Michael F Flessner

The National Institute of Diabetes and Digestive and Kidney Diseases, Maryland, United States

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Publications (62)295.95 Total impact

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    ABSTRACT: Background Hypertension is common in autosomal dominant polycystic kidney disease (ADPKD) and is associated with increased total kidney volume, activation of the renin-angiotensin-aldosterone system, and progression of kidney disease. Methods In this double-blind, placebo-controlled trial, we randomly assigned 558 hypertensive participants with ADPKD (15 to 49 years of age, with an estimated glomerular filtration rate [GFR] >60 ml per minute per 1.73 m(2) of body-surface area) to either a standard blood-pressure target (120/70 to 130/80 mm Hg) or a low blood-pressure target (95/60 to 110/75 mm Hg) and to either an angiotensin-converting-enzyme inhibitor (lisinopril) plus an angiotensin-receptor blocker (telmisartan) or lisinopril plus placebo. The primary outcome was the annual percentage change in the total kidney volume. Results The annual percentage increase in total kidney volume was significantly lower in the low-blood-pressure group than in the standard-blood-pressure group (5.6% vs. 6.6%, P=0.006), without significant differences between the lisinopril-telmisartan group and the lisinopril-placebo group. The rate of change in estimated GFR was similar in the two medication groups, with a negative slope difference in the short term in the low-blood-pressure group as compared with the standard-blood-pressure group (P<0.001) and a marginally positive slope difference in the long term (P=0.05). The left-ventricular-mass index decreased more in the low-blood-pressure group than in the standard-blood-pressure group (-1.17 vs. -0.57 g per square meter per year, P<0.001); urinary albumin excretion was reduced by 3.77% with the low-pressure target and increased by 2.43% with the standard target (P<0.001). Dizziness and light-headedness were more common in the low-blood-pressure group than in the standard-blood-pressure group (80.7% vs. 69.4%, P=0.002). Conclusions In early ADPKD, the combination of lisinopril and telmisartan did not significantly alter the rate of increase in total kidney volume. As compared with standard blood-pressure control, rigorous blood-pressure control was associated with a slower increase in total kidney volume, no overall change in the estimated GFR, a greater decline in the left-ventricular-mass index, and greater reduction in urinary albumin excretion. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; HALT-PKD [Study A] ClinicalTrials.gov number, NCT00283686 .).
    New England Journal of Medicine 11/2014; · 54.42 Impact Factor
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    ABSTRACT: Background Hypertension develops early in patients with autosomal dominant polycystic kidney disease (ADPKD) and is associated with disease progression. The renin-angiotensin-aldosterone system (RAAS) is implicated in the pathogenesis of hypertension in patients with ADPKD. Dual blockade of the RAAS may circumvent compensatory mechanisms that limit the efficacy of monotherapy with an angiotensin-converting-enzyme (ACE) inhibitor or angiotensin II-receptor blocker (ARB). Methods In this double-blind, placebo-controlled trial, we randomly assigned 486 patients, 18 to 64 years of age, with ADPKD (estimated glomerular filtration rate [GFR], 25 to 60 ml per minute per 1.73 m(2) of body-surface area) to receive an ACE inhibitor (lisinopril) and placebo or lisinopril and an ARB (telmisartan), with the doses adjusted to achieve a blood pressure of 110/70 to 130/80 mm Hg. The composite primary outcome was the time to death, end-stage renal disease, or a 50% reduction from the baseline estimated GFR. Secondary outcomes included the rates of change in urinary aldosterone and albumin excretion, frequency of hospitalizations for any cause and for cardiovascular causes, incidence of pain, frequency of ADPKD-related symptoms, quality of life, and adverse study-medication effects. Patients were followed for 5 to 8 years. Results There was no significant difference between the study groups in the incidence of the composite primary outcome (hazard ratio with lisinopril-telmisartan, 1.08; 95% confidence interval, 0.82 to 1.42). The two treatments controlled blood pressure and lowered urinary aldosterone excretion similarly. The rates of decline in the estimated GFR, urinary albumin excretion, and other secondary outcomes and adverse events, including hyperkalemia and acute kidney injury, were also similar in the two groups. Conclusions Monotherapy with an ACE inhibitor was associated with blood-pressure control in most patients with ADPKD and stage 3 chronic kidney disease. The addition of an ARB did not alter the decline in the estimated GFR. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; HALT-PKD [Study B] ClinicalTrials.gov number, NCT01885559 .).
