EAL

CKD: Potassium (2010)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

The purpose of this study was to compare the effect of ACE inhibitors with angiotensin receptor blockades (ARB) on serum potassium in subjects with early chronic kidney disease.

Inclusion Criteria:

1. 18-75 years of age.

2. Serum potassium >4.3 and <5.5 mEq/L

3. History of hypertension

4. Creatinine Clearance (CrCl) 30-80 ml/min.

Exclusion Criteria:

1. Unstable renal function or active renal disease.

2. Patients requiring diuretics for edema management.

3. Those requiring 3 or more medications for hypertension management.

4. Recent history or evidence of alcohol or drug abuse.

5. Known allergies to ACE inhibitor, angiotension II antagonists, or iodine.

6. Positive for HIV.

7. Significant hepatic disease with SGOT or SGPT > 3x upper limit of normal, or total bilirubin or alkaline phosphatase >2.5.

8. Average sitting blood pressure >200/115 mm Hg.

9. Unstable angina on treatment, or history of MI or CABG or angioplasty within 3 months of study entry.

10. History of stroke within 3 months of study entry, TIA within 6 months of study entry.

11. Ventricular tachyarrhythmias requiring therapy.

12. CHF, NYHA Class II, III or IV.

13. Pregnancy, lactation, or women of childbearing potential.

14. History of significant malabsorption or GI surgery.

15. Daily use of nonsteroidal anti-inflammatory agents (aspirin up to 325 md/day permissible) >20 d/month.

Description of Study Protocol:

Recruitment: Subjects were selected from screening through chart review of lab data, medical history, recent physical exam findings, and current medical status.

Design: Randomized, crossover, multicentered, open-label design.

Medical history and physical exam were completed on all subjects.

Subjects instructed to avoid salt substitutes.

Subjects were instructed and encouraged to follow <120 mEq/d (2,760 mg) sodium diet

Subjects were followed during a 2 wk washout period, and then randomly assigned to either valsartan (80 mg/d) or lisinopril (10 mg/d) for 4 wk, followed by a 2 wk washout period, and then 4 wk on the other medication.

Subjects were dropped from the study if diastolic blood pressure was >115 mm Hg during the first 2 wk washout period, if systolic blood pressure could not be reduced to <180 mm Hg, or diastolic blood pressure <100 mm Hg while on the randomized drug.

Subjects were asked to stop the study medications if serum K+ was >6.0 mEq/L.

Biochemical data: Blood samples were taken after each washout period, and after each study period; 24-hour urine samples were collected immediately before the blood samples were taken.

Blinding Used (if applicable): not specified.

Intervention (if applicable): randomized, crossover trial of ACE inhibitor lisinopril (10 mg/day)or ARB valsartan (80 mg/day).

Statistical Analysis: Primary analysis involved comparison of the average differences from baseline between the two antihypertensive drugs. Secondary analysis involved comparison in plasma renin levels, angiotensin II, and urinary values for potassium, aldosterone, sodium, and others.

Comparisons were made using the paired t-test for each patient. Baseline characteristics were compared between the 2 groups using chi-square or Wilcoxon signed-rank test (when relevant sample size was less than 30), as appropriate. Linear relationships between variables were examined using multiple regression analyses. Study data were also analyzed using methods of Senn, both as an alternative analysis and to test the assumption of no carryover effect from the first treatment to the second.

Data Collection Summary:

Timing of Measurements: Blood samples were taken after each washout period, and after each study period; 24-hour urine samples were collected immediately before the blood samples were taken

Dependent Variables:

GFR
plasma aldosterone
serum potassium

Independent Variables:

lisinopril or valsartan, compliance not assessed

Control Variables:

Description of Actual Data Sample:

Initial N: 37 subjects

Attrition (Final N): 35 (21 male, 14 female)

Age: mean age was 56±2 yr

Ethnicity: 19 were African-American, 16 were Caucasian

Other Relevant Demographics:

Baseline Characteristics by GFR:
	<60 ml/min	>60 ml/min	P
n	18	17	0.05
Age, yr	52±3	60±2	NS
Weight, kg	101±7	81±2	0.01
BMI	34±1	29±1	0.02

Anthropometrics: Weight was 91 ± 4 kg; BMI was 31±1.

