31 results on '"Chapman, Arlene B."'
Search Results
2. Gastrointestinal Manifestations of Autosomal-Dominant Polycystic Kidney Disease.
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Mikolajczyk, Adam E., Te, Helen S., and Chapman, Arlene B.
- Abstract
Autosomal-dominant polycystic kidney disease (ADPKD) is the most commonly inherited kidney disease, and the fourth most common cause of end-stage renal disease. ADPKD is a systemic disorder, associated with numerous extrarenal manifestations, including polycystic liver disease, the most common gastrointestinal manifestation, and diverticular disease, inguinal, and ventral hernias, pancreatic cysts, and large bile duct abnormalities. All of these gastrointestinal manifestations play a significant role in disease burden in ADPKD, particularly in the later decades of life. Thus, as ADPKD becomes more recognized, it is important for gastroenterologists to be knowledgeable of this monogenic disorder’s effects on the digestive system. [ABSTRACT FROM AUTHOR]
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- 2017
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3. A Physiologic Approach to the Pharmacogenomics of Hypertension.
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Eadon, Michael T. and Chapman, Arlene B.
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- 2016
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4. Autosomal-dominant polycystic kidney disease (ADPKD): executive summary from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.
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Chapman, Arlene B, Devuyst, Olivier, Eckardt, Kai-Uwe, Gansevoort, Ron T, Harris, Tess, Horie, Shigeo, Kasiske, Bertram L, Odland, Dwight, Pei, York, Perrone, Ronald D, Pirson, Yves, Schrier, Robert W, Torra, Roser, Torres, Vicente E, Watnick, Terry, and Wheeler, David C
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POLYCYSTIC kidney disease treatment , *POLYCYSTIC kidney disease , *FOCAL segmental glomerulosclerosis , *RENAL artery , *HYPERTENSION , *CARDIOVASCULAR disease diagnosis , *TREATMENT of chronic kidney failure , *DISEASE risk factors , *TRANSPLANTATION of organs, tissues, etc. - Abstract
Autosomal-dominant polycystic kidney disease (ADPKD) affects up to 12 million individuals and is the fourth most common cause for renal replacement therapy worldwide. There have been many recent advances in the understanding of its molecular genetics and biology, and in the diagnosis and management of its manifestations. Yet, diagnosis, evaluation, prevention, and treatment vary widely and there are no broadly accepted practice guidelines. Barriers to translation of basic science breakthroughs to clinical care exist, with considerable heterogeneity across countries. The Kidney Disease: Improving Global Outcomes Controversies Conference on ADPKD brought together a panel of multidisciplinary clinical expertise and engaged patients to identify areas of consensus, gaps in knowledge, and research and health-care priorities related to diagnosis; monitoring of kidney disease progression; management of hypertension, renal function decline and complications; end-stage renal disease; extrarenal complications; and practical integrated patient support. These are summarized in this review. [ABSTRACT FROM AUTHOR]
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- 2015
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5. Baseline predictors of central aortic blood pressure: A PEAR substudy.
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Rosenwasser, Rebecca F., Shah, Niren K., Smith, Steven M., Wen, Xuerong, Gong, Yan, Gums, John G., Nichols, Wilmer W., Chapman, Arlene B., Boerwinkle, Eric, Johnson, Julie, and Epstein, Benjamin
- Abstract
Abstract: Elevated central systolic blood pressure (BP) increases the risk of cardiovascular events and appears superior to peripheral BP for long term risk prediction. The objective of this study was to identify demographic and clinical factors associated with central pressures in patients with uncomplicated hypertension. We prospectively examined peripheral BP, central aortic BP, and arterial wall properties and wave reflection in 57 subjects with uncomplicated essential hypertension in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) Study. Significant predictors of central SBP included height, smoking status, heart rate (HR), and peripheral systolic BP (SBP), while central diastolic BP (DBP) was explained by peripheral DBP and HR. These variables accounted for nearly all of the variability in central SBP and central DBP (R
2 = 0.94 and R2 = 0.98, respectively). Central pulse pressure variability was largely explained by gender, ex-smoking status, HR, peripheral SBP, and peripheral DBP (R2 = 0.94). Central augmented pressure had a direct relationship with smoking status, peripheral SBP, and duration of hypertension, whereas it was indirectly related to height, HR, and peripheral DBP. Easily obtainable demographic and clinical factors are associated with central pressures in essential hypertensive persons. These relationships should be considered in future studies to improve assessment of BP to reduce cardiovascular risk and mortality. [Copyright &y& Elsevier]- Published
- 2014
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6. Analysis of baseline parameters in the HALT polycystic kidney disease trials.
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Torres, Vicente E, Chapman, Arlene B, Perrone, Ronald D, Bae, K Ty, Abebe, Kaleab Z, Bost, James E, Miskulin, Dana C, Steinman, Theodore I, Braun, William E, Winklhofer, Franz T, Hogan, Marie C, Oskoui, Frederic R, Kelleher, Cass, Masoumi, Amirali, Glockner, James, Halin, Neil J, Martin, Diego R, Remer, Erick, Patel, Nayana, and Pedrosa, Ivan
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POLYCYSTIC kidney disease , *KIDNEY diseases , *CHRONIC kidney failure , *RENIN-angiotensin system , *EPIDERMAL growth factor receptors , *ACE inhibitors , *PATIENTS , *DISEASE risk factors - Abstract
HALT PKD consists of two ongoing randomized trials with the largest cohort of systematically studied patients with autosomal dominant polycystic kidney disease to date. Study A will compare combined treatment with an angiotensin-converting inhibitor and receptor blocker to inhibitor alone and standard compared with low blood pressure targets in 558 early-stage disease patients with an eGFR over 60 ml/min per 1.73 m2. Study B will compare inhibitor-blocker treatment to the inhibitor alone in 486 late-stage patients with eGFR 25-60 ml/min per 1.73 m2. We used correlation and multiple regression cross-sectional analyses to determine associations of baseline parameters with total kidney, liver, or liver cyst volumes measured by MRI in Study A and eGFR in both studies. Lower eGFR and higher natural log-transformed urine albumin excretion were independently associated with a larger natural log-transformed total kidney volume adjusted for height (ln(HtTKV)). Higher body surface area was independently associated with a higher ln(HtTKV) and lower eGFR. Men had larger height-adjusted total kidney volume and smaller liver cyst volumes than women. A weak correlation was found between the ln(HtTKV) and natural log-transformed total liver volume adjusted for height or natural log liver cyst volume in women only. Women had higher urine aldosterone excretion and lower plasma potassium. Thus, our analysis (1) confirms a strong association between renal volume and functional parameters, (2) shows that gender and other factors differentially affect the development of polycystic disease in the kidney and liver, and (3) suggests an association between anthropomorphic measures reflecting prenatal and/or postnatal growth and disease severity. [ABSTRACT FROM AUTHOR]
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- 2012
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7. Imaging Approaches to Patients With Polycystic Kidney Disease.
