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Biomedical subjects

K Budde

Publications and source records attributed to K Budde.

At least 37 records · Page 2Linked to original sources
PubMed2004

[Kidney donors and kidney transplantation in the elderly].

The likelihood of terminal renal insufficiency escalates with age, increasing the risk of dying as a patient requiring dialysis. In 1999, Eurotransplant initiated the Eurotransplant Senior Programm (ESP), in which the kidneys of old donors (>64 years) are allocated to recipients 64 years and older. Allocation does not take HLA-matching into account and is performed regionally only according to blood-group-compatibility to keep the storage time short. As a consequence of the short ischemic time, and thus reduced non-immunological damage to the anyways susceptible old kidney, graft-function and graft-survival in the ESP are very good. The results of the initial 5 years of this program show that it successfully utilizes more kidneys from old donors and that more old recipients are being transplanted, with a satisfactory graft-function. Increased donor- and/or recipient age require a thorough evaluation to exclude malignant and other diseases. Furthermore, short term controls on the waiting list and following kidney transplantation are prerequisites for successful transplantation in the aged recipient. If this is guaranteed, kidney transplantation in the old recipient-even with old donor organs-is a good alternative to the morbidity of a prolonged dialysis. Nevertheless, the role of HLA-matching should be reconsidered to reduce rejections.

Aged↗
PubMed2004

Impact of cyclosporine on the development of immunosuppressive therapy.

With the advent of cyclosporine (CsA) 20 years ago, graft survival increased considerably to more than 80% at 2 years posttransplant. The early formulation of CsA, Sandimmun, is effective in preventing organ rejection, although its absorption profile means it is subject to a high degree of variability. The development of a microemulsion formulation, Neoral, provided a therapy with superior efficacy in kidney, liver, and heart transplantation with an improved pharmacokinetic profile. Calcineurin inhibitors (CNIs), including CsA, have a narrow therapeutic range, so frequent blood measurements to control drug levels are required. Recent research has demonstrated that the measurement of blood CsA concentration at 2 hours postdosing--C2 monitoring--has the potential to optimize efficacy and reduce the side effects associated with CNI use. In heart and de novo kidney transplantation, C2 monitoring may help to further reduce the incidence of acute rejection, while in maintenance renal transplant recipients, C2 monitoring can help to detect overexposure and thus allows safe dose reduction, which may improve blood pressure and renal function. C2 monitoring thus facilitates a better balance between effective Neoral immunosuppression and unwanted side effects. Today, CsA remains the cornerstone of immunosuppression, and ongoing studies aim to further optimize patient management strategies with Neoral. With other trials evaluating the impact of Neoral in combination with newer therapies such as Certican, myfortic, and FTY720, the use of CsA in transplant recipients looks set to continue.

Clinical Trials as Topic↗
PubMed2004

Enteric-coated mycophenolate sodium: safe conversion from mycophenolate mofetil in maintenance renal transplant recipients.

Mycophenolate mofetil (MMF), in combination with cyclosporine and corticosteroids, improves long-term graft function and survival in renal transplant recipients. However, optimal MMF therapy may be limited by gastrointestinal (GI) intolerance, which may result in the need for MMF dose reduction, interruption, or discontinuation, leading to increased risk of acute rejection. Enteric-coated mycophenolate sodium (EC-MPS) is an advanced formulation delivering mycophenolic acid (MPA), developed with the objective of improving MPA-related upper GI adverse events. A pivotal, 12-month, phase III, randomized, multicenter, double-blind, double-dummy, parallel group study investigated whether stable renal transplant patients can be converted from MMF to EC-MPS therapy without compromising tolerability or efficacy. Stable renal transplant recipients received either MMF, 1000 mg b.i.d. (n=159), or EC-MPS, 720 mg b.i.d. (n=163), for 12 months. The incidence of GI adverse events was comparable between both treatment groups at 3 and 6 months, but there was a trend toward reduced severity of GI side effects in the EC-MPS group. There were fewer serious adverse events with EC-MPS and significantly fewer serious infections (P<.05). This comparable safety profile for EC-MPS and MMF also extended to elderly patients and patients with diabetes at baseline. For the composite efficacy variable of biopsy-proven acute rejection, graft loss, death, or loss to follow-up, EC-MPS had a lower 12-month efficacy failure rate (EC-MPS: 7.5% vs MMF: 12.3%; P=ns). These data demonstrate that stable renal transplant recipients receiving MMF can be converted to EC-MPS with no efficacy or tolerability compromise.

