Linda Awdishu

Phenotype standardization for drug-induced kidney disease.

Drug induced kidney disease is a frequent cause of renal dysfunction; however, there are no standards to identify and characterize the spectrum of these disorders. We convened a panel of international, adult and pediatric, nephrologists and pharmacists to develop standardized phenotypes for drug induced kidney disease as part of the phenotype standardization project initiated by the International Serious Adverse Events Consortium. We propose four phenotypes of drug induced kidney disease based on clinical presentation: acute kidney injury, glomerular, tubular and nephrolithiasis, along with primary and secondary clinical criteria to support the phenotype definition, and a time course based on the KDIGO/AKIN definitions of acute kidney injury, acute kidney disease and chronic kidney disease. Establishing causality in drug induced kidney disease is challenging and requires knowledge of the biological plausibility for the specific drug, mechanism of injury, time course and assessment of competing risk factors. These phenotypes provide a consistent framework for clinicians, investigators, industry and regulatory agencies to evaluate drug nephrotoxicity across various settings. We believe that this is first step to recognizing drug induced kidney disease and developing strategies to prevent and manage this condition.

Steroids in kidney transplant patients

Any evaluation of steroids in kidney transplantation is hampered by individual variability in metabolism, the lack of clinically available steroid blood levels, and overall little attention to steroid exposure. Many feel that steroids were an essential part of chronic immunosuppression in past decades but may no longer be necessary in low-risk populations when our newer and more potent drugs are used. Potential differences in long-term outcome will be unapparent in short-term antibody induction studies in low-risk patients, particularly with low on steroid doses, as may have happened in the recent, well-done Astellas trial. In many studies, the evidence for the superiority of mycophenolate (MMF) and tacrolimus (TAC) was not as strong as the evidence for the benefit of steroids in the Canadian cyclosporine study. As the practice of steroid withdrawal has increased, we have not seen the improvement in long-term graft survival that many expected with our newer agents. Steroids have immunosuppressive effects even in doses that are low by historic standards, and side effects may not justify their abandonment.

Proteomic Analysis of Urine Exosomes Reveals Renal Tubule Response to Leptospiral Colonization in Experimentally Infected Rats

Background Infectious Leptospira colonize the kidneys of reservoir (e.g. rats) and accidental hosts such as humans. The renal response to persistent leptospiral colonization, as measured by urinary protein biosignatures, has not been systematically studied. Urinary exosomes--bioactive membrane-bound nanovesicles--contain cell-state specific cargo that additively reflect formation all along the nephron. We hypothesized that Leptospira-infection will alter the content of urine exosomes, and further, that these Leptospira-induced alterations will hold clues to unravel novel pathways related to bacterial-host interactions. Methodology/Principal findings Exosome protein content from 24 hour urine samples of Leptospira-infected rats was compared with that of uninfected rats using SDS-PAGE and liquid chromatography/tandem mass spectrometry (LC-MS/MS). Statistical models were used to identify significantly dysregulated proteins in Leptospira-infected and uninfected rat urine exosomes. In all, 842 proteins were identified by LC-MS/MS proteomics of total rat urine and 204 proteins associated specifically with exosomes. Multivariate analysis showed that 25 proteins significantly discriminated between uninfected control and infected rats. Alanyl (membrane) aminopeptidase, also known as CD13 topped this list with the highest score, a finding we validated by Western immunoblotting. Whole urine analysis showed Tamm-Horsfall protein level reduction in the infected rat urine. Total urine and exosome proteins were significantly different in male vs. female infected rats. Conclusions We identified exosome-associated renal tubule-specific responses to Leptospira infection in a rat chronic colonization model. Quantitative differences in infected male and female rat urine exosome proteins vs. uninfected controls suggest that urine exosome analysis identifies important differences in kidney function that may be of clinical and pathological significance.

