Kathleen J. Nielsen

Randomized Trial of Single-Dose Versus Divided-Dose Rabbit Anti-Thymocyte Globulin Induction in Renal Transplantation : An Interim Report

Background. The optimal dosing protocol for rabbit anti-thymocyte globulin (rATG) induction in renal transplantation has not been determined, but evidence exists that rATG infusion before renal allograft reperfusion improves early graft function. Infusing a large rATG dose over a short interval has not previously been evaluated for its effect on renal function and allograft nephropathy in a prospective, randomized comparison against conventional rATG induction. Methods. Between April 20, 2004 and December 26, 2007 we enrolled renal transplant patients into a prospective, randomized, nonblinded trial of two rATG dosing protocols (single dose, 6 mg/kg vs. divided doses, 1.5 mg/kg every other day×4; target enrollment=160) followed after 6 months by calcineurin-inhibitor withdrawal. Primary endpoints are renal function by calculated glomerular filtration rate (GFR) and chronic allograft nephropathy at protocol biopsy. We now present the early GFR data of all 160 patients and safety and efficacy data of the first 142 patients with 6 months follow up and before calcineurin inhibitor withdrawal (average follow up=23.3±11.6 months). Results. There were no differences between groups in rATG-related adverse events, patient and graft survival, acute rejection, or chronic allograft nephropathy rate at 6 months. Calculated &Dgr;GFR (POD 1–4) was significantly better in the single-dose group (P=0.02), with a trend toward improved renal function from months 2 to 6 in recipients of deceased donor kidneys (P=0.08). Conclusions. This study demonstrates that administering 6 mg/kg of rATG over 24 hr is safe and is associated with improved early renal function compared with administering rATG in alternate-day doses.

Increased Primary Non-Function in Transplanted Deceased-Donor Kidneys Flushed with Histidine-Tryptophan-Ketoglutarate Solution

Histidine‐Tryptophan‐Ketoglutarate (HTK) solution is increasingly used to flush and preserve organ donor kidneys, with efficacy claimed equivalent to University of Wisconsin (UW) solution. We observed and reported increased graft pancreatitis in pancreata flushed with HTK solution, which prompted this review of transplanting HTK‐flushed kidneys. We analyzed outcomes of deceased‐donor kidneys flushed with HTK and UW solutions with a minimum of 12 months follow‐up, excluding pediatric and multi‐organ recipients. We evaluated patient and graft survival and rejection rates, variables that might constitute hazards to graft survival and renal function. Two‐year patient survival, rejection, renal function and graft survival were not different, but early graft loss (<6 months) was worse in HTK‐flushed kidneys (p < 0.03). A Cox analysis of donor grade, cold ischemic time, panel reactive antibodies (PRA), donor race, first vs. repeat transplant, rejection and flush solution showed that only HTK use predicted early graft loss (p < 0.04; relative risk = 3.24), almost exclusively attributable to primary non‐function (HTK, n = 5 (6.30%); UW, n = 1 (0.65%); p = 0.02). Delayed graft function and early graft loss with HTK occurred only in lesser grade kidneys, suggesting it should be used with caution in marginal donors.

Single-dose rATG induction at renal transplantation: superior renal function and glucoregulation with less hypomagnesemia.

Stevens RB, Lane JT, Boerner BP, Miles CD, Rigley TH, Sandoz JP, Nielsen KJ, Skorupa JY, Skorupa AJ, Kaplan B, Wrenshall LE. Single‐dose rATG induction at renal transplantation: superior renal function and glucoregulation with less hypomagnesemia. 
Clin Transplant 2012: 26: 123–132. 
© 2011 John Wiley & Sons A/S.

A Randomized 2×2 Factorial Trial, Part 1: Single-Dose Rabbit Antithymocyte Globulin Induction May Improve Renal Transplantation Outcomes

Background 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. Methods 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. Results 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. Conclusion 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.

Albuminuria after Renal Transplantation: Maintenance with Sirolimus/Low-Dose Tacrolimus vs. Mycophenolate Mofetil/High-Dose Tacrolimus

Miles CD, Skorupa JY, Sandoz JP, Rigley TH, Nielsen KJ, Stevens RB. Albuminuria after renal transplantation: maintenance with sirolimus/low‐dose tacrolimus vs. mycophenolate mofetil/high‐dose tacrolimus. 
Clin Transplant 2011: 25: 898–904.