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El Hennawy HM, Safar O, Faifi ASA, El Hennawy MH, Alghamdi B, Ali A, Alqahtani M, Zaitoun MF, Alasmari SA, Serageldeen A, Fourtounas K, Ayyad M, Ali A, Zahran MH. Navigating risks: insights on unrelated overseas renal transplantations from two Saudi centers. BMC Nephrol 2025; 26:221. [PMID: 40316927 PMCID: PMC12046916 DOI: 10.1186/s12882-025-04143-x] [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: 11/08/2024] [Accepted: 04/21/2025] [Indexed: 05/04/2025] Open
Abstract
BACKGROUND Due to a shortage of cadaveric organs for transplantation, some Saudi patients seek to purchase kidneys in other countries. However, kidney transplantation (KT) abroad is often associated with negative outcomes. This study shared the experiences of two Saudi transplantation centers regarding unrelated KT overseas. METHODS This retrospective comparative cohort study included patients who underwent commercial KT abroad (Group I) and local patients who received living unrelated KT between September 2017 and July 2024, with available follow-up for at least one year. The primary outcome was to compare the perioperative outcomes. The secondary outcome was to compare the cumulative graft survival between both groups using cox-regression analysis. RESULTS Group I included 96 patients and group II included 108 patients. Group I had a statistically significant longer 30-day hospital stay (9.4 ± 1.6 vs. 7.9 ± 1 days, P < 0.001). Primary functioning graft was significantly lower in Group I (83.3% vs. 93.5%; p = 0.01). Group I was associated with statistically significant higher incidence of surgical site infection (SSI) (P = 0.03), lymphocele (P = 0.007) and UTI (P = 0.002). The 1-, 2-, 3-, and 5-year cumulative graft survivals were 80%, 79%, 74%, and 54%, respectively in group I compared to 98%, 97%, 90%, and 60%, respectively in group II. [HR = 2, 95% CI = 1.1-3.8, P = 0.02] CONCLUSION: Commercial transplantation graft survival rates are lower, and overall outcomes are worse than those of traditional unrelated transplantation in the midterm. Educating patients about the risks associated with overseas KT and promoting public registration for deceased organ donation could help mitigate this practice. CLINICAL TRIAL NUMBER Not applicable.
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Affiliation(s)
- Hany M El Hennawy
- Surgery Department, Section of Transplantation, Armed Forces Hospitals, Khamis Mushayte, Southern Region 101, KSA, Saudi Arabia.
| | - Omar Safar
- Urology Department, Armed Forces Hospitals, Southern Region, Khamis Mushayte, KSA, Saudi Arabia
| | - Abdullah S Al Faifi
- Surgery Department, Section of Transplantation, Armed Forces Hospitals, Khamis Mushayte, Southern Region 101, KSA, Saudi Arabia
| | - Maryam H El Hennawy
- Surgery Department, Section of Transplantation, Armed Forces Hospitals, Khamis Mushayte, Southern Region 101, KSA, Saudi Arabia
| | - Balqees Alghamdi
- Pharmacy Department, Armed Forces Hospitals, Southern Region, Khamis Mushayte, KSA, Saudi Arabia
| | - Amani Ali
- Nursing Department, Armed Forces Hospitals, Southern Region, Khamis Mushayte, KSA, Saudi Arabia
| | - Manar Alqahtani
- Nursing Department, Armed Forces Hospitals, Southern Region, Khamis Mushayte, KSA, Saudi Arabia
| | - Mohammad F Zaitoun
- Pharmacy Department, Armed Forces Hospitals, Southern Region, Khamis Mushayte, KSA, Saudi Arabia
| | - Sharifah A Alasmari
- Prince Sultan Kidney Center, King Salman Armed Forces Hospital, Tabuk, KSA, Saudi Arabia
| | - Ahmed Serageldeen
- Prince Sultan Kidney Center, King Salman Armed Forces Hospital, Tabuk, KSA, Saudi Arabia
- Nephrology and internal medicine department, Ain Shams University, Cairo, Egypt
| | | | - Mostafa Ayyad
- Prince Sultan Kidney Center, King Salman Armed Forces Hospital, Tabuk, KSA, Saudi Arabia
| | - Ahmed Ali
- Prince Sultan Kidney Center, King Salman Armed Forces Hospital, Tabuk, KSA, Saudi Arabia
| | - Mohamed H Zahran
- Prince Sultan Kidney Center, King Salman Armed Forces Hospital, Tabuk, KSA, Saudi Arabia
- Urology Department, Urology and Nephrology Center, Mansoura University, Dakahlia Governorate, Egypt
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2
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Haq K, Lin S, Dasgupta A, Obaidi Z, Bagnasco S, Maggiore U, Alachkar N. The outcome of thrombotic microangiopathy in kidney transplant recipients. BMC Nephrol 2024; 25:433. [PMID: 39609684 PMCID: PMC11606107 DOI: 10.1186/s12882-024-03846-x] [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: 07/04/2024] [Accepted: 11/04/2024] [Indexed: 11/30/2024] Open
Abstract
BACKGROUND The outcome of kidney transplant recipients with a history of complement-mediated thrombotic microangiopathy (cTMA) and those who develop post-transplant de novo TMA (dnTMA) is largely unknown. METHODS We retrospectively studied all kidney transplant recipients with end-stage kidney disease secondary to cTMA and those who developed dnTMA, between Jan 2000 and Dec 2020 in our center. RESULTS We identified 134 patients, 22 with cTMA and 112 had dnTMA. Patients with cTMA were younger at the time of TMA diagnosis (age at diagnosis, 28.9 ± 16.3. vs 46.5 ± 16.0 years; P < 0.001). T-cell mediated rejection, borderline rejection, and calcineurin inhibitor toxicity were more prevalent in the first kidney transplant biopsy (P < 0.05) in the dnTMA group, and antibody-mediated rejection was more prevalent in anytime-biopsy (P = 0.027). After adjusting for potential confounders, cTMA was associated with a sixfold increase in the hazard of transplant failure during the first-year post-transplant (adjusted hazard ratio (aHR): 6.37 [95%CI: 2.17 to18.68; P = 0.001]; the aHR decreased by 0.87 (95% CI: 0.76 to 0.99: P = 0.033) per year elapsed since transplantation. Long-term allograft survival was similar in both groups. CONCLUSION Post kidney transplant TMA is an important cause of poor allograft survival. More studies are needed to enhance our understanding and management of this disorder.
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Affiliation(s)
- Kanza Haq
- Department of Medicine, Johns Hopkins Hospital, The Johns Hopkins University School of Medicine, 600 Wolfe St. Carnegie 344B, Baltimore, MD, 21287, USA
| | - Shanshan Lin
- Department of Epidemiology, The Johns Hopkins University School of Public Health, Baltimore, MD, USA
| | - Alana Dasgupta
- Department of Renal Pathology, The Ohio State University School of Medicine, OH, Columbus, USA
| | - Zainab Obaidi
- Department of Medicine, University of Chicago, Chicago, IL, USA
| | - Serena Bagnasco
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Umberto Maggiore
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Nada Alachkar
- Department of Medicine, Johns Hopkins Hospital, The Johns Hopkins University School of Medicine, 600 Wolfe St. Carnegie 344B, Baltimore, MD, 21287, USA.
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Brook MO, Hennessy C, Hester J, Hammad S, Alzhrani A, Rombach I, Dutton S, Lombardi G, Wood KJ, Friend P, Harden PN, Issa F. Late Treatment With Autologous Expanded Regulatory T-cell Therapy After Alemtuzumab Induction Is Safe and Facilitates Immunosuppression Minimization in Living Donor Renal Transplantation. Transplantation 2024; 108:2278-2286. [PMID: 38845088 PMCID: PMC7616465 DOI: 10.1097/tp.0000000000005065] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 03/01/2024] [Accepted: 03/02/2024] [Indexed: 06/23/2024]
Abstract
BACKGROUND The TWO Study (Transplantation Without Overimmunosuppression) aimed to investigate a novel approach to regulatory T-cell (Treg) therapy in renal transplant patients, using a delayed infusion protocol at 6 mo posttransplant to promote a Treg-skewed lymphocyte repopulation after alemtuzumab induction. We hypothesized that this would allow safe weaning of immunosuppression to tacrolimus alone. The COVID-19 pandemic led to the suspension of alemtuzumab use, and therefore, we report the unique cohort of 7 patients who underwent the original randomized controlled trial protocol. This study presents a unique insight into Treg therapy combined with alemtuzumab and is therefore an important proof of concept for studies in other diseases that are considering lymphodepletion. METHODS Living donor kidney transplant recipients were randomized to receive autologous polyclonal Treg at week 26 posttransplantation, coupled with weaning doses of tacrolimus, (Treg therapy arm) or standard immunosuppression alone (tacrolimus and mycophenolate mofetil). Primary outcomes were patient survival and rejection-free survival. RESULTS Successful cell manufacturing and cryopreservation until the 6-mo infusion were achieved. Patient and transplant survival was 100%. Acute rejection-free survival was 100% in the Treg-treated group at 18 mo after transplantation. Although alemtuzumab caused a profound depletion of all lymphocytes, including Treg, after cell therapy infusion, there was a transient increase in peripheral Treg numbers. CONCLUSIONS The study establishes that delayed autologous Treg therapy is both feasible and safe, even 12 mo after cell production. The findings present a new treatment protocol for Treg therapy, potentially expanding its applications to other indications.
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Affiliation(s)
- Matthew O. Brook
- Oxford Transplant Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
- Translational Research Immunology Group, University of Oxford, Oxford, United Kingdom
| | - Conor Hennessy
- Translational Research Immunology Group, University of Oxford, Oxford, United Kingdom
| | - Joanna Hester
- Translational Research Immunology Group, University of Oxford, Oxford, United Kingdom
| | - Salim Hammad
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Science, King’s College London, London, United Kingdom
| | - Alaa Alzhrani
- Translational Research Immunology Group, University of Oxford, Oxford, United Kingdom
| | - Ines Rombach
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Science, King’s College London, London, United Kingdom
| | - Susan Dutton
- Oxford Clinical Trials Research Unit, Botnar Research Centre, University of Oxford, Oxford, United Kingdom
| | - Giovanna Lombardi
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Science, King’s College London, London, United Kingdom
| | - Kathryn J. Wood
- Translational Research Immunology Group, University of Oxford, Oxford, United Kingdom
| | - Peter Friend
- Oxford Transplant Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | - Paul N. Harden
- Oxford Transplant Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | - Fadi Issa
- Translational Research Immunology Group, University of Oxford, Oxford, United Kingdom
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Gupta S, Gea-Banacloche J, Heilman RL, Yaman RN, Me HM, Zhang N, Vikram HR, Kodali L. Impact of Early Rejection Treatment on Infection Development in Kidney Transplant Recipients: A Propensity Analysis. J Transplant 2024; 2024:6663086. [PMID: 38463548 PMCID: PMC10923621 DOI: 10.1155/2024/6663086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 01/24/2024] [Accepted: 02/21/2024] [Indexed: 03/12/2024] Open
Abstract
Introduction The impact of renal allograft rejection treatment on infection development has not been formally defined in the literature. Methods We conducted a retrospective cohort study of 185 rejection (case) and 185 nonrejection (control) kidney transplant patients treated at our institution from 2014 to 2020 to understand the impact of rejection on infection development. Propensity scoring was used to match cohorts. We collected data for infections within 6 months of rejection for the cases and 18 months posttransplant for controls. Results In 370 patients, we identified 466 infections, 297 in the controls, and 169 in the cases. Urinary tract infections (38.9%) and cytomegalovirus viremia (13.7%) were most common. Cumulative incidence of infection between the case and controls was 2.17 (CI 1.54-3.05); p < 0.001. There was no difference in overall survival (HR 0.90, CI 0.49-1.66) or graft survival (HR 1.27, CI 0.74-2.20) between the groups. There was a significant difference in overall survival (HR 2.28, CI 1.14-4.55; p = 0.019) and graft survival (HR 1.98, CI 1.10-3.56; p = 0.023) when patients with infection were compared to those without. Conclusions As previously understood, rejection treatment is a risk factor for subsequent infection development. Our data have defined this relationship more clearly. This study is unique, however, in that we found that infections, but not rejection, negatively impacted both overall patient survival and allograft survival, likely due to our institution's robust post-rejection protocols. Clinicians should monitor patients closely for infections in the post-rejection period and have a low threshold to treat these infections while also restarting appropriate prophylaxis.
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Affiliation(s)
- Simran Gupta
- Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Juan Gea-Banacloche
- Division of Clinical Research, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA
| | - Raymond L. Heilman
- Division of Nephrology, Mayo Clinic Arizona, Phoenix, Arizona, USA
- Transplant Center, Mayo Clinic Arizona, Phoenix, Arizona, USA
| | - Reena N. Yaman
- Department of Internal Medicine, Mayo Clinic Arizona, Phoenix, Arizona, USA
| | - Hay Me Me
- Division of Nephrology, Mayo Clinic Arizona, Phoenix, Arizona, USA
- Transplant Center, Mayo Clinic Arizona, Phoenix, Arizona, USA
| | - Nan Zhang
- Department of Quantitative Health Sciences, Mayo Clinic Arizona, Phoenix, Arizona, USA
| | | | - Lavanya Kodali
- Division of Nephrology, Mayo Clinic Arizona, Phoenix, Arizona, USA
- Transplant Center, Mayo Clinic Arizona, Phoenix, Arizona, USA
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Okamoto T, Hatakeyama S, Hamaya T, Matsuura T, Saito M, Nishida H, Maita S, Murakami R, Tomita H, Saitoh H, Tsuchiya N, Habuchi T, Obara W, Ohyama C. Impact of timing of rejection episode on cardiovascular events in living donor kidney transplantation: a multicenter retrospective study. J Nephrol 2023; 36:2613-2620. [PMID: 37938544 DOI: 10.1007/s40620-023-01811-9] [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: 08/17/2023] [Accepted: 10/14/2023] [Indexed: 11/09/2023]
Abstract
BACKGROUND Cardiovascular diseases are still highly prevalent after kidney transplantation. However, little is known about the impact of the timing of rejection episodes on cardiovascular disease. The study aimed to analyze the influence of the timing of rejection episodes on cardiovascular events in recipients of living donor kidney transplantation. METHODS We studied 572 living donor kidney transplant recipients from the Michinoku Renal Transplant Network (MRTN), which includes 6 centers in the Tohoku region of Japan. Fine-Gray proportional hazards regression analysis with time-dependent variables was used to assess the effect of rejection episode on cardiovascular events. Recipients were divided into three groups: those without rejection (non-rejection, 370 patients), rejection within 6 months after transplantation (early rejection, 99 patients), and rejection after 6 months (late rejection, 103 patients). The effect of timing on cardiovascular events was evaluated using Fine-Gray proportional hazards regression analysis. RESULTS During a median follow-up of 77 months, 70 patients experienced cardiovascular events. Rejection episodes were significantly associated with cardiovascular events (hazard ratio [HR]: 2.08, 95% confidence interval [CI]: 1.26-3.43, P = 0.004), along with age and dialysis vintage. The 5-year cumulative incidence of cardiovascular events was significantly higher in the late rejection group than in the early rejection group (15% vs. 3.3%, P = 0.021). However, no significant difference in 5-year cumulative cardiovascular event incidence was observed between the early rejection and non-rejection groups. Late rejection was significantly associated with cardiovascular events (HR: 2.40, 95% CI: 1.38-4.18, P = 0.002), whereas early rejection was not significantly correlated with cardiovascular event risk (HR: 1.18, P = 0.670). CONCLUSIONS Rejections occurring more than 6 months after transplantation is significantly associated with risk of cardiovascular events. TRIAL REGISTRATION NUMBER 2019-099-1, date of registration; 3 Dec. 2019, retrospectively registered.
