Impact of spontaneous donor hypothermia on graft outcomes after kidney transplantation.

A previous donor intervention trial found that therapeutic hypothermia reduced delayed graft function (DGF) after kidney transplantation. This retrospective cohort study nested in the randomized dopamine trial (ClinicalTrials.gov identifier: NCT000115115) investigates the effects of spontaneous donor hypothermia (core body temperature <36°C) on initial kidney graft function, and evaluates 5-year graft survival. Hypothermia assessed by a singular measurement in the intensive care unit 4-20 hours before procurement was associated with less DGF after kidney transplantation (odds ratio [OR] 0.56, 95% confidence interval [CI] 0.34-0.91). The benefit was greater when need for more than a single posttransplant dialysis session was analyzed (OR 0.48, 95%CI 0.28-0.82). Donor dopamine ameliorated dialysis requirement independently from hypothermia in a temporal relationship with exposure (OR 0.93, 95%CI 0.87-0.98, per hour). A lower core body temperature in the donor was associated with lower serum creatinine levels before procurement, which may reflect lower systemic inflammation and attenuated renal injury from brain death. Despite a considerable effect on DGF, our study failed to demonstrate a graft survival advantage (hazard ratio [HR] 0.83, 95%CI 0.54-1.27), whereas dopamine treatment was associated with improved long-term outcome (HR 0.95, 95%CI 0.91-0.99 per hour).

Dopamine treatment of brain-dead Fisher rats improves renal histology but not early renal function in Lewis recipients after prolonged static cold storage.

BACKGROUND: Brain death (BD) and cold preservation are major risk factors for an unfavorable transplantation outcome. Although donor dopamine treatment in brain-dead rats improves renal function and histology in allogeneic recipients, it remains to be assessed if this also holds true for the combinations of BD and prolonged static cold preservation. METHODS: BD was induced in F344 donor rats, which were subsequently treated with NaCl 1 mL/h (BD, n = 11), NaCl/hydroxy ethyl starch (BD-norm, n = 10), or 10 µg/min/kg dopamine (BD-dopa, n = 10). Renal grafts were harvested 4 h after BD and transplanted into bilateral nephrectomized Lewis recipients 6 h after cold preservation in University of Wisconsin solution. Renal function was evaluated by use of serum creatinine and urea concentrations at days 0, 1, 3, 5, and 10. Ten days after transplantation, recipients were killed and the renal allografts were processed for light microscopy and immune histology. RESULTS: Serum urea concentrations at days 5 and 10 were significantly lower in recipients that received a renal graft from dopamine-treated rats; for serum creatinine, only a trend was observed at day 10. Immune histology revealed a lower degree of ED1-positive cells in the donor dopamine-treated group. Under light microscopy, Banff classification revealed significantly less intimal arteritis in these grafts (P < .05). CONCLUSIONS: Although donor dopamine treatment clearly improves renal histology in this model, the beneficial effect on early renal function was marginal. It remains to be assessed if donor dopamine treatment has a beneficial effect on renal function in long-term follow-up.

Reduction of gastrointestinal complications in renal graft recipients after conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium.

Gastrointestinal (GI) complications such as diarrhea or indigestion frequently occur in renal graft recipients treated with mycophenolate mofetil (MMF), requiring dose reductions to reduce side effects, thereby increasing the risk of rejection episodes and graft loss. In a prospective clinical trial, the immunosuppressive therapy of renal graft recipients was converted from MMF to enteric-coated mycophenolate sodium (EC-MPS) to identify a strategy to reduce GI symptoms without dose reduction. At baseline and 6-8 weeks later patients filled in 4 questionnaires related to GI symptoms and general and health-related quality of life. In 15 German study centers, 196 renal graft recipients (mean age 49.5 ± 13.5 years; male/female, 120/76) were included; 51.0% of patients suffered from GI complications at baseline. The Gastrointestinal Symptom Rating Scale score decreased significantly (P < .001) in patients with GI complications from 2.61 ± 0.86 at baseline to 2.14 ± 0.86 at visit 2. Health-related and general quality of life improved significantly. Fifty percent of patients with GI symptoms and 34% of the total per protocol population reported an improvement of their physical condition after converting the medication. In conclusion, conversion from MMF to EC-MPS reduces GI complications in renal graft recipients, reduces the patients' physical discomfort, and maintains their quality of life. (ClinicalTrials.gov number NCT00149968.).

