Chronic kidney disease (CKD) affects the nonrenal clearance of drugs by modulating the functional expression of hepatic drug metabolizing enzymes and transporters. The impact of CKD on oxidative and conjugative metabolism has been extensively studied. However, its effect on hepatic drug reduction, an important Phase I drug metabolism pathway, has not been investigated. We aimed to assess the effect of experimental CKD on hepatic reduction using warfarin as a pharmacological probe substrate. Cytosolic and microsomal cellular fractions were isolated from liver tissue harvested from 5/6(th)-nephrectomized and control rats (n=10 per group). The enzyme kinetics for warfarin reduction were evaluated in both fractions, and formation of warfarin alcohols was used as an indicator of hepatic reductase activity. Selective inhibitors were employed to identify reductases involved in warfarin reduction. Gene and protein expression of reductases were quantified using qRT-PCR and Western blotting, respectively. Formation of RS/SR-warfarin alcohol was decreased by 39% (P<0.001) and 43% (P<0.01) in cytosol and microsomes, respectively in CKD rats versus controls. However, RR/SS-warfarin alcohol formation was unchanged in the cytosol, and a trend toward its decreased production was observed in microsomes. Gene and protein expression of cytosolic carbonyl reductase 1 and aldo-keto reductase 1C3/18, and microsomal 11?-hydroxysteroid dehydrogenase type 1 were significantly reduced by >30% (P<0.05) in CKD rats compared to controls. Collectively, these results suggest that the functional expression of hepatic reductases is selectively decreased in kidney disease. Our findings may explain one mechanism for altered nonrenal clearance, exposure, and response of drugs in CKD patients.
The effect of AKI and modern continuous RRT (CRRT) methods on drug disposition (pharmacokinetics) and response has been poorly studied. Pharmaceutical manufacturers have little incentive to perform pharmacokinetic studies in patients undergoing CRRT because such studies are neither recommended in existing US Food and Drug Administration (FDA) guidance documents nor required for new drug approval. Action is urgently needed to address the knowledge deficit. The Kidney Health Initiative has assembled a work group composed of clinicians and scientists representing academia, the FDA, and the pharmaceutical and dialysis industries with expertise related to pharmacokinetics, AKI, and/or CRRT. The work group critically evaluated key considerations in the assessment of pharmacokinetics and drug dosing in CRRT, practical constraints related to conducting pharmacokinetic studies in critically ill patients, and the generalizability of observations made in the context of specific CRRT prescriptions and specific patient populations in order to identify efficient study designs capable of addressing the knowledge deficit without impeding drug development. Considerations for the standardized assessment of pharmacokinetics and development of corresponding drug dosing recommendations in critically ill patients with AKI receiving CRRT are proposed.
Elevated concentrations of fibroblast growth factor 23 (FGF23) are postulated to promote 25-hydroxyvitamin D (25[OH]D) insufficiency in CKD by stimulating 24-hydroxylation of this metabolite, leading to its subsequent degradation; however, prospective human studies testing this relationship are lacking.
A literature review performed by the EXtracorporeal TReatments In Poisoning (EXTRIP) workgroup highlighted deficiencies in the existing literature, especially the reporting of case studies. Although general reporting guidelines exist for case studies, there are none in the specific field of extracorporeal treatments in toxicology. Our goal was to construct and propose a checklist that systematically outlines the minimum essential items to be reported in a case study of poisoned patients undergoing extracorporeal treatments. Through a modified two-round Delphi technique, panelists (mostly chosen from the EXTRIP workgroup) were asked to vote on the pertinence of a set of items to identify those considered minimally essential for reporting complete and accurate case reports. Furthermore, independent raters validated the clarity of each selected items between each round of voting. All case reports containing data on extracorporeal treatments in poisoning published in Medline in 2011 were reviewed during the external validation rounds. Twenty-one panelists (20 from the EXTRIP workgroup and an invited expert on pharmacology reporting guidelines) participated in the modified Delphi technique. This group included journal editors and experts in nephrology, clinical toxicology, critical care medicine, emergency medicine, and clinical pharmacology. Three independent raters participated in the validation rounds. Panelists voted on a total of 144 items in the first round and 137 items in the second round, with response rates of 96.3% and 98.3%, respectively. Twenty case reports were evaluated at each validation round and the independent raters' response rate was 99.6% and 98.8% per validation round. The final checklist consists of 114 items considered essential for case study reporting. This methodology of alternate voting and external validation rounds was useful in developing the first reporting guideline for case studies in the field of extracorporeal treatments in poisoning. We believe that this guideline will improve the completeness and transparency of published case reports and that the systematic aggregation of information from case reports may provide early signals of effectiveness and/or harm, thereby improving healthcare decision-making.
