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Donor Desmopressin Is Associated With Superior Graft Survival After Kidney Transplantation

Benck, Urs1; Gottmann, Uwe1; Hoeger, Simone1; Lammert, Alexander1; Rose, Daniela1; Boesebeck, Detlef2; Lauchart, Werner3; Birck, Rainer1; Weiss, Christel4; Krämer, Bernhard K.1; Yard, Benito A.1; Schnuelle, Peter1,5

doi: 10.1097/TP.0b013e318236cd4c
Clinical and Translational Research
Free
SDC

Background. A recent randomized trial showed that pretreatment of the brain-dead donor with low-dose dopamine improves immediate kidney graft function, by limiting injury from cold storage (ClinicalTrials.gov Identifier: NCT00115115). This study determines whether donor exposure to desmopressin (1-deamino-8-d-arginine-vasopressin [DDAVP]) before organ retrieval affects renal transplant outcome.

Methods. This retrospective multicenter cohort study, nested in the database of the dopamine trial, includes 264 deceased heart-beating donors with confirmed brain death and corresponding 487 renal allograft recipients transplanted at 60 European centers between March 2004 and August 2007. We assessed differences in delayed graft function, biopsy-proven acute rejections, and 2-year kidney graft survival in recipients of a DDAVP-exposed versus unexposed graft.

Results. DDAVP was associated with improved graft survival (85.4% vs. 73.6%, P=0.003). This survival benefit persisted after censoring for death with functioning graft (91.1% vs. 82.0%, P=0.01) and after adjustment for confounders including covariate adjustment from propensity scoring (hazard ratio 0.40, 95% confidence interval [CI] 0.21–0.77; P=0.006). Delayed graft function (odds ratio 0.97, 95% CI 0.57–1.65; P=0.92) and biopsy-proven acute rejections (odds ratio 1.32, 95% CI 0.70–2.49; P=0.40) were unaffected. The survival effect was enhanced after a shorter cold ischemic time less than 14 hr (91.3% vs. 77.8%, P=0.008) and after dopamine pretreatment (92.7% vs. 78.6%, P=0.006). By contrast, prolonged cold ischemic time more than or equal to 14 hr (91.2% vs. 86.5%, P=0.39) and assignment to the nondopamine group (89.7% vs. 84.8%, P=0.37) abrogated the survival advantage.

Conclusions. Donor DDAVP seems to improve renal allograft survival. Combined use of donor DDAVP and low-dose dopamine should receive further evaluation.

1 5th Department of Medicine, University Medical Centre Mannheim, Mannheim, Germany.

2 Organ Procurement Organization of Bavaria, Munich, Germany.

3 Organ Procurement Organization of Baden-Württemberg, Stuttgart, Germany.

4 Department of Biomathematics and Medical Statistics, University Medical Centre Mannheim, Mannheim, Germany.

This study was partially supported by a medical school grant from Novartis Pharmaceuticals [released in November 2002, before the study started recruiting eligible donors].

The sponsor of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

The authors declare no conflicts of interest.

The first two authors contributed equally to this manuscript.

5 Address correspondence to: Peter Schnuelle, M.D., Ph.D., 5th Department of Medicine, University Medical Centre Mannheim, Theodor Kutzer Ufer 1-3, D-68167 Mannheim, Germany.

E-mail: peter.schnuelle@umm.de

P.S. and U.B. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. P.S., U.B., U.G., S.H., A.L., D.R., D.B., W.L., R.B., B.K.K., and B.A.Y. participated in the study concept and design. P.S., U.B., D.B., and W.L. participated in the acquisition of data. P.S., U.B., U.G., and C.W. participated in the data interpretation and analysis. P.S., U.B., and C.W. participated in the statistical analysis. P.S., U.B., and U.G. participated in the writing of the paper. S.H., A.L., D.R., D.B., W.L., R.B., B.K.K., and B.A.Y. participated in the critical revision of the manuscript for important intellectual content. D.B. and W.L. provided administrative, technical, and material support. P.S. and U.B. participated in study supervision.

