- Email: [email protected]
42: Activation of Proximal Tubule Sphingosine 1-Phosphate Receptor 1 Protects Kidneys From Ischemia Reperfusion Injury Independent of Lymphocytes
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41 RECENT ERYTHROPOIESIS STIMULATING AGENT (ESA) UTILIZATION AND COSTS IN MEDICARE PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD) Fotios Kokkotos1, Robert A. Bailey2, Matthew Kerr1, Sherlynn Shen1, Mekre Senbetta2, R. Scott McKenzie2 1 Trinity Partners, LLC, Waltham, MA, USA; 2Centocor Ortho Biotech Services, LLC, Horsham, PA, USA The objective of this analysis was to evaluate recent epoetin alfa (EPO) and darbepoetin alfa (DARB) drug utilization in Medicare patients with CKD not on dialysis treated in the outpatient setting. An analysis of medical claims using the Medicare 100% Institutional Database was performed to evaluate EPO and DARB use from 20052007. Patients included had ≥1 CKD diagnosis, were ESA treatment naïve, and received ≥2 EPO or DARB doses during a treatment episode. Patients diagnosed with cancer, myelodysplastic syndrome, receiving chemotherapy, or treated with both agents were excluded. If a patient received dialysis, data were censored for the quarter prior to the 1st dialysis. A treatment episode was defined as the time from the 1st ESA dose to the last ESA dose. Patients with 2 consecutive ESA doses that were ≥1 quarter apart were excluded from the analysis. Mean cumulative ESA dose was used to calculate drug costs using April 2009 wholesale acquisition unit costs (EPO $14.44/1,000 units;DARB $5.064/mcg). The study population consisted of 18,767 EPO and 16,574 DARB treatment episodes between 2005Q2 and 2007Q4. Age group distributions and proportion of females were similar between groups. The EPO group had a lower mean (SD) Charlson Comorbidity Score [3.5(1.6) EPO vs. 3.6 (1.6) DARB, P<.001]. Mean (SD) treatment duration was 3.3 (2.4) quarters for EPO and 3.4 (2.4) quarters for DARB (P=.017). The mean (SD) cumulative dose was 312,000 (450,300) units for EPO and 1,170.5 (1,493.3) for DARB, resulting in a dose ratio of 267:1 (EPO units: DARB mcg). Based on cumulative ESA doses, drug cost was $1422 (32%) higher (P<.001) for DARB than for EPO. This study of Medicare CKD patients not on dialysis observed 32% higher drug costs for DARB vs. EPO and a dose ratio of 267:1.
42 ACTIVATION OF PROXIMAL TUBULE SPHINGOSINE 1-PHOSPHATE RECEPTOR 1 PROTECTS KIDNEYS FROM ISCHEMIA REPERFUSION INJURY INDEPENDENT OF LYMPHOCYTES Amandeep Bajwa*,§, Sang-Kyung Jo*,§,‡, Hong Ye*,§, Liping Huang*,§. Krishna R. Dondeti*,§, Diane L. Rosin†,§, Volker H. Haase¶, Timothy L. Macdonald**, Kevin R. Lynch†, and Mark D. Okusa*,§ Departments of Medicine *, Chemistry **, Pharmacology† and the Center for Immunity, Inflammation and Regenerative Medicine§, University of Virginia, Charlottesville, USA. Department of Medicine¶, Vanderbilt University Medical Center, Nashville, TN, USA. Sphingosine 1-phosphate (S1P) receptor agonists reduce kidney ischemia-reperfusion injury (IRI), an effect presumed to be mediated by S1P1 receptor (S1P1R)-induced lymphopenia. To test the hypothesis that S1P1R activation may mediate renal protection from IRI independent of lymphocytes, we investigated the effect of S1PR agonists on kidney IRI in Rag-1 KO mice, which lack T and B lymphocytes. Following IRI, less injury was observed in Rag-1 KO mice compared to WT mice as determined by plasma creatinine levels and histology. Administration of FTY720, or the selective S1P1R agonist, SEW2871, further reduced injury in Rag-1 KO mice as well as WT mice. In mouse proximal tubule cells grown in culture, lipopolysaccharide (LPS) or hypoxia/reoxygenation-induced apoptosis was significantly reduced by SEW2871 supporting a direct protective effect of S1P1R agonists on proximal tubule cells via MAP kinase and/or Akt pathways. To determine the role of proximal tubule S1P1Rs in vivo in reducing IRI we used PEPCK-CreS1P1fl/wt and PEPCKCreS1P1fl/fl mice that are deficient in proximal tubule S1P1Rs. PEPCKCreS1P1fl/wt and PEPCK-CreS1P1fl/fl mice had a significant rise in plasma creatinine after IRI to a level greater than control (PEPCK-Cre) mice. Furthermore, SEW2871 was not protective in the PEPCKCreS1P1fl/wt and PEPCK-CreS1P1fl/fl mice after IRI. These results suggest that endogenous S1P1Rs are necessary for stress-induced cell survival and S1P1R agonists mediate kidney tissue protection at least in part through a direct effect on proximal tubule S1P1Rs.