    New England Journal of Medicine 11/2014; · 54.42 Impact Factor
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    ABSTRACT: The effect of AKI and modern continuous RRT (CRRT) methods on drug disposition (pharmacokinetics) and response has been poorly studied. Pharmaceutical manufacturers have little incentive to perform pharmacokinetic studies in patients undergoing CRRT because such studies are neither recommended in existing US Food and Drug Administration (FDA) guidance documents nor required for new drug approval. Action is urgently needed to address the knowledge deficit. The Kidney Health Initiative has assembled a work group composed of clinicians and scientists representing academia, the FDA, and the pharmaceutical and dialysis industries with expertise related to pharmacokinetics, AKI, and/or CRRT. The work group critically evaluated key considerations in the assessment of pharmacokinetics and drug dosing in CRRT, practical constraints related to conducting pharmacokinetic studies in critically ill patients, and the generalizability of observations made in the context of specific CRRT prescriptions and specific patient populations in order to identify efficient study designs capable of addressing the knowledge deficit without impeding drug development. Considerations for the standardized assessment of pharmacokinetics and development of corresponding drug dosing recommendations in critically ill patients with AKI receiving CRRT are proposed.
    Clinical journal of the American Society of Nephrology : CJASN. 09/2014;
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    ABSTRACT: Polycystic liver disease (PLD), the most common extra-renal manifestation of autosomal-dominant polycystic kidney disease (ADPKD), has become more prevalent due to increased life expectancy, improved renal survival, reduced cardiovascular mortality, and renal replacement therapy. No studies have fully characterized PLD in large cohorts. We investigated whether liver and cyst volumes associate with volume of the hepatic parenchyma, results from liver laboratory tests, and patient-reported outcomes.
    Clinical Gastroenterology and Hepatology. 08/2014;
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    ABSTRACT: Kidney disease is a significant medical and public health problem. The National Institute of Diabetes and Digestive and Kidney Diseases recently asked the community to identify research objectives, which, if addressed, could improve understanding of basic kidney function and aid in prevention, treatment, and reversal of kidney disease. The Kidney Research National Dialogue invited interested parties to submit, discuss, and prioritize ideas using an interactive website; 1600 participants posted more than 300 ideas covering all areas of kidney disease, including the cystic kidney diseases. Although much is known about the genetics and pathogenesis of cystic diseases, there remain challenges to our understanding of the fundamental mechanisms of cyst formation, what genes act as modifiers to cause variable responses in different people, and how to detect and monitor disease progression. This article summarizes key research questions for cystic kidney diseases.
    Clinical journal of the American Society of Nephrology : CJASN. 06/2014;
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    ABSTRACT: The National Institute of Diabetes and Digestive and Kidney Diseases-supported Kidney Research National Dialogue asked the scientific community to formulate and prioritize research objectives aimed at improved understanding of kidney function and disease progression. Over the past 2 years, 1600 participants posted almost 300 ideas covering all areas of kidney disease. An overriding theme that evolved through these discussions is the need to move beyond pathology to take advantage of basic science and clinical research opportunities to improve diagnostic classification and therapeutic options for people with primary glomerular disease. High-priority research areas included focus on therapeutic targets in glomerular endothelium and podocytes, regenerating podocytes through developmental pathways, use of longitudinal phenotypically defined disease cohorts to improve classification schemes, identifying biomarkers, disease-specific therapeutics, autoantibody triggers, and changing the clinical research culture to promote participation in clinical trials. Together, these objectives provide a path forward for improving clinical outcomes of glomerular disease.
