-year risks, whereas the full model with race tended to overestimate risks after 3 years. No significant reclassification improvement was noted in the full model without race (NRI 0.09, 95% CI: -0.27 to 0.34; IDI 0.003, 95% CI: -0.009 to 0.019). Conclusion : Both models exhibited excellent discrimination among older adult IgAN patients. The full model without race demonstrated superior calibration in predicting the 5-year risk.
Collapse
Affiliation(s)
- Qiuyue Zhang
- Chinese PLA Medical School, Beijing, People’s Republic of China
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China
- National Key Laboratory of Kidney Diseases, Beijing, People’s Republic of China
- National Clinical Research Center for Kidney Diseases, Beijing, People’s Republic of China
- Beijing Key Laboratory of Kidney Diseases Research, Beijing, People’s Republic of China
| | - Qi Zhang
- Department of Nephrology, Capital Medical University Electric Power Teaching Hospital, Beijing, People’s Republic of China
| | - Zhiyu Duan
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China
- National Key Laboratory of Kidney Diseases, Beijing, People’s Republic of China
- National Clinical Research Center for Kidney Diseases, Beijing, People’s Republic of China
- Beijing Key Laboratory of Kidney Diseases Research, Beijing, People’s Republic of China
- Department of Nephrology, Fourth Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China
| | - Pu Chen
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China
- National Key Laboratory of Kidney Diseases, Beijing, People’s Republic of China
- National Clinical Research Center for Kidney Diseases, Beijing, People’s Republic of China
- Beijing Key Laboratory of Kidney Diseases Research, Beijing, People’s Republic of China
| | - Jing-jing Chen
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China
- National Key Laboratory of Kidney Diseases, Beijing, People’s Republic of China
- National Clinical Research Center for Kidney Diseases, Beijing, People’s Republic of China
- Beijing Key Laboratory of Kidney Diseases Research, Beijing, People’s Republic of China
| | - Ming-xv Li
- Department of Nephrology, Sixth Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China
| | - Jing-jie Zhang
- Department of Nephrology, Third Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China
| | - Yan-hong Huo
- Department of Nephrology, Seventh Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China
| | - Wu-xing Zhang
- Department of Nephrology, Eighth Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China
| | - Chen Yang
- School of Medicine, Nankai University, Tianjin, People’s Republic of China
| | - Yu Zhang
- School of Medicine, Nankai University, Tianjin, People’s Republic of China
| | - Xiangmei Chen
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China
- National Key Laboratory of Kidney Diseases, Beijing, People’s Republic of China
- National Clinical Research Center for Kidney Diseases, Beijing, People’s Republic of China
- Beijing Key Laboratory of Kidney Diseases Research, Beijing, People’s Republic of China
| | - Guangyan Cai
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China
- National Key Laboratory of Kidney Diseases, Beijing, People’s Republic of China
- National Clinical Research Center for Kidney Diseases, Beijing, People’s Republic of China
- Beijing Key Laboratory of Kidney Diseases Research, Beijing, People’s Republic of China
| |
Collapse
|
|
13
|
El Labban M, Surani S. Immunoglobulin A glomerulonephropathy: A review. World J Clin Cases 2024; 12:1388-1394. [PMID: 38576821 PMCID: PMC10989439 DOI: 10.12998/wjcc.v12.i8.1388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 01/27/2024] [Accepted: 02/25/2024] [Indexed: 03/12/2024] Open
Abstract
In this editorial, we comment on the article by Meng et al published in the World Journal of Clinical Cases. We comprehensively review immunoglobulin A nephropathy (IgAN), including epidemiology, clinical presentation, diagnosis, and management. IgAN, also known as Berger's disease, is the most frequent type of primary glomerulonephritis (GN) globally. It is mostly found among the Asian population. The presentation can be variable, from microscopic hematuria to a rapidly progressive GN. Around 50% of patients present with single or recurring episodes of gross hematuria. An upper respiratory infection and tonsillitis often precede these episodes. Around 30% of patients present microscopic hematuria with or without proteinuria, usually detected on routine examination. The diagnosis relies on having a renal biopsy for pathology and immunofluorescence microscopy. We focus on risk stratification and management of IgAN. We provide a review of all the landmark studies to date. According to the 2021 KDIGO (kidney disease: Improving Global Outcomes) guidelines, patients with non-variant form IgAN are first treated conservatively for three to six months. This approach consists of adequate blood pressure control, reduction of proteinuria with renin-angiotensin system blockade, treatment of dyslipidemia, and lifestyle modifications (weight loss, exercise, smoking cessation, and dietary sodium restrictions). Following three to six months of conservative therapy, patients are further classified as high or low risk for disease progression. High-risk patients have proteinuria ≥ 1 g/d or < 1 g/d with significant microscopic hematuria and active inflammation on kidney biopsy. Some experts consider proteinuria ≥ 2 g/d to be very high risk. Patients with high and very high-risk profiles are treated with immunosuppressive therapy. A proteinuria level of < 1 g/d and stable/improved renal function indicates a good treatment response for patients on immunosuppressive therapy.
Collapse
Affiliation(s)
- Mohamad El Labban
- Department of Internal Medicine, Mayo Cliic Health System, Mankato, MN 56001, United States
| | - Salim Surani
- Department of Medicine & Pharmacology, Texas A&M University, College Station, TX 77843, United States
| |
Collapse
|
|
14
|
Ren H, Lv W, Shang Z, Li L, Shen Q, Li S, Song Z, Cheng X, Meng X, Chen R, Zhang R. Identifying functional subtypes of IgA nephropathy based on three machine learning algorithms and WGCNA. BMC Med Genomics 2024; 17:61. [PMID: 38395835 PMCID: PMC10893719 DOI: 10.1186/s12920-023-01702-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 10/14/2023] [Indexed: 02/25/2024] Open
Abstract
BACKGROUND IgA nephropathy (IgAN) is one of the most common primary glomerulonephritis, which is a significant cause of renal failure. At present, the classification of IgAN is often limited to pathology, and its molecular mechanism has not been established. Therefore we aim to identify subtypes of IgAN at the molecular level and explore the heterogeneity of subtypes in terms of immune cell infiltration, functional level. METHODS Two microarray datasets (GSE116626 and GSE115857) were downloaded from GEO. Differential expression genes (DEGs) for IgAN were screened with limma. Three unsupervised clustering algorithms (hclust, PAM, and ConsensusClusterPlus) were combined to develop a single-sample subtype random forest classifier (SSRC). Functional subtypes of IgAN were defined based on functional analysis and current IgAN findings. Then the correlation between IgAN subtypes and clinical features such as eGFR and proteinuria was evaluated by using Pearson method. Subsequently, subtype heterogeneity was verified by subtype-specific modules identification based on weighted gene co-expression network analysis(WGCNA) and immune cell infiltration analysis based on CIBERSORT algorithm. RESULTS We identified 102 DEGs as marker genes for IgAN and three functional subtypes namely: viral-hormonal, bacterial-immune and mixed type. We screened seventeen genes specific to viral hormonal type (ATF3, JUN and FOS etc.), and seven genes specific to bacterial immune type (LIF, C19orf51 and SLPI etc.). The subtype-specific genes showed significantly high correlation with proteinuria and eGFR. The WGCNA modules were in keeping with functions of the IgAN subtypes where the MEcyan module was specific to the viral-hormonal type and the MElightgreen module was specific to the bacterial-immune type. The results of immune cell infiltration revealed subtype-specific cell heterogeneity which included significant differences in T follicular helper cells, resting NK cells between viral-hormone type and control group; significant differences in eosinophils, monocytes, macrophages, mast cells and other cells between bacterial-immune type and control. CONCLUSION In this study, we identified three functional subtypes of IgAN for the first time and specific expressed genes for each subtype. Then we constructed a subtype classifier and classify IgAN patients into specific subtypes, which may be benefit for the precise treatment of IgAN patients in future.
Collapse
Affiliation(s)
- Hongbiao Ren
- College of Bioinformatics Science and Technology, Harbin Medical University, 150086, Harbin, China
| | - Wenhua Lv
- College of Bioinformatics Science and Technology, Harbin Medical University, 150086, Harbin, China
| | - Zhenwei Shang
- College of Bioinformatics Science and Technology, Harbin Medical University, 150086, Harbin, China
| | - Liangshuang Li
- College of Bioinformatics Science and Technology, Harbin Medical University, 150086, Harbin, China
| | - Qi Shen
- College of Bioinformatics Science and Technology, Harbin Medical University, 150086, Harbin, China
| | - Shuai Li
- College of Bioinformatics Science and Technology, Harbin Medical University, 150086, Harbin, China
| | - Zerun Song
- College of Bioinformatics Science and Technology, Harbin Medical University, 150086, Harbin, China
| | - Xiangshu Cheng
- College of Bioinformatics Science and Technology, Harbin Medical University, 150086, Harbin, China
| | - Xin Meng
- College of Bioinformatics Science and Technology, Harbin Medical University, 150086, Harbin, China
| | - Rui Chen
- College of Bioinformatics Science and Technology, Harbin Medical University, 150086, Harbin, China
| | - Ruijie Zhang
- College of Bioinformatics Science and Technology, Harbin Medical University, 150086, Harbin, China.
| |
Collapse
|
|
15
|
Tunnicliffe DJ, Reid S, Craig JC, Samuels JA, Molony DA, Strippoli GF. Non-immunosuppressive treatment for IgA nephropathy. Cochrane Database Syst Rev 2024; 2:CD003962. [PMID: 38299639 PMCID: PMC10832348 DOI: 10.1002/14651858.cd003962.pub3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2024]
Abstract
BACKGROUND IgA nephropathy (IgAN) is the most common primary glomerular disease, with approximately 20% to 40% of patients progressing to kidney failure within 25 years. Non-immunosuppressive treatment has become a mainstay in the management of IgAN by improving blood pressure (BP) management, decreasing proteinuria, and avoiding the risks of long-term immunosuppressive management. Due to the slowly progressive nature of the disease, clinical trials are often underpowered, and conflicting information about management with non-immunosuppressive treatment is common. This is an update of a Cochrane review, first published in 2011. OBJECTIVES To assess the benefits and harms of non-immunosuppressive treatment for treating IgAN in adults and children. We aimed to examine all non-immunosuppressive therapies (e.g. anticoagulants, antihypertensives, dietary restriction and supplementation, tonsillectomy, and herbal medicines) in the management of IgAN. SEARCH METHODS We searched the Cochrane Kidney and Transplant Register of Studies up to December 2023 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA Randomised controlled trials (RCTs) and quasi-RCTs of non-immunosuppressive agents in adults and children with biopsy-proven IgAN were included. DATA COLLECTION AND ANALYSIS Two authors independently reviewed search results, extracted data and assessed study quality. Results were expressed as mean differences (MD) for continuous outcomes and risk ratios (RR) for dichotomous outcomes with 95% confidence intervals (CI) using random-effects meta-analysis. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS This review includes 80 studies (4856 participants), of which 24 new studies (2018 participants) were included in this review update. The risk of bias within the included studies was mostly high or unclear for many of the assessed methodological domains, with poor reporting of important key clinical trial methods in most studies. Antihypertensive therapies were the most examined non-immunosuppressive therapy (37 studies, 1799 participants). Compared to placebo or no treatment, renin-angiotensin system (RAS) inhibition probably decreases proteinuria (3 studies, 199 participants: MD - 0.71 g/24 h, 95% CI -1.04 to -0.39; moderate certainty evidence) but may result in little or no difference to kidney failure or doubling of serum creatinine (SCr), or complete remission of proteinuria (low certainty evidence). Death, remission of haematuria, relapse of proteinuria or > 50% increase in SCr were not reported. Compared to symptomatic treatment, RAS inhibition (3 studies, 168 participants) probably decreases proteinuria (MD -1.16 g/24 h, 95% CI -1.52 to -0.81) and SCr (MD -9.37 µmol/L, 95% CI -71.95 to -6.80) and probably increases creatinine clearance (2 studies, 127 participants: MD 23.26 mL/min, 95% CI 10.40 to 36.12) (all moderate certainty evidence); however, the risk of kidney failure is uncertain (1 study, 34 participants: RR 0.20, 95% CI 0.01 to 3.88; very low certainty evidence). Death, remission of proteinuria or haematuria, or relapse of proteinuria were not reported. The risk of adverse events may be no different with RAS inhibition compared to either placebo or symptomatic treatment (low certainty evidence). In low certainty evidence, tonsillectomy in people with IgAN in addition to standard care may increase remission of proteinuria compared to standard care alone (2 studies, 143 participants: RR 1.90, 95% CI 1.45 to 2.47) and remission of microscopic haematuria (2 studies, 143 participants: RR 1.93, 95% CI 1.47 to 2.53) and may decrease relapse of proteinuria (1 study, 73 participants: RR 0.70, 95% CI 0.57 to 0.85) and relapse of haematuria (1 study, 72 participants: RR 0.70, 95% CI 0.51 to 0.98). Death, kidney failure and a > 50% increase in SCr were not reported. These trials have only been conducted in Japanese people with IgAN, and the findings' generalisability is unclear. Anticoagulant therapy, fish oil, and traditional Chinese medicines exhibited small benefits to kidney function in patients with IgAN when compared to placebo or no treatment. However, compared to standard care, the kidney function benefits are no longer evident. Antimalarial therapy compared to placebo in one study reported an increase in a > 50% reduction of proteinuria (53 participants: RR 3.13 g/24 h, 95% CI 1.17 to 8.36; low certainty evidence). Although, there was uncertainty regarding adverse events from this study due to very few events. AUTHORS' CONCLUSIONS Available RCTs focused on a diverse range of interventions. They were few, small, and of insufficient duration to determine potential long-term benefits on important kidney and cardiovascular outcomes and harms of treatment. Antihypertensive agents appear to be the most beneficial non-immunosuppressive intervention for IgAN. The antihypertensives examined were predominantly angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. The benefits of RAS inhibition appear to outweigh the harms in patients with IgAN. The certainty of the evidence of RCTs demonstrating a benefit of tonsillectomy to patients with Japanese patients with IgAN was low. In addition, these findings are inconsistent across observational studies in people with IgAN of other ethnicities; hence, tonsillectomy is not widely recommended, given the potential harm of therapy. The RCT evidence is insufficiently robust to demonstrate efficacy for the other non-immunosuppressive treatments evaluated here.