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Chapman, Arlene B. and Wei, Wenjing
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POLYCYSTIC kidney disease ,KIDNEY radiography ,MEDICAL imaging systems ,MAGNETIC resonance imaging ,RENAL hypertension ,DIAGNOSTIC imaging - Abstract
Summary: Imaging is an important approach to diagnosis, monitoring, and predicting outcomes for patients with autosomal-dominant polycystic kidney disease. This article reviews three common clinical imaging techniques, ultrasonography, computed tomography, magnetic resonance imaging, and their role in the management of autosomal-dominant polycystic kidney disease. Ultrasonographic criteria for diagnosis in children and adults are reviewed. Total kidney volume, as measured by magnetic resonance imaging, is suggested as an important potential marker to determine disease progression and overall prognosis. Renal blood flow and a novel approach to interpreting noncystic renal parenchyma by computed tomography images are other innovative imaging approaches described. [Copyright &y& Elsevier]
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- 2011
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8. Pharmacogenomics of antihypertensive drugs: Rationale and design of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study.
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Johnson, Julie A., Boerwinkle, Eric, Zineh, Issam, Chapman, Arlene B., Bailey, Kent, Cooper-DeHoff, Rhonda M., Gums, John, Curry, R. Whit, Gong, Yan, Beitelshees, Amber L., Schwartz, Gary, and Turner, Stephen T.
- Abstract
Background: Selection of antihypertensive therapy is often empiric, and use of genetic information to guide drug therapy selection holds future promise. Trial design: The objective of this trial is to identify the genetic determinants of the antihypertensive and adverse metabolic responses to a thiazide diuretic (hydrochlorothiazide), a β-blocker (atenolol), and their combination. This will be accomplished through candidate gene and genome-wide association approaches. Individuals with uncomplicated hypertension (N = 800), with ages 17 and 65 years, are being enrolled. Current antihypertensive therapy is discontinued, and hypertension is confirmed, along with collection of other baseline data. Subjects are then randomized to either hydrochlorothiazide or atenolol, with 1 dose titration step, followed by assessment of response to therapy after at least 6 weeks on the target dose. Those with blood pressure >120/70 mm Hg have the second drug added, with similar dose titration and response assessment procedures. Data collected include home, office, and 24-hour ambulatory blood pressure. Biological samples collected in the fasting state include plasma, serum, DNA (buffy coat), and urine. Epstein-Barr virus transformed lymphocyte cell lines are also being created. Conclusions: Pharmacogenetic-guided therapy holds clinical potential for hypertension, but the literature in the field is limited. This trial will add substantially to our understanding of the genetic determinants of antihypertensive and adverse metabolic responses to 2 commonly used antihypertensive drug classes. [Copyright &y& Elsevier]
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- 2009
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9. Renal structure in early autosomal-dominant polycystic kidney disease (ADPKD): The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohort1.
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Chapman, Arlene B., Guay-Woodford, Lisa M., Grantham, Jared J., Torres, Vicente E., Bae, Kyongtae T., Baumgarten, Deborah A., Kenney, Philip J., King, Bernard F., Glockner, James F., Wetzel, Louis H., Brummer, Marijn E., O'Neill, W. Charles, Robbin, Michelle L., Bennett, William M., Klahr, Saulo, Hirschman, Gladys H., Kimmel, Paul L., Thompson, Paul A., and Miller, J. Philip
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POLYCYSTIC kidney disease , *RADIOGRAPHY , *CYSTIC kidney disease , *DIAGNOSTIC imaging - Abstract
Renal structure in early autosomal-dominant polycystic kidney disease (ADPKD): The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohort Background. Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by gradual renal enlargement and cyst growth prior to loss of renal function. Standard radiographic imaging has not provided the resolution and accuracy necessary to detect small changes in renal volume or to reliably measure renal cyst volumes. The Consortium for Radiologic Imaging Studies in Polycystic Kidney Disease (CRISP) is longitudinally observing ADPKD individuals using high-resolution magnetic resonance (MR) imaging to determine if change in renal and cyst volumes can be detected over a short period of time, and if they correlate with decline in renal function early in disease. Methods. Standardization studies were conducted in phantoms and four subjects at each participating clinical center. After, in the full-scale protocol, healthy ADPKD individuals 15 to 45 years old with creatinine clearance>70 mL/min underwent standardized MR renal imaging, renal iothalamate clearance, comprehensive clinical evaluation, and determination of 24-hour urinary albumin and electrolyte excretion. Stereology was used from T1-weighted images to quantify renal volume, and region-growing thresholding was used from T2-weighted images to determine cyst volume. Renal structures were evaluated in relation to demographic, clinical, and biochemical variables using means/medians, standard deviations, and Pearson correlations. Results. Reliability coefficients for MR renal and cyst volume measurements in phantoms were 99.9% and 89.2%, respectively. In the full-scale protocol, 241 ADPKD individuals (145 women and 96 men) were enrolled. Total renal, cyst, and % cyst volume were significantly greater in each decade group. Hypertensive individuals demonstrated greater renal, cyst, and % cyst volume than normotensive subjects. Age-adjusted renal (r = -0.31, P < 0.0001), cyst (r = -0.36, P < 0.0001), and % cyst volume (r = -0.35, P < 0.0001) were inversely related to glomerular filtration rate (GFR). Age-adjusted renal volume (r = 0.42, P < 0.0001), cystic (r = 0.39, P < 0.0001, and % cyst volume (r = 0.41, P < 0.0001) were related with urinary albumin excretion. Conclusion. MR measures of renal and cyst volume are reliable and accurate in patients with ADPKD. ADPKD is characterized by significant cystic involvement that increases with age. Structure (renal and cyst volume) and function (GFR) are inversely related and directly related with the presence of hypertension and urinary albumin excretion in individuals with normal renal function. [ABSTRACT FROM AUTHOR]
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- 2003
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10. Predictors of antihypertensive response to a standard dose of hydrochlorothiazide for essential hypertension.
