- Email: [email protected]
38: Heart Rate Variability (HRV) in Chronic Kidney Disease (CKD): The Renal Research Institute (RRI) CKD Study
A32
NKF 2009 Spring Clinical Meetings Abstracts
37
39
LINEAGE STUDY OF THE GDNF-EXPRESSING CELLS IN THE NEPHROGENIC MESENCHYME AND ANALYSIS OF THEIR SELF-RENEWAL POTENTIAL DURING KIDNEY DEVELOPMENT Cristina Cebrián1, Naoya Asai2, Vivette D’Agati1, Frank Costantini1. 1.Columbia University Medical Center, New York, New York. 2.Nagoya University, Nagoya, Japan. Kidney development initiates when an outgrowth of the Wolffian duct, the ureteric bud, invades the metanephric mesenchyme (MM), inducing discrete clusters of mesenchymal cells to condense around the UB tips, epithelialize and differentiate into nephrons. GDNF, which is expressed in the MM, is a critical factor for renal development and signals to the UB tips via Ret receptors. We have generated a mouse line for inducible Cre-mediated recombination in GDNF-expressing cells, and have used it to ask if these cells are nephron progenitors. In these GDNF-Cre-ERT2 animals, the expression of Cre recombinase is under control of the GDNF promoter and its activity is controlled by Tamoxifen. GDNF-Cre-ERT2 males were mated with ROSA26YFP females, which were injected with Tamoxifen to induce recombination at different time-points during gestation, irreversibly labeling the GDNF-expressing cells. We found that GDNF-positive MM cells selfrenew while they also give rise to the condensing mesenchyme, proximal and distal tubule, Henle’s loop, connecting segment, Bowman’s capsule and podocytes. No labeling was observed in blood vessels or cortical or medullary stroma. To test the role of the nephron progenitor cells in determining kidney size, GDNF-expressing cells were depleted by mating GDNF-Cre-ERT2 and ROSA26DTA mice, followed by Tamoxifen injection at different times. In these animals, recombination induced the expression of the Diphtheria Toxin A resulting in apoptotic death of the targeted cell. At birth, these animals presented a significant reduction in kidney size and nephron induction with nearly absent nephrogenic zone and fibrous outer cortex. In summary, we show that GDNF-positive cells are indeed nephron progenitors that maintain the population of renal stem cells and give rise to cells in the tubules of the nephron but not stroma. However, their self-renewal potential is limited and depletion of this population critically impairs nephron induction and renal growth.
38
PROSPECTIVE ANALYSIS OF THE INCIDENCES OF JC AND BK VIRUSES IN RENAL TRANSPLANTATION: A RECIPROCAL RELATIONSHIP: Xingxing S. Cheng, Gregory A. Storch, Daniel L. Bohl, Parmjeet Randhawa, Eugene O. Major, Caroline Ryschkewitsch, Daniel C. Brennan. Washington University School of Medicine, St. Louis, MO. Purpose: To examine the interactions between the BK and JC polyomavirus in renal transplant recipients (RTR) in the first year post-transplant. Methods: In previous studies, we characterized BK reactivation in 200 RTRs by performing quantitative PCR on urine and blood samples collected serially throughout the posttransplant year. Here, we characterized JC-reactivation in the same patients using stored samples. Results: BK and JC-viruria were detected in 35% and 16% of RTRs, respectively. The mean urine BK-viral load was approximately 400 fold higher than the JC-viral load: median load 8.98 log10 versus 6.39 log10 copies/mL. The co-detection rate was 1.5%, which is less than 5.6%, the predicted rate if BK and JC were reactivated independently (p=0.001). JC-viremia and nephropathy were not seen. The onset of JC-viruria was associated with higher levels of donor and recipient JC-specific antibody, but negatively associated with higher titers of donor and recipient BK-specific antibody. Conclusion: Reactivation of BK and JC do not occur independently or additively. BK-seropositivity and BKreactivation are associated with lower rates of JC-reactivation, while JC-seropositivity did not influence BK-reactivation.
