Heidi M. Schaefer

A randomized study evaluating cinacalcet to treat hypercalcemia in renal transplant recipients with persistent hyperparathyroidism

Persistent hyperparathyroidism (HPT) after kidney transplantation (KTx) is associated with hypercalcemia, hypophosphatemia and abnormally high levels of parathyroid hormone (PTH). In this randomized trial, cinacalcet was compared to placebo for the treatment of hypercalcemia in adult patients with persistent HPT after KTx. Subjects were randomized 1:1 to cinacalcet or placebo with randomization stratified by baseline corrected total serum calcium levels (≤11.2 mg/dL [2.80 mmol/L] or >11.2 mg/dL [2.80 mmol/L]). The primary end point was achievement of a mean corrected total serum calcium value <10.2 mg/dL (2.55 mmol/L) during the efficacy period. The two key secondary end points were percent change in bone mineral density (BMD) at the femoral neck and absolute change in phosphorus; 78.9% cinacalcet‐ versus 3.5% placebo‐treated subjects achieved the primary end point with a difference of 75.4% (95% confidence interval [CI]: 63.8, 87.1), p < 0.001. There was no statistical difference in the percent change in BMD at the femoral neck between cinacalcet and placebo groups, p = 0.266. The difference in the change in phosphorus between the two arms was 0.45 mg/dL (95% CI: 0.26, 0.64), p < 0.001 (nominal). No new safety signals were detected. In conclusion, hypercalcemia and hypophosphatemia were effectively corrected after treatment with cinacalcet in patients with persistent HPT after KTx.

Serum sickness following rabbit antithymocyte-globulin induction in a liver transplant recipient : Case report and literature review

Thymoglobulin® (Genzyme, Cambridge, MA) is an antithymocyte globulin preparation used for induction immunosuppression therapy in solid organ transplantation. It is being utilized with increasing frequency in orthotopic liver transplantation (OLT) in an effort to minimize or delay the use of calcineurin inhibitors due to their inherent nephrotoxicity. Experience with thymoglobulin in OLT remains limited. We report a case of serum sickness in a patient who received thymoglobulin following OLT. The patient experienced intermittent fevers, polyarthralgia, and acute renal failure 9 days after completion of thymoglobulin administration. The patients symptoms resolved rapidly and completely with a course of intravenous steroids. We review a set of diagnostic criteria for serum sickness and emphasize the importance of early recognition of the process. Early treatment of serum sickness with steroids or plasmapheresis is highly effective and can reduce unnecessary morbidity from this unusual sequela of induction immunosuppression with antithymocyte globulin. Liver Transpl.

Novel Once-Daily Extended-Release Tacrolimus Versus Twice-Daily Tacrolimus in De Novo Kidney Transplant Recipients: Two-Year Results of Phase 3, Double-Blind, Randomized Trial

