[Show abstract][Hide abstract] ABSTRACT: Inaccurate determination of baseline kidney function can misclassify acute kidney injury (AKI) and affect the study of AKI-related outcomes. No consensus exists on how to optimally determine baseline kidney function when multiple preadmission creatinine measurements are available.
The accuracy of commonly used methods for estimating baseline serum creatinine was compared with that of a reference standard adjudicated by a panel of board-certified nephrologists in 379 patients with AKI or CKD admitted to a tertiary referral center.
Agreement between estimating methods and the reference standard was highest when using creatinine values measured 7-365 days before admission. During this interval, the intraclass correlation coefficient (ICC) for the mean outpatient serum creatinine level (0.91 [95% confidence interval (CI), 0.88-0.92]) was higher than the most recent outpatient (ICC, 0.84 [95% CI, 0.80-0.88]; P<0.001) and the nadir outpatient (ICC, 0.83 [95% CI, 0.76-0.87; P<0.001) serum creatinine. Using the final creatinine value from a prior inpatient admission increased the ICC of the most recent outpatient creatinine method (0.88 [95% CI, 0.85-0.91]). Performance of all methods declined or was unchanged when the time interval was broadened to 2 years or included serum creatinine measured within a week of admission.
The mean outpatient serum creatinine measured within a year of hospitalization most closely approximates nephrologist-adjudicated serum creatinine values.
Clinical Journal of the American Society of Nephrology 03/2012; 7(5):712-9. DOI:10.2215/CJN.10821011 · 4.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Interindividual variation in the ability of aspirin to inhibit platelet cyclooxygenase-1 (COX-1) could account for some on-treatment cardiovascular events. Here, we sought to determine whether there are clinical phenotypes that are associated with a suboptimal pharmacological effect of aspirin. In a prospective, 2-week study, we evaluated the effect of aspirin (81 mg) on platelet COX-1 in 135 patients with stable coronary artery disease by measuring serum thromboxane B(2) (sTxB(2)) as an indicator of inhibition of platelet COX-1. A nested randomized study compared enteric-coated with immediate-release formulations of aspirin. We found that sTxB(2) was systematically higher among the 83 patients with metabolic syndrome than among the 52 patients without (median: 4.0 versus 3.02 ng/mL; P=0.013). Twelve patients (14%) with metabolic syndrome, but none without metabolic syndrome, had sTxB(2) levels consistent with inadequate inhibition of COX (sTxB(2) ≥13 ng/mL). In linear regression models, metabolic syndrome (but none of its individual components) significantly associated with higher levels of log-transformed sTxB(2) (P=0.006). Higher levels of sTxB(2) associated with greater residual platelet function measured by aggregometry-based methods. Among the randomized subset, sTxB(2) levels were systematically higher among patients receiving enteric-coated aspirin. Last, urinary 11-dehydro thromboxane B(2) did not correlate with sTxB(2), suggesting that the former should not be used to quantitate aspirin's pharmacological effect on platelets. In conclusion, metabolic syndrome, which places patients at high risk for thrombotic cardiovascular events, strongly and uniquely associates with less effective inhibition of platelet COX-1 by aspirin.
[Show abstract][Hide abstract] ABSTRACT: Frequently, prescribers fail to account for changing kidney function when prescribing medications. We evaluated the use of a computerized provider order entry intervention to improve medication management during acute kidney injury.
Quality improvement report with time series analyses.
1,598 adult inpatients with a minimum 0.5-mg/dL increase in serum creatinine level over 48 hours after an order for at least one of 122 nephrotoxic or renally cleared medications.
Passive noninteractive warnings about increasing serum creatinine level appeared within the computerized provider order entry interface and on printed rounding reports. For contraindicated or high-toxicity medications that should be avoided or adjusted, an interruptive alert within the system asked providers to modify or discontinue the targeted orders, mark the current dosing as correct and to remain unchanged, or defer the alert to reappear in the next session.
Intervention effect on drug modification or discontinuation, time to modification or discontinuation, and provider interactions with alerts.
