No robust conclusions to be drawn from clinical trials in the absence of an adequate control group.
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Cyclosporine↗
Biomedical subjects
Herwig-Ulf Meier-Kriesche
Publications and source records attributed to Herwig-Ulf Meier-Kriesche.
Switching immunosuppression medications after renal transplantation--a common practice.
BACKGROUND: The rate of change to immunosuppression discharge regimens over time is unknown. We examined the frequency of changes to initial drug treatment regimens and factors associated with a drug change following renal transplantation. METHODS: Scientific Registry of Transplant Recipients data from adult recipients who underwent primary renal transplantation between January 1998 and December 2002 were analysed. The Kaplan-Meier analysis was used to determine the frequency of regimen changes for the most common immunosuppression discharge regimens, type of change, and to examine switching between the calcineurin inhibitors tacrolimus (Tacro) and ciclosporin United States Pharmacopera (USP) modified (CsA). Cox proportional hazard regression was used to examine recipient, donor and transplant characteristics associated with a drug change. RESULTS: The majority of patients experienced a change to their discharge regimen post-transplantation, and more changes were observed within higher-risk sub-groups of patients. Switching from CsA to Tacro was more common than Tacro to CsA. Significant factors associated with a drug change included those associated with graft loss. CONCLUSIONS: Significant immunosuppression regimen changes occur during the first 4 years post-transplantation. It is possible that early graft survival benefits proven in prospective clinical trials may not translate into long-term success in clinical practice, possibly in part because efficacious regimens are not necessarily maintained long-term.
Adolescent↗
Mycophenolate mofetil-based immunosuppressive minimization and withdrawal strategies in renal transplantation: possible risks and benefits.
The toxicity of standard triple-therapy immunosuppressive regimens has been identified as a possible factor in the failure to extend long-term renal allograft survival despite a continued decline of acute rejection rates. The result has been increasing focus on the use of mycophenolate mofetil-based, low-toxicity immunosuppressive regimens, which have been shown in randomized studies to have the potential to improve long-term graft survival. This Clinical Update discusses the likely risks and benefits for switching the immunosuppressive regimen in clinical practice.
Adrenal Cortex Hormones↗
Obesity and kidney transplantation.
Obesity is an increasingly common comorbidity at the time of kidney transplantation. Obesity is also a frequent complication of kidney transplantation. The obese transplant recipient suffers adverse metabolic and cardiovascular consequences of obesity. These metabolic and cardiovascular sequelae of obesity are major contributors to morbidity and mortality after kidney transplantation. We discuss the epidemiology and pathophysiology of obesity in the kidney transplant recipient and provide an overview of clinical studies on obesity in kidney transplantation. An approach to obesity in renal transplantation, based on the evidence to date, is presented.
Comorbidity↗
The relationship between diabetes and infectious hospitalizations in renal transplant recipients.
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Aged↗
The impact of mycophenolate mofetil on long-term outcomes in kidney transplantation.
Mycophenolate mofetil (MMF) has been used in kidney and pancreas transplantation for almost 10 years. In the pivotal phase III trials, MMF use was accompanied by a dramatic reduction of rejection rates in kidney transplantation; however, the impact on graft and patient was undetermined. Analyses of the United States Renal Data System and the Scientific Registry of Transplant Recipients databases later provided a valuable measure of the impact of MMF in improving outcomes. In this review, we provide a synopsis of the prospective studies, including but not limited to the pivotal MMF approval trials, and analyses of the national transplant registries relevant to the long-term impact of MMF in kidney transplantation. Indeed, a substantial body of evidence has shown MMF treatment improves patient survival, graft survival, and death-censored graft survival in kidney transplantation. The beneficial effects of MMF have been particularly notable in high-risk recipients such as African Americans. In coming years, these benefits will require reevaluation in the context of the growing use of novel protocols combining MMF with tacrolimus or sirolimus.
Black or African American↗
Access to quality: evaluation of the allocation of deceased donor kidneys for transplantation.
Disparities in both access to the kidney transplant waiting list and waiting times for transplant candidates have been extensively documented with regard to ethnicity, gender, socioeconomic factors, and region. However, the issue of access to equivalent quality organs has garnered less attention. The principal aim of this study was to determine whether certain patient populations were more likely to receive lower quality organs. This was a retrospective cohort study of all deceased-donor adult renal transplant recipients in the United States from 1996 to 2002 (n = 45,832). Using previously reported categorization of donor quality (I to V), the propensity of transplant recipients to receive lower-quality kidneys in a cumulative logit model was evaluated. Older patients were progressively more likely to receive lower-quality organs (age > or = 65 yr, odds ratio [OR] = 2.1, P < 0.01) relative to recipients aged 18 to 24 yr. African American and Asian recipients had a greater likelihood of receiving lower-quality organs relative to non-Hispanic Caucasians. Regional allocation networks were highly variable with regard to donor quality. Neither recipient gender (OR = 1.00, P = 0.81) nor patient's primary diagnosis were associated with donor quality. Findings suggest that disparities in the quality of deceased donor kidneys to transplant recipients exist among certain patient groups that have previously documented access barriers. The extent to which these disparities are in line with broad policies of equity and potentially modifiable will have to be examined in the context of allocation policy.