Received 5 July 2011. Revision requested 5 August 2011.

Accepted 8 September 2011.

Optimized care of the heart-beating donor has the potential to improve the outcome after kidney transplantation (1–3). Deceased brain-dead donors (DBD) represent the largest proportion of the donor pool worldwide (4, 5). Organ donation from DBD is associated with a catecholamine surge, release of pro-inflammatory cytokines, hemodynamic instability frequently aggravated by diabetes insipidus, and cold preservation/reperfusion injury (6). Registry data indicate that three-drug hormonal resuscitation, including arginine-vasopressin, yields more transplantable organs and improves 1-year graft survival after heart and kidney transplantation (1, 2, 7). The synthetic arginine-vasopressin analogue desmopressin (1-deamino-8-d-arginine-vasopressin [DDAVP]) is the preferred drug for treating brain-death-related diabetes insipidus due to its V2-vasopressin receptor agonistic effect, its high antidiuretic-to-vasopressor potency, and its lengthened duration of action (8). Besides stabilizing the donor's circulation, DDAVP depletes the graft's endothelial Weibel-Palade bodies (WPB) (9). We hypothesized that depletion of WPB before transplantation will attenuate downstream inflammatory events after reperfusion, resulting in improved graft survival. The available evidence is sparse and conflicting (10, 11). A previous randomized controlled trial (RCT) of donor DDAVP failed to show any effect on graft survival (11), presumably due to lacking statistical power. This study assessed the impact of concomitant donor pretreatment with DDAVP on graft function in a larger database of 487 kidney transplant recipients, from 60 European centers. The study is nested in the randomized dopamine trial (3) and provides sufficient statistical power to detect a 10% survival benefit 2 years after transplantation.

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RESULTS

Baseline Data

The study database consisted of 487 renal transplant recipients, from 60 European centers, who received a kidney graft from 264 DBDs between March 2004 and August 2007 (3). Of the kidneys included in the dopamine trial, 296 (60.8%) came from the procurement region of Bavaria and 191 (39.2%) from Baden-Württemberg (BW). Allocation of kidneys was centrally directed by the Eurotransplant International Foundation, Leiden, The Netherlands. Eurotransplant used a computerized algorithm based on waiting time, human leukocyte antigen (HLA)-matching, country balance, and distance between donor and recipient centers to minimize cold ischemic time.

Grouping by DDAVP exposure resulted in 362 kidney graft recipients with DDAVP-positive and 125 with DDAVP-negative donors. Donors exposed to DDAVP had a higher 24-hr urine production, were more frequently treated with plasma expanders, tended to have a higher serum sodium concentration, and were more liable to experience hypotensive episodes, which was related to the underlying diabetes insipidus (Table 1). There were also between-group differences in the concomitant donor treatment with prednisolone and insulin (Table 1). Recipient and transplant characteristics were well balanced between groups, with the exception of a clinically meaningless difference in HLA mismatches (Table 2).