NKF 2010 Spring Clinical Meetings Abstracts
43 VALIDATION OF GDS-15 AS A SCREENING TOOL FOR DEPRESSION IN ELDERLY HEMODIALYSIS PATIENTS Rasheed A Balogun1, Faruk Turgut1, Seki A Balogun2, Suzanne Holroyd3 and Emaad M Abdel-Rahman1 1 Division of Nephrology, 2 Division of General Medicine, Geriatrics and Palliative Care, Department of Medicine and 3Department of Psychiatry and Neurobehavioral Science, University of Virginia Health System, Charlottesville, Virginia, USA. Depression is common and associated with increased morbidity and mortality in elderly (≥65yrs) hemodialysis (HD) patients. The Beck’s Depression inventory (BDI) and the Geriatric Depression scale (GDS) have been used in different cohorts to screen for depression. We aimed to evaluate the 15-item GDS (GDS-15) as such a tool in elderly HD patients and also compare with the BDI, a previously validated tool in younger HD patients. Both tools were administered to all participants and a geriatric psychiatrist blinded to these results evaluated for depression by the gold standard psychiatric interview. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for both tools were assessed against the psychiatric interview. Sixty two patients completed the study. Patients who were depressed by psychiatric interview had significantly higher GDS-15 and BDI scores compared to those not depressed (p<0.01 both). ROC curves showed high predictive accuracy of the GDS-15 and BDI (area under the curve, 0.808 and 0.729) versus the psychiatric interview. The GDS15 cutoff with the best diagnostic accuracy was 5, with a sensitivity of 63%, specificity of 82%, PPV of 60%, NPV of 83%. The BDI cutoff with the best diagnostic accuracy was 10, with a sensitivity of 68%, specificity of 77%, PPV of 57%, NPV of 85%. These results provide evidence that the GDS-15 shows validity in comparison to a gold standard and can be used to screen for depression in the elderly hemodialysis population.
44 CT SCANS IN ENCAPSULATING PERITONEAL SCLEROSIS (EPS): COMPARING TWO SCORING METHODS Saurabh Bansal, Nasir Siddiqui, Heena Sheth, Filitsa Bender, James Johnston, Beth Piraino, University of Pittsburgh School of Medicine, Pittsburgh, PA EPS is a serious complication of PD. Early diagnosis (dx) is critical. Clinical symptoms/signs are nausea, vomiting, anorexia, abdominal pain, and hemoperitoneum. CT imaging is critical for dx. Two scoring systems: Vijm(PDI 2009; 29; 517-22) and Tarzi(CJASN 2008;3; 1702-10) for evaluating CT scans for the dx of EPS have been published. The purpose of this study is to compare these two scoring methods. The patients (pts) with the clinical dx of EPS were identified from an IRB approved PD registry from 8/1979 to 8/2009. Electronic patient charts were reviewed for CT scans of the abdomen with IV contrast. Available CT scans were scored by a radiologist co-author (NS) using both scoring systems: Vjim, using a +/- system with 6 parameters (>3 positive parameters consistent with EPS dx,); Tarzi, using 6 parameters each scored 0-3 or 0-4 with 22 possible maximum score (a total score>4 was selected for EPS dx). For the Tarzi system, we also analyzed each parameter using >0 as + and 0 as negative. There were 8 pts with EPS dx. 5 were women and time on PD was 17136 mo. All were diagnosed after transfer to HD/transplant. Seven pts had 19 CT scans available for scoring. Fourteen scans performed after the clinical dx of EPS were + by both methods. Five CT scans were performed before the clinical dx of EPS and 4/5 were (-) by both methods; the 5th had a + score by both methods 15 mo before clinical dx. Contrasting Vijm and Tarzi respectively for + scoring for each parameter: peritoneal (perit) thickening 86 vs 93%, perit. calcifications 71 vs 71%, adhesions/tethering 64 vs 64%, bowel obstruction/dilatation 36 vs 43%, loculation 50% for both, bowel thickening 36 vs 43%. Perit. enhancement was only used by Vijm and was 100% + in EPS. The Tarzi score with clinical EPS was median 6 (4-13) and without clinical EPS was 0 (0-4). The median Vijm score was 4 (3-6) for + EPS and median 0 (0-3) for negative EPS. Both systems are congruent, easy to use, and accurate in dx EPS. The Vijm system is simpler. We recommend that all CT abdomen scans in PD patients having a Vijm score of >3 or a Tarzi score >4 should raise suspicion of EPS in the appropriate setting.
