In patients at early stages of autosomal dominant polycystic kidney disease (ADPKD), compared with standard blood-pressure control, rigorous blood-pressure control was associated with a slower increase in total kidney volume. That was one of the findings of a double-blind, placebo-controlled trial conducted recently by Robert W. Schrier, MD, and colleagues. The researchers reported study results in the New England Journal of Medicine [2014; 371(24):2255-2266].
According to the researchers, patients with ADPKD experience gradual cyst enlargement over a long period prior to the loss of kidney function; total kidney volume is measured using magnetic resonance imaging. Hypertension, which occurs early in the disease, is associated with progression to end-stage renal disease (ESRD) and death from cardiovascular causes.
Previous studies have suggested a role of the renin-angiotensin-aldosterone system (RAAS) in the pathogenesis of hypertension in patients with ADPKD. Animal studies have supported the hypothesis that activation of the RAAS may result in renal-cyst growth by means of its mitogenic effect; however, this has not been fully studied in patients with ADPKD. Further, is it unknown whether more aggressive antihypertensive therapy or an increase in the use of RAAS inhibitors delays progression to ESRD in patients with ADPKD.
The current study was designed to assess the efficacy and safety of combined treatment with lisinopril (an angiotensin-converting-enzyme inhibitor) and telmisartan (an angiotensin-receptor blocker) versus treatment with lisinopril alone, as well as standard versus low blood-pressure targets.
Eligible study participants were 15 to 49 years of age with ADPKD with estimated glomerular filtration rate (eGFR) of >60 mL/min/1.73 m2 of body-surface area. The primary outcome was the annual percentage change in total kidney volume. Secondary outcomes included rates of change in eGFR, rates of change in urinary aldosterone excretion, urinary albumin excretion, left-ventricular-mass index, and renal blood flow; frequency of hospitalization for any cause and for cardiovascular causes; quality of life; frequency of pain associated with symptoms of ADPKD; and study medication-related adverse effects.
Following application of inclusion and exclusion criteria, 558 participants were randomized to either a standard blood-pressure target (120/70 to 130/80 mm Hg) (n=284) or a low blood-pressure target (95/60 to 110/75 mm Hg) (n=274). Of those 558 participants, 75.8% (n=423) completed the trial according to the protocol. Of those, 8.7% (n=37) discontinued the study medication prior to the end of the trial; 6.1% modified their consent to less than full study participation; and 18.1% were lost to follow-up.
The study analyses included 139 patients in the standard-blood pressure group who were assigned to receive lisinopril-telmisartan and 143 in that group who were assigned to receive lisinopril-placebo; 132 in the low-blood pressure group who were assigned to receive lisinopril-telmisartan and 139 in that group who were assigned to receive lisinopril-placebo. There were differences in systolic and diastolic blood-pressure levels between the low-blood pressure group and the standard-blood-pressure group, as measured at home; the differences were maintained throughout the trial.
In the low-blood-pressure group the annual percentage increase in total kidney volume was 5.6% compared with 6.6% in the standard-blood-pressure group (P=.006). There were no significant differences between the lisinopril-telmisartan group and the lisinopril-placebo group.
The overall change in eGFR was similar in the low-blood-pressure group and the standard-blood-pressure group (-2.9 and -3.0 mL/min/1.73 m2 per year, respectively; P=.55). In the short-term phase, the decline in eGFR was significantly greater in the low-blood-pressure group than in the standard-blood-pressure group (-3.1 vs 0.5 mL/min/1.73m2 per 4 months, respectively; P<.001). In the long-term phase, the slope of the eGFR did not differ significantly between the two groups.
In the low-blood-pressure group, urinary albumin excretion decreased, whereas it increased in the standard-blood-pressure group (-3.77 per year vs 2.43% per year; P<.001). The low-blood-pressure group had a greater reduction in the left-ventricular mass index than the standard-blood-pressure group did (-1.17 vs -0.57 g per square meter per year; P<.001).
The decline in renal blood flow was similar in the two groups; however, there was greater increase in renal vascular resistance in the standard-blood-pressure group than in the low-blood-pressure group (P<.001).
There were no significant differences in the physical component scores on the 36-item Short Form General Health Survey; there was significant improvement in the mental component scores in the standard-blood-pressure group as compared with the low-blood-pressure group. At the end of the study, dizziness and light-headedness were more common in the low-blood-pressure group than in the standard-blood-pressure group (80.7% vs 64.4%; P=.02).
“In conclusion, the rate of total kidney-volume growth and the slope of the eGFR were not affected by dual blockage of the RAAS. Aggressive blood-pressure control was safe in young, hypertensive patients with ADPKD and preserved kidney function. This level of blood-pressure control, as compared with standard blood-pressure control, was associated with a modest reduction in total kidney volume over time, without differences in the slope of the eGFR. Improvement in markers of the secondary outcomes, including the left-ventricular-mass index and urinary albumin excretion, also suggests a benefit of aggressive blood-pressure control,” the researchers said.
- In patients with ADPKD, hypertension is associated with progression to end-stage renal disease and death from cardiovascular causes.
- In the low-blood-pressure group the annual percentage increase in total kidney volume was 5.6% compared with 6.6% in the standard-blood-pressure group (P=.006).
- There were no significant differences between the lisinopril-telmisartan group and the lisinopril-placebo group.