A key regulatory requirement pertaining to drug development is characterization of the role of kidney function in drug disposition and response, along with provision of corresponding renal dose adjustment recommendations. Traditionally, this information has been derived from Phase I pharmacokinetic studies in which regulatory guidance exists for pharmaceutical manufacturers on the design, conduct, analysis, and interpretation of data. Categorization and stratification of subjects into kidney function groups and dosing recommendations have historically been based on creatinine clearance estimates using the Cockcroft-Gault equation. As new estimating equations have emerged, the choice of equation for assessment of kidney function has become an area of debate. This review highlights these equations and provides recent examples of the use of quantitative models, incorporating efficacy and safety to make rational dose recommendations in subjects with impaired kidney function.
Hemoperfusion is an extracorporeal treatment based on adsorption, historically reserved for the treatment of acute poisonings. Its use was popularized in the 1970s after several in vitro and animal experiments had demonstrated its efficacy, and was even preferred over hemodialysis in the management of overdosed patients. With the advent of new and more efficient dialytic modalities, hemoperfusion is now less frequently performed in the Western world. However, hemoperfusion still remains popular in developing countries. The present article reviews the technique of hemoperfusion, the factors influencing poison clearance through adsorption and its current applications.
The Extracorporeal Treatments In Poisoning (EXTRIP) workgroup was formed to provide recommendations on the use of extracorporeal treatments (ECTR) in poisoning. Here, the workgroup presents its results for tricyclic antidepressants (TCAs). After an extensive literature search, using a predefined methodology, the subgroup responsible for this poison reviewed the articles, extracted the data, summarized findings, and proposed structured voting statements following a predetermined format. A two-round modified Delphi method was chosen to reach a consensus on voting statements and RAND/UCLA Appropriateness Method to quantify disagreement. Blinded votes were compiled, returned, and discussed in person at a meeting. A second vote determined the final recommendations. Seventy-seven articles met inclusion criteria. Only case reports, case series, and one poor-quality observational study were identified yielding a very low quality of evidence for all recommendations. Data on 108 patients, including 12 fatalities, were abstracted. The workgroup concluded that TCAs are not dialyzable and made the following recommendation: ECTR is not recommended in severe TCA poisoning (1D). The workgroup considers that poisoned patients with TCAs are not likely to have a clinical benefit from extracorporeal removal and recommends it NOT to be used in TCA poisoning.
The EXTRIP (Extracorporeal Treatments in Poisoning) Workgroup conducted a systematic review of barbiturate poisoning using a standardized evidence-based process to provide recommendations on the use of extracorporeal treatment (ECTR) in patients with barbiturate poisoning. The authors reviewed all articles, extracted data, summarized key findings, and proposed structured voting statements following a predetermined format. A 2-round modified Delphi method was used to reach a consensus on voting statements, and the RAND/UCLA Appropriateness Method was used to quantify disagreement. 617 articles met the search inclusion criteria. Data for 538 patients were abstracted and evaluated. Only case reports, case series, and nonrandomized observational studies were identified, yielding a low quality of evidence for all recommendations. Using established criteria, the workgroup deemed that long-acting barbiturates are dialyzable and short-acting barbiturates are moderately dialyzable. Four key recommendations were made. (1) The use of ECTR should be restricted to cases of severe long-acting barbiturate poisoning. (2) The indications for ECTR in this setting are the presence of prolonged coma, respiratory depression necessitating mechanical ventilation, shock, persistent toxicity, or increasing or persistently elevated serum barbiturate concentrations despite treatment with multiple-dose activated charcoal. (3) Intermittent hemodialysis is the preferred mode of ECTR, and multiple-dose activated charcoal treatment should be continued during ECTR. (4) Cessation of ECTR is indicated when clinical improvement is apparent. This report provides detailed descriptions of the rationale for all recommendations. In summary, patients with long-acting barbiturate poisoning should be treated with ECTR provided at least one of the specific criteria in the first recommendation is present.
This study was designed to prospectively evaluate the in vivo activities of drug transporters, metabolizing enzymes, and pharmacokinetics in patients with chronic kidney diseases (CKD) caused by glomerulonephritis and nonglomerular etiologies.