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Chapman, Arlene B, Schwartz, Gary L, Boerwinkle, Eric, and Turner, Stephen T
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BLOOD pressure , *ANTIHYPERTENSIVE agents , *HYPERTENSION - Abstract
Predictors of antihypertensive response to a standard dose of hydrochlorothiazide for essential hypertension. Background. Determinants of inter-individual variation in blood pressure (BP) response to antihypertensive therapy remain largely unknown. Although differences in race, age and measures of the renin-angiotensin-aldosterone system (RAAS) have been associated with variation in blood pressure response to hydrochlorothiazide, whether these characteristics make additive contributions to predicting response has not been established. We conducted a comprehensive search for predictors of BP response to a standard dose of hydrochlorothiazide in a biracial sample to estimate how much inter-individual variation in BP response could be explained by all of the identified predictors. Methods. After withdrawal of antihypertensive medications for at least four weeks (baseline) and stabilization on a diet approximating 150 mmol sodium per day, 225 African American and 280 Caucasian subjects with diagnosed essential hypertension were treated for four weeks with hydrochlorothiazide 25 mg per day. At baseline and the end of treatment, subjects were admitted to the General Clinical Research Center for measurement of activity of the RAAS and other regulators of BP. Characteristics measured at study enrollment, at baseline, and in response to drug treatment were incorporated stepwise into linear regression models in order to quantify their additive contributions to predicting BP responses to hydrochlorothiazide. Results. Black race and female gender were both associated with significantly greater systolic (SBP) and diastolic (DBP) blood pressure responses to hydrochlorothiazide. Together the combined effects of race and gender accounted for 11% inter-individual variation in SBP response (P < 0.0001) and 4% of inter-individual variation in DBP response (P < 0.0001). Additional statistically significant predictors of greater systolic and diastolic responses to... [ABSTRACT FROM AUTHOR]
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- 2002
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11. Temporal relationships between hormonal and hemodynamic changes in early human pregnancy.
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Chapman, Arlene B., Abraham, William T., Zamudio, Stacy, Coffin, Carolyn, Merouani, Aicha, Young, David, Johnson, Ann, Osorio, Fritz, Goldberg, Carol, Moore, Lorna G., Dahms, Thomas, and Schrier, Robert W.
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PREGNANCY , *KIDNEY physiology , *VASODILATION , *HEMODYNAMICS , *PHYSIOLOGY - Abstract
Temporal relationships between hormonal and hemodynamic changes in early human pregnancy. Background. The systemic hemodynamic profile of human pregnancy is characterized by a decrease in mean arterial pressure, a rise in cardiac output and plasma volume in association with an increase in renal plasma flow and glomerular filtration rate. The factors and the time course responsible for the initial hemodynamic changes seen in human pregnancy have not been completely documented. We hypothesize that systemic and renal hemodynamic changes occur early, prior to the presence of the fetal-placental unit. Methods. Thirteen women were studied prior to and immediately following conception in identical fashion at gestational weeks 6, 8, 10, 12, 24 and 36. Individuals underwent mean arterial pressure, cardiac output, inulin and PAH clearance determinations. Results. Mean arterial pressure decreased by six weeks gestation (mid follicular 81.5 ± 2.6 vs. six weeks 68.7 ± 2.0 mm tig, P < 0.001) in association with a significant increase in cardiac output, a decrease in systemic vascular resistance and an increase in plasma volume. Renal plasma flow and glomerular filtration rate increased by six weeks gestation. Plasma renin activity and aldosterone concentration increased significently by six weeks, whereas norepinephrine levels did not change throughout pregnancy. Atrial natriuretic peptide levels increased later, at 12 weeks gestation. Plasma cGMP levels decreased and cGMP clearance increased by six and eight weeks, respectively. Conclusions . Peripheral vasodilation occurs early in pregnancy prior to full placentation in association with renal vasodilation and activation of the renin-angiotensin-aldosterone system. Plasma volume expansion occurs early, followed later by increases in ANP concentration, suggesting that ANP increases in response to changes in intravasular volume. [ABSTRACT FROM AUTHOR]
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- 1998
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12. Improving clinical trial design for inquiries into the mechanisms of cyst growth in ADPKD.
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Chapman, Arlene B.
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POLYCYSTIC kidney disease , *KIDNEY diseases , *CLINICAL trials , *MEDICAL research , *CLINICAL medicine , *CYSTS (Pathology) - Abstract
Accurate and reliable estimates of kidney and cyst volume, the hallmark of disease progression in ADPKD are now available. These powerful and exciting tools make it possible to consider both short and long term randomized clinical trials in ADPKD at various stages of disease. Highlights of the work by Kistler and colleagues are now provided.Kidney International (2009) 75, 139–141. doi:10.1038/ki.2008.596 [ABSTRACT FROM AUTHOR]
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- 2009
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13. Does dopamine connect the dots in ADPKD?
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Chapman, Arlene B
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PHYSIOLOGICAL effects of dopamine , *POLYCYSTIC kidney disease , *DOPAMINE receptors , *EPITHELIAL cells , *VASODILATION , *EXCRETION , *DISEASE risk factors - Abstract
Healthy autosomal dominant polycystic kidney disease (ADPKD) patients with normal kidney function demonstrate reduced endothelial-dependent vasodilation that improves with increasing local dopamine levels. Dopamine regulates renal sodium excretion, and dopamine receptors are located on primary cilia in both vascular and renal tubular epithelial cells. The study by Lorthioir and colleagues links endothelial function and dopamine availability in ADPKD patients. [ABSTRACT FROM AUTHOR]
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- 2015
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14. Mo1362 - Annual Rate of Growth in Total Liver and Kidney Volume is a Novel Parameter when Assessing Symptom Burden from Liver Cysts in Autosomal Dominant Polycystic Kidney Disease (ADPKD).
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Mikolajczyk, Adam E., Gao, Guimin, and Chapman, Arlene B.