40
HEART RATE VARIABILITY (HRV) IN CHRONIC KIDNEY DISEASE (CKD): THE RENAL RESEARCH INSTITUTE (RRI) CKD STUDY Preeti Chandra1, Robin L. Sands1, Brenda W. Gillespie1, Nathan W. Levin2, Peter Kotanko2, Margaret Kiser3, Fred Finkelstein4, Alan Hinderliter3, Sanjay Rajagopalan5, Rajiv Saran1. 1Univ. of Michigan, Kidney Epidemiology and Cost Center, Ann Arbor, MI; 2Renal Research Institute, New York, NY; 3Dept of Medicine, Univ. of North Carolina, Chapel Hill, NC; 4Metabolism Associates, New Haven, CT; 5 Dept. of Cardiology and Radiology, Ohio State Univ., Columbus, OH. Patients with CKD are at high risk of cardiovascular disease (CVD). Associations of HRV and CVD have not been systematically studied in CKD. The RRI-CKD study (n=834) is a multicenter, prospective observational study that includes a subset who underwent 24-hr Holter [n=309; mean glomerular filtration rate (GFR) =28 ± 11.6 ml/min/1.73m2]. Predictors of HRV (time and frequency domain) were assessed using multiple linear regression, adjusting for demographics, comorbidities and key laboratory variables. Mean age was 59.5 ± 14.7 yr, subjects were 51% male and 78% white. Diabetes mellitus (DM) was present in 31%; hypertension (HT) in 88%, and history of CVD in 37%. Selected HRV variables for the CKD subjects by DM and CKD stage are shown in the Table. CKD patients had lower SDNN and SDANN, and mostly higher LF/HF than controls. Measure of HRV H eart Rate (bpm) S tandard deviation (SD) of all normal to normal R-R (NN) intervals (SDN N) S D of 5-min avearage NN intervals (SDANN) Low/High Frequency (LF/HF) R atio [median (IQR )]
Normal
Overall n=309 73.4 ± 10.5
DM n=94 72.6 ± 11.8
non-DM n=214 73.8 ± 9.9
Stage 3 n=122 73.8 ± 10.6
Stage 4 n=146 73.4 ± 10.0
HYPOTHYROIDISM INDUCED RHABDOMYOLYSIS AND ACUTE KIDNEY INJURY (AKI) Sumit Chowdhery, Elie Fein, Kalyana Janga, Subrahmanyam Nasika, Sheldon Greenberg, Kavita Sharma, Suneeta Gadde, Maimonides Medical Center, Brooklyn, NY. Muscular symptoms are often found in patients with hypothyroidism. However, cases of significant elevation of muscle enzymes (rhabdomyolysis) associated with hypothyroidism and renal failure are very rare and when it occurs, they are often attributable to more than usual exercise or the concomitant use of medications like statins or fibrates. We report a rare case of rhabdomyolysis due to hypothyroidism and recovery with thyroid replacement therapy. A 49 year old well built man with history of diabetes, hypertension and dyslipidemia was referred to our hospital for myalgia and generalized edema lasting for 6 weeks. Rhabdomyolysis was diagnosed and his niacin was stopped. Nephrotic and Nephritic syndromes were ruled out. The subject returned to the renal clinic after discharge with recurrent severe elevation in creatine phosphokinase (CPK) and creatinine. The patient continued to deny trauma or any new exercise routine. The work up during this admission revealed an elevated TSH>150mIU/L. Hashimoto’s hypothyroidism was diagnosed by antithyroglobulin antibodies and antiperoxidase antibodies. As soon as thyroid replacement was started, the entire lab panel normalized and the patient’s symptoms also improved.
Stage 5 n=39 72.5 ± 11.4
141 ± 39 107.6 ± 37.5 96.6 ± 40.7 112.2 ± 35.1 107.1 ± 37.4 110.5 ± 36.9 96.6 ± 39.2 127 ± 35
91.3 ± 32.5
81.2 ± 34.6
95.5 ± 30.6
92.3 ± 34.0
93.3 ± 31.3
78.6 ± 29.9
1.0 – 2.0
2.5 (2.7)
1.8 (2)
2.9 (2.6)
2.4 (2.5)
2.8 (2.6)
1.9 (2.3)
In multivariable analysis, SDNN was lower in diabetics (p=0.009), in women (p=0.007) and in those with lower albumin (p=0.011). LF/HF ratio was higher in those without DM or HTN (p=0.013), in men (p=0.001), in those with lower serum phosphorus (p=0.003), and in those with a history of coronary artery disease (p=0.028). Higher LF/HF ratio, but not SDNN, was associated with lower odds of a composite CVD end point (OR: 0.71, p=0.004). HRV as a risk factor for CVD in CKD warrants further exploration.
Hypothyroidism patients with rhabdomyolysis have up to 10 times elevation in CPK levels and usually associated with trauma, infection or lipid lowering medications. Here is a rare case with Hashimoto’s thyroiditis with CPK levels of 10,622 with AKI that worsened after stopping niacin too. We conclude that the degree of hypothyroidism correlated directly with higher CPK levels and worsening renal failure, and can cause rhabdomyolysis by itself.