How to Optimize Drug Delivery in Renal Replacement Therapy

Drug dosing in the setting of acute kidney injury (AKI) is complicated by several factors such as pharmacokinetic changes in renal failure, inaccuracy of renal estimating equations in this setting, lack of therapeutic drug monitoring capability for most drugs, and use of extracorporeal renal replacement. Pharmacokinetic changes include decreases in protein binding and drug metabolism. Renal estimating equations most often overestimate renal clearance in AKI. Additionally, it is well recognized that some drugs are significantly cleared by extracorporeal therapy. Patients with AKI are therefore at risk for adverse outcomes of drug therapy. It has been reported that approximately half of patients with reduced renal clearance receive drug doses that are 2.5 times higher than the recommended maximum dose. To ensure efficacy and prevent toxicity, therapeutic drug monitoring is highly recommended. However, in the absence of drug monitoring, adequate concentrations can only be inferred from clinical response. A clinician must weigh the risks and benefits of possible over‐dosing or under‐dosing based on the therapeutic index of the drug and the clinical situation. This article will review the important factors to consider for drug dosing in patients with AKI receiving continuous renal replacement therapy and sustained low‐efficiency dialysis.

Implementation of interprofessional education (IPE) in 16 U.S. medical schools: Common practices, barriers and facilitators

BACKGROUND Enhanced patient outcomes and accreditation criteria have led schools to integrate interprofessional education (IPE). While several studies describe IPE curricula at individual institutions, few examine practices across multiple institutions. PURPOSE To examine the IPE integration at different institutions and determine gaps where there is potential for improvement. METHOD In this mixed methods study, we obtained survey results from 16 U.S. medical schools, 14 of which reported IPE activities. RESULTS The most common collaboration was between medical and nursing schools (93%). The prevalent format was shared curriculum, often including integrated modules (57%). Small group activities represented the majority (64%) of event settings, and simulation-based learning, games and role-play (71%) were the most utilized learning methods. Thirteen schools (81.3%) reported teaching IPE competencies, but significant variation existed. Gaps and barriers in the study include limitations of using a convenience sample, limited qualitative analysis, and survey by self-report. CONCLUSIONS Most IPE activities focused on the physician role. Implementation challenges included scheduling, logistics and financial support. A need for effective faculty development as well as measures to examine the link between IPE learning outcomes and patient outcomes were identified.

The 6R’s of drug induced nephrotoxicity

Drug induced kidney injury is a frequent adverse event which contributes to morbidity and increased healthcare utilization. Our current knowledge of drug induced kidney disease is limited due to varying definitions of kidney injury, incomplete assessment of concurrent risk factors and lack of long term outcome reporting. Electronic surveillance presents a powerful tool to identify susceptible populations, improve recognition of events and provide decision support on preventative strategies or early intervention in the case of injury. Research in the area of biomarkers for detecting kidney injury and genetic predisposition for this adverse event will enhance detection of injury, identify those susceptible to injury and likely mitigate risk. In this review we will present a 6R framework to identify and mange drug induced kidney injury – risk, recognition, response, renal support, rehabilitation and research.

Rationale and Design of the Genetic Contribution to Drug Induced Renal Injury (DIRECT) Study

Introduction Nephrotoxicity from drugs accounts for 18% to 27% of cases of acute kidney injury. Determining a genetic predisposition may potentially be important in minimizing risk. The aims of this study are as follows: to determine whether a genetic predisposition exists for the development of drug-induced kidney disease (DIKD), using genome-wide association and whole-genome sequencing studies; to describe the frequency, course, risk factors, resolution and outcomes of DIKD cases; to investigate the role of ethnic/racial variability in the genetics of DIKD; and to explore the use of different tools establishing causality of DIKD. Methods A total of 800 patients will be enrolled worldwide and blood samples for DNA collected. Data on the patient risk factors, vital signs, laboratory parameters, drug exposure, and DIKD course will be recorded. A panel of nephrologists will adjudicate all cases. Genome-wide association studies will be conducted using population controls matched on biogeographic ancestry to determine whether there is a genetic predisposition to DIKD. The primary endpoint is the identification of specific drug-related polymorphisms associated with DIKD. Secondary endpoints include the following: frequency of DIKD by causal drug and drug combinations; DIKD genetic variability; exploration of causality assessment tools; risk factor identification; description of the course of DIKD, including mortality and dialysis dependency at hospital discharge and 28 and 90 days post-event. Results Data are currently being analyzed. Results are pending. Discussion The Genetic Contribution to Drug Induced Renal Injury (DIRECT) study will be the first observational cohort study to investigate the genetic determinants of DIKD. If the trial is positive, its findings will potentially translate into safer patient outcomes, by genotypic individualization of therapy and minimization of harm.

