Dialysis, kidney transplantation, or pancreas transplantation for patients with diabetes mellitus and renal failure: a decision analysis of treatment options.
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Patients with type 1 diabetes mellitus and end-stage renal disease may remain on dialysis or undergo cadaveric kidney transplantation, living kidney transplantation, sequential pancreas after living kidney transplantation, or simultaneous pancreas-kidney transplantation. It is unclear which of these options is most effective. The objective of this study was to determine the optimal treatment strategy for type 1 diabetic patients with renal failure using a decision analytic Markov model. Input data were obtained from the published medical literature, the United Network for Organ Sharing registry, and patient interviews. The outcome measures were life expectancy (in life-years [LY]) and quality-adjusted life expectancy (in quality-adjusted life-years [QALY]). Living kidney transplantation was associated with 18.30 LY and 10.29 QALY; pancreas after kidney transplantation, 17.21 LY and 10.00 QALY; simultaneous pancreas-kidney transplantation, 15.74 LY and 9.09 QALY; cadaveric kidney transplantation, 11.44 LY and 6.53 QALY; dialysis, 7.82 LY and 4.52 QALY. The results were sensitive to the value of several key variables. Simultaneous pancreas-kidney transplantation had the greatest life expectancy and quality-adjusted life expectancy when living kidney transplantation was excluded from the analysis. These data indicate that living kidney transplantation is associated with the greatest life expectancy and quality-adjusted life expectancy for type 1 diabetic patients with renal failure. Treatment strategies involving pancreas transplantation should be considered for patients with frequent metabolic complications of diabetes and for those patients who favor kidney-pancreas transplantation over kidney transplantation alone. For patients without a living donor, simultaneous pancreas-kidney transplantation is associated with the greatest life expectancy. (+info)
The effect of low versus high dose of streptozotocin in cynomolgus monkeys (Macaca fascilularis).
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Streptozotocin (STZ) is often used to induce diabetes in animal models. However, morbidity associated with STZ and its ability to induce diabetes vary with different dosages among different animal species, including nonhuman primates. To find an optimal dose of STZ that would cause diabetes with minimal toxicity, we compared low and high doses of STZ. Male cynomolgus monkeys (3-6 years old) were given a single dose of 100 mg/kg (high dose, 4 animals) or 55 mg/kg (low dose, 20 animals) of STZ. Blood glucose levels, intravenous glucose tolerance test (IVGTT), pancreatic biopsies, liver function tests (LFTs), liver biopsies, kidney function tests, and kidney biopsies were performed periodically. Animals from both groups developed diabetes within 24 h after administration of STZ. Serum C-peptide levels in both groups decreased from 2 to 8 ng/mL before STZ to between 0.01 and 0.6 ng/mL after STZ. Animals with the high dose of STZ developed transient vomiting within minutes after injection. During the first week after STZ injection, high-dose animals developed elevated LFTs, BUN and creatinine. In contrast, low-dose animals had normal liver and kidney function tests. Histological analysis showed that animals given the high dose of STZ developed marked steatosis of the liver and tubular injury in the kidneys, whereas animals given the low dose of STZ had normal-looking liver and kidney histology. The pancreatic islets in both groups were indistinguishable by immunoperoxidase staining for insulin, and showed either no insulin-positive cells or rare insulin-positive cells. Glucagon staining was normal. Over time, low-dose diabetic monkeys remained persistently hyperglycemic with negligible C-peptide stimulation by intravenous glucose. We conclude that low-dose STZ at 55 mg/mL successfully induces diabetes in cynomolgus monkeys with minimal liver and kidney toxicity. (+info)
MRI and magnetic resonance angiography in evaluating simultaneous pancreas-kidney transplantation.