Adult↗
Increased levels of tumor necrosis factor alpha are associated with an increased risk of cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation.
Tumor necrosis factor-alpha (TNF) has been implicated in the reactivation of cytomegalovirus (CMV) at a cellular level. We therefore hypothesized that increased posttransplantation TNF levels may be associated with the development of CMV antigenemia (CMV-Ag). We studied 134 patients undergoing allogeneic hematopoietic stem cell transplantation. After excluding CMV-negative donor and recipient pairs, 94 patients were evaluable. By cluster analysis, 2 groups were designated by TNF levels obtained between days 4 and 7 after transplantation: 58 patients had low levels (median, 0 pg/mL; range, 0-5.5 pg/mL), and 36 patients had high levels (median, 43.75 pg/mL; range, 7.5-1756 pg/mL). To determine the independent effect of TNF on the development of CMV-Ag and acute graft-versus-host disease and on survival, Kaplan-Meier and Cox models stratified by TNF patient groups were evaluated. High TNF levels were associated with a more rapid onset of CMV-Ag (P < .001) and with the occurrence of the composite end point of CMV-Ag or death (P < .001). Factors independently associated with CMV-Ag in multivariate analysis were a high TNF level (hazard ratio [HR], 2.57; P = .003) and acute graft-versus-host disease (as a time-dependent covariate; HR, 2.30; P = .010). Factors independently associated with the composite end point of CNV-Ag or death were a high TNF level (HR, 2.42; P < .001) and patient age (per year; HR, 1.93; P = .017). In conclusion, a high posttransplantation TNF level is significantly associated with the risk for developing CMV infection. Early detection of high levels of TNF may be used to identify patients at high risk for developing CMV-Ag.
Adult↗
Interleukin 12 is associated with reduced relapse without increased incidence of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.
Interleukin (IL)-12 has antitumor effects in murine studies. To evaluate this clinically, we investigated whether high levels of circulating IL-12 in patients after allogeneic hematopoietic stem cell transplantation (HSCT) are associated with improved relapse-free survival. We prospectively studied 134 patients undergoing HSCT. Median follow-up was 1158 days (range, 70-1792 days). Plasma IL-12 levels were measured before transplantation and on days 0, +4, +7, and +14 after transplantation. The highest levels were seen on days +4 and +7 and were categorized by a cluster analysis of the logarithmically transformed IL-12 concentrations, which were then correlated with relapse-free survival. Forty-six patients had low levels of IL-12 (median, 2 pg/mL; range, 0-6.5 pg/mL), 49 patients had medium levels (median, 20.5 pg/mL; range, 7-75.5 pg/mL), and 25 patients had high levels (median, 181 pg/mL; range, 84-623 pg/mL). Patients with high IL-12 levels before transplantation had the highest increase after transplantation. With a multivariate Cox model for relapse onset, with the low IL-12 level as the reference, patients in the high-IL-12 group had an adjusted hazard ratio of 0.27 (95% confidence interval, 0.09-0.79), and medium group patients had a hazard ratio of 0.65 (95% confidence interval, 0.31-1.36). The incidences of relapse at 500 days by Kaplan-Meier analysis by IL-12 group were 23.0% (high group), 40.3% (medium group), and 48.8% (low group). There was no association between IL-12 levels and the risk of acute graft-versus-host disease (GVHD; P = .51) or chronic GVHD (P = .28). In conclusion, high IL-12 levels after HSCT are associated with improved relapse-free survival without increasing the risk for GVHD. Patients with high pretransplantation IL-12 levels have an increased likelihood of higher posttransplantation IL-12 levels, possibly because of a host-graft interaction, and this may predispose to better clinical outcomes.
Acute Disease↗
Randomized calcineurin inhibitor cross over study to measure the pharmacokinetics of co-administered enteric-coated mycophenolate sodium.
Enteric-coated mycophenolate sodium (EC-MPS) (myfortic) is an advanced formulation delivering mycophenolic acid (MPA), designed to improve MPA-related upper gastrointestinal adverse events by delaying the release of MPA until the small intestine. A randomized, calcineurin inhibitor crossover, steady-state pharmacokinetic study in stable renal transplant patients receiving EC-MPS demonstrated increased MPA exposure of 19% higher, MPA C(max,ss) 19% lower and MPA C(min,ss) approximately twofold higher with tacrolimus, than cyclosporine microemulsion. No study drug-related adverse events were recorded, but mean blood glucose concentration was higher in patients receiving tacrolimus (p = 0.031). The dose changes in relation to MPA exposure in patients is dependent on the clinical situation and may not always be warranted. These observations should be taken into consideration when switching from one calcineurin inhibitor to another, but the final dosage should be based on both this pharmacokinetic data and the clinical situation.
