The results of the two HALT-PKD trials (Early PKD and Late PKD) were reported during the late breaking clinical trials session at Kidney Week 2014 and simultaneously published in NEJM. We still have many unanswered questions about how to treat patients with autosomal dominant polycystic kidney disease (PKD). However, the last few ASN sessions have seen several trials looking at improving care of patients with PKD. In 2012 the results of the TEMPO 3:4 trial were presented at ASN Kidney Week showing that tolvaptan resulted in slower increase in kidney size and less decline in eGFR over a 3 year period. Two of the fundamental question about the treatment of PKD patients are

1. What is the right BP medication(s)?
2. What is the right BP target?

One of the AIMS of both HALT-PKD trials (Early and Late PKD) was to test if the add-on of an ARB (telmisartan) to an ACE inhibitor (lisinopril) (Combo) was more provided greater kidney protection than monotherapy with an ACE inhibitor (lisinopril) (Mono). The Early PKD trial with younger patients and preserved kidney function also pushed the limit of blood pressure control to much lower levels than previously attempted. The standard blood-pressure target group was 120/70 to 130/80mmHg (Standard BP) and the low blood-pressure target group was quite low at 95/60 to 110/75 mm Hg (Low BP).

The Early PKD trial was presented by Dr. Arlene Chapman. This was a randomized double-blind, placebo-controlled trial conducted in 7 centers. 558 patients were randomized into one of four groups (Low BP- Mono, Low BP- Combo or Standard BP-Mono, Standard BP- Combo). The patients were followed for a maximum of 5 years (60 months). The primary outcome was the percentage change in the total kidney volume over time. The first secondary outcome was the rate of change in eGFR. Other secondary outcomes included albuminuria change over time and left ventricular mass index among other.

• Low BP group had less of an increase in kidney size as measured by MRI (5.6% vs. 6.6%, P=0.006).
• Combo was similar to Mono RAAS blockade in terms of kidney size.
• The rate of change in eGFR was similar in Mono versus Combo.
• No overall change in eGFR between Low and Standard BP.
• The left-ventricular-mass index decreased more in the low BP versus Standard BP 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 BP group and increased by 2.43% with the Standard BP group. (P<0.001).
• Low BP group had more dizziness and light-headedness

The Late PKD trial was presented by Vincent Torres. This was also a double-blind, placebo-controlled trial. 486 patients with ADPKD (eGFR 25 to 60) receive either an ACE inhibitor (lisinopril) (mono) or lisinopril and telmisartan (Combo). BP was targeted at 110/70 to 130/80 mm Hg in both groups. The composite primary outcome was the time to death, ESRD, or a 50% reduction from the baseline eGFR. Secondary outcomes included the rates of change in urinary aldosterone and albumin excretion, frequency of hospitalizations for any cause and for cardiovascular causes, incidence of pain, frequency of PKD-related symptoms, quality of life, and adverse study-medication effects. Patients were followed for 5 to 8 years.

• No significant difference between Mono and Combo therapy in the incidence of the composite primary outcome.
• Combo and Mono therapy controlled BP and lowered urinary aldosterone excretion similarly.
• The rates of decline in the eGFR, urinary albumin excretion, and other secondary outcomes were similar in the two groups.
• Adverse events, including hyperkalemia and acute kidney injury, were also similar.

In conclusion, these were two large trials that both showed that combination therapy with ACEi/ARB did not confer additional renoprotection over ACEi alone. The trials included patients at both ends of the spectrum of PKD from preserved kidney function to stage 3 CKD. Looks like combo therapy takes another hit in its utility to treat kidney disease. The interesting finding was in the Early PKD study where they showed that pushing the limits of BP control to less than 110 might provide benefit. They showed that kidney size, LV mass and urine albumin excretion all appeared better with targeting a lower BP. However, they did not detect a difference in overall eGFR. This was at the expense of more dizziness and light headedness. Whether or not these changes in kidney size will impact long term kidney function is a question open for debate. The changes in LV mass could also confer additional long term cardiovascular benefit. These studies provide important insights into the treatment of PKD. The debate about how to translate changes in kidney volume to long term renal function benefit will no doubt continue.

Dr. Matt Sparks, eAJKD Advisory Board member. 

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