41 RECENT ERYTHROPOIESIS STIMULATING AGENT (ESA) UTILIZATION AND COSTS IN MEDICARE PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD) Fotios Kokkotos1, Robert A. Bailey2, Matthew Kerr1, Sherlynn Shen1, Mekre Senbetta2, R. Scott McKenzie2 1 Trinity Partners, LLC, Waltham, MA, USA; 2Centocor Ortho Biotech Services, LLC, Horsham, PA, USA The objective of this analysis was to evaluate recent epoetin alfa (EPO) and darbepoetin alfa (DARB) drug utilization in Medicare patients with CKD not on dialysis treated in the outpatient setting. An analysis of medical claims using the Medicare 100% Institutional Database was performed to evaluate EPO and DARB use from 20052007. Patients included had ≥1 CKD diagnosis, were ESA treatment naïve, and received ≥2 EPO or DARB doses during a treatment episode. Patients diagnosed with cancer, myelodysplastic syndrome, receiving chemotherapy, or treated with both agents were excluded. If a patient received dialysis, data were censored for the quarter prior to the 1st dialysis. A treatment episode was defined as the time from the 1st ESA dose to the last ESA dose. Patients with 2 consecutive ESA doses that were ≥1 quarter apart were excluded from the analysis. Mean cumulative ESA dose was used to calculate drug costs using April 2009 wholesale acquisition unit costs (EPO $14.44/1,000 units;DARB $5.064/mcg). The study population consisted of 18,767 EPO and 16,574 DARB treatment episodes between 2005Q2 and 2007Q4. Age group distributions and proportion of females were similar between groups. The EPO group had a lower mean (SD) Charlson Comorbidity Score [3.5(1.6) EPO vs. 3.6 (1.6) DARB, P<.001]. Mean (SD) treatment duration was 3.3 (2.4) quarters for EPO and 3.4 (2.4) quarters for DARB (P=.017). The mean (SD) cumulative dose was 312,000 (450,300) units for EPO and 1,170.5 (1,493.3) for DARB, resulting in a dose ratio of 267:1 (EPO units: DARB mcg). Based on cumulative ESA doses, drug cost was $1422 (32%) higher (P<.001) for DARB than for EPO. This study of Medicare CKD patients not on dialysis observed 32% higher drug costs for DARB vs. EPO and a dose ratio of 267:1.
42 ACTIVATION OF PROXIMAL TUBULE SPHINGOSINE 1-PHOSPHATE RECEPTOR 1 PROTECTS KIDNEYS FROM ISCHEMIA REPERFUSION INJURY INDEPENDENT OF LYMPHOCYTES Amandeep Bajwa*,§, Sang-Kyung Jo*,§,‡, Hong Ye*,§, Liping Huang*,§. Krishna R. Dondeti*,§, Diane L. Rosin†,§, Volker H. Haase¶, Timothy L. Macdonald**, Kevin R. Lynch†, and Mark D. Okusa*,§ Departments of Medicine *, Chemistry **, Pharmacology† and the Center for Immunity, Inflammation and Regenerative Medicine§, University of Virginia, Charlottesville, USA. Department of Medicine¶, Vanderbilt University Medical Center, Nashville, TN, USA. Sphingosine 1-phosphate (S1P) receptor agonists reduce kidney ischemia-reperfusion injury (IRI), an effect presumed to be mediated by S1P1 receptor (S1P1R)-induced lymphopenia. To test the hypothesis that S1P1R activation may mediate renal protection from IRI independent of lymphocytes, we investigated the effect of S1PR agonists on kidney IRI in Rag-1 KO mice, which lack T and B lymphocytes. Following IRI, less injury was observed in Rag-1 KO mice compared to WT mice as determined by plasma creatinine levels and histology. Administration of FTY720, or the selective S1P1R agonist, SEW2871, further reduced injury in Rag-1 KO mice as well as WT mice. In mouse proximal tubule cells grown in culture, lipopolysaccharide (LPS) or hypoxia/reoxygenation-induced apoptosis was significantly reduced by SEW2871 supporting a direct protective effect of S1P1R agonists on proximal tubule cells via MAP kinase and/or Akt pathways. To determine the role of proximal tubule S1P1Rs in vivo in reducing IRI we used PEPCK-CreS1P1fl/wt and PEPCKCreS1P1fl/fl mice that are deficient in proximal tubule S1P1Rs. PEPCKCreS1P1fl/wt and PEPCK-CreS1P1fl/fl mice had a significant rise in plasma creatinine after IRI to a level greater than control (PEPCK-Cre) mice. Furthermore, SEW2871 was not protective in the PEPCKCreS1P1fl/wt and PEPCK-CreS1P1fl/fl mice after IRI. These results suggest that endogenous S1P1Rs are necessary for stress-induced cell survival and S1P1R agonists mediate kidney tissue protection at least in part through a direct effect on proximal tubule S1P1Rs.
