Chronic Kidney Disease, Hypertension, Microalbuminuria
Conditions
Keywords
hypertension, Chronic kidney disease, albuminuria, low salt diet, Angiotensin II receptor blocker
Brief summary
Purpose of this study 1. Intensive education for low salt diet will be enhance the anti-proteinuric effect of Olmesartan, a popular anti-hypertensive drug of angiotensin II receptor blocker, in Koreans compared to conventional prescription of medication. 2. Intensive education for low salt diet will decrease the amount of 24 hour-urine sodium excretion compared to control group, effectively.
Detailed description
1. Background A. The chronic kidney disease (CKD) is the one of the main burden of chronic diseases and the prevalence of CKD is increasing in worldwide. In Korea, the prevalence of CKD was reported as 13.7% among urban Korean adults in 2008 by our study group. B. It is well known the CKD is the most important risk factor to cardiovascular events, cardiovascular mortality, all cause-mortality, and hospitalization. The cost of the management for the CKD was high and it took 3.25% of all budgets for medical reimbursement in 2004 for all Koreans, which was ranked on the top of expenditure for single disease category. C. The most popular risk factors to CKD progression are aging, obesity, hyperlipidemia, diabetes mellitus, hypertension, and proteinuria. The hypertension and proteinuria also cause the cardiovascular events and increase the mortality rate. D. The inhibitors for renin-angiotensin aldosterone system, angiotensin II type I receptor blocker (ARB) and angiotensin converting enzyme inhibitor (ACEI), are well known medications to prevent cardiovascular events and renal functional deterioration to end stage renal disease(ESRD) in patients with hypertension, non-diabetic CKD, or diabetic nephropathy. One of the adverse events of ARB is the decrease of hemoglobin. Inoue et al reported the level of hemoglobin was decreased in amount of 0.45 ±0.89 g/dL after prescription of ARB and valsartan decreased the erythropoietin in 6 days after medication. The exact mechanism of decrease of hemoglobin by ARB was not fully verified but it is related to decrease effects of angiotensin II on aggravating hypoxia in the kidney and on the activation of hypoxia-inducible factor 1α (HIF1a) and then decrease the production of erythropoietin as in the report of Durmus et al. Considering that the relationships between ARB usage and decrease of proteinuria in transplanted kidney, between aggravation of hypoxia or HIF1a and CKD, and between ARB and the decrease of HIF1a or erythropoietin(EPO), we could postulate that the decrease of hemoglobin would not be a adverse effect of ARB to deteriorate patients' condition but a co-phenomenon of ARB's anti-RAS effect and a marker of ARB's effectiveness. E. The anti-proteinuric effect of ARB is decreased by high salt intake. For example, ARB treatment without low salt intake decreased proteinuria by 30% in patients with proteinuria 2-10g/day compared to baseline value and addition of low salt diet to ARB treatment further decreased proteinuria up to 25%. But, using slow salt tablets, increase of daily intake of sodium diminished the anti-proteinuric effect of ARB in diabetic nephropathy. F. The previous studies for the effect of ARB on proteinuria affected by sodium intake took the methods of controlled diet by researcher or using slow salt tablet but these method are not practical to adopt in real clinical practice. G. The moderate and mild decrease of daily sodium intake which lower the daily excretion of sodium by 55 mEq/day had an effect of decrease of proteinuria by 11% in hypertensive patients. H. The mean amount of sodium of Korean diets was reported as high as 208 mmol/day in Intersalt study, which is more than 11 g of salt. The recent reports also showed the trend of high salt-intake by Koreans. 2. Rationale So, It is worth to do this study because * high salt intake is prevalent in Koreans, * high salt diet diminishes the effect of ARB on proteinuria * the methods used in previous studies were not suitable to apply to clinical practice, * and there were no study to reveal the decrease of hemoglobin would the marker for the effect of ARB and not be a adverse event of ARB. 3. Objectives 1. Primary objective: The difference between amount of albuminuria after usage of Olmesartan and amount of albuminuria after prescription of Olmesartan with intensive diet education in intervention group is higher than the difference of albuminuria in control group. 2. Secondary objective: Item 1: In all patients, Olmesartan decreases the albuminuria. Item 2: In all patients, the change of hemoglobin after prescription of Olmesartan is proportional to the change of albuminuria and serum erythropoietin. Item 3: Intensive education for low salt diet induces the significant decrease of daily sodium excretion in Intervention group compared to control group. Item 4: Intensive education for low salt diet induces the significant decrease of blood pressure in Intervention group compared to control group. 