Collapse
Affiliation(s)
| | - Sharon Reid
- Central Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, Australia
| | - Jonathan C Craig
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
- College of Medicine and Public Health, Flinders University, Adelaide, Australia
| | - Joshua A Samuels
- Division of Pediatric Nephrology and Hypertension, UT-Houston Health Science Center, Houston, TX, USA
| | - Donald A Molony
- Internal Medicine, UT-Houston Health Science Center, Houston, TX, USA
| | - Giovanni Fm Strippoli
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
- Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| |
Collapse
|
|
16
|
Caster DJ, Lafayette RA. The Treatment of Primary IgA Nephropathy: Change, Change, Change. Am J Kidney Dis 2024; 83:229-240. [PMID: 37742867 DOI: 10.1053/j.ajkd.2023.08.007] [Citation(s) in RCA: 24] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 07/20/2023] [Accepted: 08/07/2023] [Indexed: 09/26/2023]
Abstract
IgA nephropathy (IgAN) is the most common glomerular disease in the world. However, the approach to treatment remains controversial. There has been an explosion of clinical trials over the past decade both to further examine corticosteroid use and usher in additional treatment considerations, including 2 newly approved therapies for IgAN. Sodium glucose cotransporter 2 inhibitors are proving to be effective therapy across proteinuric chronic kidney diseases, and IgAN is not likely to be an exception. Further supportive agents are looking highly promising and so are novel agents that specifically focus on the pathophysiology of this disease, including endothelin blockade, complement inhibition, and B-cell targeted strategies. We suggest a present-day approach to treatment of individuals with IgAN, expose the limitations in our knowledge, and discuss new treatments that may arise, hoping they come with evidence about optimal utilization. Change appears to be inevitable for our approach to the treatment of IgA nephropathy. This is truly an exciting and optimistic time.
Collapse
Affiliation(s)
- Dawn J Caster
- Division of Nephrology and Hypertension, University of Louisville, Louisville, Kentucky
| | - Richard A Lafayette
- Division of Nephrology, Stanford University Medical Center, Stanford, California.
| |
Collapse
|
|
17
|
Koike K, Kawamura T, Hirano K, Nishikawa M, Shimizu A, Joh K, Katafuchi R, Hashiguchi A, Yano Y, Matsuzaki K, Matsushima M, Tsuboi N, Maruyama S, Narita I, Yokoo T, Suzuki Y. Clinicopathological prognostic stratification for proteinuria and kidney survival in IgA nephropathy: a Japanese prospective cohort study. Clin Kidney J 2024; 17:sfad294. [PMID: 38213485 PMCID: PMC10783253 DOI: 10.1093/ckj/sfad294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Indexed: 01/13/2024] Open
Abstract
Background We require a clinicopathological risk stratification method for immunoglobulin A nephropathy (IgAN) to predict kidney outcomes. We examined a renal failure risk group (RF-RG) classification system created following a prior multicentre, retrospective study to determine if RF-RG could predict kidney outcomes. Methods We collected data from Japanese patients with IgAN registered between 1 April 2005 and 31 August 2015. The primary outcome was a composite 50% increase in serum creatinine from baseline or dialysis induction. The secondary outcomes were times to proteinuria remission (ProR) and haematuria remission (HemR). Results The enrolled 991 patients from 44 facilities were followed for a median of 5.5 years (interquartile range 2.5-7.5), during which 87 composite events (8.8%) occurred. RF-RG was significantly associated with the primary outcome {hazard ratio [HR] II 2.78 [95% confidence interval (CI) 1.12-6.93], III 7.15 (2.90-17.6), IV 33.4 (14.1-79.0), I as a reference, P < .001}.The discrimination performance was good [C-statistic 0.81 (95% CI 0.76-0.86)] and the time-dependent C-statistics exceeded 0.8 over 10 years. Among the 764 patients with proteinuria and 879 patients with haematuria at baseline, 515 and 645 patients showed ProR and HemR, respectively. ProR was significantly less frequent in patients with advanced disease [subdistribution HR: II 0.79 (95% CI 0.67-0.94), III 0.53 (0.41-0.66), IV 0.15 (0.09-0.23), I as a reference, P < .001]. We also observed an association between HemR and RF-RG. Conclusions RF-RG demonstrated good predictive ability for kidney outcomes.
Collapse
Affiliation(s)
- Kentaro Koike
- Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
| | - Tetsuya Kawamura
- Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
| | - Keita Hirano
- Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
- Division of Nephrology, Department of Internal Medicine, Japanese Red Cross Ashikaga Hospital, Ashikaga, Japan
| | - Masako Nishikawa
- Clinical Research Support Center, Jikei University School of Medicine, Tokyo, Japan
| | - Akira Shimizu
- Department of Analytic Human Pathology, Nippon Medical School, Tokyo, Japan
| | - Kensuke Joh
- Department of Pathology, Jikei University School of Medicine, Tokyo, Japan
| | - Ritsuko Katafuchi
- National Hospital Organization Fukuoka-Higashi Medical Center, Fukuoka, Japan
| | - Akinori Hashiguchi
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Yuichiro Yano
- Department of Advanced Epidemiology, Noncommunicable Disease Epidemiology Research Center, Shiga University of Medical Science, Shiga, Japan
- Department of Family Medicine and Community Health, Duke University, Durham, NC, USA
| | | | - Masato Matsushima
- Division of Clinical Epidemiology, Research Center for Medical Sciences, Jikei University School of Medicine, Tokyo, Japan
| | - Nobuo Tsuboi
- Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
| | - Shoichi Maruyama
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Ichiei Narita
- Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Takashi Yokoo
- Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
| | - Yusuke Suzuki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| |
Collapse
|
|
18
|
El Karoui K, Fervenza FC, De Vriese AS. Treatment of IgA Nephropathy: A Rapidly Evolving Field. J Am Soc Nephrol 2024; 35:103-116. [PMID: 37772889 PMCID: PMC10786616 DOI: 10.1681/asn.0000000000000242] [Citation(s) in RCA: 30] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Accepted: 09/19/2023] [Indexed: 09/30/2023] Open
Abstract
The pivotal event in the pathophysiology of IgA nephropathy is the binding of circulating IgA-containing immune complexes to mesangial cells, with secondary glomerular and tubulointerstitial inflammation and fibrosis. The paramount difficulty in the management of IgA nephropathy is the heterogeneity in its clinical presentation and prognosis, requiring an individualized treatment approach. Goal-directed supportive care remains the bedrock of therapy for all patients, regardless of risk of progression. Sodium-glucose transporter 2 inhibitors and sparsentan should be integral to contemporary supportive care, particularly in patients with chronic kidney damage. Pending the development of reliable biomarkers, it remains a challenge to identify patients prone to progression due to active disease and most likely to derive a net benefit from immunosuppression. The use of clinical parameters, including the degree of proteinuria, the presence of persistent microscopic hematuria, and the rate of eGFR loss, combined with the mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis, crescents score, is currently the best approach. Systemic glucocorticoids are indicated in high-risk patients, but the beneficial effects wane after withdrawal and come at the price of substantial treatment-associated toxicity. Therapies with direct effect on disease pathogenesis are increasingly becoming available. While targeted-release budesonide has garnered the most attention, anti-B-cell strategies and selective complement inhibition will most likely prove their added value. We propose a comprehensive approach that tackles the different targets in the pathophysiology of IgA nephropathy according to their relevance in the individual patient.
Collapse
Affiliation(s)
- Khalil El Karoui
- Department of Nephrology, Hôpital Tenon, Sorbonne Université, Paris, France
| | | | - An S. De Vriese
- Division of Nephrology and Infectious Diseases, AZ Sint-Jan Brugge, Brugge, Belgium
- Department of Internal Medicine, Ghent University, Ghent, Belgium
| |
Collapse
|
|
19
|
Shimizu Y, Tomino Y, Suzuki Y. IgA Nephropathy: Beyond the Half-Century. MEDICINA (KAUNAS, LITHUANIA) 2023; 60:54. [PMID: 38256315 PMCID: PMC10821440 DOI: 10.3390/medicina60010054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 12/06/2023] [Accepted: 12/22/2023] [Indexed: 01/24/2024]
Abstract
In 1968, Jean Berger first introduced the medical world to IgA nephropathy (IgAN). Fifty-five years later, its pathogenesis is still unclear, but treatments such as renin-angiotensin-aldosterone system inhibitors (RAAS-Is), tonsillectomies, and glucocorticoids are currently used worldwide. There have been great strides in the past 20 years since the discoveries of the specific dysregulation of mucosal immunity, galactose-deficient IgA1 (Gd-IgA1), and Gd-IgA1 immune complexes in patients with IgAN. According to these findings, a multi-hit hypothesis was developed, and this multi-hit hypothesis has provided several putative therapeutic targets. A number of novel agents, including molecularly targeted drugs for targets such as APRIL, plasma cells, complement systems, and endothelin, are undergoing clinical trials. Some candidate drugs have been found to be effective, with minimal side effects. Over half a century after the discovery of IgAN, these therapies will soon be available for clinical use.
Collapse
Affiliation(s)
- Yoshio Shimizu
- Division of Nephrology, Department of Internal Medicine, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni 410-2295, Shizuoka, Japan
- Shizuoka Research Center for Disaster Medicine, Juntendo University, Izunokuni 410-2295, Shizuoka, Japan
| | - Yasuhiko Tomino
- Asian Pacific Renal Research Promotion Office, Medical Corporation SHOWAKAI, 3-12-12 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
| | - Yusuke Suzuki
- Department of Nephrology, Faculty of Medicine, Juntendo University, 3-1-3 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan;
| |
Collapse
|
|
20
|
Maixnerova D, Hartinger J, Tesar V. Expanding options of supportive care in IgA nephropathy. Clin Kidney J 2023; 16:ii47-ii54. [PMID: 38053975 PMCID: PMC10695500 DOI: 10.1093/ckj/sfad201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Indexed: 12/07/2023] Open
Abstract
Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, with a potentially serious prognosis. At present, management of IgAN is primarily based on therapeutic lifestyle changes, and excellent blood pressure control and maximized supportive treatment with the combination of inhibition of the renin-angiotensin-aldosterone system with either inhibitors of angiotensin-converting enzyme or angiotensin II receptor blockers and inhibitors of sodium-glucose cotransporter-2, and possibly in the future also with endothelin antagonists. Supportive care currently represents the cornerstone of treatment of IgAN. Targeted-release formulation of budesonide should replace systemic corticosteroids in patients with higher proteinuria and active histological lesions. New treatment options are aimed at immunopathogenesis of IgAN including depletion or modulation of Galactose-deficient-Immunoglobulin A1-producing B cells, plasma cells, and the alternate and/or lectin pathway of complement. The exact place of monoclonal antibodies and complement inhibitors will need to be determined. This article reviews potential supportive therapies currently available for patients with IgAN.