BACKGROUND 1-year data from this trial showed the noninferiority of a novel once-daily extended-release tacrolimus (LCPT; Envarsus XR) to immediate-release tacrolimus (IR-Tac) twice daily after kidney transplantation. STUDY DESIGN Final 24-month analysis of a 2-armed, parallel-group, randomized, double-blind, double-dummy, multicenter, phase 3 trial. SETTING & PARTICIPANTS 543 de novo kidney recipients randomly assigned to LCPT (n=268) or IR-Tac (n=275); 507 (93.4%) completed the 24-month study. INTERVENTION LCPT tablets once daily at 0.17 mg/kg/d or IR-Tac twice daily at 0.1 mg/kg/d; subsequent doses were adjusted to maintain target trough ranges (first 30 days, 6-11 ng/mL; thereafter, 4-11 ng/mL). The intervention was 24 months; the study was double blinded for the entirety. OUTCOMES & MEASUREMENTS Treatment failure (death, transplant failure, biopsy-proven acute rejection, or loss to follow up) within 24 months. Safety end points included adverse events, serious adverse events, new-onset diabetes, kidney function, opportunistic infections, and malignancies. Pharmacokinetic measures included total daily dose (TDD) of study drugs and tacrolimus trough levels. RESULTS 24-month treatment failure was LCPT, 23.1%; IR-Tac, 27.3% (treatment difference, -4.14% [95% CI, -11.38% to +3.17%], well below the +10% noninferiority criterion defined for the primary 12-month end point). Subgroup analyses showed fewer treatment failures for LCPT versus IR-Tac among black, older, and female recipients. Safety was similar between groups. From month 1, TDD was lower for LCPT; the difference increased over time. At month 24, mean TDD for LCPT was 24% lower than for the IR-Tac group (P<0.001), but troughs were similar (means at 24 months: LCPT, 5.47 ± 0.17 ng/mL; IR-Tac, 5.8 ± 0.30 ng/mL; P=0.4). LIMITATIONS Trial participant eligibility criteria may limit the generalizability of results to the global population of de novo kidney transplant recipients. CONCLUSIONS Results suggest that once-daily LCPT in de novo kidney transplantation has comparable efficacy and safety profile to that of IR-Tac. Lower TDD reflects LCPTs improved bioavailability and absorption.

Caring for the pregnant kidney transplant recipient.

Concepcion BP, Schaefer HM. Caring for the pregnant kidney transplant recipient. 
Clin Transplant 2011: 25: 821–829.

Lower risk of urinary tract infection with low-dose trimethoprim/sulfamethoxazole compared to dapsone prophylaxis in older renal transplant patients on a rapid steroid-withdrawal immunosuppression regimen.

Giullian JA, Cavanaugh K, Schaefer H. Lower risk of urinary tract infection with low‐dose trimethoprim/sulfamethoxazole compared to dapsone prophylaxis in older renal transplant patients on a rapid steroid‐withdrawal immunosuppression regimen.
Clin Transplant 2009 DOI: 10.1111/j.1399‐0012.2009.01129.x
© 2009 John Wiley & Sons A/S.

HMG-CoA reductase inhibitors in kidney transplant recipients receiving tacrolimus: statins not associated with improved patient or graft survival

BackgroundThe beneficial effects of early statin use in kidney transplant recipients, especially those on tacrolimus-based immunosuppression, are not well established. We evaluated the predictors of statin use following kidney transplantation and examined its association with patient and allograft survival.MethodsWe examined 615 consecutive patients who underwent kidney transplant at our institution between January 1998 and January 2002. Statin use was assessed at baseline and 3, 6, 9, and 12 months following kidney transplant. Patients were followed for allograft and patient survival.Results36% of the 615 kidney transplant recipients were treated with statin treatment. Statin use increased over the course of the study period. Older age, elevated body mass index, higher triglyceride levels, hypercholesterolemia, diabetes, history of myocardial infarction were associated with higher rates of statin use; elevated alkaline phosphatase levels and CMV IgG seropositivity were associated with less statin use. Older age, elevated BMI and hypercholesterolemia remained significant predictors of increased statin use after accounting for covariates using multiple regression. The early use of statins was not associated with improvements in unadjusted patient survival [HR 0.99; 95%CI 0.72-1.37] or graft survival [HR 0.97; 95% CI 0.76-1.24]. The risks of death and graft survival were not consistently reduced with exposure to statin using either adjusted models or propensity scores in Cox Proportional Hazards models.ConclusionsIn a kidney transplant population primarily receiving tacrolimus-based immunosuppression, early statin use was not associated with significantly improved graft or patient survival.

Evaluation of living kidney donors: variables that affect donation.

