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)

The development of more selective immunosuppressive agents to mitigate transplant rejection and autoimmune diseases requires effective strategies of blocking signaling pathways in T cells. Current immunosuppressive strategies use cyclosporin A (CsA) or FK506 to inhibit calcineurin, which dephosphorylates and promotes the nuclear import of nuclear factor of activated T cells (NFAT) transcription factors. These nuclear NFATs then transactivate cytokine genes that regulate proliferative responses of T cells. Both CsA and FK506 have debilitating side effects, including nephrotoxicity, hypertension, diabetes, and seizures, that argue for the development of alternative or complementary agents. To this end, we developed cell-based assays for monitoring NFAT dynamics in nonlymphoid cells to identify small molecules that inhibit NFAT nuclear import. Interestingly, we found that the majority of these small molecules suppress NFAT signaling by interfering with "capacitative" or "store-operated" calcium mobilization, thus raising the possibility that such mobilization processes are relevant targets in immunosuppression therapy. Further, these small molecules also show dose-dependent suppression of cytokine gene expression in T cells. Significantly, the IC(50) of CsA in primary T cells was reduced by the addition of suboptimal concentrations of these compounds, suggesting the possibility that such small molecules, in combination with CsA, offer safer means of immunosuppression.
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PMID:Chemical genetics to identify NFAT inhibitors: potential of targeting calcium mobilization in immunosuppression. 1518 84

Chronic allograft nephropathy is a devastating complication of kidney transplantation that is responsible for a significant proportion of graft loss. This complication is characterized by a progressive decline in kidney function, which is not attributable to a specific cause. Many risk factors exist for the development of chronic allograft nephropathy, including donor-, recipient-, and transplant-related factors (eg, use of calcineurin inhibitors and acute rejection episodes), as well as comorbid conditions such as hypertension and hyperlipidemia. There is no definitive treatment for this complication; management has focused on minimization or withdrawal of calcineurin inhibitors in conjunction with addition of sirolimus or mycophenolate mofetil. Alterations in the immunosuppressive regimen must be done cautiously, as precipitating acute rejection will cause further damage to the allograft. Optimal control of blood pressure, particularly with the use of agents such as angiotensin II receptor blockers, in conjunction with management of dyslipidemia may be effective concurrent therapies in patients with chronic allograft nephropathy.
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PMID:Chronic allograft nephropathy: pathogenesis and management of an important posttransplant complication. 1526 52

In spite of considerable progress in immunosuppressive and supportive treatment, numerous problems persist which interfere with the success of renal transplantation. Before transplantation has been performed, factors impacting on outcome include the donor (living vs cadaver, age and HLA system) as well as the recipient (age, immunological reactivity, potential sensitization and duration of dialysis). These are the main factors that affect the outcome of the transplant, particularly in the long-term. After transplantation a number of events may put graft function at risk: potential recurrence of the primary renal disease in the allograft; 'de novo' renal disease triggered by infections, drugs or autoimmunity; and non-specific progression promoters, such as diabetes, hypertension, proteinuria, nephrotoxic agents and/or viral infections. The two most frequent causes of chronic allograft dysfunction are (i) chronic rejection (often triggered by preceding acute rejection, delayed graft function or poor compliance) and (ii) calcineurin-inhibitor nephrotoxicity (more likely to develop in kidneys of older donors or in marginal kidneys). The differential diagnosis between these two entities is generally difficult, but some histological clues (reduplication of glomerular basement membrane, obliterating vasculopathy and C4d deposits) as well as the demonstration of humoral antibodies are pointers suggesting rejection. Treatment of chronic graft dysfunction is difficult, whatever the cause, particularly in cases with advanced renal lesions. Therefore, early diagnosis is of paramount importance. In this regard, graft biopsy can be of great help. In spite of many problems and complications, not only short-term but also long-term results of renal transplantation are improving progressively, as documented by CTS data showing that in Europe for transplants performed between 1982 and 1984 the mean graft half-life was 7 years, while for transplants performed between 1997 and 1999 it was 20 years.
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PMID:Renal transplantation 2004: where do we stand today? 1557 92

