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NKF 2007 Spring Clinical Meetings Abstracts
PODOCYTE INJURY OCCURS IN THE COURSE OF PREECLAMPSIA Belinda Jim, Jacobi Medical Center, Bronx, NY, USA Nandita Singh, Jacobi Medical Center, Bronx, NY, USA Naheed Ansari, Jacobi Medical Center, Bronx, NY, USA Kisra Anis, Jacobi Medical Center, Bronx, NY, USA Peter Mundel, Mount Sinai School of Medicine, New York, NY, USA, Yasuhiro Akai, Nara Medical University, Nara, Japan Anjali Acharya, Jacobi Medical Center, Bronx, NY, USA Preeclampsia remains one of the leading causes of maternal and fetal morbidity and mortality. Though the podocyte has not traditionally been thought to be involved in preeclampsia, conditional knock out mice of VEGF in the podocyte showed typical pathologic features of preeclampsia. Our hypothesis is that the podocyte is injured in the course of preeclampsia, contrary to previous reports. We studied the expression of podocyte-specific proteins, synaptopodin and podocin, by immunofluorescence, in renal biopsies of 20 preeclampsia patients within 4 weeks of delivery. These patients excreted urinary protein ranging from 2.2 to 15 g/day. All biopsies had some degree of endotheliosis, 6/20 biopsies showed segmental sclerosis. In 11/20 samples with severe endotheliosis, +/- sclerosis, podocin expression was markedly decreased, while synaptopodin expression was either unchanged or slightly decreased. The remaining 9/20 samples which had only mild endotheliosis, showed normal synaptopodin and podocin expression. Podocin appears to be first downregulated in severe endotheliosis, followed by decreased synaptopodin expression in the presence of segmental sclerosis. Podocyte injury correlates with the degree of endotheliosis and/or segmental sclerosis in preeclampsia. The histological and immunofluorescent findings did not correlate with the severity of proteinuria. Thus, proteinuria alone may not accurately reflect the degree of glomerular and/or podocyte damage.
sFlt UPREGULATES SYNAPTOPODIN EXPRESSION IN PODOCYTES Belinda Jim, Jacobi Medical Center, Bronx, NY, USA Nandita Singh, Jacobi Medical Center, Bronx, NY, USA Kwanghee Kim, Mount Sinai School of Medicine, New York, NY, USA Naheed Ansari, Jacobi Medical Center, Bronx, NY, USA Kisra Anis, Jacobi Medical Center, Bronx, NY, USA Peter Mundel, Mount Sinai School of Medicine, New York, NY, USA Anjali Acharya, Jacobi Medical Center, Bronx, NY, USA Novel antiangiogenic factors have been recently implicated in the pathogenesis of preeclampsia. One such factor, the soluble fms-like tyrosine kinase (sFlt), an antagonist of VEGF, is found to be upregulated in preeclampsia. Since proteinuria is a hallmark of preeclampsia and that podocyte specific deletion of VEGF results in the endotheliosis, we believe that the podocyte is affected in preeclampsia, causing dysregulation of its complex actin cytoskeleton. We studied the effect of sFlt treatment on the cultured murine podocyte and the expression of synaptopodin, an actin-associated protein. Podocytes were treated with 0, 10, 20, 30, 90 ng/mL of sFlt-Fc chimera (R&D Systems) and analyzed by both immunofluorescence (IF) and western blotting (WB). After 2.5 hours of treatment, synaptopodin expression increased qualitatively on IF and upregulated by 2-fold in WB. There was, however, no further increase of synaptopodin with escalating doses. These results suggest that sFlt affects the integrity of the actin cytoskeleton of the podocyte, manifested by increased levels of synaptopodin. Since synaptopodin induces stress fiber formation via RhoA signaling, we are conducting additional studies of sFlt on the synaptopodin downstream pathway to better elucidate the role of sFlt on podocyte damage in preeclampsia.
