UMIN-CTR Clinical Trial

Public title

Intrarenal activation of renin-angiotensin system impairs circadian blood pressure rhythm.

Acronym

Intrarenal AGT and non-dipper BP rhythm

Scientific Title

Intrarenal activation of renin-angiotensin system impairs circadian blood pressure rhythm.

Scientific Title:Acronym

Intrarenal AGT and non-dipper BP rhythm

Region

Japan

Condition

Chronic kidney disease (CKD)

Classification by specialty

Cardiology

Nephrology

Classification by malignancy

Others

Genomic information

NO

Narrative objectives1

Kidneys play an important role in determining the circadian rhythm of BP. We have postulated that reduced renal capacity to excrete sodium into urine causes nocturnal elevation of blood pressure (BP), ie, nondippers, to compensate for diminished daytime natriuresis by enhancing pressure natriuresis during sleep. Furthermore, we had reported that not only in patients with reduced glomerular filtration rate (GFR), but also in patients with preserved GFR, such as diabetes mellitus or metabolic syndrome, renal capacity to excrete sodium into urine is impaired by enhanced tubular sodium reabsorption.
We also have reported that olmesartan, angiotensin II type 1 receptor blocker (ARB), could restore the circadian rhythms of BP and natriuresis from nondipper to dipper patterns in CKD, as seen with diuretics and sodium restriction, possibly by enhancing daytime sodium excretion. The more circadian rhythm was impaired at baseline, the more the ARB restored night-time BP fall.
On the other hand, Angiotensin (Ang) II, especially locally produced in the kidney, is one of the most powerful simulators of sodium-reabsorption at the various sites all the way from proximal tubule to the collecting ducts, and ARB has the possibility to suppress these sodium reabsorptions. Recently, urinary excretion of angiotensinogen (AGT), as well as AGT expression in the renal proximal tubules, has been proved to be useful marker of the intrarenal activation of renin-angiotensin system (RAS). In this study we investigate whether olmesartan can restore circadian BP rhythm more effectively in patients with activated intrarenal RAS leading to enhanced sodium reabsorption.

Basic objectives2

Pharmacodynamics

Basic objectives -Others

Trial characteristics_1

Confirmatory

Trial characteristics_2

Pragmatic

Developmental phase

Not applicable

Primary outcomes

The primary purpose of this study is to investigate whether there is a positive relationship between the intrarenal activation of renin-angiotensin system (RAS), represented by Angiotensinogen (AGT) expression in the renal-biopsy specimens or urinary excretion of AGT, and night/day ratio of blood pressure, natriuresis or albuminuria, and whether the more intrarenal RAS is activated at baseline, the more the reduction in night/day ratio of blood pressure, natriuresis or albuminuria is.

Key secondary outcomes

The secondary purpose of this study is to evaluate whether night/day ratio of urinary excretion rate of AGT shows positive relationship with night/day ratio of blood pressure, natriuresis or albuminuria, and negative one with creatinine clearance and to investigate, in case that the second biopsy is performed, whether the more AGT expression is reduced, the more night/day ratio of blood pressure, natriuresis or albuminuria is decreased. IHC for pro-renin and ACE2 expression is to be studied.

Study type

Interventional

Basic design

Single arm

Randomization

Non-randomized

Randomization unit

Blinding

Open -no one is blinded

Control

Uncontrolled

Stratification

Dynamic allocation

Institution consideration

Blocking

Concealment

No. of arms

1

Purpose of intervention

Treatment

Type of intervention

Medicine

Interventions/Control_1

After the baseline study, participants received single daily olmesartan in the morning (daily 20mg for 8 weeks). The dosage of olmesartan was increased to the highest dose tolerated, unless their systolic BP decreased below 90mmHg or patients felt postural dizziness. If these symptoms occurred, dosages of olmesartan were reduced.

Interventions/Control_2

Interventions/Control_3

Interventions/Control_4

Interventions/Control_5

Interventions/Control_6

Interventions/Control_7

Interventions/Control_8

Interventions/Control_9

Interventions/Control_10

Age-lower limit

15

years-old

<=

Age-upper limit

Not applicable

Gender

Male and Female

Key inclusion criteria

Eligibility criteria include the following: age of 15 years or more; hospitalized in Nagoya City University hospital to undergo a renal biopsy ; diagnosed as having chronic kidney disease (CKD) based on K/DOQI criteria (either kidney damage or glomerular filtration of <60 mL/min/1.73m2 for 3 months or more); and written informed consent was obtained.

Key exclusion criteria

Exclusion criteria are as follows; use of inhibitors of renin-angiotensin system or diuretics 1 month before enrollment; specific contraindication to a study drug; presence or possibility of pregnancy; HbA1c of 9.0 % or above; serious liver damage (GOT >100, or GPT >85); secondary hypertension; accelerated or malignant hypertension (progressive renal dysfunction with diastolic BP of >120-130 mmHg); serious congestive heart failure, coronary heart disease, arrhythmia, or systemic diseases; or any reason for ineligibility suggested by the attending doctor.

Target sample size

40

Name of lead principal investigator

1st name
Middle name
Last name	Michio Fukuda

Organization

Nagoya City University Graduate School of Medical Sciences

Division name

Department of Cardio-Renal Medicine and Hypertension

Zip code

Address

Mizuho-ku, Nagoya 467-8601, Japan

TEL

+81-52-853-8221

Email

m-fukuda@med.nagoya-cu.ac.jp

Name of contact person

1st name
Middle name
Last name	Michio Fukuda

Organization

Nagoya City University Graduate School of Medical Sciences

Division name

Department of Cardio-Renal Medicine and Hypertension

Zip code

Address

Mizuho-ku, Nagoya 467-8601, Japan

TEL

+81-52-853-8221

Homepage URL

Email

m-fukuda@med.nagoya-cu.ac.jp

Institute

Department of Cardio-Renal Medicine and Hypertension, Nagoya City University Graduate School of Medical Sciences

Institute

Department

Personal name

Organization

None

Organization

Division

Category of Funding Organization

Self funding

Nationality of Funding Organization

Co-sponsor

Department of Physiology and Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center

Name of secondary funder(s)

Organization

Address

Tel

Email

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

名古屋市立大学 (愛知県); Nagoya City University Hospital

Date of disclosure of the study information

2009

Year

10

Month

16

Day

URL releasing protocol

Publication of results

Unpublished

URL related to results and publications

Number of participants that the trial has enrolled

Results

data acquirement is not completed.
Twenty patients has been enrolled.

Results date posted

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

Participant flow

Adverse events

Outcome measures

Plan to share IPD

IPD sharing Plan description

Recruitment status

Enrolling by invitation

Date of protocol fixation

2009

Year

09

Month

02

Day

Date of IRB

Anticipated trial start date

2009

Year

09

Month

01

Day

Last follow-up date

2015

Year

02

Month

28

Day

Date of closure to data entry

2015

Year

12

Month

31

Day

Date trial data considered complete

2015

Year

12

Month

31

Day

Date analysis concluded

2015

Year

12

Month

31

Day

Other related information

Registered date

2009

Year

10

Month

07

Day

Last modified on

2017

Year

11

Month

03

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000003165