SAN DIEGO—During this year's American Society of Nephrology (ASN) Kidney Week, society President Ronald J. Falk, MD, gave a rousing opening address. He pleaded optimism in the treatment of patients with kidney disease and suggested that we continue our efforts to find cures. With frequent research breakthroughs and modern discoveries in every field of endeavor, the sky may well be the limit.
However, when we look for guidance in how to treat our patients here and now, the most impactful session at the annual meeting is often the presentation of late-breaking clinical trials. Here, results and impressions are given on studies that are felt to inform practice in a meaningful way. This year's session, named “High-Impact Clinical Studies,” was very exciting, allowing for new insights into patient care and new hopes for the future, and should pave the way for further investigation into best practices.
Change of ALTITUDE
Hans-Henrik Parving, MD, DMSc, presented results from the Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints (ALTITUDE), in which the renin inhibitor aliskiren was added to standard therapy in patients with type 2 diabetes plus cardiovascular disease, chronic kidney disease, or both (Abstract # HI-OR01). This study of more than 8,500 patients was stopped early because of a trend toward harm in the treatment group as shown by the main outcome, a combined endpoint of cardiovascular and renal events.
The data demonstrated increased rates of heart and brain outcomes, including death. Despite somewhat better control of blood pressure and some reduction in urinary protein, renal endpoints were not improved. Harm was seen mainly in patients with hyperkalemia (serum potassium greater than 5 meq/L) at the beginning of the study, but benefits still were absent in those with lower potassium levels. Dr. Parving appropriately summarized that adding aliskiren to standard angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy in high-risk patients with type 2 diabetes mellitus cannot be recommended.
These results from ALTITUDE, as well as the findings of the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO) 3:4 trial and the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial that are described next, were published as Online First articles by the New England Journal of Medicine to coincide with their presentations at the ASN meeting.
Up to TEMPO
Next up at the High-Impact Clinical Studies session was Vicente E. Torres, MD, PhD, reporting on the TEMPO 3:4 study, a placebo-controlled trial of the impact of tolvaptan on renal cyst growth and disease progression in patients with autosomal dominant polycystic kidney disease (Abstract # HI-OR02). This study included 1,445 subjects, with a two-to-one randomization to the active drug. Subjects took the highest tolerable dose. All participants were encouraged to maintain a high fluid intake.
Over three years, the annual increase in kidney volume was significantly lower in the tolvaptan group (2.8%) than in controls (5.5%). Likewise, those randomized to the agent showed an improvement in the secondary composite endpoint of clinical progression, with lower rates of worsening of kidney function and fewer kidney pain events, and a slower decline in kidney function, as demonstrated by an analysis of the reciprocal of serum creatinine level. There was a higher discontinuation rate in the tolvaptan group—23%, versus 14% in the placebo group—with 8.3% of the 961 patients randomized to that treatment discontinuing because of aquaretic side effects and 1.2% because of liver adverse events. Aqueresis-related side effects included thirst, urinary frequency, nocturia, and polydipsia.
The ability of tolvaptan to slow kidney growth and reduce the rate of decline in renal function appears to be very exciting. However, Dr. Torres appropriately cautioned the audience to await regulatory review of the data and very careful consideration of the risks versus benefits of treating polycystic kidney disease with tolvaptan. Additional comments focused on better understanding how effective the agent would be compared with simply increasing water intake, although it would seem that the agent is likely to be much more effective than dietary advice in increasing urine flow rates.
[To read more expert analysis of the results of the TEMPO 3:4 trial, please see the article on page 1.]
Adjust and EVOLVE
Also during the Kidney Week session, Glenn M. Chertow, MD, MPH, presented the results of the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (Abstract #HI-OR03). The study was designed to address whether treatment with a calcimimetic could improve cardiovascular outcomes in end-stage renal disease (ESRD) through the control of disordered mineral metabolism, chiefly by reducing parathyroid hormone (PTH) levels. This also was a very substantial and long trial, evaluating 3,883 hemodialysis patients for up to 64 months. These were individuals who had moderate to severe hyperparathyroidism, with a median PTH level of 693 pg/mL.
The median duration of actual drug exposure was 21.2 months in the cinacalcet group and 17.5 months in the placebo group due to a high drug discontinuation rate. Approximately two-thirds of the subjects in both arms stopped drug during the study, and 19.8% of patients in the placebo group began receiving commercially available cinacalcet before they had a primary event. However, the vast majority of patients were retained in the study and their endpoints evaluated.
For the primary endpoint, there was a 7% reduction in death and cardiovascular events in the subjects assigned to the cinacalcet group, which was not statistically significant. For the secondary endpoints, there was a 7% increase in stroke in the cinacalcet group and an 8% decrease in cardiovascular deaths, neither of which was statistically significant. Further analyses adjusting for baseline characteristics or more carefully looking at events related to drug exposure suggested a 12% to 15% reduction in the composite endpoint that was nominally significant, but the authors stated that this finding could be due to chance, bias, or confounding.
The study did confirm improvements in PTH levels and a reduction in severe hyperparathyroidism, as defined by the investigators, as well as a greater than 50% reduction in parathyroidectomy. No benefit was seen in fracture rate. In addition, there was no active protocol for optimization of diet, phosphate binders, or active vitamin D. While the rate of adverse events was high in both cinacalcet and control subjects, there were substantially more gastrointestinal and hypocalcemic events with cinacalcet, driving drug discontinuation.
