Excellent efficacy and beneficial safety during observational 5-year follow-up of rapid steroid withdrawal after renal transplantation (Harmony FU study).

BACKGROUND: We previously reported excellent efficacy and improved safety aspects of rapid steroid withdrawal (RSWD) in the randomized controlled 1-year "Harmony" trial with 587 predominantly deceased-donor kidney transplant recipients randomized either to basiliximab or rabbit antithymocyte globulin induction therapy and compared with standard immunosuppressive therapy consisting of basiliximab, low tacrolimus once daily, mycophenolate mofetil and corticosteroids. METHODS: The 5-year post-trial follow-up (FU) data were obtained in an observational manner at a 3- and a 5-year visit only for those Harmony patients who consented to participate and covered clinical events that occurred from the second year onwards. RESULTS: Biopsy-proven acute rejection and death-censored graft loss rates remained low and independent of RSWD. Rapid steroid withdrawal was an independent positive factor for patient survival (adjusted hazard ratio 0.554, 95% confidence interval 0.314-0.976; P = .041).The reduced incidence of post-transplantation diabetes mellitus in RSWD patients during the original 1-year study period was not compensated by later incidences during FU. Incidences of other important outcome parameters such as opportunistic infections, malignancies, cardiovascular morbidity/risk factors, donor-specific antibody formation or kidney function did not differ during FU period. CONCLUSIONS: With all the limitations of a post-trial FU study, the Harmony FU data confirm excellent efficacy and beneficial safety aspects of RSWD under modern immunosuppressive therapy over the course of 5 years after kidney transplantation in an immunologically low-risk, elderly population of Caucasian kidney transplant recipients. Trial registration: Clinical trial registration number: Investigator Initiated Trial (NCT00724022, FU study DRKS00005786).

A noninvasive diagnostic approach to retrospective donor HLA typing in kidney transplant patients using urine.

Antibody-mediated rejection (AMR) is a major obstacle to long-term kidney transplantation. AMR is mostly caused by donor specific HLA antibodies, which can arise before or any time after transplantation. Incomplete donor HLA typing and unavailability of donor DNA regularly preclude the assessment of donor-specificity of circulating anti-HLA antibodies. In our centre, this problem arises in approximately 20% of all post-transplant HLA-antibody assessments. We demonstrate that this diagnostic challenge can be resolved by establishing donor renal tubular cell cultures from recipient´s urine as a source of high-quality donor DNA. DNA was then verified for genetic origin and purity by fluorescence in situ hybridization and short tandem repeat analysis. Two representative cases highlight the diagnostic value of this approach which is corroborated by analysis of ten additional patients. The latter were randomly sampled from routine clinical care patients with available donor DNA as controls. In all 12 cases, we were able to perform full HLA typing of the respective donors confirmed by cross-comparison to results from the stored 10 donor DNAs. We propose that this noninvasive diagnostic approach for HLA typing in kidney transplant patients is valuable to determine donor specificity of HLA antibodies, which is important in clinical assessment of suspected AMR.

Color-coded summation images in the evaluation of renal artery stenosis before and after percutaneous transluminal angioplasty.

BACKGROUND: Endovascular therapy is the gold standard in patients with hemodynamic relevant renal artery stenosis (RAS) resistant to medical therapy. The severity grading of the stenosis as well as the result assessment after endovascular approach is predominantly based on visible estimations of the anatomic appearance. We aim to investigate the application of color-coded DSA parameters to gain hemodynamic information during endovascular renal artery interventions and for the assessment of the procedures´ technical success. METHODS: We retrospectively evaluated 32 patients who underwent endovascular renal artery revascularization and applied color-coded summation imaging on selected monochromatic DSA images. The differences in time to peak (dTTP) of contrast enhancement in predefined anatomical measuring points were analyzed. Furthermore, differences in systolic blood pressure values (SBP) and serum creatinine were obtained. The value of underlying diabetes mellitus as a predictor for clinical outcome was assessed. Correlation analysis between the patients´ gender as well as the presence of diabetes mellitus and dTTP was performed. RESULTS: Endovascular revascularization resulted in statistically significant improvement in 4/7 regions of interest. Highly significant improvement of perfusion in terms of shortened TTP values could be found at the segmental artery level and in the intrastenotical segment (p < 0.001), significant improvement prestenotical and in the apical renal parenchyma (p < 0.05). In the other anatomic regions, differences revealed not to be significant. Differences between SBP and serum creatinine levels before and after the procedure were significant (p = 0.004 and 0.0004). Patients´ gender as well as the presence of diabetes mellitus did not reveal to be predictors for the clinical success of the procedure. Furthermore, diabetes and gender did not show relevant correlation with dTTP in the parenchymal measuring points. CONCLUSIONS: The supplementary use of color-coding DSA and the data gained from parametric images may provide helpful information in the evaluation of the procedures´ technical success. The segmental artery might be a particularly suitable vascular territory for analyzing differences in blood flow characteristics. Further studies with larger cohorts are needed to further confirm the diagnostic value of this technique.