Collapse
Affiliation(s)
- Dita Maixnerova
- Department of Nephrology, General University Hospital, First Faculty of Medicine, Prague, Czech Republic
| | - Jan Hartinger
- Department of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital Prague, Prague, Czech Republic
| | - Vladimir Tesar
- Department of Nephrology, General University Hospital, First Faculty of Medicine, Prague, Czech Republic
| |
Collapse
|
|
21
|
Fulton EA, McBrearty AR, Shaw DJ, Ridyard AE. Response and survival of dogs with proteinuria (UPC > 2.0) treated with angiotensin converting enzyme inhibitors. J Vet Intern Med 2023; 37:2188-2199. [PMID: 37815154 PMCID: PMC10658551 DOI: 10.1111/jvim.16864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 08/24/2023] [Indexed: 10/11/2023] Open
Abstract
BACKGROUND Angiotensin-converting enzyme inhibitors (ACEi) are a recommended treatment for glomerular proteinuria. Frequency of response to ACEi and the association of achieving proposed urine protein-to-creatinine ratio (UPC) targets on survival is unknown. OBJECTIVES To determine response rates to ACEi therapy and whether a positive response is associated with improved survival. ANIMALS Eighty-five dogs with proteinuria (UPC > 2.0). METHODS Retrospective study including dogs (UPC > 2.0) prescribed an ACEi for treatment of proteinuria. Baseline creatinine, albumin, cholesterol, UPC, and systolic blood pressure were recorded, and cases reviewed to track UPC. Treatment response was defined as achieving a UPC of <0.5 or reduction of ≥50% from baseline within 3 months. Outcome data were collected to determine overall and 12-month survival. RESULTS Thirty-five (41%) dogs responded to ACEi treatment. Treatment response was statistically associated with both median survival time (664 days [95% confidence interval (CI): 459-869] for responders compared to 177 [95% CI: 131-223] for non-responders) and 12-month survival (79% responders alive compared to 28% non-responders). Baseline azotemia or hypoalbuminemia were also associated with a worse prognosis, with odds ratios of death at 12 months of 5.34 (CI: 1.85-17.32) and 4.51 (CI: 1.66-13.14), respectively. In the 25 dogs with normal baseline creatinine and albumin, response to treatment was associated with 12-month survival (92% responders alive compared to 54% non-responders, P = .04). CONCLUSIONS AND CLINICAL IMPORTANCE When the UPC is >2.0, achieving recommended UPC targets within 3 months appears to be associated with a significant survival benefit. Response to treatment is still associated with survival benefit in dogs with less severe disease (no azotemia or hypoalbuminemia).
Collapse
Affiliation(s)
- Emily A. Fulton
- The University of Glasgow Small Animal Hospital, School of Biodiversity, One Health and Veterinary Medicine, 464 Bearsden RoadGlasgow G61 1QHUnited Kingdom
| | - Alix R. McBrearty
- VetsNow Hospital Glasgow, 123‐145 North StreetGlasgow G3 7DAUnited Kingdom
| | - Darren J. Shaw
- Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Easter Bush CampusRoslin EH25 9RGUnited Kingdom
| | - Alison E. Ridyard
- The University of Glasgow Small Animal Hospital, School of Biodiversity, One Health and Veterinary Medicine, 464 Bearsden RoadGlasgow G61 1QHUnited Kingdom
| |
Collapse
|
|
22
|
Gleeson PJ, O'Shaughnessy MM, Barratt J. IgA nephropathy in adults-treatment standard. Nephrol Dial Transplant 2023; 38:2464-2473. [PMID: 37418237 DOI: 10.1093/ndt/gfad146] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Indexed: 07/08/2023] Open
Abstract
Immunoglobulin A nephropathy (IgAN) is the most common primary form of glomerular disease worldwide and carries a high lifetime risk of kidney failure. The underlying pathogenesis of IgAN has been characterized to a sub-molecular level; immune complexes containing specific O-glycoforms of IgA1 are central. Kidney biopsy remains the gold-standard diagnostic test for IgAN and histological features (i.e. MEST-C score) have also been shown to independently predict outcome. Proteinuria and blood pressure are the main modifiable risk factors for disease progression. No IgAN-specific biomarker has yet been validated for diagnosis, prognosis or tracking response to therapy. There has been a recent resurgence of investigation into IgAN treatments. Optimized supportive care with lifestyle interventions and non-immunomodulatory drugs remains the backbone of IgAN management. The menu of available reno-protective medications is rapidly expanding beyond blockade of the renin-angiotensin-aldosterone system to include sodium-glucose cotransporter 2 and endothelin type A receptor antagonism. Systemic immunosuppression can further improve kidney outcomes, although recent randomized controlled trials have raised concerns regarding infectious and metabolic toxicity from systemic corticosteroids. Studies evaluating more refined approaches to immunomodulation in IgAN are ongoing: drugs targeting the mucosal immune compartment, B-cell promoting cytokines and the complement cascade are particularly promising. We review the current standards of treatment and discuss novel developments in pathophysiology, diagnosis, outcome prediction and management of IgAN.
Collapse
Affiliation(s)
- Patrick J Gleeson
- Department of Renal Medicine, Cork University Hospital, Cork, Ireland
- Department of Medicine, School of Microbiology, APC Microbiome Ireland, University College Cork, Cork, Ireland
| | | | - Jonathan Barratt
- The Mayer IgA Nephropathy Laboratories, University of Leicester, Leicester, UK
| |
Collapse
|
|
23
|
Kawamura T, Hirano K, Koike K, Nishikawa M, Shimizu A, Joh K, Katafuchi R, Hashiguchi A, Matsuzaki K, Maruyama S, Tsuboi N, Narita I, Yano Y, Yokoo T, Suzuki Y. Associations of corticosteroid therapy and tonsillectomy with kidney survival in a multicenter prospective study for IgA nephropathy. Sci Rep 2023; 13:18455. [PMID: 37891208 PMCID: PMC10611761 DOI: 10.1038/s41598-023-45514-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Accepted: 10/20/2023] [Indexed: 10/29/2023] Open
Abstract
Efficacy of systemic corticosteroid therapy (CS) for long-term kidney survival in patients with IgA nephropathy (IgAN) is controversial. Therefore, prospective studies evaluating targeted therapies to lymphatic tissues in mucosal immune system responsible for production of nephritogenic IgA have been desired worldwide. Here, we aimed to evaluate the associations of CS and combination therapy of CS and tonsillectomy (CS + Tx) with kidney survival, using database from a nationwide multicenter prospective cohort study on IgAN. Primary outcome was a 50% increase in serum creatinine from baseline or dialysis induction. The analysis included 941 patients (CS/CS + Tx/non-CS 239/364/338), 85 (9.0%) of whom reached outcomes during median follow-up of 5.5 (interquartile range 2.0-8.0) years. On overlap weighting analysis with balanced baseline characteristics, CS and CS + Tx were associated with lower risk of kidney events when compared with non-CS (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.29-0.88 and HR 0.20, 95%CI 0.09-0.44, respectively). Notably, when compared with the CS, CS + Tx was associated with a lower risk of kidney events (HR 0.40, 95%CI 0.18-0.91). Present study demonstrated, keeping with favorable association of systemic CS with kidney survival, concurrent tonsillectomy as one of targeted interventions to lymphatic tissues may provide additional improvement to kidney survival in patients with IgAN.
Collapse
Affiliation(s)
- Tetsuya Kawamura
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-Ku, Tokyo, 105-8461, Japan.
| | - Keita Hirano
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-Ku, Tokyo, 105-8461, Japan
- Division of Nephrology, Department of Internal Medicine, Japanese Red Cross Ashikaga Hospital, Ashikaga, Japan
| | - Kentaro Koike
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-Ku, Tokyo, 105-8461, Japan
| | - Masako Nishikawa
- Clinical Research Support Center, The Jikei University School of Medicine, Tokyo, Japan
| | - Akira Shimizu
- Department of Analytic Human Pathology, Nippon Medical School, Tokyo, Japan
| | - Kensuke Joh
- Department of Pathology, The Jikei University School of Medicine, Tokyo, Japan
| | - Ritsuko Katafuchi
- National Hospital Organization Fukuoka-Higashi Medical Center, Fukuoka, Japan
- Division of Nephrology, Department of Internal Medicine, Kano Hospital, Fukuoka, Japan
| | - Akinori Hashiguchi
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Keiichi Matsuzaki
- Department of Public Health, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Shoichi Maruyama
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Nobuo Tsuboi
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-Ku, Tokyo, 105-8461, Japan
| | - Ichiei Narita
- Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yuichiro Yano
- Department of Advanced Epidemiology, Noncommunicable Disease (NCD) Epidemiology Research Center, Shiga University of Medical Science, Ōtsu, Shiga, Japan
- The Department of Family Medicine and Community Health, Duke University, Durham, NC, USA
| | - Takashi Yokoo
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-Ku, Tokyo, 105-8461, Japan
| | - Yusuke Suzuki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| |
Collapse
|
|
24
|
Amatruda M, Carucci NS, Chimenz R, Conti G. Immunoglobulin A vasculitis nephritis: Current understanding of pathogenesis and treatment. World J Nephrol 2023; 12:82-92. [PMID: 37766840 PMCID: PMC10520755 DOI: 10.5527/wjn.v12.i4.82] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 05/16/2023] [Accepted: 06/12/2023] [Indexed: 09/20/2023] Open
Abstract
The clinical spectrum of immunoglobulin A vasculitis nephritis (IgAVN) ranges from the relatively common transitory microscopic hematuria and/or low-grade proteinuria to nephritic or nephrotic syndrome, rapidly progressive glomerulonephritis, or even renal failure. Clinical and experimental studies have shown a multifactor pathogenesis: Infection triggers, impaired glycosylation of IgA1, complement activation, Toll-like-receptor activation and B cell proliferation. This knowledge can identify IgAVN patients at a greater risk for adverse outcome and increase the evidence for treatment recommendations.
Collapse
Affiliation(s)
- Michela Amatruda
- Pediatric Nephrology and Rheumatology Unit, AOU G Martino, University of Messina, Messina 98125, Italy
| | - Nicolina Stefania Carucci
- Pediatric Nephrology and Rheumatology Unit, AOU G Martino, University of Messina, Messina 98125, Italy
| | - Roberto Chimenz
- Pediatric Nephrology and Rheumatology Unit, AOU G Martino, University of Messina, Messina 98125, Italy
| | - Giovanni Conti
- Pediatric Nephrology and Rheumatology Unit, AOU G Martino, University of Messina, Messina 98125, Italy
| |
Collapse
|
|
25
|
Lafayette RA, Kamal FS. Considering the Treatment of IgA Nephropathy. Clin J Am Soc Nephrol 2023; 18:1113-1115. [PMID: 37533148 PMCID: PMC10564336 DOI: 10.2215/cjn.0000000000000261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/04/2023]
Affiliation(s)
- Richard A Lafayette
- Division of Nephrology , Stanford University Medical Center , Stanford , California
| | | |
Collapse
|
|
26
|
Petrou D, Kalogeropoulos P, Liapis G, Lionaki S. IgA Nephropathy: Current Treatment and New Insights. Antibodies (Basel) 2023; 12:40. [PMID: 37366657 PMCID: PMC10294861 DOI: 10.3390/antib12020040] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 05/23/2023] [Accepted: 06/09/2023] [Indexed: 06/28/2023] Open
Abstract
IgA Nephropathy (IgAN) is the most common cause of primary glomerulonephritis worldwide. Despite the histopathologic hallmark of mesangial IgA deposition, IgAN is a heterogenous autoimmune disease not only in terms of clinical presentation but also in long-term disease progression. The pathogenesis of the disease is complex and includes the generation of circulating IgA immune complexes with chemical and biological characteristics that favor mesangial deposition and reaction to mesangial under-glycosylated IgA1 accumulation, which leads to tissue injury with glomerulosclerosis and interstitial fibrosis. Patients with proteinuria over 1 g, hypertension, and impaired renal function at diagnosis are considered to be at high risk for disease progression and end-stage kidney disease (ESKD). Glucocorticoids have been the mainstay of treatment for these patients for years, but without long-term benefit for renal function and accompanied by several adverse events. A better understanding of the pathophysiology of IgAN in recent years has led to the development of several new therapeutic agents. In this review, we summarize the current therapeutic approach for patients with IgAN as well as all novel investigational agents.
