Harm Peters

Effective elimination of dabigatran by haemodialysis. A phase I single-centre study in patients with end-stage renal disease.

Dabigatran, a specific, reversible direct thrombin inhibitor, is used to prevent ischaemic and haemorrhagic strokes in patients with atrial fibrillation. As with every anticoagulant, there is a need to rapidly reverse its effects in emergency situations. In an open-label, single-centre phase I study with two fixed multiple dosing periods, we investigated the pharmacokinetics, pharmacodynamics and safety of dabigatran before, during and after 4 hour haemodialysis sessions with either 200 or 400 ml/min targeted blood flow in seven end-stage renal disease patients without atrial fibrillation. Dabigatran was administered over three days in a regimen designed to achieve peak plasma concentrations comparable to those observed in atrial fibrillation patients receiving 150 mg b.i.d. and to attain adequate distribution of dabigatran in the central and peripheral compartments. Plasma concentration-time profiles were similar in both periods on Day 3 (Cmax: 176 and 159 ng/ml). Four hours of haemodialysis removed 48.8% and 59.3% of total dabigatran from the central compartment with 200 and 400 ml/minute targeted blood flow, respectively. The anticoagulant activity of dabigatran was linearly related to its plasma levels. There was a minor redistribution of dabigatran (<16%) after the end of the haemodialysis session. In conclusion, a 4 hour haemodialysis session can rapidly eliminate a substantial amount of dabigatran from the central compartment with a concomitant marked reduction in its anticoagulant activity. There was a clinically negligible redistribution of dabigatran after haemodialysis. These results demonstrate that haemodialysis can be a suitable approach to eliminate dabigatran in emergency situations.

A phase 1, single-dose study of fresolimumab, an anti-TGF-β antibody, in treatment-resistant primary focal segmental glomerulosclerosis

Primary focal segmental glomerulosclerosis (FSGS) is a disease with poor prognosis and high unmet therapeutic need. Here, we evaluated the safety and pharmacokinetics of single-dose infusions of fresolimumab, a human monoclonal antibody that inactivates all forms of transforming growth factor-β (TGF-β), in a phase I open-label, dose-ranging study. Patients with biopsy-confirmed, treatment-resistant, primary FSGS with a minimum estimated glomerular filtration rate (eGFR) of 25 ml/min per 1.73 m2, and a urine protein to creatinine ratio over 1.8 mg/mg were eligible. All 16 patients completed the study in which each received one of four single-dose levels of fresolimumab (up to 4 mg/kg) and was followed for 112 days. Fresolimumab was well tolerated with pustular rash the only adverse event in two patients. One patient was diagnosed with a histologically confirmed primitive neuroectodermal tumor 2 years after fresolimumab treatment. Consistent with treatment-resistant FSGS, there was a slight decline in eGFR (median decline baseline to final of 5.85 ml/min per 1.73 m2). Proteinuria fluctuated during the study with the median decline from baseline to final in urine protein to creatinine ratio of 1.2 mg/mg with all three Black patients having a mean decline of 3.6 mg/mg. The half-life of fresolimumab was ∼14 days, and the mean dose-normalized Cmax and area under the curve were independent of dose. Thus, single-dose fresolimumab was well tolerated in patients with primary resistant FSGS. Additional evaluation in a larger dose-ranging study is necessary.