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- 2017
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15. The importance of quantifying genetic heterogeneity in ADPKD.
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Chapman, Arlene B
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POLYCYSTIC kidney disease , *KIDNEY diseases , *HETEROGENEITY , *MOLECULAR genetics , *PROTEIN kinase genetics - Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease. New data from Paul et al. suggest that mutations in the PKD1 and PKD2 genes may account for all cases of ADPKD. Further improvements in mutation detection methodologies are needed to determine the true relative frequency of PKD1 versus PKD2 as well as to establish the value of mutation type and location to predict disease severity in this disorder. [ABSTRACT FROM AUTHOR]
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- 2014
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16. The fetal environment: a critical phase that determines future renal outcomes in autosomal dominant polycystic kidney disease.
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Chapman, Arlene B
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BIRTH weight , *CHRONIC kidney failure , *NEWBORN infants , *HYPOGLYCEMIC agents , *VASOPRESSIN - Abstract
Orskov and colleagues demonstrate the impact of birth weight on the mean age of end-stage renal disease (ESRD) in a large Danish ADPKD cohort. Each kilogram of birth weight extended the mean age of ESRD onset by 1.7 years. Placental insufficiency, activation of the renin-angiotensin-aldosterone system, increased fetal vasopressin levels, compensatory increases in insulin like growth factor-I, and a reduction in total nephron number may all contribute to this observation. Collectively, these changes result in an accelerated pace of cyst formation and expansion, and an inability to maintain glomerular hyperfiltration during kidney expansion which results in a more rapid progression to ESRD. Therefore the intrauterine environment may play a critical role in disease severity in ADPKD. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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17. Liver Involvement in Early Autosomal-Dominant Polycystic Kidney Disease.
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Hogan, Marie C., Abebe, Kaleab, Torres, Vicente E., Chapman, Arlene B., Bae, Kyongtae T., Tao, Cheng, Sun, Hongliang, Perrone, Ronald D., Steinman, Theodore I., Braun, William, Winklhofer, Franz T., Miskulin, Dana C., Rahbari-Oskoui, Frederic, Brosnahan, Godela, Masoumi, Amirali, Karpov, Irina O., Spillane, Susan, Flessner, Michael, Moore, Charity G., and Schrier, Robert W.
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Background & Aims Polycystic liver disease (PLD), the most common extrarenal manifestation of autosomal-dominant polycystic kidney disease (ADPKD), has become more prevalent as a result of 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 are associated with volume of the hepatic parenchyma, results from liver laboratory tests, and patient-reported outcomes. Methods We performed a cross-sectional analysis of baseline liver volumes, measured by magnetic resonance imaging, and their association with demographics, results from liver laboratory and other tests, and quality of life. The data were collected from a randomized, placebo-controlled trial underway at 7 tertiary-care medical centers to determine whether the combination of an angiotensin I–converting enzyme inhibitor and angiotensin II–receptor blocker was superior to the inhibitor alone, and whether low blood pressure (<110/75 mm Hg) was superior to standard blood pressure (120–130/70–80 mm Hg), in delaying renal cystic progression in 558 patients with ADPKD, stages 1 and 2 chronic kidney disease, and hypertension (age, 15–49 y). Results We found hepatomegaly to be common among patients with ADPKD. Cysts and parenchyma contributed to hepatomegaly. Cysts were more common and liver and cyst volumes were greater in women, increasing with age. Patients with advanced disease had a relative loss of liver parenchyma. We observed small abnormalities in results from liver laboratory tests, and that splenomegaly and hypersplenism were associated with PLD severity. Higher liver volumes were associated with a lower quality of life. Conclusions Hepatomegaly is common even in early stage ADPKD and is not accounted for by cysts alone. Parenchymal volumes were larger, compared with liver volumes of patients without ADPKD or with those predicted by standardized equations, even among patients without cysts. The severity of PLD was associated with altered biochemical and hematologic features, as well as quality of life. ClinicalTrials.gov identifier: NCT00283686 . [ABSTRACT FROM AUTHOR]
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- 2015
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18. Melatonin in nighttime blood pressure in African-Americans with essential hypertension: results from two randomized placebo-controlled clinical trials (map-trials).
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Rahbari-Oskoui, Frederic F., Cotsonis, George, Bruckman, Adam A., Bliwise, Donald L., Abramson, Jerome L., Johnson, Sarah, and Chapman, Arlene B.
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- 2014
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19. Evaluation of urine biomarkers of kidney injury in polycystic kidney disease.
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Parikh, Chirag R, Dahl, Neera K, Chapman, Arlene B, Bost, James E, Edelstein, Charles L, Comer, Diane M, Zeltner, Raoul, Tian, Xin, Grantham, Jared J, and Somlo, Stefan
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BIOMARKERS , *KIDNEY injuries , *POLYCYSTIC kidney disease , *CELL proliferation , *LABORATORY mice , *GLOMERULAR filtration rate - Abstract
Progressive disruption of renal tubular integrity in the setting of increased cellular proliferation and apoptosis is a feature of autosomal dominant polycystic kidney disease (ADPKD). Here we evaluated the effect of these processes on the expression of Lcn2 (NGAL) and interleukin (IL)-18, markers of tubular injury, in rodent models and in the cyst fluid and urine of patients with ADPKD. Two mouse models where Pkd2 was inactivated, which resulted in early- or adult-onset cysts, were used to evaluate NGAL levels. Further, the Han:SPRD rat model of polycystic disease was used to study IL-18 levels. In four annual serial urine samples collected from 107 patients with ADPKD in the Consortium for Radiologic Imaging for the Study of Polycystic Kidney Disease (CRISP) study, NGAL and IL-18 excretion rates were determined in conjunction with measures of total kidney volume and estimated glomerular filtration rate (eGFR) by the Modification of Diet in Renal Disease equation. Kidneys from affected mice and rats showed prominent expression of NGAL and IL-18/IL-18R, respectively, in epithelial cells lining kidney cysts. In human ADPKD cyst fluid, both NGAL and IL-18 were elevated. In CRISP patients, the mean percentage increase in total kidney volume was 5.4/year and the mean decline in eGFR 2.4 ml/min/year. The trend of increased mean urine NGAL and IL-18 over 3 years was statistically significant; however, there was no association between tertiles of IL-18 or quartiles of NGAL and change in total kidney volume or eGFR over this period. Thus, urinary NGAL and IL-18 excretion is mildly and stably elevated in ADPKD, but does not correlate with changes in total kidney volume or kidney function. This may be due, in part, to the lack of communication between individual cysts and the urinary collecting system in this disorder. [ABSTRACT FROM AUTHOR]
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- 2012
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20. Interacting effects of gender and genotype on blood pressure response to hydrochlorothiazide.
