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82: Telomerase Is Expressed in Renal Medulla and Papilla: Regulation by Osmolarity
NKF 2009 Spring Clinical Meetings Abstracts 81
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BODY COMPOSITION AND ALL-CAUSE MORTALITY IN HEMODIALYSIS PATIENTS Cindy Huang1, Hocine Tighiouart1, Srinivasan Beddhu2, Alfred Cheung2, Dwyer, Johanna1, Garabed Eknoyan3, Gerald Beck4, Andrew Levey1,Mark Sarnak1. 1 Tufts Medical Center, Boston, MA; 2 Univ. of Utah, Salt Lake City, UT; 3Baylor College of Medicine, Houston, TX; 4Cleveland Clinic, Cleveland, OH Studies have suggested that higher body mass index (BMI) is protective in hemodialysis (HD) patients. BMI however does not differentiate between adipose tissue and muscle mass. We therefore examined the relationship of various anthropometric measures to mortality in the HEMO study. Triceps skinfold was used to assess body fat, mid-arm muscle circumference (MAMC) calculated from a standard formula (MAMC=upper arm circumference- *triceps skinfold) was use to assess muscle mass. Cox regression was used to evaluate the relationship between body fat, MAMC and BMI with all cause mortality adjusted for demographics, cardiovascular risk factors, dialysis related and nutritional factors. Mean age was 58 years (n=1846). There were 56% females, 63% African Americans, and 45% diabetics. The mean (SD) of triceps skinfold, MAMC and BMI were 1.64 (0.79) cm, 24.79 (3.84) cm and 25.46 (5.28) respectively. During a mean follow up of 4.2 years, there were 871 deaths. Higher BMI, MAMC and body fat were all associated with lower mortality in adjusted continuous analysis (Table, p<0.01). Higher quartiles of BMI and MAMC were associated with lower all-cause mortality in unadjusted models, while the higher quartiles of all three measures were protective in comparison with the lower quartiles in adjusted models (Table, p<0.01). We conclude both higher muscle mass and fat mass are associated with decreased all-cause mortality in HD patients. Table. Hazard ratios between anthropometric measures and all-cause mortality* BMI
Triceps skinfold
MAMC
Quartile 2# 0.76 (0.62-0.94) 0.74 (0.59-0.91) 0.64 (0.52-0.79) Quartile 3# 0.64 (0.52-0.79) 0.71 (0.56-0.89) 0.61 (0.49-0.76) Quartile 4# 0.58 (0.49-0.73) 0.59 (0.46-0.75) 0.59 (0.48-0.74) Continuous§ 0.82 (0.76-0.90) 0.84 (0.77-0.93) 0.87 (0.80-0.92) *Adjusted for age, sex, race, diabetes, CVD, vintage, calcium, creatinine, albumin, hematocrit, bicarbonate, phosphorous, PTH, baseline ICED score, underlying renal disease, high flux vs low flux, high dose vs standard dose randomization. # Use quartile 1 as the reference. § Per 1 SD increase of BMI, triceps skinfold or MAMC
82 TELOMERASE IS EXPRESSED IN RENAL MEDULLA AND PAPILLA: REGULATION BY OSMOLARITY Suzanne Czerniak, Teresa Wang, Wendy Ying, Diana L. Carlone, Joseph V. Bonventre, David Breault and Benjamin D. Humphreys Brigham and Women’s Hospital, Children’s Hospital and Harvard Stem Cell Institute, Boston, Massachusetts, USA Purpose: The localization and function of telomerase (mTert) expressing cells in adult kidney is unknown. In this study we sought to identify cells in kidney that express mTert and determine their function. Methods: We used a novel mTert-GFP transgenic mouse in which the mTert promoter drives GFP to define the localization and regulated expression of telomerase within the adult mammalian kidney. Results: mTert-GFP localized to collecting duct epithelia in the inner medulla and papilla but not in cortex in kidneys from mTert-GFP mice. Consistent with this, we amplified endogenous mTert mRNA from renal papilla but not from cortex. At baseline, only 5-10% of collecting duct epithelial cells expressed GFP, suggesting that telomerase expression might be dynamically regulated. We further reasoned that telomerase could function to repair damaged telomeres in the harsh environment of the inner medulla and papilla. To test this hypothesis, we administered furosemide to mTert-GFP mice. Abrogation of the medullary concentrating gradient with furosemide is known to activate the ATM/p53 DNA repair pathway in collecting duct cells both in vitro and in vivo. We observed a dramatic increase in both mTert-GFP and mTert mRNA expression both 4 and 8 hours after furosemide administration. mTert mRNA was also rapidly induced by subjecting a collecting duct cell line to rapid changes in osmolarity, a stimulus that activated the ATM/p53 DNA repair pathway in parallel. Conclusion: Telomerase is expressed in collecting duct and is induced by rapid changes in osmolarity in vitro and in vivo, consistent with a role for telomerase in the epithelial DNA repair response.
