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Resistin, a new adipokine, is related to inflammation and renal function in kidney allograft recipients.

BACKGROUND: Among patients without chronic kidney disease, resistin, an adipocytokine, has been related to inflammatory markers, coronary artery disease, and cardiovascular disease in the metabolic syndrome. Moreover, resistin up-regulates adhesion molecules. Since inflammation and endothelial cell damage or injury are invariably associated with thrombosis, atherosclerosis, and their major clinical consequences, resistin may play a role to link inflammation and CVD. The aim of this study was to correlate resistin with markers of inflammation and endothelial cell injury in 96 kidney allograft recipients. METHODS: We measured resistin and the following markers of endothelial function/injury: vWF, thrombomodulin, VCAM, hsCRP, tumor necrosis factor alpha (TNFalpha), and interleukin-6 (IL-6). RESULTS: Triglycerides, CRP (assessed by high-sensitivity method), phosphate, creatinine, IL-6, TNFalpha, vWF, prothrombin fragments 1 + 2, and resistin were elevated among kidney transplant recipients compared with the control group. Kidney allograft recipients with coronary artery disease displayed significantly higher resistin levels than those in patients without this complication. Upon univariate analysis resistin levels in kidney allograft recipients were related to hsCRP, IL-6, thrombomodulin, red blood cell count, white blood cell count, platelet count, creatinine, urea, VCAM, CSA, dose and eGFR. Upon multiple regression analysis, resistin was independently related only to creatinine, hsCRP, and white blood cell count in kidney allograft recipients. CONCLUSIONS: The relation of elevated resistin levels to markers of inflammation may represent a novel link between these conditions and adipocytokines. Renal function was a major determinant of elevated resistin in kidney allograft recipients.

Adult↗

Early posttransplantation hypertension and poor long-term renal allograft survival in pediatric patients.

OBJECTIVE: To evaluate the effect of early hypertension on long-term allograft survival in children with kidney transplantation. STUDY DESIGN: Data from a total of 159 patients (mean age, 12.8+/-4.8 years) who underwent kidney transplantation between 1978 and 1998 and whose allograft was functioning for at least 1 year were analyzed retrospectively. Patients were divided according to the presence of hypertension within the first year after transplantation. Primary outcome was time of allograft failure (death, return to dialysis, or retransplantation). RESULTS: Kaplan-Meier analysis showed that systolic (P<.0001) and diastolic (P=.016) hypertension was associated with overall worse allograft survival. Children with systolic hypertension had a significantly higher graft failure rate regardless of the type of donor, cause of kidney failure, presence or absence of acute rejection, and allograft function at 1 year after transplantation. The multivariate Cox regression model proved that systolic hypertension was a significant and independent risk factor for poor graft survival (hazard ratio [HR], 1.79; P<.0001). Other predictors included allograft function at 1 year after transplantation (HR, 0.97; P<.0001), acquired cause of end-stage kidney disease (HR, 1.96; P=.01) and age <6 years (HR, 2.61; P=.045). CONCLUSIONS: Early posttransplantation systolic hypertension strongly and independently predicts poor long-term graft survival in pediatric patients.

Acute Disease↗

Correlation of nonspecific immune monitoring with rejection or impaired function of renal allografts.

Two nonspecific immunological assays were combined with radionuclide scanning to monitor 113 patients thrice weekly following allotransplantation. The nonspecific immune assays included measurement of the percentage of active T rosette-forming cells (% A-T RFCs) and spontaneous blastogenesis (SB). An increase in SB and decrease in % A-T RFCs (greater than 1 sd of normal controls) constituted an immune event. The immune parameters were correlated with thrice weekly radionuclide studies which were computer analyzed for glomerular and tubular function. Alteration of the immunological and radionuclide parameters significantly correlated (P less than 0.001) with 90 rejection episodes displayed by 72 nonantithymocyte globulin (ATG)-treated renal allograft recipients during the first 30 postoperative days. In the absence of clinically defined rejection, changes in immune parameters correlated with (1) decline of radionuclide parameters and (2) alterations in weight, temperature, creatinine clearance, and serum creatinine, suggesting subclinical events. As a result of the effects of ATG on lymphocytes, a similar comparison could not be made for 41 other patients treated with this immunosuppressive drug. The incidence of false positive tests was 12.7%. Thus, the combination of two nonspecific immune parameters, % A-T RFCs and SB, with computerized analysis of radionuclide scans may afford a reliable index to diagnose early rejection or impaired function of renal allografts.

