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).

Lower rate of delayed graft function is observed when epidural analgesia for living donor nephrectomy is administered.

BACKGROUND: The beneficial effects of epidural analgesia (EDA) in terms of pain control and postoperative convalescence are widely known and led to a frequent use for patients who underwent living donor kidney nephrectomy. The objective of this study was to determine whether general anesthesia (GA) plus EDA compared to GA only, administered for living donor nephrectomy has effects on postoperative graft function in recipients. METHODS: In this monocentric, retrospective cohort analysis we analyzed the closed files of all consecutive donor- recipient pairs who underwent living donor kidney transplantations from 2008 to 2017. The outcome variable was delayed graft function (DGF), defined as at least one hemodialysis within seven days postoperatively, once hyperacute rejection, vascular or urinary tract complications were ruled out. Statistical analyses of continuous variables were calculated using the two-tail Student's t test and Fisher exact test for categorical variables with a significance level of p < 0.05, respectively. RESULTS: The study enclosed 291 consecutive living donor kidney transplantations. 99 kidney donors received epidural analgesia whereas 192 had no epidural analgesia. The groups showed balanced pretransplantational characteristics and comparable donors´ and recipients' risk factors. 9 out of all 291 recipients needed renal replacement therapy (RRT) during the first 7 days due to delayed graft function; none of these donors received EDA. The observed rate of DGF in recipients whose kidney donors received epidural analgesia was significantly lower (0% vs. 4.6%; p = 0.031). CONCLUSIONS: In our cohort we observed a significantly lower rate of DGF when epidural analgesia for donor nephrectomy was administered. Due to restrictions of the study design this observation needs further confirmation by prospective studies.

Rabbit-ATG or basiliximab induction for rapid steroid withdrawal after renal transplantation (Harmony): an open-label, multicentre, randomised controlled trial.

BACKGROUND: Standard practice for immunosuppressive therapy after renal transplantation is quadruple therapy using antibody induction, low-dose tacrolimus, mycophenolate mofetil, and corticosteroids. Long-term steroid intake significantly increases cardiovascular risk factors with negative effects on the outcome, especially post-transplantation diabetes associated with morbidity and mortality. In this trial, we examined the efficacy and safety parameters of rapid steroid withdrawal after induction therapy with either rabbit antithymocyte globulin (rabbit ATG) or basiliximab in immunologically low-risk patients during the first year after kidney transplantation. METHODS: In this open-label, multicentre, randomised controlled trial, we randomly assigned renal transplant recipients in a 1:1:1 ratio to receive either basiliximab induction with low-dose tacrolimus, mycophenolate mofetil, and steroid maintenance therapy (arm A), rapid corticosteroid withdrawal on day 8 (arm B), or rapid corticosteroid withdrawal on day 8 after rabbit ATG (arm C). The study was done in 21 centres across Germany. Only participants aged between 18 and 75 years with a low immunological risk who were scheduled to receive a single-organ renal transplant from either a living donor or a deceased donor were considered for enrolment. Patients receiving a second renal transplant were eligible, provided that the first allograft was not lost due to acute rejection within the first year after transplantation. Donor and recipient had to be ABO compatible. Grafts with pre-transplant existing donor-specific human leukocyte antigen (HLA) antibodies were not eligible and the recipients had to have a panel-reactive antibody concentration of 30% or less. Pregnant women and nursing mothers were excluded from the study. The primary endpoint was the incidence of biopsy-proven acute rejection (BPAR) at 12 months. All analyses were done by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00724022. FINDINGS: Between Aug 7, 2008, and Nov 30, 2013, 615 patients were randomly assigned to arm A (206), arm B (189), and arm C (192). BPAR rates were not reduced by rabbit ATG (9·9%) compared with either treatment arm A (11·2%) or B (10·6%; A versus C: p=0·75, B versus C p=0·87). As a secondary endpoint, rapid steroid withdrawal reduced post-transplantation diabetes in arm B to 24% and in arm C to 23% compared with 39% in control arm A (A versus B and C: p=0·0004). Patient survival (94·7% in arm A, 97·4% in arm B, and 96·9% in arm C) and censored graft survival (96·1% in arm A, 96·8% in arm B, and 95·8% in arm C) after 12 months were excellent and equivalent in all arms. Safety parameters such as infections or the incidence of post-transplantation malignancies did not differ between the study arms. INTERPRETATION: Rabbit ATG did not show superiority over basiliximab induction for the prevention of BPAR after rapid steroid withdrawal within 1 year after renal transplantation. Nevertheless, rapid steroid withdrawal after induction therapy for patients with a low immunological risk profile can be achieved without loss of efficacy and is advantageous in regard to post-transplantation diabetes incidence. FUNDING: Investigator Initiated Trial; financial support by Astellas Pharma GmbH, Sanofi, and Roche Pharma AG.

