Albert W. Dreisbach

The Effect of Chronic Renal Failure on Drug Metabolism and Transport

Background: Chronic renal failure (CRF) has been shown to significantly reduce the nonrenal clearance and alter bioavailability of drugs predominantly metabolized by the liver and intestine. Objectives: The purpose of this article is to review all significant animal and clinical studies dealing with the effect of CRF on drug metabolism and transport. Methods: A search of the National Library of Medicine PubMed was done with terms such as chronic renal failure, cytochrome P450 [CYP], liver metabolism, efflux drug transport and uptake transport, including relevant articles back to 1969. Results: Animal studies in CRF have shown a significant downregulation (40 – 85%) of hepatic and intestinal CYP metabolism. High levels of parathyroid hormone, cytokines and uremic toxins have been shown to reduce CYP activity. Phase II reactions and drug transporters such as P-glycoprotein and organic anion transporting polypeptide are also affected. Conclusion: CRF alters intestinal, renal and hepatic drug metabolism and transport producing a clinically significant impact on drug disposition and increasing the risk for adverse drug reactions.

The Influence of Chronic Renal Failure on Drug Metabolism and Transport

Chronic renal failure (CRF) has been shown, in animal models and clinical studies, to significantly reduce nonrenal clearance and to alter the bioavailability of predominantly metabolized drugs. Phase II reactions and drug transporters such as P‐glycoprotein (P‐gp) and organic anion transporting polypeptide (OATP) are also affected. High levels of parathyroid hormone (PTH), cytokines, and uremic toxins are implicated in some of these effects, which have a clinically significant impact on drug disposition and increase the risk of adverse drug reaction.

Antibiotic Dosing in Slow Extended Daily Dialysis

Slow extended daily dialysis (SLEDD) is the newest form of dialysis that is being used increasingly to replace continuous venovenous hemodialysis (CVVHD) for critically ill patients; it is less expensive to administer and has similar safety for patients who are prone to hemodynamic instability. Unfortunately, there are limited data regarding the appropriate dosing of antimicrobial agents for patients undergoing SLEDD. Furthermore, many nonnephrologists are not familiar with the differences between SLEDD, other continuous renal replacement therapies--for example, CVVHD--and routine hemodialysis. Thus, there is potential for inaccurate and, at worst, inadequate dosing of critical antimicrobial agents for this patient population. We review the available pharmacokinetic data on SLEDD and give preliminary recommendations for how to approach dosing in this situation.

Cigarette Smoking and Chronic Kidney Disease in African Americans in the Jackson Heart Study

Background Controversy exists regarding the association of cigarette smoking and renal dysfunction, particularly among African Americans, who are disproportionately affected by chronic kidney disease; therefore, we evaluated the relationship between cigarette smoking and rapid renal function (RRF) decline in the Jackson Heart Study. Methods and Results Rates of RRF decline were determined among 3648 African American participants enrolled at baseline in the Jackson Heart Study. RRF decline was defined as an absolute decline of estimated glomerular filtration rate of 30% from visit 1 to visit 3. There were 422 current, 659 past, and 2567 never smokers identified at visit 1. After adjustment for age, sex, body mass index, diabetes, hypertension, cholesterol, physical activity, education, alcohol consumption, and prevalent cardiovascular disease, current smokers demonstrated a significantly higher incidence of RRF decline compared with never smokers (incidence rate ratio 1.83, 95% CI 1.31–2.56). Current smokers using 1 to 19 and ≥20 cigarettes daily had an increased incidence of RRF decline (incidence rate ratios of 1.75 [95% CI 1.18–2.59] and 1.97 [95% CI 1.17–3.31], respectively). There was a significant, progressive reduction in estimated glomerular filtration rate from visit 1 to visit 3 in current and past smokers compared with never smokers. Finally, current smokers had a 1.38‐fold increase in C‐reactive protein compared with never smokers, after controlling for covariates. Conclusions In a large African American cohort, current cigarette smoking was independently associated with RRF decline in a dose‐dependent manner. There was also evidence of increased inflammation (C‐reactive protein) in current smokers, suggesting a potential mechanism for these relationships.

Association between 24-hour blood pressure variability and chronic kidney disease: a cross-sectional analysis of African Americans participating in the Jackson heart study

BackgroundStudies suggest 24-h blood pressure (BP) variability has prognostic value for cardiovascular disease. Several factors associated with high 24-h BP variability are also common among individuals with chronic kidney disease (CKD). We hypothesized 24-h BP variability would be higher for individuals with versus without CKD.MethodsWe analyzed 1,022 Jackson Heart Study participants who underwent ambulatory blood pressure monitoring (ABPM). Twenty-four hour BP variability was defined by two metrics: day-night standard deviation (SDdn) and average real variability (ARV). CKD was defined as ACR ≥30xa0mg/g or eGFR <60xa0mL/min/1.73xa0m2.ResultsThe mean SDdn of systolic BP (SBP) was 10.2u2009±u20090.2 and 9.1u2009±u20090.1xa0mmHg and the mean ARV of SBP was 9.2u2009±u20090.2 and 8.6u2009±u20090.1xa0mmHg for those with and without CKD, respectively (each pu2009≤u20090.001). After adjustment for age and sex, SDdn and ARV were 0.98xa0mmHg (95xa0% CI 0.59, 1.38) and 0.52xa0mmHg (95xa0% CI 0.18, 0.86), respectively, higher among participants with versus without CKD. These differences were not statistically significant after further multivariable adjustment including 24-h mean SBP. Older age, and higher total cholesterol and 24-h mean SBP were associated with higher SDdn and ARV of SBP among participants with CKD. Mean SDdn and ARV of diastolic BP (DBP) were higher for participants with versus without CKD but these associations were not present after multivariable adjustment.ConclusionData from the current study suggest that CKD is associated with higher 24-h BP variability, but the association is primarily explained by higher mean BP among those with CKD.