Diagnosis, Differential↗

ICAM-1 antisense oligodeoxynucleotide improves islet allograft survival and function.

Expression of intercellular adhesion molecule-1 (ICAM-1) and its ligand, leukocyte function antigen-1 (LFA-1), after pancreatic islet transplantation may affect both nonspecific and alloantigen-specific phases of graft destruction. We examined the effects of ICAM-1/LFA-1 blockade on the survival of islet allografts. Fresh C57BL/10 (H2h) pancreatic islets were transplanted under the renal subcapsular space (KC) or embolized into the liver after portal vein (PV) injection to C3H (H2k) mice. Recipients remained untreated or were treated for 7 days by i.p. administration of: ICAM-1 antisense phosphorothioate oligodeoxynucleotide (oligo) alone; anti-1CAM-1 (alphaICAM-1) monoclonal antibody (mAb) alone: alphaLFA-1 mAb alone; ICAM-1 oligo/alphaLFA mAb combination; alphaICAM-1 mAb/alphaLFA-1 mAb combination; or control oligo IP-8997 or IP-1082. In some experiments, donors were pretreated with ICAM-1 oligo. Inhibition of single ligand with 5.0 mg/kg ICAM-1 oligo (25.1 +/- 10.3), 100 microg/daily alphaICAM-1 mAb (24.2 +/- 8.0 days), or 50 microg/daily alphaLFA-1 mAb (42.8 +/- 25.9 days) prolonged the survivals of KC islet allografts in comparison with untreated controls (11.9 +/- 1.0 days; all p < 0.01). However, dual ICAM-1/LFA-1 blockade with either ICAM-1 oligo/alphaLFA-1 mAb (78.3 +/- 16.5 days) or (alphaICAM-1 mAb/aLFA-1 mAb (65.2 +/- 31.3 days) was the most effective therapy. Although pretreatment of donors with ICAM-1 oligo alone was ineffective (12.2 +/- 0.8 days; NS), a combination of donor pretreatment and recipient treatment started 1 day prior to grafting with ICAM-1 oligo (39.2 +/- 14.0 days) was more effective than the recipient treatment alone (24.6 +/- 8.8 days). Furthermore, ICAM-1/LFA-1 blockade improved islet function as evaluated by glucose tolerance test, and decreased inflammation in comparison with untreated controls. Similar in vivo results were obtained following PV administration of islet allografts. Thus, ICAM-1/LFA-1 blockade prolongs the survival of pancreatic islet allografts and improves their early function.

Animals↗

[Simultaneous pancreas-kidney transplantation for the treatment of type I diabetes with end-stage renal disease].

OBJECTIVE: To demonstrate whether simultaneous pancreas-kidney transplantation is practical for the treatment of Type I diabetes with end-stage renal disease. METHODS: Eight cases of combined pancreas-kidney transplantation were performed in our institute. The age ranged from 35 years to 48 years (average 43.46 years). All cases were diagnosed as type I diabetes with end-stage nephropathy, two cases with blindness due to retinopathy. The case history ranged from 2 years to 22 years. Pancreas allograft was placed in the right iliac fossa with pancreas exocrine drainage to bladder, whereas renal allograft the in left iliac fossa. Initial immunosuppression regimen is quadruple. RESULTS: Seven patient could be insulin free after transplantation, with normal fasting blood glucose. One patient received insulin treatment for 40 days after operation. One patient survived 1 year and 9 months after transplantation with normal functioning pancreas allograft and kidney allograft. Four patient survived 2 months with normal allograft function. Fasting blood glucose was between 4.5 and 6.2 mmol/L; Cr was between 53 and 106 micromol/L. Diet control was not necessary. Two patient died of encephalorrhagia, and 1 pancreatic vascular thrombosis and necrotic pancreatitis. CONCLUSIONS: Combined pancreas-kidney transplantation is feasible to treat type I diabetes with end-stage nephropathy. Functional pancreas allograft could be procured in the present condition. Pancreatic exocrine is drained to bladder. The diagnosis of acute rejection could be made earlier by detecting urine amylase. Heparin should be added in order to prevent pancreatic thrombosis.

Adult↗

Purine efflux from transplanted human cardiac allografts. Correlation with graft function.