TABLE 1

TABLE 1

TABLE 2

TABLE 2

Propensity scoring identified six donor-related variables that were significantly associated with the use of DDAVP: urine production during the 24 hr before organ recovery (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.07–1.37 L−1; P=0.002), use of plasma expanders (OR 2.07, 95% CI 1.25–3.40; P=0.004), duration of brain death (OR 1.87, 95% CI 1.13–3.08 per day; P=0.02), serum creatinine (OR 0.41, 95% CI 0.18–0.95 per mg/dL; P=0.04), concomitant norepinephrine (OR 0.52, 95% CI 0.28–0.98; P=0.04), and Bavaria as the region of organ procurement (OR 4.48, 95% CI 2.67–7.49; P<0.001). Bavarian donors were more likely to receive DDAVP before organ recovery (259/296 [87.5%] vs. 103/191 [53.9%], P<0.001) reflecting differences in the management of DBDs between the procurement regions. This also applied to the perfusion solution with University of Wisconsin (UW) being preferred in Bavaria (218/296 [73.6%]) and histidine-tryptophan-ketoglutarate in BW (122/191 [63.9%], Bavaria vs. BW; P<0.001). However, the kind of preservation solution did not affect 2-year graft survival at the level of statistical significance (UW solution; hazard ratio [HR] 0.86, 95% CI 0.56–1.33; P=0.50). In addition, none of the variables identified by propensity scoring (urine production before organ recovery [HR 0.98, 95% CI 0.89–1.07 L−1; P=0.61], use of plasma expanders [HR 1.05, 95% CI 0.67–1.63; P=0.84], duration of brain death [HR 1.01, 95% CI 0.66–1.56 per day; P=0.95], treatment with norepinephrine [HR 1.32, 95% CI 0.72–2.44; P=0.37], and Bavaria [HR 0.96, 95% CI 0.62–1.49; P=0.86]) was predictive of graft survival, except serum creatinine (HR 2.11, 95% CI 1.05–4.25 per mg/dL; P=0.04).

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Outcome Data

Uncensored graft survival of the entire study cohort was 86.6% and 82.4% at 1 and 2 years, respectively. At these time points, death-censored graft survival was 90.2% and 88.9%, respectively.

Donor exposure to DDAVP had no effect on early clinical events posttransplant, which were delayed graft function (DGF) and biopsy-proven acute rejections (BPAR) during in-hospital stay, in both univariate analyses and after statistical modeling to control for putative confounding influences (model 1), and inclusion of donor-specific covariates from the propensity score (model 2) (Table 3). Figure 1 displays that serum creatinine levels decreased over the first 7 days in a similar manner in both groups. No significant between-group differences were detected.

FIGURE 1.

FIGURE 1.

TABLE 3

TABLE 3

By contrast, donor DDAVP was associated with improved 2-year graft survival (85.4% vs. 73.6%, log-rank P=0.003) (Fig. 2A). The survival benefit persisted after censoring for death (91.1% vs. 82.0%, log-rank P=0.01) (Fig. 2B), which was confirmed in multiple Cox regression analyses of both model 1 and model 2 (Table 3). Because there were some differences in donor management between the two procurement regions, we performed separate analyses in strata of Bavarian and non-Bavarian kidneys. The magnitude of the 2-year survival advantage was quite similar in BW (89.2% vs. 73.4%) and Bavaria (83.9% vs. 73.9%). However, the survival benefit was not statistically significant in Bavarian organs due to the limited number of donors unexposed to DDAVP. Differences in concomitant donor treatment regarding the administration of prednisolone (HR 0.90, 95% CI 0.53–1.52; P=0.69), insulin (HR 1.43, 95% CI 0.89–2.29; P=0.14), noradrenaline (HR 1.27, 95% CI 0.66–2.45; P=0.47), and the usage of UW (HR 1.28, 95% CI 0.77–2.11; P=0.34) were no significant explanatory variables of graft survival.

FIGURE 2.

FIGURE 2.

Stratifying the analyses by the median of cold ischemic time indicated that survival curves diverged further, if the kidney was transplanted after a cold storage period under 14 hr (DDAVP 91.3% vs. no DDAVP 77.8%, log-rank P=0.008) (Fig. 3A), whereas the beneficial effect of DDAVP was abrogated in the subgroup of recipients who were transplanted with a prolonged cold ischemic time exceeding 14 hr (DDAVP 91.2% vs. no DDAVP 86.5%, log-rank P=0.39) (Fig. 3B). This survival analysis yielded analogous findings, when death was classified as failure. Because it was recently demonstrated that donor pretreatment with dopamine improves early graft function (3), we reanalyzed death-censored graft survival by DDAVP exposure in the respective subgroups of dopamine pretreatment. DDAVP was associated with profoundly improved 2-year graft survival, if the donor was pretreated with dopamine (DDAVP 92.7% vs. 78.6%, log-rank P=0.006), which was not recognized in donors from the nondopamine group (DDAVP 89.7% vs. no DDAVP 84.8%, log-rank P=0.37). Redoing the analysis without censoring yielded analogous findings.

