Hans H. Neumayer

Predictors of Success in Conversion from Calcineurin Inhibitor to Sirolimus in Chronic Allograft Dysfunction

Chronic allograft dysfunction (CAD) is a major cause of graft loss in long‐term kidney transplant recipients. To identify predictors of successful conversion from calcineurin inhibitor (CNI) to sirolimus (SRL) we investigated 59 renal transplant patients with CAD without histological signs of acute rejection. They received 12–15 mg SRL once, then 4–5 mg/day, target trough level 8–12 ng/mL. CNI dose was reduced by 50% simultaneously, and withdrawn at 1–2 months. Concomitant immunosuppression remained unchanged. After 1 year patient survival was 100% and graft survival 92%. In responders (54%) creatinine improved (2.75 ± 0.75 to 2.22 ± 0.64 mg/dL; p < 0.01). In nonresponders (46%) creatinine deteriorated (3.15 ± 1.02 to 4.44 ± 1.60 mg/dL; p < 0.01). Baseline renal function did not differ, however, baseline proteinuria (519 ± 516 vs. 1532 ± 867 mg/day, p < 0.01), histological grade of chronic allograft nephropathy (CAN) (1.2 ± 0.5 vs. 1.9 ± 0.6; p < 0.01), grade of vascular fibrous intimal thickening (1.2 ± 0.7 vs. 1.7 ± 0.7; p = 0.048) and number of acute rejections before conversion (0.73 ± 0.69 vs. 1.27 ± 0.96; p < 0.05) differed significantly between responders and nonresponders. In a multivariate analysis low proteinuria was the only independent variable. Proteinuria below 800 mg/day has a positive predictive value of 90%. Proteinuria at conversion below 800 mg/day is the only independent predictor for positive outcome in conversion from CNI to SRL in CAD.

Hemodynamic effects of immunoadsorption and subsequent immunoglobulin substitution in dilated cardiomyopathy: Three-month results from a randomized study☆

OBJECTIVESnThe objective of our study was to assess the hemodynamic effects of immunoadsorption (IA) and subsequent immunoglobulin G (IgG) substitution in comparison with the effects of conventional medical treatment in patients with dilated cardiomyopathy (DCM).nnnBACKGROUNDnVarious circulating cardiac autoantibodies have been detected among patients suffering from DCM. These antibodies are extractable by IA.nnnMETHODSnPatients with DCM (n = 18, New York Heart Association III-IV, left ventricular ejection fraction <30%) and who were on stable medication participated in the study. Hemodynamic measurements were performed using a Swan-Ganz thermodilution catheter. The patients were randomly assigned either to the treatment group with IA and subsequent IgG substitution (IA/IgG group, n = 9) or to the control group without IA/IgG (n = 9). In the IA/IgG group, the patients were initially treated in one IA session daily on three consecutive days. After the final IA session, 0.5 g/kg of polyclonal IgG was substituted. At one-month intervals, IA was then repeated for three further courses with one IA session daily on two consecutive days, until the third month.nnnRESULTSnAfter the first IA course and IgG substitution, cardiac index (CI) increased from 2.1 (+/-0.1) to 2.8 (+/-0.1) L/min/m2 (p < 0.01) and stroke volume index (SVI) increased from 27.8 (+/-2.3) to 36.2 (+/-2.5) ml/m2 (p < 0.01). Systemic vascular resistance (SVR) decreased from 1,428 (+/-74) to 997 (+/-55) dyne x s x cm(-5) (p < 0.01). The improvement in CI, SVI and SVR persisted after three months. In contrast, hemodynamics did not change throughout the three months in the control group.nnnCONCLUSIONSnImmunoadsorption and subsequent IgG substitution improves cardiovascular function in DCM.

Effect of Food on Everolimus Absorption: Quantification in Healthy Subjects and a Confirmatory Screening in Patients with Renal Transplants

Study Objective. To quantify the influence of a high‐fat meal on the oral bioavailability of the immunosuppressant everolimus in a single‐dose study in healthy subjects and to confirm the results in a small food‐effect screening assessment in patients with renal transplants who were receiving multiple‐dose everolimus.

Cytokine dialysis: an ex vivo study.