    Clinical Journal of the American Society of Nephrology 04/2014; · 5.07 Impact Factor
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    ABSTRACT: Aim: To develop and assess a semiautomated method for segmenting and counting individual renal cysts from mid-slice MR images in patients with autosomal dominant polycystic kidney disease (ADPKD). Methods: A semiautomated method was developed to segment and count individual renal cysts from mid-slice MR images in 241 subjects with ADPKD from the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease. For each subject, a mid-slice MR image was selected from each set of coronal T2-weighted MR images covering the entire kidney. The selected mid-slice image was processed with the semiautomated method to segment and count individual renal cysts. The number of cysts from the mid-slice image of each kidney was also measured by manual counting. The level of agreement between the semiautomated and manual cyst counts was compared using intraclass correlation (ICC) and a Bland-Altman plot. Results: Individual renal cysts were successfully segmented using the semiautomated method in all 241 cases. The number of cysts in each kidney measured with the semiautomated and manual counting methods correlated well (ICC = 0.96 for the right or left kidney), with a small average difference (-0.52, with higher semiautomated counts, for the right kidney, and 0.13, with higher manual counts, for the left kidney) in the semiautomated method. However, there was substantial variation in a small number of subjects; 6 of 241 participants (2.5%) had a difference in the total cyst count of more than 15. Conclusion: We have developed a semiautomated method to segment individual renal cysts from mid-slice MR images in ADPKD kidneys as a quantitative indicator of characterization and disease progression of ADPKD. © 2014 S. Karger AG, Basel.
    American Journal of Nephrology 02/2014; 39(3):210-217. · 2.62 Impact Factor
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    ABSTRACT: Objective: To evaluate whether kidney and cyst volumes can be accurately estimated based on limited area measurements from magnetic resonance (MR) images of patients with autosomal dominant polycystic kidney disease (ADPKD). Materials and Methods: MR coronal images of 178 ADPKD participants from the Consortium for Radiologic Imaging Studies of ADPKD (CRISP) were analyzed. For each MR image slice, we measured kidney and renal cyst areas using stereology and region-based thresholding methods, respectively. The kidney and cyst 'observed' volumes were calculated by summing up the area measurements of all the slices covering the kidney. To estimate the volume, we selected a coronal mid-slice in each kidney and multiplied its area by the total number of slices ('PANK2' for kidney and 'PANC2' for cyst). We then compared the kidney and cyst volumes predicted from PANK2 and PANC2, respectively, to the corresponding observed volumes, using a linear regression analysis. Results: The kidney volume predicted from PANK2 correlated extremely well with the observed kidney volume (R(2) = 0.994 for the right kidney and 0.991 for the left kidney). The linear regression coefficient multiplier to PANK2 that best fit the kidney volume was 0.637 (95% CI: 0.629-0.644) for the right kidney and 0.624 (95% CI: 0.616-0.633) for the left kidney. The correlation between the cyst volume predicted from PANC2 and the observed cyst volume was also very high (R(2) = 0.984 for the right kidney and 0.967 for the left kidney). The least squares linear regression coefficient for PANC2 was 0.637 (95% CI: 0.624-0.649) for the right kidney and 0.608 (95% CI: 0.591-0.625) for the left kidney. Conclusion: Kidney and cyst volumes can be closely approximated by multiplying the product of the mid-slice area measurement and the total number of slices in the coronal MR images of ADPKD kidneys by 0.61-0.64. This information will help save processing time needed to estimate total kidney and cyst volumes of ADPKD kidneys. © 2013 S. Karger AG, Basel.
    American Journal of Nephrology 10/2013; 38(4):333-341. · 2.62 Impact Factor
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    ABSTRACT: OBJECTIVE: To evaluate the performance of a semi-automated method for the segmentation of individual renal cysts from magnetic resonance (MR) images in patients with autosomal dominant polycystic kidney disease (ADPKD). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This semi-automated method was based on a morphologic watershed technique with shape-detection level set for segmentation of renal cysts from MR images. T2-weighted MR image sets of 40 kidneys were selected from 20 patients with mild to moderate renal cyst burden (kidney volume < 1500 ml) in the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP). The performance of the semi-automated method was assessed in terms of two reference metrics in each kidney: the total number of cysts measured by manual counting and the total volume of cysts measured with a region-based thresholding method. The proposed and reference measurements were compared using intraclass correlation coefficient (ICC) and Bland-Altman analysis. RESULTS: Individual renal cysts were successfully segmented with the semi-automated method in all 20 cases. The total number of cysts in each kidney measured with the two methods correlated well (ICC, 0.99), with a very small relative bias (0.3% increase with the semi-automated method; limits of agreement, 15.2% reduction to 17.2% increase). The total volume of cysts measured using both methods also correlated well (ICC, 1.00), with a small relative bias of <10% (9.0% decrease in the semi-automated method; limits of agreement, 17.1% increase to 43.3% decrease). CONCLUSION: This semi-automated method to segment individual renal cysts in ADPKD kidneys provides a quantitative indicator of severity in early and moderate stages of the disease.