Purine efflux from transplanted human cardiac allografts was investigated as a potential biochemical correlate to graft preservation and eventual function. Coronary sinus effluent from 14 allografts was sampled at 1, 5, 10, 15, 20, and 25 minutes after reperfusion. The plasma fraction from each sample was analyzed for hypoxanthine, xanthine, urate, inosine, and adenosine by high-performance liquid chromatography. Total organ preservation time, aortic crossclamp and bypass times, and initial cardiac index off bypass were recorded. An inotropic score was calculated from the dosages of inotropic agents each recipient required immediately after transplantation. Inosine and adenosine were not detectable in the coronary sinus effluent at any time during reperfusion. Hypoxanthine concentration rose sevenfold (p < 0.001) 1 minute after reperfusion. Xanthine concentration peaked later at 5 minutes after reperfusion, a twofold increase (p < 0.02). As reperfusion continued, hypoxanthine and xanthine concentrations returned toward baseline levels. The rise in coronary sinus xanthine concentration provides evidence for hypoxanthine degradation by xanthine oxidase during the immediate reperfusion period. The extent of hypoxanthine efflux correlated with total graft ischemic time (p < 0.05), inotropic score (p < 0.005), and the time from crossclamp release to cessation of bypass (p < 0.01). Hypoxanthine efflux can be used as a sensitive and objective biochemical indicator of graft preservation and immediate function.

Heart Transplantation↗

The outcome of delayed graft function in cadaveric renal transplants treated with low dose cyclosporine.

Thirty-three consecutive cadaveric renal transplantations performed at the National Taiwan University Hospital from November 1985 to December 1989 were reviewed to determine the effect of early function on the 1-year patient and graft survival rates. Immediate function was present in 17 transplants; delayed graft function with acute tubular necrosis occurred in 16 cases. The 16 transplants with acute tubular necrosis (ATN) were treated with low dose cyclosporine. Among them, 13 patients had delayed function which resolved after 2 to 60 days of hemodialysis, but 3 grafts did not regain function. The allograft survival rate at 1-year was 68.7% for the delayed function group and 88.2% for the immediate function group. This difference was not statistically significant (p greater than 0.05). The 1-year patient survival rate was also not significantly different (87.5% vs 88.2%). There was no relationship between graft loss and duration of ATN. However, the graft survival rate in patients with a serum creatinine level below 2 mg/dL, after recovery either from ATN or non-ATN, was better than that for patients with a serum creatinine level of more than 2 mg/dL. The difference was statistically significant (95.8% vs 50.0%, p less than 0.02). It is concluded that delayed allograft function with acute tubular necrosis does not significantly alter the 1-year survival rates of patients and grafts in low-dose cyclosporine therapy. However, it is deleterious to the 1-year survival rate of an allograft when poor functional recovery occurs in an ATN or non-ATN condition.

Adult↗

Persistent cytomegalovirus infection in kidney allografts is associated with inferior graft function and survival.

The long-term effects of cytomegalovirus (CMV) infections on kidney allografts are unknown. We examined the impact of persistent intragraft CMV infection on long-term kidney allograft function and survival. CMV was diagnosed in 82/172 renal transplant recipients by antigenemia test and viral cultures. Biopsies from 48 of 82 patients taken after CMV infection and from 15 patients with no previous CMV infection detected were available for the immunohistochemical demonstration of CMV antigens and DNA hybridization in situ. Five-year follow-up data from these 63 patients were analysed. In 17 patients, CMV antigens and/or DNA persisted in the biopsy >2 months after the last positive finding in blood or urine. Patients with persistent intragraft CMV had reduced graft survival (P = 0.041) and Cox regression analysis showed persistent CMV as a risk factor for reduced graft survival (RR: 3.5). Recipients with persistent intragraft CMV had reduced creatinine clearance 1 and 2 years after transplantation (P = 0.007) and in multivariate logistic regression analyses including several potential pre- and posttransplant risk factors, persistent CMV was an independent risk factor for lower clearance at 1 and 2 years (OR: 4.4 and 4.9). Our novel findings show that persistent intragraft CMV infection was associated with reduced kidney allograft function and survival.

Adult↗

Malignant hypertension. Recovery of kidney function after renal allograft failure.

A 28-year old patient with malignant hypertension developed endstage renal failure necessitating chronic maintenance hemodialysis for seven months and transplantation of a renal allograft that was rejected within a month. After this, with continued control of the hypertension, the patient's own kidneys gradually resumed function and achieved anendogenous creatinine clearance of 30 ml/min. She has not required further dialysis for more than nine months. Recovery of sufficient renal function to maintain homeostasis, one year after onset of uremia, indicates the prolonged antihypertensive treatment period that may be necessary to reverse the renal arteriolar changes associated with malignant hypertension. This experience further underlines the necessity of moderation in the use of nephrectomy in the management of severe hypertension.

