- Email: [email protected]
Project title: Race, renin, genes, risk, and diabetic nephropathy
tlDDK
Academic Radiology, Vol 7, No 12, December200(
National Institute of Diabetes and Digestive and Kidney Diseases ~ROJECT TITLE: MAGNETIC RESONANCEIN RENOVASCULAR HYPERTENSION GrantNumber: PIName:
5R01DK48769-03 Edelman, Robert R.
Fiscal Year: Department: Project Start: Project End: ICD: IRG:
Abstract: DESCRIPTION: (Adapted from investigator's abstract) Renal artery stenosis (RAS) is a potential remediable cause of hypertension. Without revascularization, there is continued progression of the renal artery stenosis; the eventual outcome is often end-stage renal disease, with its associated high morbidity and mortality. Although contrast angiography is considered the "gold standard" for diagnosis, it is invasive and expensive, and does not provide information about the functional significance of the lesion. Captopril renography is commonly used to screen for functional renal artery stenosis, but its accuracy is reduced with azotemia or bilateral disease, and it does not provide anatomical information. An improved noninvasive test for renal artery stenosis could be of enormous value. Recent advances in the field of computed tomographic angiography (CTA) and magnetic resonance angiography (MRA) have opened up the possibility of noninvasive angiography of the renal arteries. Each modality has shown promise in initial human studies, but significant technical limitations remain. The investigators propose technical development and clinical testing of both modalities using a combination of phantom studies, an animal model, and studies of healthy volunteers and patients. The specific aims of this proposal are: 1. To optimize the imaging parameters for 2D STAR, and breath-hold contrast-enhanced 3D and multisection 2D MRA in a pulsatile flow phantom, and in normal volunteers. Additionally, both MRA and CTA techniques will be optimized in a porcine model of renal artery stenosis. 2. To test the hypothesis that MRA and CTA accurately depicts normal renal anatomy, including accessory vessels. 3. To determine the sensitivity and specificity of MRA and CTA in patients with suspected renal artery stenosis. 4. To test the hypothesis that the use of MRA and/or CTA is cost-effective in patients with suspected renal artery stenosis. Thesaurus Terms: angiography, artery stenosis, cardiovascular disorder diagnosis, diagnosis design/evaluation, diagnosis quality/standard, hypertension, noninvasive diagnosis, renal artery computed axial tomography, disease model, health care cost/financing, magnetic resonance imaging, phantom model bioimaging/biomedical imaging, clinical research, human subject, swine
Institution:
1160
Beth Israel Deaconess Medical Center 330 Brookline Ave Boston, MA 02215
1998 01-May-96 30-Apr-00 Nat Inst Of Diabetes And Digestive And Kidney Diseases RNM
~ROJECT TITLE RACE, RENIN, GENES, RISK, AND DIABETIC NEPHROPATHY Grant Number: PI Name:
5R01DK54668-02 Hollenberg, Norman K.
Abstract: African Americans carry a 3-6 fold increased risk oof developing nephropathy as a complication of diabetes mellitus (DM), essential hypertension (HTN), and probably other conditions. Although an increased frequency and severity of HTN and socioeconomic factors that limit health care probably contribute, multiple observations indicate that more important alternative factors are also involved. Fields ranging from epidemiology and therapeutic trials to molecular biology and genetics indicate that the renin-angiotensin system (RAS) contributes to the risk of nephropathy via mechanisms that include but go beyond HTN, perhaps involving the contribution of the RAS to growth and repair hyperplasia, and hypertrophy. Our application is based on several unanticipated observations. First, in healthy African Americans, ageadjusted renal plasma flow (RPF) was substantially less than in Caucasians, assessed in an identical protocol. Moreover, despite a high salt diet, African Americans displayed an enhanced renal vasodilator response to angiotensin-converting enzymic (ACE) inhibition with captopril, which enhanced renal vascular responsiveness to angiotensin II (Ang II). This pattern (which clearly differs from that in Caucasians and is similar to our preliminary observations in patients with DM) suggests activation of the RAS. Second, in our non-insulindependent Type 2 DM patients, our preliminary data suggest a range of hitherto unrecognized RAS abnormalities reflecting inappropriate activation and autonomous renin release. Most surprising is the paradoxical extreme RAS activation at the renal tissue level Type 2 DM patients with very low plasma renin activity (PRA) and nephropathy. Evidence for a functional contribution comes from hemodynamic measurements made during pharmacological interruption of the RAS with ACE inhibitors and Ang II antagonists, and during Ang II infusion. In Type 2 DM, race is a critical determinant of risk. Third, we have made observations which indicate that