Adult↗
PubMed2004

FTY720: early clinical experience.

FTY720 is the first in a new class of immunomodulators--sphingosine 1-phosphate receptor (S1P-R) agonists. It is highly effective in prolonging allograft survival in preclinical models of transplantation. Furthermore, FTY720 acts synergistically with calcineurin inhibitors and proliferation inhibitors in these models, suggesting that use of FTY720 in combination with classical immunosuppressants may be a promising new option for transplant patients. Phase I studies conducted in stable renal transplant patients maintained on a cyclosporine (CsA)-based regimen have revealed a tolerable profile of FTY720 for transplant pharmacotherapy. The pharmacokinetics of FTY720 is characterized by linear dose-proportional exposure over a wide range of doses, only moderate interpatient variability, and a prolonged elimination half-life (t(1/2) 89 to 157 hours). These factors suggest that FTY720 can be administered according to a simple once-daily schedule, without the need for blood-level monitoring or dose titration. The pharmacodynamics of FTY720 in humans are characterized by a significant reduction in peripheral blood count by up to 85%. In contrast to the nonspecific myelosuppressive effects of other immunosuppressants, this effect of FTY720 is specific for lymphocytes, with no effect observed on monocytes or granulocytes. In combination with CsA, FTY720 was well tolerated following single or multiple dosing, without any evidence of additional toxicities, indicating that FTY720 may be useful in the future design of more effective and less toxic regimens for prevention of graft rejection.

Animals↗
PubMed2003

20-year experience with elderly donors in living renal transplantation.

PURPOSE: This study evaluates the impact of living renal donors (LD) aged 60 years and older on graft performance and patient survival in an old-for-young constellation. PATIENTS AND METHODS: We analyzed 144 consecutive LDs between January 1983 and December 2002 (19 patients 60+/125 controls). RESULTS: Mean donor age in the 60+ group was 63.7 (+/- 2.6) years and 43.7 (+/- 9.0) years for the <60 group. Mean recipient age was 42.4 (+/- 15.2) years versus 32.6 (+/- 15.3) years HLA-A, -B, and DR-mismatches were 3.16 (+/- 1.3) for the 60+ group and 3.13 (+/- 1.7) for the controls (P = NS). Rejection episodes in the first year following LD did not differ (53% versus 33%, P =.25). Mean serum creatinine for 65+ versus <65 after 1, 3, and 12 months was 1.91 +/- 1.2 versus 1.48 +/- 0.85 mg/dL (P =.16), 1.82 +/- 0.89 versus 1.29 +/- 0.35 mg/dL (P <.05) and 1.80 +/- 0.31 versus 1.37 +/- 0.38 mg/dL (P <.05) and mean creatinine clearance at 12 months 62 versus 82 mL/min (P =.06). Censored 1-, 3-, and 5-year graft survival was 100% versus 95% (P = NS), 100% versus 93% (P = NS) and 100% versus 83% (P = NS) with no significant difference in the log-rank test for Kaplan Meier. CONCLUSION: No impact of donor age was found for graft survival but function of the 65+ kidneys at 3 and 12 months was reduced. Living renal donors 60+ are acceptable for carefully allocated recipients.

Adult↗
PubMed2003

Living donor nephrectomy--no impact of genetic relationship.