Collapse
Affiliation(s)
- Dimitra Petrou
- Department of Nephrology, Second Department of Propaedeutic Internal Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece;
| | - Petros Kalogeropoulos
- Department of Nephrology, Second Department of Propaedeutic Internal Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece;
| | - George Liapis
- Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Sophia Lionaki
- Department of Nephrology, Second Department of Propaedeutic Internal Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece;
| |
Collapse
|
|
27
|
Noor SM, Abuazzam F, Mathew R, Zhang Z, Abdipour A, Norouzi S. IgA nephropathy: a review of existing and emerging therapies. FRONTIERS IN NEPHROLOGY 2023; 3:1175088. [PMID: 37675358 PMCID: PMC10479631 DOI: 10.3389/fneph.2023.1175088] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 05/03/2023] [Indexed: 09/08/2023]
Abstract
IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide. Recently, there have been multiple advances in the understanding of IgAN pathophysiology and therapeutic options. Despite the advent of new treatment options, individual risk stratification of the disease course and choosing the best treatment strategy for the patient remains challenging. A multitude of clinical trials is ongoing, opening multiple opportunities for enrollment. In this brief review we discuss the current approach to the management of IgAN and highlight the ongoing clinical trials.
Collapse
Affiliation(s)
| | | | | | | | | | - Sayna Norouzi
- Department of Nephrology, Loma Linda University, Loma Linda, CA, United States
| |
Collapse
|
|
28
|
Kim D, Wong MG. Corticosteroid Therapy in Immunoglobulin A Nephropathy: A Friend or Foe? Kidney Blood Press Res 2023; 48:392-404. [PMID: 36972570 DOI: 10.1159/000530285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 03/13/2023] [Indexed: 03/29/2023] Open
Abstract
BACKGROUND The administration of corticosteroids in addition to supportive care to delay progressive immunoglobulin A nephropathy (IgAN), the most common primary glomerulonephritis worldwide, remains controversial. This is partly due to the paucity of well-designed randomized controlled trials and well-known corticosteroid-related side effects. As a result, clinical equipoise in corticosteroid therapy exists depending on geographical regions and the clinician's preference. SUMMARY Better understanding around the pathogenesis of IgAN has prompted several clinical trials exploring the effects of immunosuppressive agents including corticosteroids. Earlier studies of corticosteroids were limited by suboptimal study designs, inadequate implementation of standard of care, and inconsistent adverse event data collection. Two well-designed, adequately powered, multi-centre randomized controlled trials, the STOP-IgAN and TESTING studies, have reported contrasting kidney outcomes that have further fuelled the clinical conundrum regarding the efficacy of corticosteroids. Both studies independently reported greater adverse events with corticosteroids. A novel targeted release formulation of budesonide, which has been hypothesized to reduce the adverse events associated with systemic corticosteroids, has shown promising results in the Phase 3 NefigaRD trial. Studies of treatments targeting B cells and the complement cascade are currently underway, and early data appear encouraging. This review provides an overview of the current literature around the understanding of the pathomechanisms and benefits and harm of corticosteroid use in IgAN. KEY MESSAGES Recent evidence suggests the use of corticosteroids in a selected cohort of people with IgAN at high risk of disease progression can improve kidney outcomes but comes with an associated risk of treatment-related adverse events, particularly with higher doses. Management decisions should therefore follow an informed patient-clinician discussion.
Collapse
Affiliation(s)
- Dana Kim
- Renal and Metabolic Division, The George Institute for Global Health, Newtown, New South Wales, Australia
- Concord Clinical School, University of Sydney, Concord, New South Wales, Australia
| | - Muh Geot Wong
- Concord Clinical School, University of Sydney, Concord, New South Wales, Australia
- Department of Renal Medicine, Concord Repatriation General Hospital, Concord, New South Wales, Australia
| |
Collapse
|
|
29
|
Benichou N, Charles P, Terrier B, Jones RB, Hiemstra T, Mouthon L, Bajema I, Berden A, Thervet E, Guillevin L, Jayne D, Karras A. PROTEINURIA AND HEMATURIA AFTER REMISSION INDUCTION ARE ASSOCIATED WITH OUTCOME IN ANCA-ASSOCIATED VASCULITIS. Kidney Int 2023; 103:1144-1155. [PMID: 36940799 DOI: 10.1016/j.kint.2023.02.029] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 02/07/2023] [Accepted: 02/16/2023] [Indexed: 03/22/2023]
Abstract
In anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), hematuria and proteinuria are biomarkers reflecting kidney involvement at diagnosis. Yet, the prognostic value of their persistence after immunosuppressive induction therapy, reflecting kidney damage or persistent disease, remains uncertain. To study this, our post-hoc analysis included participants of five European randomized clinical trials on AAV (MAINRITSAN, MAINRITSAN2, RITUXVAS, MYCYC, IMPROVE). Urine protein-creatinine ratio (UPCR) and hematuria of spot urine samples collected at the end of induction therapy (four-six months after treatment initiation) were correlated with the occurrence of a combined endpoint of death and/or kidney failure, or relapses during follow-up. Among 571 patients (59% men, median age 60), 60% had anti-proteinase 3-ANCA and 35% had anti-myeloperoxidase-ANCA, while 77% had kidney involvement. After induction therapy, 157/526 (29.8%) had persistent hematuria and 165/481 (34.3%) had UPCR of 0.05 g/mmol or more. After a median follow-up of 28 months (inter quartile range 18-42), and adjustment for age, ANCA type, maintenance therapy, serum creatinine and persistent hematuria after induction, a UPCR of 0.05 g/mmol or more after induction was associated with significant risk of death/kidney failure (adjusted Hazard Ratio (HR) 3.06, 95% confidence interval (1.09-8.59) and kidney relapse (adjusted subdistribution HR 2.22, 1.16-4.24). Persistent hematuria was associated with significant kidney relapse (adjusted subdistribution HR 2.16, (1.13-4.11) but not with relapse affecting any organ nor with death/kidney failure. Thus, in this large cohort of patients with AAV, persistent proteinuria after induction therapy was associated with death/kidney failure and kidney relapse, whereas persistent hematuria was an independent predictor of kidney relapse. Hence, these parameters must be considered to assess long-term kidney prognosis of patients with AAV.
Collapse
Affiliation(s)
- Nicolas Benichou
- Department of Nephrology, Hôpital Européen Georges Pompidou, Assistance Publique - Hôpitaux de Paris, Paris, France; Université de Paris, Paris, France.
| | - Pierre Charles
- Department of Internal Medicine, Institut Mutualiste Montsouris, Paris, France
| | - Benjamin Terrier
- Université de Paris, Paris, France; Department of Internal Medicine, National Referral Center for Rare Systemic Autoimmune Diseases, Hôpital Cochin, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Rachel B Jones
- Lupus and Vasculitis Clinic, Department of Renal Medicine, Addenbrooke's Hospital, Cambridge, UK; Department of Medicine, University of Cambridge, Cambridge, UK
| | - Thomas Hiemstra
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - Luc Mouthon
- Université de Paris, Paris, France; Department of Internal Medicine, National Referral Center for Rare Systemic Autoimmune Diseases, Hôpital Cochin, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Ingeborg Bajema
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands; Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, The Netherlands
| | - Annelies Berden
- Department of Rheumatology and Clinical immunology, Maasstad Hospital, Rotterdam, The Netherlands
| | - Eric Thervet
- Department of Nephrology, Hôpital Européen Georges Pompidou, Assistance Publique - Hôpitaux de Paris, Paris, France; Université de Paris, Paris, France
| | - Loïc Guillevin
- Université de Paris, Paris, France; Department of Internal Medicine, National Referral Center for Rare Systemic Autoimmune Diseases, Hôpital Cochin, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - David Jayne
- Lupus and Vasculitis Clinic, Department of Renal Medicine, Addenbrooke's Hospital, Cambridge, UK; Department of Medicine, University of Cambridge, Cambridge, UK
| | - Alexandre Karras
- Department of Nephrology, Hôpital Européen Georges Pompidou, Assistance Publique - Hôpitaux de Paris, Paris, France; Université de Paris, Paris, France
| | -
- Department of Nephrology, Hôpital Européen Georges Pompidou, Assistance Publique - Hôpitaux de Paris, Paris, France
| |
Collapse
|
|
30
|
Haruhara K, Kanzaki G, Tsuboi N. Nephrons, podocytes and chronic kidney disease: Strategic antihypertensive therapy for renoprotection. Hypertens Res 2023; 46:299-310. [PMID: 36224286 PMCID: PMC9899692 DOI: 10.1038/s41440-022-01061-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 08/06/2022] [Accepted: 09/05/2022] [Indexed: 02/07/2023]
Abstract
Chronic kidney disease (CKD) is one of the strongest risk factors for hypertension, and hypertension can exacerbate the progression of CKD. Thus, the management of CKD and antihypertensive therapy are inextricably linked. Research over the past decades has shown that the human kidney is more diverse than initially thought. Subjects with low nephron endowment are at increased risk of developing CKD and hypertension, which is consistent with the theory of the developmental origins of health and disease. Combined with other lifetime risks of CKD, hypertension may lead to a vicious cycle consisting of podocyte injury, glomerulosclerosis and further loss of nephrons. Of note, recent studies have shown that the number of nephrons correlates well with the number of podocytes, suggesting that these two components are intrinsically linked and may influence each other. Both nephrons and podocytes have no or very limited regenerative capacity and are destined to decrease throughout life. Therefore, one of the best strategies to slow the progression of CKD is to maintain the "numbers" of these essential components necessary to preserve renal function. To this end, both the achievement of an optimal blood pressure and a maximum reduction in urinary protein excretion are essential. Lifestyle modifications and antihypertensive drug therapy must be carefully individualized to address the potential diversity of the kidneys.
Collapse
Affiliation(s)
- Kotaro Haruhara
- grid.411898.d0000 0001 0661 2073Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Go Kanzaki
- grid.411898.d0000 0001 0661 2073Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Nobuo Tsuboi
- grid.411898.d0000 0001 0661 2073Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| |
Collapse
|
|
31
|
Ștefan G, Stancu S, Zugravu A, Petre N, Secăreanu S, Popa O, Capusa C. Immunosuppressive therapy versus supportive care in IgA nephropathy patients with stage 3 and 4 chronic kidney disease. Medicine (Baltimore) 2022; 101:e30422. [PMID: 36086774 PMCID: PMC10980450 DOI: 10.1097/md.0000000000030422] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 07/27/2022] [Indexed: 11/25/2022] Open
Abstract
The use of immunosuppressive therapy for immunoglobulin A nephropathy (IgAN) patients with stage 3 or 4 chronic kidney disease (CKD) is controversial. We performed a monocentric retrospective study on 83 consecutive IgAN patients with stage 3 or 4 CKD and proteinuria ≥0.75 g/d (age 41 [33-56] years, 72% male, estimated glomerular filtration rate 36.1 [25.4-47.5] mL/min/1.73 m2) who received uncontrolled supportive care (Supp) (n = 36), corticosteroids/corticotherapy (CS) (n = 14), or CS combined with monthly pulses of cyclophosphamide (CS + CFM) (n = 33) between 2010 and 2017. Patients were followed until composite endpoint (doubling of serum creatinine, end-stage kidney disease (dialysis or kidney transplant) or death, whichever came first) or end of study (January 2020). Patients were followed for a median of 29 (95% confidence interval = 25.2-32.7) months, and 12 (15%) patients experienced the composite endpoint. Within the limitation of a retrospective study, our results suggest no benefit from immunosuppressive therapy in patients with IgAN with stage 3 and 4 CKD as compared with supportive care. There were no differences between the 3 studied groups regarding age, estimated glomerular filtration rate, proteinuria, Oxford classification score, arterial hypertension, and therapy with renin-angiotensin system inhibitors. Mean kidney survival time for the entire cohort was 81.0 (95% confidence interval = 73.1-89.0) months, without significant differences between the 3 groups. In univariate and multivariate Cox regression analysis adjusted for IgAN progression factors, immunosuppressive therapy was not associated with better kidney survival when compared with supportive therapy.
