Effect of diuretics on plasma renin activity in primary hypertension: A systematic review and meta‐analysis

Plasma renin activity (PRA) is regarded as a marker of sodium and fluid homeostasis in patients with primary hypertension. Whether effects of diuretics on PRA differ according to class of diuretic, whether diuretics lead to a sustained increase in PRA, and whether changes in PRA relate to those in blood pressure (BP) is unknown. We performed a systematic review and meta‐analysis of trials investigating the antihypertensive effects of diuretic therapy in which PRA and/or other biomarkers of fluid homeostasis were measured before and after treatment.


| INTRODUCTION
Hypertension is the single most common cause of morbidity and mortality worldwide. 1 Retention of body sodium and water is thought to contribute to hypertension and diuretics are 1 of the major classes of antihypertensive treatment. 2 Plasma renin activity (PRA) or renin mass is thought to be a marker of sodium and fluid homeostasis and diuretics may be more effective in individuals with suppressed renin indicative of sodium retention. 3 Diuretic therapy leads to an increase Supported by an interdisciplinary studentship from the British Heart Foundation. in PRA, but it is not known whether this differs according to the class of diuretic or whether the rise in PRA after treatment varies over time, since compensatory mechanisms may lead to sodium and fluid re-accumulation. 4 Finally, it is not known whether the diuretic induced fall in blood pressure (BP) relates to the increase in PRA.
The objective of the present study was to perform a systematic review and meta-analysis of randomised clinical trials (RCTs) where diuretics were used to treat hypertension and measurements of PRA and/or another biomarker of sodium and fluid homeostasis were available to address these questions at the level of metadata for individual RCT.

| Search strategy
This systematic review and meta-analysis was carried out in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. 5

| Study selection and eligibility criteria
Papers were initially screened by title and abstract. Studies were eligible for inclusion if they were a RCT performed in hypertensive human subjects aged ≥18 years, examining antihypertensive effects of either a thiazide, thiazide-like, loop, mineralocorticoid receptor antagonist (MRA) or potassium-sparing diuretic with a duration of at least 1 week.
Studies investigating novel diuretics not licensed for clinical use were excluded as were studies in which subjects had pulmonary arterial hypertension or heart failure. All studies were required to have examined PRA or another volume biomarker with results available before and during diuretic treatment or, in the case of placebo-controlled trials, during treatment with placebo. Studies were eligible if diuretic therapy was added to either no previous therapy or to stable background treatment. The search was limited to the English language only and review articles were disregarded. Titles and abstracts were screened by 1 author (R.J.M.), and the same author reviewed the fulltext articles.

| Data collection process
Data were extracted independently by 1 author (R.J.M.) using a standard form. This included: author, year of publication, class of diuretic(s) and dose used, protocol (including presence of background therapy and whether placebo controlled), sample size, average age, sex distribution, ethnicity (if available), and prevalence of diabetes (if available). Outcome measurements were: mean (± standard deviation/standard error) of values for BP and PRA or other volume biomarker before and during diuretic (and before and during placebo treatment in placebo-controlled studies) and the difference between values on and before treatment. If standard deviations were not reported, these were calculated from standard errors, P-values or confidence intervals. The duration of diuretic treatment at the time of measurement was also recorded. Where only graphical reports of measurements such as PRA and BP were available, an estimation from the graph was taken if it was judged to be accurate to within 10%.
Units of PRA were converted to ng/mL/h if other units were used.

| Quantitative data synthesis and statistical analysis
Meta-analysis was conducted using Comprehensive Meta-Analysis Software Version 3 (Biostat, Englewood, NJ, USA). 6 Meta-analysis was performed only for PRA as there were too few studies using other volume markers to allow a meaningful analysis. Net changes in PRA were obtained as the difference from baseline after treatment with either diuretic or placebo. If there was no standard error of the mean change stated, it was estimated from the P-value, number of observations and size of the change. A random-effects model was used to compensate for between-study heterogeneity in terms of demographic inconsistencies and different diuretic dose 7 with calculation of the standardised mean difference in PRA and its 95% confidence interval (CI). Statistical heterogeneity was assessed using Cochran's Q test. 8 P < .05 was considered statistically significant and all tests were 2-tailed.

| Metaregression
Random-effects metaregression was performed using the method of moments to evaluate the association between standardized difference in PRA and duration of study at the time of measurement of PRA and between the standardized difference in PRA and change in systolic BP (SBP).

| Publication bias
Potential publication bias was assessed by inspection of Begg's funnel plot asymmetry and Egger's asymmetry tests. 9 3 | RESULTS

| Description of studies
The study selection process is detailed in a flow chart as per PRISMA guidelines ( Figure 1). The initial MEDLINE search returned 451 results, Embase 466 and Central 767 (1684 in total). After removal of duplicates there were 920 articles of which 727 were excluded based on title and abstract. The remaining 193 full-text articles were assessed for eligibility and 132 were excluded for various reasons (Figure 1).
The remaining 61 articles were included in the qualitative synthesis.
The most common biomarker measured was PRA (30/61 studies) and the most commonly used diuretics were the thiazide class. For trials in which PRA was measured, the mean age was 50.7 ± 8.37 years, and % of male subjects was 54.3 ± 21.5%. Classes of diuretic were thiazide/ thiazide-like (

| Meta-analysis: Effect of placebo and diuretic on PRA
Placebo had a negligible effect on PRA in the present analysis ( Figure 2A). Standardized difference in mean PRA after placebo was

| Metaregression: Relation of change in PRA after diuretic to duration of treatment and change in BP
Random-effects metaregression was performed to examine whether the increase in PRA varied with duration of diuretic treatment and whether change in SBP was associated with change in PRA. The increase in PRA was not significantly related to duration of treatment (slope −0.0001, 95% CI -0.02, 0.02, P = .99, Figure 3) and changes in SBP were independent of changes in PRA (coefficient −0.004, 95% CI -0.02, 0.007, P = .45, Figure 4).

| Publication bias
The  debated and it is not clear whether diuretics lead to a sustained reduction in body sodium and intravascular volume because of compensatory mechanisms leading to sodium and fluid re-accumulation.
For example, 4-6 weeks after initiation of thiazide diuretic therapy, plasma and extracellular fluid volume have been found to return to near the original level despite continued reduction in BP. [41][42][43] The main finding of the present analysis is that diuretics lead to a  The duration of studies was relatively short. There were relatively few studies performed on nonthiazide or nonthiazide-like diuretics and therefore there was limited power to detect a difference between different classes of diuretic. The MRA/potassium sparing group was mostly composed of spironolactone which in many trials was used at high dose unrepresentative of its current use in primary hypertension.
In conclusion, this systematic review and meta-analysis demonstrated that diuretic therapy in hypertension leads to a sustained increase in PRA that does not differ between classes of diuretics and is unrelated to the fall in BP. This may be due to of homeostatic mechanisms limiting effects of diuretics on sodium and fluid retention and