A sensitive, accurate, and reproducible ultra-high performance liquid chromatography-tandem mass spectrometry method was developed and validated for determination of warfarin and its alcohol metabolites (RS/SR- and RR/SS-warfarin alcohol) in 10mM Tris-HCl incubation buffer (pH 7.4). Sample preparation involved acidification with 4% formic acid, followed by liquid-liquid extraction using methyl tert-butyl ether. Chromatographic separation was achieved using a Hypersil Gold C18 (2.1mm×100mm, 1.9?m) analytical column with gradient elution of solvent A (water containing 0.01% formic acid) and solvent B (acetonitrile containing 0.1% formic acid). The flow rate was 0.4mL/min and the total run time was 5min. Detection of analytes was performed using heated electrospray ionization (negative mode) and selected reaction monitoring. Excellent linearity was observed for all analytes over the standard curve concentration ranges of 100-10,000ng/mL for warfarin, and 0.5-250ng/mL for warfarin alcohols. The intra- and inter-day accuracy and precision for analytes were within ±10.0%. Excellent recovery and negligible matrix effects were observed. The method is robust, sensitive, accurate and reproducible, and was successfully applied to in vitro enzyme kinetic studies of warfarin.
Dabigatran is an oral direct thrombin inhibitor that is Food and Drug Administration-approved for prevention of stroke in patients with atrial fibrillation. No antidote is available for reversal of dabigatrans anticoagulant effect. Despite limited clinical data, hemodialysis has been suggested as a strategy to remove dabigatran during acute bleeding. This work presents five cases, in which extracorporeal therapy was performed for dabigatran removal in acutely bleeding patients.
Dual antiplatelet therapy with aspirin and a P2Y12 receptor blocker is an established regimen to reduce the risk of ischemic event occurrence in patients with high-risk cardiovascular (CV) disease. Cigarette smoking is an important cardiovascular risk factor. However, several investigators have reported what may be termed a "new" "smokers paradox", whereby clopidogrel-treated nonsmokers appear to have either less or no CV-event reduction when compared to the substantial CV-event reduction in clopidogrel-treated smokers based on several large-scale trials. This "smokers paradox" observed in multiple clinical outcome studies is also supported by emerging "real-world" data that also suggest clopidogrel nonsmokers do not fare as well as smokers treated with clopidogrel. In support of the new "smokers paradox", pharmacodynamic studies have also shown that smoking status influences clopidogrel responsiveness in healthy volunteers, acute coronary syndrome patients, and patients treated with percutaneous coronary intervention. Finally, there is a substantial, albeit not entirely consistent, body of pharmacodynamic and clinical outcome data supporting a reduced antiplatelet effect of clopidogrel in non-smokers as compared to smokers. The clinical relevance of this interaction has never been demonstrated in a prospective trial. The focus of this review is to critically evaluate the reported interaction between cigarette smoking status and thienopyridine efficacy.
Acute kidney injury (AKI) is a common problem characterized by an inflammatory response in the kidney and oxidative stress. However, there are no interventions to prevent AKI. Glutamine is an important precursor of glutathione and has also been shown to induce heat shock proteins (HSP). Thus, glutamine may affect both oxidative stress and inflammation. This study was to explore the effects of glutamine pretreatment on nephrotoxic AKI and to investigate the underlying mechanisms. First, the effects of alternate doses of glutamine were compared in CD-1 mice with AKI induced with folic acid intra-peritoneal injection. Then the effects of glutamine quercetin (an HSP inhibitor), and quercetin+glutamine, were compared in the same AKI model. AKI were assessed with plasma creatinine, urine neutrophil gelatinase-associated lipocalin, and renal histology. Inflammatory response was monitored with renal tumor necrosis factor (TNF-?), chemkines (CXCL1 and CCL2) contents, and neutrophil infiltration. Oxidative injury was detected with reduced glutathione, malondialdehyde, and protein thiol. Glutamine provided dose-dependent renal protection. Pretreatment with quercetin, which was showed to inhibit HSP-70 expression, abolished glutamines renal-protective effects. Quercetin also abrogated glutamines beneficial effects on renal TNF-?, chemokines, and neutrophil infiltration. However, quercetin did not affect glutamines anti-oxidative effects. These results suggest that glutamines renal-protective effects are mainly related to its activation of HSP-70, which mitigates inflammatory response, renal neutrophil infiltration and subsequent AKI. Regulating neutrophil infiltration might be a potential therapeutic target for AKI.
