Blood pressure in early autosomal dominant polycystic kidney disease

Abstract

Background: Hypertension is common in autosomal dominant polycystic kidney disease (ADPKD) and is associated with increased total kidney volume, activation of the renin-angiotensin-aldosterone system, and progression of kidney disease.

Methods: In this double-blind, placebo-controlled trial, we randomly assigned 558 hypertensive participants with ADPKD (15 to 49 years of age, with an estimated glomerular filtration rate [GFR] >60 ml per minute per 1.73 m(2) of body-surface area) to either a standard blood-pressure target (120/70 to 130/80 mm Hg) or a low blood-pressure target (95/60 to 110/75 mm Hg) and to either an angiotensin-converting-enzyme inhibitor (lisinopril) plus an angiotensin-receptor blocker (telmisartan) or lisinopril plus placebo. The primary outcome was the annual percentage change in the total kidney volume.

Results: The annual percentage increase in total kidney volume was significantly lower in the low-blood-pressure group than in the standard-blood-pressure group (5.6% vs. 6.6%, P=0.006), without significant differences between the lisinopril-telmisartan group and the lisinopril-placebo group. The rate of change in estimated GFR was similar in the two medication groups, with a negative slope difference in the short term in the low-blood-pressure group as compared with the standard-blood-pressure group (P<0.001) and a marginally positive slope difference in the long term (P=0.05). The left-ventricular-mass index decreased more in the low-blood-pressure group than in the standard-blood-pressure group (-1.17 vs. -0.57 g per square meter per year, P<0.001); urinary albumin excretion was reduced by 3.77% with the low-pressure target and increased by 2.43% with the standard target (P<0.001). Dizziness and light-headedness were more common in the low-blood-pressure group than in the standard-blood-pressure group (80.7% vs. 69.4%, P=0.002).

Conclusions: In early ADPKD, the combination of lisinopril and telmisartan did not significantly alter the rate of increase in total kidney volume. As compared with standard blood-pressure control, rigorous blood-pressure control was associated with a slower increase in total kidney volume, no overall change in the estimated GFR, a greater decline in the left-ventricular-mass index, and greater reduction in urinary albumin excretion. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; HALT-PKD [Study A] ClinicalTrials.gov number, NCT00283686.).

Figure 1. Enrollment, Randomization, and Follow-up of the Study Participants

We screened 1156 participants, of whom 558 were randomly assigned to receive either lisinopril–telmisartan or lisinopril–placebo. Overall, 423 participants completed the trial according to the protocol (i.e., full study participation). Some patients modified their consent to less than full participation (i.e., discontinued the study drug, reduced the number of study assessments or visits, or both). TKV denotes total kidney volume.

Figure 2. Changes in Total Kidney Volume and Estimated Glomerular Filtration Rate (eGFR) during Follow-up and Subgroup Analyses, According to Blood-Pressure Group

The logarithm-transformed total kidney volume (Panel A) and eGFR (Panel B) over time according to blood-pressure group and prespecified subgroup analyses (Panel C) are presented. In Panels A and B, symbols represent means, and I bars 95% confidence intervals (CI); the solid lines (standard blood pressure) and dashed lines (low blood pressure) represent model-based trajectories. In Panel C, the absolute treatment effect is the between-group difference in the annual slope. P values associated with overall subgroups correspond to interactions of subgroup by month by study group; all other P values correspond to interactions of month by study group within a particular subgroup. The slope estimates for the total kidney volume were based on linear mixed-effects models with natural log transformations on the outcome and were converted to the annual percentage change. Follow-up time ranged from 5 to 8 years.

Figure 3. Changes in Total Kidney Volume and eGFR during Follow-up, and Subgroup Analyses, According to Treatment Group

The logarithm-transformed total kidney volume (Panel A) and eGFR (Panel B) over time according to treatment group and prespecified subgroup analyses (Panel C) are presented. In Panels A and B, symbols represent means, and I bars 95% confidence intervals; the solid lines (lisinopril–telmisartan) and dashed lines (lisinopril–placebo) represent model-based trajectories. In Panel C, the absolute treatment effect is the between-group difference in the annual slope. P values associated with overall subgroups correspond to interactions of subgroup by month by study group; all other P values correspond to interactions of month by study group within a particular subgroup. The slope estimates for total kidney volume were based on linear mixed-effects models with natural log transformations on the outcome and were converted to annual percentage change. Follow-up time ranged from 5 to 8 years.