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 value of neutrophil gelatinase-associated lipocalin (NGAL) as a novel marker for early detection of acute renal failure has been highlighted recently. The aim of this study was to assess whether serum NGAL correlates with kidney function in kidney allograft recipients. Serum NGAL, creatinine, and estimated glomerular filtration rate (GFR) were evaluated in 100 kidney allograft recipients on triple therapy: calcineurin inhibitor, mycophenolate mofetil or azathioprine, prednisone and healthy volunteers. Kidney transplant recipients had significantly higher NGAL than the control group. Serum NGAL in univariate analysis was strongly correlated with serum creatinine (r = 0.78). Estimated GFR (r = -0.69), on the other hand, was moderately correlated with white blood cell count (r = 0.43) and only weakly with other parameters. In multiple regression analysis, the best predictor of serum NGAL was eGFR (beta -0.69), with other predictors being white blood cell count (beta 0.25) and high sensitivity C-reactive protein (hsCRP) (beta 0.23) explaining 82% of NGAL concentration. Even a successful kidney transplantation is associated with kidney injury as reflected by elevated serum NGAL and lowered eGFR. Therefore, NGAL needs to be investigated as a potential early marker for impaired kidney function/kidney injury, especially in patients with other risk factor for kidney damage, i.e., hypertension or diabetes.
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PMID:Serum neutrophil gelatinase-associated lipocalin correlates with kidney function in renal allograft recipients. 1970 26

Kidney transplantation has become increasingly common in major health centres, making renal allograft evaluation through biopsy a common procedure. Early allograft dysfunction occurs in 30-50% of all transplants, while chronic graft failure is almost uniform at a rate of 2-4% a year. Allograft biopsy remains the gold standard for the diagnosis of graft dysfunction. Rejection, albeit the most important, is only one of many causes of allograft dysfunction. The widely accepted Banff classification has set criteria for the diagnosis of acute and chronic rejection. The major differential diagnoses are acute ischaemic injury, calcineurin inhibitor toxicity (acute and chronic), infections, including pyelonephritis and polyomavirus nephropathy, chronic obstruction/reflux, hypertension, and recurrent and de novo disease. In this review, there is an outline of the Banff criteria and their implications, the various causes of graft dysfunction, and a discussion on morphological guidelines towards the various diagnoses.
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PMID:Our approach to a renal transplant biopsy. 1985 May 67

BACKGROUND.: Sirolimus (SRL) is an important component of clinical immunosuppression in renal transplantation, but few international studies have examined how this agent is used in routine practice. METHODS.: Within a large prospective pharmacoepidemiological study, 718 de novo renal graft recipients treated with SRL in 65 centers in 10 countries were monitored for up to 5 years posttransplant to compare the principal outcomes and adverse effects by treatment regimen. RESULTS.: Principal treatment regimens were SRL without a calcineurin inhibitor (33%), SRL+cyclosporine A (CsA) (33%), and SRL+tacrolimus (TAC) (34%); 18% of subjects discontinued SRL, 124/718 (17%) developed biopsy-confirmed acute rejection (BCAR), 64/718 (9%) lost their graft, and 50/718 (7%) died during follow-up. Calculated creatinine clearance was 66+/-26 mL/min at 2 years. The most common adverse events were hypertension, hyperlipidemia, anemia, urinary tract infections, and diabetes. BCAR was significantly lower in subjects receiving SRL+TAC (hazard ratio [HR] 0.46, P=0.009) but not significantly lower in those receiving SRL+CsA (HR 0.62, P=0.102) compared with SRL without a calcineurin inhibitor. Graft loss or death did not significantly differ between treatment groups but were associated, respectively, with deceased donor grafts (HR 3.33, P<0.001) and increased age (HR 1.04, P<0.001). No improvement was observed in patients receiving mycophenolate mofetil in any treatment combination (HR 0.80, P=0.438 for BCAR; HR 0.93, P=0.849 for graft loss; and HR 0.75, P=0.531 for death). CONCLUSIONS.: SRL is most commonly used in combination with mycophenolate mofetil, CsA, or TAC. BCAR was least common in subjects receiving SRL+TAC, but other outcomes seemed comparable between the treatment regimens in routine practice.
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PMID:Prospective observational study of sirolimus as primary immunosuppression after renal transplantation. 1985 47