PURPOSE: A retrospective, single-center analysis was conducted to compare the results of living donor kidney transplantation between living unrelated (LURD) and living related (LRD) donors. PATIENTS AND METHODS: One hundred forty-seven consecutive living renal transplantations were performed at our institution, starting in 1983. Graft and patient survival were assessed as well as transplant function, including a subgroup analysis for the period of kidney transplantation. RESULTS: Mean follow up for the LRD group was 88.5 months and for the LURD cohort 34.4 months. One- and 3-year graft survival (censored for death with functioning graft) for LRD versus LURD was 97.5% versus 94.4% (P =.4) and 95.3% versus 88.8% (P =.35). Patient survival at 1 and 3 years was 95.1% versus 94.7% (P =.91) and 87.8% versus 90.0% (P =.79). Of the related recipients, 37% experienced at least one episode of rejection in the first year following renal transplantation, compared to 34% in the LURD group (P =.80). Mean serum creatinine for LRD versus LURD after 1, 3, and 12 months () was 1.52 +/- 0.81 versus 1.59 +/- 1.17 mg/dL (P =.98), 1.41 +/- 0.55 versus 1.30 +/- 0.40 mg/dL (P =.51), and 1.44 +/- 0.39 versus 1.40 +/- 0.40 mg/dL (P =.75). Mean creatinine clearance after 1 year was 82.2 versus 71.7 mL/min (P =.26). Subgroup analysis for the time between 1996 and 2002 revealed no difference between LURD and LRD. Multivariate analysis could exclude an impact of the significantly different recipient age and of first/second warm ischemic time on the endpoints described above. CONCLUSION: LURD is a good way to meet the growing organ shortage and should be encouraged.

Creatinine↗
PubMed2003

Effect of mycophenolate mofetil on IMP dehydrogenase after the first dose and after long-term treatment in renal transplant recipients.

OBJECTIVE: Mycophenolate mofetil (MMF) is routinely used as an immunosuppressant in a fixed daily dose regimen although it shows marked fluctuations in pharmacokinetics, and despite the fact that in regard to the active metabolite, mycophenolic acid (MPA), there is a well-known association between the pharmacokinetic parameters and clinical outcome. METHOD: In order to determine the time course and the variability in cellular target of MPA after renal transplantation, we investigated the pharmacodynamic response in 8 patients receiving 1 g MMF for the first time prior to renal transplantation and in 8 stable renal transplant patients maintained on long-term MMF therapy (1 g b.i.d.) for more than 1 year. The pharmacodynamic response was measured using inosine 5'-monophosphate dehydrogenase (IMPDH) activity in peripheral mononuclear cells. MPA plasma concentrations were measured in parallel, IMPDH activity in 89 healthy blood donors was used as a control. RESULTS: We observed a high interindividual variability in IMPDH activity in the 89 untreated healthy volunteers (4.0 - 32.9 nmol/h/mg protein), in 8 patients on dialysis (5.3 - 18.9 nmol/h/mg protein) and in 8 renal transplant patients under long-term MMF treatment (2.3 - 14.4 nmol/h/mg protein). The mean AUC0-12h for mycophenolic acid was 2-fold higher in patients receiving long-term treatment with MMF (62.2 +/- 16.6 mg x h/ml) compared to dialysis patients receiving 1 g MMF for the first time (31.5 +/- 15.6 mg x h/ml). Despite this pharmacokinetic difference there were no statistically significant differences in the cellular pharmacodynamic response. Minimal IMPDH activity (1.62 +/- 1.23 vs. 1.77 +/- 1.49 nmol/h/mg protein) and maximal IMPDH inhibition (87.5 +/- 0.08 vs. 77.4 +/- 18.8%) during the dosing interval were similar. CONCLUSIONS: The considerable interindividual variability in the pharmacokinetics of MMF as well as in the drug target support the use of pharmacodynamic drug monitoring to optimize MMF dosing and to reduce the risk of graft rejection and side effects.

Area Under Curve↗
PubMed2003

Cyclosporin C2hour monitoring after renal transplantation.