USE OF BLOOD TRANSFUSIONS ON THE KIDNEY TRANSPLANT WAITING LIST, 1991-2005 Hassan Ibrahim, Areef Ishani, Jon Snyder, Melissa Skeans, Qi Li; Chronic Disease Research Group, Minneapolis Medical Research Foundation, Minneapolis, MN, USA. High percentages of panel reactive antibodies (PRA) are associated with a longer time from listing to transplant and also higher likelihood of acute rejection. Exposure to blood products has been associated with greater PRA levels. We studied the trends in the use of blood transfusions (Txf) while on the waiting list for Medicare patients first added to the waiting list 1991-2005 (N=93,026). The one-year cumulative incidence of a post-listing Txf was 16% and 11% in patients listed 1991-93 and 2003-05, respectively. The rate of Txf has decreased over time, and rate of Txf did not vary greatly by months post-listing (Fig 1). Txf events were more likely in women (RR 1.39, 95% CI 1.341.44), African Americans (1.27, 1.22-1.31, ref: white), diabetics (1.34, 1.28-1.41, ref: GN), patients with blood type B or O compared with type A or AB, and patients with increased prelisting dialysis time. In both men and women, pre-transplant Txf were associated with increased odds of PRA > 10% at the time of transplantation (men OR: 1.63 (1.52-1.74), women OR: 1.62 (1.581.73)). PRA > 10% at the time of transplant was associated with an increased risk of graft failure through 6-years post-transplant in patients transplanted 1999- 2004 (RR 1.18 (1.12-1.25)). These analyses demonstrate 1) a reduction in the use of Txf during the past 15 years; 2) pre-transplant Txf are associated with increased sensitization at the time of transplant; and 3) increased sensitization is associated with increased adjusted risk of graft loss.
84 MEMBRANOUS GLOMERULONEPHRITIS SECONDARY TO SYPHILIS Nabeel Imam, Amir Izhar, Yury Gonzales, George Mutema Department of Internal Medicine, Good Samaritan Hospital, Cincinnati OH, USA Membranous glomerulonephritis (MGN) is one of the most common forms of nephrotic syndrome in adults. It is typically idiopathic, but can be secondary to other causes as well. Syphilis is one of the rarest causes of MGN and can present a diagnostic challenge. A 42-year-old male was admitted to the hospital complaining of weight gain, bilateral pedal edema, and generalized body swelling. Swelling was preceded by papular rash, which started at the trunk and abdomen and gradually developed over the palms and soles. Physical examination revealed marked periorbital edema and 3+ pre-tibial pedal edema. Urinalysis revealed proteinuria and hematuria. A twenty-four hour urine collection revealed 12.56 gm of protein. Laboratory data showed BUN was 45mg/dl and serum creatinine was 2.8mg/dl. Further workup revealed hypoalbuminemia, hypertriglyceridemia and positive serology for syphilis with a positive RPR and FTA Abs. HIV serology, hepatitis panel, ANA and ANCA were negative. Renal biopsy revealed granular deposits of IgG, C3, and C1q along the capillary basement membrane. Electron microscopy showed subepithelial deposition of immune complexes which confirmed the diagnosis of MGN. The correlation of clinical and serological findings with the renal biopsy was consistent with MGN secondary to syphilis. Treatment was initiated with IM penicillin G weekly for three weeks. The patient’s edema improved dramatically. Normalization of renal function was observed at the six-week follow-up appointment. Additionally, the rash had subsided and proteinuria improved to 0.18 gm/24 hr. Complete resolution of the patient’s nephrotic syndrome following Penicillin therapy supports syphilis as the cause of the disease. This case illustrates the association between secondary syphilis and MGN. Even though nephrotic syndrome caused by syphilis is rare, it is very important to recognize the clinical picture of syphilis and its renal complication, which is crucial for the administration of appropriate therapy.