The modification or discontinuation rate per 100 events for medications included in the interruptive alert within 24 hours of increasing creatinine level improved from 35.2 preintervention to 52.6 postintervention (P < 0.001); orders were modified or discontinued more quickly (P < 0.001). During the postintervention period, providers initially deferred 78.1% of interruptive alerts, although 54% of these eventually were modified or discontinued before patient death, discharge, or transfer. The response to passive alerts about medications requiring review did not significantly change compared with baseline.
Single tertiary-care academic medical center; provider actions were not independently adjudicated for appropriateness.
A computerized provider order entry-based alerting system to support medication management after acute kidney injury significantly increased the rate and timeliness of modification or discontinuation of targeted medications.
American Journal of Kidney Diseases 11/2010; 56(5):832-41. DOI:10.1053/j.ajkd.2010.05.024 · 5.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Platelet hyperreactivity associates with cardiovascular events in humans. Studies in mice and humans suggest that prostaglandin E2 (PGE2) regulates platelet activation. In mice, activation of the PGE2 receptor subtype 3 (EP3) promotes thrombosis, but the significance of EP3 in humans is less well understood.
To characterize the regulation of thromboxane-dependent human platelet activation by PGE2.
Platelets collected from nineteen healthy adults were studied using an agonist of the thromboxane receptor (U46,619), PGE2, and selective agonists and/or antagonists of the EP receptor subtypes. Platelet activation was assayed by (1) optical aggregometry, (2) measurement of dense granule release, and (3) single-platelet counting.
Healthy volunteers demonstrated significant interindividual variation in platelet response to PGE2. PGE2 completely inhibited U46,619-induced platelet aggregation and ATP release in 26% of subjects; the remaining 74% had partial or no response to PGE2. Antagonism of EP4 abolished the inhibitory effect of PGE2. In all volunteers, a selective EP2 agonist inhibited U46,619-induced aggregation. Furthermore, the selective EP3 antagonist DG-041 converted all PGE2 nonresponders to full responders.
There is significant interindividual variation of platelet response to PGE2 in humans. The balance between EP2, EP3, and EP4 activation determines its net effect. PGE2 can prevent thromboxane-induced platelet aggregation in an EP4-dependent manner. EP3 antagonism converts platelets of nonresponders to a PGE2-responsive phenotype. These data suggest that therapeutic targeting of EP pathways may have cardiovascular benefit by decreasing platelet reactivity.
Thrombosis Research 07/2010; 126(1):e23-9. DOI:10.1016/j.thromres.2010.04.003 · 2.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Valacyclovir, the L-valyl ester prodrug of acyclovir (ACV), is widely prescribed to treat infections caused by varicella-zoster virus or herpes simplex virus. Rarely, treatment is complicated by reversible neuropsychiatric symptoms. By mechanisms not fully understood, this occurs more frequently in the setting of renal impairment. We characterized the steady-state pharmacokinetics of ACV and its metabolites 9-[(carboxymethoxy)methyl]guanine (CMMG) and 8-hydroxy-acyclovir (8-OH-ACV) in cerebrospinal fluid (CSF) and the systemic circulation. We administered multiple doses of high-dose valacyclovir to 6 subjects with normal renal function and 3 subjects with chronic renal impairment (creatinine clearance [CrCl], approximately 15 to 30 ml/min). Dosages were 2,000 mg every 6 h and 1,500 mg every 12 h, respectively. Indwelling intrathecal catheters allowed serial CSF sampling throughout the dosing interval. The average steady-state concentrations of acyclovir, CMMG, and 8-OH-ACV were greater in both the systemic circulation and the CSF among subjects with impaired renal function than among subjects with normal renal function. However, the CSF penetration of each analyte, reflected by the CSF-to-plasma area under the concentration-time curve over the 6- or 12-h dosing interval (AUC(tau)) ratio, did not differ based on renal function. Renal impairment does not alter the propensity for ACV or its metabolites to distribute to the CSF, but the higher concentrations in the systemic circulation, as a result of reduced elimination, are associated with proportionally higher concentrations in CSF.