    Clinical Journal of the American Society of Nephrology 03/2013; · 5.07 Impact Factor
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    ABSTRACT: Background In people with early autosomal dominant polycystic kidney disease (ADPKD), average total kidney volume (TKV) is 3 times normal and increases by an average of 5% per year despite a seemingly normal glomerular filtration rate (GFR). We hypothesized that increased TKV would be a source of morbidity and diminished quality of life that would be worse in patients with more advanced disease. Study Design Cross-sectional. Setting & Participants 1,043 patients with ADPKD, hypertension, and a baseline estimated GFR (eGFR) > 20 mL/min/1.73 m2. Predictors (1) eGFR, (2) height-adjusted TKV (htTKV) in patients with eGFR > 60 mL/min/1.73 m2. Outcomes 36-Item Short Form Health Survey (SF-36) and the Wisconsin Brief Pain Survey. Measurements Questionnaires were self-administered. GFR was estimated from serum creatinine using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation. htTKV was measured by magnetic resonance imaging. Results Back pain was reported by 50% of patients, and 20% experienced it “often, usually, or always.” In patients with early disease (eGFR > 60 mL/min/1.73 m2), there was no association between pain and htTKV, except in patients with large kidneys (htTKV > 1,000 mL/m). Comparing across eGFR levels and including patients with eGFRs < 60 mL/min/1.73 m2, patients with eGFRs of 20-44 mL/min/1.73 m2 were significantly more likely to report that pain impacted on their daily lives and had lower SF-36 scores than patients with eGFRs of 45-60 and ≥60 mL/min/1.73 m2. Symptoms relating to abdominal fullness were reported by 20% of patients and were related significantly to lower eGFRs in women, but not men. Limitations TKV and liver volume were not measured in patients with eGFR < 60 mL/min/1.73 m2. The number of patients with eGFRs < 30 mL/min/1.73 m2 is small. Causal inferences are limited by cross-sectional design. Conclusions Pain is a common early symptom in the course of ADPKD, although it is not related to kidney size in early disease (eGFR > 60 mL/min/1.73 m2), except in individuals with large kidneys (htTKV > 1,000 mL/m). Symptoms relating to abdominal fullness and pain are greater in patients with more advanced (eGFR, 20-45 mL/min/1.73 m2) disease and may be due to organ enlargement, especially in women. More research about the role of TKV in quality of life and outcomes of patients with ADPKD is warranted.
    American Journal of Kidney Diseases 01/2013; · 5.29 Impact Factor
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    ABSTRACT: BACKGROUND: Experimental studies indicate that arginine vasopressin (AVP) may have deleterious effects in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD). However, the significance of AVP in human ADPKD is unclear. STUDY DESIGN: Longitudinal observational study with 8.5 (IQR, 7.7-9.0) years' follow-up (CRISP [Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease]). SETTING & PARTICIPANTS: 241 patients with ADPKD with creatinine clearance >70 mL/min. PREDICTOR: Plasma copeptin concentration, a surrogate marker for AVP. OUTCOMES: Change in measured glomerular filtration rate (mGFR, assessed by iothalamate clearance) and total kidney volume (measured by magnetic resonance imaging). MEASUREMENTS: Baseline copeptin level, plasma and urinary osmolality, and measurements of total kidney volume and mGFR during follow-up. RESULTS: In these patients (median age, 34 [IQR, 25-40] years; 38% men; median mGFR, 94 [IQR, 79-145] mL/min/1.73 m(2); median total kidney volume, 859 [IQR, 577-1,299] mL), median copeptin level was 2.9 (IQR, 1.8-5.1) pmol/L. Copeptin was not associated with plasma osmolality (P = 0.3), the physiologic stimulus for AVP release, but was associated significantly with change in total kidney volume during follow-up (P < 0.001). This association remained significant after adjusting for sex, age, cardiovascular risk factors, and diuretic use (P = 0.03). Copeptin level was associated borderline significantly with change in mGFR after adjusting for these variables (P = 0.09). LIMITATIONS: No standardization of hydration status at time of copeptin measurement. CONCLUSIONS: These data show that in ADPKD, copeptin level, as a marker for AVP, is not correlated with plasma osmolality. Most importantly, high copeptin levels are associated independently with disease progression in early ADPKD. This is in line with experimental studies that indicate a disease-promoting role for AVP.
