Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

With current immunosuppression, elevated blood pressure is found in almost 90% of renal graft recipients. Major causes of this are impairment of renal function (secondary to chronic allograft nephropathy or less frequently recurrence of primary renal disease), the use of calcineurin inhibitors as immunosuppressants, uncontrolled renin secretion by the shrunken kidneys of the recipient, stenosing lesions of the transplant artery (or the upstream arteries of the recipient), polycythemia, and genetic predisposition to hypertension of the graft donor. Even minor degrees of blood pressure elevation have a significant impact on survival of the recipient and on graft survival, presumably by amplifying vascular injury to the graft. In this respect, elevation of systolic blood pressure and an abnormal circadian blood pressure profile are of particular relevance. In contrast to previous opinion, angiotensin converting enzyme inhibitors are indicated in treatment, but given the causal role of sodium retention and graft vasoconstriction, diuretics and calcium channel blockers remain mainstays of antihypertensive treatment in the renal allograft recipient.
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PMID:Hypertension after renal transplantation. 1155 80

DE NOVO DIABETES AND CARDIOVASCULAR RISK: Certain kidney transplant recipients who develop de novo diabetes have an unfavorable cardiovascular risk profile, comparable to patients with type 2 diabetes mellitus, with advanced age, dyslipidemia, obesity and high blood pressure. MYOCARDIAL INFARCTION IN THE PERIOPERATIVE PERIOD: Among kidney transplant recipients, those whose risk factors include male gender diabetes, age over 50 years and prior revascularization procedure for coronary artery disease have a higher risk for myocardial infarction in the perioperative period. The usefulness of anticoagulant or beta-blockers as preventive treatment for these high-risk patients remains to be determined. HYPERLIPIDEMIA: A retrospective analysis of 530 kidney transplant recipients demonstrated that a very significant proportion of those with dyslipidemia are not receiving appropriate care although their lipid profile is indicative of a high or very high cardiovascular risk. MASSIVE PROTEINURIA: An angiotensin II inhibitor, losartan, has been found to be effective against massive proteinuria (> 3.5 g/l) occurring after kidney transplantation. CALCINEURIN-INHIBITOR-INDUCED HEMOLYTIC UREMIA SYNDROME: Five to ten percent of patients given calcineurin inhibitors develop a hemolytic uremia syndrome. Sirolimus appears to be a very interesting alternative for immunoprophylaxys against acute rejection.
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PMID:[Complications in kidney transplantation]. 1157 77

The immunosuppressive benefits of cyclosporine and tacrolimus in short-term and medium-term renal allograft survival are well documented. It is becoming increasingly clear that the basis of this immunosuppression, the inhibition of calcineurin, may be linked with nephrotoxicity, hypertension, hyperlipidemia, and new-onset diabetes mellitus, side effects that may lead to CRAD, death due to CVD, and late renal allograft loss. This clinical picture presents a clear need for new strategies that produce adequate immunosuppression to prevent acute rejection while simultaneously reducing the side effects associated with CNI-related therapies. Sirolimus combined with cyclosporine and tacrolimus has demonstrated an ability to reduce incidences of early acute rejection and, used as base therapy, has provided protection against acute rejection equivalent to that of cyclosporine, without the consequent nephrotoxicity associated with CNIs. In preliminary results from an ongoing clinical trial, sirolimus has been used to eliminate cyclosporine during maintenance immunosuppression, with subsequent improvements in measures of blood pressure and renal function. In addition, the antiproliferative properties of sirolimus and its ability to prevent graft vascular disease in animal studies make sirolimus a promising agent to decrease incidences of CRAD and improve long-term renal allograft survival. These findings point to a clear need to further explore both the efficacy of sirolimus immunotherapy and its long-term effects.
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PMID:Exploring treatment options in renal transplantation: the problems of chronic allograft dysfunction and drug-related nephrotoxicity. 1158 88

Cardiovascular disease is now the leading cause of death in transplant recipients. This is due, in part, to the vulnerability of these patients to a complicated set of conditions including hypertension, diabetes mellitus, and post-transplant hyperlipidaemia (PTHL). PTHL is characterised by persistent elevations in total serum cholesterol, low density lipoprotein cholesterol and triglyceride levels. The causes of PTHL are complex and not fully understood, however several classes of immunosuppressants including the corticosteroids, rapamycins and calcineurin inhibitors, appear to play a role. PTHL has been observed in most studies in which patients received calcineurin inhibitor-based regimens, and has been observed with both tacrolimus and cyclosporin. Comparing these calcineurin inhibitors with regard to the relative incidence or severity of PTHL occurring during treatment is difficult because of the use of higher doses of corticosteroids in cyclosporin-based regimens, as compared with tacrolimus-based regimens. However, current expert opinion suggests that the discrepancies in the relative incidence and severity of PTHL are largely accounted for by this difference in corticosteroid dose. At this point in time, evidence for potential differences is scant and inconclusive. Further study is needed, not only to investigate differences in lipid profile, but also of the relative effects of these immunosuppressants on long term graft function as well as on cardiovascular morbidity and mortality. PTHL can be successfully managed with a combination of dietary management, reduction and, if appropriate, withdrawal of corticosteroids, and the administration of lipid-lowering drugs. With this combination of therapeutic options, the threats to long term health posed by PTHL may be effectively addressed.
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PMID:Calcineurin inhibitors and post-transplant hyperlipidaemias. 1167 3

