Rainer Birck

Acetylcysteine for prevention of contrast nephropathy: meta-analysis

BACKGROUND Contrast nephropathy is associated with increased in-hospital morbidity and mortality and leads to extension of hospital stay in patients with chronic renal insufficiency. Acetylcysteine seems to be a safe and inexpensive way to reduce contrast nephropathy. We aimed to assess the efficacy of acetylcysteine to prevent contrast nephropathy after administration of radiocontrast media in patients with chronic renal insufficiency. METHODS We did a meta-analysis of randomised controlled trials comparing acetylcysteine and hydration with hydration alone for preventing contrast nephropathy in patients with chronic renal insufficiency. The trials were identified through a combined search of the BIOSIS+/RRM, MEDLINE, Web of Science, Current Contents Medizin, and The Cochrane Library Databases. We used incidence of contrast nephropathy 48 h after administration of radiocontrast media as an outcome measure. FINDINGS Seven trials including 805 patients were eligible according to our inclusion criteria and were analysed. Overall incidence of contrast nephropathy varied between 8% and 28%. Since significant heterogeneity was indicated by the Q statistics (p=0.016) we used a random-effects model to combine the data. Compared with periprocedural hydration alone, administration of acetylcysteine and hydration significantly reduced the relative risk of contrast nephropathy by 56% (0.435 [95% CI 0.215-0.879], p=0.02) in patients with chronic renal insufficiency. Meta-regression revealed no significant relation between the relative risk of contrast nephropathy and the volume of radiocontrast media administered or the degree of chronic renal insufficiency before the procedure. INTERPRETATION Compared with periprocedural hydration alone, acetylcysteine with hydration significantly reduces the risk of contrast nephropathy in patients with chronic renal insufficiency. The relative risk of contrast nephropathy was not related to the amount of radiocontrast media given or to the degree of chronic renal insufficiency before the procedure.

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 donors 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.

15-Deoxyspergualin in Patients with Refractory ANCA-Associated Systemic Vasculitis: A Six-Month Open-Label Trial to Evaluate Safety and Efficacy

The combination of cyclophosphamide (CYC) and oral corticosteroids is effective in the majority of patients with antineutrophil cytoplasmic antibody-associated vasculitis (AASV), but it carries substantial risk of drug-related morbidity and mortality. New regimens are desired, especially in refractory cases. The immunosuppressant 15-deoxyspergualin (DSG) is effective in experimental autoimmune disease and transplantation as well as in acute kidney transplant rejection in humans. To assess the efficacy and safety of DSG, an open label multicenter trial was conducted in patients with AASV who were either unresponsive or had contraindications for standard immunosuppressants. Included were 19 cases of Wegener granulomatosis and one case of microscopic polyangiitis. Nine of them had received CYC shortly before study entry without apparent therapeutic success. DSG (0.5 mg/kg per d) was given for 2 to 3 wk until the WBC count dropped to 3000/ micro l followed by a rest until at least a WBC of 4000/ micro l was reached again. This was repeated up to six cycles. During the study, no other immunosuppressants besides steroids were allowed. Disease improvement during treatment with DSG was achieved in 70% of cases (six cases of complete remission; eight cases of partial remission). Leucopenia occurred in each patient in a regular pattern during the cycles and was transient without exception. No mortality or septicemia was observed. Mild to moderate infections mainly in the respiratory tract were observed but resolved under adequate treatment without sequel. It is concluded that treatment with DSG is successful in patients with refractory Wegener granulomatosis under careful monitoring of WBC count.

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.

Abnormalities of CD4+ T cell subpopulations in ANCA-associated vasculitis

In patients with ANCA‐associated vasculitis (AAV), CD25 expression is increased on circulating T cells. Although in animal experiments the role of CD4+ CD25+ T‐regulatory‐cells (Treg) in protection against autoimmunity is well established, the role of these cells in AAV is unknown. To investigate the hypothesis that an increased expression of CD25 on T cells is related to persistent T cell activation and not to disturbances in Treg cells in AAV (34 patients, six of them after renal transplantation), we investigated CD25 expression in different subpopulations of CD4+ cells and FOXP3 mRNA expression by reverse transcription‐polymerase chain reaction (RT‐PCR). In addition, T cell proliferation and cytokine secretion after stimulation with anti‐CD3 and anti‐CD28 and intracellular cytokine production after stimulation with phorbol myristate acetate (PMA)‐ionomycin was determined. Controls were non‐vasculitic renal transplant patients (n = 9) and healthy controls (HC) (n = 13). In AAV the total number of lymphocytes, CD4+ lymphocytes and the percentage of naive T cells are lower than in HC and RTX. An increased percentage of CD25+ cells was found in AAV and AAV/RTX, irrespective of disease activity, but not in HC or RTX. This was confined to the naive (CD4+ CD45RBhigh) population only. FOXP3 mRNA expression in CD4+ T cells did not differ between AAV patients and healthy controls. In vitro T cell proliferation was enhanced in AAV patients compared to HC (P < 0·01). PBMC of AAV patients produced significantly less interleukin (IL)‐10 and interferon (IFN)‐γ after anti‐CD3/CD28 stimulation. The percentage of IL‐10 and IL‐12, but not IFN‐γ, IL‐4 or tumour necrosis factor (TNF)‐α‐producing cells was significantly higher in patients compared to HC. These findings were confined to the memory population of CD4+ cells. We conclude that AAV patients are lymphopenic and have low numbers of CD4+ T cells, which seem to be in a persistent state of activation.