1. Chronic kidney disease is a common complication after liver transplantation and has a major impact on graft and patient survival. 2. Pretransplant renal dysfunction is the most important determinant of posttransplant chronic kidney disease; other factors include the presence of diabetes/hypertension, acute kidney injury pre-transplant and post-transplant, and the use of calcineurin inhibitor-based immunosuppression. 3. The most common cause of end-stage renal disease post-orthotopic liver transplantation is calcineurin inhibitor toxicity, and this emphasizes the need for calcineurin inhibitor minimization protocols post-transplant. 4. The presence of chronic kidney disease post-orthotopic liver transplantation not only is important with respect to the need for renal replacement therapy and kidney transplantation but also increases cardiovascular risk dramatically. 5. The Model for End-Stage Liver Disease score is partly driven by creatinine, and it is not uncommon to have an elevated creatinine level in those who have a high Model for End-Stage Liver Disease score and are close to having an organ allocated. Thus, evaluating patients with advanced liver disease and pretransplant acute kidney injury is challenging. It is important to identify pre-liver transplant patients at high risk for early evolution of chronic kidney disease post-transplant in order to appropriately select patients for combined liver/kidney transplantation.
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PMID:Outcomes after liver transplantation: chronic kidney disease. 1987 56

1. There is a high prevalence of cardiovascular risk factors in liver transplant recipients. 2. There is a high incidence of premature onset of cardiovascular disease. 3. The choice of calcineurin inhibitor shows no long-term impact. 4. Established cardiovascular risk scores may determine an individual's risk for cardiovascular events. 5. Posttransplant arterial hypertension is a major burden. 6. Strict surveillance guidelines are needed. 7. Threshold levels for arterial blood pressure according to recommendations for high-risk individuals should be applied. 8. Therapeutic lifestyle changes should be encouraged. 9. Escalating pharmacological treatment with respect to renal function is recommended. 10. Alterations of immunosuppression should be considered.
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PMID:Long-term medical comorbidities and their management: hypertension/cardiovascular disease. 1987 22

Long-term allograft survival poses a major problem in pediatric renal transplantation, with allograft nephropathy being the principal cause of graft failure after the first post-transplant year. The mechanisms of nephron loss resulting in graft dysfunction are multiple, comprising both immunologic factors such as acute and chronic antibody- or T-cell-mediated rejection and non-immunologic components. The latter include peri-transplant injuries and renovascular lesions (renal artery stenosis, thrombosis) as well as cardiovascular risk factors such as arterial hypertension and hyperlipidemia. Another relevant issue leading to progressive nephron loss and declining kidney transplant function is acute and chronic nephrotoxicity induced by the calcineurin inhibitors (CNIs) ciclosporin (cyclosporine microemulsion) and tacrolimus. Furthermore, the presence of an abnormal lower urinary tract as well as bacterial (recurrent pyelonephritis) and viral (cytomegalovirus [CMV], polyomavirus [BK virus; BKV]) infections are crucial factors involved in the incidence of chronic allograft dysfunction and graft failure. Renovascular lesions and lower urinary tract obstruction are typical indicators for surgical intervention. The aim of treatment in pediatric patients with renal failure secondary to a dysfunctional lower urinary tract is to create a sterile, continent, and nonrefluxive reservoir. Surgical techniques such as bladder augmentation and the introduction of intermittent catheterization and anticholinergic therapy have significantly improved graft outcome. Arterial hypertension, another factor responsible for graft function deterioration in pediatric renal transplant recipients, is controlled preferably by the use of angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists, which are known to possess nephroprotective properties in addition to their potent antihypertensive effects. Although treatment of subclinical rejection with augmented immunosuppression has been associated with better graft survival, an increase of the immunosuppressive level to avoid subclinical rejection should be weighed against the risk of infection. The majority of viral infections affecting kidney allografts are caused by CMV and BKV. Antiviral CMV prophylaxis or pre-emptive therapy with ganciclovir has been shown to have beneficial effects in the pediatric renal transplant population. Treatment of BKV-induced nephropathy is based on reduction of the immunosuppressant therapy, although specific antiviral agents such as cidofovir and leflunomide are known to inhibit BKV. However, cidofovir itself is nephrotoxic and should therefore be administered cautiously to pediatric renal transplant patients. Since CNIs are likewise known for their nephrotoxic effects, especially with long-term use, alteration of the immunosuppressant regimen is necessary in case of deteriorating graft function due to CNI-induced histopathologic changes. Complete CNI avoidance seems inappropriate because, in this situation in pediatric renal transplant recipients, other relatively potent immunosuppressant agents such as lymphocyte-depleting antibodies, which are frequently accompanied by a higher incidence of infections, are needed for rejection prophylaxis. CNI withdrawal and switching of the immunosuppressant regimen from CNI therapy to sirolimus may be an option for some pediatric renal transplant patients with less advanced graft function deterioration. Nevertheless, potential adverse events such as aggravation of proteinuria, hyperlipidemia, myelosuppression, and hypergonadotropic hypogonadism have to be considered, and controlled studies are lacking. At present, an immunosuppressant maintenance therapy composed of low-dose tacrolimus or ciclosporin (CNI minimization) and mycophenolate mofetil with low-dose corticosteroids appears to be the most promising strategy to adopt in pediatric renal transplant recipients at low or normal immunologic risk.
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PMID:Treatment strategies to minimize or prevent chronic allograft dysfunction in pediatric renal transplant recipients: an overview. 1987 24