acute hyperglycemia activates the intrarenal system and induces striking Ang II-dependent vasoconstriction. Our hypothesis is that the increase in risk of nephropathy represents an interaction between genetic predisposition based on the increased frequency of an angiotensinogen (AGT) gene polymorphism that favors renin system activation, an action of obesity and insulin resistance to amplify the effect of the polymorphism on AGT; and the renal effects of hyperglycemia to activate the intrarenal system in a setting which would favor local intrarenal Ang II production. Our goal in this study is to explore preliminary evidence that RAS activation accounts for many Type 2 DM features involving renal risk, and racial differences in risk. Thesaurus Terms: African American, diabetic nephropathy, disease/disorder proneness/risk, genetic susceptibility, noninsulin dependent diabetes mellitus, racial/ethnic difference, renin/angiotensin system angiotensin II, angiotensinogen, captopril, clearance rate, genetic polymorphism, hemodynamics, hyperglycemia, kidney function, p aminohippurate, renin clinical research, human subject
Institution:
Fiscal Year: Department: Project Start: Project End: ICD: IRG:
Brigham and Women's Hospital 75 Francis St Boston, MA 02115 1999 17-Aug-98 31-Jul-03 Nat Inst of Diabetes and Digestive and Kidney Diseases ZDK1
sensitivity. Our fourth aim is to construct test media and a CD phantom or use throughout the project but particularly in Aim 1; to measure important statistical properties of the data for use in Aim 3; to analyze measurement unceI~ainty and better understand the limitations of this approach to quantitative ultrasound. Having estabfished feasibility of the techniques in the previous project period we now man on developing and refining our hardware and software tools for investigating live tissues. Thesaurus Terms: biomedical equipment development, clinical biomedical equipment, computer processing of clinical data, image processing, kidney visualization, ultrasonography blood flow measurement, computer program/software, computer system design/evaluation, computer system hardware, cyclosporine, diagnosis design/evaluation, diagnosis quality/standard, endothelin, histology, immunosuppressive, kidney circulation, kidney disorder diagnosis, mathematical model, microcirculation, noninvasive diagnosis, phantom model, vasoconstriction dog, statistics/biometry
Institution:
Fiscal Year: Department: Project Start: Project End: ICD: IRG:
University Of Kansas Medical Center Kansas City, KS 66103 1998 Radiology 01-Feb-92 31-Mar-99 Nat Inst Of Diabetes And Digestive And Kidney Diseases ZRG7
~ROJECT TITLE =ROJECT TITLE ULTRASONIC ANALYSIS OF SOFT TISSUE STRUCTURE Grant Number: PI Name:
5R01DK43007-07 Insana, Michael F.
Abstract: We propose a plan to develop instrumentation and adaptive estimation techniques for implementing quantitative ultrasound.nlethods to study renal physiology and disease mechanisms. Our first aim is to assemble an electronic system for estimating acoustic properties and forming parametric images at high speeds. The goal is to provide the means for investigating dynamic physiological processes and eventually to study human subjects. Our second aim is to investigate the sensitivity of these measurements and explore a potential solution to the important clinical problem of managing organ transplant rejection. Our third aim is to use Bayesian estimation methods to include the information acquired over the past three years on normal tissues into the estimation process and hereby improve measurement
NONINVASIVE DIAGNOSIS OF MESENTERIC ISCHEMIA WITH MRI Grant Number: PI Name:
5R29DK46901-05 Li, King C.
Abstract: DESCRIPTION (Adapted from Applicant's Abstract): The goal of this work is to establish Magnetic Resonance Imaging (MRI) as a reliable and sensitive noninvasive diagnostic test for mesenteric ischemia. This would allow for earlier diagnosis than is currently possible using existing procedures and decreased morbidity and mortality in the acute form of the disease, and for more accurate diagnosis of the chronic form for increased success of surgical treatment. To achieve this goal, To this end, the specific aims of this work would include: 1. To prove that flow-independent T2 measurements with MR would provide accurate measurements of blood oxygen saturation in the superior mesenteric vein (SMV); 2. To prove that a threshold level of blood flow which oxygen uptake decreases can be demonstrated noninvasively by simultaneous MR measurements of superior
1161
Academic Radiology, Vol 7, No 12, December200(
National Institute of Diabetes and Digestive and Kidney Diseases ~ROJECT TITLE: MAGNETIC RESONANCEIN RENOVASCULAR HYPERTENSION GrantNumber: PIName:
5R01DK48769-03 Edelman, Robert R.
