High-Impact Clinical Trials Offer New Insights into ADPKD and AKI

A total of 27 late-breaking clinical trials were presented at ASN Kidney Week 2014 in Philadelphia. These studies detailed new understandings and innovations in multiple therapeutic areas, including acute kidney injury (AKI), autosomal dominant polycystic kidney disease (ADPKD), dialysis, and diabetic nephropathy. This article highlights some of the leading science presented at the oral plenary High-Impact Clinical Trials session that potentially could influence the clinical approach of kidney health professionals in the United States and beyond.

HALT PKD trials

Two new prospective, multicenter randomized clinical trials sought to understand the influence of blood pressure control on disease progression and comorbidities in patients with ADPKD, the fourth leading cause of end stage renal disease (ESRD). A combination of two studies, the HALT PKD trials first evaluated the effects of rigorous blood pressure control on disease progression and whether combined antihypertensive therapies conferred an additional benefit.

The HALT A study enrolled 558 patients with early ADPKD to determine if rigorous blood pressure control conferred benefits over standard blood pressure control related to a reduced rate of increase in total kidney volume and greater declines in measures of heart and kidney problems (1). Healthy patients between 15 and 49 years old (with an eGFR greater than 60 mL/min/1.73 m2) were randomized to either standard blood pressure control (120–130/70–80 mm Hg) or low blood pressure control (95–110/60–75 mm Hg) groups. The primary end point was disease progression measured as percent change in total kidney volume.

Low blood pressure control was well tolerated and resulted in a 14.2 percent slower growth of total kidney volume over five years, while conferring some cardiovascular benefits. “Hypertension was very well controlled in both treatment groups,” said lead author Arlene Chapman, MD. “The results emphasize the potential importance of early detection and aggressive treatment of hypertension in ADPKD.”

In the HALT B study, researchers included 486 ADPKD patients with chronic kidney disease (CKD) stage 3 to find out if treatment with an angiotensin-converting enzyme (ACE) inhibitor was safe and by itself sufficient to achieve blood pressure control in the majority of patients (2). This time, patients were randomized to either ACE inhibitor monotherapy or ACE inhibitor plus an angiotensin-receptor blocker (ARB).

Although both treatment regimens were well tolerated, dual therapy didn’t confer any additional treatment benefit. “Both studies showed that ACE inhibitors alone or in combination with ARBs are safe and well tolerated and achieve excellent blood pressure control in the majority of patients with ADPKD,” said lead author Vincente Torres, MD, PhD. “However, both failed to demonstrate any superiority of dual blockade with an ACE-I and an ARB compared to an ACE inhibitor alone.” Hypertension in ADPKD develops early and associates with disease progression.

Glucose control could help reduce diabetic nephropathy incidence

Longitudinal data obtained in a post-trial observational study suggest that glucose control may be a key determinant for ESRD risk. The ADVANCE-ON Trial found patients who maintained strict glucose control demonstrated evidence of a sustained and significant reduction in ESRD over a long period of time with a median of nearly 10 years.

Follow-up of 8494 patients in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, which is the largest clinical trial on diabetes, revealed that intensive glucose control leads to long-term reductions in the risk of developing ESRD (3).

“Our study also suggests that the benefits are greater when treatment is begun early in the course of the disease, and in people in whom blood pressure is well-controlled,” said lead author Vlado Perkovic, MBBS, PhD, FASN. “These results suggest that finding better ways to control glucose levels is key to preventing the epidemic of kidney failure due to type 2 diabetes around the world.”

New understandings in AKI

Two studies evaluated potential therapies for AKI in the hospital setting, a common complication that can lead to kidney failure and in some cases death.

The first examined the use of aspirin and clonidine with non-cardiac surgery to determine if it could reduce the incidence of AKI. “We need treatments to prevent AKI in the surgical setting, and early data suggested taking aspirin in this regard might be beneficial,” said Amit Garg, MD, the study’s author. The substudy of the PeriOperative ISchemic Evaluation-2 (POISE-2) Trial included 6905 patients undergoing non-cardiac surgery. Investigators found that use of aspirin around the time of surgery increased the risk of major bleeding, which was associated with a greater risk of subsequent AKI. The use of clonidine (a medication used to treat hypertension) around the time of surgery increased the risk of low blood pressure, which was associated with a greater risk of subsequent AKI.