4. Study Flow * Period 1. Washout period (-8 weeks;Point 0 to 0 weeks; Point 1) 2. Olmesartan Period ( 0 week; point 1 to 8 weeks; point 2) 3. Intervention period (8 week ; point 2 to 16 weeks; point 3) * For patients with taking ACEI, other ARB, diuretics, or renin inhibitor, already; Initial wash-out period for 8 weeks, and then (point 1) prescription of Olmesartan 40 mg qd for 8 weeks, and then (point 2) allocation to Intensive group or control group for 8 weeks, and then the study will be over (point 3). * For patients without taking ACEI, other ARB, diuretics, or renin inhibitor; For initial 8 weeks, adjust the blood pressures around 140/90 mmHg, and then (point 1) prescription of Olmesartan 40 mg qd for 8 weeks, and then (point 2) allocation to Intensive group or control group for 8 weeks, and then the study will be over (point 3). * Blood pressure control Adjust the blood pressures around 140/90 mmHg with other hypertensive drugs except ACEI, other ARB, diuretics, or renin inhibitor during whole period. * Intensive diet education: For 8 weeks, dietitian will call patients to take the information according to pre-defined questionnaire, to check the daily diet habit and daily food taken, and to guide how to lessen sodium intake for 30 min at each call. The call will be done once a week for 8 weeks.
Interventions
BEHAVIORALIntensive education of low salt diet
For 8 weeks, dietitian will call patients to take the information according to pre-defined questionnaire, to check the daily diet habit and daily food taken, and to guide how to lessen sodium intake for 30 min at each call. The call will be done once a week for 8 weeks.
Sponsors
Daiichi Sankyo
Daewoong Pharmaceutical Co. LTD.
Seoul National University Bundang Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
19 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Aged 19 years or more and 75 years or less * Hypertension patients: Patients whose blood pressure is 140/90mmHg and over, patients is newly diagnosed with hypertension or is prescribed antihypertensive medications. * Hypertensive patients verified 2 times or more of albuminuria 30 mg/g cr or more in a spot urine sample with interval of 1 week or more in recent 6 months * Estimated glomerular filtration rate (GFR) by Modification of Diet in Renal Disease (MDRD) equation 30 ml/min/1.73 m2 or more * Patients who give written consent to this study by oneself
Exclusion criteria
* Blood pressure more than 160/100 mmHg * Pregnant * Serum potassium level more than 5.5 mEq/L at screening period * Patients with malignancy, acute cerebral infarction, acute myocardial infarction, unstable angina, percutaneous coronary arterial intervention (PCI), or coronary artery bypass graft (CABG) in recent 6 months * Patients with diabetes mellitus * Patients who have an allergy to Olmesartan * Patients who were involved in other clinical trial in recent 1 month or are participated in screening period * Patients taking medication(s) of corticosteroid or immunosuppressant in a screening period
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| ∆Albuminuria by 24-hour Urine Protein Excretion | changes from week 8 at week 16 (week 8 - week 16) | Change in albuminuria as a 24-hour urine protein excretion by intensive education of low salt diet during taking olmesartan \*In outcome measure data table, the 24-hour urine collection at 16th week was omitted in 3 out of 245 patients (1 for intensive education group and 2 for conventional education group). Values of each study week were mean of all participants on specific study week, but ∆albuminuria (week 8 - week 16) value was mean of ∆ values of 8 weeks-16 weeks in each individuals. Therefore, values of 3 patients were excluded in mean of ∆albuminuria (week 8 - week 16). That's why simple subtraction (week 8 - week 16) of values are not matched with the data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ∆Hemoglobin (0 Week - 16 Weeks) | 0 week, 16 weeks | The change of hemoglobin after prescription of Olmesartan |
| Na Excretion Change in 24 Hour-urine Collection Between Weeks 8 and 16 | week 8 and week 16 | Change of sodium excretion rate in 24 hour-urine collection by intensive education for low salt diet at week 16 |
| Systolic and Diastolic Blood Pressure Change Between Weeks 8 and 16 | week 8 and week 16 | Change in Systolic and Diastolic Blood Pressure from Week 8 to Week 16 in the Intensive Education Group compared to the Conventional Education Group |
Countries
South Korea
Participant flow
Recruitment details
Patients were selected from 7 centers in Korea (Seoul National University Boramae Medical Center, Seoul National University Bundang Hospital, Seoul National University Hospital, Konkuk University Hospital, Dongguk University Ilsan Hospital, Kyung Hee University Medical Center, and Seoul St. Mary's Hospital) and enrolled from Mar. 2012 to Mar. 2013.