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OBJECTIVE: To evaluate the value of magnetic resonance imaging (MRI) and three dimensional (3D) contrast magnetic resonance angiography (MRA) in the diagnosis of complications of simultaneous pancreas-kidney transplantation (SPKT), as confirmed by biopsy and digital subtraction angiography (DSA). METHODS: Five MR examinations of five patients were performed within 28 days to 2 years after surgery on GE 1.5T MR system. Imaging techniques included axial and sagittal chemical fat-suppressed T1-weighted image (T1WI) and T2-weighted image (T2WI), additional contrast axial or saggital chemical fat-suppressed T1WI were obtained after 3D contrast MRA for calculating the mean percentage of the parenchymal enhancement (MPPE) of the pancreas and kidney. 3D contrast MRA was performed with Smartprep technique. MRA data were analyzed with maximum intensity projection (MIP) and multi-planner reformat (MPR). RESULTS: In five cases of transplant pancreases, MRI found two normal pancreas grafts, one case of acute rejection, one case of chronic rejection with 70% fibrosis and one case of late pancreatitis. In five transplant kidneys, MRI detected four normal kidney grafts and one case of acute rejection with infarction. MPPE could distinguish infarction from other complications. 3D contrast MRA could display vascular complications of SPKT, such as stenosis or occlusion, aneurysm formation of transplanted vessels and narrowing at the site of anastomosis, as confirmed by DSA. CONCLUSION: With combined application of MRI and 3D contrast MRA, complications of SPKT can be clearly identified. (+info)
Laboratory assessment of immune function in renal transplant patients.
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BACKGROUND: Advances in immunosuppression have made renal transplantation an effective therapy for end stage renal failure; with low rejection rates and long graft survival times. However, the major adverse consequences, infection and malignancy have not diminished. To predict this risk a score of immune competence has been developed from the simultaneous laboratory assessment of multiple parameters of immune function. METHODS: The immune status of 152 transplant recipients (138 renal and 14 pancreas/renal) was assessed by measurement of lymphocyte subsets, mitogen-induced T-cell proliferative responses, neutrophil phagocytic capacity and reactive oxygen species (ROS) generation. A scoring system was devised based on the average number of these parameters below 10th percentile of normal. RESULTS: The most common abnormality was B-cell lymphopenia (85%) followed by reduced neutrophil ROS production (63% of patients), NK cell lymphopenia (50%), lymphocyte mitogen response (49%) and CD4 number (23%). The abnormalities were unrelated to the duration of immunosuppression (up to 15 years), and variable combinations of cyclosporine A, azathioprine, prednisolone and mycophenolate mofetil (MMF) (except for a consistent reduction in lymphocyte mitogen response in MMF treated patients). Retrospective comparison of infective episodes showed a significantly greater index of infections in patients with the worst score compared with a normal score. CONCLUSIONS: The data suggests that this quantification of immune function may allow assessment of the level of host immune defence reflecting the level of drug-induced immunosuppression and thus risks of immunosuppressive complications. (+info)
Impact of acute rejection episodes on long-term graft survival following simultaneous kidney-pancreas transplantation.
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Although it is well established that acute rejection is one of the major risk factors for chronic graft loss following kidney transplantation, its effect on long-term graft survival following simultaneous kidney-pancreas transplants (SKPTs) is less well known. We analyzed a large cohort of SKPTs and cadaver kidney transplants reported to the United Network for Organ Sharing database during 1988-97, to determine the impact of acute rejection episodes on long-term kidney and pancreas graft survival. Only patients whose kidney and pancreas grafts had survived for at least 1 year were included. Other potential risk factors influencing long-term graft survival were included in the analysis. Of the 4251 SKPTs, 45% had no acute rejection, 36% had kidney only rejection, 3% had pancreas only rejection, and 16% had both kidney and pancreas rejection within the 1st year post transplant. The 5-year kidney and pancreas graft survival rates adjusted for other risk factors were 91% and 85%, respectively; for those with no acute rejection episodes, 88% and 84%, respectively; for those with kidney only rejection, 94% and 83%, respectively; for those with pancreas only rejection; and 86% and 78%, respectively, for those with both kidney and pancreas rejection. The relative risk (RR) of kidney graft failure was 1.32 when acute rejection involved the kidney graft only, while the RR was 1.53 when the rejection involved both organs. We conclude that acute rejection episodes have a negative impact on the long-term kidney graft survival in the SKPT population similar to that in the cadaver kidney transplant population. Patients who had acute rejection episodes of both kidney and pancreas have the worst long-term graft survival. (+info)
Tolerogenic immunosuppression for organ transplantation.