Adult↗
The effects of renal transplantation on peripheral blood dendritic cells.
Recent advances allow accurate quantification of peripheral blood (PB) myeloid and plasmacytoid dendritic cell (DC) populations (mDC and pDC, respectively), although the response to renal transplantation (RT) remains unknown. Using flow cytometry, PBDC levels were quantified in patients with end stage renal disease (ESRD) undergoing RT. PBDC levels were significantly reduced in ESRD patients pre-RT compared to healthy controls, with further reduction noted immediately following a hemodialysis session. RT resulted in a dramatic decrease in both subsets, with a greater reduction of pDC levels. Both subset levels were significantly lower than in control patients undergoing abdominal surgery without RT. Subgroup analysis revealed significantly greater mDC reduction in RT recipients receiving anti-lymphocyte therapy, with preferential binding of antibody preparation to this subset. Samples from later time points revealed a gradual return of PBDC levels back to pre-transplant values concurrent with overall reduction of immunosuppression (IS). Finally, PBDC levels were significantly reduced in patients with BK virus nephropathy compared to recipients with stable graft function, despite lower overall IS. Our findings suggest that PBDC levels reflect the degree of IS in renal allograft recipients. Furthermore, PBDC monitoring may represent a novel strategy to predict important outcomes such as acute rejection, long-term graft loss and infectious complications.
Adult↗
Pharmacokinetic principles of immunosuppressive drugs.
A basic tenet of clinical pharmacology is that the pharmacologic activity of an exogenously administered agent is related to the free drug concentration available at its receptor or ligand-binding site. The discipline of pharmacokinetics can be defined as the study of the processes that lead to the availability of an agent to its site of action. In this review we will discuss basic principles of pharmacokinetics that govern the absorption, distribution, metabolism, elimination and binding of immunosuppressive drugs commonly utilized in whole organ transplantation. In a discipline such as organ transplantation, where the agents utilized carry significant toxicity and where failure of efficacy can have dire consequences, knowledge of the pharmacokinetics of the agents utilized has become a basic skill for all transplant professionals. In this review we describe some of the underlying principles that govern the disposition of the agents commonly utilized in solid organ transplantation. In addition, we hope this review will help in understanding some of the basic drug interactions encountered in transplant practice.
Biological Availability↗
The broad spectrum of quality in deceased donor kidneys.
The quality of the deceased donor organ clearly is one of the most crucial factors in determining graft survival and function in recipients of a kidney transplant. There has been considerable effort made towards evaluating these organs culminating in an amendment to allocation policy with the introduction of the expanded criteria donor (ECD) policy. Our study, from first solitary adult deceased donor transplant recipients from 1996 to 2002 in the National Scientific Transplant Registry database, presents a donor kidney risk grade based on significant donor characteristics, donor-recipient matches and cold ischemia time, generated directly from their risk for graft loss. We investigated the impact of our donor risk grade in a naive cohort on short- and long-term graft survival, as well as in subgroups of the population. The projected half-lives for overall graft survival in recipients by donor risk grade were I (10.7 years), II (10.0 years), III (7.9 years), IV (5.7 years) and V (4.5 years). This study indicates that there is great variability in the quality of deceased donor kidneys and that the assessment of risk might be enhanced by this scoring system as compared to the simple two-tiered system of the current ECD classification.
Adolescent↗
Mycophenolate sodium does not reduce the incidence of GI adverse events compared with mycophenolate mofetil.
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Clinical Trials as Topic↗
Are we frozen in time? Analysis of the utilization and efficacy of pulsatile perfusion in renal transplantation.
Preservation techniques are crucial to deceased donor kidney transplantation (DDTx), but the efficacy of pulsatile perfusion (PP) versus cold storage (CS) remains uncertain. We describe patterns of PP use and explore four fundamental questions. What kidneys are selected for PP? How does PP affect utilization of donated kidneys? What effect does PP have on outcomes? When does PP appear to be most efficacious? We examined rates of PP in DDTx in the United States from 1994 to 2003. We generated models for organ utilization, delayed graft function (DGF) and for the use of PP. We analyzed the long-term effect of PP with multivariate Cox models. The utilization rates for non-expanded criteria donors (ECDs) were similar by storage type, but for ECDs there was a significantly higher utilization rate with PP (70% with PP vs. 59% with CS, p < 0.001). Use of PP was widely variable across transplant centers. DGF rates were significantly lower with PP (27.6% vs. 19.6%). PP was associated with a mild benefit on death censored graft survival (adjusted hazard ratio = 0.88, 95% CI 0.85-0.91). Reduced DGF and significantly lower discard rates of ECDs associated with PP suggest an important utility of PP in renal transplantation. Additional evidence of improvement in graft survival, particularly in more recent years, provides further encouraging evidence for the use of PP.
