It's hard to believe another year has come and gone. 2012 proved to be a year of ups and downs in the nephrology community. Large clinical trials from the failed phase 3 bardoxalone study in diabetic nephopathy to the positive results of the tolvapan TEMPO 3/4 trial in ADPKD dominated the scene. The passing of a transplantation pioneer and Nobel Prize awardee Dr. Joseph Murry and the awarding of the 2012 Nobel prize to Drs. Lefkowitz and Kobilka for their work on G-coupled protein receptors were two stories that also garnered attention. This is by no means a complete list of all of the major news stories this year. Feel free to add to the list in the comment section below. As usual, I will summarize each of the top 10 studies/stories that you voted for in our year-end poll in increasing order of votes (in %). A total of 78 votes were received.
10. PEAK data showed that first-year mortality on dialysis was cut by 12% (14%)- Kidney Care Partners launched the Performance Excellence and Accountability in Kidney Care (PEAK) effort in 2009 in an attempt to decrease the high mortality (2009 USRDS data showed a 30% first year mortality) that is seen in patients during the first year of dialysis. The goal was to decrease first year mortality by 20%. This campaign focused on patient education, case management, nutrition, anemia management, dialysis adequacy, catheter use and psychological and social support. The results showed a cumulative 12.5% drop in first-year mortality after dialysis initiation. The data was presented to a congressional educational briefing to help maintain adequate funding of ESRD care. These results are encouraging and with more concerted efforts I hope the goal of further reduction is reached.
9. Drs. Lefkowitz and Kobilka awarded the Nobel Prize in Chemistry (15%)- Dr. Lefkowitz and his former post-doc Dr. Kobilka both received the Nobel prize in chemistry in 2012 for their body of work on G protein-coupled receptors. This important work defined how cell surface receptors mediate some of the basic physiological functions mediating both normal homeostasis and pathologic disease. The majority of medications used to treat hypertension, kidney disease and cardiovascular disease target G protein-coupled receptors. These include alpha- and beta- adrenergic receptor blockers and angiotensin receptor blockers (ARBs). This was quite an achievement that has led to the development of a large repertoire of medications to treat not only cardiovascular disease but many other diseases such as depression (SSRIs), allergies (anti-histamines), and many others. Congrats to a well deserved award. These groups are further defining how these receptors signal. An phase II clinical trial exploring the novel beta-arrestin biased angiotensin receptor ligand in heart failure is ongoing.
7. Chloride restrictive IV fluid administration shown to be superior to chloride liberal in the ICU published in JAMA (21%)- This was a provocative study performed in an ICU setting at a single center at the University of Melbourne, Australia. Joel Topf at PBF and Gearoid here on RFN have excellent blog posts about study and its implications. In short these investigators conducted a prospective, open label, sequential period study in 760 ICU patients comparing a control group with usual practices (chloride liberal) to an experimental group that instead received lactated solution (Hartmann solution), Plasma-Lyte 148 or chloride-poor 20% albumin (chloride restrictive). The primary outcome was looking at an increase in baseline creatinine to peak creatinine and AKI as dictated by RIFLE criteria. They reported that the chloride restrictive group had a lower change in creatinine (0.16) vs. chloride liberal group (0.25). Interestingly they found a significant reduction in AKI with a much lower need for acute dialysis (78 in the liberal vs. 49 in the restrictive). However, no differences were seen in mortality or length of ICU stay. As Joel stated in his PBF post "this is an intriguing paper and I look forward to more data, even if it means the surgeons were right".
7. Passing of Dr. Joseph Murray first surgeon to successfully perform a kidney transplant (21%)- Coming in at a tie for 7 in our poll is the passing of a giant in field of nephrology- Dr. Joseph Murray at age 93. Ajay Singh at The Kidney Doctor has an excellent post about Dr. Murray. In 1954 he performed the first successful kidney transplant at the Peter Bent Brigham Hospital in Boston, MA between the identical Herrick twins. This was truly a monumental achievement that ushered in a new era in the treatment of kidney failure. I would recommend reading Surgery of the Soul, a autobiography of Joseph Murray.
6. Diuretics beat ultrafiltration in decompensated CHF published in NEJM (29%)- Coming in at number 6 pitted aggressive therapy with diuretics and vasodilators (pharm group) in 94 patients versus mechanical ultrafiltration (UF group) in 94 patients with decompenstated heart failure (the CARRESS-HF trial). This trial was stopped early due to a lack of evidence of benefit as well as an excess of adverse events with ultrafitration. Before this trial was published the use of mechanical ultrafiltration was starting to garner more popularity as a means of volume removal in CHF with cardiorenal syndrome. However, this study reported that the use of stepped pharmacologic-therapy (diuretics and vasoactive agents) was superior to ultrafiltration. The pharmacologic group had a -0.04 increase in creatinine while the UF group had a +0.23 increase at 96 hrs. There was no difference in weight loss between the groups. However, there was more serious adverse events in the UF arm (72% vs. 57%) owing mainly to bleeding, renal failure (17 UF and 14 Pharm) and catheter complications. There was no difference in mortality (although there was a trend towards higher mortality in the UF group) or rehospitalization rate. This trial puts serious question to the use of UF in decompensated CHF with cardiorenal syndrome. Read the editorial accompanying this article for more perspective.