To test the hypothesis that dialysis using a new large pore membrane would achieve effective cytokine removal, blood from six volunteers was incubated with endotoxin (1 mg) and then circulated through a closed circuit with a polyamide membrane (nominal cut-off: 100 kDa). Hemodialysis was conducted at 1 or 9 L/hr of dialysate flow at the start of circulation and after 2 and 4 hours. The peak dialysate/plasma concentration ratios were 0.92 for interleukin (IL)-1&bgr;, 0.67 for IL-6, 0.94 for IL-8, 0.33 for tumor necrosis factor (TNF)-&agr;, and 0.11 for albumin. The dialysate/plasma ratios for all cytokines and albumin were decreased with increased dialysate flow from 1 to 9 L/hr (p < 0.05). Clearances for IL-1&bgr;, IL-6, and IL-8, however, were significantly improved with increased dialysate flow (p < 0.01). There was no increase in TNF-&agr; clearance (not significant) and a decrease in albumin clearance (p < 0.01). The peak clearance at 9 L/hr was 33 ml/min for IL-1&bgr;, 19 for IL-6, 51 for IL-8, 11 for TNF-&agr;, and 1.2 for albumin. No adsorption of cytokines was observed. We conclude that cytokine dialysis is achievable through a membrane with a high cut-off point with negligible albumin loss. These findings support the technical feasibility of this new approach to blood purification in sepsis.

Conversion to sirolimus for chronic allograft dysfunction: long-term results confirm predictive value of proteinuria

The aim was to evaluate long‐term graft survival and function after conversion to sirolimus (SRL) for chronic calcineurin inhibitor (CNI) toxicity and the predictive value of baseline proteinuria. This is a follow‐up conversion study of 59 renal transplant patients with deteriorating graft function and histologic signs of CNI toxicity. Previously, baseline proteinuria <800u2003mg/day was identified as a short‐term predictor for successful conversion. Follow‐up was 5.3u2003±u20030.8 (3.7–6.8)u2003years. Patient survival was 88%, graft survival 38%. Creatinine clearance at the last follow‐up was 33.7u2003±u200314u2003ml/min, proteinuria 826u2003±u2003860mg/day. Baseline proteinuria <800u2003mg/day was associated with better graft survival. In a cox analysis including proteinuria >800u2003mg, glomerular filtration rate, age at conversion, chronic Banff score at conversion and time after transplantation at conversion, higher proteinuria was associated with a relative risk of graft loss of 3.98. Prognosis of chronic allograft dysfunction is poor. However, conversion to SRL remains an option for patients with low baseline proteinuria, which can slow down deterioration of graft function during a follow‐up period of up to 5u2003years.

Incidence and outcome of metabolic disarrangements consistent with citrate accumulation in critically ill patients undergoing continuous venovenous hemodialysis with regional citrate anticoagulation

BACKGROUNDnSystemic citrate accumulation is a complication of regional citrate anticoagulation (RCA) during continuous renal replacement therapy (CRRT). Our objective was to determine the incidence of clinical signs consistent with citrate accumulation in a large and representative cohort of intensive care unit patients undergoing RCA-CRRT.nnnMETHODSnPatients treated with RCA-CRRT during 2008-2010 were retrospectively analyzed. Decreased systemic ionized calcium (iCa), increased demand for calcium substitution, elevated total calcium to iCa ratio, and metabolic acidosis were evaluated as indicators for citrate accumulation.nnnRESULTSnIn the 3-year period, 1070 patients were treated with RCA-continuous venovenous hemodialysis. Metabolic signs of citrate accumulation occurred in 32 patients (2.99%, 64.5 ± 14.0 years, 65.6% male, Acute Physiology and Chronic Health Evaluation score 34.2 ± 9.7): systemic iCa decreased to 1.01 ± 0.10 mmol/L with a simultaneous increase of the calcium substitution rate to 129% ± 26%, and the mean total calcium to iCa ratio increased to 2.51 ± 0.54. All 32 patients had therapy-resistant shock with severe lactic acidosis (pH 7.20 ± 0.11, lactate 136 ± 61 mg/dL), indicating severe intracellular hypoxia. None of the patients survived.nnnCONCLUSIONSnThe incidence of disarrangements consistent with citrate accumulation in patients undergoing RCA-continuous venovenous hemodialysis was low, taking place exclusively in patients with severe lactic acidosis due to multiorgan failure. This suggests that the appearance of citrate accumulation is secondary to a severe failure of cellular respiration.