The calcineurin inhibitors-cyclosporine and tacrolimus-are the mainstay of immunosuppressive therapy in solid organ transplantation. These drugs produce severe adverse drug effects (ADEs) such as nephrotoxicity, posttransplantation diabetes mellitus, and hypertension. Accumulated evidence suggests that the development of type 2 diabetes, hypertension, and renal failure may be associated with specific DNA genotypes. In this review, the genes involved with the development of these disease processes are compared with those implicated in calcineurin inhibitor-induced ADEs. The renin-angiotensin system genes, cytokine-encoding genes, and plasminogen activator inhibitor type 1 genes have been implicated in calcineurin inhibitor-induced nephrotoxicity, as well as in development of renal failure. A number of genes are implicated in contributing to diabetes, and these include the vitamin D receptor gene, VDR; hepatocyte nuclear factor genes, HNF; transcription factor 7-like 2 gene, TCF7L2; angiotensin-converting enzyme gene, ACE; cytokines; peroxisome proliferator-activated receptor gamma gene, PPARG; and others. Studies have suggested that the VDR, PPARG, HNF1A, and adenosine 5'-triphosphate-binding cassette ABCC8 (which encodes the sulfonylurea receptor) genes are associated with calcineurin inhibitor-induced diabetes. The genes encoding for the angiotensin-converting enzyme, endothelial constitutive nitric oxide synthase, and cytochrome P450 3A isoenzyme have been involved in the development of hypertension and in calcineurin inhibitor-induced hypertension. The genetic study of disease states can be the stepping stones for thoroughly understanding the genetic basis of ADEs. Gene polymorphisms are implicated in the development of diseases and corresponding disease-like ADEs. The disease-associated genes provide candidate genes for exploring ADEs and may provide genomic biomarkers for assessing the risk for developing severe calcineurin inhibitor-related ADEs as well as for developing preventive strategies.
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PMID:Understanding the genetic basis for adverse drug effects: the calcineurin inhibitors. 2009 93

The calcineurin inhibitors ciclosporin (cyclosporine) and tacrolimus are immunosuppressant drugs used for the prevention of organ rejection following transplantation. Both agents are metabolic substrates for cytochrome P450 (CYP) 3A enzymes - in particular, CYP3A4 and CYP3A5 - and are transported out of cells via P-glycoprotein (ABCB1). Several single nucleotide polymorphisms (SNPs) have been identified in the genes encoding for CYP3A4, CYP3A5 and P-glycoprotein, including CYP3A4 -392A>G (rs2740574), CYP3A5 6986A>G (rs776746), ABCB1 3435C>T (rs1045642), ABCB1 1236C>T (rs1128503) and ABCB1 2677G>T/A (rs2032582). The aim of this review is to provide the clinician with an extensive overview of the recent literature on the known effects of these SNPs on the pharmacodynamics of ciclosporin and tacrolimus in solid-organ transplant recipients. Literature searches were performed and all relevant primary research articles were critiqued and summarized. There is no evidence that the CYP3A4 -392A>G SNP has an effect on the pharmacodynamics of either ciclosporin or tacrolimus; however, studies have been limited. For patients prescribed ciclosporin, the CYP3A5 6986A>G SNP may influence long-term survival, possibly because of a different metabolite pattern over time. This SNP has no clear association with acute rejection during ciclosporin therapy. Despite a strong association between the CYP3A5 6986A>G SNP and tacrolimus pharmacokinetics, there is no consistent evidence of organ rejection as a result of genotype-related under-immunosuppression. This is likely to be explained by the practice of performing tacrolimus dose adjustments in the early phase after transplantation. The effect of the CYP3A5 6986A>G SNP on ciclosporin- and tacrolimus-related nephrotoxicity and development of hypertension is unclear. Similarly, the ABCB1 SNPs exert no clear influence on either ciclosporin or tacrolimus pharmacodynamics, with studies showing conflicting results in regard to the main parameters of acute rejection and nephrotoxicity. In kidney transplant patients, consideration of the donor kidney genotype rather than the recipient genotype may be more important when assessing development of nephrotoxicity. Studies with low patient numbers may account for many inconsistent results to date. The majority of studies have only evaluated the effects of individual SNPs; however, multiple polymorphisms may interact to produce a combined effect. Further haplotype analyses are likely to be useful, particularly ones that consider both donor and recipient genotype. The effects of polymorphisms associated with the pregnane X receptor, organic anion transporting polypeptides, calcineurin inhibitor target sites and immune response pathways need to be further investigated. A large standardized clinical trial is now required to evaluate the relationship between the pharmacokinetics and pharmacodynamics of CYP3A5-mediated tacrolimus metabolism, particularly in regard to the outcomes of acute rejection and nephrotoxicity. It is not yet clear whether pharmacogenetic profiling of calcineurin inhibitors will be a useful clinical tool for personalizing immunosuppressant therapy.
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PMID:Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part II. 2021 6