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BODY COMPOSITION AND ALL-CAUSE MORTALITY IN HEMODIALYSIS PATIENTS Cindy Huang1, Hocine Tighiouart1, Srinivasan Beddhu2, Alfred Cheung2, Dwyer, Johanna1, Garabed Eknoyan3, Gerald Beck4, Andrew Levey1,Mark Sarnak1. 1 Tufts Medical Center, Boston, MA; 2 Univ. of Utah, Salt Lake City, UT; 3Baylor College of Medicine, Houston, TX; 4Cleveland Clinic, Cleveland, OH Studies have suggested that higher body mass index (BMI) is protective in hemodialysis (HD) patients. BMI however does not differentiate between adipose tissue and muscle mass. We therefore examined the relationship of various anthropometric measures to mortality in the HEMO study. Triceps skinfold was used to assess body fat, mid-arm muscle circumference (MAMC) calculated from a standard formula (MAMC=upper arm circumference- *triceps skinfold) was use to assess muscle mass. Cox regression was used to evaluate the relationship between body fat, MAMC and BMI with all cause mortality adjusted for demographics, cardiovascular risk factors, dialysis related and nutritional factors. Mean age was 58 years (n=1846). There were 56% females, 63% African Americans, and 45% diabetics. The mean (SD) of triceps skinfold, MAMC and BMI were 1.64 (0.79) cm, 24.79 (3.84) cm and 25.46 (5.28) respectively. During a mean follow up of 4.2 years, there were 871 deaths. Higher BMI, MAMC and body fat were all associated with lower mortality in adjusted continuous analysis (Table, p<0.01). Higher quartiles of BMI and MAMC were associated with lower all-cause mortality in unadjusted models, while the higher quartiles of all three measures were protective in comparison with the lower quartiles in adjusted models (Table, p<0.01). We conclude both higher muscle mass and fat mass are associated with decreased all-cause mortality in HD patients. Table. Hazard ratios between anthropometric measures and all-cause mortality* BMI
Triceps skinfold
MAMC
Quartile 2# 0.76 (0.62-0.94) 0.74 (0.59-0.91) 0.64 (0.52-0.79) Quartile 3# 0.64 (0.52-0.79) 0.71 (0.56-0.89) 0.61 (0.49-0.76) Quartile 4# 0.58 (0.49-0.73) 0.59 (0.46-0.75) 0.59 (0.48-0.74) Continuous§ 0.82 (0.76-0.90) 0.84 (0.77-0.93) 0.87 (0.80-0.92) *Adjusted for age, sex, race, diabetes, CVD, vintage, calcium, creatinine, albumin, hematocrit, bicarbonate, phosphorous, PTH, baseline ICED score, underlying renal disease, high flux vs low flux, high dose vs standard dose randomization. # Use quartile 1 as the reference. § Per 1 SD increase of BMI, triceps skinfold or MAMC
82 TELOMERASE IS EXPRESSED IN RENAL MEDULLA AND PAPILLA: REGULATION BY OSMOLARITY Suzanne Czerniak, Teresa Wang, Wendy Ying, Diana L. Carlone, Joseph V. Bonventre, David Breault and Benjamin D. Humphreys Brigham and Women’s Hospital, Children’s Hospital and Harvard Stem Cell Institute, Boston, Massachusetts, USA Purpose: The localization and function of telomerase (mTert) expressing cells in adult kidney is unknown. In this study we sought to identify cells in kidney that express mTert and determine their function. Methods: We used a novel mTert-GFP transgenic mouse in which the mTert promoter drives GFP to define the localization and regulated expression of telomerase within the adult mammalian kidney. Results: mTert-GFP localized to collecting duct epithelia in the inner medulla and papilla but not in cortex in kidneys from mTert-GFP mice. Consistent with this, we amplified endogenous mTert mRNA from renal papilla but not from cortex. At baseline, only 5-10% of collecting duct epithelial cells expressed GFP, suggesting that telomerase expression might be dynamically regulated. We further reasoned that telomerase could function to repair damaged telomeres in the harsh environment of the inner medulla and papilla. To test this hypothesis, we administered furosemide to mTert-GFP mice. Abrogation of the medullary concentrating gradient with furosemide is known to activate the ATM/p53 DNA repair pathway in collecting duct cells both in vitro and in vivo. We observed a dramatic increase in both mTert-GFP and mTert mRNA expression both 4 and 8 hours after furosemide administration. mTert mRNA was also rapidly induced by subjecting a collecting duct cell line to rapid changes in osmolarity, a stimulus that activated the ATM/p53 DNA repair pathway in parallel. Conclusion: Telomerase is expressed in collecting duct and is induced by rapid changes in osmolarity in vitro and in vivo, consistent with a role for telomerase in the epithelial DNA repair response.