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Affiliation(s)
- Teppei Okamoto
- Department of Urology, Hirosaki University School of Medicine, 5 Zaifu-Cho, Hirosaki, Aomori, 036-8562, Japan
| | - Shingo Hatakeyama
- Department of Urology, Hirosaki University School of Medicine, 5 Zaifu-Cho, Hirosaki, Aomori, 036-8562, Japan.
| | - Tomoko Hamaya
- Department of Urology, Hirosaki University School of Medicine, 5 Zaifu-Cho, Hirosaki, Aomori, 036-8562, Japan
| | - Tomohiko Matsuura
- Department of Urology, Iwate Medical University, 1-1-1 Idaidori, Yahaba-Cho, Shiwa-Gun, Morioka, Iwate, 028-3694, Japan
| | - Mitsuru Saito
- Department of Urology, Akita University School of Medicine, 1-1-1, Hondo, Akita, 010-8543, Japan
| | - Hayato Nishida
- Department of Urology, Yamagata University School of Medicine, 2-2-2 Iidanishi, Yamagata, 990-9885, Japan
| | - Shinya Maita
- Department of Urology, Iwate Prefectural Isawa Hospital, 61 Mizusawaryuugababa, Oshu, Iwate, 023-0864, Japan
| | - Reiichi Murakami
- Department of Cardiology and Nephrology, Hirosaki University School of Medicine, 5 Zaifu-Cho, Hirosaki, Aomori, 036-8562, Japan
| | - Hirofumi Tomita
- Department of Cardiology and Nephrology, Hirosaki University School of Medicine, 5 Zaifu-Cho, Hirosaki, Aomori, 036-8562, Japan
| | - Hisao Saitoh
- Department of Urology, Oyokyo Kidney Research Institute, 90 Kozawa Yamazaki, Hirosaki, Aomori, 036-8243, Japan
| | - Norihiko Tsuchiya
- Department of Urology, Yamagata University School of Medicine, 2-2-2 Iidanishi, Yamagata, 990-9885, Japan
| | - Tomonori Habuchi
- Department of Urology, Akita University School of Medicine, 1-1-1, Hondo, Akita, 010-8543, Japan
| | - Wataru Obara
- Department of Urology, Iwate Medical University, 1-1-1 Idaidori, Yahaba-Cho, Shiwa-Gun, Morioka, Iwate, 028-3694, Japan
| | - Chikara Ohyama
- Department of Urology, Hirosaki University School of Medicine, 5 Zaifu-Cho, Hirosaki, Aomori, 036-8562, Japan
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Heo GY, Jang Y, Choi H, Kim YC, Han SS, Kim HW, Lee J, Huh KH, Kim BS, Yang J. Impact of ABO incompatibility and early antibody-mediated rejection on chronic antibody-mediated rejection in kidney transplant patients. J Nephrol 2023; 36:2571-2580. [PMID: 37106218 DOI: 10.1007/s40620-023-01643-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Accepted: 04/05/2023] [Indexed: 04/29/2023]
Abstract
INTRODUCTION Early antibody-mediated rejection has been reported to increase chronic antibody-mediated rejection and decrease graft survival in kidney transplantation. However, the impact of early antibody-mediated rejection in ABO-incompatible kidney transplantation remains unclear. METHODS We retrospectively analyzed living-donor kidney transplantation patients from two Korean centers. Patients were categorized based on ABO compatibility and early antibody-mediated rejection within 1 year. The primary outcome was chronic antibody-mediated rejection. The secondary outcomes were production of de novo donor-specific antibody and composite kidney outcome, defined as graft loss or a decline in estimated glomerular filtration rate to below 30 mL/min/1.73 m2. RESULTS A total of 1639 patients were analyzed, including 1292 patients who underwent ABO-compatible kidney transplantation and 347 patients who underwent ABO-incompatible kidney transplantation. ABO-incompatible kidney transplantation had a lower risk of de novo donor-specific antibody production (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.48-0.95) and chronic antibody-mediated rejection (HR 0.33, 95% CI 0.12-0.92) with a comparable risk of the composite kidney outcome (HR 1.06, 95% CI 0.71-1.59) compared to ABO-compatible kidney transplantation. When outcomes of ABO-incompatible kidney transplantation were analyzed according to early antibody-mediated rejection, ABO-incompatible kidney transplantation without antibody-mediated rejection had a lower risk of de novo donor-specific antibody production (HR 0.60, 95% CI 0.41-0.88) and chronic antibody-mediated rejection (HR 0.28, 95% CI 0.09-0.91) than ABO-compatible kidney transplantation without antibody-mediated rejection. However, ABO-incompatible kidney transplantation with antibody-mediated rejection showed a higher risk of de novo donor-specific antibody production and similar risk of chronic antibody-mediated rejection compared to ABO-compatible kidney transplantation without antibody-mediated rejection. CONCLUSIONS ABO-incompatible kidney transplantation showed a lower risk of de novo donor-specific antibody production and chronic antibody-mediated rejection compared to ABO-compatible kidney transplantation; however, early antibody-mediated rejection abrogated these beneficial effects of ABO-incompatible kidney transplantation.
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Affiliation(s)
- Ga Young Heo
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yunyoung Jang
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hyungwook Choi
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yong Chul Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Seung Seok Han
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hyung Woo Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Juhan Lee
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Kyu Ha Huh
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Beom Seok Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jaeseok Yang
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
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Zhang H, Cavazzoni CB, Hanson BL, Bechu ED, Podestà MA, Azzi J, Blazar BR, Chong AS, Kreisel D, Alessandrini A, Sage PT. Transcriptionally Distinct B Cells Infiltrate Allografts After Kidney Transplantation. Transplantation 2023; 107:e47-e57. [PMID: 36398326 PMCID: PMC9877106 DOI: 10.1097/tp.0000000000004398] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND Following allogeneic kidney transplantation, a substantial proportion of graft loss is attributed to the formation of donor-specific antibodies and antibody-mediated rejection. B cells infiltrate kidney grafts during antibody-mediated rejection; however, the origins, repertoires, and functions of these intrarenal B cells remain elusive. METHODS Here, we use murine allogeneic kidney transplant models to study the origins, transcriptional programming and B cell receptor repertoire of intragraft B cells, and in vitro stimulation assays to evaluate the ability of intragraft B cells to promote CD4+ T cell expansion. RESULTS B cells infiltrate kidney grafts in settings of allogeneic, but not syngeneic, transplantation. Intragraft B cells have characteristics of activation but are transcriptionally distinct from germinal center B cells and resemble innate-like B cells. B cell receptor sequencing demonstrates that the majority of intragraft B cells do not originate from lymph node germinal center B cells and are largely germline. Class-switched intragraft B cells are rare but can be donor-specific and produce IgG capable of binding to the kidney allograft. Lastly, intrarenal B cells are capable of stimulating naive T cells but have an altered ability to promote T follicular helper cell expansion. CONCLUSIONS Together, these data demonstrate that intrarenal B cells during transplant rejection are transcriptionally distinct from lymph node B cells.
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Affiliation(s)
- Hengcheng Zhang
- Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115
| | - Cecilia B. Cavazzoni
- Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115
| | - Benjamin L. Hanson
- Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115
| | - Elsa D. Bechu
- Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115
| | - Manuel A. Podestà
- Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115
- Renal Division, Department of Health Sciences, Università degli Studi di Milano, Milano, Italy
| | - Jamil Azzi
- Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115
| | - Bruce R. Blazar
- Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, 55455
| | - Anita S. Chong
- Department of Surgery, Section of Transplantation, University of Chicago, Chicago, IL, USA
| | - Daniel Kreisel
- Departments of Surgery, Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | - Alessandro Alessandrini
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Peter T. Sage
- Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115
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8
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Karthikeyan B, Sharma RK, Mehrotra S, Gupta A, Kaul A, Bhaudauria DS, Prasad N. Comparative Analysis of Determinants and Outcome of Early and Late Acute Antibody Mediated Rejection (ABMR). Indian J Nephrol 2023; 33:22-27. [PMID: 37197045 PMCID: PMC10185016 DOI: 10.4103/ijn.ijn_375_20] [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: 08/01/2020] [Revised: 09/26/2020] [Accepted: 10/10/2021] [Indexed: 12/29/2022] Open
Abstract
Introduction Antibody-mediated rejection (ABMR) is one of the major determinants of graft survival. Although diagnostic precision and treatment options have improved, response to therapy and graft survival has not improved very significantly. The phenotypes of early and late acute ABMR differ in many ways. In this study, we assessed the clinical characteristics, response to therapy, DSA positivity, and outcomes of early and late ABMR. Methods During the study period, 69 patients with acute ABMR diagnosed on renal graft histopathology were included with a median follow-up of 10 months after rejection. Recipients were stratified into early acute ABMR (<3 months of transplant; n = 29) and late acute ABMR (>3 months of transplant; n = 40). Graft survival, patient survival, response to therapy, and doubling of serum creatinine were assessed and compared between the two groups. Results Baseline characteristics and immunosuppression protocols were comparable between the early and late ABMR groups. Late acute ABMR had an increased risk of doubling of serum creatinine than the early ABMR group (P = 0.002). Graft and patient survival were not statistically different between the two groups. Response to therapy was inferior in the late acute ABMR group (P = 0.00). Pretransplant DSA was present in 27.6% in the early ABMR group. Late acute ABMR was frequently associated with nonadherence or suboptimal immunosuppression and low DSA positivity (15%). Infections such as CMV, bacterial, and fungal infections were similar in the earlier and late ABMR groups. Conclusion Late acute ABMR group had a poor response to anti-rejection therapy and also an increased risk of doubling of serum creatinine compared to the early acute ABMR group. There was also a tendency toward increased graft loss in late acute ABMR patients. Late acute ABMR patients are more frequently associated with nonadherence/suboptimal immunosuppression. There was also a low incidence of anti-HLA DSA positivity in late ABMR.
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Affiliation(s)
- Balasubramanian Karthikeyan
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Raj K. Sharma
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Sonia Mehrotra
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Amit Gupta
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Anupama Kaul
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Dharmendra S. Bhaudauria
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Narayan Prasad
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
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9
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Ishikawa S, Tasaki M, Ikeda M, Nakagawa Y, Saito K, Tomita Y. Pretransplant BMI Should Be <25 in Japanese Kidney Transplant Recipients: A Single-Center Experience. Transplant Proc 2023; 55:72-79. [PMID: 36528408 DOI: 10.1016/j.transproceed.2022.10.058] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 09/24/2022] [Accepted: 10/18/2022] [Indexed: 12/23/2022]
Abstract
BACKGROUND The aim of this study was to determine the appropriate body mass index (BMI) in Japanese kidney transplant (KTx) recipients. We analyzed the effects of pre- and post-transplant (Tx) obesity on graft and patient survival, perioperative complications, post-transplant diabetes mellitus (PTDM), and cardiovascular disease (CVD) in Japanese KTx recipients. METHODS This retrospective study included 269 recipients who underwent KTx from 2008 through 2020 at Niigata University Hospital. Obesity was defined as a body mass index (BMI) ≥25 kg/m2. We examined the association between pre- and post-Tx obesity and graft survival, patient survival, the incidence of PTDM and CVD, and perioperative surgical complications. RESULTS The graft survival rate was lower in the pre-Tx BMI ≥25 kg/m2 group, although there was no significant difference in patient survival. There was no difference in graft and patient survival between the post-Tx BMI ≥25 kg/m2 group and the <25 kg/m2 group. A pre-Tx BMI ≥25 kg/m2 was an independent risk factor for biopsy-proven allograft rejection. New-onset DM after transplantation was significantly more common in the BMI ≥25 kg/m2 group than in the BMI <25 kg/m2 group (36% vs 13%; P = .002). The incidence of CVD was significantly higher in the post-Tx BMI ≥30 kg/m2 group than in the BMI <30 kg/m2 group (50% vs 11%; P = .023). There were no differences in surgical operating time, intraoperative blood loss, or perioperative complications between the obese and non-obese groups. CONCLUSION Pre-Tx BMI ≥25 kg/m2 may be a risk factor for allograft rejection and graft loss. Post-Tx BMI should be <25 kg/m2 to reduce the risk for PTDM.
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Affiliation(s)
- Shoko Ishikawa
- Department of Urology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
| | - Masayuki Tasaki
- Department of Urology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Masahiro Ikeda
- Department of Urology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yuki Nakagawa
- Department of Urology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Kazuhide Saito
- Department of Urology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yoshihiko Tomita
- Department of Urology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
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10
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Alsaqa'aby M, Alissa D, Hussein M, Almudaiheem HY, Al-Jedai A. Cost-Utility of Immunosuppressive Therapy Post-Renal Transplantation in Saudi Arabia: The Saudi Ministry of Health Perspective. Value Health Reg Issues 2023; 33:56-64. [PMID: 36244306 DOI: 10.1016/j.vhri.2022.08.014] [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: 04/14/2022] [Revised: 08/17/2022] [Accepted: 08/31/2022] [Indexed: 01/09/2023]
Abstract
OBJECTIVES Chronic kidney disease is ranked fourth among the top 10 causes of death in Saudi Arabia. Renal transplantation has been recognized as the treatment of choice compared with long-term dialysis to maintain graft survival and prolong a patient's healthy living. Immunosuppressants (ISs) must be administered lifelong. The choice between IS therapies can be challenging because of the similarity in efficacy with some differences in adverse events profile. The objective of this study was to assess the cost-effectiveness of different IS regimens in Saudi Arabia. METHODS A 25-year Markov model was developed based on a previously published study from the Saudi Ministry of Health payer perspective. Efficacy parameters were driven from the literature, whereas cost data were estimated from the Ministry of Health database. A Monte Carlo simulation was conducted to test the base-case model results' robustness. RESULTS All comparators resulted in 6.2 quality-adjusted life-years (QALYs) except for Advagraf® treatment (5.5 QALYs). Generic tacrolimus plus mycophenolate mofetil (MMF) will cost 70 701.45 US dollars ($) (Saudi riyal 265 130.44) per patient to gain 6.2 QALYs over 25 years' time horizon. In the improved adherence scenario, Envarsus® plus generic MMF generated 9.6 QALYs with a cost of $59 849 per patient. Monte Carlo simulation results have shown that generic tacrolimus is still the cheapest treatment option compared with other treatment arms. CONCLUSIONS The current analysis suggested that all IS options are not cost-effective strategies relative to the willingness-to-pay threshold of $20 000. Nevertheless, Envarsus plus generic MMF regimen could become the most cost-effective regimen at different willingness-to-pay thresholds.
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Affiliation(s)
- Mai Alsaqa'aby
- Pharmaceutical Care Division, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Dema Alissa
- Therapeutic Affairs Deputyship, Ministry of Health, Riyadh, Saudi Arabia; Colleges of Medicine and Pharmacy, Al-Faisal University, Riyadh, Saudi Arabia
| | - Mohammed Hussein
- Biostatistics and Bioinformatics, King Abdullah International Medical Research Centre, National Guard Health Affairs, Riyadh, Saudi Arabia
| | | | - Ahmed Al-Jedai
- Therapeutic Affairs Deputyship, Ministry of Health, Riyadh, Saudi Arabia; Colleges of Medicine and Pharmacy, Al-Faisal University, Riyadh, Saudi Arabia.
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11
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Abstract
Transplant rejection remains a challenge especially in the field of vascularized composite allotransplantation (VCA). To blunt the alloreactive immune response' stable levels of maintenance immunosupression are required. However' the need for lifelong immunosuppression poses the risk of severe side effects, such as increased risk of infection, metabolic complications, and malignancies. To balance therapeutic efficacy and medication side effects, immunotolerance promoting immune cells (especially regulatory T cells [Treg]) have become of great scientific interest. This approach leverages immune system mechanisms that usually ensure immunotolerance toward self-antigens and prevent autoimmunopathies. Treg can be bioengineered to express a chimeric antigen receptor or a T-cell receptor. Such bioengineered Treg can target specific antigens and thereby reduce unwanted off-target effects. Treg have demonstrated beneficial clinical effects in solid organ transplantation and promising in vivo data in VCAs. In this review, we summarize the functional, phenotypic, and immunometabolic characteristics of Treg and outline recent advancements and current developments regarding Treg in the field of VCA and solid organ transplantation.
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12
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von Samson-Himmelstjerna FA, Esser G, Schulte K, Kolbrink B, Krautter M, Schwenger V, Weinmann-Menke J, Matschkal J, Schraml F, Pahl A, Braunisch M, Amann K, Feldkamp T, Kunzendorf U, Renders L, Heemann U. Study protocol: the TRAnsplant BIOpsies (TRABIO) study - a prospective, observational, multicentre cohort study to assess the treatment of kidney graft rejections. BMJ Open 2022; 12:e048122. [PMID: 35450886 PMCID: PMC9024278 DOI: 10.1136/bmjopen-2020-048122] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
INTRODUCTION Despite continued efforts, long-term outcomes of kidney transplantation remain unsatisfactory. Kidney graft rejections are independent risk factors for graft failure. At the participating centres of the TRAnsplant BIOpsies study group, a common therapeutic standard has previously been defined for the treatment of graft rejections. The outcomes of this strategy will be assessed in a prospective, observational cohort study. METHODS AND ANALYSIS A total of 800 kidney transplantation patients will be enrolled who undergo a graft biopsy because of deteriorating kidney function. Patients will be stratified according to the Banff classification, and the influence of the treatment strategy on end points will be assessed using regression analysis. Primary end points will be all-cause mortality and graft survival. Secondary end points will be worsening of kidney function (≥30% decline of estimated Glomerular Filtration Rate [eGFR] or new-onset large proteinuria), recurrence of graft rejection and treatment response. Baseline data and detailed histopathology data will be entered into an electronic database on enrolment. During a first follow-up period (within 14 days) and subsequent yearly follow-ups (for 5 years), treatment strategies and clinical course will be recorded. Recruitment at the four participating centres started in September 2016. As of August 2020, 495 patients have been included. ETHICS AND DISSEMINATION Ethical approval for the study has been obtained from the ethics committee of Kiel (AZ B 278/16) and was confirmed by the committees of Munich, Mainz and Stuttgart. The results will be reported in a peer-reviewed journal, according to the Strengthening the Reporting of Observational Studies in Epidemiology criteria. TRIAL REGISTRATION NUMBER ISRCTN78772632; Pre-results.