The manifestations of gout can be abolished permanently by lifelong urate-lowering therapy maintaining serum urate levels under 360 mmol/l, as this ensures dissolution of pathogenic crystals of monosodium urate monohydrate. Benzbromarone has been withdrawn from the market, leaving allopurinol as the only urate-lowering drug readily available in France. Allopurinol may induce unacceptable side effects, and in patients with dose-limiting renal failure it may not be sufficiently effective. Because allopurinol can induce serious side effects when given concomitantly with purine antimetabolites, it is contraindicated in organ transplant recipients. In patients who cannot tolerate allopurinol, dietary treatment, discontinuation of diuretic agents, and use of losartan or fenofibrate to treat concomitant hypertension or dyslipidemia, respectively, may ensure adequate control of serum urate levels. Desensitization to allopurinol can be attempted in patients with mild cutaneous hypersensitivity reactions but is difficult to perform and rarely used. Uricosuric agents may be helpful in patients with normal or diminished urate excretion. Probenecid is available in France from hospital pharmacies, and benzbromarone can be prescribed via a time-limited authorization procedure. Rasburicase, an Aspergillus urate oxidase produced by genetic engineering, is indicated to prevent acute hyperuricemia induced by chemotherapy for hematological malignancies. Factors that limit the use of rasburicase include the absence of a marketing authorization, the need for parenteral administration, and the absence of validated treatment schedules. Patients with renal failure precluding the use of effective allopurinol dosages are good candidates for benzbromarone therapy. Organ transplant recipients can be given benzbromarone, within the current restrictions to its use; alternatively, mycophenolate mofetil can be substituted for calcineurin inhibitors, which elevate serum urate levels, or for azathioprine, which contraindicates the use of allopurinol.
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PMID:Current management of gout in patients unresponsive or allergic to allopurinol. 1558 27

Modem immunosupressive agents have greatly reduced incidence and severity of acute renal allograft rejection. One-year graft survival rate of 95% can be easily achieved with optimal immunosuppressive regimens. However, long-term kidney transplant survival has improved poorly. At present, chronic allograft nephropathy (CAN) and recipients death (mainly due to circulatory complications, neoplasms and infections) are most common reasons of graft loss in the second and subsequent years after transplantation. Moreover adverse effects of immunosuppressive drugs (nephrotoxicity, arterial hypertension, dyslipidaemia, post-transplant diabetes mellitus) can account for development of CAN. Regimens with combination of at least two drugs are administered to recipients, as it allows for using minimal effective doses and reduces the risk of adverse effects. Narrow therapeutic window of most immunosuppressive agents forces clinicians to adequately monitor serum concentration of the drug or its metabolite. Early postransplant period requires higher doses, which then are reduced. Immunosuppressive regimen is individualized, to minimize the risk of acute rejection, but also to avoid overimmunosuppression and its complications. Presently there are two trends in immunosuppressive schemes: first one to withdraw glycocorticosteroids and the other one to reduce dose or withdraw calcineurin inhibitors, mostly because of their nephrotoxicity.
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PMID:[Immunossupresive drugs in renal transplantation]. 1566 7