FIGURE 3.

FIGURE 3.

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DISCUSSION

This study indicates that DDAVP administration in the DBD is associated with improved graft survival after kidney transplantation. Censoring for death confirms that the advantageous effect is actually related to graft survival itself, rather than to all-cause mortality. Numerous efforts have been made to reduce the deleterious effects of prolonged cold ischemia (12). Hence, it is particularly interesting that the survival advantage attributable to DDAVP occurred exclusively in patients who were transplanted after a short cold ischemic time below 14 hr, while the benefit was abrogated when cold storage exceeded 14 hr.

Apart from its antidiuretic effect, DDAVP binds to endothelial V2-vasopressin receptors, which results in cyclic adenosine monophosphate-mediated exocytosis of WPB (13). These secretory storage granules harbor preformed pro-thrombotic and pro-inflammatory constituents, whose rapid release enables the activated endothelium to react to stressors within minutes without necessitating previous protein biosynthesis (14). In organ transplantation, exposure to hypoxia during cold preservation and shear stress during reperfusion induce the exocytosis of WPBs (9, 15), releasing von Willebrand factor, interleukin-8, the adhesion molecule P-selectin, and the Tie2-antagonist angiopoietin-2. These WPB constituents account, at least in part, for the deleterious effects of reperfusion injury, because von Willebrand factor facilitates platelet adhesion (13), while interleukin-8 attracts leukocytes (16) which are tethered to the endothelium by P-selectin (17). Angiopoietin-2 plays a critical role in subsequent leukocyte transmigration by destabilizing the endothelial cells and in sensitizing the endothelium to the effects of tumor necrosis factor alpha-induced gene transcription (9, 18). This positive feedback loop after reperfusion may ultimately translate in accelerated transplant vasculopathy (19), a major drawback for long-term graft survival.

The disadvantage of fully viable WPB constituents does not necessarily challenge the benefit of a shorter cold ischemic time (20). Notably, in our cohort 80% of transplants were performed within the 18-hr time window where cold ischemia was not found to be detrimental for the outcome of the renal graft (20). Pretreatment of the DBD with DDAVP will disarm the graft's endothelium from injurious WPB constituents before transplantation, thereby ameliorating reperfusion injury. During cold storage, the endothelium undergoes depletion of the WPBs in a time-dependent manner (15), which may explain why DDAVP was ineffective when cold ischemic time exceeded 14 hr. Cold preservation hampers the constitutive turnover and repletion of WPB before reperfusion.

A recent human study indicates that the inflammatory response after reperfusion does not necessarily determine intermediate graft prognosis (21). This is in line with our observation that DDAVP increases long-term graft survival, while early clinical events such as DGF and BPAR remained unaffected. Our suggestion of a novel pharmacologic approach to protect the graft through WPB depletion parallels previous experimental studies. Qian et al. (22) reported that inhibition of WPB release by inducible nitric oxide synthase resulted in superior graft survival after murine cardiac transplantation. In experimental kidney transplantation, blocking P-selectin prevented ischemia/reperfusion-induced graft failure (17, 23).

Our findings extend an earlier RCT from Paris showing that donor treatment with DDAVP does not compromise initial graft function after kidney transplantation. Neither was any effect on long-term function detectable, because the trial was not designed to investigate graft survival. More importantly, the reported mean cold ischemia of 28 hr may have prevented the detection of DDAVP's protective potential (11). Because mean cold ischemic time has decreased to 14 hr in the Eurotransplant area at present (12), the generalizability of the French trial to current transplant conditions seems to be limited. Our results are supported by an incidental finding of Nijboer et al. (24) who observed superior renal function 1 and 3 years after transplantation, when the donor was treated with DDAVP. DDAVP seems to exert protection particularly in recipients of dopamine pretreated grafts in our study. Both dopamine and a short cold ischemic time preserve endothelial cell integrity (25–28), which is apparently a prerequisite for the WPBs' critical role in the endothelial stress response. Given that DDAVP's action on WPB exocytosis in donors before organ retrieval is causative for improving transplant outcome, it is conceivable that the survival advantage only became apparent in kidney grafts that were either pretreated with dopamine or subjected to short cold ischemia.