Pre-assignment details
We screened 312 patients before 8 weeks of study initiation, and 269 patients were enrolled. During the 1st 8 weeks of this study (ARB run-in), 13 patients were withdrawn. After that, 256 patients were randomized, 11 participants were dropped out between 8th week and 16th week, and 245 who completed the trial were included in the analysis .
Participants by arm
| Arm | Count |
|---|---|
| Conventional Education of Low-salt Diet Group Education for low salt diet will be conducted as in office with brief communication with a patient and a physician. | 131 |
| Intensive Education of Low-salt Diet Group For 8 weeks, dietitian will call patients to take the information according to pre-defined questionnaire, to check the daily diet habit and daily food taken, and to guide how to lessen sodium intake for 30 min at each call. The call will be done once a week for 8 weeks.
Intensive education for low salt diet : For 8 weeks, dietitian will call patients to take the information according to pre-defined questionnaire, to check the daily diet habit and daily food taken, and to guide how to lessen sodium intake for 30 min at each call. The call will be done once a week for 8 weeks. | 125 |
| Total | 256 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 |
| Overall Study | diagnosed DM | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Protocol Violation | 1 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Intensive Education of Low-salt Diet Group | Conventional Education of Low-salt Diet Group | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 24 Participants | 33 Participants |
| Age, Categorical Between 18 and 65 years | 116 Participants | 107 Participants | 223 Participants |
| Age, Continuous | 48.2 years STANDARD_DEVIATION 12.2 | 50.7 years STANDARD_DEVIATION 14.3 | 49.5 years STANDARD_DEVIATION 13.3 |
| Region of Enrollment Korea, Republic of | 125 participants | 131 participants | 256 participants |
| Sex: Female, Male Female | 54 Participants | 64 Participants | 118 Participants |
| Sex: Female, Male Male | 71 Participants | 67 Participants | 138 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 131 | 2 / 125 |
| serious Total, serious adverse events | 0 / 131 | 0 / 125 |
Outcome results
Primary
∆Albuminuria by 24-hour Urine Protein Excretion
Change in albuminuria as a 24-hour urine protein excretion by intensive education of low salt diet during taking olmesartan \*In outcome measure data table, the 24-hour urine collection at 16th week was omitted in 3 out of 245 patients (1 for intensive education group and 2 for conventional education group). Values of each study week were mean of all participants on specific study week, but ∆albuminuria (week 8 - week 16) value was mean of ∆ values of 8 weeks-16 weeks in each individuals. Therefore, values of 3 patients were excluded in mean of ∆albuminuria (week 8 - week 16). That's why simple subtraction (week 8 - week 16) of values are not matched with the data.