Modulation of brain dead induced inflammation by vagus nerve stimulation.

Because the vagus nerve is implicated in control of inflammation, we investigated if brain death (BD) causes impairment of the parasympathetic nervous system, thereby contributing to inflammation. BD was induced in rats. Anaesthetised ventilated rats (NBD) served as control. Heart rate variability (HRV) was assessed by ECG. The vagus nerve was electrically stimulated (BD + STIM) during BD. Intestine, kidney, heart and liver were recovered after 6 hours. Affymetrix chip-analysis was performed on intestinal RNA. Quantitative PCR was performed on all organs. Serum was collected to assess TNFalpha concentrations. Renal transplantations were performed to address the influence of vagus nerve stimulation on graft outcome. HRV was significantly lower in BD animals. Vagus nerve stimulation inhibited the increase in serum TNFalpha concentrations and resulted in down-regulation of a multiplicity of pro-inflammatory genes in intestinal tissue. In renal tissue vagal stimulation significantly decreased the expression of E-selectin, IL1beta and ITGA6. Renal function was significantly better in recipients that received a graft from a BD + STIM donor. Our study demonstrates impairment of the parasympathetic nervous system during BD and inhibition of serum TNFalpha through vagal stimulation. Vagus nerve stimulation variably affected gene expression in donor organs and improved renal function in recipients.

Prospective age-matching in elderly kidney transplant recipients--a 5-year analysis of the Eurotransplant Senior Program.

Renal transplantation faces challenges: the organ shortage resulting in extended waiting times and an aging population resulting in death with a functioning graft. The Eurotransplant Senior Program (ESP) allocates kidneys within a narrow geographic area from donors aged >/=65 years to recipients >/=65 years regardless of HLA. This analysis investigates the impact of the ESP on waiting time, graft and patient survival. The ESP group (n = 1406, old to old) was compared to two groups allocated via the Eurotransplant Kidney Allocation System (ETKAS) with either similar donor age (old to any [O/A], donor age >/=65, n = 446) or recipient age (any to old, [A/O], recipient age 60-64, n = 1687). All patients were transplanted between 1999 and 2004. Since initiation of the ESP (1999), availability of elderly donors doubled and waiting time for ESP patients decreased. Local allocation led to shorter cold ischemia time (11.9 vs. >17.0 h, p < 0.001) and less delayed graft function (DGF, ESP 29.7% vs. O/A 36.2%, p = 0.047) but 5-10% higher rejection rates. Graft and patient survival were not negatively affected by the ESP allocation when compared to the standard allocation. The ESP age matching of elderly donors and recipients is an effective allocation system for organs from elderly donors.

Effect of pre-treatment with catecholamines on cold preservation and ischemia/reperfusion-injury in rats.