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Schwartz, Gary L., Turner, Stephen T., Chapman, Arlene B., and Boerwinkle, Eric
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HYPERTENSION , *DIURETICS , *GENETIC polymorphisms , *ANGIOTENSIN converting enzyme - Abstract
Background. Genetic factors may influence blood pressure (BP) response to diuretic therapy through their effects on activity of the renin-angiotensin-aldosterone system (RAAS). The insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene is associated with variation in serum ACE activity and may influence BP in a gender-specific manner. Methods. We measured the I/D polymorphism in 206 non-Hispanic women (130 blacks, 76 whites) and 170 non-Hispanic men (62 blacks, 108 whites) with essential hypertension (age 48 ± 7 years, mean ± SD) who underwent monotherapy with hydrochlorothiazide (HCTZ) 25 mg daily for four weeks. Results. In both genders, serum ACE activity increased in a co-dominant fashion in association with the D-allele (P < 0.001 for both genders). In regression models that considered the effects of baseline BP, race, gender, age, waist-to-hip ratio, and measures of the RAAS, there was significant interaction between the effects of the ACE genotype and gender on the responses of both systolic and diastolic BP to HCTZ (for systolic BP response, P = 0.03; for diastolic BP response, P = 0.001). Among women, mean declines in systolic and diastolic BP were greater in II than in DD homozygotes; whereas among men, mean declines in systolic and diastolic BP were greater in DD than in II homozygotes. In models that included the effects of race, gender, age, and waist-to-hip ratio, there was also significant interaction between the effects of the ACE genotype and gender on pre-treatment urinary aldosterone excretion (P = 0.01) and change in urinary aldosterone excretion in response to HCTZ (P = 0.007). The genotypes that were associated with the greatest BP responses to HCTZ (II homozygotes in women and DD homozygotes in men) had the lowest pre-treatment urinary aldosterone excretion and the greatest increase in urinary aldosterone excretion in response to HCTZ. Conclusion. The relationship between the ACE I/D... [ABSTRACT FROM AUTHOR]
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- 2002
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21. Reproducibility of genotypes as measured by the affymetrix GeneChip® 100K Human Mapping Array set
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Fridley, Brooke L., Turner, Stephen T., Chapman, Arlene B., Rodin, Andrei S., Boerwinkle, Eric, and Bailey, Kent R.
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GENETIC polymorphisms , *NUCLEOTIDES , *NUCLEIC acids , *MATHEMATICAL analysis - Abstract
Abstract: Genotyping errors that are undetected in genome-wide association studies using single nucleotide polymorphisms (SNPs) may degrade the likelihood of detecting true positive associations. To estimate the frequency of genotyping errors and assess the reproducibility of genotype calls, we analyzed two sets of duplicate data, one dataset containing twenty blind duplicates and another dataset containing twenty-eight nonrandom duplicates, from a genome-wide association study using Affymetrix GeneChip®100 K Human Mapping Arrays. For the twenty blind duplicates the overall agreement in genotyping calls as measured with the Kappa statistics, was 0.997, with a discordancy rate of 0.27%. For the twenty-eight nonrandom duplicates, the overall agreement was lower, 0.95, with a higher discordancy rate of 4.53%. The accuracy and probability of concordancy were inversely related to the genotyping uncertainty score, i.e., as the genotyping uncertainty score increased, the concordancy and probability of concordant calls decreased. Lowering of the uncertainty score threshold for rejection of genotype calls from the Affymetrix recommended value of 0.25 to 0.20 resulted in an increased predicted accuracy from 92.6% to 95% with a slight increase in the “No Call” rate from 1.81% to 2.33%. Hence, we suggest using a lower uncertainty score threshold, say 0.20, which will result in higher accuracy in calls at a modest decrease in the call rate. [Copyright &y& Elsevier]
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- 2008
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22. Effect of plasma MicroRNA on antihypertensive response to beta blockers in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) studies.
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Solayman, Mohamed H., Langaee, Taimour Y., Gong, Yan, Shahin, Mohamed H., Turner, Stephen T., Chapman, Arlene B., Gums, John G., Boerwinkle, Eric, Beitelshees, Amber L., El-Hamamsy, Manal, El-Wakeel, Lamia, Cooper-DeHoff, Rhonda M., Badary, Osama A., and Johnson, Julie A.
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MICRORNA , *ANTIHYPERTENSIVE agents , *ADRENERGIC beta blockers , *PHARMACOGENOMICS , *PHARMACEUTICAL chemistry - Abstract
Abstract β-blockers show variable efficacy as antihypertensives. Herein, we evaluated plasma miRNAs as biomarkers for defining antihypertensive response to β-blockers. Expression of 22 β-blocker pharmacodynamics-related miRNAs was assessed in baseline plasma samples from 30 responders and 30 non-responders to metoprolol from the PEAR-2 study (Discovery). Logistic regression was performed to identify miRNAs significantly associated with metoprolol response. Those miRNAs were profiled in baseline plasma samples from 25 responders and 25 non-responders to atenolol from the PEAR study (validation). In discovery, miR-101, miR-27a, miR-22, miR-19a, and let-7e were significantly associated with metoprolol response (P = 0.01, 0.017, 0.025, 0.025, and 0.04, respectively). In validation, miR-19a was significantly associated with atenolol response (P = 0.038). Meta-analysis between PEAR-2 and PEAR revealed significant association between miR-19a (P = 0.004), miR-101 (P = 0.006), and let-7e (P = 0.012) and β-blocker response. Hence, miR-19a, miR-101, and let-7e, which regulate β1-adrenergic receptor and other β-blocker pharmacodynamics-related genes, may be biomarkers for antihypertensive response to β-blockers. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]
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- 2019
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23. Closeout of the HALT-PKD trials.
