Protopic
Post-transplant diabetes mellitus: the last 10 years with tacrolimus.

Backman LA.

Department of Transplantation and Liver Surgery, Sahlgrenska University Hospital, SE-413 45 Gothenburg, Sweden. lars.backman surgery.gu.se

Post-transplant diabetes mellitus (PTDM) is a key risk factor for cardiovascular disease, which itself is a leading cause of death with a functioning graft. In a published review of the literature on PTDM and immunosuppression, most cases of PTDM were diagnosed within the first 3 months post-transplantation. In renal transplantation, the type of immunosuppressive regimen accounted for 74% of the variability recorded in the 12 month cumulative incidence of PTDM between studies (P = 0.0004), with inclusion of corticosteroids and/or high-dose ciclosporin or tacrolimus being the main risk factors for development of PTDM. Other key risk factors were recipient age and non-white ethnicity. The diabetic potential of any immunosuppressive protocol depends on the combination of agents used and the corresponding doses. Therefore, we conducted an analysis to investigate the impact of different tacrolimus-based regimens employed over the past decade together with the time of study initiation on the incidence of PTDM. There was a progressive decline in the incidence of PTDM with year of study initiation, from 20% in the early 1990s to 0-5% most recently. The low incidences of PTDM were achieved with those protocols employing lower blood levels of tacrolimus and/or corticosteroid elimination. These results emphasize the importance of reducing the immunosuppressive medication load and the role of corticosteroids in the development of PTDM. Evolving tacrolimus-based immunosuppressive protocols for renal transplantation over the last 10 years, particularly in terms of tacrolimus dosing and corticosteroid elimination, has led to a reduction in PTDM-related morbidity without compromising efficacy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15575021&dopt=Abstract tacrolimus Protopic



Protopic
Association of hepatitis C with posttransplant diabetes in renal transplant patients on tacrolimus.

Bloom RD, Rao V, Weng F, Grossman RA, Cohen D, Mange KC.

Renal-Electrolyte and Hypertension Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. rdbloom mail.med.upenn.edu

Posttransplant diabetes mellitus (PTDM) remains a common complication of immunosuppression. Although multiple risk factors have been implicated, none have been clearly identified as predisposing to the increased PTDM frequency observed in patients on tacrolimus. Hepatitis C virus (HCV) has been associated with diabetes and is a significant renal transplant comorbidity. In this study, records of 427 kidney recipients who had no known diabetes before transplantation were retrospectively examined. A multivariate logistic regression model was fit with covariates that had unadjusted relationships with PTDM to examine the independent relationship of HCV and the odds of development of PTDM by 12 mo posttransplant. A potential interaction between HCV and the use of tacrolimus as maintenance therapy on the odds of the development of PTDM was examined. Overall, PTDM occurred more frequently in HCV(+) than HCV(-) patients (39.4% versus 9.8%; P = 0.0005). By multivariate logistic regression, HCV (adjusted odds ratio [OR], 5.58; 95% confidence interval [CI], 2.63 to 11.83; P = 0.0001), weight at transplantation (adjusted OR 1.028; 95% CI, 1.00 to 1.05; P = 0.001), and tacrolimus (adjusted OR, 2.85; 95% CI, 1.01 to 5.28; P = 0.047) were associated with PTDM. A significant interaction (P = 0.0001) was detected between HCV status and tacrolimus use for the odds of PTDM. Among the HCV(+) cohort, PTDM occurred more often in tacrolimus-treated than cyclosporine A-treated patients (57.8% versus 7.7%; P < 0.0001). PTDM rates in HCV(-) patients were similar between the two calcineurin inhibitors (10.0% versus 9.4%; P = 0.521, tacrolimus versus cyclosporine A). In conclusion, HCV is strongly associated with PTDM in renal transplant recipients and appears to account for the increased diabetogenicity observed with tacrolimus.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11961026&dopt=Abstract tacrolimus Protopic



Protopic
Daclizumab induction, tacrolimus, mycophenolate mofetil and steroids as an immunosuppression regimen for primary kidney transplant recipients.

Ciancio G, Burke GW, Suzart K, Roth D, Kupin W, Rosen A, Olson L, Esquenazi V, Miller J.

Department of Surgery, Division of Transplantation, University of Miami School of Medicine, Miami, FL 33101, USA.