Collapse
Affiliation(s)
- Gabriel Ștefan
- University of Medicine and Pharmacy Carol Davila, Bucharest, Romania
- Dr. Carol Davila Teaching Hospital of Nephrology, Bucharest, Romania
| | - Simona Stancu
- University of Medicine and Pharmacy Carol Davila, Bucharest, Romania
- Dr. Carol Davila Teaching Hospital of Nephrology, Bucharest, Romania
| | - Adrian Zugravu
- University of Medicine and Pharmacy Carol Davila, Bucharest, Romania
- Dr. Carol Davila Teaching Hospital of Nephrology, Bucharest, Romania
| | - Nicoleta Petre
- University of Medicine and Pharmacy Carol Davila, Bucharest, Romania
- Dr. Carol Davila Teaching Hospital of Nephrology, Bucharest, Romania
| | - Silviu Secăreanu
- University of Medicine and Pharmacy Carol Davila, Bucharest, Romania
| | - Otilia Popa
- University of Medicine and Pharmacy Carol Davila, Bucharest, Romania
- Dr. Carol Davila Teaching Hospital of Nephrology, Bucharest, Romania
| | - Cristina Capusa
- University of Medicine and Pharmacy Carol Davila, Bucharest, Romania
- Dr. Carol Davila Teaching Hospital of Nephrology, Bucharest, Romania
| |
Collapse
|
|
32
|
Wu J, Wei X, Li J, Gan Y, Zhang R, Han Q, Liang P, Zeng Y, Yang Q. Plasma exosomal IRAK1 can be a potential biomarker for predicting the treatment response to renin-angiotensin system inhibitors in patients with IgA nephropathy. Front Immunol 2022; 13:978315. [PMID: 36091017 PMCID: PMC9459338 DOI: 10.3389/fimmu.2022.978315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Accepted: 08/09/2022] [Indexed: 11/25/2022] Open
Abstract
Background Renin-angiotensin system inhibitors (RASi) are the first choice and basic therapy for the treatment of IgA nephropathy (IgAN) with proteinuria. However, approximately 40% of patients have no response to RASi treatment. The aim of this study was to screen potential biomarkers for predicting the treatment response of RASi in patients with IgAN. Methods We included IgAN patients who were treatment-naive. They received supportive treatment, including a maximum tolerant dose of RASi for 3 months. According to the degree of decrease in proteinuria after 3 months of follow-up, these patients were divided into a sensitive group and a resistant group. The plasma of the two groups of patients was collected, and the exosomes were extracted for high-throughput sequencing. The screening of hub genes was performed using a weighted gene co-expression network (WGCNA) and filtering differentially expressed genes (DEGs). We randomly selected 20 patients in the sensitive group and 20 patients in the resistant group for hub gene validation by real-time quantitative polymerase chain reaction (qRT−PCR). A receiver operating characteristic (ROC) curve was used to evaluate hub genes that predicted the efficacy of the RASi response among the 40 validation patients. Results After screening 370 IgAN patients according to the inclusion and exclusion criteria and the RASi treatment response evaluation, there were 38 patients in the sensitive group and 32 patients in the resistant group. IRAK1, ABCD1 and PLXNB3 were identified as hub genes by analyzing the high-throughput sequencing of the plasma exosomes of the two groups through WGCNA and DEGs screening. The sequencing data were consistent with the validation data showing that these three hub genes were upregulated in the resistant group compared with the sensitive group. The ROC curve indicated that IRAK1 was a good biomarker to predict the therapeutic response of RASi in patients with IgAN. Conclusions Plasma exosomal IRAK1 can be a potential biomarker for predicting the treatment response of RASi in patients with IgAN.
Collapse
|
|
33
|
Wang YM, Shaw K, Zhang GY, Chung EY, Hu M, Cao Q, Wang Y, Zheng G, Wu H, Chadban SJ, McCarthy HJ, Harris DC, Mackay F, Grey ST, Alexander SI. Interleukin-33 Exacerbates IgA Glomerulonephritis in Transgenic Mice Overexpressing B Cell Activating Factor. J Am Soc Nephrol 2022; 33:966-984. [PMID: 35387873 PMCID: PMC9063894 DOI: 10.1681/asn.2021081145] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 02/06/2022] [Indexed: 11/03/2022] Open
Abstract
BACKGROUND The cytokine IL-33 is an activator of innate lymphoid cells 2 (ILC2s) in innate immunity and allergic inflammation. B cell activating factor (BAFF) plays a central role in B cell proliferation and differentiation, and high levels of this protein cause excess antibody production, including IgA. BAFF-transgenic mice overexpress BAFF and spontaneously develop glomerulonephritis that resembles human IgA nephropathy. METHODS We administered IL-33 or PBS to wild-type and BAFF-transgenic mice. After treating Rag1-deficient mice with IL-33, with or without anti-CD90.2 to preferentially deplete ILC2s, we isolated splenocytes, which were adoptively transferred into BAFF-transgenic mice. RESULTS BAFF-transgenic mice treated with IL-33 developed more severe kidney dysfunction and proteinuria, glomerular sclerosis, tubulointerstitial damage, and glomerular deposition of IgA and C3. Compared with wild-type mice, BAFF-transgenic mice exhibited increases of CD19+ B cells in spleen and kidney and ILC2s in kidney and intestine, which were further increased by administration of IL-33. Administering IL-33 to wild-type mice had no effect on kidney function or histology, nor did it alter the number of ILC2s in spleen, kidney, or intestine. To understand the role of ILC2s, splenocytes were transferred from IL-33-treated Rag1-deficient mice into BAFF-transgenic mice. Glomerulonephritis and IgA deposition were exacerbated by transfer of IL-33-stimulated Rag1-deficient splenocytes, but not by ILC2 (anti-CD90.2)-depleted splenocytes. Wild-type mice infused with IL-33-treated Rag1-deficient splenocytes showed no change in kidney function or ILC2 numbers or distribution. CONCLUSIONS IL-33-expanded ILC2s exacerbated IgA glomerulonephritis in a mouse model. These findings indicate that IL-33 and ILC2s warrant evaluation as possible mediators of human IgA nephropathy.
Collapse
Affiliation(s)
- Yuan Min Wang
- Centre for Kidney Research, The Children’s Hospital at Westmead, The University of Sydney, Westmead, New South Wales, Australia
| | - Karli Shaw
- Centre for Kidney Research, The Children’s Hospital at Westmead, The University of Sydney, Westmead, New South Wales, Australia
| | - Geoff Yu Zhang
- Centre for Kidney Research, The Children’s Hospital at Westmead, The University of Sydney, Westmead, New South Wales, Australia
| | - Edmund Y.M. Chung
- Centre for Kidney Research, The Children’s Hospital at Westmead, The University of Sydney, Westmead, New South Wales, Australia
| | - Min Hu
- Centre for Transplantation and Renal Research, University of Sydney at Westmead Millennium Institute, Westmead, New South Wales, Australia
| | - Qi Cao
- Centre for Transplantation and Renal Research, University of Sydney at Westmead Millennium Institute, Westmead, New South Wales, Australia
| | - Yiping Wang
- Centre for Transplantation and Renal Research, University of Sydney at Westmead Millennium Institute, Westmead, New South Wales, Australia
| | - Guoping Zheng
- Centre for Transplantation and Renal Research, University of Sydney at Westmead Millennium Institute, Westmead, New South Wales, Australia
| | - Huiling Wu
- Kidney Node Laboratory, The Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, Australia
- Department of Renal Medicine, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
| | - Steven J. Chadban
- Kidney Node Laboratory, The Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, Australia
- Department of Renal Medicine, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
| | - Hugh J. McCarthy
- Centre for Kidney Research, The Children’s Hospital at Westmead, The University of Sydney, Westmead, New South Wales, Australia
| | - David C.H. Harris
- Centre for Transplantation and Renal Research, University of Sydney at Westmead Millennium Institute, Westmead, New South Wales, Australia
| | - Fabienne Mackay
- QIMR, University of Queensland, Brisbane, Queensland, Australia
| | - Shane T. Grey
- Transplantation Immunology Group, Garvan Institute of Medical Research, Sydney, Australia
| | - Stephen I. Alexander
- Centre for Kidney Research, The Children’s Hospital at Westmead, The University of Sydney, Westmead, New South Wales, Australia
| |
Collapse
|
|
34
|
Sethi S, De Vriese AS, Fervenza FC. Acute glomerulonephritis. Lancet 2022; 399:1646-1663. [PMID: 35461559 DOI: 10.1016/s0140-6736(22)00461-5] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 02/10/2022] [Accepted: 02/28/2022] [Indexed: 12/12/2022]
Abstract
Glomerulonephritis is a heterogeneous group of disorders that present with a combination of haematuria, proteinuria, hypertension, and reduction in kidney function to a variable degree. Acute presentation with full blown nephritic syndrome or rapidly progressive glomerulonephritis is uncommon and is mainly restricted to patients with post-infectious glomerulonephritis, anti-neutrophil cytoplasmic antibodies-associated vasculitis, and anti-glomerular basement membrane disease. Most frequently, patients present with asymptomatic haematuria and proteinuria with or without reduced kidney function. All glomerulonephritis disorders can show periods of exacerbation, but disease flairs characteristically occur in patients with IgA nephropathy or C3 glomerulopathy. The gold standard for the diagnosis of a glomerulonephritis is a kidney biopsy, with a hallmark glomerular inflammation that translates into various histopathological patterns depending on the location and severity of the glomerular injury. Traditionally, glomerulonephritis was classified on the basis of the different histopathological patterns of injury. In the last few years, substantial progress has been made in unravelling the underlying causes and pathogenetic mechanisms of glomerulonephritis and a causal approach to the classification of glomerulonephritis is now favoured over a pattern-based approach. As such, glomerulonephritis can be broadly classified as immune-complex glomerulonephritis (including infection-related glomerulonephritis, IgA nephropathy, lupus nephritis, and cryoglobulinaemic glomerulonephritis), anti-neutrophil cytoplasmic antibodies-associated (pauci-immune) glomerulonephritis, anti-glomerular basement membrane glomerulonephritis, C3 glomerulopathy, and monoclonal immunoglobulin-associated glomerulonephritis. We provide an overview of the clinical presentation, pathology, and the current therapeutic approach of the main representative disorders in the spectrum of glomerulonephritis.
Collapse
Affiliation(s)
- Sanjeev Sethi
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - An S De Vriese
- Division of Nephrology and Infectious Diseases, AZ Sint-Jan Brugge, Brugge, Belgium; Department of Internal Medicine, Ghent University, Ghent, Belgium
| | | |
Collapse
|
|
35
|
Neuen BL, Tighiouart H, Heerspink HJ, Vonesh EF, Chaudhari J, Miao S, Chan TM, Fervenza FC, Floege J, Goicoechea M, Herrington WG, Imai E, Jafar TH, Lewis JB, Li PKT, Locatelli F, Maes BD, Perrone RD, Praga M, Perna A, Schena FP, Wanner C, Wetzels JF, Woodward M, Xie D, Greene T, Inker LA, on behalf of CKD-EPI Clinical Trials. Acute Treatment Effects on GFR in Randomized Clinical Trials of Kidney Disease Progression. J Am Soc Nephrol 2022; 33:291-303. [PMID: 34862238 PMCID: PMC8819983 DOI: 10.1681/asn.2021070948] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 10/28/2021] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Acute changes in GFR can occur after initiation of interventions targeting progression of CKD. These acute changes complicate the interpretation of long-term treatment effects. METHODS To assess the magnitude and consistency of acute effects in randomized clinical trials and explore factors that might affect them, we performed a meta-analysis of 53 randomized clinical trials for CKD progression, enrolling 56,413 participants with at least one estimated GFR measurement by 6 months after randomization. We defined acute treatment effects as the mean difference in GFR slope from baseline to 3 months between randomized groups. We performed univariable and multivariable metaregression to assess the effect of intervention type, disease state, baseline GFR, and albuminuria on the magnitude of acute effects. RESULTS The mean acute effect across all studies was -0.21 ml/min per 1.73 m2 (95% confidence interval, -0.63 to 0.22) over 3 months, with substantial heterogeneity across interventions (95% coverage interval across studies, -2.50 to +2.08 ml/min per 1.73 m2). We observed negative average acute effects in renin angiotensin system blockade, BP lowering, and sodium-glucose cotransporter 2 inhibitor trials, and positive acute effects in trials of immunosuppressive agents. Larger negative acute effects were observed in trials with a higher mean baseline GFR. CONCLUSION The magnitude and consistency of acute GFR effects vary across different interventions, and are larger at higher baseline GFR. Understanding the nature and magnitude of acute effects can help inform the optimal design of randomized clinical trials evaluating disease progression in CKD.