Time frame: changes from week 8 at week 16 (week 8 - week 16)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Conventional Education of Low-salt Diet Group | ∆Albuminuria by 24-hour Urine Protein Excretion | 24hr-urine albumin (8th week) | 483.5 mg/day | Standard Deviation 646.7 |
| Conventional Education of Low-salt Diet Group | ∆Albuminuria by 24-hour Urine Protein Excretion | 24hr-urine albumin (16th week);n=124, 118 | 487.3 mg/day | Standard Deviation 688.8 |
| Conventional Education of Low-salt Diet Group | ∆Albuminuria by 24-hour Urine Protein Excretion | Mean of ∆albuminuria (week 8-week 16); n=124, 118 | -0.4 mg/day | Standard Deviation 371.9 |
| Intensive Education of Low-salt Diet Group | ∆Albuminuria by 24-hour Urine Protein Excretion | 24hr-urine albumin (8th week) | 569.9 mg/day | Standard Deviation 718.9 |
| Intensive Education of Low-salt Diet Group | ∆Albuminuria by 24-hour Urine Protein Excretion | 24hr-urine albumin (16th week);n=124, 118 | 417.4 mg/day | Standard Deviation 597 |
| Intensive Education of Low-salt Diet Group | ∆Albuminuria by 24-hour Urine Protein Excretion | Mean of ∆albuminuria (week 8-week 16); n=124, 118 | 154.0 mg/day | Standard Deviation 489.6 |
Comparison: Differences with two-tailed P\<0.05 were considered statistically significant.p-value: 0.006t-test, 2 sided
p-value: 0.99Mixed Models Analysis
p-value: 0.001Mixed Models Analysis
Secondary
∆Hemoglobin (0 Week - 16 Weeks)
The change of hemoglobin after prescription of Olmesartan
Time frame: 0 week, 16 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Conventional Education of Low-salt Diet Group | ∆Hemoglobin (0 Week - 16 Weeks) | Hemoglobin (week 16) | 13.3 g/dL | Standard Deviation 1.7 |
| Conventional Education of Low-salt Diet Group | ∆Hemoglobin (0 Week - 16 Weeks) | Hemoglobin (week 8) | 13.5 g/dL | Standard Deviation 1.8 |
| Conventional Education of Low-salt Diet Group | ∆Hemoglobin (0 Week - 16 Weeks) | Hemoglobin changes from week 0 at week 16 | 0.46 g/dL | Standard Deviation 0.9 |
| Conventional Education of Low-salt Diet Group | ∆Hemoglobin (0 Week - 16 Weeks) | Hemoglobin (week 0) | 13.8 g/dL | Standard Deviation 1.7 |
| Intensive Education of Low-salt Diet Group | ∆Hemoglobin (0 Week - 16 Weeks) | Hemoglobin changes from week 0 at week 16 | 0.62 g/dL | Standard Deviation 0.96 |
| Intensive Education of Low-salt Diet Group | ∆Hemoglobin (0 Week - 16 Weeks) | Hemoglobin (week 8) | 13.7 g/dL | Standard Deviation 1.7 |
| Intensive Education of Low-salt Diet Group | ∆Hemoglobin (0 Week - 16 Weeks) | Hemoglobin (week 16) | 13.4 g/dL | Standard Deviation 1.7 |
| Intensive Education of Low-salt Diet Group | ∆Hemoglobin (0 Week - 16 Weeks) | Hemoglobin (week 0) | 14.0 g/dL | Standard Deviation 1.8 |
p-value: 0.187t-test, 2 sided
Secondary
Na Excretion Change in 24 Hour-urine Collection Between Weeks 8 and 16
Change of sodium excretion rate in 24 hour-urine collection by intensive education for low salt diet at week 16
Time frame: week 8 and week 16
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Conventional Education of Low-salt Diet Group | Na Excretion Change in 24 Hour-urine Collection Between Weeks 8 and 16 | week 8 | 155.5 mEq/day | Standard Deviation 71.1 |
| Conventional Education of Low-salt Diet Group | Na Excretion Change in 24 Hour-urine Collection Between Weeks 8 and 16 | week 16; n=124, 118 | 147.1 mEq/day | Standard Deviation 66.1 |