The transition clinic in chronic kidney disease care.

People with advanced chronic kidney disease and evidence of progression have a high risk of renal replacement therapy. Specialized transition clinics could offer a better option for preparing these patients for dialysis, transplantation or conservative care. This review focuses on the different aspects of such transition clinics. We discuss which patients should be referred to these units and when referral should take place. Patient involvement in the decision-making process is important and requires unbiased patient education. There are many themes, both patient-centred and within the healthcare structure, that will influence the process of shared decision-making and the modality choice. Aspects of placing an access for haemodialysis and peritoneal dialysis are reviewed. Finally, we discuss the importance of pre-emptive transplantation and a planned dialysis start, all with a focus on multidisciplinary collaboration at the transition clinic.

Repeated kidney re-transplantation-the Eurotransplant experience: a retrospective multicenter outcome analysis.

In Eurotransplant kidney allocation system (ETKAS), candidates can be considered unlimitedly for repeated re-transplantation. Data on outcome and benefit are indeterminate. We performed a retrospective 15-year patient and graft outcome data analysis from 1464 recipients of a third or fourth or higher sequential deceased donor renal transplantation (DDRT) from 42 transplant centers. Repeated re-DDRT recipients were younger (mean 43.0 vs. 50.2 years) compared to first DDRT recipients. They received grafts with more favorable HLA matches (89.0% vs. 84.5%) but thereby no statistically significant improvement of patient and graft outcome was found as comparatively demonstrated in 1st DDRT. In the multivariate modeling accounting for confounding factors, mortality and graft loss after 3rd and ≥4th DDRT (P < 0.001 each) and death with functioning graft (DwFG) after 3rd DDRT (P = 0.001) were higher as compared to 1st DDRT. The incidence of primary nonfunction (PNF) was also significantly higher in re-DDRT (12.7%) than in 1st DDRT (7.1%; P < 0.001). Facing organ shortage, increasing waiting time, and considerable mortality on dialysis, we question the current policy of repeated re-DDRT. The data from this survey propose better HLA matching in first DDRT and second DDRT and careful selection of candidates, especially for ≥4th DDRT.

[Interstitial nephritis]. / Interstitielle Nephritis.

Acute interstitial nephritis (AIN) is a rare, often underdiagnosed condition and a common cause of renal failure. Drugs are the leading cause. The underlying pathophysiological condition is often a type IV hypersensitivity reaction. There are also rarer idiopathic forms, which often remain unrecognized. Additionally, the pathophysiological mechanisms are poorly understood, so that only very few promising forms of treatment are available. For some medications the overall risk is low but the side effects are relevant for the clinical routine due to the fact that they are frequently prescribed. In addition, the development of new approaches, such as immunotherapy also leads to side effects that cannot be completely predicted. For many diseases the occurrence of acute kidney injury increases the mortality and morbidity. A potentially irreversible chronic renal failure increases the incidence of further comorbidities and reduces the quality of life. Treatment is difficult and mostly empirical.

Matched-pair analysis of renal function in the immediate postoperative period: a comparison of living kidney donors versus patients nephrectomized for renal cell cancer.

PURPOSE: Living kidney donation (LKD) involves little risk for the donor and provides excellent functional outcome for transplant recipients. However, contradictory data exist on the incidence and degree of impaired renal function (IRF) in the donor. Only few studies compared the incidence of IRF in donors with that of patients having undergone radical nephrectomy (RN). METHODS: From 1992 to 2012, 94 healthy subjects underwent an open nephrectomy for living kidney donation at the University Medical Center of Würzburg. These patients were compared with matched subjects who had the same surgical procedure for renal cell carcinoma at the Carl-Thiem Hospital Cottbus (1:1 matching using propensity scores). RESULTS: In the LKD-group, no complication ≥ Grade 3 according to the Clavien-Dindo classification occurred. Donors had a preoperative median estimated glomerular filtration rate (eGFR) of 85.1 ml/min which changed to 54.4, 57.0 and 61.0 ml/min (all p < 0.001 in comparison with baseline) on postoperative days 7-10, 365 and 730, respectively. While median eGFR between LKD- and RN-groups was nearly equal (85.1 vs. 85.3 ml/min; p = 0.786), median immediate postoperative eGFR was significantly lower in the LKD-group (54.3 vs. 60 ml/min; p = 0.002). Furthermore, in LKD, the percentage decrease compared with baseline was significantly higher (34.4 vs. 32 %; p = 0.017). CONCLUSIONS: In living kidney donors, median eGFR decreased by 34.4 % immediately after surgery. Compared with matched RN-patients, immediate postoperative IRF is significantly more pronounced. One explanation may be that in kidney tumor patients, compensatory adaptive filtration activity of the contralateral kidney sets in already preoperatively.