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RISK FACTORS FOR PROGRESSION OF KIDNEY DISEASE: A LONGITUDINAL STUDY IN A COMMUNITY PRACTICE Claudine Jurkovitz1, Edward Ewen1, James Bowen1, Joseph Jackson2, William Weintraub1.1Christiana Care Health System, Newark, DE, USA, 2Bristol Myers Squibb, Princeton, NJ, USA The purpose of this study was to examine the effect of blood pressure on the decline of kidney function using electronic medical records. Patients 18 years or older were included if they had at least 2 serum creatinines measured at one year interval. MDRD glomerular filtration rates (GFR) at baseline (BL) and follow-up (FU) were calculated as well as the slope of the GFR changes and the systolic and diastolic follow-up BP averages. BL-BP was stratified into 4 stages; Normal: BP<140/90; Mild: 140-159/90-99; Moderate:160-179/100-109 Severe: ≥180/110. A logistic regression was used to estimate the association between the decline in GFR defined as a slope<0 (dependent variable) and BP stages after adjusting for BL GFR, age, race, sex, diabetes. A total of 4,253 patients were eligible. The median FU time was 3.3 years (max 7.8 years). Below are the population characteristics. Normal Mild Moderate Severe (55.6%) (32.1%) (10.3%) (2.1%) Female (%) 63.6 63.4 66.8 70.8 Black (%) 38.1 47.5 48.3 50.6 Age (Mean years) 53.4 57.0 58.7 62.4 Diabetes (%) 22.5 23.0 22.4 30.3 FU SBP (Mean) 125 135 140 145 FU DBP (Mean) 76 81 83 83 Decline in GFR (%) 39.7 44.8 47.6 58.4 The adjusted odds ratios (OR) and 95%CI associated with BP stages were 1.2 (1.1-1.4), 1.4 (1.1-1.7), and 2.0(1.3-3.2) for mild, moderate, severe compared to normal BP. Other risk factors included age, being black (OR=1.2 (1.1-1.4)) and having diabetes (OR=1.8 (1.5-2.1)). Although the average follow-up SBP and DBP were within or slightly higher normal ranges, patients with high baseline BP were more likely to experience a GFR decline than those with normal baseline BP suggesting that more aggressive BP treatment is warranted especially in patients with severe baseline BP.
INVESTIGATION OF NEPHROGENIC FIBROSING DERMOPATHY AND ASSOCIATION WITH GADOLINIUMCONTAINING MRI CONTRAST Alexander Kallen1, Michael Jhung1, Theresa Hess1, Steven Cheng2, George Turabelidze3, Georges Saab4, Liana Abramova2, Matthew Arduino1, Priti Patel1. 1Division of Healthcare Quality Promotion, CDC, Atlanta, Georgia; 2 Washington University School of Medicine; 3 Missouri Department of Health, St. Louis, Missouri,; and 4 University of Missouri, Columbia, Missouri. Nephrogenic Fibrosing Dermopathy (NFD) is a fibrosing disorder of unknown etiology that has been described in patients with renal disease. In May 2006, a cluster of NFD was identified at a hospital in Missouri. An investigation and case control study were conducted to identify risk factors for NFD. Case-patients were identified from hospital records. A confirmed case-patient was defined as a patient identified between January 2002 and August 2006 with clinical and pathologic findings of NFD. Confirmed case-patients and controls that had sufficient information covering the 6 months prior to diagnosis were included in the casecontrol study. Three controls were matched to each case by location and date of NFD diagnosis. A total of 28 cases were identified. Confirmed case-patients (n=19) and controls (n=57) were included in the case-control study. Casepatients and controls were similar with respect to demographic characteristics. In univariate analysis, exposure to gadoliniumcontaining MRI contrast in the preceding year (MOR 7.99, 95% CI 2.22-28.77); presence of dependent edema (MOR 7.11, 95% CI 1.9525.82); history of deep venous thrombosis (MOR 5.05, 95% CI 1.2520.42); and hypothyroidism (MOR 4.10, 95% CI 1.14-14.70) were all associated with NFD. Case-patients were not more likely than controls to be on high-dose epoetin alfa. In multivariate analysis, exposure to gadolinium-containing MRI contrast in the prior year (MOR 8.97, 95% CI 1.28-63.01) remained associated with NFD. In this study, exposure to gadolinium-containing contrast was highly associated with NFD. Use of these agents should be avoided except when medically necessary in patients with advanced renal disease.
