Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Between 1966 and 1997, over 10 000 pancreas transplants were performed worldwide, 88% of these being simultaneous kidney-pancreas transplantations (SKPTs). The overall 1-year patient survival rate exceeds 90%, and the graft survival (complete insulin independence) rate is 80%. SKPT should be regarded as the treatment of choice in carefully selected patients with type 1 (insulin-dependent; IDDM) diabetes mellitus and advanced nephropathy, because of its ability to offer superior glycaemic control and an improved quality of life. Studies have shown that the addition of a pancreas transplant does not appear to jeopardise either the patient or the kidney transplant, as many centres report either similar or improved survival rates after SKPT compared with kidney transplantation alone. Indications for solitary pancreas transplantation are based on the presence of early, well defined diabetic complications or glucose hyperlability with poor quality of life. Improvements in quality of life and possible prevention of further morbidity associated with diabetes makes pancreas transplantation an important therapeutic option for selected diabetic patients. According to registry data from the United Network for Organ Sharing (UNOS) Registry, rejection accounts for 32% of graft failures in the first year after pancreas transplantation. Most pancreas transplant centres employ quadruple drug immunosuppression with antilymphocyte induction with either a monoclonal or polyclonal agent. Maintenance immunosuppression involves triple therapy, consisting of a calcineurin inhibitor (cyclosporin or tacrolimus), corticosteroids and an antimetabolite (azathioprine or mycophenolate mofetil). Before 1995, nearly all pancreas transplant recipients were managed with the original formulation of cyclosporin ('Sandimmun'). In the past 2 years, tacrolimus-based therapy has been used in approximately 20% of cases and a new microemulsion formulation of cyclosporin ('Neoral') has replaced the original formulation in contemporary post-transplant immunosuppression. In addition, mycophenolate mofetil is replacing azathioprine as part of the standard immunosuppressive regimen after pancreas transplantation. At present, a number of centres are conducting various trials with new drug combinations including either cyclosporin microemulsion or tacrolimus in combination with corticosteroids and mycophenolate mofetil with or without antibody induction therapy. The current array of new immunosuppressive agents is providing more effective control of rejection and permitting solitary pancreas transplantation to become an accepted treatment option in diabetic patients without advanced complications. Immunosuppressive strategies will continue to evolve to achieve effective control of rejection while minimising injury to the allograft and risk to the patient. In addition, new regimens must not only address the issue of specific drug toxicities but also long term economic, metabolic and quality-of-life outcomes.
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PMID:Pancreas transplantation for diabetes mellitus: a guide to recipient selection and optimum immunosuppression. 1802 Jun 7

Two-hour postdose cyclosporine (C2) monitoring is becoming an accepted method of therapeutic drug monitoring, although it is not known whether C2 monitoring is superior to tacrolimus (FK)-based immunosuppression. The purpose of this trial was to compare the safety, efficacy, and pharmacoeconomics of cyclosporine A (CsA) monitored by C2 levels versus FK monitored by trough levels in de novo liver transplant recipients. After informed consent, 60 de novo liver transplant recipients were randomized in a 1:1 fashion to receive either FK (trough, 6-10 ng/mL) or CsA (C2, 600-1200 ng/mL) and corticosteroids. The 2 groups were similar for gender, race, indication for liver disease, and age. At 1 year, patient survival was similar (93% for FK versus 90% for C2). One patient in the FK arm was retransplanted because of recurrent hepatitis C virus (HCV). Early acute rejection occurred in 27% of FK-treated patients and 23% of CsA-treated recipients [P = not significant (NS)]. Recurrent HCV occurred in 21% of FK-treated patients and 61% of CsA-treated patient (P = 0.04). The incidence of other infections, new onset diabetes mellitus, requirement for antihypertensives, and requirement for cholesterol medications were similar between the groups. Annual calcineurin inhibitor costs were lower in the C2 arm ($5432 +/- 2091 for C2 versus $8291 +/- 3948 for FK, P = 0.001). Annual pretransplant drug costs ($2292 +/- 2331 for C2 versus $2831 +/- 2358 for FK, P = NS) and 1-year posttransplant drug costs ($17,214 +/- 16,600 for C2 versus $15,151 +/- 11,699 for FK, P = NS) were similar. In conclusion, immunosuppression with CsA, monitored by C2 levels, is safe, effective, and economical in liver transplant recipients and provides immunosuppression at least equivalent to that of FK.
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PMID:A randomized, prospective, pharmacoeconomic trial of neoral 2-hour postdose concentration monitoring versus tacrolimus trough concentration monitoring in de novo liver transplant recipients. 1823 91