Risk Factors and Management of Leukopenia After Kidney Transplantation: A Single-Center Experience.

BACKGROUND: Leukopenia is a common complication after kidney transplantation. The etiology is multifactorial, with medication adverse effects and cytomegalovirus infection as main causes. Optimal strategies to prevent or treat posttransplant leukopenia remain unknown. We aimed to identify risk factors for leukopenia and to investigate the benefit of switching the immunosuppressive therapy to hydrocortisone as a continuous infusion. METHODS: We retrospectively evaluated all patients with leukopenia after kidney transplantation between 2007 and 2017 at our center relative to age- and sex-matched controls. RESULTS: Leukopenia was associated with the degree of rejection therapy before leukopenia, the immunosuppressive therapy before transplantation, and an induction therapy with rabbit antithymocyte globulin. Patients with leukopenia exhibited increased mortality, an increased incidence of bacterial and viral infections, and more acute rejections. Switching to hydrocortisone as a continuous infusion in patients with severe leukopenia decreased the duration of leukopenia and the incidence of subsequent viral infections, especially with cytomegalovirus. CONCLUSION: Leukopenia is a risk factor for infectious complications and mortality, and it is associated with acute rejection. Switching immunosuppressive therapy to hydrocortisone as a continuous infusion is a safe approach to reduce the duration of leukopenia and the incidence of viral infections.

Therapy with lopinavir/ritonavir and hydroxychloroquine is associated with acute kidney injury in COVID-19 patients.

BACKGROUND: Acute kidney injury (AKI) is an independent risk factor for mortality, which affects about 5% of hospitalized coronavirus disease-2019 (COVID-19) patients and up to 25-29% of severely ill COVID-19 patients. Lopinavir/ritonavir and hydroxychloroquine show in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and have been used for the treatment of COVID-19. Both, lopinavir and hydroxychloroquine are metabolized by cytochrome P450 (CYP) 3A4. The impact of a triple therapy with lopinavir/ritonavir and hydroxychloroquine (triple therapy) on kidney function in COVID-19 is currently not known. METHODS: We retrospectively analyzed both non-ICU and ICU patients with COVID-19 receiving triple therapy for the incidence of AKI. Patients receiving standard therapy served as a control group. All patients were hospitalized at the University Hospital of Freiburg, Germany, between March and April 2020. A matched-pair analysis for the National Early Warning Score (NEWS) 2 was performed to control for the severity of illness among non-intensive care unit (ICU) patients. RESULTS: In non-ICU patients, the incidence of AKI was markedly increased following triple therapy (78.6% vs. 21.4% in controls, p = 0.002), while a high incidence of AKI was observed in both groups of ICU patients (triple therapy: 80.0%, control group: 90.5%). ICU patients treated with triple therapy showed a trend towards more oliguric or anuric kidney injury. We also observed a linear correlation between the duration of the triple therapy and the maximum serum creatinine level (p = 0.004, R2 = 0.276, R = 0.597). CONCLUSION: Triple therapy is associated with an increase in the incidence of AKI in non-ICU COVID-19 patients. The underlying mechanisms may comprise a CYP3A4 enzyme interaction, and may be relevant for any future therapy combining hydroxychloroquine with antiviral agents.

Early Postoperative Use of Diuretics After Kidney Transplantation Showed Increase in Delayed Graft Function.

PURPOSE: In acute renal injury, diuretics are widely considered to be harmful. Nevertheless, they are used frequently after kidney transplantation. We hypothesized that diuretics administered in the early postoperative treatment after kidney transplantation increase the incidence of delayed graft function (DGF). METHODS: In this monocentric, retrospective cohort analysis, we screened the closed files of all consecutive patients who underwent kidney transplantation from 2011 to 2017. The outcome variable was DGF, defined as at least 1 hemodialysis within 7 days postoperatively. To stratify for baseline characteristics such as waiting time or cold ischemic period, we employed a propensity score-matched analysis. Further statistical processing included basic descriptive statistics, Mann-Whitney U test, and binary logistic regression analysis. RESULTS: The unmatched cohort included 445 patients and showed a significantly increased rate of DGF for patients who received either furosemide or mannitol or a combination of both (5% vs 25%; P < .001). Mannitol (odds ratio [OR]: 4.094) and furosemide (OR: 2.915) showed a significant correlation with DGF in the multivariate regression analysis. Propensity score-based matching resulted in a matched cohort of 214 patients with balanced baseline risk variables. In this matched cohort, the rate of DGF was significantly increased in patients who received diuretics in the early postoperative treatment (7% vs 16%; P = .031). CONCLUSION: Our results show that postoperatively administered diuretics are associated with an increased rate of DGF even in a cohort with balanced preoperative risk variables. This study supports recently published reviews, which call diuretics in the transplantation process into question.