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Affiliation(s)
| | - Grit Esser
- Department of Nephrology & Hypertension, University Hospital Schleswig-Holstein - Campus Kiel, Kiel, Germany
| | - Kevin Schulte
- Department of Nephrology & Hypertension, University Hospital Schleswig-Holstein - Campus Kiel, Kiel, Germany
| | - Benedikt Kolbrink
- Department of Nephrology & Hypertension, University Hospital Schleswig-Holstein - Campus Kiel, Kiel, Germany
| | - Markus Krautter
- Transplant Center, Department of Nephrology, Klinikum Stuttgart, Stuttgart, Germany
| | - Vedat Schwenger
- Transplant Center, Department of Nephrology, Klinikum Stuttgart, Stuttgart, Germany
| | - Julia Weinmann-Menke
- Department of Nephrology, University Medical Center Mainz, Department of Internal Medicine I, Mainz, Germany
| | - Julia Matschkal
- Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, München, Germany
| | - Florian Schraml
- Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, München, Germany
| | - Anne Pahl
- Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, München, Germany
| | - Matthias Braunisch
- Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, München, Germany
| | - Kerstin Amann
- Department of Nephropathology, University Hospital Erlangen, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Thorsten Feldkamp
- Department of Nephrology & Hypertension, University Hospital Schleswig-Holstein - Campus Kiel, Kiel, Germany
| | - Ulrich Kunzendorf
- Department of Nephrology & Hypertension, University Hospital Schleswig-Holstein - Campus Kiel, Kiel, Germany
| | - Lutz Renders
- Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, München, Germany
| | - Uwe Heemann
- Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, München, Germany
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Teng L, Shen L, Zhao W, Wang C, Feng S, Wang Y, Bi Y, Rong S, Shushakova N, Haller H, Chen J, Jiang H. SLAMF8 Participates in Acute Renal Transplant Rejection via TLR4 Pathway on Pro-Inflammatory Macrophages. Front Immunol 2022; 13:846695. [PMID: 35432371 PMCID: PMC9012444 DOI: 10.3389/fimmu.2022.846695] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 03/03/2022] [Indexed: 01/10/2023] Open
Abstract
Background Acute rejection (AR) in kidney transplantation is an established risk factor that reduces the survival rate of allografts. Despite standard immunosuppression, molecules with regulatory control in the immune pathway of AR can be used as important targets for therapeutic operations to prevent rejection. Methods We downloaded the microarray data of 15 AR patients and 37 non-acute rejection (NAR) patients from Gene Expression Omnibus (GEO). Gene network was constructed, and genes were classified into different modules using weighted gene co-expression network analysis (WGCNA). Kyoto Encyclopedia of Genes and Genomes (KEGG) and Cytoscape were applied for the hub genes in the most related module to AR. Different cell types were explored by xCell online database and single-cell RNA sequencing. We also validated the SLAMF8 and TLR4 levels in Raw264.7 and human kidney tissues of TCMR. Results A total of 1,561 differentially expressed genes were filtered. WGCNA was constructed, and genes were classified into 12 modules. Among them, the green module was most closely associated with AR. These genes were significantly enriched in 20 pathway terms, such as cytokine–cytokine receptor interaction, chemokine signaling pathway, and other important regulatory processes. Intersection with GS > 0.4, MM > 0.9, the top 10 MCC values and DEGs in the green module, and six hub genes (DOCK2, NCKAP1L, IL2RG, SLAMF8, CD180, and PTPRE) were identified. Their expression levels were all confirmed to be significantly elevated in AR patients in GEO, Nephroseq, and quantitative real-time PCR (qRT-PCR). Single-cell RNA sequencing showed that AR patient had a higher percentage of native T, CD1C+_B DC, NKT, NK, and monocytes in peripheral blood mononuclear cells (PBMCs). Xcell enrichment scores of 20 cell types were significantly different (p<0.01), mostly immune cells, such as B cells, CD4+ Tem, CD8+ T cells, CD8+ Tcm, macrophages, M1, and monocytes. GSEA suggests that highly expressed six hub genes are correlated with allograft rejection, interferon γ response, interferon α response, and inflammatory response. In addition, SLAMF8 is highly expressed in human kidney tissues of TCMR and in M1 phenotype macrophages of Raw264.7 cell line WGCNA accompanied by high expression of TLR4. Conclusion This study demonstrates six hub genes and functionally enriched pathways related to AR. SLAMF8 is involved in the M1 macrophages via TLR4, which contributed to AR process.
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Affiliation(s)
- Lisha Teng
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Nephropathy, Hangzhou, China
- Institute of Nephropathy, Zhejiang University, Hangzhou, China
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Lingling Shen
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Nephropathy, Hangzhou, China
- Institute of Nephropathy, Zhejiang University, Hangzhou, China
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Wenjun Zhao
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Nephropathy, Hangzhou, China
- Institute of Nephropathy, Zhejiang University, Hangzhou, China
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Cuili Wang
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Nephropathy, Hangzhou, China
- Institute of Nephropathy, Zhejiang University, Hangzhou, China
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Shi Feng
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Nephropathy, Hangzhou, China
- Institute of Nephropathy, Zhejiang University, Hangzhou, China
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Yucheng Wang
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Nephropathy, Hangzhou, China
- Institute of Nephropathy, Zhejiang University, Hangzhou, China
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Yan Bi
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Nephropathy, Hangzhou, China
- Institute of Nephropathy, Zhejiang University, Hangzhou, China
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Song Rong
- Department of Nephrology, Hannover Medical School, Hannover, Germany
| | - Nelli Shushakova
- Department of Nephrology, Hannover Medical School, Hannover, Germany
| | - Hermann Haller
- Department of Nephrology, Hannover Medical School, Hannover, Germany
| | - Jianghua Chen
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Nephropathy, Hangzhou, China
- Institute of Nephropathy, Zhejiang University, Hangzhou, China
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Hong Jiang
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Nephropathy, Hangzhou, China
- Institute of Nephropathy, Zhejiang University, Hangzhou, China
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
- *Correspondence: Hong Jiang,
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14
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Tawhari M, Radwi M. A Three-Year Experience With Overseas Kidney Transplantation in a Tertiary Transplant Center in Saudi Arabia. Cureus 2022; 14:e23988. [PMID: 35419250 PMCID: PMC8994614 DOI: 10.7759/cureus.23988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/09/2022] [Indexed: 11/06/2022] Open
Abstract
Background Overseas kidney transplantation is known to be associated with adverse outcomes. In this study, we aim to present a detailed analysis of our three years of experience with overseas kidney transplantation at one of the largest kidney transplant referral sites in the Kingdom of Saudi Arabia. Materials and methods A retrospective cohort study included patients who underwent kidney transplantation overseas and were subsequently followed up at King Abdulaziz Medical City from January 2016 to July 31, 2019. In addition, we compared the outcomes of the patients who underwent kidney transplantation overseas with a cohort of patients who were transplanted locally within the same period. Patients in both cohorts had to have at least one year of follow-up post-transplantation. Results We included a total of 51 patients who underwent kidney transplantation overseas. The mean age of the cohort was 44.7 years, and 69% were male. Almost 60% of the cohort had one or no comorbidity prior to transplant, with hypertension (84%) and diabetes mellitus (37%) being the leading comorbidities. The cause of end-stage kidney disease was unknown in 55% of our patients. In those who had an identifiable cause, lupus nephropathy and diabetes were the most common causes of kidney failure. In comparison with the locally transplanted cohort, no difference was detected between these groups in their baseline characteristics, type or number of comorbidities, medical or surgical complications postoperatively, and one-year mortality. However, we found that the graft rejection rate was significantly higher in patients transplanted overseas (OR=5.4, p<0.001). In addition, the proportion of patients who received anti-thymocyte globulin (ATG) induction was also less in the group with overseas kidney transplantation (58% vs. 22%, p<0.001). Conclusion Overseas transplantation is associated with an increased risk for graft rejection. Our study suggests that overseas kidney transplantation is possibly driven by a lack of donors, especially cadaveric. Counseling patients about risks associated with overseas kidney transplantation and encouraging the public to register for organ donation after death may help curb out this practice.
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Affiliation(s)
- Mohammed Tawhari
- Nephrology, King Abdulaziz Medical City, Riyadh, SAU
- Nephrology, King Abdullah International Medical Research Center, Riyadh, SAU
- Nephrology, King Saud Bin Abdulaziz University for Health Sciences, College of Medicine, Riyadh, SAU
| | - Mansoor Radwi
- Department of Hematology, University of Jeddah, College of Medicine, Jeddah, SAU
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15
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Pakfetrat M, Malekmakan L, Jafari N, Sayadi M. Survival Rate of Renal Transplant and Factors Affecting Renal Transplant Failure. EXP CLIN TRANSPLANT 2022; 20:265-272. [PMID: 35037612 DOI: 10.6002/ect.2021.0430] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES The most important complication in kidney transplant is acute/chronic rejection. In this study, we investigated the factors affecting kidney rejection and transplant survival. MATERIALS AND METHODS In this survival analysis study, 352 patients (mean follow-up of 12.9 ± 4.4 years) who underwent renal biopsy due to increased creatinine level from 2012 to 2016 were identified by glomerular filtration rate level and rejection. Probable factors affecting renal function and survival rate after transplant rejection were assessed. P < .05 was considered as significant. RESULTS Among our study patients, 40.9% developed early and 59.1% developed late acute kidney injury. Graft survival rates at 1 and 5 years were 98.9% and 68.5%, respectively, which was significant when rejection type was considered (P = .002). In addition, patient survival rates at 1 and 5 years were 99.7% and 98.6%, respectively. Graft survival at 5 years was significantly lower among older subjects, those with diabetes, those who received deceased donor organs, and those with late acute kidney injury (P < .002). Patient survival was significantly higher among young patients, those with systemic lupus erythematosus, those who received living donor organs, and those without cytomegalovirus infection (P < .003). CONCLUSIONS We observed that recipient age, type of donor, underlying disease, infection, and late acute kidney injury had great negative impacts on renal dysfunction and survival. In our center, because of the large number of kidney transplants from deceased donors, the necessity of antithymocyte globulin induction therapy was considered, since this study showed that patients who received rabbit antithymocyte globulin induction had better outcomes.
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Affiliation(s)
- Maryam Pakfetrat
- From the Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,From the Department of Nephrology, Shiraz University of Medical Sciences, Shiraz, Iran.,From the Emergency Medicine Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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16
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Deville KA, Seifert ME. Biomarkers of alloimmune events in pediatric kidney transplantation. Front Pediatr 2022; 10:1087841. [PMID: 36741087 PMCID: PMC9895094 DOI: 10.3389/fped.2022.1087841] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 12/28/2022] [Indexed: 01/21/2023] Open
Abstract
Alloimmune events such as the development of de novo donor-specific antibody (dnDSA), T cell-mediated rejection (TCMR), and antibody-mediated rejection (ABMR) are the primary contributors to kidney transplant failure in children. For decades, a creatinine-based estimated glomerular filtration rate (eGFR) has been the non-invasive gold standard biomarker for detecting clinically significant alloimmune events, but it suffers from low sensitivity and specificity, especially in smaller children and older allografts. Many clinically "stable" children (based on creatinine) will have alloimmune events known as "subclinical acute rejection" (based on biopsy) that merely reflect the inadequacy of creatinine-based estimates for alloimmune injury rather than a distinct phenotype from clinical rejection with allograft dysfunction. The poor biomarker performance of creatinine leads to many unnecessary surveillance and for-cause biopsies that could be avoided by integrating non-invasive biomarkers with superior sensitivity and specificity into current clinical paradigms. In this review article, we will present and appraise the current state-of-the-art in monitoring for alloimmune events in pediatric kidney transplantation. We will first discuss the current clinical standards for assessing the presence of alloimmune injury and predicting long-term outcomes. We will review principles of biomarker medicine and the application of comprehensive metrics to assess the performance of a given biomarker against the current gold standard. We will then highlight novel blood- and urine-based biomarkers (with special emphasis on pediatric biomarker studies) that have shown superior diagnostic and prognostic performance to the current clinical standards including creatinine-based eGFR. Finally, we will review some of the barriers to translating this research and implementing emerging biomarkers into common clinical practice, and present a transformative approach to using multiple biomarker platforms at different times to optimize the detection and management of critical alloimmune events in pediatric kidney transplant recipients.
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Affiliation(s)
- Kyle A Deville
- Division of Pediatric Nephrology, Department of Pediatrics, University of Alabama Heersink School of Medicine, Birmingham, AL, United States
| | - Michael E Seifert
- Division of Pediatric Nephrology, Department of Pediatrics, University of Alabama Heersink School of Medicine, Birmingham, AL, United States
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17
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Berchtold L, Filzer A, Achermann R, Devetzis V, Dahdal S, Bonani M, Schnyder A, Golshayan D, Amico P, Huynh-Do U, de Seigneux S, Arampatzis S, on behalf of Swiss Transplant Cohort Study Collaborators. Impact of Hyponatremia after Renal Transplantation on Decline of Renal Function, Graft Loss and Patient Survival: A Prospective Cohort Study. Nutrients 2021; 13:nu13092995. [PMID: 34578871 PMCID: PMC8468476 DOI: 10.3390/nu13092995] [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: 07/15/2021] [Revised: 08/19/2021] [Accepted: 08/25/2021] [Indexed: 12/02/2022] Open
Abstract
Background: Hyponatremia is one of the most common electrolyte disorders observed in hospitalized and ambulatory patients. Hyponatremia is associated with increased falls, fractures, prolonged hospitalisation and mortality. The clinical importance of hyponatremia in the renal transplant field is not well established, so the aim of this study was to determine the relationships between hyponatremia and mortality as main outcome and renal function decline and graft loss as secondary outcome among a prospective cohort of renal transplant recipients. Methods: This prospective cohort study included 1315 patients between 1 May 2008 and 31 December 2014. Hyponatremia was defined as sodium concentration below 136 mmol/L at 6 months after transplantation. The main endpoint was mortality. A secondary composite endpoint was also defined as: rapid decline in renal function (≥5 mL/min/1.73 m2 drop of the eGFR/year), graft loss or mortality. Results: Mean sodium was 140 ± 3.08 mmol/L. 97 patients displayed hyponatremia with a mean of 132.9 ± 3.05 mmol/L. Hyponatremia at 6 months after transplantation was associated neither with mortality (HR: 1.02; p = 0.97, 95% CI: 0.47–2.19), nor with the composite outcome defined as rapid decline in renal function, graft loss or mortality (logrank test p = 0.9). Conclusions: Hyponatremia 6 months after transplantation is not associated with mortality in kidney allograft patients.
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Affiliation(s)
- Lena Berchtold
- Service of Nephrology, Department of Internal Medicine Specialties, University Hospital of Geneva, 1205 Geneva, Switzerland; (L.B.); (S.d.S.)
| | - Anja Filzer
- University Clinic for Nephrology and Hypertension, Inselspital, Bern University Hospital of Bern, 3010 Bern, Switzerland; (A.F.); (V.D.); (S.D.); (U.H.-D.)
| | - Rita Achermann
- Department of Transplant Immunology and Nephrology, University Hospital Basel, 4031 Basel, Switzerland; (R.A.); (P.A.)
| | - Vasileios Devetzis
- University Clinic for Nephrology and Hypertension, Inselspital, Bern University Hospital of Bern, 3010 Bern, Switzerland; (A.F.); (V.D.); (S.D.); (U.H.-D.)
| | - Suzan Dahdal
- University Clinic for Nephrology and Hypertension, Inselspital, Bern University Hospital of Bern, 3010 Bern, Switzerland; (A.F.); (V.D.); (S.D.); (U.H.-D.)
| | - Marco Bonani
- Division of Nephrology, University Hospital Zurich, 8091 Zurich, Switzerland;
| | - Aurelia Schnyder
- Clinic for Nephrology and Transplant Medicine, Hospital of St. Gallen, 9007 St. Gallen, Switzerland;
| | - Dela Golshayan
- Centre for Organ Transplantation (CTO), 1011 Lausanne, Switzerland;
| | - Patrizia Amico
- Department of Transplant Immunology and Nephrology, University Hospital Basel, 4031 Basel, Switzerland; (R.A.); (P.A.)
| | - Uyen Huynh-Do
- University Clinic for Nephrology and Hypertension, Inselspital, Bern University Hospital of Bern, 3010 Bern, Switzerland; (A.F.); (V.D.); (S.D.); (U.H.-D.)
| | - Sophie de Seigneux
- Service of Nephrology, Department of Internal Medicine Specialties, University Hospital of Geneva, 1205 Geneva, Switzerland; (L.B.); (S.d.S.)
| | - Spyridon Arampatzis
- University Clinic for Nephrology and Hypertension, Inselspital, Bern University Hospital of Bern, 3010 Bern, Switzerland; (A.F.); (V.D.); (S.D.); (U.H.-D.)
- Correspondence: ; Tel.: +41-31-632-3111
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Luan D, Dadhania DM, Ding R, Muthukumar T, Lubetzky M, Lee JR, Sharma VK, August P, Mueller FB, Schwartz JE, Suthanthiran M. FOXP3 mRNA Profile Prognostic of Acute T Cell-mediated Rejection and Human Kidney Allograft Survival. Transplantation 2021; 105:1825-1839. [PMID: 33031221 PMCID: PMC8024419 DOI: 10.1097/tp.0000000000003478] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND T cell-mediated rejection (TCMR) is the most frequent type of acute rejection and is associated with kidney allograft failure. Almost 40% of TCMR episodes are nonresponsive to therapy, and molecular mechanisms for the nonresponsiveness are unknown. Our single-center study identified that urinary cell FOXP3 mRNA abundance predicts TCMR reversibility and allograft survival. METHODS We developed PCR assays and measured absolute copy numbers of transcripts for FOXP3, CD25, CD3E, perforin, and 18S rRNA in 3559 urines from 480 kidney allograft recipients prospectively enrolled in the multicenter Clinical Trials in Organ Transplantation-04. In this replication study, we investigated the association between mRNA profile and TCMR diagnosis, TCMR reversibility, and allograft survival. RESULTS 18S rRNA normalized levels of mRNA for FOXP3 (P = 0.01, Kruskal-Wallis test), CD25 (P = 0.01), CD3E (P < 0.0001), and perforin (P < 0.0001) were diagnostic of TCMR, but only FOXP3 mRNA level predicted TCMR reversibility (ROC AUC = 0.764; 95% confidence interval, 0.611-0.917; P = 0.008). Multivariable logistic regression analyses showed that urinary cell FOXP3 mRNA level predicted reversal, independent of clinical variables. A composite model of clinical variables and FOXP3 mRNA (AUC = 0.889; 95% CI, 0.781-0.997; P < 0.001) outperformed FOXP3 mRNA or clinical variables in predicting TCMR reversibility (P = 0.01, likelihood ratio test). Multivariable Cox proportional hazards regression analyses showed that FOXP3 mRNA level predicts kidney allograft survival (P = 0.047) but not after controlling for TCMR reversal (P = 0.477). CONCLUSIONS Urinary cell level of FOXP3 mRNA is diagnostic of TCMR, predicts TCMR reversibility, and is prognostic of kidney allograft survival via a mechanism involving TCMR reversal.