NKF 2009 Spring Clinical Meetings Abstracts
37
39
LINEAGE STUDY OF THE GDNF-EXPRESSING CELLS IN THE NEPHROGENIC MESENCHYME AND ANALYSIS OF THEIR SELF-RENEWAL POTENTIAL DURING KIDNEY DEVELOPMENT Cristina Cebrián1, Naoya Asai2, Vivette D’Agati1, Frank Costantini1. 1.Columbia University Medical Center, New York, New York. 2.Nagoya University, Nagoya, Japan. Kidney development initiates when an outgrowth of the Wolffian duct, the ureteric bud, invades the metanephric mesenchyme (MM), inducing discrete clusters of mesenchymal cells to condense around the UB tips, epithelialize and differentiate into nephrons. GDNF, which is expressed in the MM, is a critical factor for renal development and signals to the UB tips via Ret receptors. We have generated a mouse line for inducible Cre-mediated recombination in GDNF-expressing cells, and have used it to ask if these cells are nephron progenitors. In these GDNF-Cre-ERT2 animals, the expression of Cre recombinase is under control of the GDNF promoter and its activity is controlled by Tamoxifen. GDNF-Cre-ERT2 males were mated with ROSA26YFP females, which were injected with Tamoxifen to induce recombination at different time-points during gestation, irreversibly labeling the GDNF-expressing cells. We found that GDNF-positive MM cells selfrenew while they also give rise to the condensing mesenchyme, proximal and distal tubule, Henle’s loop, connecting segment, Bowman’s capsule and podocytes. No labeling was observed in blood vessels or cortical or medullary stroma. To test the role of the nephron progenitor cells in determining kidney size, GDNF-expressing cells were depleted by mating GDNF-Cre-ERT2 and ROSA26DTA mice, followed by Tamoxifen injection at different times. In these animals, recombination induced the expression of the Diphtheria Toxin A resulting in apoptotic death of the targeted cell. At birth, these animals presented a significant reduction in kidney size and nephron induction with nearly absent nephrogenic zone and fibrous outer cortex. In summary, we show that GDNF-positive cells are indeed nephron progenitors that maintain the population of renal stem cells and give rise to cells in the tubules of the nephron but not stroma. However, their self-renewal potential is limited and depletion of this population critically impairs nephron induction and renal growth.
38
PROSPECTIVE ANALYSIS OF THE INCIDENCES OF JC AND BK VIRUSES IN RENAL TRANSPLANTATION: A RECIPROCAL RELATIONSHIP: Xingxing S. Cheng, Gregory A. Storch, Daniel L. Bohl, Parmjeet Randhawa, Eugene O. Major, Caroline Ryschkewitsch, Daniel C. Brennan. Washington University School of Medicine, St. Louis, MO. Purpose: To examine the interactions between the BK and JC polyomavirus in renal transplant recipients (RTR) in the first year post-transplant. Methods: In previous studies, we characterized BK reactivation in 200 RTRs by performing quantitative PCR on urine and blood samples collected serially throughout the posttransplant year. Here, we characterized JC-reactivation in the same patients using stored samples. Results: BK and JC-viruria were detected in 35% and 16% of RTRs, respectively. The mean urine BK-viral load was approximately 400 fold higher than the JC-viral load: median load 8.98 log10 versus 6.39 log10 copies/mL. The co-detection rate was 1.5%, which is less than 5.6%, the predicted rate if BK and JC were reactivated independently (p=0.001). JC-viremia and nephropathy were not seen. The onset of JC-viruria was associated with higher levels of donor and recipient JC-specific antibody, but negatively associated with higher titers of donor and recipient BK-specific antibody. Conclusion: Reactivation of BK and JC do not occur independently or additively. BK-seropositivity and BKreactivation are associated with lower rates of JC-reactivation, while JC-seropositivity did not influence BK-reactivation.