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Moore, Charity G., Spillane, Susan, Simon, Gertrude, Maxwell, Barbara, Rahbari-Oskoui, Frederic F., Braun, William E., Chapman, Arlene B., Schrier, Robert W., Torres, Vicente E., Perrone, Ronald D., Steinman, Theodore I., Brosnahan, Godela, Czarnecki, Peter G., Harris, Peter C., Miskulin, Dana C., Flessner, Michael F., Bae, K. Ty, Abebe, Kaleab Z., and Hogan, Marie C.
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POLYCYSTIC kidney disease treatment , *BLOOD pressure measurement , *ANTIHYPERTENSIVE agents , *CLINICAL trials , *MEDICAL databases - Abstract
Background The HALT Polycystic Kidney Disease Trials Network consisted of two randomized, double blind, placebo-controlled trials among patients with autosomal dominant polycystic kidney disease. The trials involved 5–8 years of participant follow-up with interventions in blood pressure and antihypertensive therapy. We provide a framework for designing and implementing closeout near the end of a trial while ensuring patient safety and maintaining scientific rigor and study morale. Methods We discuss issues and resolutions for determining the last visit, tapering medications, and unblinding of participants to study allocation and results. We also discuss closure of clinical sites and Data Coordinating Center responsibilities to ensure timely release of study results and meeting the requirements of regulatory and funding authorities. Results Just over 90% of full participants had a 6-month study visit prior to their last visit preparing them for trial closeout. Nearly all patients wanted notification of study results (99%) and treatment allocation (99%). All participants were safely tapered off study and open label blood pressure medications. Within 6 months, the trials were closed, primary papers published, and 805 letters distributed to participants with results and allocation. DCC obligations for data repository and clinicaltrials.gov reporting were completed within 12 months of the last study visit. Conclusions Closeout of our trials involved years of planning and significant human and financial resources. We provide questions for investigators to consider when planning closeout of their trials with focus on (1) patient safety, (2) dissemination of study results and (3) compliance with regulatory and funding responsibilities. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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24. Promoters of Human Cosmc and T-synthase Genes Are Similar in Structure, Yet Different in Epigenetic Regulation.
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Junwei Zeng, Rongjuan Mi, Yingchun Wang, Yujing Li, Li Lin, Bing Yao, Lina Song, van Die, Irma, Chapman, Arlene B., Cummings, Richard D., Peng Jin, and Tongzhong Ju
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PROMOTERS (Genetics) , *SYNTHASES , *GALACTOSYLTRANSFERASE genetics , *EPIGENETICS , *BIOSYNTHESIS - Abstract
The T-synthase (Core 1 β3-galactosyltransferase) and its molecular chaperone Cosmc regulate the biosynthesis of mucin type O-glycans on glycoproteins, and evidence suggests that both T-synthase and Cosmc are transcriptionally suppressed in several human diseases, although the transcriptional regulation of these two genes is not understood. Here we characterized the promoters essential for human Cosmc and T-synthase transcription. The upstream regions of the genes lack a conventional TATA box but contain CpG-islands: cCpG-I and cCpG-II for Cosmc and tCpG for T-synthase. Using luciferase reporter assays, site-directed mutagenesis, ChIP assays, and Mithramycin A treatment, we identified the core promoters within cCpG-II and tCpG, which contain two binding sites for Kruppel-like transcription factors (KLF), including SP1/SP3, respectively. Methylome analysis of Tn4 B cells, which harbor a silenced Cosmc, confirmed the hypermethylation of Cosmc core promoter, but not for that of T-synthase. These results demonstrate that Cosmc and T-synthase are transcriptionally regulated at a basal level by SP/KLF family transcription factors, which explains their ubiquitous and coordinated expression, and also indicates that they are differentially epigenetically regulated beyond X-chromosome imprinting. These results are important in understanding the regulation of these genes that have roles in human diseases, such as IgA Nephropathy and cancer. [ABSTRACT FROM AUTHOR]
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- 2015
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25. A comparison of ultrasound and magnetic resonance imaging shows that kidney length predicts chronic kidney disease in autosomal dominant polycystic kidney disease.
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Bhutani, Harpreet, Smith, Vikram, Rahbari-Oskoui, Frederic, Mittal, Ankush, Grantham, Jared J, Torres, Vicente E, Mrug, Michal, Bae, Kyongtae T, Wu, Zhiyuan, Ge, Yinghui, Landslittel, Doug, Gibbs, Patrice, O'Neill, W Charles, and Chapman, Arlene B
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POLYCYSTIC kidney disease treatment , *KIDNEY diseases , *KIDNEY disease diagnosis , *MAGNETIC resonance imaging , *KIDNEY failure , *MEDICAL research , *GENETICS , *DISEASE risk factors - Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is marked by gradual renal cyst and kidney enlargement and ultimately renal failure. Magnetic resonance-based, height-adjusted total kidney volume (htTKV) over 600 cc/m predicts the development of CKD stage 3 within 8 years in the Consortium for Radiologic Imaging in Polycystic Kidney Disease cohort. Here we compared simultaneous ultrasound and magnetic resonance imaging to determine whether ultrasound and kidney length (KL) predict future CKD stage 3 over longer periods of follow-up. A total of 241 ADPKD patients, 15-46 years, with creatinine clearance of 70 ml/min and above had iothalamate clearance, magnetic resonance, and ultrasound evaluations. Participants underwent an average of five repeat clearance measurements over a mean follow-up of 9.3 years. Ultrasound and magnetic resonance-based TKV and KL were compared using Bland-Altman plots and intraclass correlations. Each measure was tested to predict future CKD stage 3. Relatively strong intraclass correlations between ultrasound and magnetic resonance were found for both htTKV and KL (0.81 and 0.85, respectively). Ultrasound and magnetic resonance-based htTKV and KL predicted future CKD stage 3 similarly (AUC of 0.87, 0.88, 0.87, and 0.88, respectively). An ultrasound kidney length over 16.5 cm and htTKV over 650 ml/min had the best cut point for predicting the development of CKD stage 3. Thus, kidney length alone is sufficient to stratify the risk of progression to renal insufficiency early in ADPKD using either ultrasound or magnetic resonance imaging. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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26. Epigenetic Silencing of the Chaperone Cosmc in Human Leukocytes Expressing Tn Antigen.