In sum, this trial somewhat disappoints in not proving a cardiovascular or mortality benefit of cinacalcet in the unadjusted intention-to-treat analysis. It is uncertain whether we might get further clarification of the role of calcimimetic therapy in dialysis patients.
[For more about the EVOLVE trial and what the results mean for clinical care, please read the article on page 1.]
Early Data from EUVAS
Rachel B. Jones, MBBS, next gave a summary of a randomized trial of mycophenolate mofetil (MMF) versus cyclophosphamide (CYC) for remission induction in antineutrophil-cytoplasmic antibody (ANCA)-associated vasculitis (Abstract #HI-OR04). This was an effort of the European Vasculitis Study Group (EUVAS). The objective was to try and find a safer, yet efficacious, way to achieve remission in subjects with ANCA-associated vasculitis.
In this trial, 140 subjects with newly diagnosed ANCA-associated vasculitis were randomized to treatment with oral MMF (2–3 mg/day) or six to 10 pulses of intravenous CYC (15 mg/kg). Patients with severe disease—including rapid rise in creatinine or acute, severe organ involvement—were excluded.
Data were presented for the first six months of the study only. The evaluation was for non-inferiority in reaching remission, defined as not having the confidence interval extend beyond a 12% lower rate. Remission was defined as achieving and sustaining a Birmingham Vasculitis Activity Score (BVAS) of 0 on the appropriate reduced dose of steroid.
Overall remission was seen in approximately two-thirds of both groups (66% vs 69%) but was slightly lower in the MMF group. The non-inferiority measure was narrowly missed. In a secondary analysis defining remission simply by sustaining a BVAS of 0 regardless of steroid dose, non-inferiority was established (87% MMF vs 77% CYC). Adverse events were similar across the two groups, with a greater rate of infection among subjects in the MMF group that was not statistically significant. There were no clear differences in dialysis or death.
These results are of great interest. Whether the study ultimately allows for the use of mycophenolate mofetil in place of cyclophosphamide (or potentially even rituximab) in patients with a more mild presentation of vasculitis will have to await a longer term analysis not only looking at six-month remission but also relapse rates, longer term complication rates, and perhaps even cost-effectiveness. We will need to stay tuned for progress on this study and this fascinating disease.
USRDS Analyzes Coronary Interventions
On behalf of the United States Renal Data System (USRDS), Charles A. Herzog, MD, presented data regarding survival of US dialysis patients after surgical versus percutaneous coronary intervention (Abstract #HI-OR05). This has been an important area of concern for some time.
In this analysis, the USRDS database was reviewed and a comparison made between patients who received bare-metal or drug-eluting stents (BMS or DES, respectively) and patients who underwent coronary artery bypass surgery (CAB, with or without the use of internal mammary grafts).
Between 2004 and 2006, overall mortality was better with CAB then with either BMS (hazard ratio [HR]=1.27) or with DES (HR=1.08), although there was a trade-off, with earlier complications and deaths associated with coronary artery bypass surgery.
In the 2007–2009 interval, coronary artery bypass was still superior to bare-metal stents (HR=1.25) in terms of mortality, but there was no difference between DES and CAB in the adjusted analysis. However, patients undergoing coronary artery bypass with internal mammary grafts had the best long-term survival.
Interestingly, in both time intervals, patients utilizing peritoneal dialysis did worse with coronary interventions (HR=1.21 to 1.43).
This analysis, retrospective and generated using administrative claims data, could not further define comparative efficacy. Still, in light of the recent report of the superiority of coronary artery bypass compared with stenting in diabetic patients (NOT ON DIALYSIS), this data should be useful in counseling dialysis subjects with ESRD.
Diabetes in Donors
The final report from the High-Impact Clinical Studies session focused on the safety of living organ donation for individuals with impaired glucose tolerance (Abstract #HI-OR06). Sindhu Chandran, MD, shared observational data on 35 living donors who had serum glucose greater than 100 mg/dL but did not meet criteria for diabetes at the time of donation. The mean post-donation follow-up was 10.2 years.
As indicated by medical history at study enrollment, four of the 35 donors had developed diabetes—one controlled by diet and three by oral medication. In terms of fasting sugar, 24 subjects had mean fasting glucose less than 100 mg/dL, 10 showed impaired glucose tolerance, and one showed a fasting sugar greater than 125 mg/dL. Three subjects had a hemoglobin A1c (HbA1c) of 6.5% or greater.
All of the diabetics came from the group of donors with baseline fasting glucose greater than 110 mg/dL. Interestingly, 15 of the subjects were hypertensive by history, with 12 on medication. The group's renal function and albuminuria remained normal, except for two of the donors with diabetes who developed microalbuminuria.
Thus, in this small group, the rate of progression to diabetes was low (10%) among donors with impaired glucose tolerance, and renal function was intact, with only two subjects having mildly increased albuminuria. However, before this practice gathers more routine acceptance, a larger population with longer follow-up should be evaluated and compared with controls who do not have baseline impaired glucose tolerance.
Made Its Mark
Taken together, these presentations shaped an impactful clinical study session that made its mark. While not putting us on the road toward a cure (yet), it identified several ways in which we can improve the care of patients with kidney disease. These studies stand as examples to build upon for a better understanding of kidney disease and for the assessment of interventions that will ultimately enhance lives.