BACKGROUND: Recent reports have demonstrated the efficacy of interleukin-2-receptor blockers in lowering the incidence of early acute rejection in cyclosporine-treated kidney recipients when compared to patients not induced with an antibody product. The addition of daclizumab to a tacrolimus-mycophenolate mofetil-based immunosuppressive protocol was tested to evaluate whether there might be an additional reduction of the risk of rejection after renal transplantation. METHODS: Since March 1998, we studied the effect of daclizumab in a nonrandomized, prospective study of 233 sequential recipients of first renal transplant. They were retrospective compared with a control group of 225 renal transplant recipients receiving a 10-day course of OKT3 induction, and tacrolimus, mycophenolate mofetil, and methylprednisolone maintenance. The study group received the same immunosuppressive regimen with the addition of daclizumab at 1 mg/kg for five doses over 10 weeks in the place of OKT3 therapy. There was at least 1HLA DR antigen compatibility match present between all donors and recipients. Patients were followed for 1 year after renal transplantation for the incidence of biopsy-proven acute rejection, patient and graft survival, and adverse events. RESULTS: At 12 months, patient and graft survival for the daclizumab was 98 and 96 vs. 96 and 94% for the OKT3 group, respectively, and were not statistically different. Acute rejection rates (<6 months) were lower in the daclizumab group as compared with the OKT3 group, i.e., 5 (2.1%) vs. 16 (7.1%) (P=0.011) respectively. The incidence of infection requiring hospitalization appeared to be lower with daclizumab (7.3 vs. 16%, P<0.0036) with a similar trend with cyclomegalovirus infection, i.e., 1.6 vs. 4%, respectively (P=0.14). CONCLUSIONS: The combination of daclizumab, tacrolimus, mycophenolate mofetil, and steroids is safe and effective for kidney transplant recipients in lowering the incidence of early acute rejection and without any increase in morbidity when compared to our previous protocol, which may have an eventual impact in long-term graft survival.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11965039&dopt=Abstract tacrolimus Protopic



Protopic
Improving long-term renal transplant outcomes with tacrolimus: speculation vs evidence.

First MR.

Research and Development, Fujisawa Healthcare, Inc., Three Parkway North, Deerfield, IL 60015-2548, USA. roy_first fujisawa.com

Achieving long-term graft survival and optimal patient health are ultimate clinical goals in renal transplantation. Many factors negatively impact long-term transplant outcomes, including graft rejection, renal dysfunction and increased cardiovascular burden. Additionally, glucose metabolism disturbance, also a cardiovascular risk factor, influences morbidity and mortality. As such, careful consideration of the immunosuppressive strategy and its impact on these factors is critical to optimizing outcomes. Large-scale clinical trials and registry studies conducted over the past decade have demonstrated tacrolimus to be a cornerstone immunosuppressant in renal transplantation. Compared with ciclosporin treatment, tacrolimus has been shown to be associated with decreased acute and chronic rejection, improved renal function over the long term post-transplant, as evidenced by lower serum creatinine concentrations and a slower decline in the glomerular filtration rate, and a superior cardiovascular risk profile, as demonstrated by lower incidences of hyperlipidaemia and hypertension. The incidence of new-onset diabetes in patients receiving tacrolimus is low due to continued refinement of tacrolimus-based regimens and a better understanding of the effects of tacrolimus on metabolic parameters. Together, these findings may translate into improved long-term transplant outcomes with tacrolimus-based immunosuppression. In fact, long-term follow-up results from multicentre trials plus data from registry analyses are already documenting improved survival with this cornerstone immunosuppressant.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15575022&dopt=Abstract tacrolimus Protopic



Protopic
Renal function: defining long-term success.

Pascual J, Marcen R, Ortuno J.

Department of Nephrology, Ramon y Cajal Hospital, Ctra Colmenar Viejo Km9.1, Madrid 28034, Spain. jpascual.hrc salud.madrid.org

One of the leading causes of late graft loss is chronic allograft nephropathy, characterized in part by deteriorating renal function. Registry data have demonstrated that renal function within the first year post-transplant is an important predictor of long-term transplant outcome, with serum creatinine concentrations < or =1.5 mg/dl at 6 or 12 months being associated with the highest rate of 5 year graft survival. These findings are supported by a retrospective, pooled analysis of two multicentre trials in the USA, as well as by our own data showing that serum creatinine concentrations may be predictive of long-term survival as early as 1 month post-transplant. Analysis of 216 renal transplantations carried out at our centre (1996-2000) using immunosuppressive therapy based on tacrolimus, corticosteroids and azathioprine (n = 51) or mycophenolate mofetil (MMF; n = 70) vs ciclosporin microemulsion, azathioprine and corticosteroids (n = 95) showed that the best 3 year graft survival was achieved with tacrolimus/MMF therapy. While serum creatinine concentrations at this time point were similar for the tacrolimus and ciclosporin treatment groups (1.69 and 1.65 mg/dl, respectively), the proportion of patients with functioning grafts was significantly higher in the tacrolimus group (84 vs 67%, P = 0.007). Similar findings of improved renal function or graft outcomes with tacrolimus- vs ciclosporin-based therapy have been reported in other single-centre and multicentre trials and a USRDS registry survey. Accumulating data suggest that renal function compares well between tacrolimus-based and calcineurin inhibitor (CNI)-sparing regimens. Consequently, the vast majority of renal transplant recipients maintain good long-term renal function with tacrolimus cornerstone immunosuppression without adopting CNI minimization or withdrawal strategies.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15575023&dopt=Abstract tacrolimus Protopic