Human Leucocyte Antigen-Matching Can Improve Long Term Outcome of Renal Allografts from Donors Older Than 75 Years.

BACKGROUND: Renal transplantation is the therapy of choice for kidney failure. The Eurotransplant Senior Program (ESP) has been established to allocate kidneys ≥65 years to recipients of the same age group considered a regional allocation with short cold ischemia (CIT) but not human-leukocyte-antigen (HLA)-matching. The acceptance of organs aged ≥75 years is also still controversial within the ESP. METHODS: In a multicenter approach, 179 kidney grafts ≥75 years (mean donor age 78 years) that were transplanted in 174 patients in 5 German transplant centers were analyzed. The primary focus of the analysis was long-term outcome of the grafts and the impact of CIT, HLA matching, and recipient related risk factors. RESULTS: The mean graft survival was 59 months (median 67 months) with a mean donor age of 78.3 ± 2.9 years. Grafts with 0 to 3 HLA-mismatches had a significantly better overall graft survival compared to grafts with ≥4 mismatches (69 months vs 54 months; P = .008). The mean CIT was short (11.9 ± 5.3 hours) and had no impact on graft survival. CONCLUSION: Recipients receiving a kidney graft from donors aged ≥75 years can benefit from nearly 5 years of survival with a functioning graft. Even minimal HLA matching may improve long term allograft survival.

Rescue Allocation Modes in Eurotransplant Kidney Transplantation: Recipient Oriented Extended Allocation Versus Competitive Rescue Allocation-A Retrospective Multicenter Outcome Analysis.

BACKGROUND: Whenever the kidney standard allocation (SA) algorithms according to the Eurotransplant (ET) Kidney Allocation System or the Eurotransplant Senior Program fail, rescue allocation (RA) is initiated. There are 2 procedurally different modes of RA: recipient oriented extended allocation (REAL) and competitive rescue allocation (CRA). The objective of this study was to evaluate the association of patient survival and graft failure with RA mode and whether or not it varied across the different ET countries. METHODS: The ET database was retrospectively analyzed for donor and recipient clinical and demographic characteristics in association with graft outcomes of deceased donor renal transplantation (DDRT) across all ET countries and centers from 2014 to 2021 using Cox proportional hazards methods. RESULTS: Seventeen thousand six hundred seventy-nine renal transplantations were included (SA 15 658 [89%], REAL 860 [4.9%], and CRA 1161 [6.6%]). In CRA, donors were older, cold ischemia times were longer, and HLA matches were worse in comparison with REAL and especially SA. Multivariable analyses showed comparable graft and recipient survival between SA and REAL; however, CRA was associated with shorter graft survival. Germany performed 76% of all DDRTs after REAL and CRA and the latter mode reduced waiting times by up to 2.9 y. CONCLUSIONS: REAL and CRA are used differently in the ET countries according to national donor rates. Both RA schemes optimize graft utilization, lead to acceptable outcomes, and help to stabilize national DDRT programs, especially in Germany.

Kidney Transplantation After Rescue Allocation-the Eurotransplant Experience: A Retrospective Multicenter Outcome Analysis.