| Conventional Education of Low-salt Diet Group | Na Excretion Change in 24 Hour-urine Collection Between Weeks 8 and 16 | ∆Na excretion (week 8 - week 16);n=124, 118 | 9.0 mEq/day | Standard Deviation 54.5 |
| Intensive Education of Low-salt Diet Group | Na Excretion Change in 24 Hour-urine Collection Between Weeks 8 and 16 | week 8 | 157.4 mEq/day | Standard Deviation 74.7 |
| Intensive Education of Low-salt Diet Group | Na Excretion Change in 24 Hour-urine Collection Between Weeks 8 and 16 | week 16; n=124, 118 | 122.1 mEq/day | Standard Deviation 59.9 |
| Intensive Education of Low-salt Diet Group | Na Excretion Change in 24 Hour-urine Collection Between Weeks 8 and 16 | ∆Na excretion (week 8 - week 16);n=124, 118 | 35.4 mEq/day | Standard Deviation 64.4 |
p-value: 0.001t-test, 2 sided
Secondary
Systolic and Diastolic Blood Pressure Change Between Weeks 8 and 16
Change in Systolic and Diastolic Blood Pressure from Week 8 to Week 16 in the Intensive Education Group compared to the Conventional Education Group
Time frame: week 8 and week 16
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Conventional Education of Low-salt Diet Group | Systolic and Diastolic Blood Pressure Change Between Weeks 8 and 16 | Systolic BP at week 8 | 121.8 mm Hg | Standard Deviation 18.4 |
| Conventional Education of Low-salt Diet Group | Systolic and Diastolic Blood Pressure Change Between Weeks 8 and 16 | Systolic BP at week 16 | 121.2 mm Hg | Standard Deviation 14.9 |
| Conventional Education of Low-salt Diet Group | Systolic and Diastolic Blood Pressure Change Between Weeks 8 and 16 | sBP changes from week 8 at week 16 | 0.6 mm Hg | Standard Deviation 15.1 |
| Conventional Education of Low-salt Diet Group | Systolic and Diastolic Blood Pressure Change Between Weeks 8 and 16 | Diastolic BP at week 8 | 73.4 mm Hg | Standard Deviation 11.6 |
| Conventional Education of Low-salt Diet Group | Systolic and Diastolic Blood Pressure Change Between Weeks 8 and 16 | Diastolic BP at week 16 | 74.8 mm Hg | Standard Deviation 10.5 |
| Conventional Education of Low-salt Diet Group | Systolic and Diastolic Blood Pressure Change Between Weeks 8 and 16 | dBP changes from week 8 at week 16 | -0.7 mm Hg | Standard Deviation 10 |
| Intensive Education of Low-salt Diet Group | Systolic and Diastolic Blood Pressure Change Between Weeks 8 and 16 | Diastolic BP at week 16 | 73.1 mm Hg | Standard Deviation 10.4 |
| Intensive Education of Low-salt Diet Group | Systolic and Diastolic Blood Pressure Change Between Weeks 8 and 16 | Systolic BP at week 8 | 122.1 mm Hg | Standard Deviation 14 |
| Intensive Education of Low-salt Diet Group | Systolic and Diastolic Blood Pressure Change Between Weeks 8 and 16 | Diastolic BP at week 8 | 73.6 mm Hg | Standard Deviation 11 |
| Intensive Education of Low-salt Diet Group | Systolic and Diastolic Blood Pressure Change Between Weeks 8 and 16 | Systolic BP at week 16 | 120.4 mm Hg | Standard Deviation 14.9 |
| Intensive Education of Low-salt Diet Group | Systolic and Diastolic Blood Pressure Change Between Weeks 8 and 16 | dBP changes from week 8 at week 16 | 0.5 mm Hg | Standard Deviation 9.8 |
| Intensive Education of Low-salt Diet Group | Systolic and Diastolic Blood Pressure Change Between Weeks 8 and 16 | sBP changes from week 8 at week 16 | 1.7 mm Hg | Standard Deviation 14.6 |
p-value: >0.05t-test, 2 sided
p-value: 0.585t-test, 2 sided