Ignite Creation Date:
2024-05-05 @ 9:46 PM
Last Modification Date:
2024-10-26 @ 10:09 AM
Study NCT ID:
NCT00962286
Status:
TERMINATED
Last Update Posted:
2011-08-04
First Post:
2009-08-18
Brief Title:
Effect of Furosemide on Obesity-induced Glomerular Hyperfiltration
Sponsor:
Rabin Medical Center
Organization:
Rabin Medical Center
Study Overview
Official Title:
None
Status:
TERMINATED
Status Verified Date:
2009-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
The blood pressure did not decrease following furosemide administration
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Background Obesity is associated with a high prevalence of chronic kidney disease The glomerular hyperfiltration associated with obesity may play a role in the pathogenesis of obesity associated chronic kidney disease Attenuation of hyperfiltration by pharmacological means may slow down the development and progression of chronic renal failure The investigators have previously shown that acetazolamide a proximally acting diuretic that activates TGF by increasing solute delivery to the macula densa abates glomerular hyperfiltration The present study was designed to test the hypothesis that this decrease in hyperfiltration is specific to acetazolamide and not due to a non specific diuretic effect The aim of the present study is to evaluate the effects of the administration of furosemide po to subjects with severe obesity on glomerular hemodynamics
Methods Ten obese subjects will participate in the study They will undergo measurement of glomerular filtration rate inulin clearance GFR renal plasma flow RPF p-aminohippuric acid clearance filtration fraction fractional excretion of lithium FE LI and blood pressure before and after administration of oral furosemide 20 to 40 mg bid for 3 days The effects of furosemide on glomerular hemodynamics in obese subjects will be compared to the previously studied effects of acetazolamide
Methods Ten obese subjects will participate in the study They will undergo measurement of glomerular filtration rate inulin clearance GFR renal plasma flow RPF p-aminohippuric acid clearance filtration fraction fractional excretion of lithium FE LI and blood pressure before and after administration of oral furosemide 20 to 40 mg bid for 3 days The effects of furosemide on glomerular hemodynamics in obese subjects will be compared to the previously studied effects of acetazolamide
Detailed Description:
Almost half of the causes of death in the industrial world are due to cardio-vascular disease Two of the main risk factors for CV disease have become much more prevalent during the last decades reaching epidemic dimensions in the 21st century hypertension and obesity In 2003-2004 66 of the adult US population had a BMI over 25 while 32 had a BMI over 30 Hypertension is more prevalent in obese than in lean subjects The cause and effect relationship between these two conditions is supported by the fact that weight loss is associated with a decrease in blood pressure
Salt retention by the kidney is one of the important mechanisms involved in the pathogenesis of hypertension in obesity Studies in animal models and in humans showed that increased salt reabsorption occurs in the tubules in obesity Another renal functional abnormality occurring in obesity is glomerular hyperfiltration characterized by increased RPF and increased GFR up to twice the normal level The structural basis to these functional abnormalities is renal hypertrophy and glomerular enlargement
These functional and structural abnormalities have deleterious consequences
1 Increased urinary albumin excretion Microalbuminuria an important risk factor for CV disease has a high prevalence in obese subjects
2 Increased risk for the development of focal segmental glomerulosclerosis the so-called obesity related glomerulopathy The incidence of this disease has multiplied 10 times within 15 yrs in the USA
3 Increased rate of progression of chronic renal insufficiency in kidney disease not primarily caused by obesity Following initial glomerular damage from any cause the number of remnant functioning glomeruli decreases The consequent compensatory increase in single nephron filtration rate of these remnant glomeruli leads to further glomerular damage in kidney disease not related to obesity In the obese with chronic renal damage the obesity related hyperfiltration amplifies the compensatory augmentation in single nephron GFR of remnant nephrons thus worsening glomerular damage irrespective of the cause of the primary insult
The clinical relevance of these abnormalities is reflected in the sharp increase in the risk of developing end stage renal disease in the obese This relative risk independently of confounders as diabetes mellitus hypertension and dyslipidemia is 3 to 5 depending on the severity of obesity
