Harold C. Yang

Adverse effect of donor vasopressor support on immediate and one-year kidney allograft function

BACKGROUND This purpose of this study was to determine if there was a significant difference between the rates of acute tubular necrosis (ATN) and long-term graft survival in renal allografts procured from donors requiring inotropic support (DRIS) and those from donors not requiring inotropic support. METHODS Eighty-two consecutive cadaveric renal transplant patients were prospectively followed in our local procurement area, the Delaware Valley Transplant Program. Forty-eight patients received organs from DRIS (> 10 mcg/kg per minute of dopamine, dobutamine, epinephrine, and norepinephrine alone or in combination), and 34 did not. RESULTS Allografts from the non-DRIS group had an immediate function rate of 82.4% and a 1-year function rate of 91.2%. In comparison, the DRIS grafts had an immediate function rate of 58.3% and a 1-year function rate of 72.9%. These differences were statistically significant. The mean serum creatinine in the non-DRIS group was 1.46 +/- 0.58 mg/dl, whereas in the DRIS cohort it was 1.89 +/- 0.93 mg/dl. CONCLUSIONS Kidneys transplanted from DRIS had significantly (1) poorer immediate function, (2) worse 1-year survival rates, and (3) higher serum creatinine at 1 year. We conclude that recipients receiving organs from donors requiring inotropic support are at a higher risk of developing ATN after surgery and experience reduced 1-year function.

Tacrolimus/“low-dose” mycophenolate mofetil versus microemulsion cyclosporine/“low-dose” mycophenolate mofetil after kidney transplantation—1-year follow-up of a prospective, randomized clinical trial

INCE its introduction, cyclosporine, a macrolide molecule that inhibits expression of interleukin-2 by lymphocytes, when administered prophylactically in combination with corticosteroids and/or azathioprine, has dramatically improved results of solid organ transplantation. 1 Recently, microemulsion formulation of cyclosporine (Neoral), when compared with CsA, was found to provide better immunosuppression, primarily due to improvement in drug bioavailability. 2 In a multicenter clinical trial, tacrolimus (FK 506), another macrolide molecule with mode of action similar to CsA, was found to be more effective than CsA in the prevention of rejection in renal transplant recipients. 3 Mycophenolate mofetil (MMF), the morpholinoethylester of mycophenolic acid, is an uncompetitive, reversible inhibitor of eukaryotic inosine monophosphate dehydrogenase, a key enzyme in the de novo pathway of purine synthesis during lymphocyte proliferation. 4 In European, tricontinental, and American multicenter clinical trials, MMF in 2- and 3-g doses, when compared with azathioprine/placebo, significantly reduced the incidence of acute rejection in renal transplant recipients. 5‐7

Elevation of Renal Glutathione Enhances Ischemic Injury

In a previous study, we tested the hypothesis that an elevated level of renal glutathione (GSH) would protect the kidney from ischemic injury. However, prior elevation of GSH with GSH monoethylester enhanced then injury induced by 35 min of ischemia and blood reflow [Scaduto RC Jr, Gattone VH, Grotyohann LW, et al; Effect of an altered glutathione content on renal ischemic injury. Am J Physiol 1988;255:F911-F921]. Additionally, GSH monoethylester produced morphologic alterations in the absence of ischemia. Thus the greater ischemic injury observed after GSH ester pretreatment could have been due to a synergistic effect between the events caused by ischemia and the pretreatment. The present study was conducted to evaluate the utility of elevating renal GSH levels by administration of GSH. Administration of GSH (1 mmol/kg body weight) caused a 3-fold elevation of renal GSH levels and a 6-fold elevation of renal cysteine levels after 60 min without causing changes in renal morphology or GFR. After 35 min of renal artery occlusion and 90 min of blood reflow, animals pretreated with GSH had a much greater decline in GFR than untreated control animals. This enhancement of renal ischemic injury in GSH-treated animals was similar to that observed following administration of GSH monoethylester. We conclude that administration of GSH is the method of choice for elevation of renal GSH and that elevation of renal GSH leads to an enhanced ischemia-induced injury which is independent of the method employed to elevate renal GSH.

The effect of glutathione content on renal function following warm ischemia

Reperfusion after ischemia produces tissue injury due to free radicals generated during the reflow period. Glutathione (GSH) mediates against this oxidant damage by scavenging free radicals and protecting cells against injury. In an attempt to reduce the injury caused by free radicals, rat kidneys were pretreated with GSH monoethyl ester to elevate renal GSH fivefold. Previous studies in a renal artery occlusion model showed that pretreated kidneys in comparison to untreated controls were functionally impaired as measured by glomerular filtration rate, urine flow rate, and histology. To eliminate systemic effects of the pretreatment, kidneys were subjected to a fixed period of warm ischemia but flushed of blood and transplanted into nonpretreated syngeneic recipients. As before, pretreated kidneys exhibited marked functional impairment. We conclude that (i) elevation of renal GSH with GSH monoethyl ester enhances rather than prevents renal dysfunction and (ii) the enhancement of renal ischemic injury following pretreatment is not due to nonspecific systemic effects of GSH monoethyl ester pretreatment.

A comparative study of 500 mg BID and 250 mg BID of prophylactic oral ganciclovir in post–kidney transplant “CMV at risk” recipients

HUMAN cytomegalovirus (CMV) is a ubiquitous pathogen that is the major cause of morbidity and mortality in immunocompromised individuals, such as organ transplant recipients. As many as 70%–80% of recipients of solid organ transplants show evidence of CMV infection. It is well recognized that the incidence of posttransplant CMV infection depends on various factors including overall immunosuppression, underlying CMV status of both donor and recipients, and antiviral prophylaxis. Recently, we reported on the effectiveness of an oral formulation of ganciclovir in reducing CMV infection in kidney transplant recipients. This study prospectively examines the efficacy of two different regimens of oral ganciclovir in microemulsion cyclosporine/“low-dose” mycophenolate mofetil (MMF)-treated renal transplant patients.