Treatment of organ donors with catecholamines reduces acute rejection episodes and improves long-term graft survival after renal transplantation. The aim of this study was to investigate the effect of catecholamine pre-treatment on ischemia/reperfusion (I/R)- and cold preservation injury in rat kidneys. I/R-injury was induced by clamping the left kidney vessels for 60 min along with a contralateral nephrectomy. Cold preservation injury was induced by storage of the kidneys for 24 h at +4 degrees Celsius in University of Wisconsin solution, followed by syngeneic transplantation. Rats were pre-treated with either dopamine (DA), dobutamine (DB), or norepinephrine (2, 5, and 10 microg/kg/min, each group) intravenously via an osmotic minipump for 24 h before I/R- and cold preservation injury. Pre-treatment with DA (2 or 5 microg/kg/min) and DB (5 microg/kg/min) improved recovery of renal function after I/R-injury and dose dependently reduced mononuclear and major histocompatibility complex class II-positive cells infiltrating the kidney after I/R-injury. One day after I/R-injury, upregulation of transforming growth factor (TGF)-beta 1 and 2 and phosphorylation of p42/p44 mitogen-activated protein kinases was observed in kidneys of animals treated with DA or DB. DA (5 microg/kg/min) and DB (5 microg/kg/min) pre-treatment reduced endothelial cell damage after 24 h of cold preservation. Only DA pre-treatment improved renal function and reduced renal inflammation after 24 h of cold preservation and syngeneic transplantation. Our results demonstrate a protective effect of pre-treatment with catecholamines on renal inflammation and function after I/R- or cold preservation injury. This could help to explain the potent organoprotective effects of catecholamine pre-treatment observed in human kidney transplantation.

Cyclosporine nephrotoxicity.

Cyclosporine (CsA) is the current primary immunosuppressant for the prevention of allograft rejection in solid organ transplantation. However, owing to its molecular mechanism of action the drug is associated with various adverse side effects (eg, nephrotoxicity). Histological changes appear as obliterative vasculopathy of the afferent arteriole and tubulointerstitial fibrosis in advanced cases. The underlying pathomechanisms of this condition reflect an altered release of vasoactive substances, such as angiotensin II, endothelin, prostaglandins, and nitric oxide as well as the stimulation of proliferative genes such as transforming growth factor-beta, osteopontin, and collagen I and IV. Potential strategies for the prevention of nephrotoxicity are discussed.

Impact of donor dopamine on immediate graft function after kidney transplantation.

Optimizing medical donor management may have a considerable impact on transplantation outcome. This study investigated the effect of donor dopamine on initial graft function in renal allograft recipients, involving 254 consecutive recipients of a cadaver kidney, aged 18-74 years, transplanted between 1990 and 2003. Immunosuppression was based on cyclosporine. Patients were grouped according to donor use of dopamine during intensive care. Delayed graft function (DGF), and serial creatinine concentrations were compared between the groups. Dopamine-treated and -untreated donors were very similar regarding hemodynamics and renal function. Delayed graft function occurred in 47/158 treated and 48/96 untreated kidneys (p = 0.001). Donor dopamine was associated with a more rapid decrease of s-creatinine, which became obvious on the first postoperative day. Of patients in the treated and untreated group, respectively, 81.9% and 65.8% reached a s-creatinine level less than 2 mg/dL during the first month (p = 0.005). Donor dopamine remained predictive of a normalized s-creatinine level [HR 1.71; 95% CI 1.22-2.41] after controlling for confounding factors by multivariate Cox regression. Donor dopamine is associated with improvements of initial graft function after kidney transplantation. The beneficial effect of dopamine is achievable without side-effects for the recipients, and correlates with superior long-term graft survival.

Effects of catecholamine application to brain-dead donors on graft survival in solid organ transplantation.

BACKGROUND: In a recent single-center study, donor use of catecholamines was identified to reduce kidney allograft rejection. This study investigates the effects of donor employment of adrenergic agents on graft survival in a large data base, including liver and heart transplants. METHODS: The study was based on the registry of the Eurotransplant International Foundation including 2415 kidney, 755 liver, and 720 heart transplants performed between January 1 and December 31, 1993. A total of 1742 donor record forms referring to the cadaveric donor activities in 1993 were systematically reviewed with regard to employment of adrenergic agents. Catecholamine use was simply coded dichotomously and divided into three strata according to zero, single, and combined application. Multivariate Cox regression including age, gender, cause of brain death, cold ischemia, HLA-mismatching, number of previous transplants, and urgency in liver transplants was applied for statistical analysis. RESULTS: Donor employment of catecholamines was associated with increased 4-year graft survival after kidney transplantation (hazard ratio [HR], 0.85; 95% confidence interval [95% CI], 0.74-0.98). The benefit is conferred in a dose-dependent manner and compares in quantitative terms with prospective HLA matching on class I and class II antigens (HR, 0.90; 95% CI, 0.84-0.97). Use of norepinephrine was predictive of initial nonfunction after heart transplantation (HR, 1.66; 95% CI, 1.14-2.43), but did not compromise liver grafts (HR, 0.94; 95% CI, 0.67-1.32). CONCLUSIONS: Optimizing the management of brain-dead organ donors, including the possibility of selective administration of adrenergic agents, may provide a major benefit on graft survival without adverse side effects for the recipients. Further investigation on best use of adrenergic drugs, optimum dosage, and duration is warranted.