Considering the role of hyperfiltration in the pathogenesis of CKD in the obese attenuation of hyperfiltration by pharmacological means may slow down the development and progression of chronic renal failure One of the tools available is activating TGF Tubuloglomerular feedback TGF refers to the alterations in GFR that can be induced by changes in tubular flow rate An increase in the delivery of chloride to the macula densa results in a reduction in GFR resulting in a decrease in the tubular flow rate delivered to the macula densa An increase in chloride delivery to the macula densa can be obtained by administrating acetazolamide a diuretic acting on the proximal tubule We have previously shown that administration of acetazolamide to obese subjects results in attenuation of glomerular hyperfiltration
The aim of the present study is to show that the effect of acetazolamide on GFR is specific and not due to its diuretic effect We will study the effects of furosemide a diuretic which does not activate TGF on GFR and RPF in obese subjects
METHODS
Inclusion criteria
10 obese men BMI30 aged 18 to 55 with glomerular hyperfiltration creatinine clearance130 mlmin will be included in the study
Exclusion criteria
Any of the following conditions
Heart failure
Known allergy to furosemide inulin or amino-hippurate
Pharmacologic treatment for hypertension cardiac disease diabetes mellitus
Treatment with corticosteroids or NSAID
Methods
A 24-hour urine collection will be performed during the week prior to the renal function test studies for assessment of sodium intake Subjects will receive 300 mg of lithium carbonate at 2200 the day before the renal function tests They will be instructed to drink 250 ml of water at bedtime Renal function tests will start at 0800 am after a 10-hour fast excepting a drink of 250 ml of water at 0700 am Intravenous catheters will be placed in each upper limb for infusion of clearance markers and blood sampling After blood sampling for urea creatinine proteins glucose electrolytes blood gases insulin renin aldosterone Hba1c CBC A priming dose of inulin 50 mgkg and p-aminohippuric acid 8 mgkg will be administered Thereafter inulin and p-aminohippuric acid will be infused continuously A 200-300 ml water load will be given during the first 60-min prime Four accurately timed urine collections of 40-60 minutes will then be obtained by spontaneous voiding Peripheral venous blood will be drawn to bracket each urine collection Arterial pressure will be measured by a trained observer after 30 minutes of rest in the supine position using an electronic oscillometric blood pressure measuring device Datascope Accutorr The cuff will be appropriately sized to the diameter of the arm and the arm positioned at the heart level At least 4 measurements will be performed during the study each measurement being the mean of 3 readings
Subjects will be started on furosemide 20 mg every 12 hours starting on day 1 at 1500 after the renal function studies Nine doses will be taken the last dose on day 4 at 7 am
In case the blood pressure does not decrease following 20 mg bid furosemide administration the study will be repeated after 4 weeks using a dose of 40 mg bid
Laboratory procedures Plasma and urinary concentrations of inulin and p-aminohippuric acid will be analyzed by colorimetric methods 2223 Lithium in serum and urine will be measured using the ICP-OES Inductively Coupled Plasma Optical Emission Spectrometer method Urine microalbumin will be determined by competitive chemiluminescent enzyme immunoassay Imulite DPC Los Angeles CA USA
Calculations GFR will be determined from the average value for the timed inulin clearances and renal plasma flow RPF - from the average value for the timed p-aminohippurate clearances The fractional excretion of lithium FE Li will be calculated as lithium clearance GFR using two timed urine collections FE Li will be determined as the average value for these two measurements Statistical Analysis The significance of differences between groups will be evaluated by paired and unpaired two-tailed Students t-test The Students t-test will be applied to non-normally distributed data albumin excretion rate and fractional lithium excretion after log transformation P005 will be considered as significant The response to treatment with furosemide will be compared to the previously studied response to treatment with acetazolamide
Salt retention by the kidney is one of the important mechanisms involved in the pathogenesis of hypertension in obesity Studies in animal models and in humans showed that increased salt reabsorption occurs in the tubules in obesity Another renal functional abnormality occurring in obesity is glomerular hyperfiltration characterized by increased RPF and increased GFR up to twice the normal level The structural basis to these functional abnormalities is renal hypertrophy and glomerular enlargement
These functional and structural abnormalities have deleterious consequences
1 Increased urinary albumin excretion Microalbuminuria an important risk factor for CV disease has a high prevalence in obese subjects
2 Increased risk for the development of focal segmental glomerulosclerosis the so-called obesity related glomerulopathy The incidence of this disease has multiplied 10 times within 15 yrs in the USA
