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ACUTE KIDNEY INJURY IS ASSOCIATED WITH THE USE OF INTRAVENOUS VANCOMYCIN IN HOSPITALIZED PATIENTS Neville R. Dossabhoy 1, 2, Rebecca Gascoyne2, Daniel Brignac2, and Karina Sulaiman1, 2

1. Nephrology Section, LSUHSC, Shreveport, LA, USA 2. Department of Medicine, VA Medical Center, Shreveport, LA, USA Background: Vancomycin has largely ceased to be considered a major cause of drug-related Acute Kidney Injury (AKI) in the years since its reformulation. However, recent reports have suggested that increased levels of vancomycin, especially in combination with aminoglycoside use, may be associated with an increase in creatinine. Purpose: To determine if an association exists between vancomycin use and AKI; and correlate serum vancomycin levels with plasma creatinine levels in hospitalized patients receiving vancomycin. Methods: We expanded our previous retrospective chart review, to now include 768 hospitalized patients who had received vancomycin over a 2-year period. Those who had end stage renal disease, incomplete data or had received less than two doses of vancomycin were excluded (166). Data collected included patient demographics, comorbid conditions, and serial vancomycin levels and creatinine values. Data were analyzed using Student's t-test to compare mean maximum vancomycin trough levels in AKI vs. non-AKI patients, and linear regression analysis to elucidate dose-dependent relationship between maximum vancomycin trough levels and creatinine and change in creatinine. Results: Our analysis included 602 patients for whom there were complete data, of whom 176 (29%) developed AKI as defined by an increase in creatinine by > 0.5mg/dL or by > 25% of baseline. The mean maximum vancomycin trough level in the patients who did not develop AKI was 13.2+5.9 mcg/mL, and that in the AKI group was 17.7+8.0 (p< 0.0001). Conclusion: AKI is associated with the use of intravenous vancomycin, especially at higher doses. Although dose-dependent toxicity could not be established, 29% of the patients developed AKI. Attention should be paid to drug levels, and the dose of vancomycin should be adjusted in a timely fashion in order to prevent AKI. Its use should be monitored closely.

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HEMOGLOBIN A1C AND 5-YEAR SURVIVAL IN 2,798 CHRONICPERITONEAL DIALYSIS PATIENTS WITH DIABETES MELLITUSUyen Duong, Rajnish Mehrotra, Csaba P Kovesdy, Jennie Jing, Mahesh Krishnan, Allen R Nissenson, Kamyar Kalantar-Zadeh. Harold Simmons Center, Harbor-UCLA, Torrance, CA; VA Salem; DaVita, El Segundo, CA.

Background: In chronic peritoneal dialysis (PD) pts, the association of hemoglobin A1c & mortality may be confounded by glucose loading in PD fluid, which may lead to worsened metabolic control in PD.

Methods: We examined a large cohort of all diabetic PD pts who underwent PD treatment for at least 45 days in any Legacy DaVita dialysis clinic over 5 yrs (7/2001-6/2006).

Results: We identified 2,798 diabetic PD pts who had A1c measures during their base calendar quarter; they were 57.4±13.0 yrs old and included 44% women, 20% Blacks & 16% Hispanics. A1c was categorized into 7 groups of <5%, >=10% and 1% increments in-between. A J-shaped trend with significant death hazard ratios (HR) was noted. Taking A1c 5-5.9% as reference, A1c>=10% had a 5-yr death HR (and 95% confidence interval [CI]) of 1.13 (0.90-1.43), 1.43 (1.13-1.81) and 1.43 (1.12-1.82) repre-senting the unadjusted, case-mix and additional malnutrition-inflammation complex syndrome (MICS) adjusted respectively (see figure).

Hemoglobin A1c (%)<5 5 to <6 6 to <7 7 to <8 8 to <9 9 to <10 =>10

C

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

UnadjustedCase-mix Case-mix+MICS

Conclusions: In this large national cohort of diabetic PD patients, a hemoglobin A1c>10% appears associated with relative risk of death of 1.43 compared to those pts with a A1c of 5-6%. Clinical trials to examine the benefit of tighter glycemic control in PD ps are indicated