The effects of donor DDAVP on renal allograft survival are robust and of considerable clinical relevance. Nonetheless, several study limitations have to be acknowledged: First, the post hoc character indicates that our results remain nonconfirmatory. Second, as in all observational studies, our data are susceptible to potential confounding. To address the latter issue, we reanalyzed all outcome measures in two separate models of multivariate adjustment. For bias reduction, the technique of propensity scoring was applied through regression adjustment (29). In addition, the data were reanalyzed in strata of the procurement regions. None of the principal study findings was affected hereby. Nevertheless, it cannot be fully excluded that an unknown extraneous factor may have distorted results leading to a nonrandom error, because DDAVP exposure was driven by the clinical assessment of the donor centers. Third, we used the administration of DDAVP as a dichotomous variable for data analysis, because we lack detailed information on cumulative doses, timing, and duration of DDAVP treatment from the standardized donor information forms. Contrasting the drug's antidiuretic effect (8), DDAVP depletes the endothelial WPBs in a dose-independent manner. In fact, endothelial cells become progressively unresponsive to repeated administration of DDAVP over short intervals (<24 hr) (13, 30). Therefore, we consider this limitation to be of minor relevance.

A major strength of our study is that it is nested in the database of a large multicenter RCT (3). This implicates that the data were prospectively assessed and all study endpoints were prespecified, which enhances the internal validity of the study. The outcome measure of long-term graft survival is definitely the hardest endpoint available in kidney transplantation. Our study was carried out under real-life conditions in a multicenter setting, where transplant recipients were not exposed to protocol-mandated interventions. This enhances the generalizability of the presented results. Given DDAVP's pharmacologic mechanism of action, we can also provide a biologic plausibility to explain our findings. Nonetheless, the proposed interaction between DDAVP and WPBs lacks biopsy or other measured evidence in our study to move beyond the theoretical at present.

In conclusion, this study indicates that optimized care of the DBD before organ retrieval has the potential to substantially improve the outcome after kidney transplantation. In so doing, both preserving the graft's endothelial viability during cold ischemia and disarming endothelial cells from their injurious WPB constituents before reperfusion seems to offer a complementary pharmacologic approach. Standard use of combined donor pretreatment with low-dose dopamine and DDAVP should receive further evaluation by a RCT in kidney transplantation.

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MATERIALS AND METHODS

Study Design and Patients

Rationale, design, and execution of the dopamine trial have been delineated elsewhere (3). The randomized dopamine trial (ClinicalTrials.gov Identifier: NCT00115115) was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice, and the International Conference on Harmonisation guidelines. The protocol was reviewed and approved by the Institutional Review Board (Independent Ethics Committee of the Medical Faculty of Mannheim, Germany) and the kidney advisory committee of the Eurotransplant International Foundation, Leiden, The Netherlands. In brief, between March 2004 and August 2007, 264 DBDs from two procurement regions in Germany—Bavaria and BW—were included in the trial. After confirmed brain death, and consent for donation, in accordance with national guidelines and transplantation legislation, eligible DBDs needed to be hemodynamically stable without catecholamine support, except norepinephrine at a dose not exceeding 0.4 μg/kg/min. All donors had to have a serum creatinine less than 1.3 mg/dL on admission and less than 2 mg/dL before randomization. All eligible donors were closely monitored to maintain hemodynamic stability within predefined thresholds for intervention.

Donor characteristics were obtained from standardized donor information forms, including dichotomous data on the coadministration of DDAVP. DDAVP was administered using intravenous bolus doses of 1 to 2 μg, followed by repeated maintenance doses of 0.5 to 1 μg every 2 to 12 hr, to limit urine output less than 200 mL/hr. All kidneys were preserved using static cold storage before transplantation.