40
HEART RATE VARIABILITY (HRV) IN CHRONIC KIDNEY DISEASE (CKD): THE RENAL RESEARCH INSTITUTE (RRI) CKD STUDY Preeti Chandra1, Robin L. Sands1, Brenda W. Gillespie1, Nathan W. Levin2, Peter Kotanko2, Margaret Kiser3, Fred Finkelstein4, Alan Hinderliter3, Sanjay Rajagopalan5, Rajiv Saran1. 1Univ. of Michigan, Kidney Epidemiology and Cost Center, Ann Arbor, MI; 2Renal Research Institute, New York, NY; 3Dept of Medicine, Univ. of North Carolina, Chapel Hill, NC; 4Metabolism Associates, New Haven, CT; 5 Dept. of Cardiology and Radiology, Ohio State Univ., Columbus, OH. Patients with CKD are at high risk of cardiovascular disease (CVD). Associations of HRV and CVD have not been systematically studied in CKD. The RRI-CKD study (n=834) is a multicenter, prospective observational study that includes a subset who underwent 24-hr Holter [n=309; mean glomerular filtration rate (GFR) =28 ± 11.6 ml/min/1.73m2]. Predictors of HRV (time and frequency domain) were assessed using multiple linear regression, adjusting for demographics, comorbidities and key laboratory variables. Mean age was 59.5 ± 14.7 yr, subjects were 51% male and 78% white. Diabetes mellitus (DM) was present in 31%; hypertension (HT) in 88%, and history of CVD in 37%. Selected HRV variables for the CKD subjects by DM and CKD stage are shown in the Table. CKD patients had lower SDNN and SDANN, and mostly higher LF/HF than controls. Measure of HRV H eart Rate (bpm) S tandard deviation (SD) of all normal to normal R-R (NN) intervals (SDN N) S D of 5-min avearage NN intervals (SDANN) Low/High Frequency (LF/HF) R atio [median (IQR )]
Normal
Overall n=309 73.4 ± 10.5
DM n=94 72.6 ± 11.8
non-DM n=214 73.8 ± 9.9
Stage 3 n=122 73.8 ± 10.6
Stage 4 n=146 73.4 ± 10.0
HYPOTHYROIDISM INDUCED RHABDOMYOLYSIS AND ACUTE KIDNEY INJURY (AKI) Sumit Chowdhery, Elie Fein, Kalyana Janga, Subrahmanyam Nasika, Sheldon Greenberg, Kavita Sharma, Suneeta Gadde, Maimonides Medical Center, Brooklyn, NY. Muscular symptoms are often found in patients with hypothyroidism. However, cases of significant elevation of muscle enzymes (rhabdomyolysis) associated with hypothyroidism and renal failure are very rare and when it occurs, they are often attributable to more than usual exercise or the concomitant use of medications like statins or fibrates. We report a rare case of rhabdomyolysis due to hypothyroidism and recovery with thyroid replacement therapy. A 49 year old well built man with history of diabetes, hypertension and dyslipidemia was referred to our hospital for myalgia and generalized edema lasting for 6 weeks. Rhabdomyolysis was diagnosed and his niacin was stopped. Nephrotic and Nephritic syndromes were ruled out. The subject returned to the renal clinic after discharge with recurrent severe elevation in creatine phosphokinase (CPK) and creatinine. The patient continued to deny trauma or any new exercise routine. The work up during this admission revealed an elevated TSH>150mIU/L. Hashimoto’s hypothyroidism was diagnosed by antithyroglobulin antibodies and antiperoxidase antibodies. As soon as thyroid replacement was started, the entire lab panel normalized and the patient’s symptoms also improved.
Stage 5 n=39 72.5 ± 11.4
141 ± 39 107.6 ± 37.5 96.6 ± 40.7 112.2 ± 35.1 107.1 ± 37.4 110.5 ± 36.9 96.6 ± 39.2 127 ± 35
91.3 ± 32.5
81.2 ± 34.6
95.5 ± 30.6
92.3 ± 34.0
93.3 ± 31.3
78.6 ± 29.9
1.0 – 2.0
2.5 (2.7)
1.8 (2)
2.9 (2.6)
2.4 (2.5)
2.8 (2.6)
1.9 (2.3)
In multivariable analysis, SDNN was lower in diabetics (p=0.009), in women (p=0.007) and in those with lower albumin (p=0.011). LF/HF ratio was higher in those without DM or HTN (p=0.013), in men (p=0.001), in those with lower serum phosphorus (p=0.003), and in those with a history of coronary artery disease (p=0.028). Higher LF/HF ratio, but not SDNN, was associated with lower odds of a composite CVD end point (OR: 0.71, p=0.004). HRV as a risk factor for CVD in CKD warrants further exploration.
Hypothyroidism patients with rhabdomyolysis have up to 10 times elevation in CPK levels and usually associated with trauma, infection or lipid lowering medications. Here is a rare case with Hashimoto’s thyroiditis with CPK levels of 10,622 with AKI that worsened after stopping niacin too. We conclude that the degree of hypothyroidism correlated directly with higher CPK levels and worsening renal failure, and can cause rhabdomyolysis by itself.