1. As long-term survival improves after liver transplantation, cardiovascular complications are emerging as a major cause of late morbidity and mortality. It seems reasonable to correct the potentially reversible cardiovascular risk factors of diabetes, hyperlipidemia, and obesity, in addition to hypertension. 2. The results of liver transplantation in diabetics are acceptable in terms of morbidity, mortality, and prevalence of posttransplant diabetes, but the poor outcomes described in some series suggest that more extensive testing for macro- and microvascular disease may become necessary. 3. The management of diabetes in liver transplant recipients is not substantially different from its management in non-transplant patients, except that steroid reduction or withdrawal and minimizing doses of calcineurin inhibitors are beneficial. 4. Hyperlipidemia occurs in all solid-organ transplantation, with prevalence rates the lowest for liver transplant recipients. Following liver transplantation, between 15% and 40% of recipients on average have increased plasma cholesterol levels and about 40% have hypertriglyceridemia. Dietary changes, weight reduction, exercise and statins are the mainstays of therapy. 5. Retrospective studies suggest that long-term survival of obese recipients after liver transplantation does not differ from nonobese recipients. Posttransplant weight gain occurs in most recipients, and approximately two thirds become overweight. The management of posttransplant obesity is similar to that in non-transplant settings.
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PMID:Long-term management of the liver transplant patient: diabetes, hyperlipidemia, and obesity. 1168 72

The identification of genetic mutations underlying familial structural heart disease has provided exciting new insights into how alterations in structural components of the cardiomyocyte lead to different forms of cardiomyopathy. Specifically, mutations in components of the sarcomere are frequently associated with hypertrophic cardiomyopathy, whereas mutations in cytoskeletal proteins lead to dilated cardiomyopathy. In addition, extrinsic stresses such as hypertension and valvular disease can produce myocardial remodeling that is very similar to that observed in genetic cardiomyopathy. For myocardial remodeling to occur, changes in gene expression must occur; therefore, changes in contractile function or wall stress must be communicated to the nucleus via signal transduction pathways. The identity of these signaling pathways has become a key question in molecular biology. Numerous signaling molecules have been implicated in the development of hypertrophy and failure, including the beta-adrenergic receptor, G alpha(q) and downstream effectors, mitogen-activated protein kinase pathways, and the Ca(2+)-regulated phosphatase, calcineurin. In the past it has been difficult to discern which signaling molecules actually contributed to disease progression in vivo; however, the development of numerous transgenic and knockout mouse models of cardiomyopathy is now allowing the direct testing of stimulatory and inhibitory molecules in the mouse heart. From this work it has been possible to identify signaling molecules and pathways that are required for different aspects of disease progression in vivo. In particular, a number of signaling pathways have now been identified that may be key regulators of changes in myocardial structure and function in response to mutations in structural components of the cardiomyocyte. Myocardial structure and signal transduction are now merging into a common field of research that will lead to a more complete understanding of the molecular mechanisms that underly heart disease.
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PMID:From the sarcomere to the nucleus: role of genetics and signaling in structural heart disease. 1170 29

Although only very few new immunosuppressive drugs have been approved over the past two decades, the introduction of each new drug has progressively reduced the incidence of acute rejection and raised hopes that there would be an increase in long-term allograft survival. It is now consistently possible to achieve acute rejection rates of between 10 and 20%, and in many studies the rate has fallen below 10%. This is important, as acute rejection is one of the most important factors reducing the long-term survival of the allograft as a consequence of the development of chronic allograft nephropathy. The availability of these new agents has allowed experimentation with diverse protocols that explore the possibility of reduced exposure to calcineurin inhibitors and corticosteroids. These include both 'avoidance' and 'withdrawal' protocols. The target of rapamycin inhibitors, sirolimus and everolimus, have extended this paradigm. It is possible, but not yet proved, that their antiproliferative effect on smooth muscle will retard the vascular remodelling characteristic of chronic allograft nephropathy, atherosclerosis and hypertension. This review concentrates on the current progress being made in clinical immunosuppression, and includes data presented at the Transplant 2001 meeting of the American Society of Transplantation and the American Society of Transplant Surgeons, held in May 2001.
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PMID:Progress in the clinical application of immunosuppressive drugs in renal transplantation. 1170 3