    American Journal of Kidney Diseases 10/2012; · 5.29 Impact Factor
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    ABSTRACT: Sleep-disordered breathing (SDB) is an increasingly recognized risk factor for cardiovascular disease (CVD). Limited data are available from large African American cohorts. We examined the prevalence, burden, and correlates of sleep symptoms suggestive of SDB and risk for obstructive sleep apnea (OSA) in the Jackson Heart Study (JHS), an all-African-American cohort of 5301 adults. Data on selected daytime and nighttime sleep symptoms were collected using a modified Berlin questionnaire during the baseline examination. Risk of OSA was calculated according to published prediction model. Age and multivariable-adjusted logistic regression models were used to examine the associations between potential risk factors and measures of sleep. Sleep symptoms, burden, and risk of OSA were high among men and women in the JHS and increased with age and obesity. Being married was positively associated with sleep symptoms among women. In men, poor to fair perceived health and increased levels of stress were associated with higher odds of sleep burden, whereas prevalent hypertension and CVD were associated with higher odds of OSA risk. Similar associations were observed among women with slight variations. Sleep duration <7h was associated with increased odds of sleep symptoms among women and increased sleep burden among men. Moderate to severe restless sleep was consistently and positively associated with odds of adverse sleep symptoms, sleep burden, and high risk OSA. Sleep symptoms in JHS had a strong positive association with features of visceral obesity, stress, and poor perceived health. With increasing obesity among younger African Americans, these findings are likely to have broad public health implications.
    Sleep Medicine 07/2012; 13(8):1039-49. · 3.49 Impact Factor
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    ABSTRACT: The aim of this study was to simulate clinically observed intraperitoneal kinetics of dialysis fluid volume and solute concentrations during peritoneal dialysis. We were also interested in analyzing relationships between processes in the peritoneal cavity and processes occurring in the peritoneal tissue and microcirculation. A spatially distributed model was formulated for the combined description of volume and solute mass balances in the peritoneal cavity and flows across the interstitium and the capillary wall. Tissue local parameters were assumed dependent on the interstitial hydration and vasodilatation induced by glucose. The model was fitted to the average volume and solute concentration profiles from dwell studies in 40 clinically stable patients on chronic ambulatory peritoneal dialysis using a 3.86% glucose dialysis solution. The model was able to describe the clinical data with high accuracy. An increase in the local interstitial pressure and tissue hydration within the distance of 2.5 mm from the peritoneal surface of the tissue was observed. The penetration of glucose into the tissue and removal of urea, creatinine, and sodium from the tissue were restricted to a layer located within 2 mm from the peritoneal surface. The initial decline of sodium concentration (sodium dip) was observed not only in intraperitoneal fluid but also in the tissue. The distributed model can provide a precise description of the relationship between changes in the peritoneal tissue and intraperitoneal dialysate volume and solute concentration kinetics. Computer simulations suggest that only a thin layer of the tissue within 2-3 mm from the peritoneal surface participates in the exchange of fluid and small solutes between the intraperitoneal dialysate and blood.
    AJP Renal Physiology 02/2012; 302(10):F1331-41. · 4.42 Impact Factor
  • Zhi He, Rebecca Potter, Xiarong Li, Michael Flessner
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    ABSTRACT: Peritoneal dialysis requires large solution volumes that increase abdominal girth and stretch the mesothelial cells of the abdominal wall. To address the hypothesis that stretch stimulates those cells to increase synthesis and production of inflammatory cytokines, we grew MeT-5A human mesothelial cells to confluence and placed the cells in growth arrest on BioFlex Collagen membranes (Flexcell International Corporation, Hillsborough, NC, U.S.A.). After 48 hours, cells were either left stationary (STA) or cycled using a 3000T system (Flexcell International Corporation) with a sinusoidal stretch (STR) frequency of 10 cycles per minute and an amplitude of 30%. The supernatant and cells of individual wells were removed at 0, 4, 12, 24, 48, 72, and 96 hours. Supernatant was assayed by ELISA for transforming growth factor beta (TGF-beta), interleukin 6 (IL-6), and vascular endothelial growth factor (VEGF). After trypsinization, the total number of viable cells in each well was estimated from the lack of trypan blue staining. Total RNA from the cells was extracted, and real-time reverse-transcriptase polymerase chain reaction was used to determine messenger RNA (mRNA) for IL-6, TGF-beta, VEGF, TGF-beta receptors 2 and 3 (TGF-beta-R2, -R3), kinase insert domain receptor (KDR), and FMS-related tyrosine kinase 1 (Flt1). Because of decline of cell numbers and viability, results for STR were compared with those for STA at each time interval up to 72 hours. The mRNA for TGF-beta, VEGF, TGF-beta-R3, and KDR were significantly higher in the STR group throughout the 72 hours, and STR IL-6 mRNA declined nonsignificantly. Normalized to the number of viable cells, supernatant IL-6, TGF-beta, and VEGF were not significantly different between the groups. We conclude that mechanical stress from mesothelial stretch does not enhance mesothelial cell secretion oflL-6, TGF-f, or VEGF, but does increase expression ofTGF-P, VEGF, and their corresponding cell receptors TGF-f-R3 and KDR.