NKF 2010 Spring Clinical Meetings Abstracts
43 VALIDATION OF GDS-15 AS A SCREENING TOOL FOR DEPRESSION IN ELDERLY HEMODIALYSIS PATIENTS Rasheed A Balogun1, Faruk Turgut1, Seki A Balogun2, Suzanne Holroyd3 and Emaad M Abdel-Rahman1 1 Division of Nephrology, 2 Division of General Medicine, Geriatrics and Palliative Care, Department of Medicine and 3Department of Psychiatry and Neurobehavioral Science, University of Virginia Health System, Charlottesville, Virginia, USA. Depression is common and associated with increased morbidity and mortality in elderly (≥65yrs) hemodialysis (HD) patients. The Beck’s Depression inventory (BDI) and the Geriatric Depression scale (GDS) have been used in different cohorts to screen for depression. We aimed to evaluate the 15-item GDS (GDS-15) as such a tool in elderly HD patients and also compare with the BDI, a previously validated tool in younger HD patients. Both tools were administered to all participants and a geriatric psychiatrist blinded to these results evaluated for depression by the gold standard psychiatric interview. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for both tools were assessed against the psychiatric interview. Sixty two patients completed the study. Patients who were depressed by psychiatric interview had significantly higher GDS-15 and BDI scores compared to those not depressed (p<0.01 both). ROC curves showed high predictive accuracy of the GDS-15 and BDI (area under the curve, 0.808 and 0.729) versus the psychiatric interview. The GDS15 cutoff with the best diagnostic accuracy was 5, with a sensitivity of 63%, specificity of 82%, PPV of 60%, NPV of 83%. The BDI cutoff with the best diagnostic accuracy was 10, with a sensitivity of 68%, specificity of 77%, PPV of 57%, NPV of 85%. These results provide evidence that the GDS-15 shows validity in comparison to a gold standard and can be used to screen for depression in the elderly hemodialysis population.
44 CT SCANS IN ENCAPSULATING PERITONEAL SCLEROSIS (EPS): COMPARING TWO SCORING METHODS Saurabh Bansal, Nasir Siddiqui, Heena Sheth, Filitsa Bender, James Johnston, Beth Piraino, University of Pittsburgh School of Medicine, Pittsburgh, PA EPS is a serious complication of PD. Early diagnosis (dx) is critical. Clinical symptoms/signs are nausea, vomiting, anorexia, abdominal pain, and hemoperitoneum. CT imaging is critical for dx. Two scoring systems: Vijm(PDI 2009; 29; 517-22) and Tarzi(CJASN 2008;3; 1702-10) for evaluating CT scans for the dx of EPS have been published. The purpose of this study is to compare these two scoring methods. The patients (pts) with the clinical dx of EPS were identified from an IRB approved PD registry from 8/1979 to 8/2009. Electronic patient charts were reviewed for CT scans of the abdomen with IV contrast. Available CT scans were scored by a radiologist co-author (NS) using both scoring systems: Vjim, using a +/- system with 6 parameters (>3 positive parameters consistent with EPS dx,); Tarzi, using 6 parameters each scored 0-3 or 0-4 with 22 possible maximum score (a total score>4 was selected for EPS dx). For the Tarzi system, we also analyzed each parameter using >0 as + and 0 as negative. There were 8 pts with EPS dx. 5 were women and time on PD was 17136 mo. All were diagnosed after transfer to HD/transplant. Seven pts had 19 CT scans available for scoring. Fourteen scans performed after the clinical dx of EPS were + by both methods. Five CT scans were performed before the clinical dx of EPS and 4/5 were (-) by both methods; the 5th had a + score by both methods 15 mo before clinical dx. Contrasting Vijm and Tarzi respectively for + scoring for each parameter: peritoneal (perit) thickening 86 vs 93%, perit. calcifications 71 vs 71%, adhesions/tethering 64 vs 64%, bowel obstruction/dilatation 36 vs 43%, loculation 50% for both, bowel thickening 36 vs 43%. Perit. enhancement was only used by Vijm and was 100% + in EPS. The Tarzi score with clinical EPS was median 6 (4-13) and without clinical EPS was 0 (0-4). The median Vijm score was 4 (3-6) for + EPS and median 0 (0-3) for negative EPS. Both systems are congruent, easy to use, and accurate in dx EPS. The Vijm system is simpler. We recommend that all CT abdomen scans in PD patients having a Vijm score of >3 or a Tarzi score >4 should raise suspicion of EPS in the appropriate setting.