Accurate assessment of kidney function is an important component of determining appropriate drug dosing regimens. Nearly all manufacturer-recommended dosage adjustments are based on creatinine clearance ranges derived from clinical pharmacokinetic studies performed during the drug development process. The Cockcroft-Gault (CG) equation provides an estimate of creatinine clearance and is the equation most commonly used to determine drug dosages in patients with impaired kidney function. The Modification of Diet in Renal Disease (MDRD) study equation has also been proposed for this purpose. Published studies report that drug dosages determined by the two equations do not agree in 10-40% of cases. However, interpretation and comparison of these studies are complicated by the variable creatinine methods used for calculating CG and MDRD estimates, the patient populations studied, and a lack of outcomes data demonstrating the clinical significance of dosing discrepancies. Moreover, the impact of reporting standardized serum creatinine values on the accuracy of the CG equation and corresponding drug dosing regimens have been questioned. Currently, no prospective pharmacokinetic studies have been conducted with use of the MDRD equation to generate dosing recommendations, and limited data are available to support its use in some patient populations representing demographic extremes. Collectively, these issues have resulted in considerable confusion among clinicians and have fueled a healthy debate on whether or not to use the MDRD equation to determine drug dosages. Each of these issues is reviewed, and a proposed algorithm for using creatinine-based kidney function assessments in drug dosing is provided. Knowledge of the advantages, limitations, and clinical role of each equation will facilitate their safe and effective use in drug dosing.
Contrary to popular opinion, application of extracorporeal therapies for poisonings predates their use for ESRD. Despite this observation, the science of blood purification in toxicology remains desperately stagnant today. In fact, much of our current knowledge is derived from George Schreiners 1958 review. Original publications are almost exclusively composed of case reports and case series, from which good inference is impossible. Until randomized controlled trials become available, the medical community would be well served by a group mandated to systematically review available literature, extract relevant information, provide recommendations based on current evidence, and propose research initiatives. The EXtracorporeal TReatments In Poisoning workgroup, formed by several international experts in different medical fields and represented by over 20 societies, now has this mission.
ESRD is associated with systemic oxidative stress, an important nontraditional risk factor for the development of cardiovascular disease. Since interventions aimed at reducing oxidative stress may be beneficial, we examined the pharmacokinetics and pharmacodynamics of the widely used antioxidant N-acetylcysteine (NAC) after oral administration in patients with ESRD.
There has been a remarkable rise in the number of kidney transplant recipients (KTR) in the US over the last decade. Increasing use of potent immunosuppressants, which are also potentially diabetogenic and atherogenic, can result in worsening of pre-existing medical conditions as well as development of post-transplant disease. This, coupled with improving long-term survival, is putting tremendous pressure on transplant centers that were not designed to deliver primary care to KTR. Thus, increasing numbers of KTR will present to their primary care physicians (PCP) post-transplant for routine medical care. Similar to native chronic kidney disease patients, KTRs are vulnerable to cardiovascular disease as well as a host of other problems including bone disease, infections and malignancies. Deaths related to complications of cardiovascular disease and malignancies account for 60-65% of long-term mortality among KTRs. Guidelines from the National Kidney Foundation and the European Best Practice Guidelines Expert Group on the management of hypertension, dyslipidemia, smoking, diabetes and bone disease should be incorporated into the long-term care plan of the KTR to improve outcomes. A number of transplant centers do not supply PCPs with protocols and guidelines, making the task of the PCP more difficult. Despite this, PCPs are expected to continue to provide general preventive medicine, vaccinations and management of chronic medical problems. In this narrative review, we examine the common medical problems seen in KTR from the PCPs perspective. Medical management issues related to immunosuppressive medications are also briefly discussed.
The length of stay (LOS) in intensive care unit (ICU) nonsurvivors is not often reported, but represents an important indicator of the use of resources. LOS in ICU nonsurvivors may also be a marker of cultural and organizational differences between units. In this study based on the national intensive care registries in Finland, Sweden, and Norway, we aimed to report intensive care mortality and to document resource use as measured by LOS in ICU nonsurvivors.
Patients with chronic kidney disease (CKD) represent a significant and growing segment of the US population. A mounting body of experimental and clinical evidence indicates that nonrenal drug clearance is altered in patients with CKD. Specific nonrenal clearance (CL(NR)) pathways that are affected have been identified in experimental models, and include cytochrome P450 enzymes, P-glycoprotein, and organic anion-transporting polypeptides. Altered CL(NR) of several drugs has been described in clinical pharmacokinetics studies, but to date the specific CL(NR) pathways that are affected in CKD patients and result in clinically significant changes in drug exposure have not been definitively established, and the mechanism has not been elucidated. Accumulated uremic toxins may downregulate or directly inhibit drug metabolism and transport pathways, and may do so in a reversible manner. Future Food and Drug Administration recommendations pertaining to the conduct of pharmacokinetic studies in CKD will undoubtedly facilitate the search for the CL(NR) path less traveled, clarify the mechanisms involved, improve our understanding of the clinical significance of altered CL(NR) of individual drugs, and lead to more comprehensive drug dosing recommendations for patients with CKD. This review summarizes our current understanding of this field, focusing on recent developments in the search for the CL(NR) "path less traveled" in CKD.