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BACKGROUND: Insight into the mechanisms of organ engraftment and acquired tolerance has made it possible to facilitate these mechanisms, by tailoring the timing and dosage of immunosuppression in accordance with two therapeutic principles: recipient pretreatment, and minimum use of post-transplant immunosuppression. We aimed to apply these principles in recipients of renal and extrarenal organ transplants. METHODS: 82 patients awaiting kidney, liver, pancreas, or intestinal transplantation were pretreated with about 5 mg/kg of a broadly reacting rabbit antithymocyte globulin during several hours. Post-transplant immunosuppression was restricted to tacrolimus unless additional drugs were needed to treat breakthrough rejection. After 4 months, patients on tacrolimus monotherapy were considered for dose-spacing to every other day or longer intervals. FINDINGS: We frequently saw evidence of immune activation in graft biopsy samples, but unless this was associated with graft dysfunction or serious immune destruction, treatment usually was not intensified. Immunosuppression-related morbidity was virtually eliminated. 78 (95%) of 82 patients survived at 1 year and at 13-18 months. Graft survival was 73 (89%) of 82 at 1 year and 72 (88%) of 82 at 13-18 months. Of the 72 recipients with surviving grafts, 43 are on spaced doses of tacrolimus monotherapy: every other day (n=6), three times per week (11), twice per week (15), or once per week (11). INTERPRETATION: The striking ability to wean immunosuppression in these recipients indicates variable induction of tolerance. The simple therapeutic principles are neither drug-specific nor organ-specific. Systematic application of these principles should allow improvements in quality of life and long-term survival after organ transplantation. (+info)
A compartmental pharmacokinetic model of cyclosporin and its predictive performance after Bayesian estimation in kidney and simultaneous pancreas-kidney transplant recipients.
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BACKGROUND: Therapeutic drug monitoring of cyclosporin A (CsA) is an obvious necessity because of its unpredictable absorption and narrow therapeutic window. The use of limited sampling models (LSMs) has improved the estimation of the systemic exposure [area under curve (AUC)] compared with C(0h) monitoring, but these equations are rigid and not reliable in patients with an abnormal absorption profile. We developed and validated a limited sampling (t=0, 2 and 3 h) strategy, based on a compartmental population pharmacokinetic (PK) model for CsA after kidney transplantation alone (KTA) and simultaneous pancreas-kidney transplant (SPKT) recipients, a group of patients with unpredictable absorption kinetics. METHODS: A two-compartment model with lag time and first-order absorption was calculated using a PK software package from data of 20 KTA and SPKT recipients and validated prospectively in 20 KTA and 20 SPKT recipients. Calculated population PK parameters were individualized for each of the remaining 40 patients based on their CsA dosing and on one or a combination of measured CsA blood concentrations using the Bayesian fitting method. AUCs were calculated from individualized PK parameters. AUCs were also calculated using previously published LSMs. Relationships between AUCs calculated by the models and the 'golden standard' AUC (trapezoidal rule) were investigated by Pearson correlation test. RESULTS AND CONCLUSIONS: A population two-compartment model is presented to reliably estimate the CsA AUC in KTA and SPKT recipients. The performance of the model to estimate the AUC is comparable to the performance of two published LSMs in KTA patients, but markedly better in SPKT patients. Combined with Bayesian fitting, the model is very flexible since sampling times are not rigid and can be varied as long as dosing and sampling times are recorded accurately. The model has already proven to be clinically useful and is currently used to further investigate CsA in an integrated pharmacokinetic/pharmacodynamic model. (+info)
Histological grading of chronic pancreas allograft rejection/graft sclerosis.
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Chronic rejection (CR) of pancreas allografts needs to be accurately defined and diagnosed. We propose a grading scheme designed for percutaneous needle biopsies (C0-CIII). Grading is based on the semi-quantitative determination of fibrosis and corresponding proportional loss of exocrine parenchyma. Pancreas biopsies (n = 141) from 46 patients were studied. Twenty-six patients lost graft function after a mean time of 25.5 months, whereas 20 patients retained good graft function during a mean follow-up of 67.7 months. Sequential biopsies showed gradual progression of CR over time (p = 0.0001), and good correlation was found between the CR grade and the time elapsed from transplantation (p = 0.0001). The CR grade was predictive of the remaining time of graft function (54.3 months for C0, 24.6 months for CI, 9.7 months for CII and 1.6 months for CIII p = 0.00001). Preceding episodes of acute rejection (AR) were more frequent and more severe, and often occurred late in patients with graft loss due to CR (p = 0.04). Reproducibility among pathologists from different institutions was excellent for grades C0 (Kappa 0.9) and CIII (0.87), substantial for Grade CII (0.61) and moderate for Grade CI (0.59). The proposed grading scheme provides a reliable and reproducible tool for the assessment of CR in percutaneous needle biopsies, with definite prognostic significance. (+info)