Improvement of postischemic acute renal failure with the novel orally active endothelin-A receptor antagonist LU 135252 in the rat.

The endothelin (ET) system may play an important role in the pathogenesis of acute renal failure (ARF). We hypothesize that the course of ARF in an ischemia-reperfusion model will be markedly attenuated by the orally active ET(A)-receptor antagonist LU 135252 (LU) because of an improvement of renal perfusion. ARF was induced in rats by clamping both renal arteries for 60 min. The study was divided into two parts. In part 1, Rats received LU orally (100 mg/kg/day) starting 1 h after induction of ARF for 14 days. Cr(s), Cl(cr) and FE(na) were measured on days 1, 6, 9, and 14 after ARF. Cr(s) was lower in the treatment group on days 1 [1.3 +/- 0.31 mg/dl (n = 9) vs. 2.7 +/- 0.46 mg/dl (n = 10); p < 0.05] and 6 [0.5 +/- 0.1 mg/dl (n = 9) vs. 1.0 +/- 0.2 mg/dl (n = 9); p < 0.05], and Cl(cr) was higher on day 1 [0.9 +/- 0.17 ml/min (n = 9) vs. 0.2 +/- 0.1 ml/min (n = 8); p < 0.05] and 6 [1.8 +/- 0.29 ml/min (n = 9) vs. 1.0 +/- 0.21 ml/min (n = 9); p < 0.05] compared with vehicle. Additionally, FE(na) was lower in treated rats on day 1 [1 +/- 0.4% (n = 9) vs. 8 +/- 3% (n = 8); p < 0.051 compared with vehicle. In part 2, ARF was induced as described. Treated animals received 10 mg/kg LU on days 0, 1, 3, 6, 9, and 14 after ARF as an i.v. bolus injection. RBF, cortex blood flow (CBF), and medulla blood flow (MBF) were measured after application of LU on the same days: LU induced an increase in RBF (day 1: 14 +/- 5.3%, n = 6, p = 0.04; day 3: 15 +/- 2.8%, n = 8; p = 0.0008; day 6: 21 +/- 5.8%, n = 6, p = 0.02; day 9: 13 +/- 4%, n = 6; p = 0.03) and CBF (day 1: 8 +/- 2.2%, n = 7, p = 0.03; day 3: 7 +/- 2.5%, n = 7; p = 0.05; day 6: 18 +/- 4.8%, n = 6, p = 0.04; day 9: 10 +/- 2.5%, n = 6; p = 0.008) up to the first 9 days. MBF did increase on days 1 (9 +/- 3.1%, n = 6; p = 0.04) and 6 (13 +/- 3.6%, n = 6; p = 0.03). Our data confirm the hypothesis that ET plays a major role in the genesis of ARF associated with ischemia-reperfusion.

Effects of Donor Pre-Treatment With Dopamine on Survival After Heart Transplantation A Cohort Study of Heart Transplant Recipients Nested in a Randomized Controlled Multicenter Trial

OBJECTIVES We determined the outcome of cardiac allografts from multiorgan donors enrolled in a randomized trial of donor pre-treatment with dopamine. BACKGROUND Treatment of the brain-dead donor with low-dose dopamine improves immediate graft function after kidney transplantation. METHODS A cohort study of 93 heart transplants from 21 European centers was undertaken between March 2004 and August 2007. We assessed post-transplant left ventricular function (LVF), requirement of a left ventricular assist device (LVAD) or biventricular assist device (BVAD), need for hemofiltration, acute rejection, and survival of recipients of a dopamine-treated versus untreated graft. RESULTS Donor dopamine was associated with improved survival 3 years after transplantation (87.0% vs. 67.8%, p = 0.03). Fewer recipients of a pre-treated graft required hemofiltration after transplant (21.7% vs. 40.4%, p = 0.05). Impaired LVF (15.2% vs. 21.3%, p = 0.59), requirement of a LVAD (4.4% vs. 10.6%, p = 0.44), and biopsy-proven acute rejection (19.6% vs. 14.9%, p = 0.59) were not statistically different between groups. Post-transplant impaired LVF (hazard ratio [HR]: 4.95; 95% confidence interval [CI]: 2.08 to 11.79; p < 0.001), requirement of LVAD (HR: 6.65; 95% CI: 2.40 to 18.45; p < 0.001), and hemofiltration (HR: 2.83; 95% CI: 1.20 to 6.69; p = 0.02) were predictive of death. The survival benefit remained (HR: 0.33; 95% CI: 0.12 to 0.89; p = 0.03) after adjustment for various risks affecting mortality, including pre-transplant LVAD/BVAD, inotropic support, and impaired kidney function. CONCLUSIONS Treatment of brain-dead donors with dopamine of 4 μg/kg/min will not harm cardiac allografts but appears to improve the clinical course of the heart allograft recipient. (Prospective Randomized Trial to Evaluate the Efficacy of Donor Preconditioning With Dopamine on Initial Graft Function After Kidney Transplantation; NCT00115115).