Pretransplant cardiovascular evaluation and posttransplant cardiovascular risk

Modern immunosuppression has expanded access to kidney transplantation by limiting the risk of rejection. However, cardiovascular disease (CVD) remains the principal cause of death with a functioning graft, threatening the long-term survival of transplant recipients. The article reviews the leading risk factors for cardiovascular morbidity both before and after kidney transplantation. Evidence linking poor renal function to CVD is discussed. The function of immunosuppression in exacerbating the risk of both nephrotoxicity and CVD is explored through means of a clinical case study. Underlying kidney disease, hypertension, hyperlipidemia, and diabetes are recognized risk factors for CVD both before and after kidney transplantation. Worsening kidney function and posttransplant immunosuppression exacerbate the risk. Although underlying medical conditions and demographic factors are not easily modifiable, immunosuppression has been recognized as a suitable target. Multiple risk factors converge to increase the risk of cardiovascular events and cardiovascular mortality after kidney transplantation. Clinicians are charged with isolating and treating modifiable risk factors to reduce the risk to long-term survival.

An evaluation of sirolimus in renal transplantation

Introduction: Sirolimus is a powerful antiproliferative immunosuppressive drug approved for the prevention of kidney allograft rejection. By its unique mechanism of action, sirolimus provides a multitude of clinical potential and has been used effectively in different drug combinations. Extensive experience has been gained regarding the best timing of its application, side effect profile and potential benefits and limitations compared with other immunosuppressive drugs. Areas covered: The authors evaluate the recent experience with sirolimus in kidney transplantation. Pivotal randomized controlled trials were used to provide an overview with special attention to pharmacokinetic and dynamic aspects of sirolimus, its current clinical use as well as perspectives for its future role. Expert opinion: Sirolimus enriches the possibilities of immunosuppressive therapies after renal transplantation. Beneficial effects toward kidney function by allowing CNI sparing, lower incidence of malignancies and less viral infections have been suggested. Sirolimus should be used cautiously in de novo patients for reasons of wound healing. An early conversion to a sirolimus-based CNI-free regimen has shown promising results, whereas late conversion is more challenging. Finally, sirolimus-associated side effects are causing tolerability concerns and frequent discontinuations. Future research should aim to better define the therapeutic window and those patients most likely to benefit.

Intermittent hirudin versus continuous heparin for anticoagulation in continuous renal replacement therapy.

Background: Besides possible bleeding complications a further problem in anticoagulation during continuous renal replacement therapy (CRRT) is the development of heparin‐induced thrombocytopenia type II (HIT II) where further anticoagulation with heparin is contraindicated. The application of continuous hirudin as alternative for heparin caused bleeding complications by comparable filter efficacy. Aim of this prospective‐controlled pilot study was to compare the efficacy and safety of intermittent hirudin and continuous heparin for anticoagulation during CRRT in critically ill patients. Methods: 26 patients receiving CRRT were randomly allocated to two groups: Heparin group (14 patients): continuous administration of 250 IU/h heparin, dose was adjusted in 125 IU/h steps with a targeted activated clotting time (ACT) of 180–210 s. Hirudin group (12 patients): initial bolus application of 2–2–5 µg/kg hirudin, dose was adjusted in 2 µg/kg bolus steps with a targeted ecarin clotting time (ECT) > 80 s. Observation time was 96 hours. Results: Measured filter run time was virtually longer for heparin. No bleeding complications were observed in the hirudin group, two bleeding complications in the heparin group. Conclusions: Intermittent hirudin can be used safely for anticoagulation in CRRT. However, the in tendency better filter survival for heparin elucidates the need for further investigations to find the right dosage equilibrium between filter clotting and bleeding complications.

Identification and Therapeutic Management of Highly Sensitized Patients Undergoing Renal Transplantation

Sensitization is generally referred to as the development of alloantibodies, specifically anti-human leukocyte antigen (HLA) immunoglobulin G (IgG) antibodies, most commonly caused by pregnancy, blood transfusion or a previous transplant. Despite being a well known phenomenon, there has not been a general consensus on its definition, monitoring or management. Today, 25% of the patients waitlisted for kidney transplant in the US have a panel reactive antibody (PRA) of >10% while, in the Eurotransplant zone, 14% have a PRA of >5%. Sensitized patients have more difficulty in finding a well HLA-matched donor, and have a higher risk of experiencing longer waiting times, more rejection episodes and eventually inferior long-term graft or patient survival. We review the currently available strategies in identifying and managing highly sensitized patients undergoing renal transplantation. We discuss the progress and limitations in laboratory techniques to elaborate on challenges in defining sensitized patients. The main management options (i.e. the Acceptable Mismatch Program, donor exchange programmes and the desensitization approach) and their mechanisms, related policies, advantages and outcomes, as well as medications and methods being investigated, are updated. In addition, particular emphasis is given to sensitization prevention, a practice that is neglected with our increasing ability to suppress the immune system.