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Affiliation(s)
- Danny Luan
- Division of Nephrology and Hypertension, Department of Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, NY, USA
| | - Darshana M. Dadhania
- Division of Nephrology and Hypertension, Department of Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, NY, USA
- Department of Transplantation Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, NY, USA
| | - Ruchuang Ding
- Division of Nephrology and Hypertension, Department of Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, NY, USA
| | - Thangamani Muthukumar
- Division of Nephrology and Hypertension, Department of Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, NY, USA
- Department of Transplantation Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, NY, USA
| | - Michelle Lubetzky
- Division of Nephrology and Hypertension, Department of Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, NY, USA
- Department of Transplantation Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, NY, USA
| | - John R. Lee
- Division of Nephrology and Hypertension, Department of Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, NY, USA
- Department of Transplantation Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, NY, USA
| | - Vijay K. Sharma
- Division of Nephrology and Hypertension, Department of Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, NY, USA
| | - Phyllis August
- Division of Nephrology and Hypertension, Department of Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, NY, USA
- Department of Transplantation Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, NY, USA
| | - Franco B. Mueller
- Division of Nephrology and Hypertension, Department of Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, NY, USA
| | - Joseph E. Schwartz
- Division of Nephrology and Hypertension, Department of Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, NY, USA
- Department of Psychiatry and Behavioral Health, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, USA
| | - Manikkam Suthanthiran
- Division of Nephrology and Hypertension, Department of Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, NY, USA
- Department of Transplantation Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, NY, USA
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19
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Differentiating Acute Rejection From Preeclampsia After Kidney Transplantation. Obstet Gynecol 2021; 137:1023-1031. [PMID: 33957644 DOI: 10.1097/aog.0000000000004389] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 03/15/2021] [Indexed: 11/25/2022]
Abstract
OBJECTIVE To evaluate the clinical and laboratory characteristics in pregnancy that differentiate preeclampsia from acute renal allograft rejection and to investigate the maternal, neonatal, and graft sequelae of these diagnoses. METHODS We conducted a retrospective case-controlled registry study of data abstracted from Transplant Pregnancy Registry International deliveries between 1968 and 2019. All adult kidney transplant recipients with singleton pregnancies of at least 20 weeks of gestation were included. Acute rejection was biopsy proven and preeclampsia was diagnosed based on contemporary criteria. Variables were compared using χ2, Fisher exact, and Wilcoxon rank sum tests as appropriate. Multivariable linear regression was used to analyze preterm birth. Kaplan-Meier curves with log-rank test and Cox proportional hazards model were used to compare graft loss over time. RESULTS There were 26 pregnant women with biopsy-confirmed acute rejection who were matched by the year they conceived to 78 pregnant women with preeclampsia. Recipients with acute rejection had elevated peripartum serum creatinine levels (73% vs 14%, P<.001), with median intrapartum creatinine of 3.90 compared with 1.15 mg/dL (P<.001). Conversely, only patients with preeclampsia had a significant increase in proteinuria from baseline. Although there were no significant differences in maternal outcomes, graft loss within 2 years postpartum (42% vs 10%) and long-term graft loss (73% vs 35%) were significantly increased in recipients who experienced acute rejection (P<.001 for both). The frequency of delivery before 32 weeks of gestation was 53% with acute rejection and 20% with preeclampsia. After controlling for hypertension and immunosuppressant use, acute rejection was associated with higher frequency of delivery at less than 32 weeks of gestation (adjusted odds ratio 4.04, 95% CI 1.10-15.2). CONCLUSION In pregnancy, acute rejection is associated with higher creatinine levels, and preeclampsia is associated with increased proteinuria. Acute rejection in pregnancy carries a risk of prematurity and graft loss beyond that of preeclampsia for kidney transplant recipients. FUNDING SOURCE The Transplant Pregnancy Registry International is supported in part by an educational grant from Veloxis Pharmaceuticals.
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20
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Pai A, Swan JT, Wojciechowski D, Qazi Y, Dholakia S, Shekhtman G, Abou-Ismail A, Kumar D. Clinical Rationale for a Routine Testing Schedule Using Donor-Derived Cell-Free DNA After Kidney Transplantation. Ann Transplant 2021; 26:e932249. [PMID: 34210952 PMCID: PMC8259349 DOI: 10.12659/aot.932249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Kidney transplant recipients require meticulous clinical and laboratory surveillance to monitor allograft health. Conventional biomarkers, including serum creatinine and proteinuria, are lagging indicators of allograft injury, often rising only after significant and potentially irreversible damage has occurred. Immunosuppressive medication levels can be followed, but their utility is largely limited to guiding dosing changes or assessing adherence. Kidney biopsy, the criterion standard for the diagnosis and characterization of injury, is invasive and thus poorly suited for frequent surveillance. Donor-derived cell-free DNA (dd-cfDNA) is a sensitive, noninvasive, leading indicator of allograft injury, which offers the opportunity for expedited intervention and can improve long-term allograft outcomes. This article describes the clinical rationale for a routine testing schedule utilizing dd-cfDNA surveillance at months 1, 2, 3, 4, 6, 9, and 12 during the first year following kidney transplantation and quarterly thereafter. These time points coincide with major immunologic transition points after transplantation and provide clinicians with molecular information to help inform decision making.
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Affiliation(s)
- Akshta Pai
- Division of Renal Diseases and Hypertension, University of Texas McGovern Medical School, Houston, TX, USA
| | - Joshua T Swan
- Department of Pharmacy, Houston Methodist, Houston, TX, USA.,Department of Surgery Research and Center for Outcomes Research, Houston Methodist Academic Institute, Houston, TX, USA
| | - David Wojciechowski
- Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Yasir Qazi
- Division of Nephrology, University of Southern California, Los Angeles, CA, USA
| | | | | | | | - Dhiren Kumar
- Division of Nephrology, Virginia Commonwealth University, Richmond, VA, USA
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21
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El Fekih R, Hurley J, Tadigotla V, Alghamdi A, Srivastava A, Coticchia C, Choi J, Allos H, Yatim K, Alhaddad J, Eskandari S, Chu P, Mihali AB, Lape IT, Lima Filho MP, Aoyama BT, Chandraker A, Safa K, Markmann JF, Riella LV, Formica RN, Skog J, Azzi JR. Discovery and Validation of a Urinary Exosome mRNA Signature for the Diagnosis of Human Kidney Transplant Rejection. J Am Soc Nephrol 2021; 32:994-1004. [PMID: 33658284 PMCID: PMC8017553 DOI: 10.1681/asn.2020060850] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 12/26/2020] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Developing a noninvasive clinical test to accurately diagnose kidney allograft rejection is critical to improve allograft outcomes. Urinary exosomes, tiny vesicles released into the urine that carry parent cells' proteins and nucleic acids, reflect the biologic function of the parent cells within the kidney, including immune cells. Their stability in urine makes them a potentially powerful tool for liquid biopsy and a noninvasive diagnostic biomarker for kidney-transplant rejection. METHODS Using 192 of 220 urine samples with matched biopsy samples from 175 patients who underwent a clinically indicated kidney-transplant biopsy, we isolated urinary exosomal mRNAs and developed rejection signatures on the basis of differential gene expression. We used crossvalidation to assess the performance of the signatures on multiple data subsets. RESULTS An exosomal mRNA signature discriminated between biopsy samples from patients with all-cause rejection and those with no rejection, yielding an area under the curve (AUC) of 0.93 (95% CI, 0.87 to 0.98), which is significantly better than the current standard of care (increase in eGFR AUC of 0.57; 95% CI, 0.49 to 0.65). The exosome-based signature's negative predictive value was 93.3% and its positive predictive value was 86.2%. Using the same approach, we identified an additional gene signature that discriminated patients with T cell-mediated rejection from those with antibody-mediated rejection (with an AUC of 0.87; 95% CI, 0.76 to 0.97). This signature's negative predictive value was 90.6% and its positive predictive value was 77.8%. CONCLUSIONS Our findings show that mRNA signatures derived from urinary exosomes represent a powerful and noninvasive tool to screen for kidney allograft rejection. This finding has the potential to assist clinicians in therapeutic decision making.
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Affiliation(s)
- Rania El Fekih
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - James Hurley
- Exosome Diagnostics, a Bio-Techne brand, Waltham, Massachusetts
| | | | - Areej Alghamdi
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - Anand Srivastava
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts
| | | | - John Choi
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - Hazim Allos
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - Karim Yatim
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - Juliano Alhaddad
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - Siawosh Eskandari
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - Philip Chu
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - Albana B. Mihali
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - Isadora T. Lape
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - Mauricio P. Lima Filho
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - Bruno T. Aoyama
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - Anil Chandraker
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - Kassem Safa
- Transplant Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - James F. Markmann
- Transplant Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Leonardo V. Riella
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts
| | | | - Johan Skog
- Exosome Diagnostics, a Bio-Techne brand, Waltham, Massachusetts
| | - Jamil R. Azzi
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts
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22
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Rahimishahmirzadi M, Jevnikar AM, House AA, Luke PP, Humar A, Silverman MS, Shalhoub SM, Hosseini-Moghaddam SM. Late-onset allograft rejection, cytomegalovirus infection, and renal allograft loss: Is anti-CMV prophylaxis required following late-onset allograft rejection? Clin Transplant 2021; 35:e14285. [PMID: 33713374 DOI: 10.1111/ctr.14285] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 02/09/2021] [Accepted: 03/08/2021] [Indexed: 11/29/2022]
Abstract
Renal transplant recipients remain at risk of delayed-onset cytomegalovirus (CMV) infection occurring beyond a complete course of prophylaxis. In this retrospective cohort, all 278 patients who received renal allografts from deceased donors from 2014 to 2016 were followed until September 1, 2019. We determined the effect of early-vs late-onset acute rejection (EAR vs LAR [ie, occurring beyond 12 months after transplantation]) on CMV infection and subsequently long-term allograft outcome. Median (IQR) duration of follow-up was 1186.0 (904.7-1531.2) days. Seventy patients including 49 patients with EAR and 21 with LAR received augmented immunosuppression. In the same interval, 40 patients developed CMV infection (36 patients beyond 90 days after transplantation [90%]). In logistic regression analysis, D+/R- CMV serostatus (OR: 5.5, 95% CI: 2.5-12.2) and LAR (OR: 7.9, 95% CI: 2.8-22.2) significantly increased the risk of CMV infection. In Cox proportional hazard model, delayed-onset CMV infection (HR: 2.51, 95% CI: 1.08-5.86) and LAR (HR: 5.46, 95% CI: 2.26-13.14) significantly increased the risk of allograft loss. Patients with LAR are at risk of late-onset CMV infection. Post-LAR, targeted prophylaxis may reduce the risk of CMV infection and subsequently allograft loss. Further studies are required to demonstrate the effect of targeted prophylaxis following LAR.
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Affiliation(s)
| | - Anthony M Jevnikar
- Multiorgan Transplant Program, London Health Sciences Centre, Western University, London, ON, Canada
| | - Andrew A House
- Multiorgan Transplant Program, London Health Sciences Centre, Western University, London, ON, Canada
| | - Patrick P Luke
- Multiorgan Transplant Program, London Health Sciences Centre, Western University, London, ON, Canada
| | - Atul Humar
- Division of Infectious Diseases, Transplant Infectious Diseases Program, University Health Network, Toronto, ON, Canada.,Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Michael S Silverman
- Division of Infectious Diseases, Department of Medicine, Western University, London, ON, Canada
| | - Sarah M Shalhoub
- Multiorgan Transplant Program, London Health Sciences Centre, Western University, London, ON, Canada.,Division of Infectious Diseases, Department of Medicine, Western University, London, ON, Canada
| | - Seyed M Hosseini-Moghaddam
- Multiorgan Transplant Program, London Health Sciences Centre, Western University, London, ON, Canada.,Division of Infectious Diseases, Department of Medicine, Western University, London, ON, Canada.,Division of Infectious Diseases, Transplant Infectious Diseases Program, University Health Network, Toronto, ON, Canada.,Department of Medicine, University of Toronto, Toronto, ON, Canada
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23
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Hundemer GL, Srivastava A, Jacob KA, Krishnasamudram N, Ahmed S, Boerger E, Sharma S, Pokharel KK, Hirji SA, Pelletier M, Safa K, Kulvichit W, Kellum JA, Riella LV, Leaf DE. Acute kidney injury in renal transplant recipients undergoing cardiac surgery. Nephrol Dial Transplant 2021; 36:185-196. [PMID: 32892219 DOI: 10.1093/ndt/gfaa063] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Acute kidney injury (AKI) is a key risk factor for chronic kidney disease in the general population, but has not been investigated in detail among renal transplant recipients (RTRs). We investigated the incidence, severity and risk factors for AKI following cardiac surgery among RTRs compared with non-RTRs with otherwise similar clinical characteristics. METHODS We conducted a retrospective cohort study of RTRs (n = 83) and non-RTRs (n = 83) who underwent cardiac surgery at two major academic medical centers. Non-RTRs were matched 1:1 to RTRs by age, preoperative (preop) estimated glomerular filtration rate and type of cardiac surgery. We defined AKI according to Kidney Disease: Improving Global Outcomes criteria. RESULTS RTRs had a higher rate of AKI following cardiac surgery compared with non-RTRs [46% versus 28%; adjusted odds ratio 2.77 (95% confidence interval 1.36-5.64)]. Among RTRs, deceased donor (DD) versus living donor (LD) status, as well as higher versus lower preop calcineurin inhibitor (CNI) trough levels, were associated with higher rates of AKI (57% versus 33% among DD-RTRs versus LD-RTRs; P = 0.047; 73% versus 36% among RTRs with higher versus lower CNI trough levels, P = 0.02). The combination of both risk factors (DD status and higher CNI trough level) had an additive effect (88% AKI incidence among patients with both risk factors versus 25% incidence among RTRs with neither risk factor, P = 0.004). CONCLUSIONS RTRs have a higher risk of AKI following cardiac surgery compared with non-RTRs with otherwise similar characteristics. Among RTRs, DD-RTRs and those with higher preop CNI trough levels are at the highest risk.
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Affiliation(s)
- Gregory L Hundemer
- Division of Renal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.,Division of Nephrology, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada
| | - Anand Srivastava
- Division of Renal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.,Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Kirolos A Jacob
- Department of Cardiothoracic Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Neeraja Krishnasamudram
- Division of Renal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Salman Ahmed
- Division of Renal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Emily Boerger
- Division of Renal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Shreyak Sharma
- Division of Renal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Kapil K Pokharel
- Division of Renal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Sameer A Hirji
- Division of Cardiac Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Marc Pelletier
- Division of Cardiac Surgery, University Hospitals, Case Western Reserve University, Cleveland, OH, USA
| | - Kassem Safa
- Transplant Center and Division of Nephrology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Win Kulvichit
- Department of Critical Care Medicine, Center for Critical Care Nephrology, University of Pittsburgh, Pittsburgh, PA, USA
| | - John A Kellum
- Department of Critical Care Medicine, Center for Critical Care Nephrology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Leonardo V Riella
- Division of Renal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - David E Leaf
- Division of Renal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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24
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Zhang H, Wang Z, Zhang J, Gui Z, Han Z, Tao J, Chen H, Sun L, Fei S, Yang H, Tan R, Chandraker A, Gu M. Combined Immunotherapy With Belatacept and BTLA Overexpression Attenuates Acute Rejection Following Kidney Transplantation. Front Immunol 2021; 12:618737. [PMID: 33732243 PMCID: PMC7959759 DOI: 10.3389/fimmu.2021.618737] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Accepted: 01/14/2021] [Indexed: 01/11/2023] Open
Abstract
Background Costimulatory blockade provides new therapeutic opportunities for ensuring the long-term survival of kidney grafts. The adoption of the novel immunosuppressant Belatacept has been limited, partly due to concerns regarding higher rates and grades of acute rejection in clinical trials. In this study, we hypothesized that a combined therapy, Belatacept combined with BTLA overexpression, may effectively attenuate acute rejection after kidney transplantation. Materials and Methods The rat kidney transplantation model was used to investigate graft rejection in single and combined therapy. Graft function was analyzed by detecting serum creatinine. Pathological staining was used to observe histological changes in grafts. The expression of T cells was observed by immunohistochemistry and flow cytometry. In vitro, we constructed an antigen-stimulated immune response by mixed lymphocyte culture, treated with or without Belatacept and BTLA-overexpression adenovirus, to observe the proliferation of receptor cells and the expression of cytokines. In addition, western blot and qRT-PCR analyses were performed to evaluate the expression of CTLA-4 and BTLA at various time points during the immune response. Results In rat models, combined therapy reduced the serum creatinine levels and prolonged graft survival compared to single therapy and control groups. Mixed acute rejection was shown in the allogeneic group and inhibited by combination treatment. Belatacept reduced the production of DSA and the deposition of C4d in grafts. Belatacept combined with BTLA overexpression downregulated the secretion of IL-2 and IFN-γ, as well as increasing IL-4 and IL-10 expression. We also found that Belatacept combined with BTLA overexpression inhibited the proliferation of spleen lymphocytes. The duration of the elevated expression levels of CTLA-4 and BTLA differentially affected the immune response. Conclusion Belatacept combined with BTLA overexpression attenuated acute rejection after kidney transplantation and prolonged kidney graft survival, which suggests a new approach for the optimization of early immunosuppression after kidney transplantation.