Location: United States

Summary of Results:

Metabolic and hemodynamic data:
Blood pressure, mm Hg
Systolic	146±4	153±4	NS
Diastolic	87±2	89±2	NS
Serum creatinine, mg/dL	1.6±0.1	1.1±0.1	0.0005
GFR, Ml/min	43±2	88±5	0.0005
Serum K+, MEq/L	4.6±0.1	4.3±0.1	0.04
Renin activity, Ng/ml/hr	2.4±0.7	0.5±0.1	0.01
Angiotensin II, Pg/mL	31±4	22±2	0.05
Aldosterone, Pg/ml	6.3±0.8	7.1±1	NS

Metabolic/ hemodynamic Changes with Treatment (GFR <60 ml/min):
	Baseline		Post Treatment
	ARB+	ACE+	ARB+	ACE+
Blood pressure, mm Hg
Systolic	146	148	138	139a
Diastolic	87	88	83	84a
Serum creatinine, mg/dL	1.6	1.5	1.6	1.5
GFR, Ml/min	43	42	43	43
Serum K+, MEq/L	4.5	4.6	4.6	4.9a
Renin activity, Ng/ml/hr	3	3	11a	7a
Angiotensin II, Pg/mL	30	31	39	23a
Aldosterone, Pg/ml	5.9	6.8	4.4	3.6a
aP<0.05 compared to baseline value
ARB+= angiotensin receptor blockade = valsartan; ACE += angiotension converting enzyme = lisinopril.

For the total group, serum K+ changes were not significantly different between the valsartan (ARB) or losinopril (ACE) treatments; there was no change in GFR or serum creatinine with either medication.

For the subgroup with GFR <60 ml/min, those who received the ACE (lisinopril) demonstrated significant increase in serum K+ of 0.28 mEq/L above the mean baseline of 4.6 mEq/L (P=0.04). This increase in serum K+ was also accompanied by a decrease in plasma aldosterone (P=0.003).

Relative to the total group, the change in serum K+ from baseline to post-treatment in the lisinopril (ACE) group was increased among those with GFR <60 ml/min. Those taking valsartan (ARB) however demonstrated a smaller rise in serum K+, 0.12 mEq/L above baseline (P=0.10), a 43% lower value when compared with the change in those who received lisinopril.

Author Conclusion:

In the presence of renal insufficiency, the angiotension receptor blockade medication valsartan did not raise serum K+ to the same degree as the ACE inhibitor, lisinopril. This differential effect on serum K+ is related to a relatively smaller reduction in plasma aldosterone by the angiotensin receptor blockade therapy and is not related to changes in GFR. This study provides evidence that serum K+ increases are less likely with angiotension receptor blockade therapy compared with ACE inhibitor therapy in people with renal insufficiency.

Funding Source:

Reviewer Comments:

This study did not report using a dietitian to instruct patients on a sodium-restricted diet. Also, urine sodium was not measured to monitor sodium intake.

This study demonstrates the importance of monitoring serum potassium in subjects taking ACE inhibitors with a GFR <60 ml/min.

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		???
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	???
3.	Were study groups comparable?		N/A
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	N/A
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	N/A
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	N/A
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
4.	Was method of handling withdrawals described?		???
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	No
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	???
	4.4.	Were reasons for withdrawals similar across groups?	???
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
5.	Was blinding used to prevent introduction of bias?		Yes
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	???
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	Yes
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		???
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	Yes
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	N/A
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	???
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	No
	6.6.	Were extra or unplanned treatments described?	???
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	Yes
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	???
	7.7.	Were the measurements conducted consistently across groups?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	N/A
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	N/A
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	No
	10.2.	Was the study free from apparent conflict of interest?	Yes