Protopic
Good metabolic control using tacrolimus-based immunosuppressants in primary cadaveric renal transplantation in Chinese--a preliminary report.

Chow KM, Szeto CC, Li PK.

Department of Med cine and Therapeutics, The Chinese University of Hong Kong, Shatin, SAR.

Metabolic complications are common with tacrolimus therapy. Recent evidence suggests that there is ethnical variability in the side-effect profile of tacrolimus. We performed an open-label study to examine the metabolic profile of tacrolimus-based immunosuppressive therapy in 10 consecutive adult Chinese patients after cadaveric renal transplantation. One case withdrew because of parvovirus infection. The mean age of the remaining nine cases was 33 +/- 2.9 yr. Mean tacrolimus whole blood trough level at 0 and 12 months were 11.4 +/- 1.8 and 7.0 +/- 0.7 ng/mL, respectively. The dosage at corresponding time points were 0.31 +/- 0.001 and 0.10 +/- 0.003 mg/kg, respectively. We found no difference in lipid profile, blood pressure control, and most importantly, fasting glucose level, before and I yr after tacrolimus therapy. Standard 75-g oral glucose tolerance test and whole blood HbAlc level were normal in all patients. Our preliminary data suggest good short-term safety among Chinese renal transplantation recipients after tacrolimus-based immunosuppressants, with a very low incidence of hyperglycemia, hypertension and dyslipidemia. The long-term implications and the underlying explanation for this ethnical difference require further investigations.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11982613&dopt=Abstract tacrolimus Protopic



Protopic
Quality of life in kidney recipients: comparison of tacrolimus and cyclosporine-microemulsion.

Reimer J, Franke GH, Philipp T, Heemann U.

Department of Nephrology, University of Essen, Center for Medicine, Germany.

Treatment of end-stage renal disease (ESRD) is evaluated by survival, quality of life (QOL) and cost-effectiveness. Little is known about the influence of immunosuppressive agents on global and disease-specific QOL in kidney recipients. In winter 1997/98 (t0) as well as in winter 1998/99 (t1), all kidney recipients of our University were asked to participate in a QOL study. The psychodiagnostic approach combined a global QOL-measure (SF-36 Health Survey) and a disease-specific questionnaire (ESRD-SCL, Nephron 1999). Inclusion criteria for the final analysis were (a) participation in both surveys and (b) eligibility after the matching procedure: patients with tacrolimus-based immunosuppressive regimen were matched to patients with cyclosporin-microemulsion (CsA-ME)-based immunosuppressive-regimen as to age, gender and duration of graft function. Group data were compared by performing a two-variate ('immunosuppression', 'time') analysis of variance. Both groups consisted of 63 patients. Analysis of QOL revealed statistically significant advantages for the tacrolimus treated patients concerning global (SF-36 'Physical Component Summary') as well as disease-specific QOL (ESRD-SCLTM 'Global Severity Index'; both p < 0.05). In detail, these results were due to statistically significant better QOL in tacrolimus treated patients as to the SF-36 subscales 'Physical Functioning' and 'General Health' (p < 0.05) and the ESRD-SCL subscales 'Limited Physical Capacity' (p < 0.05), 'Cardial and Renal Dysfunction' (p < 0.01) and 'Increased Growth of Gum and Hair' (p < 0.001). The factor 'time' did not contribute statistically significant to explanation of variance. In terms of QOL in kidney recipients, tacrolimus is superior to CsA-ME. Tacrolimus improves disease-specific QOL and also shows slight advantages concerning global QOL compared with CsA-ME. To record differentiated aspects of QOL in kidney recipients, the diagnostic approach should include a global QOL measure completed by a sensitive disease-specific instrument.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11982615&dopt=Abstract tacrolimus Protopic