Everolimus in heart transplantation: does it finally have a home?

This editorial approves the use of everolimus to wean calcineurin inhibitors (by 7­11 weeks postoperative) as safe and effective with improved first-year renal function and reduced intimal thickness by intravascular ultrasound. See article by Andreassen et al on page 1828.

Development of proteinuria after switch to sirolimus-based immunosuppression in long-term cardiac transplant patients.

Calcineurin-inhibitor therapy can lead to renal dysfunction in heart transplantation patients. The novel immunosuppressive (IS) drug sirolmus (Srl) lacks nephrotoxic effects; however, proteinuria associated with Srl has been reported following renal transplantation. In cardiac transplantation, the incidence of proteinuria associated with Srl is unknown. In this study, long-term cardiac transplant patients were switched from cyclosporine to Srl-based IS. Concomitant IS consisted of mycophenolate mofetil +/- steroids. Proteinuria increased significantly from a median of 0.13 g/day (range 0-5.7) preswitch to 0.23 g/day (0-9.88) at 24 months postswitch (p = 0.0024). Before the switch, 11.5% of patients had high-grade proteinuria (>1.0 g/day); this increased to 22.9% postswitch (p = 0.006). ACE inhibitor and angiotensin-releasing blocker (ARB) therapy reduced proteinuria development. Patients without proteinuria had increased renal function (median 42.5 vs. 64.1, p = 0.25), whereas patients who developed high-grade proteinuria showed decreased renal function at the end of follow-up (median 39.6 vs. 29.2, p = 0.125). Thus, proteinuria may develop in cardiac transplant patients after switch to Srl, which may have an adverse effect on renal function in these patients. Srl should be used with ACEi/ARB therapy and patients monitored for proteinuria and increased renal dysfunction.

Effect of mycophenolate mofetil therapy on inosine monophosphate dehydrogenase induction in red blood cells of heart transplant recipients.

BACKGROUND: Mycophenolic acid is reported to provide effective immunosuppression by inhibiting inosine monophosphate dehydrogenase. In an attempt to monitor the biological effects of long-term therapy with mycophenolate mofetil, we measured levels of guanosine 5' triphosphate and adenosine 5' triphosphate in red blood cells (RBCs) of patients after heart transplantations. METHODS: Fifty-two patients enrolled in the study were randomly assigned to one of two groups. Patients in the control group (n = 27) received cyclosporine A (INN, ciclosporin), azathioprine, and prednisone. Patients in the study group (n = 25) were switched from azathioprine to mycophenolate mofetil 3 months after the heart transplantation. Adenosine 5' triphosphate and guanosine 5' triphosphate levels were determined by means of HPLC. The activities of inosine monophosphate dehydrogenase and hypoxanthine-guanine phosphoribosyltransferase, which are responsible for guanine nucleotide formation, were measured in RBCs by radiochemical methods. RESULTS: Adenosine 5' triphosphate levels were unchanged in patients treated with mycophenolate mofetil, whereas those of the control group who received azathioprine (from 142 +/- 26 pmol/10(6) RBCs to 165 +/- 25 pmol/10(6) RBCs; P <.001) increased. As the length of mycophenolate mofetil therapy increased, patients in the study group showed significantly elevated guanosine 5' triphosphate levels (15.6 +/- 6.1 pmol/10(6) RBCs versus 6.6 +/- 2.1 pmol/10(6) RBCs; P <.001) and a 5-fold increase in inosine monophosphate dehydrogenase activity (108.6 +/- 13.3 pmol/mg of protein per hour versus 22.5 +/- 1.7 pmol/mg of protein per hour; P <.001) compared with the control group. In addition, a slight but significant enhancement of hypoxanthine-guanine phosphoribosyltransferase activity was seen in the mycophenolate mofetil group. CONCLUSIONS: Our studies have shown that long-term administration of mycophenolate mofetil is associated with increasing guanosine 5' triphosphate levels in RBCs as the result of an induction of inosine monophosphate dehydrogenase and hypoxanthine-guanine phosphoribosyltransferase activities in erythrocytes.