Approximately 10000 deceased donor organs are available yearly for 85 000 US patients awaiting kidney transplant. Living kidney donation is essential to close this gap and offers better survival rates. However, nationally, 80% of potential donors evaluated fail to donate. Nurse coordinators who perform predonation screening and education need additional insight into the large number of potential donors who fail to complete the donation process. Reasons for nondonation in donor candidates undergoing medical evaluation, and variables affecting nondonation at Vanderbilt University Medical Center between 2004 and 2009 are examined. Multivariable logistic regression models are used to test the effects of age and race on donation status and reasons for nondonation. Summary data are frequencies, percentages, and means (SD). The sample included 706 candidates (63% female, 80% white; mean age, 40 [SD, 12] years). Almost half (46%) received clearance to donate. Undiagnosed hypertension (14%), abnormal glucose tolerance (10%), and proteinurea (9%) were the most prevalent medical reasons for nondonation. About 13% of candidates changed their minds during evaluation. Analyses demonstrated an increased likelihood of older candidates (P < .001) and a decreased likelihood of white candidates (P = .007) being excluded from donation. Within the nondonation group, increased age was associated with undiagnosed hypertension and abnormal glucose tolerance (both race-adjusted, P = .01). Younger candidates (race-adjusted, P = .003) and African Americans (age-adjusted, P = .04) were more likely to decide against donation. The most prevalent medical reasons for nondonation could be identified through enhanced prescreening, and improved preevaluation education could decrease nondonation rates.

Allograft Nephrectomy after Transplant Failure: Should It Be Performed in All Patients Returning to Dialysis?

Although considerable advances in the field of transplantation have improved short-term outcomes, little impact has been made on the long-term success of transplant allografts. As a result, a substantial proportion of patients will ultimately return to dialysis and the milieu of ESRD. Approximately 20% of all renal patients on the transplant waiting list in the United States have had a previously failed allograft.1 This population has high mortality with 10-yr survival of <40% and with some suggesting that continued efforts to maintain the allograft through the use of low-dosage immunosuppression as contributing.2 In this issue of JASN , Ayus et al. 3 report that patients who have failed allografts, return to dialysis, and undergo allograft nephrectomy have improved survival as compared with those in whom the allograft is retained. This is an interesting finding and one that will generate considerable discussion in the transplant community and further fuel the debate regarding the role of transplant nephrectomy in the treatment of this particular subset of patients. We agree there may be beneficial effects of transplant nephrectomy, but one should not generalize the findings of Ayus et al. recommending removal of allografts to all patients …

Mortality After Kidney Transplantation: What Lessons Can We Learn from Regional and Country Variation?

Kim and colleagues interrogating the Scientific Registry of Transplant Recipients (SRTR) from U.S. government mandated data collection and the Canadian Organ Procurement Register (CORR), report variant renal transplant mortality rates between the two countries. The transplant community has struggled with how to satisfy the moral and scientific imperative of reporting outcomes data in our field and the potential for raw data being misunderstood even culminating in false conclusion. To address this dialectic, members of United Network of Organ Sharing (UNOS), the organization tasked by Congress to collect and report transplant outcomes data, developed an explanatory algorithm which takes into account demographic and case-mix differences that define regions in the USA so that the public can interpret the raw data against expected norms. We believe the publication of the raw outcomes data in Kim et al., while hypothesis generating, demands further interpretation and explication. We would advance at least four possible explanations for the outcomes differences reported in this issue of the Journal which we will explore in turn; (1) the possible bias generated when mandatory registries are compared to those voluntary; (2) case-mix differences with particular reference to differences in the denominator in morbidity data in terms of comorbid burden; (3) differences in longterm practice both preand post-transplant; and finally, (4) differences imposed by the composition of the health care delivery systems between the two countries.

Long-Term Management of the Kidney Transplant Recipient

Due to the successes of kidney transplantation, patients with allografts are enjoying long-term survival. In addition to care of the allograft with lifelong administration of immunosuppressive medications, common medical conditions must be recognized and managed appropriately. With constraints on the transplant centers and patient considerations of finance and geography, it is recognized that community providers will play an ever increasing role in the care of the kidney transplant recipient. Guidelines for understanding and managing some of the more important common general medical problems, including care as it relates to cardiovascular disease, chronic kidney disease, transplant-related issues, and general health maintenance, are reviewed in this article.