BACKGROUND: At Eurotransplant (ET), kidneys are transferred to "rescue allocation" (RA), whenever the standard allocation (SA) algorithms Eurotransplant Kidney Allocation System (ETKAS) and Eurotransplant Senior Program (ESP) fail. We analyzed the outcome of RA. METHODS: Retrospective patient clinical and demographic characteristics association analyses were performed with graft outcomes for 2422 recipients of a deceased donor renal transplantation (DDRT) after RA versus 25 481 after SA from 71 centers across all ET countries from 2006 to 2018. RESULTS: Numbers of DDRTs after RA increased over the time, especially in Germany. RA played a minor role in ESP versus ETKAS (2.7% versus 10.4%). RA recipients and donors were older compared with SA recipients and donors, cold ischemia times were longer, waiting times were shorter, and the incidence of primary nonfunction was comparable. Among ETKAS recipients, HLA matching was more favorable in SA (mean 3.7 versus 2.5). In multivariate modeling, the incidence of graft loss in ETKAS recipients was reduced in RA compared with SA (subdistribution hazard ratio, 0.80; 95% confidence interval [0.70-0.91], P < 0.001), whereas other outcomes (mortality, death with functioning graft (DwFG)) were not significantly different. None of the 3 outcomes were significantly different when comparing RA with SA within the ESP program. CONCLUSIONS: Facing increased waiting times and mortality on dialysis due to donor shortage, this study reveals encouragingly positive DDRT outcomes following RA. This supports the extension of RA to more patients and as an alternative tool to enable transplantation in patients in countries with prohibitively long waiting times or at risk of deterioration.

Donor antigen-specific regulatory T-cell function affects outcome in kidney transplant recipients.

Chronic transplant dysfunction, a major impediment to long-term allograft survival, is caused by several factors including an ongoing alloimmune response termed chronic rejection. To define some of these factors further, we selected 107 patients mismatched to their donors from 623 patients transplanted at a single center. Patients were categorized according to their immunosuppressive treatment and further divided into those with stable or chronic allograft dysfunction. Donor human lymphocyte antigen allopeptide-specific T-cell lines were then generated from stable patients and those with biopsy-proven chronic allograft nephropathy. Increased amounts of CD4+CD25+ regulatory T cells (Tregs) and Treg-associated gene expression profiles were found in cell lines derived from the patients with stable compared with those with chronic allograft dysfunction. Furthermore, a higher percentage of Tregs was found in patients with stable graft function on tacrolimus-based compared with cyclosporine-based immunosuppression protocols. Patients with stable graft function had a significantly higher expression of interleukin (IL)-4 and IL-10, whereas the cytokines IL-2, IL-17, and interferon-γ were significantly higher in patients with allograft dysfunction in vitro. Thus, enhancing the operational role of naturally occurring donor-specific Tregs in allograft recipients by adjusting the immunosuppression protocol may be advantageous particularly for patients with ongoing chronic rejection.

Risk factors for Pneumocystis jiroveci pneumonia (PcP) in renal transplant recipients.

BACKGROUND: Pneumocystis jiroveci pneumonia (PcP) is a potentially life-threatening complication in renal transplant recipients with increased reports during the past few years. Individual risk factors for susceptibility to PcP are incompletely understood. METHODS: We retrospectively analysed 60 cases of confirmed PcP, diagnosed in six German transplant centres between 2004 and 2008, as well as 60 matched controls. RESULTS: Compared with controls, PcP cases revealed the following significant differences: PcP cases had a poorer renal function (eGFR 31 vs. 42 mL/min in controls), more biopsy-proven rejections (18 vs. 5 patients), more frequent treatment with mycophenolate mofetil (53 vs. 44 patients) and less frequent treatment with interleukin-2 receptor antagonist (20 vs. 32 patients). According to centre policy, in those years, none of the patients or controls had received PcP prophylaxis after transplantation. Of the 60 patients with PcP, 30% developed the disease after the currently recommended duration of prophylactic treatment, 27% died in the course of the disease and 45% required treatment in the ICU. CONCLUSIONS: Our case-control study reveals a novel risk profile for PcP. Renal transplant recipients with more pronounced renal insufficiency following rejection episodes and treated with intensified immunosuppression are at particular risk for PcP.

[Kidney as pacemaker for cardiovascular aging]. / Die Niere als Schrittmacher kardiovaskulärer Alterung.

Kidney patients age faster and vascular risk factors intensify the process. Lifetime is reduced up to 16 years in patients with diabetes mellitus type 2 and kidney disease. SGLT2 inhibitors play a significant role in maintaining organ function. By inhibiting the SGLT2 transporter in the proximal tubule of the kidneys, energy and water are continuously excreted and metabolic processes that are counter-regulated are set in motion. This hypometabolic adaptation supports organ functions and induces longevity. Kidney protection extends life expectancy of patients with diabetes mellitus type 2.Also patients with heart failure benefit and a 3-stage therapy is newly being discussed. The beta blocker is combined with an SGLT2 inhibitor in the first stage. In the second stage, the angiotensin receptor/neprilysin inhibitor and then a mineralocorticoid receptor antagonist (MRA) is used. These therapies have a complementary effect.

