Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The major causes of renal transplant loss are death from vascular, malignant or infectious disease, and loss of the allograft from chronic renal dysfunction associated with the development of graft fibrosis and glomerulosclerosis. Chronic allograft nephropathy (CAN) is the histologic description of the fibrosis, vascular and glomerular damage occurring in renal allografts. Clinical programs rely on monitoring change in serum creatinine for identification of patients at risk of CAN, but this change occurs late in the course of the disease, and underestimates the severity of pathologic change. CAN has several causes: ischemia-reperfusion injury, ineffectively or untreated clinical and subclinical rejection, and superimposed calcineurin inhibitor nephrotoxicity, exacerbating pre-existing donor disease. Once established, interstitial fibrosis and arteriolar hyalinosis lead to progressive glomerulosclerosis over the subsequent years. There have been a number of approaches to treatment aimed at reducing the impact of CAN, mostly centered around avoidance of calcineurin inhibitors through their elimination in all, or just selected, patients. These immunosuppression strategies combine corticosteroids with azathioprine or mycophenolate mofetil, and/or sirolimus and everolimus. Late identification of CAN in individual patients has meant that strategies for intervening to prevent chronic renal allograft dysfunction and subsequent graft loss tend to be "too little and far too late."
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PMID:Chronic renal allograft dysfunction. 1612 Aug 19

Death-associated protein kinase (DAPK) is a calcium calmodulin-regulated serine/threonine protein kinase involved in ischemic neuronal death. In situ hybridization experiments show that DAPK mRNA expression is up-regulated in brain following a global ischemic insult and down-regulated in ischemic tissues after focal ischemia. DAPK is inactive in normal brain tissues, where it is found in its phosphorylated state and becomes rapidly and persistently dephosphorylated and activated in response to ischemia in vivo. A similar dephosphorylation pattern is detected in primary cortical neurons subjected to oxygen glucose deprivation or N-methyl-D-aspartate (NMDA)-induced toxicity. Both a calcineurin inhibitor, FK506, and a selective NMDA receptor antagonist, MK-801, inhibit the dephosphorylation of DAPK after in vitro ischemia. This indicates that DAPK could be activated by NMDA receptor-mediated calcium flux, activation of calcineurin, and subsequent DAPK dephosphorylation. Moreover, concomitantly to dephosphorylation, DAPK is proteolytically processed by cathepsin after ischemia. Furthermore, a selective DAPK inhibitor is neuroprotective in both in vitro and in vivo ischemic models. These results indicate that DAPK plays a key role in mediating ischemic neuronal injury.
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PMID:Death-associated protein kinase is activated by dephosphorylation in response to cerebral ischemia. 1620 52

Renal transplantation is by far the best therapeutic option for end-stage kidney disease with respect to quality of life, psychosocial rehabilitation, and even patient survival. Optimal immunosuppressive therapy should provide effective prophylaxis of both acute rejection and chronic allograft dysfunction. Thus immunosuppressive therapy should help to maintain good renal function and could help to prevent premature death of the recipient. With the introduction of new immunosuppressants over the last decade a dramatic reduction of acute rejection rates from approximately 50% to 15-30% could be achieved. However, the search for novel immunosuppressive drugs continues, drugs which not only lead to effective prevention of acute rejection, but also have an impact on chronic allograft dysfunction and prevent further deterioration of this multifactorial process. Based on a short presentation of the "three signal model" of immunoactivation, the most important mechanisms and characteristics of the presently available immunosuppressants are described. Because the immunosuppressive objectives change over time, a phase-dependent adaptation is necessary. At present, most centers in Germany use an immunosuppressive combination therapy, consisting of a calcineurin inhibitor (CNI; cyclosporine or tacrolimus), a glucocorticoid (prednisolone or methylprednisolone), and mycophenolic acid (MPA), which is eventually combined with an antibody (e.g., IL-2R antibody) for induction. In contrast to the clear situation 10 years ago, highly specialized knowledge is required today with respect to mechanism of action, side effects, and potential interactions. This may enable the physician to adopt patient-oriented optimal immunosuppression. In the near future more individualized treatment options will be employed, which are adapted to the characteristics and side effects of the immunosuppressant, as well as to the characteristics of the donor, the recipient, and the transplanted organ such as immunology and ischemia. Another aspect is the reduction or elimination of some immunosuppressants at the earliest possible time. With new diagnostic and genetic markers the relationship between recipient and transplanted organ will be characterized better in the future and therapy will become more individualized. Altogether, these measures as well as optimized supportive therapy will help to further improve the longevity of the transplanted organ.
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PMID:[Modern immunosuppression following renal transplantation. Standard or tailor made?]. 1632 15