Dopamine treatment in brain-dead rats mediates anti-inflammatory effects: the role of hemodynamic stabilization and D-receptor stimulation

Brain death (BD) is associated with profound inflammation in end‐organs. Dopamine (DA) treatment reduces this inflammatory response, but the underlying mechanisms remain thus far largely unknown. In this study, we investigated if the anti‐inflammatory effect of DA was related to hemodynamic stabilization and by which receptors it was mediated. BD was induced in F344 donor rats. DA was given either before BD for 24 h or after BD induction during a definite time. Adrenergic or D‐receptor blockers were administered to inhibit the receptor stimulation mediated by DA. Hemodynamic changes were recorded and kidneys were harvested after 6 h of BD. Mean arterial pressure was completely normalized by DA treatment. DA pretreatment before BD induction and treatment during BD both significantly inhibited the monocyte infiltration. The anti‐inflammatory as well as its blood pressure stabilizing effect was abrogated by concomitant application of adrenergic receptor blockers. In contrast, concomitant application of D‐receptor blockers only abrogated the anti‐inflammatory effect, but did not affect blood pressure stabilization. In contrast, pergolide and adrenergic receptor blockers completely normalized the blood pressure, but did not affect renal inflammation. Hence, DA might reduce BD‐induced monocyte infiltration possibly by hemodynamic stabilization, D‐receptor activation, or a combination of both.

Complementary and Alternative Medications Consumed by Renal Patients in Southern Germany

BACKGROUND Complementary and alternative medicine (CAM) is frequently used in the general population, yet scant data are available regarding the prevalence of these medications in patients with end-stage renal disease (ESRD). OBJECTIVE To survey patients with ESRD regarding their use of CAM and health foods. METHODS Consecutive patients treated with dialysis or renal transplantation for ESRD were approached by nephrologists of 5 renal centers to report their usage of and knowledge on CAM and health foods by answering a questionnaire. Of 180 approached patients, 164 returned completed questionnaires for analysis. RESULTS Fifty-seven percent of dialysis patients and 49% of transplant patients reported to be regular CAM-consumers. CAM consumption was positively associated with female sex and negatively with diabetes as comorbidity. Forty-one different CAM products had been named, with mineral supplements and vitamins ranking first. Besides CAM, many renal patients had regularly consumed herbal teas and citrus-juices (50% and 35%, respectively). Close to 40% of the documented CAM/health food consumptions have potential risks for patients because of constituents that either accumulate in renal failure or interact with pharmaceutical medication. However, only about 50% of dialysis patients, but 73% of transplant patients used to inform their physicians about CAM consumption (P = .005). Awareness about interaction risks linked to CAM was especially low in dialysis patients when compared to transplant patients (39% versus 78%, P < .0001) and increased when physicians had routinely questioned patients about their CAM consumption. Currently, however, patients reported that only a minority of physicians had taken an active interest into consumption of these substances. CONCLUSION Consumption of CAM and health food is common among renal patients. Physicians are currently not adequately informed about CAM consumption by their patients. Because many products are at risk to either accumulate or cause interactions with medication, physicians should take an active role to inform themselves.

Anca-associated Vasculitis Following Influenza Vaccination: Causal Association or Mere Coincidence?

Whether autoimmune or rheumatic disease may be precipitated after vaccination is controversially discussed among experts. Here we describe 4 cases of new onset or relapsing antineutrophil cytoplasmic antibodies associated vasculitis occurring in timely association with influenza vaccination. In the literature different subtypes of vasculitis have been repeatedly reported after influenza vaccination. Several trials in patients with preexisting auto-immune disease failed to indicate an increased risk for disease recurrence after influenza vaccination but these investigations might be underpowered to detect this very rare but relevant side effect. Although our report does not prove a causal association between vaccination and vasculitis, it seems possible that in rare cases vaccination might induce vasculitic disease.