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Affiliation(s)
- Hengcheng Zhang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Zijie Wang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jiayi Zhang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zeping Gui
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhijian Han
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jun Tao
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hao Chen
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Li Sun
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Shuang Fei
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Haiwei Yang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ruoyun Tan
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Anil Chandraker
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Min Gu
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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25
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Outcomes of kidney transplantation over a 16-year period in Korea: An analysis of the National Health Information Database. PLoS One 2021; 16:e0247449. [PMID: 33606787 PMCID: PMC7894945 DOI: 10.1371/journal.pone.0247449] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 02/06/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND This study investigated the outcomes of kidney transplantation (KT) over a 16-year period in Korea and identified risk factors for graft failure using a nationwide population-based cohort. METHODS We investigated the Korean National Health Insurance Service-National Health Information Database. Health insurance claims for patients who underwent KT between 2002 and 2017 were analyzed. RESULTS The data from 18,331 patients who underwent their first KT were reviewed. The percentage of antithymocyte globulin (ATG) induction continuously increased from 2.0% in 2002 to 23.5% in 2017. Rituximab began to be used in 2008 and had increased to 141 patients (9.6%) in 2013. Acute rejection occurred in 17.3% of all patients in 2002 but decreased to 6.3% in 2017. The rejection-free survival rates were 78.8% at 6 months after KT, 76.1% after 1 year, 67.5% after 5 years, 61.7% after 10 years, and 56.7% after 15 years. The graft survival rates remained over 80% until 12 years after KT, and then rapidly decreased to 50.5% at 16 years after KT. In Cox's multivariate analysis, risk factors for graft failure included being male, more recent KT, KT from deceased donor, use of ATG, basiliximab, or rituximab, tacrolimus use as an initial calcineurin inhibitor, acute rejection history, and cytomegalovirus infection. CONCLUSIONS ATG and rituximab use has gradually increased in Korea and more recent KT is associated with an increased risk of graft failure. Therefore, meticulous preoperative evaluation and postoperative management are necessary in the case of recent KT with high risk of graft failure.
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26
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A Propensity Score-weighted Comparison of Outcomes Between Living and Standard Criteria Deceased Donor Kidney Transplant Recipients. Transplantation 2021; 104:e317-e327. [PMID: 32496358 DOI: 10.1097/tp.0000000000003337] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND Consider a theoretical situation in which 2 patients with similar baseline characteristics receive a kidney transplant on the same day: 1 from a standard criteria deceased donor, the other from a living donor. Which kidney transplant will last longer? METHODS We conducted a population-based cohort study using linked administrative healthcare databases from Ontario, Canada, from January 1, 2005, to March 31, 2014, to evaluate several posttransplant outcomes in individuals who received a kidney transplant from a standard criteria deceased donor (n = 1523) or from a living donor (n = 1373). We used PS weighting using overlap weights, a novel weighting method that emphasizes the population of recipients with the most overlap in baseline characteristics. RESULTS Compared with recipients of a living donor, the rate of all-cause graft failure was not statistically higher for recipients of a standard criteria deceased donor (hazard ratio, 1.1; 95% confidence interval [CI], 0.8-1.6). Recipients of a standard criteria deceased donor, compared with recipients of a living donor had a higher rate of delayed graft function (23.6% versus 18.7%; odds ratio, 1.3; 95% CI, 1.0-1.6) and a longer length of stay for the kidney transplant surgery (mean difference, 1.7 d; 95% CI, 0.5-3.0). CONCLUSIONS After accounting for many important donor and recipient factors, we failed to observe a large difference in the risk of all-cause graft failure for recipients of a standard criteria deceased versus living donor. Some estimates were imprecise, which meant we could not rule out the presence of smaller clinically important effects.
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Benjamens S, Alghamdi SZ, Rijkse E, te Velde-Keyzer CA, Berger SP, Moers C, de Borst MH, Slart RHJA, Dor FJMF, Minnee RC, Pol RA. Aorto-Iliac Artery Calcification and Graft Outcomes in Kidney Transplant Recipients. J Clin Med 2021; 10:325. [PMID: 33477285 PMCID: PMC7829792 DOI: 10.3390/jcm10020325] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 01/09/2021] [Accepted: 01/14/2021] [Indexed: 12/22/2022] Open
Abstract
While the association of vascular calcification with inferior patient outcomes in kidney transplant recipients is well-established, the association with graft outcomes has received less attention. With this dual-centre cohort study, we aimed to determine the clinical impact of recipient pre-transplant aorto-iliac calcification, measured on non-contrast enhanced computed tomography (CT)-imaging within three years prior to transplantation (2005-2018). We included 547 patients (61.4% male, age 60 (interquartile range 51-68) years), with a median follow-up of 3.1 (1.4-5.2) years after transplantation. The aorto-iliac calcification score (CaScore) was inversely associated with one-year estimated-glomerular filtration rate (eGFR) in univariate linear regression analysis (standard β -3.3 (95% CI -5.1 to -1.5, p < 0.0001), but not after adjustment for potential confounders, including donor and recipient age (p = 0.077). In multivariable Cox regression analyses, a high CaScore was associated with overall graft failure (p = 0.004) and death with a functioning graft (p = 0.002), but not with death-censored graft failure and graft function decline. This study demonstrated that pre-transplant aorto-iliac calcification is associated with one-year eGFR in univariate, but not in multivariable linear regression analyses. Moreover, this study underlines that transplantation in patients with a high CaScore does not result in earlier transplant function decline or worse death censored graft survival, although ongoing efforts for the prevention of death with a functioning graft remain essential.
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Affiliation(s)
- Stan Benjamens
- Department of Surgery, Division of Transplant Surgery, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; (S.Z.A.); (C.M.); (R.A.P.)
- Medical Imaging Center, Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands;
| | - Saleh Z. Alghamdi
- Department of Surgery, Division of Transplant Surgery, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; (S.Z.A.); (C.M.); (R.A.P.)
| | - Elsaline Rijkse
- Department of Surgery, Division of HPB and Transplant Surgery, Erasmus MC University Medical Center, 3015 CE Rotterdam, The Netherlands; (E.R.); (R.C.M.)
| | - Charlotte A. te Velde-Keyzer
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; (C.A.t.V.-K.); (S.P.B.); (M.H.d.B.)
| | - Stefan P. Berger
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; (C.A.t.V.-K.); (S.P.B.); (M.H.d.B.)
| | - Cyril Moers
- Department of Surgery, Division of Transplant Surgery, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; (S.Z.A.); (C.M.); (R.A.P.)
| | - Martin H. de Borst
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; (C.A.t.V.-K.); (S.P.B.); (M.H.d.B.)
| | - Riemer H. J. A. Slart
- Medical Imaging Center, Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands;
- Department of Biomedical Photonic Imaging, Faculty of Science and Technology, University of Twente, 7522 NB Enschede, The Netherlands
| | - Frank J. M. F. Dor
- Imperial College Renal and Transplant Centre, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London W12 0HS, UK;
- Department of Surgery & Cancer, Imperial College, London SW7 2BU, UK
| | - Robert C. Minnee
- Department of Surgery, Division of HPB and Transplant Surgery, Erasmus MC University Medical Center, 3015 CE Rotterdam, The Netherlands; (E.R.); (R.C.M.)
| | - Robert A. Pol
- Department of Surgery, Division of Transplant Surgery, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; (S.Z.A.); (C.M.); (R.A.P.)
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Massicotte-Azarniouch D, Sood MM, Fergusson DA, Knoll GA. Validation of the International Classification of Disease 10th Revision Codes for Kidney Transplant Rejection and Failure. Can J Kidney Health Dis 2020; 7:2054358120977390. [PMID: 33403117 PMCID: PMC7747098 DOI: 10.1177/2054358120977390] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 10/29/2020] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Clinical research requires that diagnostic codes captured from routinely collected health administrative data accurately identify individuals with a disease. OBJECTIVE In this study, we validated the International Classification of Disease 10th Revision (ICD-10) definition for kidney transplant rejection (T86.100) and for kidney transplant failure (T86.101). DESIGN Retrospective cohort study. SETTING A large, regional transplantation center in Ontario, Canada. PATIENTS All adult kidney transplant recipients from 2002 to 2018. MEASUREMENTS Chart review was undertaken to identify the first occurrence of biopsy-confirmed rejection and graft loss for all participants. For each observation, we determined the first date a single ICD-10 code T86.100 or T86.101 was recorded as a hospital encounter discharge diagnosis. METHODS Using chart review as the gold standard, we determined the sensitivity, specificity, and positive predictive value (PPV) for the ICD-10 codes T86.100 and T86.101. RESULTS Our study population comprised of 1,258 kidney transplant recipients. The prevalence of rejection and death-censored graft loss were 15.6 and 9.1%, respectively. For the ICD-10 rejection code (T86.100), sensitivity was 72.9% (95% confidence interval [CI], 66.6-79.2), specificity 97.5% (96.5-98.4), and PPV 83.8% (78.3-89.4). For the ICD-10 graft loss code (T86.101), sensitivity was 21.2% (95% CI, 13.2-29.3), specificity 86.3% (84.3-88.3), and PPV 11.7% (7.0-16.4). LIMITATIONS Single-center study which may limit generalizability of our findings. CONCLUSIONS A single ICD-10 code for kidney transplant rejection (T86.100) was present in 84% of true kidney transplant rejections and is an accurate way of identifying kidney transplant recipients with rejection using administrative health data. The ICD-10 code for graft failure (T86.101) performed poorly and should not be used for administrative health research.
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Affiliation(s)
| | - Manish M. Sood
- Division of Nephrology, Kidney Research Center, Department of Medicine, University of Ottawa, ON, Canada
| | - Dean A. Fergusson
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, ON, Canada
| | - Greg A. Knoll
- Division of Nephrology, Kidney Research Center, Department of Medicine, University of Ottawa, ON, Canada
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Good-Weber M, Roos M, Mueller TF, Rüsi B, Fehr T. Tailored immunosuppression after kidney transplantation - a single center real-life experience. BMC Nephrol 2020; 21:501. [PMID: 33228545 PMCID: PMC7686677 DOI: 10.1186/s12882-020-02137-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 10/29/2020] [Indexed: 11/30/2022] Open
Abstract
Background Kidney allograft survival continuously improved with introduction of novel immunosuppressants. However, also immunologically challenging transplants (blood group incompatibility and sensitized recipients) increase. Between 2006 and 2008, a new tailored immunosuppression scheme for kidney transplantation was implemented at the University Hospital in Zurich, together with an ABO-incompatible transplant program and systematic pre- and posttransplant anti-human leukocyte antigen (HLA) antibody screening by Luminex technology. This study retrospectively evaluated the results of this tailored immunosuppression approach with a particular focus on immunologically higher risk transplants. Methods A total of 204 consecutive kidney transplantations were analyzed, of whom 14 were ABO-incompatible and 35 recipients were donor-specific anti-HLA antibodies (DSA) positive, but complement-dependent cytotoxicity crossmatch (CDC-XM) negative. We analyzed patient and graft survival, acute rejection rates and infectious complications in ABO-compatible versus -incompatible and in DSA positive versus negative patients and compared those with a historical control group. Results Overall patient, death-censored allograft survival and non-death-censored allograft survival at 4 years were 92, 91 and 87%, respectively. We found that (1) there were no differences between ABO-compatible and -incompatible and between DSA positive and DSA negative patients concerning acute rejection rate and graft survival; (2) compared with the historical control group there was a significant decrease of acute rejection rates in sensitized patients who received an induction with thymoglobulin; (3) there was no increased rate of infection among the patients who received induction with thymoglobulin compared to no induction therapy. Conclusions We observed excellent overall mid-term patient and graft survival rates with our tailored immunosuppression approach. Induction with thymoglobulin was efficient and safe in keeping rejection rates low in DSA positive patients with a negative CDC-XM. Supplementary Information The online version contains supplementary material available at 10.1186/s12882-020-02137-5.
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Affiliation(s)
- Miriam Good-Weber
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Malgorzata Roos
- Department of Biostatistics, Epidemiology, Biostatistics and Prevention Institute, University Zurich, Zurich, Switzerland
| | - Thomas F Mueller
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Barbara Rüsi
- HLA Typing Laboratory, University Hospital Zurich, Zurich, Switzerland
| | - Thomas Fehr
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland. .,Department of Internal Medicine, Cantonal Hospital Graubünden, Loestrasse 170, 7000, Chur, Switzerland.
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Liposomal Delivery Improves the Efficacy of Prednisolone to Attenuate Renal Inflammation in a Mouse Model of Acute Renal Allograft Rejection. Transplantation 2020; 104:744-753. [PMID: 31929419 PMCID: PMC7147400 DOI: 10.1097/tp.0000000000003060] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Supplemental Digital Content is available in the text. Background. Systemic exposure to high-dose corticosteroids effectively combats acute rejection after kidney transplantation, but at the cost of substantial side effects. In this study, a murine acute renal allograft rejection model was used to investigate whether liposomal-encapsulated prednisolone (LP) facilitates local exposure to enhance its therapeutic effect. Methods. Male BalbC recipients received renal allografts from male C57BL/6J donors. Recipients were injected daily with 5 mg/kg cyclosporine A and received either 10 mg/kg prednisolone (P), or LP intravenously on day 0, 3, and 6, or no additional treatment. Functional magnetic resonance imaging (fMRI) was performed on day 6 to study allograft perfusion and organs were retrieved on day 7 for further analysis. Results. Staining of polyethylene-glycol-labeled liposomes and high performance liquid chromatography analysis revealed accumulation in the LP treated allograft. LP treatment induced the expression of glucocorticoid responsive gene Fkbp5 in the allograft. Flow-cytometry of allografts revealed liposome presence in CD45+ cells, and reduced numbers of F4/80+ macrophages, and CD3+ T-lymphocytes upon LP treatment. Banff scoring showed reduced interstitial inflammation and tubulitis and fMRI analysis revealed improved allograft perfusion in LP versus NA mice. Conclusions. Liposomal delivery of prednisolone improved renal bio-availability, increased perfusion and reduced cellular infiltrate in the allograft, when compared with conventional prednisolone. Clinical studies should reveal if treatment with LP results in improved efficacy and reduced side effects in patients with renal allograft rejection.
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Yi Z, Keung KL, Li L, Hu M, Lu B, Nicholson L, Jimenez-Vera E, Menon MC, Wei C, Alexander S, Murphy B, O’Connell PJ, Zhang W. Key driver genes as potential therapeutic targets in renal allograft rejection. JCI Insight 2020; 5:136220. [PMID: 32634125 PMCID: PMC7455082 DOI: 10.1172/jci.insight.136220] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 06/24/2020] [Indexed: 01/09/2023] Open
Abstract
Acute rejection (AR) in renal transplantation is an established risk factor for reduced allograft survival. Molecules with regulatory control among immune pathways of AR that are inadequately suppressed, despite standard-of-care immunosuppression, could serve as important targets for therapeutic manipulation to prevent rejection. Here, an integrative, network-based computational strategy incorporating gene expression and genotype data of human renal allograft biopsy tissue was applied, to identify the master regulators - the key driver genes (KDGs) - within dysregulated AR pathways. A 982-meta-gene signature with differential expression in AR versus non-AR was identified from a meta-analysis of microarray data from 735 human kidney allograft biopsy samples across 7 data sets. Fourteen KDGs were derived from this signature. Interrogation of 2 publicly available databases identified compounds with predicted efficacy against individual KDGs or a key driver-based gene set, respectively, which could be repurposed for AR prevention. Minocycline, a tetracycline antibiotic, was chosen for experimental validation in a murine cardiac allograft model of AR. Minocycline attenuated the inflammatory profile of AR compared with controls and when coadministered with immunosuppression prolonged graft survival. This study demonstrates that a network-based strategy, using expression and genotype data to predict KDGs, assists target prioritization for therapeutics in renal allograft rejection.