Urinary CYP eicosanoid excretion correlates with glomerular filtration in African-Americans with chronic kidney disease.

Previous studies have indicated that cytochrome P450 (CYP) metabolites of arachidonic acid (AA), i.e., 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs), play an important role in the regulation of renal tubular and vascular function. The present study for the first time profiled HETEs and epoxygenase derived dihydroxyeicosatetraenoic acid diHETEs levels in spot urines and plasma in 262 African American patients from the University of Mississippi Chronic Kidney Disease Clinic and 31 African American controls. Significant correlations in eGFR and urinary 20-HETE/creatinine and 19-HETE/creatinine levels were observed. The eGFR increased by 17.47 [p=0.001] and 60.68 [(p=0.005]ml/min/for each ng/mg increase in 20-HETE and 19-HETE levels, respectively. Similar significant positive associations were found between the other urinary eicosanoids and eGFR and also with 19-HETE/urine creatinine concentration and proteinuria. We found that approximately 80% of plasma HETEs and 30% diHETEs were glucuronidated and the fractional excretion of 20-HETE was less than 1%. These results suggest that there is a significant hepatic source of urinary 20-HETE glucuronide and EETs with extensive renal biotransformation to metabolites which may play a role in the pathogenesis of CKD.

Drug Metabolism and Chronic Kidney Disease

CKD alters protein binding, volume of distribution, and elimination of drugs cleared by the kidneys. However, animal and clinical data demonstrate changes in the non-renal clearance and bioavailability of drugs eliminated by hepatic and intestinal transport and metabolism in CKD. Cytochrome P450 (phase I reactions) and phase II reactions, such as glucuronidation and acetylation, are for the most part down-regulated in CKD. Efflux transporters, such as p-glycoprotein and multi-drug resistance protein, and uptake transporters, such as organic anion and cation transporters, are also altered. Metabolism of endogenous substrates, such as fatty acids, hormones and vitamin D, are also affected. High levels of parathyroid hormone (PTH), cytokines, and uremic toxins may play mechanistic roles. These effects have a clinically significant impact on drug disposition and increase the risk of adverse drug events.

Allelic Variants in Arhgef11 via the Rho-Rock Pathway Are Linked to Epithelial–Mesenchymal Transition and Contributes to Kidney Injury in the Dahl Salt-Sensitive Rat

Previously, genetic analyses identified that variants in Arhgef11 may influence kidney injury in the Dahl salt-sensitive (S) rat, a model of hypertensive chronic kidney disease. To understand the potential mechanism by which altered expression and/or protein differences in Arhgef11 could play a role in kidney injury, stably transduced Arhgef11 knockdown cell lines as well as primary cultures of proximal tubule cells were studied. Genetic knockdown of Arhgef11 in HEK293 and NRK resulted in reduced RhoA activity, decreased activation of Rho-ROCK pathway, and less stress fiber formation versus control, similar to what was observed by pharmacological inhibition (fasudil). Primary proximal tubule cells (PTC) cultured from the S exhibited increased expression of Arhgef11, increased RhoA activity, and up regulation of Rho-ROCK signaling compared to control (small congenic). The cells were also more prone (versus control) to TGFβ-1 induced epithelial-mesenchymal transition (EMT), a hallmark feature of the development of renal interstitial fibrosis, and characterized by development of spindle shape morphology, gene expression changes in EMT markers (Col1a3, Mmp9, Bmp7, and Ocln) and increased expression of N-Cadherin and Vimentin. S derived PTC demonstrated a decreased ability to uptake FITC-albumin compared to the small congenic in vitro, which was confirmed by assessment of albumin re-uptake in vivo by infusion of FITC-albumin and immunofluorescence imaging. In summary, these studies suggest that genetic variants in the S form of Arhgef11 via increased expression and/or protein activity play a role in promoting kidney injury in the S rat through changes in cell morphology (Rho-Rock and/or EMT) that impact the function of tubule cells.

Recurring extracorporeal circuit clotting during continuous renal replacement therapy in fungal sepsis: successful treatment with argatroban.

The relative effectiveness of anticoagulation strategies during continuous renal replacement therapy (CRRT) may vary according to the clinical circumstances. In this study, the case of a 46-year-old man who developed fungal mediastinitis with the pathogen Scedosporium prolificans after coronary bypass surgery is reported. Numerous debridements and multiple antifungal agents were not effective in this patient. Miltefosine, a non-Food and Drug Administration-approved agent, was started after institutional review board request and approval. CRRT was initiated with regional citrate anticoagulation (RCA) for clinical sepsis with acute kidney injury. Subsequently, crescendo clotting of the extracorporeal circuit (ECC) occurred. Multiple interventions, including escalating RCA, adding increasing heparin to RCA and exchanging the dialysis catheter, were not effective. Argatroban anticoagulation was started without further ECC clotting, and the patient recovered from both acute kidney injury and septic shock, despite continued miltefosine administration. Sepsis may contribute to recurrent ECC clotting. Argatroban, a direct thrombin inhibitor, had a disproportionate effectiveness to maintain ECC patency in this patient.