Therapeutic drug monitoring of cyclosporin A (CsA) is essential because of its variable pharmacokinetics in individual patients and its narrow therapeutic window. In the past, standard trough level (C0) monitoring has been used, and although this method is currently the routine strategy, it has been shown that a single blood concentration measurement 2 hours after CsA administration (C2hour) is a significantly more accurate predictor of drug exposure and clinical events than trough concentrations. The CsA absorption profiling, in particular the measurement of C2hour, is a much more sensitive approach to assessing the pharmacokinetics and predicting the clinical effect in the individual patient. However, there are limited prospective data available examining the risks and benefits of C2hour monitoring in renal transplant recipients. Most studies focus on the early post-transplant phase, but there is little experience with C2hour monitoring in maintenance patients. Our experience in 127 stable long-term renal allograft recipients suggests that the therapeutic window for C2hour levels in patients during maintenance is lower than previously anticipated. Repeat determinations of both C0 and C2hour levels in 46 patients to determine precision of C2hour monitoring showed a high intrapatient variability. We observed only a slightly better coefficient of variation for C2hour than for C0 in repeat determinations. This suggests that drug monitoring using C2hour levels in transplant patients may provide a more accurate and reliable measure of drug exposure in the individual patient. However, CsA absorption showed only a weak correlation with dose during repeated measurements, suggesting high variability in absorption in these stable patients. We conclude that an adequate C2hour level soon after transplantation is associated with a reduced risk of acute rejection in adult renal transplant recipients. It is important to identify slow and poor absorbers in the initial phase after transplantation in order to avoid inappropriate increases in CsA dose. In maintenance patients, C2hour values between 500 and 600 ng/ml are effective and safe for providing effective rejection prophylaxis. Although mean C2hour levels do not seem to identify patients at risk of rejection, they may help to identify excessive immunosuppression and to improve long-term survival by reducing CsA toxicity.

Absorption↗
PubMed2003

Pharmacodynamics of FTY720, the first member of a new class of immune-modulating therapeutics in transplantation medicine.

FTY is a novel immunomodulator currently undergoing clinical investigation and has the potential of improving immunosuppressive therapy after organ transplantation. Previous experimental studies in animals have shown that FTY has a unique mechanism of action. We have studied the pharmacodynamic effects of FTY in stable renal allograft recipients taking part in a phase I clinical trial. As in various animal models including non-human primates, a single oral dose of FTY (0.25 - 3.5 mg) significantly reduced peripheral lymphocyte count by 30 - 70%. The peripheral lymphocyte count returned to baseline within 24 hours. Only in those patients treated with the highest dose of FTY (3.5 mg), did peripheral lymphopenia persist for more than 96 hours. FTY reduced all lymphocyte subsets, T cells more than B cells and CD4+ cells more than CD8+ cells. The reduction in CD3+CD62L+ cell counts was more pronounced, whereas CD3+CCR5+ cell counts were less affected in comparison to the total number of CD3+ lymphocytes. We found only slightly increased apoptosis rates (< 5%) in peripheral lymphocytes, and this change does not explain the marked reduction in lymphocyte count. In cultured human lymphocytes only suprapharmacological doses of 10 microM FTY induced apoptosis (20.6 +/- 2.8%) after a 4-h incubation. More important, clinically relevant doses of 0.1 microM FTY increased lymphocyte mobility 2-fold. No effect of FTY on anti-CD3mAb-stimulated lymphocyte proliferation was detected and there was no change in phagocytosis rates in whole-blood cultures incubated with FTY. Further studies are necessary to investigate the mechanism of action of FTY in detail.

Apoptosis↗
PubMed2003

Treating type 2 diabetes in renal insufficiency: the role of pioglitazone.

The advent of new antidiabetic drugs is of special importance for diabetic patients with already impaired renal function since renal insufficiency is a relative or absolute contraindication for several of the established hypoglycemic drugs. Pioglitazone is a novel oral hypoglycemic agent that increases insulin responsiveness in target tissues. Pioglitazone and its active metabolites are excreted mainly via the liver. Drug exposure remains almost constant across a wide range of renal function since there is no accumulation of the drug or its active metabolites during repeated dosing in renal insufficiency. The pharmacokinetic properties of pioglitazone are ideally suited for patients with renal insufficiency. Although there are possible side effects (mainly fluid retention and weight gain and--very rarely--hepatotoxicity). Pioglitazone has a good safety profile in diabetic patients with impaired renal function.

Area Under Curve↗