Fiscal Year: Department: Project Start: Project End: ICD: IRG:
Abstract: DESCRIPTION: (Adapted from investigator's abstract) Renal artery stenosis (RAS) is a potential remediable cause of hypertension. Without revascularization, there is continued progression of the renal artery stenosis; the eventual outcome is often end-stage renal disease, with its associated high morbidity and mortality. Although contrast angiography is considered the "gold standard" for diagnosis, it is invasive and expensive, and does not provide information about the functional significance of the lesion. Captopril renography is commonly used to screen for functional renal artery stenosis, but its accuracy is reduced with azotemia or bilateral disease, and it does not provide anatomical information. An improved noninvasive test for renal artery stenosis could be of enormous value. Recent advances in the field of computed tomographic angiography (CTA) and magnetic resonance angiography (MRA) have opened up the possibility of noninvasive angiography of the renal arteries. Each modality has shown promise in initial human studies, but significant technical limitations remain. The investigators propose technical development and clinical testing of both modalities using a combination of phantom studies, an animal model, and studies of healthy volunteers and patients. The specific aims of this proposal are: 1. To optimize the imaging parameters for 2D STAR, and breath-hold contrast-enhanced 3D and multisection 2D MRA in a pulsatile flow phantom, and in normal volunteers. Additionally, both MRA and CTA techniques will be optimized in a porcine model of renal artery stenosis. 2. To test the hypothesis that MRA and CTA accurately depicts normal renal anatomy, including accessory vessels. 3. To determine the sensitivity and specificity of MRA and CTA in patients with suspected renal artery stenosis. 4. To test the hypothesis that the use of MRA and/or CTA is cost-effective in patients with suspected renal artery stenosis. Thesaurus Terms: angiography, artery stenosis, cardiovascular disorder diagnosis, diagnosis design/evaluation, diagnosis quality/standard, hypertension, noninvasive diagnosis, renal artery computed axial tomography, disease model, health care cost/financing, magnetic resonance imaging, phantom model bioimaging/biomedical imaging, clinical research, human subject, swine
Institution:
1160
Beth Israel Deaconess Medical Center 330 Brookline Ave Boston, MA 02215
1998 01-May-96 30-Apr-00 Nat Inst Of Diabetes And Digestive And Kidney Diseases RNM
~ROJECT TITLE RACE, RENIN, GENES, RISK, AND DIABETIC NEPHROPATHY Grant Number: PI Name:
5R01DK54668-02 Hollenberg, Norman K.
Abstract: African Americans carry a 3-6 fold increased risk oof developing nephropathy as a complication of diabetes mellitus (DM), essential hypertension (HTN), and probably other conditions. Although an increased frequency and severity of HTN and socioeconomic factors that limit health care probably contribute, multiple observations indicate that more important alternative factors are also involved. Fields ranging from epidemiology and therapeutic trials to molecular biology and genetics indicate that the renin-angiotensin system (RAS) contributes to the risk of nephropathy via mechanisms that include but go beyond HTN, perhaps involving the contribution of the RAS to growth and repair hyperplasia, and hypertrophy. Our application is based on several unanticipated observations. First, in healthy African Americans, ageadjusted renal plasma flow (RPF) was substantially less than in Caucasians, assessed in an identical protocol. Moreover, despite a high salt diet, African Americans displayed an enhanced renal vasodilator response to angiotensin-converting enzymic (ACE) inhibition with captopril, which enhanced renal vascular responsiveness to angiotensin II (Ang II). This pattern (which clearly differs from that in Caucasians and is similar to our preliminary observations in patients with DM) suggests activation of the RAS. Second, in our non-insulindependent Type 2 DM patients, our preliminary data suggest a range of hitherto unrecognized RAS abnormalities reflecting inappropriate activation and autonomous renin release. Most surprising is the paradoxical extreme RAS activation at the renal tissue level Type 2 DM patients with very low plasma renin activity (PRA) and nephropathy. Evidence for a functional contribution comes from hemodynamic measurements made during pharmacological interruption of the RAS with ACE inhibitors and Ang II antagonists, and during Ang II infusion. In Type 2 DM, race is a critical determinant of risk. Third, we have made observations which indicate that