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NKF 2007 Spring Clinical Meetings Abstracts
PODOCYTE INJURY OCCURS IN THE COURSE OF PREECLAMPSIA Belinda Jim, Jacobi Medical Center, Bronx, NY, USA Nandita Singh, Jacobi Medical Center, Bronx, NY, USA Naheed Ansari, Jacobi Medical Center, Bronx, NY, USA Kisra Anis, Jacobi Medical Center, Bronx, NY, USA Peter Mundel, Mount Sinai School of Medicine, New York, NY, USA, Yasuhiro Akai, Nara Medical University, Nara, Japan Anjali Acharya, Jacobi Medical Center, Bronx, NY, USA Preeclampsia remains one of the leading causes of maternal and fetal morbidity and mortality. Though the podocyte has not traditionally been thought to be involved in preeclampsia, conditional knock out mice of VEGF in the podocyte showed typical pathologic features of preeclampsia. Our hypothesis is that the podocyte is injured in the course of preeclampsia, contrary to previous reports. We studied the expression of podocyte-specific proteins, synaptopodin and podocin, by immunofluorescence, in renal biopsies of 20 preeclampsia patients within 4 weeks of delivery. These patients excreted urinary protein ranging from 2.2 to 15 g/day. All biopsies had some degree of endotheliosis, 6/20 biopsies showed segmental sclerosis. In 11/20 samples with severe endotheliosis, +/- sclerosis, podocin expression was markedly decreased, while synaptopodin expression was either unchanged or slightly decreased. The remaining 9/20 samples which had only mild endotheliosis, showed normal synaptopodin and podocin expression. Podocin appears to be first downregulated in severe endotheliosis, followed by decreased synaptopodin expression in the presence of segmental sclerosis. Podocyte injury correlates with the degree of endotheliosis and/or segmental sclerosis in preeclampsia. The histological and immunofluorescent findings did not correlate with the severity of proteinuria. Thus, proteinuria alone may not accurately reflect the degree of glomerular and/or podocyte damage.
sFlt UPREGULATES SYNAPTOPODIN EXPRESSION IN PODOCYTES Belinda Jim, Jacobi Medical Center, Bronx, NY, USA Nandita Singh, Jacobi Medical Center, Bronx, NY, USA Kwanghee Kim, Mount Sinai School of Medicine, New York, NY, USA Naheed Ansari, Jacobi Medical Center, Bronx, NY, USA Kisra Anis, Jacobi Medical Center, Bronx, NY, USA Peter Mundel, Mount Sinai School of Medicine, New York, NY, USA Anjali Acharya, Jacobi Medical Center, Bronx, NY, USA Novel antiangiogenic factors have been recently implicated in the pathogenesis of preeclampsia. One such factor, the soluble fms-like tyrosine kinase (sFlt), an antagonist of VEGF, is found to be upregulated in preeclampsia. Since proteinuria is a hallmark of preeclampsia and that podocyte specific deletion of VEGF results in the endotheliosis, we believe that the podocyte is affected in preeclampsia, causing dysregulation of its complex actin cytoskeleton. We studied the effect of sFlt treatment on the cultured murine podocyte and the expression of synaptopodin, an actin-associated protein. Podocytes were treated with 0, 10, 20, 30, 90 ng/mL of sFlt-Fc chimera (R&D Systems) and analyzed by both immunofluorescence (IF) and western blotting (WB). After 2.5 hours of treatment, synaptopodin expression increased qualitatively on IF and upregulated by 2-fold in WB. There was, however, no further increase of synaptopodin with escalating doses. These results suggest that sFlt affects the integrity of the actin cytoskeleton of the podocyte, manifested by increased levels of synaptopodin. Since synaptopodin induces stress fiber formation via RhoA signaling, we are conducting additional studies of sFlt on the synaptopodin downstream pathway to better elucidate the role of sFlt on podocyte damage in preeclampsia.
