Slowing Progression and Treating Blood Pressure in ADPKD Patients?

 

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease and accounts for approximately 10% of all patients currently on dialysis in the United States. It is characterized by a relentless growth of cysts in the kidney that ultimately leads to kidney failure in almost all patients. The optimal blood pressure target to slow progression of ADPKD, and whether to use dual renin-angiotensin-aldosterone system (RAAS) blockers (dual blockade) to slow progression, had hitherto remained unanswered. Two major studies HALT-PKD [study A and study B] published in the New England Journal of Medicine (NEJM)1,2 provide important insights on how blood pressure (BP) should be managed.

These two studies, study A and study B, looked at different populations of ADPKD patients. Study A recruited younger patients with mild renal dysfunction (estimated glomerular filtration rate [eGFR] ≈91 mL/min/1.73m2), whereas study B recruited older patients with more severe renal impairment (eGFR ≈48 mL/min/1.73m2).

Study A by Schreir and colleagues1 was a 2-by-2 factorial design, placebo controlled double blind randomized trial of 558 hypertensive subjects with a mean eGFR of approximately 91 mL/min/1.73m2. The research questions were whether a low BP target of 95/60 to 110/75 mmHg was superior to a standard target of 120/70 to 130/80 mmHg, and whether dual RAAS blockade (with lisinopril and telmisartan) was superior to single blockade (lisinopril alone) in slowing % change in total kidney volume.

The lower BP target in study A was associated with a significantly slower annual percentage increase in total kidney volume (≈14% benefit), although without differences in the slope of the estimated GFR. This benefit seemed greatest among men, patients under the age of 30 years, and individuals with large kidneys. Left-ventricular-mass index and urinary albumin excretion were also better in patients assigned to the low BP arm. Dizziness and lightheadedness were more common in patients in the low BP arm, compared to those assigned to the standard-blood-pressure target. However, no benefit to dual RAAS blockade over the use of lisinopril alone was observed.

Study B by Torres et al.2 was similarly designed to study A but recruited patients with more advanced renal impairment. Four hundred and eighty six patients were enrolled with a mean eGFR of ≈48 mL/min/1.73m2. The research question was whether there was a benefit of dual RAAS blockade (lisinopril+telmisartan) versus an angiotensin converting enzyme inhibitor alone (lisinopril). No difference was observed between the two arms of the study for the composite primary end point of time to death, end-stage renal disease, or a 50% reduction from the baseline eGFR.

These studies had some important limitations. First, in study A the primary outcome measure was not a hard end point—increase in kidney volume adjusted for various covariates simply doesn’t resonate as powerfully as a clinically meaningful outcome such as the slope of eGFR decline, doubling of serum creatinine, or the likelihood of starting dialysis. And, since change in kidney function was not different between the low and standard BP arms, it raises questions about the clinical significance of a change in kidney volume. That said, kidney volume is probably quite a powerful direct indicator of disease progression in ADPKD and the lack of change in kidney function over the duration of the study could reflect relatively short follow-up for a disease that progresses over decades and a relatively small sample size limiting statistical power. The other major limitation in the HALT PKD studies was that patients in both study A and B were treated with some form of renin-angiotensin blockade and the benefit of blood pressure reduction without the use of RAAS blockade could not be evaluated. Perhaps the benefit of treatment with lisinopril is all a function of blood pressure reduction given that both groups received RAAS blockade?

Despite these and other limitations both of the HALT-PKD studies provide valuable insights into how blood pressure should be managed in patients with ADPKD.

My conclusions are the following:

Patients with mild ADPKD

  • Aggressively treat blood pressure aiming for a systolic range of 95 to 110 mmHg in patients with mild ADPKD.
    • Men with ADPKD, particularly with large kidneys, age <30 years of age benefit most from aggressive BP treatment.
  • Use RAAS blockade to control blood pressure, but avoid dual blockade. In both younger and older ADPKD patients, lisinopril was well tolerated.
  • Be careful with aggressive BP treatment since it may be associated with symptoms of dizziness and lightheadedness.

Patients with more advanced ADPKD

  • Aim for a BP target of 120/80 mmHg; a benefit of a lower BP goal in these patients has not been demonstrated, but more aggressive individualized treatment should be considered.
  • Dual blockade with an ACEi and ARB in patients with more advanced renal impairment does not slow the progression of ADPKD and should be avoided.

References

  1. Schrier RW, Abebe KZ, Perrone RD, et al.; HALT-PKD Trial Investigators. Blood pressure in early autosomal dominant polycystic kidney disease. N Engl J Med. 2014 Dec 11;371(24):2255-66. doi: 10.1056/NEJMoa1402685.
  2. Torres VE, Abebe KZ, Chapman AB, et al. HALT-PKD Trial Investigators. Angiotensin blockade in late autosomal dominant polycystic kidney disease. N Engl J Med. 2014 Dec 11;371(24):2267-76. doi: 10.1056/NEJMoa1402686. Epub 2014 Nov 15.