Adult↗

Significance of anticardiolipin antibodies on short and long term allograft survival and function following kidney transplantation.

The significance of anticardiolipin antibodies (ACAs) prior to renal transplantation is unclear. We studied a cohort of 337 patients who underwent renal transplantation from 1996 to 2001. Follow-up continued until allograft loss, patient death or 31 December 2002. The primary outcome was a composite endpoint of death-censored allograft loss or a 25% reduction in estimated glomerular filtration rate (GFR) from 1-month post-transplant. Secondary outcomes were allograft loss, a 25% reduction in GFR, acute rejection and creatinine at 1 year. IgG and IgM ACA titers were positive (> or =15) in 18.1% of recipients. There were no significant differences at baseline between recipients, except coumadin therapy in those with positive ACA titers (20% vs. 7.4%). Post-transplant, there was no increase in the primary outcome in ACA-positive patients, even after adjustment for anticoagulation with coumadin (HR = 1.42 [0.68, 2.96]). There was no difference in secondary outcomes between those with or without positive titers. Two of five patients with very high titers (>50) who were not anticoagulated had early graft loss. A positive ACA titer prior to kidney transplantation was not associated with inferior renal outcomes after transplantation, although more research is required to address the prognostic significance of very high ACA titers.

Adult↗

Use of glucose disappearance rates (kG) to monitor endocrine function of pancreas allografts.

We have reported that a decline in glucose disappearance rate (kG) in pancreas transplant recipients is associated with pancreatic rejection. The purpose of this study was to determine test-retest reliability of kG monitoring and to establish the kG criteria for diagnosing abnormal graft function. Six healthy non-diabetic volunteers and 14 stable pancreas recipients underwent 2 intravenous glucose tolerance tests 7 d apart. All kG values in non-diabetic volunteers had < 15% variation between the two determinations (r = 0.96, P < or = 0.0006). Similarly, 13/14 recipients experienced < 20% variation in kG with one patients experiencing a 23% variation (r = 0.90, P < or = 0.0001). Using a 20% change from baseline as the reference value, we monitored 28 pancreas recipients for 2-36 months post-transplant. Of 253 kG values, 160 (64%) did not exceed the 20% change from baseline, 65 (26%) declined > 20% and 28 (11%) increased > 20%. Of 160 stable kG values, 154 (96%) were associated with normal graft function while 6 (4%) occurred in the context of rejection. Of 65 kG values declining by > or = 20%, 47 (72%) accurately identified acute rejections diagnosed by biopsy (70%) or response to treatment (30%), 12 (19%) were associated with identifiable causes of increased insulin resistance and only in 6 (9%) cases a cause for the decline was unidentifiable. The kG values with > 20% rise from baseline were, in 15%, associated with identifiable causes of decreased insulin resistance. The sensitivity of the kG as a marker for rejection was 88.7%, specificity 91%, positive predictive value 72.3%, negative predictive value 96.8%, and accuracy 90.5%. These data confirm that a > 20% deterioration of glucose disappearance rate is associated with pancreas allograft rejection, and confirms the utility of kG monitoring in clinical follow-up of pancreas transplant recipients.

Adult↗

Reticuloendothelial function in human renal allograft recipients.

The phagocytic and metabolic functions of the reticuloendothelial system (RES) were determined, by measuring the plasma clearance rate of 125I-labelled microaggregated human serum albumin and the increase in plasma metabolites of this test substance, in patients with chronic renal failure and in renal transplant recipients at different times after transplantation. All transplant recipients received triple immunosuppressive therapy consisting of azathioprine, corticosteroids, and antilymphocyte globulin. The intravascular clearance of microaggregated albumin was significantly depressed in patients when tested at 1 to 12 days (P less than 0.001), 1 to 4 months (P less than 0.02), and 6 to 9 months (P less than 0.001) after transplantation compared to pretransplantation. The 1- to 3-year transplant survivors had a normal RES phagocytosis. Furthermore, the metabolic RES function in all groups of transplant recipients except the group of patients tested at 1 to 4 months after transplantation was significantly impaired compared to pretransplantation. Administration of antilymphocyte globulin and extremely high daily doses of steroids were probably responsible for the significant depression in the RES functions recorded immediately post-transplantation. The further development of the phagocytic ability of the RES was shown to be correlated to the cumulative dose of steroids given over the last 12 months. The azathioprine regime seemed to have no influence on the RES functions.