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Rongjuan Mi, Lina Song, Yingchun Wang, Xiaokun Ding, Junwei Zeng, Lehoux, Sylvain, Aryal, Rajindra P., Jianmei Wang, Crew, Vanja K., Van Die, Irma, Chapman, Arlene B., Cummings, Richard D., and Tongzhong Ju
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GENE silencing , *MOLECULAR chaperones , *ENDOPLASMIC reticulum , *GALACTOSYLTRANSFERASES , *LEUCOCYTES , *ANTIGENS - Abstract
Cosmc is the specific molecular chaperone in the endoplasmic reticulum for T-synthase, a Golgi β3-galactosyltransferase that generates the core 1 O-glycan, Galβ1-3GalNAcα-Ser/Thr, in glycoproteins. Dysfunctional Cosmc results in the formation of inactive T-synthase and consequent expression of the Tn antigen (GalNAcα1-Ser/Thr), which is associated with several human diseases. However, the molecular regulation of expression of Cosmc, which is encoded by a single gene on Xq24, is poorly understood. Here we show that epigenetic silencing of Cosmc through hypermethylation of its promoter leads to loss of Cosmc transcripts in Tn4 cells, an immortalized B cell line from a male patient with a Tn-syndrome-like phenotype. These cells lack T-synthase activity and express the Tn antigen. Treatment of cells with 5-aza-2β-deoxycytidine causes restoration of Cosmc transcripts, restores T-synthase activity, and reducesTnantigen expression. Bisulfite sequencing shows thatCGdinucleotides in the Cosmc core promoter are hypermethylated. Interestingly, several other X-linked genes associated with glycosylation are not silenced in Tn4 cells, and we observed no correlation of a particular DNA methyltransferase to aberrant methylation of Cosmc in these cells. Thus, hypermethylation of the Cosmc promoter in Tn4 cells is relatively specific. Epigenetic silencing of Cosmc provides another mechanism underlying the abnormal expression of the Tn antigen, which may be important in understanding aberrant Tn antigen expression in human diseases, including IgA nephropathy and cancer. [ABSTRACT FROM AUTHOR]
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- 2012
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27. Renal CD14 expression correlates with the progression of cystic kidney disease.
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Juling Zhou, Xiaosen Ouyang, Xiangqin Cui, Schoeb, Trenton R., Smythies, Lesley E., Johnson, Martin R., Guay-Woodford, Lisa M., Chapman, Arlene B., and Mrug, Michal
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KIDNEY diseases , *MONOCYTES , *ACUTE kidney failure , *HEREDITY , *NEPHROLOGY - Abstract
Monocyte and macrophage markers are among the most highly overexpressed genes in cpk mouse kidneys with severely progressive renal cystic disease. We show here that one of these markers, CD14, is abnormally transcribed, activated and shed in cystic kidneys. However, these abnormalities were not associated with an increased number of interstitial CD14-positive mononuclear cells. Instead, we found that most non-cystic and cystic renal tubular epithelia were CD14-positive; even distal nephron-derived principal cells. Cd14 was significantly overexpressed in the kidneys of 5-day-old cpk mice and further increased as the disease progressed. In the cpk model with variable rates of cystic kidney enlargement (due to an intercross of two distinct genetic backgrounds), Cd14 expression positively correlated with kidney volume, exceeding the correlation with MCP-1, an established marker of autosomal-dominant polycystic kidney disease (ADPKD). In 16 patients with ADPKD, the baseline urinary CD14 level showed some tendency to correlate with the 2-year change in total kidney volume; however, the tendency was not statistically significant. But the association was significant when the analysis was confined to males. Clearly more studies need to be done to evaluate the utility of CD14 as a marker for outcomes in ADPKD. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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28. Characterization of large rearrangements in autosomal dominant polycystic kidney disease and the PKD1/TSC2 contiguous gene syndrome.
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Consugar, Mark B., Wong, Wai C., Lundquist, Patrick A., Rossetti, Sandro, Kubly, Vickie J., Walker, Denise L., Rangel, Laureano J., Aspinwall, Richard, Niaudet, W. Patrick, Özen, Seza, David, Albert, Velinov, Milen, Bergstralh, Eric J., Bae, Kyongtae T., Chapman, Arlene B., Guay-Woodford, Lisa M., Grantham, Jared J., Torres, Vicente E., Sampson, Julian R., and Dawson, Brian D.
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DNA damage , *POLYCYSTIC kidney disease , *REARRANGEMENTS (Chemistry) , *MICROBIOLOGICAL assay , *GENETIC regulation , *PATIENTS - Abstract
Large DNA rearrangements account for about 8% of disease mutations and are more common in duplicated genomic regions, where they are difficult to detect. Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in either PKD1 or PKD2. PKD1 is located in an intrachromosomally duplicated region. A tuberous sclerosis gene, TSC2, lies immediately adjacent to PKD1 and large deletions can result in the PKD1/TSC2 contiguous gene deletion syndrome. To rapidly identify large rearrangements, a multiplex ligation-dependent probe amplification assay was developed employing base-pair differences between PKD1 and the six pseudogenes to generate PKD1-specific probes. All changes in a set of 25 previously defined deletions in PKD1, PKD2 and PKD1/TSC2 were detected by this assay and we also found 14 new mutations at these loci. About 4% of the ADPKD patients in the CRISP study were found to have gross rearrangements, and these accounted for about a third of base-pair mutation negative families. Sensitivity of the assay showed that about 40% of PKD1/TSC contiguous gene deletion syndrome families contained mosaic cases. Characterization of a family found to be mosaic for a PKD1 deletion is discussed here to illustrate family risk and donor selection considerations. Our assay improves detection levels and the reliability of molecular testing of patients with ADPKD.Kidney International (2008) 74, 1468–1479; doi:10.1038/ki.2008.485; published online 24 September 2008 [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
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29. Magnetic resonance measurements of renal blood flow as a marker of disease severity in autosomal-dominant polycystic kidney disease.