Intensive Supportive Care plus Immunosuppression in IgA Nephropathy

BACKGROUND The outcomes of immunosuppressive therapy, when added to supportive care, in patients with IgA nephropathy are uncertain. METHODS We conducted a multicenter, open-label, randomized, controlled trial with a two-group, parallel, group-sequential design. During a 6-month run-in phase, supportive care (in particular, blockade of the renin-angiotensin system) was adjusted on the basis of proteinuria. Patients who had persistent proteinuria with urinary protein excretion of at least 0.75 g per day were randomly assigned to receive supportive care alone (supportive-care group) or supportive care plus immunosuppressive therapy (immunosuppression group) for 3 years. The primary end points in hierarchical order were full clinical remission at the end of the trial (protein-to-creatinine ratio <0.2 [with both protein and creatinine measured in grams] and a decrease in the estimated glomerular filtration rate [eGFR] of <5 ml per minute per 1.73 m(2) of body-surface area from baseline) and a decrease in the eGFR of at least 15 ml per minute per 1.73 m(2) at the end of the trial. The primary end points were analyzed with the use of logistic-regression models. RESULTS The run-in phase was completed by 309 of 337 patients. The proteinuria level decreased to less than 0.75 g of urinary protein excretion per day in 94 patients. Of the remaining 162 patients who consented to undergo randomization, 80 were assigned to the supportive-care group, and 82 to the immunosuppression group. After 3 years, 4 patients (5%) in the supportive-care group, as compared with 14 (17%) in the immunosuppression group, had a full clinical remission (P=0.01). A total of 22 patients (28%) in the supportive-care group and 21 (26%) in the immunosuppression group had a decrease in the eGFR of at least 15 ml per minute per 1.73 m(2) (P=0.75). There was no significant difference in the annual decline in eGFR between the two groups. More patients in the immunosuppression group than in the supportive-care group had severe infections, impaired glucose tolerance, and weight gain of more than 5 kg in the first year of treatment. One patient in the immunosuppression group died of sepsis. CONCLUSIONS The addition of immunosuppressive therapy to intensive supportive care in patients with high-risk IgA nephropathy did not significantly improve the outcome, and during the 3-year study phase, more adverse effects were observed among the patients who received immunosuppressive therapy, with no change in the rate of decrease in the eGFR. (Funded by the German Federal Ministry of Education and Research; STOP-IgAN ClinicalTrials.gov number, NCT00554502.).

Curriculum development for the workplace using Entrustable Professional Activities (EPAs) : AMEE Guide No. 99

Abstract This Guide was written to support educators interested in building a competency-based workplace curriculum. It aims to provide an up-to-date overview of the literature on Entrustable Professional Activities (EPAs), supplemented with suggestions for practical application to curriculum construction, assessment and educational technology. The Guide first introduces concepts and definitions related to EPAs and then guidance for their identification, elaboration and validation, while clarifying common misunderstandings about EPAs. A matrix-mapping approach of combining EPAs with competencies is discussed, and related to existing concepts such as competency milestones. A specific section is devoted to entrustment decision-making as an inextricable part of working with EPAs. In using EPAs, assessment in the workplace is translated to entrustment decision-making for designated levels of permitted autonomy, ranging from acting under full supervision to providing supervision to a junior learner. A final section is devoted to the use of technology, including mobile devices and electronic portfolios to support feedback to trainees about their progress and to support entrustment decision-making by programme directors or clinical teams.

A safe citrate anticoagulation protocol with variable treatment efficacy and excellent control of the acid-base status.

Objective:Citrate anticoagulation is an excellent alternative to heparin anticoagulation for critically ill patients requiring continuous renal replacement therapy. In this article, we provide a safe and an easy-to-handle citrate anticoagulation protocol with variable treatment doses and excellent control of the acid–base status. Design:Prospective observational study. Setting:University hospital. Patients:One hundred sixty-two patients with acute renal failure requiring renal replacement therapy were enrolled in the study. Intervention:A continuous venovenous hemodialysis-based citrate anticoagulation protocol using a 4% trisodium solution, a specially designed dialysate fluid, and a continuous calcium infusion were used. The study period was 6 days. Hemofilters were changed routinely after 72 hours of treatment. The patients were grouped according to body weight, with patients below 60 kg body weight in group 1, patients with at least 60 kg and up to 90 kg body weight in group 2, and patients with a body weight of above 90 kg in group 3. Dialysate flow was adapted according to body size and matched approximately 2 L/hr for a patient with average body size. Blood flow, citrate flow, and calcium flow were adjusted according to the dialysate flow used. Measurements and Main Results:Median filter run time was 61.5 hours (interquartile range: 34.5–81.1 hours). Only 5% of all hemofilters had to be changed because of clotting. The prescribed treatment dose was achieved in all patients. Acid–base and electrolyte control were excellent in all groups. In the rare cases of metabolic disarrangement during citrate anticoagulation, acid–base values were rapidly corrected by modifying either the dialysate flow or alternatively the blood flow rate. Eight patients (5%) developed signs of citrate accumulation indicated by an increase of the total calcium >3 mmol/L or a need for high calcium substitution. Conclusions:We provide a safe and an easy-to-handle citrate anticoagulation protocol that allows an excellent acid–base and electrolyte control in critically ill patients with acute renal failure. The protocol can be adapted to patients’ need, allowing a wide spectrum of treatment doses.

