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 lowdose dopamine improves early graft function in human renal transplant recipients. Design, Setting, and Patients Randomized, open-label, multicenter, parallelgroup 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 µg/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; PϽ.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; PϽ.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.

No abstract

No abstract

The role of immunosuppression in IgA nephropathy (IgAN) is controversial. In the Supportive Versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy (STOP-IgAN) Trial, 162 patients with IgAN and proteinuria >0.75 g/d after 6 months of optimized supportive care were randomized into two groups: continued supportive care or additional immunosuppression (GFR≥60 ml/min per 1.73 m: 6-month corticosteroid monotherapy; GFR=30-59 ml/min per 1.73 m: cyclophosphamide for 3 months followed by azathioprine plus oral prednisolone). Coprimary end points were full clinical remission and GFR loss ≥15 ml/min per 1.73 m during the 3-year trial phase. In this secondary intention to treat analysis, we separately analyzed data from each immunosuppression subgroup and the corresponding patients on supportive care. Full clinical remission occurred in 11 (20%) patients receiving corticosteroid monotherapy and three (6%) patients on supportive care (odds ratio, 5.31; 95% confidence interval, 1.07 to 26.36; =0.02), but the rate did not differ between patients receiving immunosuppressive combination and controls on supportive care (11% versus 4%, respectively;=0.30). The end point of GFR loss ≥15 ml/min per 1.73 m did not differ between groups. Only corticosteroid monotherapy transiently reduced proteinuria at 12 months. Severe infections, impaired glucose tolerance, and/or weight gain in the first year were more frequent with either immunosuppressive regimen than with supportive care. In conclusion, only corticosteroid monotherapy induced disease remission in a minority of patients who had IgAN with relatively well preserved GFR and persistent proteinuria. Neither immunosuppressive regimen prevented GFR loss, and both associated with substantial adverse events.

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.

No abstract

Ipilimumab is besides the BRAF inhibitor vemurafenib the first officially approved medical treatment for metastatic melanoma, which results in improved survival. Ipilimumab leads to a release of a CTLA4-mediated inhibition of T-cell immunoreactions. Therefore, patients may also suffer from immune-related adverse events affecting different organs, which are typically treated by high-dose corticosteroids. Ipilimumab-induced hypophysitis (iH) has been reported in up to 17% of melanoma patients in clinical trials.Here we present 5 patients with metastatic melanoma and 2 patients with prostate cancer who developed hypophysitis after ipilimumab therapy. Patients were treated by high-dose corticosteroid therapy resulting in the resolution of local inflammation but not of pituitary deficiencies. Partial or complete hypopituitarism remained in all patients. Pharmacotherapy with high-dose corticosteroids caused complications in 5 patients, necessitating hospitalization in 4. 2 of the 3 patients with progressive disease died, while 3 patients had stable disease and 1 patient showed tumor regression after discontinuation of ipilimumab.In summary, with regard to safety and simplicity of hormonal substitution therapy we have to scrutinize high-dose corticosteroid therapy, though it only improves inflammation but not neuro-endocrine function and may cause further morbidity. Regression of the tumor depends on the ipilimumab-mediated immune events, in which high-dose and long-term corticosteroid therapy for iH appears to be counter-intuitive. Herein, we discuss screening and the diagnostic as well as therapeutic management of iH in metastatic cancer patients from an endocrinologic perspective.

Donor heart allografts are extremely susceptible to prolonged static cold storage. Because donor treatment with low-dose dopamine improves clinical outcome after heart transplantation, we tested the hypothesis that dopamine and its lipophilic derivate, N-octanoyl dopamine (NOD), protect cardiomyocytes from cold storage injury. Neonatal rat cardiomyocytes were treated with dopamine or NOD or left untreated and subsequently subjected to static cold storage (8-12 hours). Dopamine-and NOD-treated cardiomyocytes displayed a better viability compared with untreated cells after hypothermia. In untreated cardiomyocytes, cell damage was reflected by lactate dehydrogenase (LDH) release and a decrease in intracellular ATP. NOD was approximately 20-fold more potent than dopamine. Similarly to cardiomyocytes in vitro, rat hearts perfused with NOD before explantation showed significantly lower LDH release after static cold storage. ATP regeneration and spontaneous contractions after cold storage and rewarming only occurred in treated cardiomyocytes. Hypothermia severely attenuated isoprenaline-induced cAMP formation in control but not in dopamine-or NOD-treated cells. Esterified derivates of NOD with redox potential and lipophilic side chains reduced cell damage during cold storage similarly to NOD. In contrast to dopamine, neither NOD nor its derivates induced a significant b-adrenoceptor-mediated elevation of cellular cAMP levels. The b 1 -adrenoceptor antagonist atenolol and D 1 /D 2 receptor antagonist fluphenazine had no impact on the protective effect of NOD or dopamine. We conclude that dopamine as well as NOD treatment mitigates cold preservation injury to cardiomyocytes. The beneficial effects are independent of b-adrenoceptor or dopaminergic receptor stimulation but correlate with redox potential and lipophilic properties.