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King, Bernard F., Torres, Vicente E., Brummer, Marijn E., Chapman, Arlene B., Bae, Kyongtae T., Glockner, James F., Arya, Kraisthith, Felmlee, Joel P., Grantham, Jared J., Guay-Woodford, Lisa M., Bennett, William M., Klahr, Saulo, Hirschman, Gladys H., Kimmel, Paul L., Thompson, Paul A., and Miller, J. Phillip
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POLYCYSTIC kidney disease , *MAGNETIC resonance , *BLOOD flow - Abstract
Magnetic resonance measurements of renal blood flow as a marker of disease severity in autosomal-dominant polycystic kidney disease. Background. Autosomal-dominant polycystic kidney disease (ADPKD) is an inherited disorder characterized by renal cyst growth, early development of hypertension, and late occurrence of renal insufficiency. Despite evidence for the importance of nephroangiosclerosis in the progression of renal insufficiency in ADPKD, evaluation of renal blood flow (RBF) as a surrogate marker of disease severity has received little attention. Methods. Flow phantoms and repeat RBF measurements assessed accuracy and reproducibility. One hundred twenty-seven ADPKD subjects with creatinine clearances >70 mL/min underwent measurements of RBF, total, and cyst renal volumes, and % cyst volumes by magnetic resonance (MR) and of glomerular filtration rate (GFR). Renal vascular resistance (RVR) was calculated. MR blood flow sequences utilized a two-dimensional cine phase-contrast breath-hold pulse sequence perpendicular to the renal arteries. Flow rates were calculated utilizing FLOW software. Volumetric analysis was performed using stereology and region-based thresholding. Results. Excellent accuracy and intraobserver and interobserver reproducibility were demonstrated. Anatomic (total kidney volume, total cyst volume, and % cyst volume), hemodynamic (RBF and RVR), and functional (GFR) parameters were strongly correlated. Left polycystic kidneys were larger and had more severe disease. Regression analysis showed that age, diagnosis of hypertension, anatomic parameters and hemodynamic parameters were significant predictors of GFR. Multiple linear regression analysis identified age and hemodynamic parameters only as separate predictors of GFR. Anatomic, hemodynamic, and functional parameters discriminated between normotensive and hypertensive subjects despite antihypertensive treatments. Conclusion. Renal hemodynamic parameters measured by MR correlate with anatomic and functional indices of disease severity, are the strongest predictors of renal function, and deserve further consideration as an outcome measure in clinical trials to guide therapy in ADPKD. [ABSTRACT FROM AUTHOR]
- Published
- 2003
- Full Text
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30. The role of parental hypertension in the frequency and age of diagnosis of hypertension in offspring with autosomal-dominant polycystic kidney disease.
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Schrier, Robert W., Johnson, Ann M., McFann, Kim, and Chapman, Arlene B.
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GENETIC disorders , *HYPERTENSION , *POLYCYSTIC kidney disease - Abstract
The role of parental hypertension in the frequency and age of diagnosis of hypertension in offspring with autosomal-dominant polycystic kidney disease. Hypertension in autosomal-dominant polycystic kidney disease (ADPKD) patients is associated with more rapid progression of renal disease and a high incidence of left ventricular hypertrophy (LVH). The present study was undertaken to examine the role of parental hypertension in the occurrence of hypertension in 475 ADPKD offspring. Adult subjects participating in an ongoing study of the natural history of ADPKD were included in the analysis if they were diagnosed with ADPKD, had a known affected parent, and knew the hypertensive status of both parents. When the affected parent was hypertensive, the ADPKD male (82% versus 62%, P < 0.05) and female (61% versus 37%, P < 0.005) offspring had a significantly higher frequency of hypertension than when the ADPKD-affected parent was normotensive. The median age of diagnosis of hypertension was also significantly earlier in both male (33 years versus 40 years, P < 0.05) and female (38 years versus 50 years, P < 0.05) ADPKD patients when their affected parents were hypertensive as compared with normotensive. These effects of hypertension in the affected parent on hypertension in the ADPKD offspring were independent of age, renal volume, and renal function in the offspring. Hypertension in unaffected parents also increased the frequency of hypertension in the ADPKD female (69% versus 53%, P < 0.01), but not male (89% versus 77%, NS) subjects. The results indicate that parental hypertension influences the frequency of hypertension in ADPKD patients. [ABSTRACT FROM AUTHOR]
- Published
- 2003
- Full Text
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31. Recurrence of intracranial aneurysms in autosomal-dominant polycystic kidney disease.
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Belz, Mark M., Fick-Brosnahan, Godela M., Hughes, Richard L., Rubinstein, David, Chapman, Arlene B., Johnson, Ann M., Mcfann, Kim K., Kaehny, William D., and Gabow, Patricia A.
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INTRACRANIAL aneurysms , *POLYCYSTIC kidney disease - Abstract
Recurrence of intracranial aneurysms in autosomal-dominant polycystic kidney disease. Background. The natural history of intracranial aneurysms (ICAs) in individuals with autosomal-dominant polycystic kidney disease (ADPKD) is poorly defined. Methods. We followed twenty ADPKD subjects, eleven with ruptured and nine with intact ICA, for 15.2 ± 8.1 years (range, 6.0 to 33.2 years). Initial diagnosis was by four-vessel cerebral angiography in eighteen subjects. Follow-up examinations were four-vessel cerebral angiography in fourteen and magnetic resonance angiography (MRA) in six subjects. We examined the occurrence of new ICAs, an increase in size of existing ICAs, recurrent rupture or surgical intervention, and death. Results. Age at initial diagnosis of ICA was 37.7 ± 10.4 years (range, 20.2 to 53.1 years). Seventeen subjects (85%) had an anterior and three (15%) had a posterior ICA at initial diagnosis. On restudy, five subjects (25%) had a significant change, consisting of new ICAs in a different location in all five and an increase in size of an existing ICA in two of the five. All subjects with ruptured ICA and one subject with intact ICA had undergone surgery at the time of initial diagnosis. Ten subjects (50%) underwent further surgery 8.1 ± 6.1 years later (1.3 to 17 years). No subject died during follow-up and one subject experienced a recurrent RICA (RICA). We were unable to identify risk factors associated with development of a new ICA or increase in size of an existing ICA. Conclusion. Individuals with ADPKD and ICA appear to be at moderate risk for new ICAs and increase in size of existing ICAs; mortality and risk of recurrent rupture, however, appear to be low. [ABSTRACT FROM AUTHOR]
- Published
- 2003
- Full Text
- View/download PDF
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