FTY720 (fingolimod) in renal transplantation

Abstract:  FTY720 (Fingolimod) is a novel immunomodulator with a mode of action that is completely different from classical immunosuppressants. FTY is a structural and functional analogue of the natural serum lipid, sphingosine, and is the first in a new class of drugs called sphingosine 1‐phosphate receptor (S1P‐R) modulators. This review discusses the recent findings on the mechanism of action, preclinical models and outlines the results of the ongoing clinical development program. FTY is highly effective in prolonging allograft survival in preclinical models of transplantation and in experimental models of autoimmune diseases. In clinical trials, this novel compound was investigated in de novo renal transplantation and in multiple sclerosis. Pharmacokinetics are characterized by a prolonged absorption phase, a large volume of distribution, and a long elimination half‐life. FTY induces a rapid and transient decrease in lymphocyte counts, which supports the modulatory effects of the drug on lymphocyte sequestration. The most common adverse event was asymptomatic transient bradycardia, a pharmacodynamic effect modulated by atrial S1 P‐R. FTY failed to show an improvement in efficacy for the prevention of renal allograft rejection in two large phase III studies. FTY treatment regimens were associated with impaired renal function and the development of macula edema. Consequently, the further development in renal transplantation was stopped. Because initial clinical studies strongly suggest that FTY is highly effective in multiple sclerosis FTY is now being explored in phase III studies for the treatment of demyelinating diseases, Ongoing studies in multiple sclerosis are eagerly awaited because they may provide novel therapeutic options for patients with autominnue diseases.

Relaxin: Exploring the antifibrotic potential of a pregnancy hormone

Excess accumulation of extracellular matrix proteins has been well recognized as a key feature of chronic kidney diseases. Renal fibrosis, particularly tubulointerstitial fibrosis, parallels the progressive loss of organ function, which ultimately leads to overt renal failure and the need for dialysis. Driven by distinct causes like hypertension, chronic inflammation, elevated blood glucose, or postrenal obstruction, development of kidney fibrosis is mediated and fine-tuned by a variety of cytokines, growth factors, and soluble factors. Among others, transforming growth factor-beta (TGF-b) is of pivotal importance because of its ability to regulate both matrix protein synthesis and degradation in a distinctive profibrotic manner. As the knowledge about TGF-b and matrix protein biology and pathophysiology has substantially increased over the recent years, new strategies to tackle renal fibrosis have been developed that are centered around the cascade of TGF-b generation, TGF-b signaling, and matrix protein deposition and degradation. An emerging novel therapeutic approach to target fibrosis is relaxin, a small peptide hormone that is endogenously produced by corpus luteum of the ovary. The name relaxin is derived from its unique ability to soften connective tissue of the reproductive tract in pregnancy (i.e., to relax the cervix and the pubic ligament to facilitate delivery) [1]. Relaxin has received additional interest because it mediates the profound vascular effects seen in pregnancy, too. The general hemodynamic changes and, especially, the changes in renal hemodynamics in pregnancy (decline in renal vascular resistance, increase in renal plasma flow and GFR) are mediated in large parts by relaxin through actions on nitric oxide and endothelin receptor B activation [1, 2]. Of particular interest to nephrologists, relaxin blocks the renal hemodynamic effects of angiotensin II independently of pregnancy [3]. These vascular effects appear largely dependent on the activation of matrix-metalloproteases (MMP), enzymes that digest and remove collagens and other matrix proteins [1, 2, 4]. Activation of MMPs by relaxin has been