[Show abstract][Hide abstract] ABSTRACT: Animal models of acute renal injury suggest that the epidermal growth factor receptor (EGFR) axis may have a beneficial role in the recovery from acute renal injury, but recent reports describe detrimental effects of EGFR activation in chronic renal injury. Expression of the EGFR ligand heparin-binding EGF-like growth factor (HB-EGF) increases following renal injury, but the effects of this sustained upregulation have not been well studied. Here, stable overexpression of soluble HB-EGF (sHB-EGF) in mouse inner medullary collecting duct (IMCD) cells led to marked phenotypic changes: sHB-EGF-expressing cells demonstrated a fibroblast-like morphology, did not form epithelial sheets, exhibited cytoplasmic projections, decreased expression of epithelial markers, and increased expression of fibroblast-specific protein-1. They also demonstrated anchorage-independent growth and formed tumors when injected subcutaneously into nude mice. Quantitative RT-PCR and a luciferase reporter assay suggested that sHB-EGF repressed transcription of E-cadherin, and a concomitant TGF-beta-independent upregulation of the E-cadherin repressor Snail-2 was observed. Stable downregulation of Snail-2 in sHB-EGF-overexpressing cells restored epithelial characteristics (E-cadherin and cytokeratin expression) but did not alter their anchorage-independent growth. In summary, sustained exposure to sHB-EGF induces epithelial-to-mesenchymal transition of IMCD cells, in part by upregulating the E-cadherin transcriptional repressor Snail-2.
American journal of physiology. Renal physiology 03/2009; 296(5):F957-65. DOI:10.1152/ajprenal.90490.2008 · 3.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dopamine is a major regulator of proximal tubule salt reabsorption and is a modulator of renin release. Dopamine has been reported to stimulate renin release in vitro through activation of D1-like receptors. However, previous studies investigating dopamine regulation of renin release in vivo have provided contradictory results, indicating stimulation, inhibition, or no effect. We have reported previously that macula densa cyclooxygenase-2 (COX-2) is suppressed by dopamine. Because macula densa COX-2 stimulates renal renin expression, our current studies investigated dopamine regulation of renal renin release and synthesis in vivo. Acute treatment with a D1-like receptor agonist, fenoldopam, significantly inhibited renin release, as did acute inhibition of proximal tubule salt reabsorption with acetazolamide. In catechol-O-methyl transferase knockout (COMT(-/-)) mice, which have increased kidney dopamine levels because of deletion of the major intrarenal dopamine metabolizing enzyme, there was attenuation in response to a low-salt diet of the increases of renal cortical COX-2 and renin expression and renin release. A high-salt diet led to significant decreases in renal renin expression but much less significant decreases in COMT(-/-) mice than wild type mice, resulting in higher renal renin expression in COMT(-/-) mice. In high salt-treated wild-type mice or COX-2 knockout mice on a normal salt diet, fenoldopam stimulated renal renin expression. These results suggest that dopamine predominantly inhibits renal renin expression and release by inhibiting macula densa COX-2, but suppression of renal cortical COX-2 activity reveals a contrasting effect of dopamine to stimulate renal renin expression through activation of D1-like receptors.
[Show abstract][Hide abstract] ABSTRACT: It has been estimated that approximately 11% of the US adult population has chronic kidney disease (CKD), and it has been demonstrated that the prevalence of hypertension rises significantly as renal function declines. Even mild CKD significantly increases mortality risk, and cardiovascular disease remains the main cause of death among these patients. Although CKD patients have generally been excluded from trials testing the effect of lowering blood pressure on cardiovascular outcomes, guidelines suggest lowering blood pressure in hopes of reducing cardiovascular mortality and slowing the progression of renal disease. The preferred antihypertensive agents among these patients are drugs that block the renin-angiotensin system. In most hypertensive CKD patients, however, multiple agents are necessary to reach blood pressure targets. In general, diuretics and calcium channel blockers are added subsequently as adjunctive therapy. Hopefully, with increased recognition of the unique aspects of treating hypertension in this population, end-stage renal disease and cardiovascular morbidity and mortality will be delayed or avoided in the millions of patients with CKD.
Current Hypertension Reports 01/2005; 6(6):462-8. DOI:10.1007/s11906-004-0042-4 · 3.44 Impact Factor