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COST ASSESSMENT OF PATIENTS WITH EXCESSIVE HOSPITAL STAYS IN AN INNER CITY HOSPITALEgbosimba, Florence C. Rutgers University, NJ, Hannah Nelson, Praneetha Puskuri, Anjali Acharya, Jacobi Medical Center, Bronx, NY, USA. The compound annual growth rate in the number of ESRD dialysis patients has been 3% - 4%. Dialysis revenue is related to payor mix and patient mix. It is impossible to choose payor mix especially in an inner city, safety net hospital system like ours. 25% of patients presenting to our hospital in need of dialysis are uninsured. We rely on hemodialysis units outside our facility for chronic dialysis as we are solely an in patient dialysis facility. This results in hospital stay until completion of insurance application and approval. A cost assessment of this problem has been done below using a typical hypothetical patient who under these circumstances has a stay of 45 days. Average (avg) cost to community hospitals /patient / day $1,468 Total Stay of patient above 45 days Cost of stay of first 20 days (D) (1,468 x20) $29,384 Cost of stay of remaining 25 D ($734/D, ½ full cost) $18,350 Total cost of stay for patient (29,384 +18350) $47,734 Avg length of stay of insured dialysis patients at Jacobi 15 days Potential number of admissions to same bed in 45 days 3 patients

(45/15) Avg payment (Medicare, 2008)/ dialysis patient (JMC) $22,292 Opportunity Cost of other dialysis admissions ($22,292 x 3)

$66,876

Potential Revenue Lost (due to long admission of patient)

$22,292

Number of such patients at any given time 7 The potential revenue lost is $156,044 Opportunity Cost of diagnosis other than ESRD, may be much greater because the average length-of-stay for such patients is only 6 days. Safety net hospitals bear an inordinate financial burden to provide life sustaining therapy. This is only expected to worsen with the new proposed payment system. Strategies like providing peritoneal dialysis to such patients needs to be emphasized and looked into.

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MECHANISMS OF EPITHELIAL CELLS INJURY IN DIABETES: ROLE OF SIGNALING PATHWAYS MEDIATED BY NADPH OXIDASES Assaad Antoine EID*#, Bridget Fagg*, Yves Gorin*, Karen Block*, Jeffrey Barnes* and Hanna Abboud*. *From the department of Medicine/Nephrology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. #A.A. Eid, Ph.D., postdoctoral fellow at UTHSCSA, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. Supported by a postdoctoral fellowship from the NKF. Glomerular epithelial cells or podocytes play a critical role in maintaining the structure and function of the glomerular filtration barrier. In diabetes, podocyte injury contributes to increased urinary albumin excretion (albuminuria), one of the most important prognostic risk factors for kidney disease progression. The aim of this project is to understand the mechanisms by which diabetes causes podocyte injury. We have recently shown (EID et al. Diabetes 2009) that high glucose (HG)/hyperglucemia-induced podocyte loss, together with increased generation of reactive oxygen species (ROS) derived from the sequential activation of 2 family of oxidants-generating enzymes, cytochrome P450 and NADPH oxidases. Inhibition of selected cytochrome P450 isoforms (CYP 4A) prevented podocyte injury and reduced proteinuria in OVE26 mice, a mice model of type 1 diabetes. The mechanism(s) by which glucose activates NADPH oxidases and result in podocyte injury and proteinuria are not known. We are currently investigating the role of the energy sensor AMP-activated protein kinase (AMPK). Our data indicate that exposure of mouse podocytes to HG inactivates AMPK. This is associated with increase in Nox1 and Nox4 mRNA and protein expression and activation of NAD(P)H dependent superoxide anion generation. HG also results in increased expression of p53 and apoptosis. The effects of HG on NADPH oxidase activity, Nox mRNAs and protein expression and apoptosis are blocked by AICAR, an AMPK activator. Nox1 and Nox4 siRNAs mimic the effect of AICAR and significantly reduce p53 expression and podocyte apoptosis. In isolated glomeruli of OVE26 mice, there is an inactivation of AMPK accompanied by an increase in the expression and activity of NOX oxidases and upregulation of p53. These changes are reversed by treatment of OVE26 mice with AICAR. Moreover, Treatment of OVE26 mice with AICAR decreased podocytes loss and ameliorates albuminuria. These data indicate a critical role of AMPK in the regulation of NADPH oxidases and podocyte apoptosis. Our work may identify novel cellular mechanism of kidney injury and set the stage to explore new therapeutic approaches to treat diabetic nephropathy.

NKF 2010 Spring Clinical Meetings AbstractsA52