Adult↗

Reduced graft function (with or without dialysis) vs immediate graft function--a comparison of long-term renal allograft survival.

BACKGROUND: Delayed graft function (DGF) is a common complication in cadaveric kidney transplants affecting graft outcome. However, the incidence of DGF differs widely between centres as its definition is very variable. The purpose of this study was to define a parameter for DGF and immediate graft function (IGF) and to compare the graft outcome between these groups at our centre. METHODS: The renal allograft function of 972 first cadaveric transplants performed between 1990 and 2001 in the Republic of Ireland was examined. The DGF and IGF were defined by a creatinine reduction ratio (CRR) between time 0 of transplantation and day 7 post-transplantation of <70 and >70%, respectively. Recipients with reduced graft function (DGF) not requiring dialysis were defined as slow graft function (SGF) patients. The serum creatinine at 3 months, 6 months, 1, 2 and 5 years after transplantation was compared between these groups of recipients. The graft survival rates at 1, 3 and 5 years and the graft half-life for DGF, SGF and IGF recipients were also assessed. RESULTS: Of the 972 renal transplant recipients, DGF was seen in 102 (10.5%) patients, SGF in 202 (20.8%) recipients and IGF in 668 (68.7%) patients. Serum creatinine levels were significantly different between the three groups at 3 and 6 months, 1, 2 and 5 years. Graft survival at 5 years for the DGF patients was 48.5%, 60.5% for SGF recipients and 75% for IGF patients with graft half-life of 4.9, 8.7 and 10.5 years, respectively. CONCLUSION: This study has shown that the CRR at day 7 correlates with renal function up to 5 years post-transplantation and with long-term graft survival. We have also demonstrated that amongst patients with reduced graft function after transplantation, two groups with significantly different outcomes exist.

Adult↗

Viral IL-10-induced immunosuppression requires Th2 cytokines and impairs APC function within the allograft.

Previous reports demonstrated that retroviral mediated gene transfer of viral IL-10 (vIL-10) prolongs allograft survival by decreasing donor-specific cytotoxic T lymphocyte precursor (CTLp) and IL-2-secreting helper T lymphocyte precursor (HTLp) frequency within graft-infiltrating cells (GIC). This report now shows that vIL-10 efficacy is dependent on CD4(+) T cells, suggesting that immunosuppression may involve a switch from a Th1 to a Th2 alloresponse. In support of this, anti-IL-4 or anti-murine IL-10 (anti-mIL-10) mAbs, but not anti-IFN-gamma mAb, administered at the time of vIL-10 gene transfer prevents enhanced graft survival. Because Th switching involves APC function, GIC were examined for their ability to present alloantigen. GIC from vIL-10-treated grafts were shown to be mostly of recipient (CBA) origin, yet were unable to elicit alloproliferative responses from donor type (C57BL/6) or third party (BALB/c) responders. The inability of vIL-10-treated GIC to stimulate the MLR was not due to the generation of negative regulatory cells or the production of immunosuppressive cytokines such as IL-4, mIL-10, or TGFbeta. Using fractionated GIC subpopulations, the number of recipient type cells in the allografts was modestly reduced by vIL-10 gene transfer, while maintaining both APC phenotype and alloantigen presenting function. Conversely, after vIL-10 gene transfer, donor type GIC were unable to participate in direct alloantigen presentation. Therefore, local immunosuppression induced by vIL-10 gene transfer is CD4 T cell and IL-4 and mIL-10 dependent, and impairs direct alloantigen presentation through an alteration of donor type APC function.

Animals↗

Influence of normal central venous pressure on onset of function in renal allografts.

The central venous pressure was kept above 5 cmH2O during the perioperative and early postoperative period as guidance for fluid replacement in 31 patients receiving a renal graft (group B). In 30 other transplant recipients the central venous pressure was not measured (group A). The two groups were otherwise comparable. Onset of graft function within the first 3 postoperative days was significantly more frequent in group B than in group A (62% vs. 30%), despite absence of difference in the measurable warm and cold ischemic periods. Fluid replacement guided by the central venous pressure thus is concluded to reduce the number of kidneys with delayed function in the immediate postoperative period.

Body Weight↗