Simvastatin attenuates ventilator-induced lung injury in mice

IntroductionMechanical ventilation (MV) is a life saving intervention in acute respiratory failure without alternative. However, particularly in pre-injured lungs, even protective ventilation strategies may evoke ventilator-induced lung injury (VILI), which is characterized by pulmonary inflammation and vascular leakage. Adjuvant pharmacologic strategies in addition to lung protective ventilation to attenuate VILI are lacking. Simvastatin exhibited anti-inflammatory and endothelial barrier stabilizing properties in vitro and in vivo.MethodsMice were ventilated (12 ml/kg; six hours) and subjected to simvastatin (20 mg/kg) or sham treatment. Pulmonary microvascular leakage, oxygenation, pulmonary and systemic neutrophil and monocyte counts and cytokine release in lung and blood plasma were assessed. Further, lung tissue was analyzed by electron microscopy.ResultsMechanical ventilation induced VILI, displayed by increased pulmonary microvascular leakage and endothelial injury, pulmonary recruitment of neutrophils and Gr-1high monocytes, and by liberation of inflammatory cytokines in the lungs. Further, VILI associated systemic inflammation characterized by blood leukocytosis and elevated plasma cytokines was observed. Simvastatin treatment limited pulmonary endothelial injury, attenuated pulmonary hyperpermeability, prevented the recruitment of leukocytes to the lung, reduced pulmonary cytokine levels and improved oxygenation in mechanically ventilated mice.ConclusionsHigh-dose simvastatin attenuated VILI in mice by reducing MV-induced pulmonary inflammation and hyperpermeability.

Decreased renal corin expression contributes to sodium retention in proteinuric kidney diseases

Patients with proteinuric kidney diseases often have symptoms of salt and water retention. It has been hypothesized that dysregulated sodium absorption is due to increased proteolytic cleavage of epithelial sodium channels (ENaCs) and increased Na,K-ATPase expression. Microarray analysis identified a reduction in kidney corin mRNA expression in rat models of puromycin aminonucleoside-induced nephrotic syndrome and acute anti-Thy1 glomerulonephritis (GN). As atrial natriuretic peptide (ANP) resistance is a mechanism accounting for volume retention, we analyzed the renal expression and function of corin; a type II transmembrane serine protease that converts pro-ANP to active ANP. Immunohistochemical analysis found that corin colocalized with ANP. The nephrotic and glomerulonephritic models exhibited concomitant increased pro-ANP and decreased ANP protein levels in the kidney consistent with low amounts of corin. Importantly, kidneys from corin knockout mice had increased amounts of renal β-ENaC and its activators, phosphodiesterase (PDE) 5 and protein kinase G II, when compared to wild-type mice. A similar expression profile was also found in cell culture suggesting the increase in PDE5 and kinase G II could account for the increase in β-ENaC seen in nephrotic syndrome and GN. Thus, we suggest that corin might be involved in the salt retention seen in glomerular diseases.

Nephrogenic systemic fibrosis versus contrast‐induced nephropathy: Risks and benefits of contrast‐enhanced MR and CT in renally impaired patients

Magnetic resonance imaging (MRI) and computed tomography (CT) have become essential to diagnostic evaluation of many, or most, important medically and surgically treated diseases. It is important to consider comprehensively the implications in making decisions when choosing one or the other cross‐sectional imaging modality. Factors to consider include the relative risks of the contrast agent. Other factors include the relative procedural risks, including radiation risks and the relative expected diagnostic yield of the examination technique ( 1 , 2 ). In this review we describe both nephrogenic systemic fibrosis and contrast‐induced nephropathy to compare the implications with regard to relative risks and benefits of contrast‐enhanced MRI or CT in patients with impaired renal function. J. Magn. Reson. Imaging 2009;30:1350–1356.