The Influence of Antithymocyte Globulin Dose on the Incidence of CMV Infection in High-risk Kidney Transplant Recipients Without Pharmacological Prophylaxis

Abstract

Background. Optimizing antithymocyte globulin (ATG) dosage is critical, particularly for high-risk kidney transplant (KT) recipients without cytomegalovirus (CMV) prophylaxis. Methods. We studied 630 KT recipients with expanded criteria donors or panel reactive antibody ≥50% at Hospital do Rim, Brazil (January 1, 2013 to May 21, 2015) to determine whether a single ATG dose was safe and effective in patients without CMV prophylaxis. Patients received ≥4 doses (1–1.5 mg/kg/per dose) until June 17, 2014, when the induction protocol changed to a single ATG dose (3 mg/kg). We used Cox regression to compare the risk of CMV infection and acute rejection (AR) among KT recipients by ATG dose. Results. Adjusting for clinical and transplant factors, a single ATG dose was associated with a lower risk of CMV infection (adjusted hazard ratio [aHR]: 0.63; 95% confidence interval [CI], 0.42-0.93; P = 0.02) and a similar risk of AR (aHR: 1.16; 95% CI, 0.47-2.83; P = 0.8), compared to multiple doses. We found no differences in death-censored graft loss (5.0% versus 4.8%, aHR: 1.06; 95% CI, 0.51-2.23; P = 0.9) or mortality (4.7% versus 3.4%; aHR: 1.42; 95% CI, 0.62-3.24; P = 0.4) at 1-year post-KT by ATG dose. Conclusions. In our study of high-risk KT recipients without CMV prophylaxis, a single ATG dose decreased the risk of CMV infection without increasing the risk of AR or compromising graft or patient survival.

Decreased incidence of acute rejection without increased incidence of cytomegalovirus (CMV) infection in kidney transplant recipients receiving rabbit anti‐thymocyte globulin without CMV prophylaxis – a cohort single‐center study

“…We are still using this drug combination based on the large US cohort analysis showing similar long‐term outcomes compared with mycophenolate, despite higher incidence of acute rejection [8]. Furthermore, in our kidney transplant population, the tolerability of mycophenolate is lower [4] and the incidence of CMV infection/disease is higher, thus limiting its use to higher risk patients [5].…”

“…First, the annual cost of the combination of tacrolimus and mycophenolate is 2.8 times higher compared with tacrolimus and azathioprine (US$ 1048.00 vs. US$ 368.00) for each patient receiving standard doses of each drug combination, based on the unitary cost paid by the national public unified health system (https://paineldeprecos.planejamento.gov.br/). Secondly, the incidence of CMV infection/disease is higher among patients receiving rATG 3 mg/kg in combination with tacrolimus and mycophenolate (62.5%) [5] than in those receiving tacrolimus and azathioprine in this analysis (33.7%). Finally, additional US$ 7654.00 would be necessary only to provide CMV prophylaxis for 90 days with valganciclovir, regardless of the immunosuppressive drug combination.…”

“…Yet, in our local population, tolerability and safety of mycophenolate is limited by the disproportional incidence of gastrointestinal, bone marrow and cytomegalovirus (CMV) infection adverse events, leading to premature drug discontinuation [4]. Hence, this drug combination is limited to higher risk patients, namely highly sensitized patients and those at higher risk to develop delayed graft function [5]. Accordingly, the combination of tacrolimus (TAC), azathioprine (AZA), and prednisone (PRED) has been used in low immunological risk KTR.…”

Antithymocyte induction dosing and incidence of opportunistic viral infections using steroid‐free maintenance immunosuppression

“…Of the potential adverse effects, infection is often the most immediate concern given the high incidence and potential severity in the post‐transplant population 7 . Opportunistic viral infections, particularly cytomegalovirus (CMV), are common post‐transplant and have been associated with rATG induction particularly at higher doses 8‐11 . However, existing literature utilizes varying rATG cutoffs to define low‐dose versus high‐dose cumulative rATG therapy though most commonly the split is made between 3 and 5 mg/kg 8,12‐16 …”

“…The available evidence supporting lower doses of rATG to minimize the risk of infection has been previously studied in populations receiving triple maintenance immunosuppression with a calcineurin inhibitor 8,12‐14 . Currently, there is limited literature evaluating rATG induction dosing and incidence of opportunistic viral infections when using steroid‐free maintenance immunosuppression.…”