Duodenal Exclusion but Not Sleeve Gastrectomy Preserves Insulin Secretion, Making It the More Effective Metabolic Procedure.

INTRODUCTION: There is an ongoing debate on which procedure provides the best treatment for type 2 diabetes. Furthermore, the pathomechanisms of diabetes improvement of partly anatomically differing operations is not fully understood. METHODS: A loop duodenojejunostomy (DJOS) with exclusion of one third of intestinal length, a sleeve gastrectomy (SG), or a combination of DJOS + SG was performed in 8-week-old male ZDF rats. One, three, and six months after surgery, an oral glucose tolerance test and measurements of GLP-1, GIP, insulin, and bile acids were conducted. RESULTS: After an initial (4 weeks) equal glucose control, DJOS and DJOS + SG showed significantly lower glucose levels than SG 3 and 6 months after surgery. There was sharp decline of insulin levels in SG animals over time, whereas insulin levels in DJOS and DJOS + SG were preserved. GIP levels were significantly larger in both groups containing a sleeve at all three time points, whereas GLP-1 was equal in all groups at all time. Bile acid levels were significantly higher in the DJOS compared to the SG group at all time points. Interestingly, the additional SG in the DJOS + SG group led to lower bile acid levels 1 and 6 months postoperatively. CONCLUSION: The effect of SG on glucose control was transient, whereas a duodenal exclusion was the more effective procedure in this model due to a sustained pancreatic function with a preserved insulin secretion.

Five-Year Long-Term Followup of a Primary Lymph node Gastrinoma: Is a Pancreaticoduodenectomy Justified?

Background. Gastrinoma-positive lymph nodes and failed localization of the primary tumor during surgical exploration are described. Specialists suppose that these lymph nodes are metastases rather than a primary gastrinoma. Methods. Case report with a five-year long-term followup. A 60-year-old patient with an confirmed gastrinoma was treated in our department. All preoperative evaluations including somatostatin-receptor-scintigraphy and F-Dopa PET failed to localize the gastrinoma. Explorative laparotomy revealed a gastrinoma in two peripancreatic lymph nodes. Despite extensive intraoperative exploration, no primary gastrinoma could be detected in typical localization. Results. Over a period of 5 years, the patient's gastrin level stayed in the normal range and the patient seems to be completely cured. Conclusion. A prophylactic partial pancreatoduodenectomy is not indicated to avoid recurrence, since complete biochemical cure by local resection of the lymph node gastrinoma is possible.

The new adhesion prophylaxis membrane A-part--from in vitro testing to first in vivo results.

INTRODUCTION: Formation of postoperative intra-abdominal adhesions is a severe problem in surgery. Apart from standard surgical procedures, a variety of different substances is available to prevent adhesions, but no universal method has been developed so far. A membrane consisting of polyvinyl alcohol (PVA) and carboxymethylcellulose (CMC) has been demonstrated to be antiadhesive. Here, the in vitro testing and first in vivo results in a rabbit sidewall model are reported. MATERIALS AND METHODS: A-part membrane contains a PVA/CMC mixture in a thickness of 40 microm. The composition, dissolution, tensile strength, and elasticity were examined to characterize the membrane in vitro. Experiments in vivo were carried out using a 'rabbit sidewall model' in which a standardized peritoneal trauma was covered with a 5 x 6 cm A-part membrane. Adhesion formation in A-part-treated animals was compared with that in Adept (15 mL/kg body weight) and untreated controls. RESULTS: An 80/20 PVA/CMC mixture forms a stable, elastic, transparent membrane, which can easily be placed intraoperatively. The dissolution shows a half-life of about 2 weeks [day 15: (45.1 +/- 4.9)% SD], which affords good adhesion protection during the initial critical phase of adhesion formation. In wet conditions, the membrane follows abdominal movements without tearing (tensile strength 5.0 +/- 4.2 N/cm SD; elasticity 29.5%). In a rabbit sidewall model, A-part membrane significantly reduced adhesion development by (83.1 +/- 31.5)% SD compared with the control and the Adept group (p < 0.001). CONCLUSION: The properties of the A-part membrane suggest that it may be useful as an antiadhesive in surgery. A-part is effective in in vivo testing as determined in a rabbit sidewall model.