3 Increased rate of progression of chronic renal insufficiency in kidney disease not primarily caused by obesity Following initial glomerular damage from any cause the number of remnant functioning glomeruli decreases The consequent compensatory increase in single nephron filtration rate of these remnant glomeruli leads to further glomerular damage in kidney disease not related to obesity In the obese with chronic renal damage the obesity related hyperfiltration amplifies the compensatory augmentation in single nephron GFR of remnant nephrons thus worsening glomerular damage irrespective of the cause of the primary insult
The clinical relevance of these abnormalities is reflected in the sharp increase in the risk of developing end stage renal disease in the obese This relative risk independently of confounders as diabetes mellitus hypertension and dyslipidemia is 3 to 5 depending on the severity of obesity
Considering the role of hyperfiltration in the pathogenesis of CKD in the obese attenuation of hyperfiltration by pharmacological means may slow down the development and progression of chronic renal failure One of the tools available is activating TGF Tubuloglomerular feedback TGF refers to the alterations in GFR that can be induced by changes in tubular flow rate An increase in the delivery of chloride to the macula densa results in a reduction in GFR resulting in a decrease in the tubular flow rate delivered to the macula densa An increase in chloride delivery to the macula densa can be obtained by administrating acetazolamide a diuretic acting on the proximal tubule We have previously shown that administration of acetazolamide to obese subjects results in attenuation of glomerular hyperfiltration
The aim of the present study is to show that the effect of acetazolamide on GFR is specific and not due to its diuretic effect We will study the effects of furosemide a diuretic which does not activate TGF on GFR and RPF in obese subjects
METHODS
Inclusion criteria
10 obese men BMI30 aged 18 to 55 with glomerular hyperfiltration creatinine clearance130 mlmin will be included in the study
Exclusion criteria
Any of the following conditions
Heart failure
Known allergy to furosemide inulin or amino-hippurate
Pharmacologic treatment for hypertension cardiac disease diabetes mellitus
Treatment with corticosteroids or NSAID
Methods
A 24-hour urine collection will be performed during the week prior to the renal function test studies for assessment of sodium intake Subjects will receive 300 mg of lithium carbonate at 2200 the day before the renal function tests They will be instructed to drink 250 ml of water at bedtime Renal function tests will start at 0800 am after a 10-hour fast excepting a drink of 250 ml of water at 0700 am Intravenous catheters will be placed in each upper limb for infusion of clearance markers and blood sampling After blood sampling for urea creatinine proteins glucose electrolytes blood gases insulin renin aldosterone Hba1c CBC A priming dose of inulin 50 mgkg and p-aminohippuric acid 8 mgkg will be administered Thereafter inulin and p-aminohippuric acid will be infused continuously A 200-300 ml water load will be given during the first 60-min prime Four accurately timed urine collections of 40-60 minutes will then be obtained by spontaneous voiding Peripheral venous blood will be drawn to bracket each urine collection Arterial pressure will be measured by a trained observer after 30 minutes of rest in the supine position using an electronic oscillometric blood pressure measuring device Datascope Accutorr The cuff will be appropriately sized to the diameter of the arm and the arm positioned at the heart level At least 4 measurements will be performed during the study each measurement being the mean of 3 readings
Subjects will be started on furosemide 20 mg every 12 hours starting on day 1 at 1500 after the renal function studies Nine doses will be taken the last dose on day 4 at 7 am
In case the blood pressure does not decrease following 20 mg bid furosemide administration the study will be repeated after 4 weeks using a dose of 40 mg bid
Laboratory procedures Plasma and urinary concentrations of inulin and p-aminohippuric acid will be analyzed by colorimetric methods 2223 Lithium in serum and urine will be measured using the ICP-OES Inductively Coupled Plasma Optical Emission Spectrometer method Urine microalbumin will be determined by competitive chemiluminescent enzyme immunoassay Imulite DPC Los Angeles CA USA
Calculations GFR will be determined from the average value for the timed inulin clearances and renal plasma flow RPF - from the average value for the timed p-aminohippurate clearances The fractional excretion of lithium FE Li will be calculated as lithium clearance GFR using two timed urine collections FE Li will be determined as the average value for these two measurements Statistical Analysis The significance of differences between groups will be evaluated by paired and unpaired two-tailed Students t-test The Students t-test will be applied to non-normally distributed data albumin excretion rate and fractional lithium excretion after log transformation P005 will be considered as significant The response to treatment with furosemide will be compared to the previously studied response to treatment with acetazolamide
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None