Treatment of chronic renal allograft rejection in rats with a low-molecular-weight heparin (reviparin).

BACKGROUND: Low-molecular-weight heparin (LMWH) has been shown to prolong survival of rat cardiac allografts independently from immunosuppressive treatment. Furthermore, long-term treatment reduces the development of chronic graft vascular disease after experimental heart transplantation. The aim of the present study was to determine whether treatment with the LMWH reviparin has a beneficial effect on chronic rejection in a rat renal allograft model. METHODS: Kidneys of Fisher (F344) rats were transplanted into unilaterally nephrectomized Lewis (LEW) recipients. LEW-->LEW isografts served as controls. Animals were treated with cyclosporine (5 mg/kg/d) for the first 10 days. Nephrectomy of the remaining kidney was performed after 10 days. Allografted animals were treated either with reviparin (2 mg/kg/d subcutaneously) for 24 weeks (Allo-24), from week 12 to 24 (Allo-12), or with vehicle for 24 weeks. Proteinuria was determined at regular intervals. Kidneys were harvested after 24 weeks for histomorphological and immunohistochemical evaluation. RESULTS: No major bleeding complications were observed in reviparin-treated animals. Proteinuria was significantly reduced in allografted animals both by early as well as by late-onset treatment with reviparin. Transplant glomerulopathy was diminished in Allo-24 and in Allo-12 groups compared to vehicle-treated animals, whereas tubulointerstitial inflammation was influenced only in animals immediately treated with reviparin. Immunohistochemical studies demonstrated a marked reduction of renal monocyte and T-cell infiltration as well as expression of MHC II by treatment with reviparin. CONCLUSIONS: Treatment with the LMWH reviparin significantly improved chronic renal allograft rejection in the F344-to-LEW rat model, both after early and late start of therapy. Although the exact mechanisms of this beneficial effect remain unclear, our data offer a potential new therapeutical approach for prevention of chronic allograft nephropathy.

Dopamine induces the expression of heme oxygenase-1 by human endothelial cells in vitro.

BACKGROUND: In a retrospective study of the kidney transplantations performed at our institution, we found that the administration of dopamine (DA) to the organ donors resulted in a significant improvement of long-term organ survival of the retrieved kidneys. To study the mechanisms underlying the organ protection associated with the administration of DA prior to transplantation, we questioned whether DA induces the antioxidative enzyme heme oxygenase-1 (HO-1) in cultured endothelial cells. METHODS: Human umbilical vein endothelial cells (HUVECs) in culture were incubated with varying concentrations of DA for different time periods. Cells were subsequently assessed for the expression of HO-1 by Western blot and semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The presence of DA resulted in a dose- and time-dependent up-regulation of HO-1 both on RNA and protein level, whereas HO-1 was barely detectable under basal conditions. RT-PCR indicated the increased presence of HO-1 messenger RNA after 2 hours of incubation with DA, which peaked after 24 hours. The induction of HO-1 antigen was detectable after eight hours, as visualized by Western blot analysis. The addition of the antioxidant agents ascorbic acid and N-acetyl-cysteine both lead to dose-dependent inhibition of DA-mediated HO-1 induction. DA-mediated up-regulation of HO-1 was not influenced by the addition of either the D2-receptor antagonist haloperidol or the D1-receptor antagonist SCH 23390. CONCLUSION: We conclude that DA induces the expression of the protective enzyme HO-1 in cultured endothelial cells by an oxidative mechanism. These findings may explain the beneficial effect of DA administration to kidney donors and indicate the potential role of DA in organ preconditioning.