Collapse
Affiliation(s)
- Brendon L. Neuen
- The George Institute for Global Health, University of New South Wales, Sydney, Australia
| | - Hocine Tighiouart
- Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, Massachusetts
- Tufts Clinical and Translational Science Institute, Tufts University, Boston, Massachusetts
| | - Hiddo J.L. Heerspink
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, Netherlands
| | - Edward F. Vonesh
- Department of Preventive Medicine, Northwestern University, Chicago, Illinois
| | - Juhi Chaudhari
- Division of Nephrology, Tufts Medical Center, Boston, Massachusetts
| | - Shiyuan Miao
- Division of Nephrology, Tufts Medical Center, Boston, Massachusetts
| | - Tak Mao Chan
- Department of Medicine, University of Hong Kong, Pokfulam, Hong Kong
| | - Fernando C. Fervenza
- Division of Nephrology and Hypertension and Department of Medicine, Mayo Clinic Rochester, Minnesota
| | - Jürgen Floege
- Division of Nephrology, RWTH Aachen University, Aachen, Germany
| | - Marian Goicoechea
- Department of Nephrology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - William G. Herrington
- Medical Research Council Population Health Research Unit at the University of Oxford Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Enyu Imai
- Nakayamadera Imai Clinic, Takarazuka, Japan
| | - Tazeen H. Jafar
- Program in Health Services and Systems Research, Duke-NUS Medical School, Singapore, Singapore
- Duke Global Health Institute, Duke University, Durham, North Carolina
| | - Julia B. Lewis
- Division of Nephrology, Vanderbilt University, Nashville, Tennessee
| | - Philip Kam-Tao Li
- Division of Nephrology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong
| | | | - Bart D. Maes
- Department of Nephrology, AZ Delta, Roeselare, Belgium
| | | | - Manuel Praga
- Nephrology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Annalisa Perna
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Francesco P. Schena
- Renal, Dialysis and Transplant Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Christoph Wanner
- Division of Nephrology, University Hospital of Würzburg, Würzburg, Germany
| | - Jack F.M. Wetzels
- Department of Nephrology, Radboud Institute for Health Sciences, Nijmegen, The Netherlands
| | - Mark Woodward
- The George Institute for Global Health, University of New South Wales, Sydney, Australia
- The George Institute for Global Health, Imperial College London, United Kingdom
| | - Di Xie
- Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Tom Greene
- Division of Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, Utah
| | - Lesley A. Inker
- Division of Nephrology, Tufts Medical Center, Boston, Massachusetts
| | | |
Collapse
|
|
36
|
Zanoni F, Khairallah P, Kiryluk K, Batal I. Glomerular Diseases of the Kidney Allograft: Toward a Precision Medicine Approach. Semin Nephrol 2022; 42:29-43. [PMID: 35618394 PMCID: PMC9139085 DOI: 10.1016/j.semnephrol.2022.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
The continual development of potent immunosuppressive regimens has led to a decreased incidence of acute rejection and improvement of short-term kidney allograft survival. In contrast to acute rejection, glomerular diseases of the kidney allograft are being encountered more frequently and are emerging as leading causes of late kidney allograft failure. Although data on the pathogeneses of glomerular diseases in the kidney allograft are sparse, cumulative evidence suggests that post-transplant glomerular diseases may be the result of inherited predispositions and immunologic triggers. Although studying immunologic signals and performing genome-wide association studies are ideal approaches to tackle glomerular diseases in the kidney allograft, such studies are challenging because of the lack of adequately powered cohorts. In this review, we focus on the most commonly encountered recurrent and de novo glomerular diseases in the kidney allograft. We address the important advances made in understanding the immunopathology and genetic susceptibility of glomerular diseases in the native kidney and how to benefit from such knowledge to further our knowledge of post-transplant glomerular diseases. Defining genomic and immune predictors for glomerular diseases in the kidney allograft would support novel donor-recipient matching strategies and development of targeted therapies to ultimately improve long-term kidney allograft survival.
Collapse
Affiliation(s)
- Francesca Zanoni
- Medicine, Nephrology, Columbia University Irving Medical Center, New York, NY, USA
| | | | - Krzysztof Kiryluk
- Medicine, Nephrology, Columbia University Irving Medical Center, New York, NY, USA
| | - Ibrahim Batal
- Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA,Corresponding Author: Ibrahim Batal MD, Department of Pathology and Cell Biology, Renal Division, Columbia University Irving Medical Center, 630 W 168th street, VC14-238, New York, NY 10032, Phone: 212-305-9669, Fax: 212-342-5380,
| |
Collapse
|
|
37
|
Oh TR, Choi HS, Oh SW, Oh J, Lee DW, Kim CS, Ma SK, Kim SW, Bae EH. Association between the progression of immunoglobulin A nephropathy and a controlled status of hypertension in the first year after diagnosis. Korean J Intern Med 2022; 37:146-153. [PMID: 32872745 PMCID: PMC8747919 DOI: 10.3904/kjim.2020.205] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 07/09/2020] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND/AIMS Hypertension is considered a risk factor in immunoglobulin A nephropathy (IgAN). However, after IgAN diagnosis, the relationship between early blood pressure control and renal prognosis remains unclear. This study aimed to analyze the association between the prognosis of IgAN patients and a controlled status of hypertension within the first year of IgAN diagnosis. METHODS We retrospectively analyzed 2,945 patients diagnosed with IgAN by renal biopsy. The patients were divided into 'normal,' 'new-onset,' 'well-controlled,' and 'poorly-controlled' groups using blood pressure data from two consecutive measurements performed within a year. The Kaplan-Meier survival analysis and Cox proportional-hazards regression model were used to survey the independent association between recovery from hypertension and the risk of IgAN progression. The primary endpoint was IgAN progression defined as the initiation of dialysis or kidney transplantation. RESULTS Before IgAN diagnosis, 1,239 patients (42.1%) had been diagnosed with hypertension. In the fully adjusted Cox proportional-hazards models, the risk of IgAN progression increased by approximately 1.7-fold for the prevalence of hypertension. In the subgroup analyses, the 'well-controlled' group showed a statistically significant risk of IgAN progression (hazard ratio [HR], 3.19; 95% confidence interval [CI], 1.103 to 9.245; p = 0.032). Moreover, the 'new-onset' and 'poorly-controlled' groups had an increased risk of IgAN progression compared to the 'normal' group (HR, 2.58; 95% CI, 1.016 to 6.545; p = 0.046 and HR, 3.85;95% CI, 1.541 to 9.603; p = 0.004, respectively). CONCLUSION Although hypertension was well-controlled in the first year after IgAN diagnosis, it remained a risk factor for IgAN progression.
Collapse
Affiliation(s)
- Tae Ryom Oh
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju,
Korea
| | - Hong Sang Choi
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju,
Korea
| | - Se Won Oh
- Department of Internal Medicine, Korea University Anam Hospital, Seoul,
Korea
| | - Jieun Oh
- Department of Internal Medicine, Hallym University Kangdong Sacred Heart Hospital, Seoul,
Korea
| | - Dong Won Lee
- Department of Internal Medicine, Pusan National University School of Medicine, Yangsan,
Korea
| | - Chang Seong Kim
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju,
Korea
| | - Seong Kwon Ma
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju,
Korea
| | - Soo Wan Kim
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju,
Korea
| | - Eun Hui Bae
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju,
Korea
| |
Collapse
|
|
38
|
Kurokawa M, Maehara K, Kaku Y, Honjo S. Necessity and choice of therapy for Henoch-Schönlein purpura nephritis. Pediatr Int 2022; 64:e15282. [PMID: 36134650 DOI: 10.1111/ped.15282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 06/16/2022] [Accepted: 06/18/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Henoch-Schönlein purpura nephritis often resolves spontaneously, without treatment, making decisions regarding therapeutic interventions difficult. METHODS Fifty-four patients who were diagnosed as having Henoch-Schönlein purpura nephritis between April 2004 and March 2018, and developed hematuria and/or proteinuria, were studied retrospectively. The observation period ended at the disappearance of hematuria or proteinuria, or the last observation date before December 2019 for each patient. Twenty-four of the patients received no treatment (Group A), 19 underwent renin-angiotensin-aldosterone system inhibitors only (B), 4 experienced steroid pulse therapy and combination therapy only (C) and the remaining 7 received steroid pulse therapy and combination therapy following renin-angiotensin-aldosterone system inhibitors (C). Clinical characteristics were examined according to the treatment method. Survival analysis for persistent urinary abnormalities was performed according to treatment modality, with multiple treatment records created per subject, if necessary. RESULTS The highest urine protein/creatinine levels were significantly higher in groups B and C than in group A. The lowest estimated glomerular filtration rate was not significantly different among the three groups. In groups A and B, proteinuria resolved in >90% of patients. Survival analysis showed that steroid pulse therapy and combination therapy was not related to the better resolution of hematuria or proteinuria than renin-angiotensin-aldosterone system inhibitors. CONCLUSIONS Several patients with Henoch-Schönlein purpura nephritis went into remission either without treatment or with renin-angiotensin-aldosterone system inhibitors alone. The treatment plan for patients with Henoch-Schönlein purpura nephritis needs to be determined carefully.
Collapse
Affiliation(s)
- Mari Kurokawa
- Department of Nephrology, Fukuoka Children's Hospital, Fukuoka, Japan.,Division of Pediatrics, National Hospital Organization Fukuokahigashi Medical Center, Koga, Japan
| | - Kenji Maehara
- Department of Nephrology, Fukuoka Children's Hospital, Fukuoka, Japan
| | - Yoshitsugu Kaku
- Department of Nephrology, Fukuoka Children's Hospital, Fukuoka, Japan
| | - Satoshi Honjo
- Department of Pediatrics, National Hospital Organization, Fukuoka National Hospital, Fukuoka, Japan
| |
Collapse
|
|
39
|
Huerta A, Mérida E, Medina L, Fernandez M, Gutierrez E, Hernandez E, Lopez P, Sevillano A, Portolés J, Trimarchi H, Praga M. Corticosteroids and mycophenolic acid analogs in IgA nephropathy with progressive decline in kidney function. Clin Kidney J 2021; 15:771-777. [PMID: 35371455 PMCID: PMC8967683 DOI: 10.1093/ckj/sfab244] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Indexed: 11/13/2022] Open
Abstract
Abstract
Background
A randomized controlled trial (RCT) demonstrated a beneficial effect of corticosteroids (CS) plus cyclophosphamide followed by azathioprine in progressive IgA nephropathy (IgAN). Although treatment with CS and mycophenolic acid analogs (MPAA) remains controversial in IgAN, there is no information about their effect in progressive IgAN.
Methods
Patients with progressive IgAN, defined by a decrease in estimated glomerular filtration rate (eGFR) of at least 10 ml/min/1.73 m2 in the 12 months prior to the start of treatment, proteinuria ≥ 0.75 g/24h despite maximum tolerated doses of renin-angiotensin system blockers (RASB) and persistent hematuria, who had received treatment with CS+MPAA were included in this retrospective study. The main outcome was the difference between the eGFR slope from the start of treatment with CS+MPAA to the last visit with this treatment with respect to the eGFR slope during the 12 months prior to start of treatment.
Results
Twenty-five patients were included in the study. Mean duration of CS+MPAA treatment was 24.7±15.2 months. In the 12 months prior to treatment the median rate of kidney function decline was -23 [-32 to -16] ml/min/1.73 m2 per year. After the onset of treatment, the median eGFR slope was +5 [+3 to +9] ml/min/1.73 m2 per year (P = 0.001 with respect to the 12 months prior to treatment). Proteinuria decreased from 1.8 (1.0-2.5) g/day at baseline to 0.6 (0.3-1.2) g/day at the end of treatment (P = 0.01) and hematuria disappeared in 40% of the patients. There were no serious adverse effects requiring treatment discontinuation.
