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Drug-dose modification in chronic kidney disease (CKD) utilizes glomerular filtration rate (GFR) with the implicit assumption that multiple renal excretory processes decline in parallel as CKD progresses. We compiled published pharmacokinetic data to evaluate if GFR predicts renal clearance changes as a function of CKD severity. For each drug, we calculated ratio of renal clearance to filtration clearance (Rnf). Of 21 drugs with Rnf >0.74 in subjects with GFR >90 mL/min (implying filtration and secretion), 13 displayed significant change in Rnf vs. GFR (slope of linear regression statistically different from zero), which indicates failure of GFR to predict changes in secretory clearance. The dependence was positive ( n = 3; group A) or negative ( n = 10; group B). Eight drugs showed no correlation (group C). Investigated drugs were small molecules, mostly hydrophilic, and ionizable, with some characterized as renal transporter substrates. In conclusion, dosing adjustments in CKD require refinement; in addition to GFR, biomarkers of tubular function are needed for secreted drugs. [ABSTRACT FROM AUTHOR]

Background: In chronic kidney disease (CKD), inadequate nutritional intake, inflammation, and increased oxidative stress have been the major contributing factors in malnutrition pathogenesis. However, there is still a paucity of evidence assessing the magnitude of the effect of tooth loss on malnutrition in CKD populations. The authors hypothesize that among patients with CKD, tooth loss may affect nutritional status, using the National Health and Nutrition Examination Survey 1988 to 1994 (NHANES III). Methods: Glomerular filtration rate (GFR) was estimated based on cystatin C levels using the relevant equation. Grinary albumin-to-creatinine ratio (albuminuria) was calculated in milligrams per gram with a cutoff point of 30 mg/g. CKD was defined based on estimated GFR <60 mL/minute/ 1,73m² and albuminuria ≥30 mg/g. The cutoff point for serum albumin was set at 3.7 g/dL. Tooth loss categories were based on the number of missing and replaced teeth. Results: A total of 2,749 patients was included and stratified based on their oral health status. There was a statistically significant correlation between tooth loss and the proportion of patients with low protein and caloric intake (P = 0.02 and 0.01, respectively). Serum albumin reached a frequency peak in the fully edentulous group without dentures (group 4, 19.2%). In the same group, individuals had lower protein (30.1%) and caloric intake (30.2%) (P - 0.01 and 0.02, respectively). Furthermore, logistic regression analysis confirmed the significant role of tooth loss on serum albumin and protein and energy intake in this population even after adjusting for confounding variables. Conclusion: Tooth loss independently predicts low energy and protein intake, as well as serum albumin levels, biomarkers of malnutrition in CKD. [ABSTRACT FROM AUTHOR]

