Dataset Information

Reassessing Rabbit Antithymocyte Globulin Induction in Kidney Transplantation (RETHINK): An Analysis of the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) Registry.

ABSTRACT:

Background

There is no consensus on rabbit antithymocyte globulin (rATG) dose used for induction immunosuppression in pediatric kidney transplants. We aimed to identify whether a lower rATG dose provides safe and effective immunosuppression compared with a higher dose.

Methods

We retrospectively analyzed all first-time kidney transplant recipients (aged <21 y) in the North American Pediatric Renal Trials and Collaborative Studies registry since 1998 on mycophenolate mofetil- and tacrolimus-based immunosuppression with rATG induction. An a priori cutoff of 7.5?mg/kg cumulative rATG dose was used to identify low (<7.5?mg/kg) and high (?7.5?mg/kg) exposure groups. Primary outcome was time to first-acute rejection episode. Secondary outcomes included graft function, patient survival, hospitalizations due to infections, and time to first-posttransplant lymphoproliferative disorder episode.

Results

Four hundred fifty-five patients met inclusion criteria (59% male, 49% whites, 26% blacks, 38% living donor source). Median cumulative rATG dose was 6.8?mg/kg with a median of 5 doses and a median 1.5?mg/kg/dose introduced at a median of postoperative 0 days. Sixty-four percent received <7.5?mg/kg total rATG. There was no difference in age at transplant, gender, race, end-stage renal disease causes, or HLA mismatch among groups. Time to first-acute rejection was similar (P?=?0.07). There was no significant difference in graft or patient survival or time to posttransplant lymphoproliferative disorder. Hospitalization for infection rates was similar.

Conclusions

These data demonstrate a wide variation in cumulative rATG induction dose. A smaller rATG dose <7.5?mg/kg may provide effective and safe immunosuppression compared with a higher dose.

SUBMITTER: Ashoor IF

PROVIDER: S-EPMC7447457 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Publications

Reassessing Rabbit Antithymocyte Globulin Induction in Kidney Transplantation (RETHINK): An Analysis of the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) Registry.

Ashoor Isa F IF Martz Karen K Galbiati Shirley S Beyl Robbie A RA Dharnidharka Vikas R VR

Transplantation direct 20200821 9

<h4>Background</h4>There is no consensus on rabbit antithymocyte globulin (rATG) dose used for induction immunosuppression in pediatric kidney transplants. We aimed to identify whether a lower rATG dose provides safe and effective immunosuppression compared with a higher dose.<h4>Methods</h4>We retrospectively analyzed all first-time kidney transplant recipients (aged <21 y) in the North American Pediatric Renal Trials and Collaborative Studies registry since 1998 on mycophenolate mofetil- and t ...[more]

PMID: 32903852

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Project description:We conducted a randomized and unblinded 2 × 2 sequential-factorial trial, composed of an induction arm (part 1) comparing single-dose (SD) versus divided-dose rabbit antithymocyte globulin (rATG), and a maintenance arm (part 2) comparing tacrolimus minimization versus withdrawal. We report the long-term safety and efficacy of SD-rATG induction in the context of early steroid withdrawal and tacrolimus minimization or withdrawal.Patients (n=180) received 6 mg/kg rATG, SD or four alternate-day doses (1.5 mg/kg/dose), with early steroid withdrawal and tacrolimus or sirolimus maintenance. After 6 months targeted maintenance levels were tacrolimus, 2 to 4 ng/mL and sirolimus, 4 to 6 ng/mL or, if calcineurin inhibitor-withdrawn, sirolimus 8 to 12 ng/mL with mycophenolate mofetil 2 g two times per day. Primary endpoints were renal function (abbreviated modification of diet in renal disease) and chronic graft histopathology (Banff). Secondary endpoints included patient survival, graft survival, biopsy-proven rejection, and infectious or noninfectious complications.Follow-up averaged longer than 4 years. Tacrolimus or sirolimus and mycophenolate mofetil exposure was identical between groups. The SD-rATG associated with improved renal function (2-36 months; P<0.001) in deceased donor recipients. The SD-rATG associated with quicker lymphocyte, CD4 T cell, and CD4-CD8 recovery and fewer infections. Cox multivariate hazard modeling showed divided-dose-rATG (P=0.019), deceased donor (P=0.003), serious infection (P=0.0.018), and lower lymphocyte count (P=0.001) associated with increased mortality. Patients with all four covariates showed a 27-fold increased likelihood of death (P=0.00002). Chronic graft histopathology, rejection rates, and death-censored graft survival were not significantly different between groups.The SD-rATG induction improves the 3-year renal function in recipients of deceased donor kidneys. This benefit, along with possibly improved patient survival and fewer infections suggest that how rATG is administered may impact its efficacy and safety.

Project description:BackgroundRabbit-generated antithymocyte globulins (ATGs), which target human T cells, are widely used as immunosuppressive agents during treatment of kidney allograft recipients. However, ATGs can induce immune complex diseases, including serum sickness disease (SSD). Rabbit and human IgGs have various antigenic differences, including expression of the sialic acid Neu5Gc and ?-1-3-Gal (Gal), which are not synthesized by human beings. Moreover, anti-Neu5Gc antibodies have been shown to preexist and be elicited by immunization in human subjects. This study aimed to assess the effect of SSD on long-term kidney allograft outcome and to compare the immunization status of grafted patients presenting with SSD following ATG induction treatment.MethodsWe analyzed data from a cohort of 889 first kidney graft recipients with ATG induction (86 with SSD [SSD(+)] and 803 without SSD [SSD(-)]) from the Données Informatisées et Validées en Transplantation data bank. Two subgroups of SSD(+) and SSD(-) patients that had received ATG induction treatment were then assessed for total anti-ATG, anti-Neu5Gc, and anti-Gal antibodies using ELISA assays on sera before and after transplantation.ResultsSSD was significantly associated with long-term graft loss (>10 years, P = 0.02). Moreover, SSD(+) patients exhibited significantly elevated titers of anti-ATG (P = 0.043) and anti-Neu5Gc (P = 0.007) IgGs in late post-graft samples compared with SSD(-) recipients.ConclusionIn conclusion, our data indicate that SSD is a major contributing factor of late graft loss following ATG induction and that anti-Neu5Gc antibodies increase over time in SSD(+) patients.FundingThis study was funded by Société d'Accélération du Transfert de Technologies Ouest Valorisation, the European FP7 "Translink" research program, the French National Agency of Research, Labex Transplantex, the Natural Science and Engineering Research Council of Canada, and the Canadian Foundation for Innovation.

Dataset Information

Reassessing Rabbit Antithymocyte Globulin Induction in Kidney Transplantation (RETHINK): An Analysis of the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) Registry.

Background

Methods

Results

Conclusions

Publications

Reassessing Rabbit Antithymocyte Globulin Induction in Kidney Transplantation (RETHINK): An Analysis of the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) Registry.

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