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Affiliation(s)
- Zhengzi Yi
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Karen L. Keung
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia
- Department of Nephrology, Prince of Wales Hospital, Sydney, Australia
| | - Li Li
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Sema4, Stamford, Connecticut, Connecticut, USA
| | - Min Hu
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, Australia
| | - Bo Lu
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia
| | - Leigh Nicholson
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia
| | - Elvira Jimenez-Vera
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia
| | - Madhav C. Menon
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Chengguo Wei
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Stephen Alexander
- Faculty of Medicine and Health, University of Sydney, Sydney, Australia
- Nephrology Department, The Children’s Hospital at Westmead, Sydney, Australia
| | - Barbara Murphy
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Philip J. O’Connell
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, Australia
- Department of Nephrology, Westmead Hospital, Sydney, Australia
| | - Weijia Zhang
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Noppakun K, Kittipanyaworakun T, Ruengorn C, Vongsanim S, Saikam A, Khamlueang N. Plasma volume treated with double filtration plasmapheresis and outcomes of acute antibody-mediated rejection in kidney transplant recipients: A retrospective cohort study. Ther Apher Dial 2020; 25:341-349. [PMID: 32666667 DOI: 10.1111/1744-9987.13560] [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: 04/25/2020] [Revised: 06/17/2020] [Accepted: 07/13/2020] [Indexed: 11/29/2022]
Abstract
A retrospective cohort study was conducted to evaluate the association between the plasma volume treated by double filtration plasmapheresis and allograft outcomes for the treatment of acute antibody-mediated rejection in kidney transplant recipients. Patients were divided into two groups: group 1, plasma volume treated between 1 and <1.3 total plasma volume and group 2, plasma volume treated ≥1.3 total plasma volume. Primary outcome was ≥50% reduction of serum creatinine rising from baseline value at 1 month. A total of 32 courses (146 sessions) of double filtration plasmapheresis were performed; 17 and 15 courses in group 1 and group 2, respectively. Primary outcome occurred in 41% of group 1 and 40% of group 2 (adjusted risk ratio 1.15 [95%CI, 0.48-2.76]). Graft loss at 1 year did not differ between the two groups (adjusted hazard ratio 0.65 [95%CI, 0.23-1.87]). Infection tendency seemed to be higher in group 2 (40% vs 18%, P = .243).
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Affiliation(s)
- Kajohnsak Noppakun
- Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Kidney Transplant and Research Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Pharmacoepidemiology and Statistics Research Center (PESRC), Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand
| | - Thanapat Kittipanyaworakun
- Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Chidchanok Ruengorn
- Pharmacoepidemiology and Statistics Research Center (PESRC), Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand.,Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand
| | - Surachet Vongsanim
- Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Kidney Transplant and Research Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Anchalee Saikam
- Kidney Transplant and Research Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Nikhom Khamlueang
- Kidney Transplant and Research Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
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Howson P, Irish AB, D'Orsogna L, Chakera A, Swaminathan R, Perry G, De Santis D, Tolentino R, Wong G, Lim WH. Allograft and Patient Outcomes Between Indigenous and Nonindigenous Kidney Transplant Recipients. Transplantation 2020; 104:847-855. [PMID: 32224814 DOI: 10.1097/tp.0000000000002891] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Kidney transplant outcomes of indigenous Australians are poorer compared with nonindigenous Australians, but it is unknown whether the type of acute rejection differs between these patient groups or whether rejection mediates the effect between ethnicity, death-censored graft failure (DCGF), and death with a functioning graft (DWFG). METHODS Biopsy-proven acute rejection (BPAR) rates and types were compared between indigenous and nonindigenous recipients. The associations between ethnicity, BPAR, DCGF, and DWFG were examined using adjusted competing risk analyses, and mediation analysis was conducted to determine whether BPAR mediated the adverse effects between ethnicity and outcomes. RESULTS Fifty-seven (9.3%) of 616 patients who have received kidney-only transplants between 2000 and 2010 in Western Australia were indigenous. Compared with nonindigenous recipients, BPAR rates were higher in indigenous recipients (42 versus 74 episodes/100 recipients, P < 0.01), with an excess of antibody-mediated rejections. During a median follow-up of 8 years, indigenous recipients were more likely to experience BPAR, DCGF, and DWFG compared with nonindigenous recipients, with adjusted subdistribution hazard ratio of 1.94 (1.39-2.70), 1.53 (0.85-2.76; P = 0.159), and 2.14 (1.13-4.06; P = 0.020), respectively. Although 70% of the effect between ethnicity and DCGF was mediated by BPAR, no similar association was found for DWFG. CONCLUSIONS Indigenous recipients experienced poorer allograft and patient outcomes compared with nonindigenous recipients, with BPAR an important determinant for DCGF. Future research identifying other risk factors and mediators associated with patient survival in indigenous recipients should be considered a priority.
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Affiliation(s)
- Prue Howson
- Department of Renal Medicine, Sir Charles Gairdner Hospital, WA, Australia
| | - Ashley B Irish
- Department of Renal Medicine, Fiona Stanley Hospital, WA, Australia
| | - Lloyd D'Orsogna
- Department of Clinical Immunology, Fiona Stanley Hospital, WA, Australia
- School of Medicine, University of Western Australia, Perth, Australia
| | - Aron Chakera
- Department of Renal Medicine, Sir Charles Gairdner Hospital, WA, Australia
| | | | - Gregory Perry
- Department of Renal Medicine, Royal Perth Hospital, WA, Australia
| | - Dianne De Santis
- Department of Clinical Immunology, Fiona Stanley Hospital, WA, Australia
| | - Raelene Tolentino
- Western Australia Country Health Service, Aboriginal Health Strategy and Country Health Connection, WA, Australia
| | - Germaine Wong
- Sydney School of Public Health, University of Sydney, Sydney, Australia
- Centre for Transplant and Renal Research, Westmead Hospital, Sydney, Australia
- Centre for Kidney Research, The Children's Hospital at Westmead, Sydney, Australia
| | - Wai H Lim
- Department of Renal Medicine, Sir Charles Gairdner Hospital, WA, Australia
- School of Medicine, University of Western Australia, Perth, Australia
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Michielsen LA, van Zuilen AD, Verhaar MC, Wisse BW, Kamburova EG, Joosten I, Allebes WA, van der Meer A, Baas MC, Spierings E, Hack CE, van Reekum FE, Bots ML, Drop ACAD, Plaisier L, Seelen MAJ, Sanders JSF, Hepkema BG, Lambeck AJ, Bungener LB, Roozendaal C, Tilanus MGJ, Voorter CE, Wieten L, van Duijnhoven EM, Gelens MACJ, Christiaans MHL, van Ittersum FJ, Nurmohamed SA, Lardy NM, Swelsen W, van der Pant KA, van der Weerd NC, Ten Berge IJM, Bemelman FJ, Hoitsma A, van der Boog PJM, de Fijter JW, Betjes MGH, Heidt S, Roelen DL, Claas FH, Otten HG, Hilbrands LB. Effect of initial immunosuppression on long-term kidney transplant outcome in immunological low-risk patients. Nephrol Dial Transplant 2019; 34:1417-1422. [PMID: 30561730 DOI: 10.1093/ndt/gfy377] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Accepted: 11/10/2018] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Few studies have evaluated the effect of different immunosuppressive strategies on long-term kidney transplant outcomes. Moreover, as they were usually based on historical data, it was not possible to account for the presence of pretransplant donor-specific human-leukocyte antigen antibodies (DSA), a currently recognized risk marker for impaired graft survival. The aim of this study was to evaluate to what extent frequently used initial immunosuppressive therapies increase graft survival in immunological low-risk patients. METHODS We performed an analysis on the PROCARE cohort, a Dutch multicentre study including all transplantations performed in the Netherlands between 1995 and 2005 with available pretransplant serum (n = 4724). All sera were assessed for the presence of DSA by a luminex single-antigen bead assay. Patients with a previous kidney transplantation, pretransplant DSA or receiving induction therapy were excluded from the analysis. RESULTS Three regimes were used in over 200 patients: cyclosporine (CsA)/prednisolone (Pred) (n = 542), CsA/mycophenolate mofetil (MMF)/Pred (n = 857) and tacrolimus (TAC)/MMF/Pred (n = 811). Covariate-adjusted analysis revealed no significant differences in 10-year death-censored graft survival between patients on TAC/MMF/Pred therapy (79%) compared with patients on CsA/MMF/Pred (82%, P = 0.88) or CsA/Pred (79%, P = 0.21). However, 1-year rejection-free survival censored for death and failure unrelated to rejection was significantly higher for TAC/MMF/Pred (81%) when compared with CsA/MMF/Pred (67%, P < 0.0001) and CsA/Pred (64%, P < 0.0001). CONCLUSION These results suggest that in immunological low-risk patients excellent long-term kidney graft survival can be achieved irrespective of the type of initial immunosuppressive therapy (CsA or TAC; with or without MMF), despite differences in 1-year rejection-free survival.
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Affiliation(s)
- Laura A Michielsen
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Arjan D van Zuilen
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Marianne C Verhaar
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Bram W Wisse
- Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Elena G Kamburova
- Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Irma Joosten
- Laboratory Medicine, Lab. Medical Immunology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Wil A Allebes
- Laboratory Medicine, Lab. Medical Immunology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Arnold van der Meer
- Laboratory Medicine, Lab. Medical Immunology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Marije C Baas
- Radboud Institute for Health Sciences, Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Eric Spierings
- Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Cornelis E Hack
- Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Franka E van Reekum
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Michiel L Bots
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Adriaan C A D Drop
- Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Loes Plaisier
- Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Marc A J Seelen
- Department of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Jan-Stephan F Sanders
- Department of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Bouke G Hepkema
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Annechien J Lambeck
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Laura B Bungener
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Caroline Roozendaal
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Marcel G J Tilanus
- Department of Transplantation Immunology, Tissue Typing Laboratory, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Christien E Voorter
- Department of Transplantation Immunology, Tissue Typing Laboratory, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Lotte Wieten
- Department of Transplantation Immunology, Tissue Typing Laboratory, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Elizabeth M van Duijnhoven
- Department of Internal Medicine, Division of Nephrology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Mariëlle A C J Gelens
- Department of Internal Medicine, Division of Nephrology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Maarten H L Christiaans
- Department of Internal Medicine, Division of Nephrology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Frans J van Ittersum
- Department of Nephrology, Amsterdam UMC, VU University Medical Center, Amsterdam, The Netherlands
| | - Shaikh A Nurmohamed
- Department of Nephrology, Amsterdam UMC, VU University Medical Center, Amsterdam, The Netherlands
| | - Neubury M Lardy
- Department of Immunogenetics, Sanquin, Amsterdam, The Netherlands
| | - Wendy Swelsen
- Department of Immunogenetics, Sanquin, Amsterdam, The Netherlands
| | - Karlijn A van der Pant
- Renal Transplant Unit, Department of Internal Medicine, Amsterdam UMC, Academic Medical Center, Amsterdam, The Netherlands
| | - Neelke C van der Weerd
- Renal Transplant Unit, Department of Internal Medicine, Amsterdam UMC, Academic Medical Center, Amsterdam, The Netherlands
| | - Ineke J M Ten Berge
- Renal Transplant Unit, Department of Internal Medicine, Amsterdam UMC, Academic Medical Center, Amsterdam, The Netherlands
| | - Frederike J Bemelman
- Renal Transplant Unit, Department of Internal Medicine, Amsterdam UMC, Academic Medical Center, Amsterdam, The Netherlands
| | - Andries Hoitsma
- Dutch Organ Transplant Registry (NOTR), Dutch Transplant Foundation (NTS), Leiden, The Netherlands
| | | | - Johan W de Fijter
- Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
| | - Michiel G H Betjes
- Department of Nephrology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Sebastiaan Heidt
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
| | - Dave L Roelen
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
| | - Frans H Claas
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
| | - Henderikus G Otten
- Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Luuk B Hilbrands
- Radboud Institute for Health Sciences, Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
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Regulatory T-cell Number in Peripheral Blood at 1 Year Posttransplant as Predictor of Long-term Kidney Graft Survival. Transplant Direct 2019; 5:e426. [PMID: 30882031 PMCID: PMC6411222 DOI: 10.1097/txd.0000000000000871] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Revised: 01/17/2019] [Accepted: 01/17/2019] [Indexed: 12/21/2022] Open
Abstract
Supplemental digital content is available in the text. Background Regulatory T (Treg) cells play a role in limiting kidney transplant rejection and can potentially promote long-term transplant tolerance. There are no large prospective studies demonstrating the utility of peripheral blood Treg cells as biomarkers for long-term graft outcome in kidney transplantation. The aim of our study was to analyze the influence of the absolute number of peripheral blood Treg cells after transplantation on long-term death-censored graft survival. Methods We monitored the absolute numbers of Treg cells by flow cytometry in nonfrozen samples of peripheral blood in 133 kidney transplant recipients, who were prospectively followed up to 2 years after transplantation. Death-censored graft survival was determined retrospectively in January 2017. Results The mean time of clinical follow-up was 7.4 ± 2.9 years and 24.1% patients suffered death-censored graft loss (DCGL). Patients with high Treg cells 1 year after transplantation and above the median value (14.57 cells/mm3), showed better death-censored graft survival (5-year survival, 92.5% vs 81.4%, Log-rank P = .030). One-year Treg cells showed a receiver operating characteristic - area under curve of 63.1% (95% confidence interval, 52.9–73.2%, P = 0.026) for predicting DCGL. After multivariate Cox regression analysis, an increased number of peripheral blood Treg cells was a protective factor for DCGL (hazard ratio, 0.961, 95% confidence interval, 0.924–0.998, P = 0.041), irrespectively of 1-year proteinuria and renal function. Conclusions Peripheral blood absolute numbers of Treg cells 1 year after kidney transplantation predict a better long-term graft outcome and may be used as prognostic biomarkers.
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Jones-Hughes T, Snowsill T, Haasova M, Coelho H, Crathorne L, Cooper C, Mujica-Mota R, Peters J, Varley-Campbell J, Huxley N, Moore J, Allwood M, Lowe J, Hyde C, Hoyle M, Bond M, Anderson R. Immunosuppressive therapy for kidney transplantation in adults: a systematic review and economic model. Health Technol Assess 2018; 20:1-594. [PMID: 27578428 DOI: 10.3310/hta20620] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND End-stage renal disease is a long-term irreversible decline in kidney function requiring renal replacement therapy: kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation, followed by immunosuppressive therapy (induction and maintenance therapy) to reduce the risk of kidney rejection and prolong graft survival. OBJECTIVES To review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect(®), Novartis Pharmaceuticals UK Ltd) and rabbit anti-human thymocyte immunoglobulin (rATG) (Thymoglobulin(®), Sanofi) as induction therapy, and immediate-release tacrolimus (TAC) (Adoport(®), Sandoz; Capexion(®), Mylan; Modigraf(®), Astellas Pharma; Perixis(®), Accord Healthcare; Prograf(®), Astellas Pharma; Tacni(®), Teva; Vivadex(®), Dexcel Pharma), prolonged-release tacrolimus (Advagraf(®) Astellas Pharma), belatacept (BEL) (Nulojix(®), Bristol-Myers Squibb), mycophenolate mofetil (MMF) (Arzip(®), Zentiva; CellCept(®), Roche Products; Myfenax(®), Teva), mycophenolate sodium (MPS) (Myfortic(®), Novartis Pharmaceuticals UK Ltd), sirolimus (SRL) (Rapamune(®), Pfizer) and everolimus (EVL) (Certican(®), Novartis) as maintenance therapy in adult renal transplantation. METHODS Clinical effectiveness searches were conducted until 18 November 2014 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science (via ISI), Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted until 18 November 2014 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Database (via Wiley Online Library), Web of Science (via ISI), Health Economic Evaluations Database (via Wiley Online Library) and the American Economic Association's electronic bibliography (via EconLit, EBSCOhost). Included studies were selected according to predefined methods and criteria. A random-effects model was used to analyse clinical effectiveness data (odds ratios for binary data and mean differences for continuous data). Network meta-analyses were undertaken within a Bayesian framework. A new discrete time-state transition economic model (semi-Markov) was developed, with acute rejection, graft function (GRF) and new-onset diabetes mellitus used to extrapolate graft survival. Recipients were assumed to be in one of three health states: functioning graft, graft loss or death. RESULTS Eighty-nine randomised controlled trials (RCTs), of variable quality, were included. For induction therapy, no treatment appeared more effective than another in reducing graft loss or mortality. Compared with placebo/no induction, rATG and BAS appeared more effective in reducing biopsy-proven acute rejection (BPAR) and BAS appeared more effective at improving GRF. For maintenance therapy, no treatment was better for all outcomes and no treatment appeared most effective at reducing graft loss. BEL + MMF appeared more effective than TAC + MMF and SRL + MMF at reducing mortality. MMF + CSA (ciclosporin), TAC + MMF, SRL + TAC, TAC + AZA (azathioprine) and EVL + CSA appeared more effective than CSA + AZA and EVL + MPS at reducing BPAR. SRL + AZA, TAC + AZA, TAC + MMF and BEL + MMF appeared to improve GRF compared with CSA + AZA and MMF + CSA. In the base-case deterministic and probabilistic analyses, BAS, MMF and TAC were predicted to be cost-effective at £20,000 and £30,000 per quality-adjusted life-year (QALY). When comparing all regimens, only BAS + TAC + MMF was cost-effective at £20,000 and £30,000 per QALY. LIMITATIONS For included trials, there was substantial methodological heterogeneity, few trials reported follow-up beyond 1 year, and there were insufficient data to perform subgroup analysis. Treatment discontinuation and switching were not modelled. FUTURE WORK High-quality, better-reported, longer-term RCTs are needed. Ideally, these would be sufficiently powered for subgroup analysis and include health-related quality of life as an outcome. CONCLUSION Only a regimen of BAS induction followed by maintenance with TAC and MMF is likely to be cost-effective at £20,000-30,000 per QALY. STUDY REGISTRATION This study is registered as PROSPERO CRD42014013189. FUNDING The National Institute for Health Research Health Technology Assessment programme.