acute hyperglycemia activates the intrarenal system and induces striking Ang II-dependent vasoconstriction. Our hypothesis is that the increase in risk of nephropathy represents an interaction between genetic predisposition based on the increased frequency of an angiotensinogen (AGT) gene polymorphism that favors renin system activation, an action of obesity and insulin resistance to amplify the effect of the polymorphism on AGT; and the renal effects of hyperglycemia to activate the intrarenal system in a setting which would favor local intrarenal Ang II production. Our goal in this study is to explore preliminary evidence that RAS activation accounts for many Type 2 DM features involving renal risk, and racial differences in risk. Thesaurus Terms: African American, diabetic nephropathy, disease/disorder proneness/risk, genetic susceptibility, noninsulin dependent diabetes mellitus, racial/ethnic difference, renin/angiotensin system angiotensin II, angiotensinogen, captopril, clearance rate, genetic polymorphism, hemodynamics, hyperglycemia, kidney function, p aminohippurate, renin clinical research, human subject
Institution:
Fiscal Year: Department: Project Start: Project End: ICD: IRG:
Brigham and Women's Hospital 75 Francis St Boston, MA 02115 1999 17-Aug-98 31-Jul-03 Nat Inst of Diabetes and Digestive and Kidney Diseases ZDK1
sensitivity. Our fourth aim is to construct test media and a CD phantom or use throughout the project but particularly in Aim 1; to measure important statistical properties of the data for use in Aim 3; to analyze measurement unceI~ainty and better understand the limitations of this approach to quantitative ultrasound. Having estabfished feasibility of the techniques in the previous project period we now man on developing and refining our hardware and software tools for investigating live tissues. Thesaurus Terms: biomedical equipment development, clinical biomedical equipment, computer processing of clinical data, image processing, kidney visualization, ultrasonography blood flow measurement, computer program/software, computer system design/evaluation, computer system hardware, cyclosporine, diagnosis design/evaluation, diagnosis quality/standard, endothelin, histology, immunosuppressive, kidney circulation, kidney disorder diagnosis, mathematical model, microcirculation, noninvasive diagnosis, phantom model, vasoconstriction dog, statistics/biometry
Institution:
Fiscal Year: Department: Project Start: Project End: ICD: IRG:
University Of Kansas Medical Center Kansas City, KS 66103 1998 Radiology 01-Feb-92 31-Mar-99 Nat Inst Of Diabetes And Digestive And Kidney Diseases ZRG7
~ROJECT TITLE =ROJECT TITLE ULTRASONIC ANALYSIS OF SOFT TISSUE STRUCTURE Grant Number: PI Name:
5R01DK43007-07 Insana, Michael F.
Abstract: We propose a plan to develop instrumentation and adaptive estimation techniques for implementing quantitative ultrasound.nlethods to study renal physiology and disease mechanisms. Our first aim is to assemble an electronic system for estimating acoustic properties and forming parametric images at high speeds. The goal is to provide the means for investigating dynamic physiological processes and eventually to study human subjects. Our second aim is to investigate the sensitivity of these measurements and explore a potential solution to the important clinical problem of managing organ transplant rejection. Our third aim is to use Bayesian estimation methods to include the information acquired over the past three years on normal tissues into the estimation process and hereby improve measurement
NONINVASIVE DIAGNOSIS OF MESENTERIC ISCHEMIA WITH MRI Grant Number: PI Name:
5R29DK46901-05 Li, King C.
Abstract: DESCRIPTION (Adapted from Applicant's Abstract): The goal of this work is to establish Magnetic Resonance Imaging (MRI) as a reliable and sensitive noninvasive diagnostic test for mesenteric ischemia. This would allow for earlier diagnosis than is currently possible using existing procedures and decreased morbidity and mortality in the acute form of the disease, and for more accurate diagnosis of the chronic form for increased success of surgical treatment. To achieve this goal, To this end, the specific aims of this work would include: 1. To prove that flow-independent T2 measurements with MR would provide accurate measurements of blood oxygen saturation in the superior mesenteric vein (SMV); 2. To prove that a threshold level of blood flow which oxygen uptake decreases can be demonstrated noninvasively by simultaneous MR measurements of superior
1161