Role of Pharmacogenomics in Kidney Disease and Injury

There has been considerable excitement in the kidney community surrounding the research findings on the genetic contributions to kidney diseases. However, positive outcomes of personalized therapeutic interventions can be circumvented by unpredictable pharmacokinetics of prescribed drugs. Furthermore, unpredictable drug disposition can result in toxicities such as kidney injury. Patient covariates, disease covariates, and pharmacogenetics all contribute to variability in drug disposition. Further treatment personalization and avoidance of drug- and biologic- induced kidney injury will require extensive knowledge and expertise in renal clinical pharmacology. The current review will focus on the pharmacogenetics of drugs and biologics used in the treatment of glomerular kidney diseases and drugs implicated in inducing kidney injury phenotypes.

Using Simulation to Improve First-Year Pharmacy Students’ Ability to Identify Medication Errors Involving the Top 100 Prescription Medications

Objective. To evaluate first-year pharmacy students’ ability to identify medication errors involving the top 100 prescription medications. Design. In the first quarter of a 3-quarter pharmacy self-care course, a didactic lecture on the most common prescribing and dispensing prescription errors was presented to first-year pharmacy students (P1) in preparation for a prescription review simulation done individually and as a group. In the following quarter, they were given a formal prescription review workshop before a second simulation involving individual and group review of a different set of prescriptions. Students were evaluated based on the number of correctly checked prescriptions and a self-assessment of their confidence in reviewing prescriptions. Assessment. All 63 P1 students completed the prescription review simulations. The individual scores did not significantly change, but group scores improved from 79 (16.2%) in the fall quarter to 98.6 (4.7%) in the winter quarter. Students perceived improvement of their prescription checking skills, specifically in their ability to fill a prescription on their own, identify prescribing and dispensing errors, and perform pharmaceutical calculations. Conclusion. A prescription review module consisting of a didactic lecture, workshop and simulation-based methods to teach prescription analysis was successful at improving first year pharmacy students’ knowledge, confidence, and application of these skills.

Vancomycin Removal During High-Volume Peritoneal Dialysis in Acute Kidney Injury Patients: A Prospective Cohort Clinical Study

Introduction Vancomycin pharmacokinetic data in patients with acute kidney injury (AKI) on high-volume peritoneal dialysis (HVPD) are lacking. The aims were to study the pharmacokinetics of i.v. vancomycin in patients with AKI treated by HVPD who received an i.v. dose of vancomycin (15–20 mg/kg), to determine the vancomycin removal, and to establish vancomycin dosing and evaluation pharmacokinetics target attainment achievement for the empirical treatment of patients with AKI treated by HVPD. Methods Vancomycin was administered 1 hour before dialysis start. Samples of all dialysate were collected for a 24-hour period. Blood samples were collected after 1, 2, 4, and 24 hours of therapy. Vancomycin concentrations were determined using a liquid chromatographic (high-performance liquid chromatography)–fluorescence method. Pharmacokinetic calculations were completed assuming a 1-compartment model. Results Ten patients completed the study. The mean vancomycin dose administered was 18.0 ± 2.95 mg/kg (14.7–21.8 mg/kg) on the day of study (first day) and the mean percentage of vancomycin removal by HVPD was 21.7% ± 2.2% (16%–29%). Peritoneal clearance was 8.1 ± 2.2 ml/min (5.3–12 ml/min). The serum vancomycin half-life was 71.2 ± 24.7 hours (42–110 hours) during HVPD session, the maximum serum concentration was 26.2 ± 3.5 mg/l, which occurred 1 hour after vancomycin administration and HVPD start. Area under the curve (AUC)0–24/minimum inhibitory concentration (MIC) ratio ≥400 was achieved in all patients when MIC = 1 mg/l was considered. Conclusion HVPD removes considerable amounts of vancomycin in septic patients with AKI. Administration of 18 mg/kg vancomycin each 48 to 72 hours in patients with AKI undergoing HVPD was required to reach and maintain therapeutic concentrations.