Ignite Creation Date:
2024-05-05 @ 10:37 PM
Last Modification Date:
2024-10-26 @ 10:21 AM
Study NCT ID:
NCT01146288
Status:
COMPLETED
Last Update Posted:
2015-06-04
First Post:
2010-06-16
Brief Title:
Effect of Acetazolamide and Furosemide on Obesity-induced Glomerular Hyperfiltration
Sponsor:
Rabin Medical Center
Organization:
Rabin Medical Center
Study Overview
Official Title:
Effect of Acetazolamide and Furosemide on Obesity-induced Glomerular Hyperfiltration
Status:
COMPLETED
Status Verified Date:
2015-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
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 diseaseThe 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 tubuloglomerular feedbackTGF 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 compare the effects of furosemide and acetazolamide on glomerular hemodynamics in subjects with severe obesity
Methods
A randomized double-blind crossover controlled design will be used Fifteen obese subjects and ten subjects with normal body weight will participate in the study Obese subjects will undergo measurement of glomerular filtration rate GFRinulin clearance renal plasma flow RPF p-aminohippuric acid clearance filtration fraction fractional excretion of lithium FE LI and blood pressure before and after intravenous administration of furosemide 2 mg and acetazolamide 5 mgkg BW Ten subjects with normal body weight will undergo measurement of renal function without administration of diuretics
Obesity is associated with a high prevalence of chronic kidney diseaseThe 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 tubuloglomerular feedbackTGF 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 compare the effects of furosemide and acetazolamide on glomerular hemodynamics in subjects with severe obesity
Methods
A randomized double-blind crossover controlled design will be used Fifteen obese subjects and ten subjects with normal body weight will participate in the study Obese subjects will undergo measurement of glomerular filtration rate GFRinulin clearance renal plasma flow RPF p-aminohippuric acid clearance filtration fraction fractional excretion of lithium FE LI and blood pressure before and after intravenous administration of furosemide 2 mg and acetazolamide 5 mgkg BW Ten subjects with normal body weight will undergo measurement of renal function without administration of diuretics
Detailed Description:
BACKGROUND Almost half of the causes of death in the industrial world are due to cardio-vascular CV 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 USA population had a body mass indexBMIover 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 renal plasma flow RPF and increased glomerular filtration rateGFR 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 chronic kidney disease 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 tubuloglomerular feedback 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 in comparison with acetazolamide
Methods
A 24-hour urine collection will be performed during the week prior to the renal function test studies for assessment of sodium intake
Obese subjects A randomized double-blind crossover controlled design will be used Two renal function studies will be performed one before and after intravenous furosemide and the second before and after intravenous acetazolamide 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 and a 200-300 ml po water load will be given Thereafter inulin and p-aminohippuric acid will be infused continuously After the first 60 minutes 8 accurately timed urine collections of 30 to 40 minutes will 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 The cuff will be appropriately sized to the diameter of the arm and the arm positioned at the heart level At least 8 measurements will be performed during the study each measurement being the mean of 3 readings After the first 4 timed urine collections participants will receive intravenous furosemide 2 mg5min or intravenous acetazolamide 5 mgkg5 min Four other times urine collections will be performed thereafter Subjects will be randomized to receive during the first study either furosemide or acetazolamide The second study will be performed one to two weeks after the first study using the drug that had not administrated during the first study
Subjects with normal body weight will undergo measurement of renal function without administration of diuretics one renal function study same protocol like obese subjects with 4 urine collections only
Laboratory procedures Plasma and urinary concentrations of inulin and p-aminohippuric acid will be analyzed by colorimetric methods Lithium in serum and urine will be measured Urine microalbumin will be determined by competitive chemiluminescent enzyme immunoassay
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 response to treatment with acetazolamide using ANOVA
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 renal plasma flow RPF and increased glomerular filtration rateGFR 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 chronic kidney disease 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 tubuloglomerular feedback 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 in comparison with acetazolamide
Methods
A 24-hour urine collection will be performed during the week prior to the renal function test studies for assessment of sodium intake
Obese subjects A randomized double-blind crossover controlled design will be used Two renal function studies will be performed one before and after intravenous furosemide and the second before and after intravenous acetazolamide 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 and a 200-300 ml po water load will be given Thereafter inulin and p-aminohippuric acid will be infused continuously After the first 60 minutes 8 accurately timed urine collections of 30 to 40 minutes will 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 The cuff will be appropriately sized to the diameter of the arm and the arm positioned at the heart level At least 8 measurements will be performed during the study each measurement being the mean of 3 readings After the first 4 timed urine collections participants will receive intravenous furosemide 2 mg5min or intravenous acetazolamide 5 mgkg5 min Four other times urine collections will be performed thereafter Subjects will be randomized to receive during the first study either furosemide or acetazolamide The second study will be performed one to two weeks after the first study using the drug that had not administrated during the first study
Subjects with normal body weight will undergo measurement of renal function without administration of diuretics one renal function study same protocol like obese subjects with 4 urine collections only
Laboratory procedures Plasma and urinary concentrations of inulin and p-aminohippuric acid will be analyzed by colorimetric methods Lithium in serum and urine will be measured Urine microalbumin will be determined by competitive chemiluminescent enzyme immunoassay
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 response to treatment with acetazolamide using ANOVA
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