Impact of the Banff '97 classification for histological diagnosis of rejection on clinical outcome and renal function parameters after kidney transplantation.

BACKGROUND: Data on a systematic correlation of specific pathomorphologic lesions in renal allograft biopsy specimens with clinical outcome parameters are crucial to determine the relevance of kidney biopsy findings after transplantation for graft prognosis. Specific histologic lesions of the revised Banff '97 classification were correlated with clinical follow-up data. METHODS: The analysis was done on a series of 48 consecutive renal allograft biopsy specimens. Logistic regression was used to compare for response to rejection treatment dependent on histologic grading. Cox regression was applied to analyze the impact of the histologic findings on graft failure during ongoing follow-up. RESULTS: Severity of acute rejection was statistically associated with unresponsiveness to antirejection treatment (odds ratio 2.39, 95% confidence interval 1.13-5.03) and predicted an increased risk of graft failure (hazard ratio 2.16, 95% confidence interval 1.48-3.14). Intimal arteritis (hazard ratio 1.85, 95% confidence interval 1.40-2.45) was the only determinate of a poor survival prognosis. Mean serum creatinine level and the need for antihypertensive drugs were significantly higher in the Banff I-III graded groups after 1 and 2 years of follow-up, whereas patients with borderline rejection were not significantly different from the control group. CONCLUSION: We confirmed a significant association between the revised Banff '97 classification and graft outcome. Intimal arteritis was the only significant predictor of a poor survival probability. The distinction of borderline rejection and Banff grade I rejection seems to be important from a prognostic point of view.

Idiopathic myelofibrosis with extramedullary hematopoiesis in the kidneys.

Extramedullary hematopoiesis is a common finding in idiopathic myelofibrosis and is usually found in liver and spleen. We report on a patient with biopsy-proven myeloid metaplasia and fibrosis of the renal parenchyma as a rare cause of chronic renal failure. The renal biopsy specimen showed numerous infiltrates of hematopoietic cells expressing growth factors like M-CSF, GM-CSF, IL-1beta and PDGF while TGF-beta was not elevated. These findings suggest that hematopoietic growth factors play a key role in the pathogenesis of this condition causing proliferating fibrosis and enlargement of the kidneys.

Donor catecholamine use reduces acute allograft rejection and improves graft survival after cadaveric renal transplantation.

BACKGROUND: Epidemiological data implicate that renal transplants from living unrelated donors result in superior survival rates as compared with cadaveric grafts, despite a higher degree of human lymphocyte antigen (HLA) mismatching. We undertook a center-based case control study to identify donor-specific determinants affecting early outcome in cadaveric transplantation. METHODS: The study database consisted of 152 consecutive cadaveric renal transplants performed at our center between June 1989 and September 1998. Of these, 24 patients received a retransplant. Donor kidneys were allocated on the basis of prospective HLA matching according to the Eurotransplant rules of organ sharing. Immunosuppressive therapy consisted of a cyclosporine-based triple-drug regimen. In 67 recipients, at least one acute rejection episode occurred during the first month after transplantation. They were taken as cases, and the remaining 85 patients were the controls. Stepwise logistic regression was done on donor-specific explanatory variables obtained from standardized Eurotransplant Necrokidney reports. In a secondary evaluation, the impact on graft survival in long-term follow-up was further measured by applying a Cox regression model. The mean follow-up of all transplant recipients was 3.8 years (SD 2.7 years). RESULTS: Donor age [odds ratio (OR) 1.05; 95% CI, 1.02 to 1.08], traumatic brain injury as cause of death (OR 2.75; 95% CI, 1.16 to 6. 52), and mismatch on HLA-DR (OR 3.0; 95% CI, 1.47 to 6.12) were associated with an increased risk of acute rejection, whereas donor use of dopamine (OR 0.22; 95% CI, 0.09 to 0.51) and/or noradrenaline (OR 0.24; 95% CI, 0.10 to 0.60) independently resulted in a significant beneficial effect. In the multivariate Cox regression analysis, both donor treatment with dopamine (HR 0.44; 95% CI, 0.22 to 0.84) and noradrenaline (HR 0.30; 95% CI, 0.10 to 0.87) remained a significant predictor of superior graft survival in long-term follow-up. CONCLUSIONS: Our data strongly suggest that the use of catecholamines in postmortal organ donors during intensive care results in immunomodulating effects and improves graft survival in long-term follow-up. These findings may at least partially be explained by down-regulating effects of adrenergic substances on the expression of adhesion molecules (VCAM, E-selectin) in the vessel walls of the graft.