USE OF BLOOD TRANSFUSIONS ON THE KIDNEY TRANSPLANT WAITING LIST, 1991-2005 Hassan Ibrahim, Areef Ishani, Jon Snyder, Melissa Skeans, Qi Li; Chronic Disease Research Group, Minneapolis Medical Research Foundation, Minneapolis, MN, USA. High percentages of panel reactive antibodies (PRA) are associated with a longer time from listing to transplant and also higher likelihood of acute rejection. Exposure to blood products has been associated with greater PRA levels. We studied the trends in the use of blood transfusions (Txf) while on the waiting list for Medicare patients first added to the waiting list 1991-2005 (N=93,026). The one-year cumulative incidence of a post-listing Txf was 16% and 11% in patients listed 1991-93 and 2003-05, respectively. The rate of Txf has decreased over time, and rate of Txf did not vary greatly by months post-listing (Fig 1). Txf events were more likely in women (RR 1.39, 95% CI 1.341.44), African Americans (1.27, 1.22-1.31, ref: white), diabetics (1.34, 1.28-1.41, ref: GN), patients with blood type B or O compared with type A or AB, and patients with increased prelisting dialysis time. In both men and women, pre-transplant Txf were associated with increased odds of PRA > 10% at the time of transplantation (men OR: 1.63 (1.52-1.74), women OR: 1.62 (1.581.73)). PRA > 10% at the time of transplant was associated with an increased risk of graft failure through 6-years post-transplant in patients transplanted 1999- 2004 (RR 1.18 (1.12-1.25)). These analyses demonstrate 1) a reduction in the use of Txf during the past 15 years; 2) pre-transplant Txf are associated with increased sensitization at the time of transplant; and 3) increased sensitization is associated with increased adjusted risk of graft loss.
84 MEMBRANOUS GLOMERULONEPHRITIS SECONDARY TO SYPHILIS Nabeel Imam, Amir Izhar, Yury Gonzales, George Mutema Department of Internal Medicine, Good Samaritan Hospital, Cincinnati OH, USA Membranous glomerulonephritis (MGN) is one of the most common forms of nephrotic syndrome in adults. It is typically idiopathic, but can be secondary to other causes as well. Syphilis is one of the rarest causes of MGN and can present a diagnostic challenge. A 42-year-old male was admitted to the hospital complaining of weight gain, bilateral pedal edema, and generalized body swelling. Swelling was preceded by papular rash, which started at the trunk and abdomen and gradually developed over the palms and soles. Physical examination revealed marked periorbital edema and 3+ pre-tibial pedal edema. Urinalysis revealed proteinuria and hematuria. A twenty-four hour urine collection revealed 12.56 gm of protein. Laboratory data showed BUN was 45mg/dl and serum creatinine was 2.8mg/dl. Further workup revealed hypoalbuminemia, hypertriglyceridemia and positive serology for syphilis with a positive RPR and FTA Abs. HIV serology, hepatitis panel, ANA and ANCA were negative. Renal biopsy revealed granular deposits of IgG, C3, and C1q along the capillary basement membrane. Electron microscopy showed subepithelial deposition of immune complexes which confirmed the diagnosis of MGN. The correlation of clinical and serological findings with the renal biopsy was consistent with MGN secondary to syphilis. Treatment was initiated with IM penicillin G weekly for three weeks. The patient’s edema improved dramatically. Normalization of renal function was observed at the six-week follow-up appointment. Additionally, the rash had subsided and proteinuria improved to 0.18 gm/24 hr. Complete resolution of the patient’s nephrotic syndrome following Penicillin therapy supports syphilis as the cause of the disease. This case illustrates the association between secondary syphilis and MGN. Even though nephrotic syndrome caused by syphilis is rare, it is very important to recognize the clinical picture of syphilis and its renal complication, which is crucial for the administration of appropriate therapy.