Conclusions
CS + MPAA is an effective treatment in IgAN patients with a sustained decline in kidney function accompanied by persistent proteinuria and hematuria despite optimized conservative treatment. Prospective studies are needed to confirm these results.
Collapse
Affiliation(s)
- Ana Huerta
- Department of Nephrology, Hospital Universitario Puerta del Hierro Majadahonda, Madrid, Spain
- REDInREN ISCIII 016/009, Spain
| | - Eva Mérida
- REDInREN ISCIII 016/009, Spain
- Department of Nephrology, Hospital Hospital Universitario Doce de Octubre, Madrid, Spain
| | - Laura Medina
- Department of Nephrology, Hospital Universitario Infanta Leonor, Madrid, Spain
| | - Maria Fernandez
- Department of Nephrology, Hospital Hospital Universitario Doce de Octubre, Madrid, Spain
| | - Eduardo Gutierrez
- REDInREN ISCIII 016/009, Spain
- Department of Nephrology, Hospital Hospital Universitario Doce de Octubre, Madrid, Spain
| | - Eduardo Hernandez
- REDInREN ISCIII 016/009, Spain
- Department of Nephrology, Hospital Hospital Universitario Doce de Octubre, Madrid, Spain
| | - Paula Lopez
- Department of Nephrology, Hospital Universitario Puerta del Hierro Majadahonda, Madrid, Spain
| | - Angel Sevillano
- REDInREN ISCIII 016/009, Spain
- Department of Nephrology, Hospital Hospital Universitario Doce de Octubre, Madrid, Spain
| | - Jose Portolés
- Department of Nephrology, Hospital Universitario Puerta del Hierro Majadahonda, Madrid, Spain
- REDInREN ISCIII 016/009, Spain
| | - Hernan Trimarchi
- Department of Nephrology, Hospital Británico de Buenos Aires, Argentina
| | - Manuel Praga
- REDInREN ISCIII 016/009, Spain
- Research Institute Hospital Universitario 12 de Octubre (imas12), Madrid, Spain
- Department of Medicine, Complutense University, Madrid, Spain
| |
Collapse
|
|
40
|
Yang J, Okpe A, Pathak A. In Every Man, There Is a Child: Henoch-Schönlein Purpura in an Adult With Liver Cirrhosis. Cureus 2021; 13:e18270. [PMID: 34692357 PMCID: PMC8526072 DOI: 10.7759/cureus.18270] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/25/2021] [Indexed: 11/17/2022] Open
Abstract
Henoch-Schönlein purpura (HSP), also known as immunoglobulin A (IgA) vasculitis, is a small-vessel vasculitis characterized by IgA deposits in various organs in the body producing a unique constellation of symptoms. This disease predominantly affects the skin (palpable purpura), joints (arthritis/arthralgia), gut (abdominal pain), and kidneys (nephritic syndrome-IgA nephropathy [IgAN]). The pathogenesis of HSP in children is usually secondary to an immune reaction after viral infections. In adults, few cases of HSP/IgA vasculitis have been reported secondary to altered metabolism of IgA in patients with alcoholic liver cirrhosis. Here, we report an unusual case of HSP/IgA vasculitis. The patient presented with signs of alcoholic liver cirrhosis with abdominal pain and ascites along with a lower extremity purpuric rash. The patient had significant findings of liver cirrhosis with radiographic evidence of cirrhotic liver with esophageal varices and splenorenal shunt and elevated serum ascites albumin gradient. Urinalysis revealed proteinuria with microscopic hematuria, further evaluated with a kidney biopsy. Microscopic analysis revealed focal segmental endocapillary and extracapillary proliferative glomerulonephritis with focal necrotizing features, consistent with IgAN/HSP nephritis. Treatment was initiated with high-dose steroids and cyclophosphamide infusions. Alcohol-induced endotoxin release and inflammation lead to high amounts of circulating IgA due to increased intestinal permeability and reduced hepatic clearance. Further disease development is caused by IgA deposits in affected organs (skin and kidney in our case). We hypothesize that the development of disease for the patient was secondary to altered IgA processing in decompensated alcoholic cirrhosis.
Collapse
Affiliation(s)
- Jiajia Yang
- Molecular Pharmacology and Physiology, University of South Florida Morsani College of Medicine, Tampa, USA
| | - Andrew Okpe
- Internal Medicine, St. Peter's University Hospital, New Brunswick, USA
| | - Amogh Pathak
- Internal Medicine, St. Peter's University Hospital, New Brunswick, USA
| |
Collapse
|
|
41
|
Rovin BH, Adler SG, Barratt J, Bridoux F, Burdge KA, Chan TM, Cook HT, Fervenza FC, Gibson KL, Glassock RJ, Jayne DR, Jha V, Liew A, Liu ZH, Mejía-Vilet JM, Nester CM, Radhakrishnan J, Rave EM, Reich HN, Ronco P, Sanders JSF, Sethi S, Suzuki Y, Tang SC, Tesar V, Vivarelli M, Wetzels JF, Floege J. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int 2021; 100:S1-S276. [PMID: 34556256 DOI: 10.1016/j.kint.2021.05.021] [Citation(s) in RCA: 1104] [Impact Index Per Article: 276.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 05/25/2021] [Indexed: 12/13/2022]
|
|
42
|
Non-immunosuppressive therapies for childhood IgA nephropathy. Pediatr Nephrol 2021; 36:3057-3065. [PMID: 33594462 DOI: 10.1007/s00467-021-04954-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 01/06/2021] [Accepted: 01/15/2021] [Indexed: 10/22/2022]
Abstract
IgA nephropathy (IgAN) is the most common chronic primary glomerulonephritis in both children and adults, and 20-30% of patients with persistent hematuria/proteinuria progress to kidney failure within 20 years. In Japan, most cases of childhood IgAN are detected by school screening programs during the early onset of the disease when hematuria/proteinuria are asymptomatic and kidney function is normal. Therefore, it is possible to follow the detailed clinical course and appropriate therapeutic interventions from early onset of the disease. Data on non-immunosuppressive therapies for children with IgAN are highly limited. The Japanese Pediatric IgA Nephropathy Treatment Study Group was organized in 1989 to conduct clinical trials and accumulate data on treatments for childhood IgAN. In this review, we focus on non-immunosuppressive therapies, notably with renin-angiotensin-aldosterone system (RAAS) inhibitors for childhood IgAN and related clinical trials conducted primarily in Japan. We also describe the anti-inflammatory and antiproteinuric effects of RAAS inhibitors in IgAN, differences in treatment regimens because of the acute and active pathological features of childhood IgAN, adverse events of RAAS inhibitors, other non-immunosuppressive treatment options, and future directions.
Collapse
|
|
43
|
Inker LA, Heerspink HJL, Tighiouart H, Chaudhari J, Miao S, Diva U, Mercer A, Appel GB, Donadio JV, Floege J, Li PKT, Maes BD, Locatelli F, Praga M, Schena FP, Levey AS, Greene T. Association of Treatment Effects on Early Change in Urine Protein and Treatment Effects on GFR Slope in IgA Nephropathy: An Individual Participant Meta-analysis. Am J Kidney Dis 2021; 78:340-349.e1. [PMID: 33775708 PMCID: PMC8384669 DOI: 10.1053/j.ajkd.2021.03.007] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 03/03/2021] [Indexed: 01/18/2023]
Abstract
RATIONALE & OBJECTIVE An early change in proteinuria is considered a reasonably likely surrogate end point in immunoglobulin A nephropathy (IgAN) and can be used as a basis for accelerated approval of therapies, with verification in a postmarketing confirmatory trial. Glomerular filtration rate (GFR) slope is a recently validated surrogate end point for chronic kidney disease progression and may be considered as the end point used for verification. We undertook a meta-analysis of clinical trials in IgAN to compare treatment effects on change in proteinuria versus change in estimated GFR (eGFR) slope. STUDY DESIGN Individual patient-level meta-analysis. SETTING & STUDY POPULATIONS Individual data of 1,037 patients from 12 randomized trials. SELECTION CRITERIA FOR STUDIES Randomized trials of IgAN with proteinuria measurements at baseline and 6 (range, 2.5-14) months and at least a further 1 year of follow-up for the clinical outcome. ANALYTICAL APPROACH For each trial, we estimated the treatment effects on proteinuria and on the eGFR slope, computed as the total slope starting at baseline or the chronic slope starting 3 months after randomization. We used a Bayesian mixed-effects analysis to relate the treatment effects on proteinuria to effects on GFR slope across these studies and developed a prediction model for the treatment effect on the GFR slope based on the effect on proteinuria. RESULTS Across all studies, treatment effects on proteinuria accurately predicted treatment effects on the total slope at 3 years (median R2 = 0.88; 95% Bayesian credible interval [BCI], 0.06-1) and on the chronic slope (R2 = 0.98; 95% BCI, 0.29-1). For future trials, an observed treatment effect of approximately 30% reduction in proteinuria would confer probabilities of at least 90% for nonzero treatment benefits on the total and chronic slopes of eGFR. We obtained similar results for proteinuria at 9 and 12 months and total slope at 2 years. LIMITATIONS Study population restricted to 12 trials of small sample size, leading to wide BCIs. There was heterogeneity among trials with respect to study design and interventions. CONCLUSIONS These results provide new evidence supporting that early reduction in proteinuria can be used as a surrogate end point for studies of chronic kidney disease progression in IgAN.
Collapse
Affiliation(s)
- Lesley A Inker
- Division of Nephrology, Tufts Medical Center, Boston, MA.
| | - Hiddo J L Heerspink
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Hocine Tighiouart
- Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA; Tufts Clinical and Translational Science Institute, Tufts University, Boston, MA
| | - Juhi Chaudhari
- Division of Nephrology, Tufts Medical Center, Boston, MA
| | - Shiyuan Miao
- Division of Nephrology, Tufts Medical Center, Boston, MA
| | - Ulysses Diva
- Biometrics, Travere Therapeutics Inc, San Diego, CA
| | - Alex Mercer
- Clinical Drug Development, JAMCO Pharma Consulting AB, Stockholm, Sweden
| | - Gerald B Appel
- Division of Nephrology, Columbia University Medical Center and the New York Presbyterian Hospital, New York, NY
| | | | - Jürgen Floege
- Division of Nephrology and Immunology, RWTH Aachen University, Aachen, Germany
| | - Philip K T Li
- Division of Nephrology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong
| | - Bart D Maes
- Department of Nephrology, AZ Delta, Roeselare, Belgium
| | | | - Manuel Praga
- Instituto de Investigación Hospital Universitario 12 de Octubre, i+12, Complutense University, Madrid, Spain
| | - Francesco P Schena
- Renal, Dialysis and Transplant Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Andrew S Levey
- Division of Nephrology, Tufts Medical Center, Boston, MA
| | - Tom Greene
- Departments of Population Health Sciences and Internal Medicine, University of Utah, Salt Lake City, UT
| |
Collapse
|
|
44
|
Abstract
Immunoglobulin A (IgA) vasculitis (IgAV), previously called Henoch-Schönlein purpura, is characterized by IgA-dominant immune deposits affecting small vessels and often involves the skin, gastrointestinal tract, joints, and kidneys. IgAV is the most common cause of systemic vasculitis in children. The long-term prognosis is dependent on renal involvement: IgAV with nephritis (IgAVN) can progress to renal failure. IgAVN is an inflammatory disease, providing a rationale for the use of corticosteroids. However, data supporting the use of corticosteroids in patients with established IgAVN of any severity remain limited, although most clinicians use them. Even in patients with severe forms of IgAVN, methylprednisolone pulses added to oral corticosteroids appears to improve renal outcomes. Considering the multihit hypothesis for the pathogenesis of IgAVN, involving many other immune agents, there is a strong rationale for the use of other immunosuppressive drugs in patients with IgAVN, including mycophenolic acid, cyclophosphamide, rituximab, calcineurin inhibitors, and complement inhibitors. Thus, these immunosuppressive treatments have also been evaluated in IgAVN, usually in corticosteroid-dependent or corticosteroid-resistant forms and in small retrospective studies. However, their efficacy has not been proven. Thus, the risk of progression to renal failure and the ongoing debate about the best management of IgAVN justifies the interest in investigating and identifying treatments that can potentially preserve renal function in patients with IgAVN. This review reports on the efficacy of the different drugs currently used for the treatment of IgAVN in adults and children.