SDZ RAD (everolimus, Certican is a novel macrolide immunosuppressant that blocks growth factor-driven transduction signals in the T-cell response to alloantigen. After stimulation of the IL-2 receptor on the activated T-cell, SDZ RAD inhibits p70S6 kinase, acting at a later stage in the T-cell mediated response than do cyclosporine and other calcineurin inhibitors (CNIs). Unlike the CNIs, SDZ RAD is a proliferation signal inhibitor, blocking growth factor-driven proliferation of both hematopoietic and nonhematopoietic cells. These activities are complementary to those of cyclosporine and provide a rationale for the addition of SDZ RAD to cyclosporine-based immunosuppression, with the potential for minimizing CNI nephrotoxicity, reducing the incidence of acute rejection, and favoring long-term graft survival. Potential also exists for beneficial effects on other factors that may influence the development of chronic rejection. These factors include comorbid diseases such as hypertension, which may affect transplant vasculopathy, and opportunistic infection with cytomegalovirus (CMV) and other viruses, which may increase the risk of chronic rejection. The synergistic effect of SDZ RAD and cyclosporine has been confirmed in preclinical models, with graft survival being significantly prolonged in rat models of kidney and heart allotransplantation. Clinical experience with SDZ RAD in cyclosporine-based immunosuppression, including low-dose cyclosporine regimens, has also resulted in predictable and favorable clinical outcomes. Low rates of acute rejection, excellent rates of patient and graft survival, lower incidence of CMV infections, better cholesterol, triglyceride and creatinine profiles, and better renal function have been demonstrated with SDZ RAD and lower doses of cyclosporine (Neoral; Novartis) in recipients of renal transplants. These findings, combined with good tolerability rates and an acceptable side-effect profile, indicate that the synergistic profile of SDZ RAD in combination with nontoxic dosages of CNI's and IL2 inhibitors will further improve longterm results in renal transplantation.
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PMID:Early clinical experience with a novel rapamycin derivative. 1180 23

Success in solid organ transplantation with minimal complications can now be achieved for most patients, and a remarkable rate of graft and patient survival can also be expected. However, the potential for adverse events and comorbid conditions increases with longer graft survival. Although the immunosuppressive regimen is central to the outcome of the transplant recipient and directly impacts the survival of the graft, chronic use of immunosuppressive agents is associated with metabolic disturbances such as hypertension, hyperlipidemia, loss of bone density, nephrotoxicity, and diabetes, which may contribute to other comorbid conditions. In addition, changes in appearance, gingival hyperplasia, hirsutism, alopecia, and weight gain disrupt quality of life and may lead to noncompliance with the immunosuppressive regimen. New immunosuppressive medications, including mycophenolate mofetil, sirolimus, basiliximab, and daclizumab, have allowed for experimentation with new regimens designed to reduce or allow discontinuation of corticosteroids and calcineurin inhibitors. This review highlights the impact and cost of immunosuppressive side effects and the potential for new immunosuppressive regimens to reduce this substantial clinical burden in transplantation.
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PMID:Reducing adverse effects of immunosuppressive agents in kidney transplant recipients. 1187 Dec 76

Ongoing improvements in immunosuppression and posttransplantation care have dramatically improved patient and graft outcomes after transplantation. The frequency of graft loss due to acute rejection has declined considerably as a result of the availability of a variety of more potent immunosuppressive agents and probably also because of refined clinical care and follow-up. Complications of long-term administration of corticosteroids (steroids) and calcineurin inhibitors, however, have become increasingly apparent as patients live longer with their transplant, and attention is shifting to long-term issues. Use of both steroids and calcineurin inhibitors is associated with metabolic toxicities such as hypertension, hyperlipidemia, diabetes, bone loss, and cataracts. These contribute to posttransplantation morbidity and may negatively affect patient and allograft survival. A variety of troublesome cosmetic side effects, such as hirsutism, gingival hyperplasia, alopecia, obesity, and cushingoid appearance, also are associated with these drugs. These effects can detract from patient self-esteem and compliance with the immunosuppressive regimen. In the past 2 decades, the introduction of second-generation immunosuppressive drugs, such as tacrolimus, mycophenolate mofetil, sirolimus, and anti-interleukin-2 receptor monoclonal antibodies, has provided some alternatives to classic immunosuppressant choices. Patients experiencing undesirable adverse events now can be converted to another immunosuppressive regimen that ultimately will improve graft and patient survival rates and improve quality of life after transplantation.
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PMID:Strategies to reduce toxicities and improve outcomes in renal transplant recipients. 1189 90


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