Erythropoietin has emerged as a potential therapy for the treatment of ischemic tissue injury. In erythroid cells, the JAK2/Y343/STAT5 signaling axis has been shown to be necessary for stress but not steady-state erythropoiesis. The requirement for STAT5 activation in erythropoietin-mediated protection from ischemic injury has not been well-studied. To answer this question, we induced reproducible necrotic ischemic injury in primary mouse renal tubular epithelial cells (RTEC) in vitro. Using RTEC from erythropoietin receptor mutant mice with differential STAT5 signaling capabilities, we demonstrated first, that EPO administration either before or during injury significantly protects against mild-moderate but not severe necrotic cell death; and second, the JAK2/Y343/STAT5 signaling axis is required for protection against ischemic injury in primary mouse RTEC. In addition, we identified Pim-3, a prosurvival STAT5 target gene, as responsive to EPO in the noninjured kidney both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Context: The arteriovenous fistula is the preferred type of vascular access for hemodialysis because of lower thrombosis and infection rates and lower health care expenditures compared with synthetic grafts or central venous catheters. Early failure of fistulas due to thrombosis or inadequate maturation is a barrier to increasing the prevalence of fistulas among patients treated with hemodialysis. Small, inconclusive trials have suggested that antiplatelet agents may reduce thrombosis of new fistulas.Objective: To determine whether clopidogrel reduces early failure of hemodialysis fistulas.Design, Setting, and Participants: Randomized, double-blind, placebo-controlled trial conducted at 9 US centers composed of academic and community nephrology practices in 2003-2007. Eight hundred seventy-seven participants with end-stage renal disease or advanced chronic kidney disease were followed up until 150 to 180 days after fistula creation or 30 days after initiation of dialysis, whichever occurred later.Intervention: Participants were randomly assigned to receive clopidogrel (300-mg loading dose followed by daily dose of 75 mg; n = 441) or placebo (n = 436) for 6 weeks starting within 1 day after fistula creation.Main Outcome Measures: The primary outcome was fistula thrombosis, determined by physical examination at 6 weeks. The secondary outcome was failure of the fistula to become suitable for dialysis. Suitability was defined as use of the fistula at a dialysis machine blood pump rate of 300 mL/min or more during 8 of 12 dialysis sessions.Results: Enrollment was stopped after 877 participants were randomized based on a stopping rule for intervention efficacy. Fistula thrombosis occurred in 53 (12.2%) participants assigned to clopidogrel compared with 84 (19.5%) participants assigned to placebo (relative risk, 0.63; 95% confidence interval, 0.46-0.97; P = .018). Failure to attain suitability for dialysis did not differ between the clopidogrel and placebo groups (61.8% vs 59.5%, respectively; relative risk, 1.05; 95% confidence interval, 0.94-1.17; P = .40).Conclusion: Clopidogrel reduces the frequency of early thrombosis of new arteriovenous fistulas but does not increase the proportion of fistulas that become suitable for dialysis. Trial Registration clinicaltrials.gov Identifier: NCT00067119. [ABSTRACT FROM AUTHOR]

A 67-year-old woman is admitted to the surgical service with a high fever, a painful and distended abdomen, jaundice, and almost complete anuria. A urinalysis revealed dark red-brown urine notable for albuminuria, erythrocytes, leukocytes, and casts. The patient was treated with antibiotics, but continued to have oligoanuria. On the eighth day of hospitalization, the following laboratory tests were obtained: serum potassium, 13.7 mEq/L; BUN, 396 mg/dl. At this time the patient was noted to be encephalopathic with deteriorating clinical condition. Renal replacement therapy was initiated. The characteristics of the initial dialysis treatment are described in Table 1. After the initial dialysis treatment, the patient went on to become nonoliguric, followed by gradual recovery of urea clearance. She survived her acute illness, left the hospital, and at 7 months posthospitalization was doing quite well. [ABSTRACT FROM AUTHOR]

Examines predictive measures of vascular access thrombosis. Manifestation of early thrombosis due to the failure on the maturation of arteriovenous fistula; Investigation on the prevention of thrombosis and prolonging of vascular access life; Measurement of access flow rate by isotope infusion and thermal dilution.

Background: Altered drug metabolism has been demonstrated in patients with end-stage renal disease (ESRD). The aim of this study was to evaluate the acute effect of hemodialysis (HD) on CYP3A4 activity.Methods: 12 ESRD patients undergoing chronic HD and 12 matched control subjects participated. Hepatic CYP3A4 activity was assessed using the 14C-erythromycin breath test (EBT). The EBT was administered two hours pre- and repeated two hours post-hemodialysis and once in controls. Breath samples were collected at baseline and various time points up to 120 min after dosing, and then analyzed for 14C using scintillation counting. The traditional 20-min flux measure and the novel 1/Tmax parameter were determined.Results: The flux of 14CO2 at the 20-minute time point, expressed as the % of the administered dose exhaled per hour, increased by 27% post-dialysis, from 2.34±0.8 to 2.98±1.04 (p<0.05). Pre- and post-HD values were similar to those observed in control subjects (2.70±0.59; p=NS). Pre- and post-HD 1/Tmax values approached but did not achieve a statistically significance difference (0.056±0.01 and 0.067±0.02, respectively, p=0.07). Pre-HD 1/Tmax was lower than control (0.064±0.01, p<0.05) and normalized after dialysis.Conclusions: These results suggest that hemodialysis acutely improves hepatic CYP3A4 activity and indicate that increased diligence is warranted when prescribing CYP3A substrates to ESRD patients.Clinical Pharmacology & Therapeutics (2005) 79, P23–P23; doi: 10.1016/j.clpt.2005.12.081 [ABSTRACT FROM AUTHOR]