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RISK FACTORS FOR PROGRESSION OF KIDNEY DISEASE: A LONGITUDINAL STUDY IN A COMMUNITY PRACTICE Claudine Jurkovitz1, Edward Ewen1, James Bowen1, Joseph Jackson2, William Weintraub1.1Christiana Care Health System, Newark, DE, USA, 2Bristol Myers Squibb, Princeton, NJ, USA The purpose of this study was to examine the effect of blood pressure on the decline of kidney function using electronic medical records. Patients 18 years or older were included if they had at least 2 serum creatinines measured at one year interval. MDRD glomerular filtration rates (GFR) at baseline (BL) and follow-up (FU) were calculated as well as the slope of the GFR changes and the systolic and diastolic follow-up BP averages. BL-BP was stratified into 4 stages; Normal: BP<140/90; Mild: 140-159/90-99; Moderate:160-179/100-109 Severe: ≥180/110. A logistic regression was used to estimate the association between the decline in GFR defined as a slope<0 (dependent variable) and BP stages after adjusting for BL GFR, age, race, sex, diabetes. A total of 4,253 patients were eligible. The median FU time was 3.3 years (max 7.8 years). Below are the population characteristics. Normal Mild Moderate Severe (55.6%) (32.1%) (10.3%) (2.1%) Female (%) 63.6 63.4 66.8 70.8 Black (%) 38.1 47.5 48.3 50.6 Age (Mean years) 53.4 57.0 58.7 62.4 Diabetes (%) 22.5 23.0 22.4 30.3 FU SBP (Mean) 125 135 140 145 FU DBP (Mean) 76 81 83 83 Decline in GFR (%) 39.7 44.8 47.6 58.4 The adjusted odds ratios (OR) and 95%CI associated with BP stages were 1.2 (1.1-1.4), 1.4 (1.1-1.7), and 2.0(1.3-3.2) for mild, moderate, severe compared to normal BP. Other risk factors included age, being black (OR=1.2 (1.1-1.4)) and having diabetes (OR=1.8 (1.5-2.1)). Although the average follow-up SBP and DBP were within or slightly higher normal ranges, patients with high baseline BP were more likely to experience a GFR decline than those with normal baseline BP suggesting that more aggressive BP treatment is warranted especially in patients with severe baseline BP.
INVESTIGATION OF NEPHROGENIC FIBROSING DERMOPATHY AND ASSOCIATION WITH GADOLINIUMCONTAINING MRI CONTRAST Alexander Kallen1, Michael Jhung1, Theresa Hess1, Steven Cheng2, George Turabelidze3, Georges Saab4, Liana Abramova2, Matthew Arduino1, Priti Patel1. 1Division of Healthcare Quality Promotion, CDC, Atlanta, Georgia; 2 Washington University School of Medicine; 3 Missouri Department of Health, St. Louis, Missouri,; and 4 University of Missouri, Columbia, Missouri. Nephrogenic Fibrosing Dermopathy (NFD) is a fibrosing disorder of unknown etiology that has been described in patients with renal disease. In May 2006, a cluster of NFD was identified at a hospital in Missouri. An investigation and case control study were conducted to identify risk factors for NFD. Case-patients were identified from hospital records. A confirmed case-patient was defined as a patient identified between January 2002 and August 2006 with clinical and pathologic findings of NFD. Confirmed case-patients and controls that had sufficient information covering the 6 months prior to diagnosis were included in the casecontrol study. Three controls were matched to each case by location and date of NFD diagnosis. A total of 28 cases were identified. Confirmed case-patients (n=19) and controls (n=57) were included in the case-control study. Casepatients and controls were similar with respect to demographic characteristics. In univariate analysis, exposure to gadoliniumcontaining MRI contrast in the preceding year (MOR 7.99, 95% CI 2.22-28.77); presence of dependent edema (MOR 7.11, 95% CI 1.9525.82); history of deep venous thrombosis (MOR 5.05, 95% CI 1.2520.42); and hypothyroidism (MOR 4.10, 95% CI 1.14-14.70) were all associated with NFD. Case-patients were not more likely than controls to be on high-dose epoetin alfa. In multivariate analysis, exposure to gadolinium-containing MRI contrast in the prior year (MOR 8.97, 95% CI 1.28-63.01) remained associated with NFD. In this study, exposure to gadolinium-containing contrast was highly associated with NFD. Use of these agents should be avoided except when medically necessary in patients with advanced renal disease.