Despite dramatic improvements in immunosuppression, late graft loss after kidney transplantation remains a common and difficult problem. Histologic evaluation may reveal changes related to BK polyomavirus infection, hypertension, or calcineurin inhibitor toxicity, which can help to guide therapy. The designation chronic allograft nephropathy should thus be reserved for biopsies with tubular atrophy and interstitial fibrosis without an apparent cause. Although the cause clearly includes both antigen-dependent and antigen-independent events, the approach remains largely to exclude immune mechanisms. Although this review discusses the potential contribution of antibody to chronic injury, it focuses on the basic elements of kidney injury, the role of parenchymal cells in promoting injury, and the proliferative and inflammatory responses that accompanying injury. Strategies to manage these recipients include close attention to accompanying hypertension, diabetes, and hyperlipidemia, as well as consideration for altering immunosuppression; however, therapies that limit epithelial-to-mesenchymal transition or directly block fibrosis pathways may reduce chronic allograft fibrosis and may prove to be useful. Understanding the basic pathogenesis sufficiently to allow early intervention may finally benefit patients who are at high risk for tubular atrophy and interstitial fibrosis and promote their long-term graft function.
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PMID:Late kidney allograft loss: what we know about it, and what we can do about it. 1830 4

Tacrolimus gained FDA approval for use in liver transplantation in 1994 and, approximately 3 years later, was approved for the prevention of acute rejection in kidney transplantation. Over the last decade tacrolimus has become the calcineurin inhibitor of choice for the prevention of rejection in renal transplantation. The objective of this study was to provide a review and update of the literature on the use of tacrolimus in renal transplantation. Numerous clinical trials have shown tacrolimus to be superior to cyclosporine in the prevention of acute rejection and recent trials have demonstrated superiority of tacrolimus over cyclosporine in terms of allograft survival. Post-transplant diabetes remains more common with tacrolimus than cyclosporine, despite lower doses of both tacrolimus and corticosteroids. A novel once-daily dosage form of tacrolimus has recently been developed and is approved for use in Europe. Tacrolimus remains an important immunosuppressant for the prevention of acute rejection. The prolonged-release formulation may improve compliance and possibly long-term outcomes.
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PMID:The role of tacrolimus in renal transplantation. 1831 64

Cardiovascular disease is the major cause of death in renal transplant recipients. Renal transplant recipients share the same cardiovascular risk factors as the general population, including hypertension, hyperlipidemia, diabetes mellitus, smoking, and positive family history. However, renal transplant recipients are also exposed to transplant-specific risk factors such as chronic immunosuppression. Most renal transplant recipients receive combinations or permutations of immunosuppressive drugs including a calcineurin inhibitor (cyclosporine or tacrolimus), a mammalian target of rapamycin (mTOR) inhibitor (sirolimus), an antiproliferative drug (mycophenolate mofetil and azathioprine), and corticosteroids. Cyclosporine and tacrolimus can induce glucose intolerance, hypertension, and hyperlipidemia. Sirolimus can induce hyperlipidemia. Corticosteroids can induce glucose intolerance, hypertension, hyperlipidemia, and weight gain. Central to the development of metabolic complications in renal transplant recipients is insulin resistance induced by immunosuppressive drugs. Insulin resistance is considered to be the central pathophysiological feature of metabolic syndrome, which is linked to increased risk of cardiovascular disease and to chronic renal failure. Therefore, metabolic syndrome likely contributes to cardiovascular disease and chronic renal allograft dysfunction in renal transplant recipients. Treatment of metabolic complications in renal transplant recipients is difficult, as conversion to an alternate immunosuppressive drug may lead to introduction of new metabolic complications, and as discontinuation of immunosuppressive therapy may lead to rejection. Future research should focus on designing immunosuppressive regimens that have minimal effects on insulin resistance and metabolic complications but that are effective in preventing acute rejection and in prolonging both allograft and patient survival.
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PMID:Immunosuppression and metabolic syndrome in renal transplant recipients. 1837 Jun 95

Pre-liver transplant renal dysfunction is associated with decreased survival following transplantation and is also a prognostic indicator of posttransplant chronic kidney disease. Selection of patients for combined liver/kidney transplantation versus orthotopic liver transplantation alone (OLTa) is often difficult given the lack of a reliable method to predict which patients will have ongoing severe renal dysfunction in the absence of concomitant kidney transplantation. We hypothesized that most patients with pretransplant renal dysfunction (serum creatinine > or = 1.5 mg/dL for at least 2 weeks prior to and at time of transplant) will not experience a rapid decline in estimated glomerular filtration rates (eGF) post-OLTa to the point of necessitating consideration for kidney transplantation, even in the setting of calcineurin inhibitor-based immunosuppression. We performed a single-center retrospective study of 60 OLTa patients with pretransplant renal dysfunction transplanted between 2000 and 2005. Kaplan-Meier analysis was performed of the time interval to develop eGFR < 20 mL/minute post-OLTa. At OLTa, the mean patient age was 59 years, and median serum creatinine was 1.8 mg/dL; 42% patients were hepatitis C-positive, 32% were diabetic, 38% had kidney dysfunction > 12 weeks, and 5% were receiving hemodialysis. After 36 months median follow-up post-OLTa, only 8 patients (13%) with significant renal dysfunction pre-OLTa achieved eGFR < 20 mL/minute. Patients with pretransplant kidney dysfunction > 12 weeks were at increased risk for eGFR < 20 mL/minute (hazard ratio = 5.3, P = 0.04), a risk that escalated after adjustment for age and serum creatinine at transplant (hazard ratio = 8.9, P = 0.01). Significant predictors of eGFR < 20 mL/minute post-OLTa in this patient cohort were the presence of diabetes and the serum creatinine level at transplant. In conclusion, few patients with preexisting renal dysfunction, especially if <12 weeks duration, experience a significant drop in eGFR post-OLTa.
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PMID:Transplantation: impact of pretransplant renal insufficiency. 1843 66