Long-term results of a staged approach: continent urinary diversion in preparation for renal transplantation.

PURPOSE: We provide the long-term results of renal transplantation into continent urinary intestinal reservoirs as a planned 2-stage procedure. MATERIALS AND METHODS: Between November 1990 and January 2009, 18 patients underwent cadaveric or living related renal transplantation into continent urinary reservoirs (continent cutaneous diversion 16, orthotopic substitution 2). All patients were prospectively followed. RESULTS: Of these patients 15 are currently free of dialysis. At a mean followup of 89.2 months (range 2 to 188) 13 patients had a serum creatinine ranging from 0.6 to 3.1 mg/dl (mean 1.49) after the first transplantation. Two patients underwent a second transplantation 12 and 122 months after loss of the transplant for renal vein thrombosis and chronic allograft dysfunction, respectively. Two additional patients had to resume hemodialysis 62 and 109 months after renal transplantation. The second transplantation was delayed mainly due to compliance problems. One patient died of fulminant septicemia after laparotomy elsewhere for bowel obstruction with normal renal function before that episode. The continence mechanism needed correction in 3 patients, and 2 further revisions were required for ureteral kinking and lymphocele. The patients with orthotopic substitution (2) voided to completion and showed complete continence. All patients with cutaneous diversion were continent day and night with easy catheterization. CONCLUSIONS: This study is among the largest single series to date of renal transplantation into continent urinary diversions. Long-term followup confirms that this approach is a safe and socially well accepted treatment option in carefully selected patients.

Impact of mycophenolate mofetil on wound complications and lymphoceles after kidney transplantation.

BACKGROUND/AIMS: Despite improved efficacy, modern immunosuppressive agents may show unanticipated side effects. In this study we investigated the possible interactions of mycophenolate mofetil (MMF) with wound healing and lymphocele formation. METHODS: We conducted a retrospective single-center analysis in 144 patients receiving a cyclosporine A-based immunosuppression with prednisolone and either MMF (n = 77) or azathioprine (AZA, n = 77). Endpoints were incidences of lymphocele formation and non-primary wound healing during 6 months' follow-up. RESULTS: AZA-treated patients had more rejection episodes and consecutively more steroid pulses, both being potential risk factors for endpoints. No graft was lost in any group and graft function was comparable. AZA patients demonstrated a trend for more frequent wound infections. Fluid accumulation around the graft, however, was more frequent in the MMF group (OR = 2.6; p = 0.03). Consequently, more drainage maneuvers (17 vs. 5 interventions) and sclerotherapies (8 vs. 0 interventions) were undertaken in MMF patients. Pre-assigned risk factors for lymphoceles reported before did not differ between both cohorts; patients experiencing acute rejection episodes had even less symptomatic lymphoceles (n = 23). CONCLUSION: We found a possible relationship between the administration of MMF and lymphocele formation. To avoid the hazard of reinterventions, the prolongation of hospitalization and impairment of graft function, it requires awareness and attention in patients treated with this immunosuppressant.

Comparison of different algorithms for the assessment of cardiovascular risk after kidney transplantation by the time of entering waiting list.

BACKGROUND: The prevalence of cardiovascular disease is high among patients with chronic kidney disease and cardiovascular events (CVE) remain the leading cause of death after kidney transplantation (KT). We performed a retrospective analysis of 389 KT recipients to assess if the European Society of Cardiology Score (ESC-Score), Framingham Heart Study Score (FRAMINGHAM), Prospective Cardiovascular Munster Study Score (PROCAM-Score) or Assessing cardiovascular risk using Scottish Intercollegiate Guidelines Network Score (ASSIGN-Score) algorithms can predict cardiovascular risk after KT at the time of entering the waiting list. METHODS: 389 KT candidates were scored by the time of entering the waiting list. Pearsons chi-square test, cox regression analysis and survival estimates were performed to evaluate the reliability of the cardiovascular scoring models after successful KT. RESULTS: During a follow-up of 8 ± 5.8 years, 96 patients (30%) died due to cardiovascular problems, whereas 13.9% suffered non-fatal CVE. Graft loss occurred in 84 patients (21.6%). Predictors of CVE, survival and graft loss were age and the length of end-stage kidney disease. All scores performed well in assessing the risk for CVE (P < 0.01). Receiver-operating characteristic analysis using the ESC-SCORE, as an example, suggested a cut-off for risk stratification and clinical decisions. CONCLUSIONS: We found all tested scores were reliable for cardiovascular assessment. We suggest using cardiac scores for risk assessment before KT and then taking further steps according to current guidelines.