The paradigm that chronic rejection causes all progressive late allograft failure has been replaced by a hypothesis of cumulative damage, where a series of time-dependent immune and nonimmune mechanisms injure the kidney and lead to chronic interstitial fibrosis and tubular atrophy, representing a final common pathway of injury and its consequent fibrotic healing response. Allograft damage is common, progressive, time-dependent, clinically important and modified by immunosuppression. Early after transplantation, tubulointerstitial damage is predominantly related to ischemia reperfusion injury, acute tubular necrosis, acute and subclinical rejection and/or calcineurin inhibitor nephrotoxicity, superimposed on preexisting donor disease. Later, cellular inflammation lessens and is replaced by microvascular and glomerular injury from calcineurin inhibitor nephrotoxicity, hypertension, immune-mediated fibrointimal vascular hyperplasia, transplant glomerulopathy and capillary injury, polyoma virus and/or recurrent glomerulonephritis. Additional mechanisms of injury include internal architectural disruption of the kidney, cortical ischemia, persistent chronic inflammation, replicative senescence, cytokine excess and fibrosis induced by epithelial-to-mesenchymal transition. Current understanding of the etiology, pathophysiology and evolution of pathological changes are detailed. An approach to histological assessment of the individual failing graft are presented and a series of postulates are defined for future studies of chronic allograft nephropathy.
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PMID:Chronic allograft nephropathy: current concepts and future directions. 1653 63

Delayed graft function (DGF) in kidney transplantation is associated with an increased risk of acute rejection. Myeloid dendritic cells (DCs) are involved in graft rejection, whereas plasmacytoid DCs may play a role in inducing tolerance. We evaluated the presence and phenotype of the DCs in renal graft biopsies of 15 patients with DGF collected before and 7-15 days after transplantation. Biopsies taken from normal patients and from transplant recipients with acute calcineurin inhibitors (CNIs) nephrotoxicity served as a control group. Specific markers of myeloid, plasmacytoid, and mature DCs were imaged by confocal microscopy and immunohistochemistry. In normal kidneys and pre-transplant biopsies, sparse niches of myeloid and plasmacytoid cells were found but these were significantly increased with few mature cells during DGF. This same pattern was seen in acute rejection but with overall higher cell numbers. In CNI nephrotoxicity, myeloid cells were slightly increased but plasmacytoid cells were significantly higher than in DGF. Using a pig model, we found that a short period of warm ischemia followed by reperfusion led to myeloid cell infiltration of the kidney. Our data suggest that ischemia-reperfusion injury may cause an imbalance between intragraft myeloid and plasmacytoid DCs, which might be related to DGF and acute rejection.
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PMID:Ischemia-reperfusion injury-induced abnormal dendritic cell traffic in the transplanted kidney with delayed graft function. 1768 57

Renal transplant patients lose their grafts most frequently from chronic allograft nephropathy and their lives from cardiac disease, malignancy, and infection. These are thus the challenges for renal transplant programs for this decade, just as acute rejection was the challenge of the last two decades. Most immunosuppressive protocols aim to minimize acute allograft rejection through heavy induction strategies and powerful but toxic maintenance therapies, counterbalanced by powerful and expensive infection prophylaxis. However, while the short-term results have improved steadily from the 1980s, and despite all the current efforts, the long-term success rates of renal transplants have not improved. Future aims include controlling both rejection and the long-term consequences of toxicity and infection risk. The biological facts that have determined our approach to the use of immunosuppressants have required us to try to balance the conflicting need for control of the allograft response and the inevitable toxicities of our drugs. The early period after transplantation requires maximum immunosuppressive efficacy with minimal ischemia reperfusion and good surgical-related wound healing. The latter period after transplantation requires less immunosuppressive efficacy and avoidance of chronic nephrotoxicity, cardiovascular, and malignancy risk factors. This usually leads to an induction strategy using a biological agent; a calcineurin inhibitor; an antiproliferative agent; and variable use of corticosteroids. In the long term, there are a variety of strategies for dose reduction or elimination of calcineurin inhibitors, incorporation of mammalian target of rapamycin inhibitors, and variable approaches to the risks of continued low-dose corticosteroids. The multiplicity of alternative strategies available testifies to the absence of evidence for a single dominant protocol and the urgent need to determine the relevant early indicators for measuring long-term success.
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PMID:Addressing the challenges for improving long-term outcomes in renal transplantation. 1910 Sep