    Advances in peritoneal dialysis. Conference on Peritoneal Dialysis 01/2012; 28:2-9.
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    ABSTRACT: Serum sodium concentration is the clinical index of systemic water balance. Although disordered water balance is common and morbid, little is known about genetic effects on serum sodium concentration at the population level. Prior studies addressed only participants of European descent and either failed to demonstrate significant heritability or showed only modest effect. We investigated heritability of serum sodium concentration in large cohorts reflecting a range of races/ethnicities, including the Framingham Heart Study (FHS, non-Hispanic Caucasian), the Heredity and Phenotype Intervention Heart Study (HAPI, Amish Caucasian), the Jackson Heart Study (JHS, African American), the Strong Heart Family Study (SHFS, American Indian), and the Genetics of Kidney Disease in Zuni Indians Study (GKDZI, American Indian). Serum sodium was transformed for the osmotic effect of glucose, and participants with markedly elevated glucose or reduced estimated glomerular filtration rate (eGFR) were excluded. Using a standard variance components method, incorporating covariates of age, glucose, and eGFR, we found heritability to be high in African American and American Indian populations and much more modest in non-Hispanic Caucasian populations. Estimates among females increased after stratification on sex and were suggestive among female participants in FHS (0.18 ± 0.12, P = 0.057) and male participants in JHS (0.24 ± 0.16, P = 0.067) and statistically significant among female participants in JHS (0.44 ± 0.09, P = 1 × 10 ⁻⁷), SHFS (0.59 ± 0.05, P = 9.4 × 10⁻⁴⁶), and GKDZI (0.46 ± 0.15, P = 1.7 × 10⁻⁴), and male participants in HAPI (0.18 ± 0.12, P = 0.03) and SHFS (0.67 ± 0.07, P = 5.4 × 10⁻²⁶). Exclusion of diuretic users increased heritability among females and was significant in all cohorts where data were available. In aggregate, these data strongly support the heritability of systemic water balance and underscore sex and ethnicity-specific effects.
    Physiological Genomics 12/2011; 44(3):220-8. · 2.81 Impact Factor
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    ABSTRACT: African Americans develop hypertension earlier with more target manifestations than whites despite having a higher glomerular filtration rate (GFR) for any level of serum creatinine. STUDY DESIGN & PARTICIPANTS: This study tested the hypothesis that increased GFR and sodium reabsorption in African Americans is associated with increased metabolic work and medullary hypoxia in 49 nondiabetic patients with essential hypertension (29 whites and 20 African Americans) following a constant-sodium diet (150 mEq/d) and renin-angiotensin system blockade. Ethnicity, age, measured GFR, sodium excretion, and body mass index. We examined cortical and medullary volumes and blood flows using multidetector computed tomography and intrarenal deoxyhemoglobin (R2*) using blood oxygen level-dependent magnetic resonance. Blood pressure and sodium excretion were similar, whereas African Americans were more obese and had higher iothalamate GFRs. Renal cortical volumes did not differ, but medullary volumes adjusted for body size and age were higher in African Americans (32.3 ± 11.2 vs 25.1 ± 7.4 cm(3)/m(2) body surface area; P < 0.001). Sodium reabsorption and blood flows were higher in African Americans. Basal cortical deoxyhemoglobin values were similar between ethnic groups, whereas medullary R2* was higher in African Americans (39.7 ± 5.1 vs 36.3 ± 6.5/s; P = 0.02), but decreased to levels similar to whites after furosemide treatment. Levels of the circulating isoprostane prostaglandin F(2α) were higher in African Americans and daily urinary prostaglandin F(2α) excretion in African Americans correlated directly with renal blood flow (R = 0.71; P < 0.01). Studies were limited to treated volunteers with normal kidney function without knowledge of prior nutrient intake. These data show for the first time that increased sodium reabsorption in obese African American patients with hypertension was associated with enlarged medullary volumes, functional hypoxia related to solute reabsorption, and a direct relationship between blood flows and urinary isoprostane levels. Our results support a model of increased oxygen consumption and oxidative stress in African Americans that may accelerate hypertension and target-organ injury compared with white patients with essential hypertension.