Improved long-term results with thymoglobuline induction therapy after cardiac transplantation: a comparison of two different rabbit-antithymocyte globulines.

BACKGROUND: The aim of this retrospective single center analysis was to compare possible long-term benefits of two different rabbit-antithymocyte globuline (ATG) induction therapies after cardiac transplantation. PATIENTS AND METHODS: A total of 484 primary cardiac transplanted patients received induction therapy with two different rabbit-ATGs (thymoglobuline: n=342, ATG-fresenius: n=142). All patients received immunosuppressive maintenance therapy with cyclosporine, azathioprine, and prednisolone. Cardiac rejection was assessed by serial endomyocardial biopsies. Surveillance of graft arteriosclerosis was performed by angiograms 1, 3, and 5 years after transplantation. RESULTS: Five-year survival was significantly better in the thymoglobuline group (76 vs. 60%). Thymoglobuline patients had a lower rate of death from rejection (2.3 vs. 10%; P<0.01) and graft arteriosclerosis (0.88 vs. 5.6%; P<0.01). After 5 years, freedom from rejection was 72% in the thymoglobuline group compared to 42% in the ATG-fresenius group (P<0.01). Graft arteriosclerosis appeared in 14% of thymoglobuline patients and in 28% of ATG-fresenius patients (P<0.01). Viral infections occurred more often in thymoglobuline patients (53 vs. 39%, P<0.05) although there was no difference in appearance of cytomegalovirus disease (17 vs. 13%). Freedom from posttransplant malignant disease was comparable between the two groups. CONCLUSION: These results suggest that there are differences between rabbit ATG products. The superior prevention of rejection with thymoglobuline may be the reason for the lower rate of graft arteriosclerosis.

Introducing a mouse model of brain death.

Experimental animal models of brain death increasing intracranial pressure (ICP) by inflating an intracranial placed balloon-catheter are well established and used in transplant-associated studies. Our aim was to develop an experimental mouse model of brain death (BD) and to compare explosive and gradual brain death induction under ICP monitoring. We therefore induced BD in female OF-1 mice by injecting 40 microl saline every 5 min into an intracranial placed balloon increasing ICP rapidly [BD ex, n=7], or gradually [BD grad, n=7] with 20 microl volume every 5 min under electroencephalogram (EEG) and ICP monitoring until BD occurred. The major criterion for BD was a flat-line-EEG, confirmed by cessation of spontaneous respiration and maximally dilated and fixed pupils. ICP, central activity and heart rate were continuously monitored during the entire 6h follow-up. In sham-operated controls [control, n=7] a burr hole was drilled but no balloon inserted. The BD groups showed equal ICP levels at the time of BD. Both groups had increased heart rates (HR) 15 min after BD, HR decreased to 402+/-29.39 bpm (beats per minute) [BD ex] and 409.33+/-26.46 bpm [BD grad] (n.s. vs. control) by 30 min after the inflation of the balloon, but only BD ex showed a significant decrease in HR compared to control, progressively decreasing thereafter. On the basis of these results, we conclude that the mouse model of brain death can be performed in a standardized, reproducible and successful way.

Pre- and early postoperative risk factors for death after cardiac transplantation: a single center analysis.

Due to the limited number of donor organs, death on the waiting list and waiting time for cardiac transplantation have markedly increased. A pressing need of appropriate selection criteria for patients who would benefit most from transplantation is apparent. The purpose of this study is to identify pre- and early postoperative risk factors that influence long term survival after cardiac transplantation. 702 consecutive patients who underwent cardiac transplantation between 3/1984 and 12/1997 were analyzed retrospectively for the influence of different pre- and early postoperative risk factors on early (30 days) and late death (5 years). Univariate and multivariate regression analysis revealed risk factors for early as well as late death. Predictors of early death were higher preoperative PVR, retransplantation, longer ischemic time, postoperative acute kidney failure and longer intubation time. Risk factors for late death were early transplant era, previous cardiac surgery, patients awaiting transplantation in a hospital, prolonged stay in an intensive care unit, and any rejection during the first month after transplantation. These results demonstrate that pre- and early postoperative risk factors have significant influence on early and long term survival.