Sirolimus (rapamycin) is a macrocyclic lactone isolated from a strain of Streptomyces hygroscopicus that inhibits the mammalian target of rapamycin (mTOR)-mediated signal-transduction pathways, resulting in the arrest of cell cycle of various cell types, including T- and B-lymphocytes. Sirolimus has been demonstrated to prolong graft survival in various animal models of transplantation, ranging from rodents to primates for both heterotopic, as well as orthotopic organ grafting, bone marrow transplantation and islet cell grafting. In human clinical renal transplantation, sirolimus in combination with ciclosporin (cyclosporine) efficiently reduces the incidence of acute allograft rejection. Because of the synergistic effect of sirolimus on ciclosporin-induced nephrotoxicity, a prolonged combination of the two drugs inevitably leads to progressive irreversible renal allograft damage. Early elimination of calcineurin inhibitor therapy or complete avoidance of the latter by using sirolimus therapy is the optimal strategy for this drug. Prospective randomised phase II and III clinical studies have confirmed this approach, at least for recipients with a low to moderate immunological risk. For patients with a high immunological risk or recipients exposed to delayed graft function, sirolimus might not constitute the best therapeutic choice--despite its ability to enable calcineurin inhibitor sparing in the latter situation--because of its anti-proliferative effects on recovering renal tubular cells. Whether lower doses of sirolimus or a combination with a reduced dose of tacrolimus would be advantageous in these high risk situations remains to be determined. Clinically relevant adverse effects of sirolimus that require a specific therapeutic response or can potentially influence short- and long-term patient morbidity and mortality as well as graft survival include hypercholesterolaemia, hypertriglyceridaemia, infectious and non-infectious pneumonia, anaemia, lymphocele formation and impaired wound healing. These drug-related adverse effects are important determinants in the choice of a tailor-made immunosuppressive drug regimen that complies with the individual patient risk profile. Equally important in the latter decision is the lack of severe intrinsic nephrotoxicity associated with sirolimus and its advantageous effects on arterial hypertension, post-transplantation diabetes mellitus and esthetic changes induced by calcineurin inhibitors. Mild and transient thrombocytopenia, leukopenia, gastrointestinal adverse effects and mucosal ulcerations are all minor complications of sirolimus therapy that have less impact on the decision for choosing this drug as the basis for tailor-made immunosuppressive therapy. It is clear that sirolimus has gained a proper place in the present-day immunosuppressive armament used in renal transplantation and will contribute to the development of a tailor-made immunosuppressive therapy aimed at fulfilling the requirements outlined by the individual patient profile.
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PMID:Benefit-risk assessment of sirolimus in renal transplantation. 1569 Dec 25

Kidney transplantation is the best treatment for patients with end-stage renal disease, both in terms of survival benefit and quality of life. The major limitation is the continuing shortage of kidneys suitable for transplantation, reinforcing the need to maximise graft survival. After the first year of transplantation, chronic renal allograft dysfunction (CRAD) is the first cause of late graft deterioration and failure. CRAD has been defined as a progressive renal dysfunction, independent of acute rejection, drug toxicity and recurrent or de novo nephropathy, with features on biopsy of chronic allograft nephropathy (CAN) characterised by vascular intimal hyperplasia, tubular atrophy, interstitial fibrosis and chronic transplant glomerulopathy. Protocol biopsy-based studies have demonstrated a high and early prevalence of CAN lesions during the first year in patients with normal and stable renal function. Beyond 1 year, the injuries associated with calcineurin inhibitors (CNIs) appear to be very common. The physiopathology of CRAD is complex and multifactorial. Both alloantigen-dependent factors (acute rejection, HLA matching, donor-specific antibodies, inadequate immunosuppression) and alloantigen-independent factors (donor age, brain death, ischaemia/reperfusion injuries, hypertension, hyperlipidaemia, cytomegalovirus, CNI-related nephrotoxicity) are involved. Consequently, CRAD appears as a dynamic process, evolving with time, and immunosuppressive regimens need to be modulated in order to provide the most suitable treatment at the different phases of its natural history. On the basis of this scheme, the new paradigm would be the use of a CNI-based regimen during the period of maximal risk of (subclinical) acute rejection, followed by a conversion to a CNI-free regimen in order to avoid the long-term consequences of nephrotoxicity. Fortunately, new agents are being introduced in clinical practice providing a large range of combinations and allowing individualisation of immunosuppressive regimens. Large, prospective, multicentre trials are warranted, and the challenge is to define new endpoints of CRAD and to determine the best therapeutic strategy.
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PMID:Combating chronic renal allograft dysfunction : optimal immunosuppressive regimens. 1574 97