    American Journal of Kidney Diseases 11/2011; 59(2):229-37. · 5.29 Impact Factor
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    ABSTRACT: Progressive renal fibrosis is a characteristic of all the diseases that cause renal failure and is invariably accompanied by a prominent leukocyte infiltration in the kidney. The goal of this study was to determine the association between the circulating specific leukocyte types and incident chronic kidney disease (CKD). In a cohort of 10,056 middle-aged white and African American adults, levels of circulating neutrophils, lymphocytes, and monocytes were measured at baseline; blood pressure (BP) and serum creatinine were measured and estimated glomerular filtration rate (eGFR) was calculated at baseline and 3 and 9 years later; and surveillance for first hospitalization or death with CKD was carried out over a mean follow-up of 7.4 years (maximum, 11.9 years). Increased neutrophil levels and decreased lymphocyte levels were significantly associated with greater CKD incidence after adjustment for covariates. African Americans tended to have similar but stronger patterns of association between circulating leukocytes and CKD incidence than whites, although the differences between race groups were not statistically significant. We also found that eGFR and BP were higher at each visit in African Americans than whites between ages 45 and 65. These findings support a potential role for circulating specific leukocytes in the pathogenesis of kidney dysfunction, especially in African Americans, indicating the leukocyte-related renal mechanism of essential hypertension (HT).
    Journal of the American Society of Hypertension (JASH) 11/2011; 6(2):100-8.
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    ABSTRACT: Chronic kidney disease (CKD) is an increasing global public health concern, particularly among populations of African ancestry. We performed an interrogation of known renal loci, genome-wide association (GWA), and IBC candidate-gene SNP association analyses in African Americans from the CARe Renal Consortium. In up to 8,110 participants, we performed meta-analyses of GWA and IBC array data for estimated glomerular filtration rate (eGFR), CKD (eGFR <60 mL/min/1.73 m(2)), urinary albumin-to-creatinine ratio (UACR), and microalbuminuria (UACR >30 mg/g) and interrogated the 250 kb flanking region around 24 SNPs previously identified in European Ancestry renal GWAS analyses. Findings were replicated in up to 4,358 African Americans. To assess function, individually identified genes were knocked down in zebrafish embryos by morpholino antisense oligonucleotides. Expression of kidney-specific genes was assessed by in situ hybridization, and glomerular filtration was evaluated by dextran clearance. Overall, 23 of 24 previously identified SNPs had direction-consistent associations with eGFR in African Americans, 2 of which achieved nominal significance (UMOD, PIP5K1B). Interrogation of the flanking regions uncovered 24 new index SNPs in African Americans, 12 of which were replicated (UMOD, ANXA9, GCKR, TFDP2, DAB2, VEGFA, ATXN2, GATM, SLC22A2, TMEM60, SLC6A13, and BCAS3). In addition, we identified 3 suggestive loci at DOK6 (p-value = 5.3×10(-7)) and FNDC1 (p-value = 3.0×10(-7)) for UACR, and KCNQ1 with eGFR (p = 3.6×10(-6)). Morpholino knockdown of kcnq1 in the zebrafish resulted in abnormal kidney development and filtration capacity. We identified several SNPs in association with eGFR in African Ancestry individuals, as well as 3 suggestive loci for UACR and eGFR. Functional genetic studies support a role for kcnq1 in glomerular development in zebrafish.