Effects of donor pretreatment with dopamine on graft function after kidney transplantation: a randomized controlled trial.

CONTEXT: Kidney graft function after transplantation can be improved through pharmacological donor pretreatment to limit organ injury from cold preservation. OBJECTIVE: To determine whether pretreatment of brain-dead donors with low-dose dopamine improves early graft function in human renal transplant recipients. DESIGN, SETTING, AND PATIENTS: Randomized, open-label, multicenter, parallel-group trial of 264 deceased heart-beating donors and 487 subsequent renal transplants performed at 60 European centers between March 2004 and August 2007 (final follow-up, December 31, 2008). Eligible donors were stable under low-dose norepinephrine with a normal serum creatinine concentration on admission. INTERVENTIONS: Donors were randomized to receive low-dose dopamine (4 mug/kg/min). MAIN OUTCOME MEASURES: Dialysis requirement during first week after transplantation. RESULTS: Dopamine was infused for a median of 344 minutes (IQR, 215 minutes). Dialysis was significantly reduced in recipients of a dopamine-treated graft. Fewer recipients in the treatment group needed multiple dialyses (56/227; 24.7%; 95% CI, 19.0%-30.3%; vs 92/260; 35.4%; 95% CI, 29.5%-41.2%; P = .01). The need for multiple dialyses posttransplant was associated with allograft failure after 3 years (HR, 3.61; 95% CI, 2.39-5.45; P < .001), whereas a single dialysis was not (HR, 0.67; 95% CI, 0.21-2.18; P = .51). Besides donor dopamine (OR, 0.54; 95% CI, 0.35-0.83; P = .005), cold ischemic time (OR, 1.07; 95% CI, 1.02-1.11 per hour; P = .001), donor age (OR, 1.03; 95% CI, 1.01-1.05 per year; P < .001), and recipient body weight (OR, 1.02; 95% CI, 1.01-1.04 per kg; P = .009) were independent explanatory variables in a multiple logistic regression model. Dopamine resulted in significant but clinically meaningless increases in the donor's systolic blood pressure (3.8 mm Hg; 95% CI, 0.7-6.9 mm Hg; P = .02) and urine production before surgical recovery of the kidneys (29 mL; 95% CI, 7-51 mL; P = .009) but had no influence on outcome. CONCLUSION: Donor pretreatment with low-dose dopamine reduces the need for dialysis after kidney transplantation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00115115.

Effects of Dopamine Donor Pretreatment on Graft Survival after Kidney Transplantation: A Randomized Trial.

BACKGROUND AND OBJECTIVES: Donor dopamine improves initial graft function after kidney transplantation due to antioxidant properties. We investigated if a 4 µg/kg per minute continuous dopamine infusion administered after brain-death confirmation affects long-term graft survival and examined the exposure-response relationship with treatment duration. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Five-year follow-up of 487 renal transplant patients from 60 European centers who had participated in the randomized, multicenter trial of dopamine donor pretreatment between 2004 and 2007 (ClinicalTrials.gov identifier: NCT00115115). RESULTS: Follow-up was complete in 99.2%. Graft survival was 72.6% versus 68.7% (P=0.34), and 83.3% versus 80.4% (P=0.42) after death-censoring in treatment and control arms according to trial assignment. Although infusion times varied substantially in the treatment arm (range 0-32.2 hours), duration of the dopamine infusion and all-cause graft failure exhibited an exposure-response relationship (hazard ratio, 0.96; 95% confidence interval [95% CI], 0.92 to 1.00, per hour). Cumulative frequency curves of graft survival and exposure time of the dopamine infusion indicated a maximum response rate at 7.10 hours (95% CI, 6.99 to 7.21), which almost coincided with the optimum infusion time for improvement of early graft function (7.05 hours; 95% CI, 6.92 to 7.18). Taking infusion time of 7.1 hours as threshold in subsequent graft survival analyses indicated a relevant benefit: Overall, 81.5% versus 68.5%; P=0.03; and 90.3% versus 80.2%; P=0.04 after death-censoring. CONCLUSIONS: We failed to show a significant graft survival advantage on intention-to-treat. Dopamine infusion time was very short in a considerable number of donors assigned to treatment. Our finding of a significant, nonlinear exposure-response relationship disclosed a threshold value of the dopamine infusion time that may improve long-term kidney graft survival.