Calcineurin inhibitors potentially contribute to risk of cardiovascular events through the development of new-onset diabetes mellitus, hypertension and hyperlipidemia. The exact extent to which calcineurin inhibitors affect these risk factors is difficult to establish since pre-existing renal disease and concomitant immunosuppressive agents (such as steroids or TOR inhibitors) also exert an effect. Clinical trials have consistently shown a higher incidence of new-onset diabetes mellitus with tacrolimus, which has been borne out in large-scale registry analyses. However, the risk of hypertension is approximately 5% higher with cyclosporine than tacrolimus, as is the risk of hyperlipidemia. Statin therapy is effective in treating dyslipidemia and has significant benefits in renal transplant patients. An individualized approach to choice of calcineurin inhibitor, by which cyclosporine or tacrolimus are selected based on the patient's particular risk profile, may thus help to reduce the toll of cardiovascular mortality among renal transplant recipients in the future.
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PMID:Assessing the relative risk of cardiovascular disease among renal transplant patients receiving tacrolimus or cyclosporine. 1577 54

Chronic allograft nephropathy (CAN) is an anatomical and clinical alteration, characterized by proteinuria, hypertension and a progressive decline in kidney function, which begins at variable times (months, years) and can lead to the loss of the transplanted organ. CAN pathogenesis, which remains to be fully clarified, involves both immunological (early acute rejection, hyperimmunization, HLA-mismatches between donor and recipient, suboptimal immunosuppression, etc) and non-immunological factors (ischemia/reperfusion injury, reduced nephron mass, age differences between donor and recipient, dialysis time, hypertension, dislipidemia, proteinuria, etc). The possible prevention strategies for CAN consist of procedures aimed at the reduction of some potential risk factors: optimization of the conditions for organ explantation, diminution of ischemia/reperfusion injury, aggressive pharmacological treatment of acute rejection episodes, routine utilization of anti-hypertensive and hypolipidemic agents, and appropriate and rational immunosuppressive regimen. Moreover, some categories of immunosuppressive drugs, such as calcineurin inhibitors, can have a nephrotoxic effect, often regardless of therapeutic dosage. The introduction in clinical practice of novel immunosuppressive drugs with no nephrotoxicity, like mycophenolate mofetil and rapamycin, makes therapeutical strategies able to reduce the incidence of CAN feasible.
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PMID:[Therapy strategies in the prevention of chronic allograft nephropathy]. 1578

The crucial functions of atrial natriuretic peptide (ANP) and endothelial nitric oxide/NO in the regulation of arterial blood pressure have been emphasized by the hypertensive phenotype of mice with systemic inactivation of either the guanylyl cyclase-A receptor for ANP (GC-A-/-) or endothelial nitric-oxide synthase (eNOS-/-). Intriguingly, similar levels of arterial hypertension are accompanied by marked cardiac hypertrophy in GC-A-/-, but not in eNOS-/-, mice, suggesting that changes in local pathways regulating cardiac growth accelerate cardiac hypertrophy in the former and protect the heart of the latter. Our recent observations in mice with conditional, cardiomyocyte-restricted GC-A deletion demonstrated that ANP locally inhibits cardiomyocyte growth. Abolition of these local, protective effects may enhance the cardiac hypertrophic response of GC-A-/- mice to persistent increases in hemodynamic load. Notably, eNOS-/- mice exhibit markedly increased cardiac ANP levels, suggesting that increased activation of cardiac GC-A can prevent hypertensive heart disease. To test this hypothesis, we generated mice with systemic inactivation of eNOS and cardiomyocyte-restricted deletion of GC-A by crossing eNOS-/- and cardiomyocyte-restricted GC-A-deficient mice. Cardiac deletion of GC-A did not affect arterial hypertension but significantly exacerbated cardiac hypertrophy and fibrosis in eNOS-/- mice. This was accompanied by marked cardiac activation of both the mitogen-activated protein kinase (MAPK) ERK 1/2 and the phosphatase calcineurin. Our observations suggest that local ANP/GC-A/cyclic GMP signaling counter-regulates MAPK/ERK- and calcineurin/nuclear factor of activated T cells-dependent pathways of cardiac myocyte growth in hypertensive eNOS-/- mice.
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PMID:Local atrial natriuretic peptide signaling prevents hypertensive cardiac hypertrophy in endothelial nitric-oxide synthase-deficient mice. 1579 9


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