Collapse
|
|
45
|
Sahebnasagh A, Saghafi F, Azimi S, Salehifar E, Hosseinimehr SJ. Pharmacological Interventions for the Prevention and Treatment of Kidney Injury Induced by Radiotherapy: Molecular Mechanisms and Clinical Perspectives. Curr Mol Pharmacol 2021; 15:607-619. [PMID: 34429052 DOI: 10.2174/1874467214666210824123212] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 05/31/2021] [Accepted: 06/15/2021] [Indexed: 11/22/2022]
Abstract
More than half of cancer patients need radiotherapy during the course of their treatment. Despite the beneficial aspects, the destructive effects of radiation beams on normal tissues lead to oxidative stress, inflammation, and cell injury. Kidneys are affected during radiotherapy of abdominal malignancies. Radiation nephropathy eventually leads to the release of factors triggering systemic inflammation. Currently, there is no proven prophylactic or therapeutic intervention for the management of radiation-induced nephropathy. This article reviews the biomarkers involved in the pathophysiology of radiation-induced nephropathy and its underlying molecular mechanisms. The efficacy of compounds with potential radio-protective properties on amelioration of inflammation and oxidative stress is also discussed. By outlining the approaches for preventing and treating this critical side effect, we evaluate the potential treatment of radiation-induced nephropathy. Available preclinical and clinical studies on these compounds are also scrutinized.
Collapse
Affiliation(s)
- Adeleh Sahebnasagh
- Clinical Research Center, Department of Internal Medicine, North Khorasan University of Medical Sciences, Bojnurd. Iran
| | - Fatemeh Saghafi
- Department of Clinical Pharmacy, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shahid Sadoughi University of Medical Sciences, Yazd. Iran
| | - Saeed Azimi
- Student Research Committee, Department of Clinical Pharmacy, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran. Iran
| | - Ebrahim Salehifar
- Pharmaceutical Sciences Research Center, Hemoglobinopathy Institute, Sari. Iran
| | - Seyed Jalal Hosseinimehr
- Department of Radiopharmacy, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari. Iran
| |
Collapse
|
|
46
|
Campbell KN. Corticosteroids Should Be Used to Treat Slowly Progressive IgA Nephropathy: COMMENTARY. KIDNEY360 2021; 2:1084-1086. [PMID: 35368351 PMCID: PMC8786091 DOI: 10.34067/kid.0006832020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 01/18/2021] [Indexed: 02/04/2023]
Affiliation(s)
- Kirk N. Campbell
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| |
Collapse
|
|
47
|
Huo Z, Ye H, Ye P, Xiao G, Zhang Z, Kong Y. Comparative efficacy of different renin angiotensin system blockade therapies in patients with IgA nephropathy: a Bayesian network meta-analysis of 17 RCTs. PeerJ 2021; 9:e11661. [PMID: 34268008 PMCID: PMC8269645 DOI: 10.7717/peerj.11661] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 06/01/2021] [Indexed: 12/27/2022] Open
Abstract
Background IgA nephropathy (IgAN) is still one of the most prevalent forms of primary glomerulonephritis globally. However, no guidelines have clearly indicated which kinds of renin angiotensin system blockade therapies (ACEIs or ARBs or their combination) in patients with IgAN result in a greater reduction in proteinuria and a better preservation of kidney function. Thus, we conducted a Bayesian network analysis to evaluate the relative effects of these three therapy regimens in patients with IgAN. Methods The protocol was registered in PROSPERO with ID CRD42017073726. We comprehensively searched the PubMed, the Cochrane Library, Embase, China Biology Medicine disc, WanFang and CNKI databases for studies published since 1993 as well as some grey literature according to PICOS strategies. Pairwise meta-analysis and Bayesian network analysis were conducted to evaluate the effect of different regimens. Results Seventeen randomized controlled trials (RCTs) involving 1,006 patients were analyzed. Co-administration of ACEIs and ARBs had the highest probability (92%) of being the most effective therapy for reducing proteinuria and blood pressure, but ACEIs would be the most appropriate choice for protecting kidney function in IgAN. Conclusion The combination of ACEIs and ARBs seems to have a significantly better antiproteinuric effect and a greater reduction of blood pressure than ACEI or ARB monotherapy in IgAN. ACEIs appear to be a more renoprotective therapy regimen among three therapies.
Collapse
Affiliation(s)
- Zhihao Huo
- Nephrology Department, The First People's Hospital of Foshan, Foshan, China.,National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Clinical Research Center for Kidney Disease, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Huizhen Ye
- Nephrology Department, The First People's Hospital of Foshan, Foshan, China.,Staff Health Care Department, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Peiyi Ye
- Nephrology Department, The First People's Hospital of Foshan, Foshan, China
| | - Guanqing Xiao
- Nephrology Department, The First People's Hospital of Foshan, Foshan, China
| | - Zhe Zhang
- Nephrology Department, The First People's Hospital of Foshan, Foshan, China
| | - Yaozhong Kong
- Nephrology Department, The First People's Hospital of Foshan, Foshan, China
| |
Collapse
|
|
48
|
Seikrit C, Rauen T, Stamellou E, Floege J. Precision medicine in immunoglobulin A nephropathy: still a journey ahead. Nephrol Dial Transplant 2021; 36:24-30. [PMID: 34153983 DOI: 10.1093/ndt/gfab032] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Indexed: 11/12/2022] Open
Abstract
Immunoglobulin A nephropathy (IgAN) is the most common primary glomerular disease worldwide and since its first description extensive research has identified a number of key central pathogenetic contributors, including genetic, immunological and environmental factors. Along with its multifaceted pathophysiology, the clinical presentation of IgAN varies, ranging from mild forms with only minor urinary findings and preserved renal function to cases that rapidly progress to end-stage renal disease. Because of this, early identification of patients at risk for a progressive course is urgently needed. The search for valid and easily accessible biomarkers showed urinary Dickkopf-3 as a promising candidate to predict the course of kidney function. In addition, a recently established IgAN risk prediction tool derived from an international cohort of IgAN patients allows estimation of the risk of a 50% loss of kidney function over several years upon diagnosis. This might serve as a significant tool to individually predict the course of renal function by combining biometric, clinical, histological and treatment information at the time of diagnosis. Today there is no doubt that a comprehensive supportive treatment regimen is the main pillar for all IgAN patients. The value of an additional immunosuppressive treatment in IgAN patients at risk for disease progression is less clear. Early risk stratification and individualized therapies would be desirable for IgAN patients to facilitate the choice of treatment strategies, which is still a matter of ongoing discussion.
Collapse
Affiliation(s)
- Claudia Seikrit
- Division of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, Aachen, Germany
| | - Thomas Rauen
- Division of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, Aachen, Germany
| | - Eleni Stamellou
- Division of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, Aachen, Germany
| | - Jürgen Floege
- Division of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, Aachen, Germany
| |
Collapse
|
|
49
|
Park S, Baek CH, Park SK, Kang HG, Han SH, Ryu DR, Kim DK, Oh KH, Joo KW, Kim YS, Moon KC, Chin HJ, Lee H. Increasing prescription of renin-angiotensin-aldosterone system blockers associated with improved kidney prognosis in Korean IgA nephropathy patients. Clin Kidney J 2021; 14:1673-1680. [PMID: 34084463 PMCID: PMC8162855 DOI: 10.1093/ckj/sfaa204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND We aimed to describe the characteristics of immunoglobulin A nephropathy (IgAN) in Korea with assessment for time trends. METHODS We performed a multicenter retrospective observational cohort study including biopsy-confirmed native IgAN cases from four tertiary hospitals in Korea. Time eras of diagnosis were stratified into 1979-2003, 2004-9 and 2010-17. The prognostic variable was progression to end-stage kidney disease (ESKD) analyzed by multivariable Cox regression analysis. RESULTS We included 1366 (from 1979 to 2003), 1636 (from 2004 to 2009) and 1442 (from 2010 to 2017) IgAN patients in this study. In the recent periods, IgAN had relatively better clinical characteristics, as patients had higher estimated glomerular filtration rates and lower baseline blood pressures than before. The use of renin-angiotensin-aldosterone system (RAAS) blockers increased from 57.7% in 1979-2003 to 80.0% in 2010-17. During a median follow-up duration of 11.3 years, 722 patients progressed to ESKD with an incidence rate of 12.5 per 1000 person-years. The 10-year risk of progression to ESKD was lower in 2010-17 compared with that of 1979-2003 [adjusted hazard ratio 0.692 (95% confidence interval 0.523-0.915)], even after adjustment for multiple clinicopathologic characteristics. The use of RAAS blockers was a significant mediator (P < 0.001) for the association between time trends and lower 10-year ESKD risk. CONCLUSIONS Clinicopathologic characteristics of IgAN in Korea have changed over time. Although the limitation of a retrospective observational study remains, the result showed that the prognosis of IgAN has improved over the study period, possibly related to increased prescription of RAAS blockers.
Collapse
Affiliation(s)
- Sehoon Park
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Armed Forces Capital Hospital, Gyeonggi-do, Korea
| | - Chung Hee Baek
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Su-Kil Park
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hee Gyung Kang
- Department of Pediatrics, Seoul National University Hospital, Seoul, Korea
- Korean GlomeruloNEphritis sTudy (KoGNET) Group, Korean Society of Nephrology, Seoul, Korea
| | - Seung Hyeok Han
- Korean GlomeruloNEphritis sTudy (KoGNET) Group, Korean Society of Nephrology, Seoul, Korea
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Dong-Ryeol Ryu
- Korean GlomeruloNEphritis sTudy (KoGNET) Group, Korean Society of Nephrology, Seoul, Korea
| | - Dong Ki Kim
- Korean GlomeruloNEphritis sTudy (KoGNET) Group, Korean Society of Nephrology, Seoul, Korea
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
- Kidney Research Institute, Seoul National University, Seoul, Korea
| | - Kook-Hwan Oh
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Kwon Wook Joo
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
- Kidney Research Institute, Seoul National University, Seoul, Korea
| | - Yon Su Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
- Kidney Research Institute, Seoul National University, Seoul, Korea
| | - Kyung Chul Moon
- Kidney Research Institute, Seoul National University, Seoul, Korea
- Department of Pathology, Seoul National University Hospital, Seoul, Korea
| | - Ho Jun Chin
- Korean GlomeruloNEphritis sTudy (KoGNET) Group, Korean Society of Nephrology, Seoul, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
- Kidney Research Institute, Seoul National University, Seoul, Korea
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul, Korea
| | - Hajeong Lee
- Korean GlomeruloNEphritis sTudy (KoGNET) Group, Korean Society of Nephrology, Seoul, Korea
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| |
Collapse
|
|
50
|
IgA Vasculitis and IgA Nephropathy: Same Disease? J Clin Med 2021; 10:jcm10112310. [PMID: 34070665 PMCID: PMC8197792 DOI: 10.3390/jcm10112310] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 05/17/2021] [Accepted: 05/19/2021] [Indexed: 12/14/2022] Open
Abstract
Many authors suggested that IgA Vasculitis (IgAV) and IgA Nephropathy (IgAN) would be two clinical manifestations of the same disease; in particular, that IgAV would be the systemic form of the IgAN. A limited number of studies have included sufficient children or adults with IgAN or IgAV (with or without nephropathy) and followed long enough to conclude on differences or similarities in terms of clinical, biological or histological presentation, physiopathology, genetics or prognosis. All therapeutic trials available on IgAN excluded patients with vasculitis. IgAV and IgAN could represent different extremities of a continuous spectrum of the same disease. Due to skin rash, patients with IgAV are diagnosed precociously. Conversely, because of the absence of any clinical signs, a renal biopsy is practiced for patients with an IgAN to confirm nephropathy at any time of the evolution of the disease, which could explain the frequent chronic lesions at diagnosis. Nevertheless, the question that remains unsolved is why do patients with IgAN not have skin lesions and some patients with IgAV not have nephropathy? Larger clinical studies are needed, including both diseases, with a common histological classification, and stratified on age and genetic background to assess renal prognosis and therapeutic strategies.
Collapse
|