Nocturia is a frequently encountered problem in clinical practice and a reason for nephrology consultation. Many studies have clearly shown the negative effect of nocturia on several aspects of health-related quality of life and morbidity. Age-associated physiological, structural, hormonal, and histological changes play an important role in the increasing incidence of nocturia in elderly individuals. Besides urologic conditions, nocturia may also be the initial presenting symptom in chronic kidney disease, as well as other systemic diseases. Therefore, it is essential to understand the complex pathophysiology among these factors to establish a precise diagnosis and appropriate management strategies. This review will provide an overview of the effect of aging on the kidneys and urinary system, the pathophysiology, clinical assessment, and treatment strategies of nocturia, and its effect on health-related quality of life.
ESRD can affect the pharmacokinetic disposition of drugs subject to nonrenal clearance. Cytochrome P450 (CYP) enzymes, including CYP3A, and multiple intestinal and hepatic drug transporters are thought to mediate this process, but the extent to which kidney disease alters the function of these proteins in humans is unknown. We used midazolam and fexofenadine to assess CYP3A (intestinal and hepatic) and drug transport, respectively, in patients with ESRD and healthy control subjects. We evaluated the effect of uremia on CYP3A and transporter expression in vitro by incubating normal rat hepatocytes and enterocytes with serum drawn from study participants. ESRD dramatically reduced nonrenal transporter function, evidenced by a 63% decrease in clearance (P < 0.001) and a 2.8-fold increase in area under the plasma concentration-time curve for fexofenadine (P = 0.002), compared with control subjects. We did not observe significant differences in midazolam or 1-hydroxymidazolam clearance or area under the curve after oral administration, suggesting that CYP3A function is not changed by ESRD. Changes in hepatocyte and enterocyte protein expression in the presence of uremic serum were consistent with in vivo results. These findings demonstrate a mechanism for altered drug disposition in kidney disease, which may partially account for the high rates of drug toxicity in this population.
Kidney disease alters the pharmacokinetic disposition of many medications, requiring dosage adjustment to maintain therapeutic serum concentrations. The Cockcroft-Gault (CG) equation is used for pharmacokinetic studies and drug dosage adjustments, but the Modification of Diet in Renal Disease (MDRD) Study equation is more accurate and more often reported by clinical laboratories than the CG equation.
The EXtracorporeal TReatments In Poisoning (EXTRIP) workgroup was formed to provide recommendations on the use of extracorporeal treatment (ECTR) in poisoning. To test and validate its methods, the workgroup reviewed data for thallium (Tl).
Extracorporeal treatments (ECTRs), such as hemodialysis and hemoperfusion, are used in poisoning despite a lack of controlled human trials demonstrating efficacy. To provide uniform recommendations, the EXTRIP group was formed as an international collaboration among recognized experts from nephrology, clinical toxicology, critical care, or pharmacology and supported by over 30 professional societies. For every poison, the clinical benefit of ECTR is weighed against associated complications, alternative therapies, and costs. Rigorous methodology, using the AGREE instrument, was developed and ratified. Methods rely on evidence appraisal and, in the absence of robust studies, on a thorough and transparent process of consensus statements. Twenty-four poisons were chosen according to their frequency, available evidence, and relevance. A systematic literature search was performed in order to retrieve all original publications regardless of language. Data were extracted on a standardized instrument. Quality of the evidence was assessed by GRADE as: High = A, Moderate = B, Low = C, Very Low = D. For every poison, dialyzability was assessed and clinical effect of ECTR summarized. All pertinent documents were submitted to the workgroup with a list of statements for vote (general statement, indications, timing, ECTR choice). A modified Delphi method with two voting rounds was used, between which deliberation was required. Each statement was voted on a Likert scale (1-9) to establish the strength of recommendation. This approach will permit the production of the first important practice guidelines on this topic.
Patients with chronic kidney disease (CKD) represent 13% of the American population. CKD has been shown to significantly alter drug disposition of nonrenally eliminated drugs. Indeed, modifications in the expression and function of intestinal and hepatic drug metabolism enzymes and uptake and efflux transporters have been reported. Uremic toxins, inflammatory cytokines, and parathyroid hormone have been implicated as causes. These changes can have an important clinical impact on drug disposition and lead to unintended toxicity if they are administered without dose adjustment in patients with impaired kidney function. This review summarizes recent preclinical and clinical studies and presents the current understanding of the effect of CKD on drug absorption, distribution, metabolism, and excretion.
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