The introduction of cyclosporine in the early 1980s meant a decisive improvement in post-transplant outcomes for all solid-organ transplants and, in particular, it allowed heart transplantation to emerge as a viable therapeutic option for patients with end-stage cardiac failure. Many factors, including recipient and donor selection, organ preservation and the technical aspects of the transplant itself, influence post-operative outcomes following heart transplantation but the continued need to treat the recipient's immune response plays a key role in determining long-term outcomes. Thereby interactions between immunosuppressive drugs used in different combinations play an important role in patients' outcome. After more than two decades, significant controversy still exists as to the best immunosuppressive regimen for long-term maintenance. During the 1990s and 2000s, newer immunosuppressive medications, specifically, tacrolimus, mycophenolate mofetil, sirolimus, everolimus and the IL-2 receptor blockers (daclizumab and basiliximab), were introduced that allow the clinician several options to try to minimize side effects and maximize the desired therapeutic effects. The side effects involve direct organ toxicity (e.g. renal and hepatic dysfunction), metabolic disturbances, (e.g. diabetes, hyperlipidemia and hypertension), neurotoxicity, and several other significant adverse events, such as cholestasis and myelosuppression. Newer immunosuppressive drugs can impair wound healing, induce lung toxicity and produce various cytopenic states. Steroids continue to plague patients with their well-known side effects. This article reviews the current data on the benefits and risks of the various therapeutic regimens available, which are analyzed under three main themes: calcineurin inhibitor based therapies, calcineurin minimization protocols and calcineurin free regimens.
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PMID:Impact of different long-term maintenance immunosuppressive therapy strategies on patients' outcome after heart transplantation. 2043 59

Mammalian target of rapamycin (mTOR) is the core component of two complexes, mTORC1 and mTORC2. mTORC1 is inhibited by rapamycin and analogues. mTORC2 is impeded only in some cell types by prolonged exposure to these compounds. mTOR activation is linked to tubular cell proliferation in animal models and human autosomal dominant polycystic kidney disease (ADPKD). mTOR inhibitors impede cell proliferation and cyst growth in polycystic kidney disease (PKD) models. After renal transplantation, two small retrospective studies suggested that mTOR was more effective than calcineurin inhibitor-based immunosuppression in limiting kidney and/or liver enlargement. By inhibiting vascular remodeling, angiogenesis, and fibrogenesis, mTOR inhibitors may attenuate nephroangiosclerosis, cyst growth, and interstitial fibrosis. Thus, they may benefit ADPKD at multiple levels. However, mTOR inhibition is not without risks and side effects, mostly dose-dependent. Under certain conditions, mTOR inhibition interferes with adaptive increases in renal proliferation necessary for recovery from injury. They restrict Akt activation, nitric oxide synthesis, and endothelial cell survival (downstream from mTORC2) and potentially increase the risk for glomerular and peritubular capillary loss, vasospasm, and hypertension. They impair podocyte integrity pathways and may predispose to glomerular injury. Administration of mTOR inhibitors is discontinued because of side effects in up to 40% of transplant recipients. Currently, treatment with mTOR inhibitors should not be recommended to treat ADPKD. Results of ongoing studies must be awaited and patients informed accordingly. If effective, lower dosages than those used to prevent rejection would minimize side effects. Combination therapy with other effective drugs could improve tolerability and results.
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PMID:Prospects for mTOR inhibitor use in patients with polycystic kidney disease and hamartomatous diseases. 2049 48


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