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Affiliation(s)
- Tracey Jones-Hughes
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Tristan Snowsill
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Marcela Haasova
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Helen Coelho
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Louise Crathorne
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Chris Cooper
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Ruben Mujica-Mota
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Jaime Peters
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Jo Varley-Campbell
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Nicola Huxley
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Jason Moore
- Exeter Kidney Unit, Royal Devon and Exeter Foundation Trust Hospital, Exeter, UK
| | - Matt Allwood
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Jenny Lowe
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Chris Hyde
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Martin Hoyle
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Mary Bond
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Rob Anderson
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
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Haasova M, Snowsill T, Jones-Hughes T, Crathorne L, Cooper C, Varley-Campbell J, Mujica-Mota R, Coelho H, Huxley N, Lowe J, Dudley J, Marks S, Hyde C, Bond M, Anderson R. Immunosuppressive therapy for kidney transplantation in children and adolescents: systematic review and economic evaluation. Health Technol Assess 2018; 20:1-324. [PMID: 27557331 DOI: 10.3310/hta20610] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND End-stage renal disease is a long-term irreversible decline in kidney function requiring kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation followed by induction and maintenance immunosuppressive therapy to reduce the risk of kidney rejection and prolong graft survival. OBJECTIVES To systematically review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect,(®) Novartis Pharmaceuticals) and rabbit antihuman thymocyte immunoglobulin (Thymoglobuline,(®) Sanofi) as induction therapy and immediate-release tacrolimus [Adoport(®) (Sandoz); Capexion(®) (Mylan); Modigraf(®) (Astellas Pharma); Perixis(®) (Accord Healthcare); Prograf(®) (Astellas Pharma); Tacni(®) (Teva); Vivadex(®) (Dexcel Pharma)], prolonged-release tacrolimus (Advagraf,(®) Astellas Pharma); belatacept (BEL) (Nulojix,(®) Bristol-Myers Squibb), mycophenolate mofetil (MMF) [Arzip(®) (Zentiva), CellCept(®) (Roche Products), Myfenax(®) (Teva), generic MMF is manufactured by Accord Healthcare, Actavis, Arrow Pharmaceuticals, Dr Reddy's Laboratories, Mylan, Sandoz and Wockhardt], mycophenolate sodium, sirolimus (Rapamune,(®) Pfizer) and everolimus (Certican,(®) Novartis Pharmaceuticals) as maintenance therapy in children and adolescents undergoing renal transplantation. DATA SOURCES Clinical effectiveness searches were conducted to 7 January 2015 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science [via Institute for Scientific Information (ISI)], Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (HTA) (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted to 15 January 2015 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Databases (via Wiley Online Library), Web of Science (via ISI), Health Economic Evaluations Database (via Wiley Online Library) and EconLit (via EBSCOhost). REVIEW METHODS Titles and abstracts were screened according to predefined inclusion criteria, as were full texts of identified studies. Included studies were extracted and quality appraised. Data were meta-analysed when appropriate. A new discrete time state transition economic model (semi-Markov) was developed; graft function, and incidences of acute rejection and new-onset diabetes mellitus were used to extrapolate graft survival. Recipients were assumed to be in one of three health states: functioning graft, graft loss or death. RESULTS Three randomised controlled trials (RCTs) and four non-RCTs were included. The RCTs only evaluated BAS and tacrolimus (TAC). No statistically significant differences in key outcomes were found between BAS and placebo/no induction. Statistically significantly higher graft function (p < 0.01) and less biopsy-proven acute rejection (odds ratio 0.29, 95% confidence interval 0.15 to 0.57) was found between TAC and ciclosporin (CSA). Only one cost-effectiveness study was identified, which informed NICE guidance TA99. BAS [with TAC and azathioprine (AZA)] was predicted to be cost-effective at £20,000-30,000 per quality-adjusted life year (QALY) versus no induction (BAS was dominant). BAS (with CSA and MMF) was not predicted to be cost-effective at £20,000-30,000 per QALY versus no induction (BAS was dominated). TAC (with AZA) was predicted to be cost-effective at £20,000-30,000 per QALY versus CSA (TAC was dominant). A model based on adult evidence suggests that at a cost-effectiveness threshold of £20,000-30,000 per QALY, BAS and TAC are cost-effective in all considered combinations; MMF was also cost-effective with CSA but not TAC. LIMITATIONS The RCT evidence is very limited; analyses comparing all interventions need to rely on adult evidence. CONCLUSIONS TAC is likely to be cost-effective (vs. CSA, in combination with AZA) at £20,000-30,000 per QALY. Analysis based on one RCT found BAS to be dominant, but analysis based on another RCT found BAS to be dominated. BAS plus TAC and AZA was predicted to be cost-effective at £20,000-30,000 per QALY when all regimens were compared using extrapolated adult evidence. High-quality primary effectiveness research is needed. The UK Renal Registry could form the basis for a prospective primary study. STUDY REGISTRATION This study is registered as PROSPERO CRD42014013544. FUNDING The National Institute for Health Research HTA programme.
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Affiliation(s)
- Marcela Haasova
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Tristan Snowsill
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Tracey Jones-Hughes
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Louise Crathorne
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Chris Cooper
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Jo Varley-Campbell
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Ruben Mujica-Mota
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Helen Coelho
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Nicola Huxley
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Jenny Lowe
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Jan Dudley
- Department of Paediatric Nephrology, Bristol Royal Hospital for Children (University Hospitals Bristol NHS Foundation Trust), Bristol, UK
| | - Stephen Marks
- Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Chris Hyde
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Mary Bond
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Rob Anderson
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
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Abstract
Donor-specific antibodies have become an established biomarker predicting antibody-mediated rejection. Antibody-mediated rejection is the leading cause of graft loss after kidney transplant. There are several phenotypes of antibody-mediated rejection along post-transplant course that are determined by the timing and extent of humoral response and the various characteristics of donor-specific antibodies, such as antigen classes, specificity, antibody strength, IgG subclasses, and complement binding capacity. Preformed donor-specific antibodies in sensitized patients can trigger hyperacute rejection, accelerated acute rejection, and early acute antibody-mediated rejection. De novo donor-specific antibodies are associated with late acute antibody-mediated rejection, chronic antibody-mediated rejection, and transplant glomerulopathy. The pathogeneses of antibody-mediated rejection include not only complement-dependent cytotoxicity, but also complement-independent pathways of antibody-mediated cellular cytotoxicity and direct endothelial activation and proliferation. The novel assay for complement binding capacity has improved our ability to predict antibody-mediated rejection phenotypes. C1q binding donor-specific antibodies are closely associated with acute antibody-mediated rejection, more severe graft injuries, and early graft failure, whereas C1q nonbinding donor-specific antibodies correlate with subclinical or chronic antibody-mediated rejection and late graft loss. IgG subclasses have various abilities to activate complement and recruit effector cells through the Fc receptor. Complement binding IgG3 donor-specific antibodies are frequently associated with acute antibody-mediated rejection and severe graft injury, whereas noncomplement binding IgG4 donor-specific antibodies are more correlated with subclinical or chronic antibody-mediated rejection and transplant glomerulopathy. Our in-depth knowledge of complex characteristics of donor-specific antibodies can stratify the patient's immunologic risk, can predict distinct phenotypes of antibody-mediated rejection, and hopefully, will guide our clinical practice to improve the transplant outcomes.
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Affiliation(s)
- Rubin Zhang
- Section of Nephrology, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana
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Patel KS, Stephany BR, Barnes JF, Bauer SR, Spinner ML. Renal Transplant Acute Rejection with Lower Mycophenolate Mofetil Dosing and Proton Pump Inhibitors or Histamine-2 Receptor Antagonists. Pharmacotherapy 2017; 37:1507-1515. [PMID: 28976570 DOI: 10.1002/phar.2037] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND Pharmacokinetic data show reduced mycophenolic acid levels in renal transplant recipients taking mycophenolate mofetil (MMF) and proton pump inhibitors (PPIs) concomitantly. This reduced exposure could increase rejection risk. The typical initial MMF dose post renal transplantation is 2 g/day, which often requires dose reduction secondary to side effects. Existing studies have not shown significant acute rejection differences for patients taking MMF-PPI versus patients taking MMF-ranitidine. OBJECTIVE The purpose of this study was to evaluate clinical outcomes in renal transplant recipients receiving a lower MMF dose than previously studied (1.5 g/day) and either a PPI or histamine-2 receptor antagonist (H2RA). METHODS This retrospective cohort study included adult subjects receiving a renal transplant between January 1, 2009, and June 30, 2013. Comparison groups were defined based on acid-suppressing therapy class prescribed at discharge from transplantation. The primary outcome was acute rejection incidence within 1 year posttransplantation. RESULTS Of 728 renal transplant recipients screened, 522 were included: 183 taking a PPI and 339 taking an H2RA. There was no significant difference in acute rejection within 1 year (H2RA 19% versus PPI 14%, p=0.12) or 3 months (4% vs 5%, p=0.44, respectively) posttransplantation. Maintenance immunosuppression (MMF dose and tacrolimus troughs) was similar between groups at 3 months and 1 year. Graft and patient survivals were favorable (> 95%), and graft function at 1 year was stable and similar between groups. CONCLUSION Despite taking lower MMF doses than previously studied, subjects on a PPI compared to an H2RA were not at increased risk of acute rejection within 1 year posttransplantation.
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Affiliation(s)
- Kajal S Patel
- Department of Pharmacy, Cleveland Clinic, Cleveland, Ohio
| | - Brian R Stephany
- Department of Nephrology and Hypertension, Cleveland Clinic, Cleveland, Ohio
| | - Julie F Barnes
- Department of Pharmacy, Cleveland Clinic, Cleveland, Ohio
| | - Seth R Bauer
- Department of Pharmacy, Cleveland Clinic, Cleveland, Ohio
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Diagnostic Lessons from a Complex Case of Postintestinal Transplantation Enteropathy. Case Rep Transplant 2017; 2017:2498423. [PMID: 28845319 PMCID: PMC5563400 DOI: 10.1155/2017/2498423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2017] [Revised: 06/04/2017] [Accepted: 07/04/2017] [Indexed: 11/20/2022] Open
Abstract
Recent advances in the field of intestinal transplantation have been mitigated by the incidence of allograft rejection. In such events, early identification and appropriate timing of antirejection therapy are crucial in retaining graft function. We present the case of a patient who suffered severe postintestinal transplantation allograft enteropathy, primarily characterized by extensive mucosal ulcerations, and was refractory to all conventional therapy. This progressed as chronic rejection; however crucially this was not definitively diagnosed until allograft function had irreversibly diminished. We argue that the difficulties encountered in this case can be attributed to the inability of our current array of investigative studies and diagnostic guidelines to provide adequate clinical guidance. This case illustrates the importance of developing reliable and specific markers for guiding the diagnosis of rejection and the use of antirejection therapeutics in this rapidly evolving field of transplant surgery.
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Salcido-Ochoa F, Hue SSS, Peng S, Fan Z, Li RL, Iqbal J, Allen Jr JC, Loh AHL. Histopathological analysis of infiltrating T cell subsets in acute T cell-mediated rejection in the kidney transplant. World J Transplant 2017; 7:222-234. [PMID: 28900605 PMCID: PMC5573898 DOI: 10.5500/wjt.v7.i4.222] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 05/21/2017] [Accepted: 07/03/2017] [Indexed: 02/05/2023] Open
Abstract
AIM To compare the differential immune T cell subset composition in patients with acute T cell-mediated rejection in the kidney transplant with subset composition in the absence of rejection, and to explore the association of their respective immune profiles with kidney transplant outcomes.
METHODS A pilot cross-sectional histopathological analysis of the immune infiltrate was performed using immunohistochemistry in a cohort of 14 patients with acute T cell-mediated rejection in the kidney transplant and 7 kidney transplant patients with no rejection subjected to biopsy to investigate acute kidney transplant dysfunction. All patients were recruited consecutively from 2012 to 2014 at the Singapore General Hospital. Association of the immune infiltrates with kidney transplant outcomes at up to 54 mo of follow up was also explored prospectively.
RESULTS In comparison to the absence of rejection, acute T cell-mediated rejection in the kidney transplant was characterised by numerical dominance of cytotoxic T lymphocytes over Foxp3+ regulatory T cells, but did not reach statistical significance owing to the small sample size in our pilot study. There was no obvious difference in absolute numbers of infiltrating cytotoxic T lymphocytes, Foxp3+ regulatory T cells and Th17 cells between the two patient groups when quantified separately. Our exploratory analysis on associations of T cell subset quantifications with kidney transplant outcomes revealed that the degree of Th17 cell infiltration was significantly associated with shorter time to doubling of creatinine and shorter time to transplant loss.
CONCLUSION Although this was a small pilot study, results support our suspicion that in kidney transplant patients the immune balance in acute T cell-mediated rejection is tilted towards the pro-rejection forces and prompt larger and more sophisticated studies.
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Affiliation(s)
- Francisco Salcido-Ochoa
- Tregs and HLA Research Force and Renal Medicine Department, Singapore General Hospital, Singapore 169856, Singapore
| | - Susan Swee-Shan Hue
- Tregs and HLA Research Force and Department of Pathology, National University Hospital, Singapore 119074, Singapore
| | - Siyu Peng
- Tregs and HLA Research Force and Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore
| | - Zhaoxiang Fan
- Tregs and HLA Research Force and Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore
| | - Reiko Lixiang Li
- Department of Pathology and Laboratory Medicine, KK Women’s and Children’s Hospital, Singapore 229899, Singapore
| | - Jabed Iqbal
- Department of Pathology, Singapore General Hospital, Singapore 169856, Singapore,
| | - John Carson Allen Jr
- Centre for Quantitative Medicine, Duke-NUS Graduate Medical School, Singapore 169856, Singapore
| | - Alwin Hwai Liang Loh
- Department of Pathology, Singapore General Hospital, Singapore 169856, Singapore,
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Webster AC, Wu S, Tallapragada K, Park MY, Chapman JR, Carr SJ, Cochrane Kidney and Transplant Group. Polyclonal and monoclonal antibodies for treating acute rejection episodes in kidney transplant recipients. Cochrane Database Syst Rev 2017; 7:CD004756. [PMID: 28731207 PMCID: PMC6483358 DOI: 10.1002/14651858.cd004756.pub4] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND Registry data shows that the incidence of acute rejection has been steadily falling. Approximately 10% to 35% of kidney recipients will undergo treatment for at least one episode of acute rejection within the first post-transplant year. Treatment options include pulsed steroid therapy, the use of an antibody preparation, the alteration of background immunosuppression, or combinations of these options. Over recent years, new treatment strategies have evolved, and in many parts of the world there has been an increase in use of tacrolimus and mycophenolate and a reduction in the use of cyclosporin and azathioprine use as baseline immunosuppression to prevent acute rejection. There are also global variations in use of polyclonal and monoclonal antibodies to treat acute rejection. This is an update of a review published in 2006. OBJECTIVES The aim of this systematic review was to: (1) to evaluate the relative and absolute effects of different classes of antibody preparation in preventing graft loss and resolving cellular or humoral rejection episodes when used as a treatment for first episode of rejection in kidney transplant recipients; (2) evaluate the relative and absolute effects of different classes of antibody preparation in preventing graft loss and resolving cellular or humoral rejection episodes when used as a treatment for steroid-resistant rejection in kidney transplant recipients; (3) determine how the benefits and adverse events vary for each type of antibody preparation; and (4) determine how the benefits and harms vary for different formulations of antibody within each type. SEARCH METHODS We searched the Cochrane Kidney and Transplant Specialised Register to 18 April 2017 through contact with the Information Specialist using search terms relevant to this review. SELECTION CRITERIA Randomised controlled trials (RCTs) in all languages comparing all mono- and polyclonal antibody preparations, given in combination with any other immunosuppressive agents, for the treatment of cellular or humoral graft rejection, when compared to any other treatment for acute rejection were eligible for inclusion. DATA COLLECTION AND ANALYSIS Two authors independently assessed the risk of bias of the included studies and extracted data. Statistical analyses were performed using a random-effects model and results expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI). MAIN RESULTS We included 11 new studies (18 reports, 346 participants) in this update, bring the total number of included studies to 31 (76 reports, 1680 participants). Studies were generally small, incompletely reported, especially for potential harms, and did not define outcome measures adequately. The risk of bias was inadequate or unclear risk for random sequence generation (81%), allocation concealment (87%) and other bias (87%). There were, however, a predominance of low risk of bias for blinding (75%) and incomplete outcome data (80%) across all the studies. Selective reporting had a mixture of low (58%), high (29%), and unclear (13%) risk of bias.Seventeen studies (1005 participants) compared therapies for first acute cellular rejection episodes. Antibody therapy was probably better than steroid in reversing acute cellular rejection (RR 0.50, 95% CI 0.30 to 0.82; moderate certainty) and preventing subsequent rejection (RR 0.70, 95% CI 0.50 to 0.99; moderate certainty), may be better for preventing graft loss (death censored: (RR 0.80, 95% CI 0.57 to 1.12; low certainty) but there was little or no difference in death at one year. Adverse effects of treatment (including fever, chills and malaise following drug administration) were probably reduced with steroid therapy (RR 23.88, 95% CI 5.10 to 111.86; I2 = 16%; moderate certainty).Twelve studies (576 patients) investigated antibody treatment for steroid-resistant rejection. There was little or no benefit of muromonab-CD3 over ATG or ALG in reversing rejection, preventing subsequent rejection, or preventing graft loss or death. Two studies compared the use of rituximab for treatment of acute humoral rejection (58 patients). Muromonab-CD3 treated patients suffered three times more than those receiving either ATG or T10B9, from a syndrome of fever, chills and malaise following drug administration (RR 3.12, 95% CI 1.87 to 5.21; I2 = 31%), and experienced more neurological side effects (RR 13.10 95% CI 1.43 to 120.05; I2 = 36%) (low certainty evidence).There was no evidence of additional benefit from rituximab in terms of either reversal of rejection (RR 0.94, 95% CI 0.54 to 1.64), or graft loss or death 12 months (RR 1.0, 95% CI 0.23 to 4.35). Rituximab plus steroids probably increases the risk of urinary tract infection/pyelonephritis (RR 5.73, 95% CI 1.80 to 18.21). AUTHORS' CONCLUSIONS In reversing first acute cellular rejection and preventing graft loss, any antibody is probably better than steroid, but there is little or no difference in subsequent rejection and patient survival. In reversing steroid-resistant rejection there was little or no difference between different antibodies over a period of 12 months, with limited data beyond that time frame. In treating acute humoral rejection, there was no evidence that the use of antibody therapy conferred additional benefit in terms of reversal of rejection, or death or graft loss.Although this is an updated review, the majority of newer included studies provide additional evidence from the cyclosporin/azathioprine era of kidney transplantation and therefore conclusions cannot necessarily be extrapolated to patients treated with more contemporary immunosuppressive regimens which include tacrolimus/mycophenolate or sirolimus. However, many kidney transplant centres around the world continue to use older immunosuppressive regimes and the findings of this review remain strongly relevant to their clinical practice.Larger studies with standardised reproducible outcome criteria are needed to investigate the outcomes and risks of antibody treatments for acute rejection in kidney transplant recipients receiving contemporary immunosuppressive regimes.