Impact of renal cadaveric transplantation on survival in end-stage renal failure: evidence for reduced mortality risk compared with hemodialysis during long-term follow-up.

Despite a superior quality of life and a favorable cost effectiveness, it has not been well established thus far whether renal cadaveric transplantation contributes to superior survival probability of end-stage renal disease patients in Europe, because the mortality rate on dialysis is lower compared with the United States. This analysis was undertaken to compare the mortality of wait-listed patients and transplant recipients during long-term follow-up, including the possibility of a retransplant in a single-center study. The study cohort included 309 consecutive patients, ages 17 to 72 yr, being registered on the waiting list of the Renal Transplantation Center of Mannheim since the initiation of the transplantation program on June 3, 1989. Follow-up was terminated on September 30, 1997, with a mean of 4.15 yr. A total of 144 renal cadaveric transplants (four retransplants) was performed during the follow-up period. A Cox regression model considering the time-dependent exposure to the different therapy modalities was applied for statistical analysis. Patients being removed from the waiting list or coming back to dialysis after transplantation were censored at time of withdrawal or graft failure. Transplantation resulted in a lower hazard ratio, which was 0.36 (95% confidence interval, 0.15 to 0.87) when the hazard of the wait-listed group was taken as 1.00. The underlying incidence rate of death was 0.026 per patient-year (0.032 on dialysis versus 0.016 with functioning graft). Performing the evaluation on an intention-to-treat basis without censoring the lower risk of the transplanted group was still pronounced according to a hazard ratio of 0.44 (95% confidence interval, 0.22 to 0.89). Thus, patients receiving a renal cadaveric transplantation have a substantial survival advantage over corresponding end-stage renal disease patients on the waiting list even in the setting of a single transplantation center where mortality on regular dialysis therapy was comparatively low.

Prospective evaluation of pretransplant blood transfusions in cadaver kidney recipients.

BACKGROUND: A beneficial effect of pretransplant transfusions on graft survival was demonstrated in the early 1970s. In the mid-1980s, however, retrospective studies showed that transfusions had lost their graft-protective effect in the cyclosporine era. During the last 10 years, deliberate transfusion pretreatment of transplant patients has been discontinued. METHODS: Within a collaborative project of 14 transplant centers, prospective recipients of cadaver kidney grafts were randomized to receive either three pretransplant transfusions or transplants without transfusions. RESULTS; The graft survival rate was significantly higher in the 205 transfusion recipients than in the 218 patients who did not receive transfusions (at 1 year: 90+/-2% vs. 82+/-3%, P=0.020; at 5 years: 79+/-3% vs. 70+/-4%, P=0.025). Cox regression analysis showed that this effect was independent of age, gender, underlying disease, prophylaxis with antilymphocyte antibodies, and preformed lymphocytotoxins. CONCLUSIONS; Transfusion pretreatment improves the outcome of cadaver kidney transplants even with the use of modern immunosuppressive regimens.