Cadaver↗
Kidneys from deceased donors: maximizing the value of a scarce resource.
Donor age is a significant risk factor for graft loss after kidney transplantation. We investigated the question whether significant graft years were being lost through transplantation of younger donor kidneys into older recipients with potentially shorter lifespans than the organs they receive. We examined patient and graft survival for deceased donor kidney transplants performed in the United States between the years 1990 and 2002 by Kaplan-Meier plots. We categorized the distribution of deceased donor kidneys by donor and recipient age. Subsequently, we calculated the actual and projected graft survival of transplanted kidneys from younger donors with the patient survival of transplant recipients of varying ages. Over the study period, 16.4% (9250) transplants from donors aged 15-50 were transplanted to recipients over the age of 60. At the same time, 73.6% of donors above the age of 50 were allocated to recipients under the age of 60. The graft survival of grafts from younger donors significantly exceeded the patient survival of recipients over the age of 60. The overall projected improvement in graft survival, by excluding transplantation of younger kidneys to older recipients, was approximately 3 years per transplant. Avoiding the allocation of young donor kidneys to elderly recipients, could have significantly increased the overall graft life, by a total 27,500 graft years, between 1990 and 2002, with projected cost savings of about 1.5 billion dollars.
Adolescent↗
Sirolimus in combination with tacrolimus is associated with worse renal allograft survival compared to mycophenolate mofetil combined with tacrolimus.
Cyclosporine (CsA) nephrotoxicity is enhanced by sirolimus (SRL). Tacrolimus is perceived to be less nephrotoxic than CsA, and therefore, CsA has been largely replaced by tacrolimus (TAC) when calcineurin inhibitors are used with SRL. We analyzed 44 915 adult renal transplants in the Scientific Renal Transplant Registry (SRTR) from 2000 to 2004. Three thousand five hundred twenty-four (7.8%) patients received a baseline immunosuppressive regimen of TAC/SRL, with an inferior overall (log-rank p<0.001) and death-censored graft survival (p<0.001) as compared to TAC/MMF (N=27 007). This effect was confirmed in multivariate Cox models; the adjusted hazard ratio (AHR) for overall graft loss with TAC/SRL was 1.47 (95% CI=1.32, 1.63) and for CsA/SRL 1.38 (95% CI=1.20, 1.59) relative to TAC/MMF. These effects were most apparent in high-risk transplants. Six-month acute rejection rates were low (11.5-12.6%) and not different between groups. In summary, national data indicate that TAC/SRL as compared to TAC/MMF is associated with significantly worse renal allograft survival in all subgroups of patients and, in particular, higher-risk transplants. These results have to be interpreted in the context of the inherent limitations of any retrospective database analysis and evaluated in context with data from prospective clinical trials.
Adolescent↗
Low dendritic cell count after allogeneic hematopoietic stem cell transplantation predicts relapse, death, and acute graft-versus-host disease.
Dendritic cells (DCs) are key antigen-presenting cells with a potential role in tumor vaccines. We investigated the hypothesis that early reconstitution of DCs after allogeneic hematopoietic stem cell transplantation (SCT) improves survival. We also correlated DC reconstitution with complications of relapse and acute graft-versus-host disease (aGVHD). Fifty patients underwent transplantation between February 2000 and March 2003, with a median follow-up of 501 days (range, 136-1263 days). Most (92%) received blood stem cells, and the remainder received bone marrow from HLA-matched sibling donors for predominantly high-risk hematologic malignancies. Around the time of engraftment, peripheral blood underwent flow cytometry analysis for DCs, and the cells were divided as DC1 and DC2. Using Kaplan-Meier analysis, patients with lower DC counts (< 4.97 cells/microL) were found to have significantly worse survival (P =.002), increased incidence of relapse (P =.002), higher incidence of aGVHD onset (P =.0005), and a composite end point of relapse or death (P =.0017). A Cox proportional hazards multivariate model adjusted for important covariates confirmed that low DC count is independently associated with death (hazard ratio [HR], 3.8; P =.02), time to relapse (HR, 11.6; P =.001), and aGVHD (HR, 3.3; P =.04). Sensitivity and specificity rates for low DC count in predicting death or relapse are 73% and 75%, respectively. Low numbers of circulating DCs significantly increase the risk for relapse and acute GVHD and predict death after allogeneic SCT.
Acute Disease↗