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Affiliation(s)
- Angela C Webster
- The University of SydneySydney School of Public HealthEdward Ford Building A27SydneyNSWAustralia2006
- The University of Sydney at WestmeadCentre for Transplant and Renal Research, Westmead Millennium InstituteWestmeadNSWAustralia2145
| | - Sunny Wu
- The Children's Hospital at WestmeadCentre for Kidney ResearchCorner Hawkesbury and Darcy RoadsWestmeadNSWAustralia2145
| | - Krishna Tallapragada
- The Children's Hospital at WestmeadCentre for Kidney ResearchCorner Hawkesbury and Darcy RoadsWestmeadNSWAustralia2145
| | - Min Young Park
- The Children's Hospital at WestmeadCentre for Kidney ResearchCorner Hawkesbury and Darcy RoadsWestmeadNSWAustralia2145
| | - Jeremy R Chapman
- Westmead Millennium Institute, The University of Sydney at WestmeadCentre for Transplant and Renal ResearchDarcy RdWestmeadNSWAustralia2145
| | - Sue J Carr
- University Hospitals of LeicesterRenal DepartmentGwendolen RdLeicesterUKLE5 4PW
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Vanhove T, Goldschmeding R, Kuypers D. Kidney Fibrosis: Origins and Interventions. Transplantation 2017; 101:713-726. [PMID: 27941433 PMCID: PMC7228593 DOI: 10.1097/tp.0000000000001608] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Revised: 10/24/2016] [Accepted: 11/10/2016] [Indexed: 02/06/2023]
Abstract
All causes of renal allograft injury, when severe and/or sustained, can result in chronic histological damage of which interstitial fibrosis and tubular atrophy are dominant features. Unless a specific disease process can be identified, what drives interstitial fibrosis and tubular atrophy progression in individual patients is often unclear. In general, clinicopathological factors known to predict and drive allograft fibrosis include graft quality, inflammation (whether "nonspecific" or related to a specific diagnosis), infections, such as polyomavirus-associated nephropathy, calcineurin inhibitors (CNI), and genetic factors. The incidence and severity of chronic histological damage have decreased substantially over the last 3 decades, but it is difficult to disentangle what effects individual innovations (eg, better matching and preservation techniques, lower CNI dosing, BK viremia screening) may have had. There is little evidence that CNI-sparing/minimization strategies, steroid minimization or renin-angiotensin-aldosterone system blockade result in better preservation of intermediate-term histology. Treatment of subclinical rejections has only proven beneficial to histological and functional outcome in studies in which the rate of subclinical rejection in the first 3 months was greater than 10% to 15%. Potential novel antifibrotic strategies include antagonists of transforming growth factor-β, connective tissue growth factor, several tyrosine kinase ligands (epidermal growth factor, platelet-derived growth factor, vascular endothelial growth factor), endothelin and inhibitors of chemotaxis. Although many of these drugs are mainly being developed and marketed for oncological indications and diseases, such as idiopathic pulmonary fibrosis, a number may hold promise in the treatment of diabetic nephropathy, which could eventually lead to applications in renal transplantation.
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Affiliation(s)
- Thomas Vanhove
- 1 Department of Microbiology and Immunology, KU Leuven-University of Leuven, Leuven, Belgium. 2 Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium. 3 Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands
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Single center experience of subclinical rejections and BK nephropathies by kidney allografts' surveillance biopsies. Adv Med Sci 2017; 62:110-115. [PMID: 28242482 DOI: 10.1016/j.advms.2016.07.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Revised: 07/05/2016] [Accepted: 07/07/2016] [Indexed: 11/20/2022]
Abstract
PURPOSE Acute rejection of the kidney allograft remains the most important factor affecting the long-term graft outcome and is a major predictor of development of chronic damage and graft loss. Several studies have shown that early detection and treatment of subclinical rejection episodes may be beneficial for the graft outcome. The role of protocol (surveillance) biopsies and the value of donor specific antibodies (DSA) monitoring are still debatable. METHODS This is a prospective observational study involving seventeen kidney recipients transplanted in north-eastern part of Poland who underwent "zero", 3-month and 12-month allograft biopsies as well as DSA assessment. RESULTS Histologic analysis of the biopsies showed subclinical acute cellular rejection in 17.6% of patients (two tubulointerstitial, one vascular) at 3-months post transplantation, and additional case of borderline rejection at the 12-month point. Moreover, two cases (11.8%) of polyomavirus BK nephropathy were diagnosed (one at 3 and one at 12 month point). None of the patients developed de novo DSA. CONCLUSIONS Our protocol biopsies allowed us to detect significant proportion of patients with subclinical, but histologically relevant acute cellular rejection and BK nephropathy. Early therapeutic intervention had beneficial effects in a 4-year follow up.
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Fliser D, Dellanna F, Koch M, Wiggenhauser A. Early low-dose erythropoiesis-stimulating agent therapy and progression of moderate chronic kidney disease: a randomized, placebo-controlled trial. Nephrol Dial Transplant 2017; 32:279-287. [PMID: 28186540 DOI: 10.1093/ndt/gfw418] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 10/25/2016] [Indexed: 01/13/2023] Open
Abstract
Background It is unknown whether early intervention with low-dose erythropoiesis-stimulating agents (ESAs) in non-anaemic patients delays progression of chronic kidney disease (CKD). Methods In a single-blind, 24-month trial, adults with estimated glomerular filtration rate (eGFR) 30–59 mL/min/1.73 m2 and either Type 2 diabetes mellitus or previous kidney transplantation were randomized to low-dose continuous erythropoiesis receptor activator (CERA; monthly dose 30–75 µg; n = 115) or placebo (n = 120). The primary endpoint was the annual change in eGFR (abbreviated Modification of Diet in Renal Disease formula). Results Mean (standard deviation) eGFR was 40.7 (9.8) mL/min/1.73 m2 versus 39.8 (9.2) mL/min/1.73 m2 at baseline for CERA and placebo, respectively, and 39.0 (11.6) g/dL versus 39.7 (10.6) g/dL at the final visit. The median (interquartile range) annual reduction in eGFR was 0.5 (−2.2, 3.8) mL/min/1.73 m2 with CERA versus 0.4 (−2.0, 3.2) mL/min/1.73 m2 with placebo (P = 0.657). No significant difference in the annual change in eGFR was observed between treatment groups in the subpopulations with Type 2 diabetes or kidney transplant. Adverse events with a suspected relation to study drug occurred in 22.0% and 16.2% of patients randomized to CERA or placebo, respectively, and adverse events led to study drug discontinuation in 11.0% and 8.5% of patients. Conclusions Patients with moderate CKD and Type 2 diabetes or previous kidney transplantation showed stable renal function that was unaffected by administration of low-dose ESA. In addition, there was no clinically meaningful effect of 2-year low-dose ESA treatment on albuminuria, an important surrogate marker of kidney injury.
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Affiliation(s)
- Danilo Fliser
- Department of Internal Medicine IV, Saarland University Medical Centre, Kirrbergerstrasse, Homburg/Saar, Germany
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Factors influencing renal graft survival: 7-Year experience of a single center. Medicina (B Aires) 2017; 53:224-232. [DOI: 10.1016/j.medici.2017.07.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Revised: 06/29/2017] [Accepted: 07/17/2017] [Indexed: 11/22/2022] Open
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Cellular and molecular profiling of graft injury post renal transplantation. Curr Opin Organ Transplant 2016; 22:36-45. [PMID: 27941467 DOI: 10.1097/mot.0000000000000377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW Continues advancements in assessing methods for biomolecules that have assisted to identify surrogate candidate biomarkers that can be used to monitor the transplanted organ. These high-throughput methods can help researchers to significantly speed up the identification and the validation steps, which are crucial factors for biomarker discovery efforts. However, this task in transplantation confronts multiple limitations. The review summarizes main findings using 'omics approaches in the evaluation of different types of allograft injury with the overarching aim of evaluating the next steps for transferring the available data to the clinical setting. RECENT FINDINGS Significant discoveries have been made about the molecular and cellular mechanisms that associate with graft injury that may lead to early biomarkers of graft injury (prediction and diagnosis) with the goal of improving long-term outcomes by extending the lifespan of the graft and/or identifying new therapeutic targets. SUMMARY Common efforts among researchers are needed for transferring biomarkers to the clinical setting and, moreover, elucidate pathways that may allow for early interventions to avoid fibrosis progression and graft loss. Large and prospective studies for validation of current available data under strict analytical evaluation are needed to move biomarkers from the discovery phase to validation and clinical implementation.
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Grabner A, Kentrup D, Pawelski H, Mühlmeister M, Biermann C, Edemir B, Heitplatz B, Van Marck V, Bettinger T, Pavenstädt H, Schlatter E, Stypmann J, Tiemann K, Reuter S. Renal Contrast-Enhanced Sonography Findings in a Model of Acute Cellular Allograft Rejection. Am J Transplant 2016; 16:1612-9. [PMID: 26613381 DOI: 10.1111/ajt.13648] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Accepted: 11/22/2015] [Indexed: 01/25/2023]
Abstract
Noninvasive methods to diagnose and differentiate acute cellular rejection from acute tubular necrosis or acute calcineurin inhibitor toxicity are still missing. Because T lymphocytes play a decisive role in early states of rejection, we investigated the suitability and feasibility of antibody-mediated contrast-enhanced ultrasound by using microbubbles targeted to CD3(+) , CD4(+) , or CD8(+) T cells in different models of renal disease. In an established rat renal transplantation model, CD3-mediated ultrasound allows the detection of acute rejection as early as on postoperative day 2. Ultrasound signal intensities increased with the severity of inflammation. Further, an early response to therapy could be monitored by using contrast-enhanced sonography. Notably, acute tubular necrosis occurring after ischemia-reperfusion injury as well as acute calcineurin inhibitor toxicity could easily be differentiated. Finally, the quantified ultrasound signal correlated significantly with the number of infiltrating T cells obtained by histology and with CD3 mRNA levels, as well as with chemokine CXCL9, CXCL11, and CCL19 mRNA but not with KIM-1 mRNA expression, thereby representing the severity of graft inflammation but not the degree of kidney injury. In summary, we demonstrate that antibody-mediated contrast-enhanced ultrasound targeting T lymphocytes could be a promising tool for an easy and reproducible assessment of acute rejection after renal transplantation.
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Affiliation(s)
- A Grabner
- Department of Medicine D, Experimental Nephrology, University of Münster, Münster, Germany
| | - D Kentrup
- Department of Medicine D, Experimental Nephrology, University of Münster, Münster, Germany
| | - H Pawelski
- Department of Medicine D, Experimental Nephrology, University of Münster, Münster, Germany
| | - M Mühlmeister
- Department of Medicine D, Experimental Nephrology, University of Münster, Münster, Germany
| | - C Biermann
- Department of Medicine D, Experimental Nephrology, University of Münster, Münster, Germany
| | - B Edemir
- Department of Medicine, Hematology and Oncology, University of Halle, Halle, Germany
| | - B Heitplatz
- Department of Pathology, University of Münster, Münster, Germany
| | - V Van Marck
- Department of Pathology, University of Münster, Münster, Germany
| | | | - H Pavenstädt
- Department of Medicine D, Experimental Nephrology, University of Münster, Münster, Germany
| | - E Schlatter
- Department of Medicine D, Experimental Nephrology, University of Münster, Münster, Germany
| | - J Stypmann
- Department of Cardiovascular Medicine, University of Münster, Münster, Germany
| | - K Tiemann
- Department of Cardiology, Otypka Heart Center and Department of Nuclear Medicine, Technical University Munich, Munich, Germany
| | - S Reuter
- Department of Medicine D, Experimental Nephrology, University of Münster, Münster, Germany
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Pratschke J, Dragun D, Hauser IA, Horn S, Mueller TF, Schemmer P, Thaiss F. Immunological risk assessment: The key to individualized immunosuppression after kidney transplantation. Transplant Rev (Orlando) 2016; 30:77-84. [PMID: 26965071 DOI: 10.1016/j.trre.2016.02.002] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 02/10/2016] [Indexed: 12/18/2022]
Abstract
The wide range of immunosuppressive therapies and protocols permits tailored planning of the initial regimen according to the immunological risk status of individual patients. Pre-transplant risk assessment can include many factors, but there is no clear consensus on which parameters to take into account, and their relative importance. In general younger patients are known to be at higher risk for acute rejection, compounded by higher rates of non-adherence in adolescents. Donor age and recipient gender do not appear to exert a meaningful effect on risk of rejection per se, but black recipient ethnicity remains a well-established risk factor even under modern immunosuppression regimens. Little difference in risk is now observed between deceased- and living-donor recipients. Immunological risk assessment has developed substantially in recent years. Cross-match testing with cytotoxic analysis has long been supplemented by flow cytometry, but development of solid-phase single-bead antigen testing of solubilized human leukocyte antigens (HLA) to detect donor-specific antibodies (DSA) permits a far more nuanced stratification of immunological risk status, including the different classes and intensities of HLA antibodies Class I and/or II, including HLA-DSA. Immunologic risk evaluation is now often based on a combination of these tests, but other assessments are becoming more widely introduced, such as measurement of non-HLA antibodies against angiotensin type 1 (AT1) receptors or T-cell ELISPOT assay of alloantigen-specific donor. Targeted densensitization protocols can improve immunological risk, notably for DSA-positive patients with negative cytotoxicity and flow cross-match. HLA mismatch remains an important and undisputed risk factor for rejection. Delayed graft function also increases the risk of subsequent acute rejection, and the early regimen can be modified in such cases. Overall, there is a shift towards planning the immunosuppressive regimen based on pre-transplant immunology testing although certain conventional risk factors retain their importance.
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Affiliation(s)
- Johann Pratschke
- Department of General, Visceral and Transplantation Surgery, Charité University Hospital, Berlin, Germany.
| | - Duska Dragun
- Department of Nephrology and Intensive Care Medicine, Charite Campus Virchow Clinic, Berlin, Germany
| | - Ingeborg A Hauser
- Department of Nephrology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Sabine Horn
- Division of Nephrology, Medical University of Graz, Graz, Austria
| | - Thomas F Mueller
- Division of Nephrology, University Hospital Zürich, Zürich, Switzerland
| | - Peter Schemmer
- Department of General, Visceral and Transplant Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Friedrich Thaiss
- Department Internal Medicine, Division of Nephrology & University Transplant Center, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
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Novosel MK, Bistrup C. Discontinuation of steroids in ABO-incompatible renal transplantation. Transpl Int 2016; 29:464-70. [PMID: 26706618 DOI: 10.1111/tri.12735] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Revised: 10/12/2015] [Accepted: 12/16/2015] [Indexed: 12/16/2022]
Abstract
A steroid-free protocol for ABO-compatible renal transplantation has been used at our center since 1983. To minimize the adverse effects of steroids, we also developed a steroid sparing protocol for ABO-incompatible renal transplantation in 2008. The present study is a report of our results. A retrospective review of the first 50 ABO-incompatible renal transplantations performed at a single university center. If no immunological events occurred in the post-transplant period, prednisolone tapering was initiated approximately 3 months after transplantation. Forty-three patients completed prednisolone tapering after 289 ± 58 days. Three patients died during follow-up, and four patients lost graft function. None of these adverse events were rejection related. Eleven patients experienced rejections; seven were on prednisolone and four were after weaning from prednisolone. All patients responded well to antirejection treatment. Overall, 1-year rejection rate was 19%. One- and 3-year graft survival was 94% and 91%, respectively. One-year post-transplant median serum creatinine was 123 μmol/L. We found acceptable rejection rates, graft survival, and creatinine levels in patients undergoing ABO-incompatible renal transplantations with a steroid sparing protocol. However, a longer follow-up of a lager cohort is needed before firm conclusions can be made.
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Affiliation(s)
- Marija Kristina Novosel
- Division of Nephrology, Department of Medicine, Fredericia Hospital - Part of Lillebaelt Hospital, Fredericia, Denmark.,Department of Nephrology, Odense University Hospital, Odense, Denmark
| | - Claus Bistrup
- Department of Nephrology, Odense University Hospital, Odense, Denmark
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