The availability of new drugs has prompted transplant physicians to devise new immunosuppressive protocols without the calcineurin inhibitors cyclosporine and tacrolimus in order to reduce the incidence of their side effects, particularly nephrotoxicity. However, recent data suggest that these drugs still procure the longest organ survival after transplant. In addition, although they have been used for a long time, it is not clear which calcineurin inhibitor is to be preferred: tacrolimus seems most effective in reducing the acute rejection rate, possibly associated with a better glomerular filtration rate in the following years, but its benefit in the long run is not definitely established. It may allow a dose reduction of steroids, which is of particular interest in pediatric age, but it is associated with a higher incidence of severe side effects, in particular post-transplant lymphoproliferative disorders and diabetes. In recent protocols, the reduction of the dose of this drug has led to a reduction of these side effects, even though they are still more frequent than side effects observed during cyclosporine treatment.
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PMID:[Controversies about the use of calcineurin inhibitors in pediatric patients]. 1882 24

Tacrolimus, a calcineurin inhibitor, has become an increasingly valuable tool in the treatment of dermatological disorders during the last few years. However, its effect on wound healing is still under investigation and remains the subject of safety concerns. A 75-year old woman with lichen planus, diabetes mellitus, and a foot ulcer was prescribed tacrolimus for the treatment of her lichen planus. After starting the treatment, her ulcer healed and the medication was discontinued. Shortly thereafter, re-ulceration occurred, treatment was re-introduced, and the wound continued to heal until treatment was discontinued. When the third course of tacrolimus was prescribed, the ulcer started healing again but a diagnosis of osteomyelitis necessitated surgical intervention. A review of the literature suggests that tacrolimus does not adversely affect healing in vivo or in vitro and may facilitate healing lower extremity skin ulcers, especially those of inflammatory origin. Studies are needed to clarify which lower extremity wounds would improve with tacrolimus.
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PMID:The effect of tacrolimus on lower extremity ulcers: a case study and review of the literature. 1848 May 4

To assess non-immunological complications affecting renal transplant patients in the first six months after transplantation in Al-Karama hospital, Baghdad, Iraq, we studied 68 patients (49 males, 19 females) attending the clinic during the year 2006. Forty six (67%) patients received kidneys from related and 22 (33%) from unrelated donors. The patients revealed the following complications: post transplant hypertension in 28 (41%) patient, infection (mostly bacterial) in 27 (37%), new onset diabetes in 11 (16%), calcineurin inhibitor toxicity in 10 (14%), anemia in 8 (12%), surgical complications in 7 (10%), slow graft recovery in 4 (6%), cardiovascular complications in 3 (4%), and Kaposi sarcoma in 2 (2.9%). Transient hyperglycemia, hypertension, infection and diabetes mellitus were the commonest early complications of renal transplantation. The incidence of complications is comparable to the average reported in the literature, especially in this region of the world.
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PMID:Early non-immunological post transplant complications: a single center experience. 1858 32

New classes of agents have sequentially increased the specificity of post-transplant immunosuppression, leading to profound improvements in success rates after renal transplantation. The next era will focus on increased long-term survival rates through optimal use of existing agents and the rational development of drugs based on prior identification of specific immunologic targets. Conventionally, long-term outcomes after kidney transplantation have been assessed by surrogate markers, notably acute rejection, but graft-threatening complications such as development of new-onset diabetes mellitus and polyomavirus nephropathy must be addressed if long-term survival rates are to be improved. Mycophenolic acid therapy must be administered optimally to ensure that adequate exposure is achieved in the immediate post-transplant period and, subsequently, by avoiding underdosing due to gastrointestinal events. Chronic allograft nephropathy remains a major concern, and protocol-led, reliable monitoring strategies are essential to enable early intervention, for example, through introduction of proliferation signal inhibitor therapy with concomitant calcineurin inhibitor reduction or withdrawal. The range of immunosuppressive regimens now available and in development, together with improved assessment of patients' risk profiles for immunologic events and comorbid disease, offers the opportunity for further individualization of immunosuppression after renal transplantation.
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PMID:Immunosuppression in renal transplantation: some aspects for the modern era. 1865 62


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