Ischemia-reperfusion injury (IRI) in the early posttransplant period affects immediate graft function and late allograft dysfunction. This study determines the influence of pharmacologic preconditioning with a calcineurin inhibitor on IRI in a syngeneic F344 rat kidney transplant model. Donor rats were pretreated with one dose of cyclosporine (10 mg/kg) or tacrolimus (1 mg/kg) administered at 24 hr or 7 days before being subjected to 2 hr of cold ischemia and then transplanted. Pharmacologic preconditioning significantly improved renal function, as assessed by serum creatinine and inulin clearance, and histologic score versus vehicle-treated rats. There were no differences between cyclosporine and tacrolimus in the measured outcomes. This renoprotective effect, although not complete, was seen with only one dose of calcineurin inhibitor, and the effect was sustained for at least 7 days before IRI. This approach may represent a viable pharmacologic intervention to decrease IRI at the time of organ transplantation.
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PMID:Donor preconditioning with a calcineurin inhibitor improves outcome in rat syngeneic kidney transplantation. 1920 36

Urinary neutrophil gelatinase-associated lipocalin (NGAL) may represent an early, predictive biomarker of delayed graft function due to ischemia-reperfusion injury. Unfortunately, creatinine is an unreliable indicator of acute changes in kidney function. NGAL was proposed as a novel early marker for detection of acute renal failure. Therefore, the aim of the study was to assess whether NGAL and cystatin C predicted outcomes among 41 consecutive patients undergoing kidney transplantation. Serum NGAL and cystatin C were evaluated before, as well as 1, 3, 6, and 10 days after kidney transplantation using commercially available kits. Serum creatinine was assessed at each time. We observed a significant fall in serum NGAL as early as 1 day following kidney transplantation. Serum cystatin C decreased significantly 3 days after transplantation. Before transplantation, serum NGAL was related to creatinine and cystatin C. At each time point, serum NGAL was related positively to serum creatinine, cystatin C, and negatively to urine volume. In patients with delayed graft function, there was no fall in serum NGAL or cystatin C. Our findings may have important implications for the clinical management of patients undergoing kidney transplantation. The "window of opportunity" to distinguish between acute rejection and calcineurin inhibitor nephrotoxicity is narrow in delayed graft function. Time is limited to introduce proper treatment after the initiating insult. Therefore, NGAL needs to be investigated as a potential early marker for delayed graft function, especially in the settings of early dialysis treatment or antirejection therapy.
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PMID:Neutrophil gelatinase-associated lipocalin and cystatin C could predict renal outcome in patients undergoing kidney allograft transplantation: a prospective study. 1924 1

The proportion of expanded criteria donor (ECD) kidneys transplanted in North America is steadily increasing. By definition, graft survival is shorter for ECD than standard criteria donor (SCD) kidneys. Seeking to identify factors associated with low posttransplant glomerular filtration rates (GFR), we retrospectively reviewed data on 390 consecutive patients transplanted in our center from January 1999 to December 2006 including 78% SCD and 22% ECD by UNOS criteria. We analyzed donor and patient characteristics, HLA mismatches, cold ischemia time (CIT) and delayed graft function (DGF). Pulsatile perfusion was not used. The average CIT was 14.6 hours for all SCD and ECD cases. All patients received thymoglobulin, a calcineurin inhibitor, mycophenolate mofetil, and steroids. The only factor associated with low estimated GFR in the entire ECD cohort was CIT. The average CIT for the ECD group was 18.3 hours, whereas it was only 13.6 hours for those in the SCD group (P < .001). We observed that at 6 months posttransplant, those in the ECD group are 2.2 times more likely (odds ratio, 2.23; 95% confidence interval, 1.065-4.654; P = .033) to have an estimated GFR < or =50 mL/min/1.73 m(2) compared with those in the SCD group for CIT up to 18 hours. The higher odds ratio for low estimated GFR was sustained at 3 years posttransplant. In our center, a lengthy CIT was an early risk factor associated with impaired renal function. We concluded that all efforts should be made to reduce CIT.
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PMID:Lengthy cold ischemia time is a modifiable risk factor associated with low glomerular filtration rates in expanded criteria donor kidney transplant recipients. 1985 32

Delayed graft function (DGF) has one of the greatest effects on short- and long-term outcomes of cadaveric renal allografts. Ischemia reperfusion injury in the context of cold ischemia time and acute calcineurin inhibitor (CNI) nephrotoxicity is a major factor predisposing to DGF. A drug regimen consisting of prostaglandin E(1) (PGE(1)) furosemide and dopamine has been used to reduce DGF after kidney transplantation. Prostaglandin E(1) has multiple anti-ischemic and tissue-protective abilities, furosemide improves diuresis, and dopamine augments renal blood flow and urinary volume. To evaluate a potential positive effect of this drug regimen on the primary function of cadaveric renal allografts, we performed a retrospective single-center study that compared 100 patients who received this regimen with a control group. The results showed no significant improvement in renal function. In contrast, plasma levels of creatinine and urea were increased in the drug regimen group. Thus, the effectiveness of PGE(1) in combination with high-dose furosemide and dopamine in diminishing DGF was not demonstrated in this trial.
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PMID:Effect of perioperative administration of a drug regimen on the primary function of human renal allografts. 2062 Apr 67


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