Compared with placebo, neither aspirin nor clonidine altered the risk of most AKI observed after major non-cardiac surgery. “Approximately 200 million adults undergo major non-cardiac surgery each year, and among patients taking aspirin prior to surgery there is substantial practice variability as to whether it is held or not in the perioperative period,” the study investigators noted (4).

Another AKI study evaluated the use of mesenchymal stem cells in patients undergoing cardiac bypass surgery. The ACT-AKI study built on previous work that demonstrated the cells’ potential to prevent AKI and promote recovery of renal function after it occurred. A trial of 156 patients who developed AKI following cardiac surgery found that treatment with certain stem cells did not shorten the time it took patients to achieve complete kidney recovery, nor did it decrease their risk of dying prematurely or needing dialysis. Unfortunately, “AKI is a common condition and there is no effective treatment,” the researchers said (5).

Advances in dialysis reported

Several studies reported research on innovations in care for patients on dialysis. The first study examined a new approach to in-stent restenosis, a common problem in this population. It included 265 dialysis patients, and found that the Fluency® Plus Endovascular Stent Graft—which is placed inside a blocked stent to re-open it and allow adequate blood to flow and dialysis to take place—was superior to balloon angioplasty alone through 6 months. The Fluency® Plus Endovascular Stent Graft was better for restoring blood flow and keeping the area open longer. “In-stent restenosis is a common problem in the care of ESRD patients. This study represents the first level-1 evidence for the use of stent-grafts in the treatment of both arteriovenous fistula and arteriovenous graft stenosis,” said lead author Alexander Yevzlin, MD (6).

Another, ACTIVE Dialysis Multinational Trial, examined the use of extended hemodialysis hours to determine if it would improve patient outcomes. Among 200 patients on dialysis, extending weekly dialysis hours for 12 months did not improve quality of life, but was linked with improvements in some laboratory measures (such as potassium and phosphate blood levels) and a reduced need for blood pressure medications (7).

Disclosure information is available at http://www.asn-online.org/education/kidneyweek/2014/program-faculty.aspx. Funding information is available in the Kidney Week 2014 Abstract Supplement at http://www.asn-online.org/abstracts.

References

1. 

Chapman AB, et al. HALT Progression of Polycystic Kidney Disease (HALT PKD) Trials: Primary Results of a 2x2 Factorial Trial in Early Stage CKD. J Am Soc Nephrol 25 (Suppl); 2014:B1.

2. 

Torres VE, et al. HALT Progression of Polycystic Kidney Disease Trials: Primary Results of a Randomized Trial in Moderately Advanced Stage CKD. J Am Soc Nephrol 25 (Suppl); 2014:B1.

3. 

Perkovic V, et al. ADVANCE-ON: Long Term Benefits Of Intensive Glucose Control For End-Stage Kidney Disease. J Am Soc Nephrol 25 (Suppl); 2014:B1.

4. 

Garg AX. Effect of Perioperative Aspirin and Clonidine on Acute Kidney Injury. J Am Soc Nephrol 25 (Suppl); 2014:B2.

5. 

Swaminathan M, et al. ACT-AKI: A Phase 2 Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of AC607 for the Treatment of Acute Kidney Injury in Cardiac Surgery Subjects. J Am Soc Nephrol 25 (Suppl); 2014:B3.

6. 

Yevzlin AS, et al. Six-Month Results of the RESCUE Trial: Fluency® Plus Endovascular Stent Graft versus PTA for In-stent Restenosis. J Am Soc Nephrol 25 (Suppl); 2014:B2.

7. 

Impact of Extended Weekly Hemodialysis Hours on Quality of Life and Clinical Outcomes: the ACTIVE Dialysis Multinational Trial. J Am Soc Nephrol 25 (Suppl); 2014:B2.