    PLoS Genetics 09/2011; 7(9):e1002264. · 8.52 Impact Factor
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    ABSTRACT: Serum urate concentrations are highly heritable and elevated serum urate is a key risk factor for gout. Genome-wide association studies (GWAS) of serum urate in African American (AA) populations are lacking. We conducted a meta-analysis of GWAS of serum urate levels and gout among 5820 AA and a large candidate gene study among 6890 AA and 21 708 participants of European ancestry (EA) within the Candidate Gene Association Resource Consortium. Findings were tested for replication among 1996 independent AA individuals, and evaluated for their association among 28 283 EA participants of the CHARGE Consortium. Functional studies were conducted using (14)C-urate transport assays in mammalian Chinese hamster ovary cells. In the discovery GWAS of serum urate, three loci achieved genome-wide significance (P< 5.0 × 10(-8)): a novel locus near SGK1/SLC2A12 on chromosome 6 (rs9321453, P= 1.0 × 10(-9)), and two loci previously identified in EA participants, SLC2A9 (P= 3.8 × 10(-32)) and SLC22A12 (P= 2.1 × 10(-10)). A novel rare non-synonymous variant of large effect size in SLC22A12, rs12800450 (minor allele frequency 0.01, G65W), was identified and replicated (beta -1.19 mg/dl, P= 2.7 × 10(-16)). (14)C-urate transport assays showed reduced urate transport for the G65W URAT1 mutant. Finally, in analyses of 11 loci previously associated with serum urate in EA individuals, 10 of 11 lead single-nucleotide polymorphisms showed direction-consistent association with urate among AA. In summary, we identified and replicated one novel locus in association with serum urate levels and experimentally characterize the novel G65W variant in URAT1 as a functional allele. Our data support the importance of multi-ethnic GWAS in the identification of novel risk loci as well as functional variants.
    Human Molecular Genetics 07/2011; 20(20):4056-68. · 7.69 Impact Factor
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    ABSTRACT: To address the hypothesis that sterile intraperitoneal (ip) catheters alone promote a progressive foreign body reaction (FBR), silicone catheters were surgically implanted in C57BL mice. Controls (CON) underwent sham operations. After 1-5 wk (E1-E5 for catheter-bearing mice), catheters were recovered, and the adherent cell layer (ACL) was separated and cultured to demonstrate sterility. Transperitoneal transport experiments were performed to determine the mass transfer coefficients of mannitol (MTCM) and albumin (MTCA) and the osmotic filtration flux (Josm). After euthanasia, tissue samples were analyzed for submesothelial thickness, angiogenesis, and cytokine immunohistochemistry (IHC). Progressive increases with time were observed in submesothelial thickness (μm: CON, 18.8±12.3; E1, 46.1±20.0; E2, 72.0±17.9; E4, 97.3±20.0; E5, 131.7±10.3; P<0.003), angiogenesis (no. of vessels/mm of peritoneum: CON, 10.7±9.4; E1, 15.4±15.6; E2, 27.0±14.0; E4, 39.8±15.7; E5, 90.1±8.1; P<0.0003), MTCA (6.5±1.5×10(-5) cm/min, mean CON; 18.0±1.1×10(-5) cm/min, mean E1-E5, P<0.0001), Josm (0.0013±0.0001 cm/min, mean CON; 0.0017±0.0001 cm/min, mean E1-E5, P<0.01). No significant differences were found for MTCM. IHC demonstrated strong staining for all treated animals and correlated with the ACL. This mouse model demonstrates that ip silicone catheters result in progressive FBR, altering the submesothelial anatomy and transperitoneal transport, and will form the basis for mechanistic studies in genetically-altered animals.
    AJP Renal Physiology 10/2010; 300(1):F283-9. · 4.42 Impact Factor

Publication Stats

512 Citations
295.95 Total Impact Points


  • 2012–2014
    • The National Institute of Diabetes and Digestive and Kidney Diseases
      Maryland, United States
  • 2011
    • National Institutes of Health
      • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
      Bethesda, MD, United States
  • 2009
    • Ghent University
      • Department of Surgery
      Gent, VLG, Belgium
  • 2005–2009
    • Polish Academy of Sciences
      • Instytut Biocybernetyki i Inżynierii Biomedycznej im. Macieja Nałęcza
      Warsaw, Masovian Voivodeship, Poland
  • 2002–2009
    • University of Mississippi Medical Center
      • School of Medicine
      Jackson, MS, United States
  • 2006–2008
    • University of Mississippi
      • Department of Neurology
      Mississippi, United States