Eligible recipients were aged 18 years or older and had to fulfill the usual criteria of a renal transplant candidate. Before wait-listing, they gave their consent that depersonalized medical data will be transmitted to Eurotransplant for scientific analyses. Transplant and recipient baseline characteristics were obtained from the Eurotransplant database. Recipient follow-up data were assessed using a standardized case report form. Only routine parameters were requested, including class and doses of immunosuppressive therapy during the 24 hr before and after transplantation, dialysis requirement, occurrence, and severity of BPAR and date and cause of allograft failure, and recipient death when this occurred. Anonymity of donors and recipients was ensured by the use of Eurotransplant code numbers for data collection.

We analyzed the effects of donor DDAVP by using the predefined study endpoints of the randomized dopamine trial (3). Grouping was based on donor DDAVP administration during intensive care before organ recovery. Efficacy endpoints were the incidence of DGF, as assessed by the requirement of single or multiple dialyzes sessions within the first week after transplantation, the incidence and severity of BPAR within 30 days posttransplant, and patient/allograft survival during 2 years after transplantation.

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Statistical Analysis

The study database provides a statistical power of 84% to detect a 10% difference in graft survival at a significance level of 0.05 given a cumulative event rate of 18% in the entire study population and taking into account that 362 kidney grafts were exposed to DDAVP whereas 125 remained unexposed. Quantitative data were evaluated using the two-sample Student t test. For qualitative data, the χ2- or the 2-sided Fisher exact test was applied, as appropriate. Cumulative and death-censored graft survival was calculated according to the Kaplan-Meier method, and group differences were assessed by the log-rank test. Multiple logistic regression analyses of the dichotomous study endpoints—DGF and BPAR—were carried out to control for putative confounding factors. In analogy, a multiple Cox proportional hazards model was applied for the analysis of graft survival until 2 years after transplantation, with and without censoring for death with a functioning graft. All outcome measures were evaluated by two separate regression models. In the first model, donor and recipient age and gender, cause of brain death, concomitant donor treatment (insulin and/or prednisolone), preservation solution, cold ischemic time, number of HLA mismatches, panel reactivity more than 5%, waiting time, and history of a previous transplant were included as possible explanatory variables. For bias reduction, the technique of propensity scoring was used through covariance adjustment in the second regression model (29). The propensity score defined as the conditional probability of assignment to a particular treatment was estimated by stepwise logistic regression of DDAVP administration on donor-specific covariates (31, 32). Propensity scoring considered the following variables: age, gender, cause of brain death, duration of brain death, occurrence of hypotensive episodes or cardiac arrest, serum creatinine, hypernatremia (defined as serum sodium concentration >145 mmol/L), systolic and diastolic blood pressure, urine output during the 24 hr before organ recovery, concomitant treatment with dopamine, noradrenaline, glucocorticoids, insulin, plasma expanders, and the region of organ procurement (Bavaria/BW). Stepwise backward selection was applied by defining a P more than or equal to 0.10 as an exit criterion for removal of the covariate from the full model. Significant variables in the propensity score were subsequently incorporated as additional covariates in the second regression models.

All results are presented as OR or HR, respectively, with a 95% CI for a one-unit change in the variable. Significance was defined according to a two-sided P less than 0.05 in all analyses. Statistical analyses were carried out with Stata Statistical Software for MS Windows (Stata Corp., College Station, TX).

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ACKNOWLEDGMENTS

This study is embedded in the database of an investigator-driven clinical trial conducted by the University Medical Centre Mannheim, Germany. The authors thank John H. Clorius (German Cancer Research Center, Heidelberg) for proofreading the manuscript and all collaborating transplantation centers who provided data to the trial. None of the collaborators were compensated for their contributions.

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Keywords:

Brain-dead donor; Renal transplantation; Graft survival; Endothelium; Reperfusion injury

© 2011 Lippincott Williams & Wilkins, Inc.