4. Results of ALTITUDE trial using aliskiren combined with ACEi and ARB published in NEJM (30%)- Coming in at at tie for 4th was the ALTITUDE trial. The results were presented at ASN Kidney Week in San Diego this year and published simultaneously in the NEJM. This was a large prospective double blinded placebo controlled trial involving 838 centers in 36 countries. 8606 patients with type 2 diabetes were randomly assigned to 2 groups- Placebo + ARB or ACEi or Aliskiren (300mg) + ARB or ACEi. This trial was stopped early after the planned second interim efficacy analysis where they concluded that the increased rate of adverse events was not offset by any measurable cardiovascular or renal benefit from aliskiren and in fact favored the placebo arm. The primary end-point was a composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resus, nonfatal MI, nonfatal stroke, heart failure hospitalization, ESRD, death from renal failure, doubling of serum creatinine. The primary end point was reached in 783 patients in the aliskiren arm and 732 in the placebo arm. (P=0.12 CI 0.98 to 1.20). BP was lower in the aliskiren group as was the amount of albuminuria. However, there were no differences in secondary renal end point. There was an increase in adverse events in the aliskiren arm most notably hyperkalemia and hypotension. This was a large well conducted trial that does not the support the addition of direct renin blockade to ACEi or ARB therapy in patients with type 2 diabetes and chronic kidney disease.
4. Supreme Court upholding of the Affordable Care Act (30%)- The Supreme Court determined that the Affordable Care Act (ACA) was constitutional with the exception of the mandatory medicaid expansion earlier this year. Dr. Barry Staube, former Chief Medical Officer of CMS and current Director of the Marwood Group discussed how the ACA will affect patients with kidney disease and their providers in a brief commentary at eAJKD.
3. Results from the EVOLVE trial using cinacalcet in ESRD published in NEJM (33%)- Coming in at number 3 is the behemoth EVOLVE trial also presented at ASN Kidney Week in San Diego this year and published in NEJM. This was the largest and longest randomized clinical trial ever performed in patients on dialysis. Joel Topf reported on this story at eAJKD and in more detail at PBF. The trial was designed to test the hypothesis that treatment with cinacalet (an allosteric modifier of the calcium sensing receptor, a G protein-coupled receptor) would reduce the risks of death and nonfatal cardiovascular events among patients with secondary hyperparathyriodism who were undergoing dialysis. They found that the main cardiovascular end-point was not significantly different from the placebo arm nor was all cause mortality. However, as pointed out by Joel and discussed in the NEJM article, the cinacalcet group was on average older (55 yrs vs. 54) and age-adjusted analysis did show a "nominally" significant reduction in mortality. A significant reduction in parathyroidectomy was also noted. Side effects were seen in both groups but were more frequent with cinacalcet (hypocalcemia, nausea and vomiting). How this study will change practice will be born out in time. I applaud all of the investigators in pursuing an important issue that is germane to both patients and providers.
2. Phase 3 clinical trial (BEACON) testing bardoxolone in diabetic nephropathy abruptly stopped (38%)- The biggest shock of the year comes in at number 2. Just a few weeks before ASN Kidney Week came the announcement from Reata that the BEACON trial was stopped. They cited "excess serious adverse events and mortality in patients taking bardoxolone". RFN first picked up the story back in 2010 when I posted on preliminary results from the first 24 weeks of the 52 week phase IIb study that was presented at ASN that year. At that time it was noted that patients in the bardoxolone group had a mean elevation in eGFR of 10 ml/min when compared with the placebo arm. This was odd given that our most successful therapies, ACE inhibitors and ARBs typically lead to a drop in glomerular pressure and a slight rise in creatinine when started. In addition it was also noted that there were higher rates of nausea, decreased appetite, hypomagnesemia and muscle spasms with bardoxolone. The full results of the 52 week study were eventually published in NEJM and commented on by Gearoid. Again the rise in eGFR and higher adverse event rates were noted with bardoxolone but now additionally a rise in albuminuria was seen. Some interesting potential mechanisms for this emerged, including a down regulation in megalin which Gearoid posted on and the idea that albuminuria is not a perfect surrogate for future changes in renal function was also raised and commented on at PBF. With the above as backdrop, bardoxolone was the RFN number 5 story of the year in 2011. When the phase 3 study folded, Reata bailed on Kidney Week, no attempt to impart lessons learned or what next steps for the scientific community might be, just disappeared. Bardoxolone received a lot of hype and there was hope that this drug would represent a significant new treatment for patients with diabetic nephropathy. Looks like the end of the road for bardoxolone.
1. Results from TEMPO 3:4 trial using tovaptan in ADPKD published in NEJM (51%)- The major bright spot of the year was at ASN Kidney Week in San Diego to a packed late-breaking clinical trial audience when the TEMPO 3:4 results were presented. This was also reported by Joel at eAJKD. This was a randomized double blinded placebo controlled clinical trial comparing the vasopression antagonist tolvaptan to placebo in patients with Autosomal Dominant Polycystic Kidney Disease. This study showed that tolvaptan, as compared with placebo, slowed the increase in total kidney volume and the decline in kidney function over a 3-year period in patients with ADPKD. This is a major breakthrough, but several questions remain. How will these results this hold up over time and will this drug decrease the rate of progression to ESRD. Furthermore, the cost of tolvaptan is considerable and this therapy would be lifelong if proven effective.
Again, quite a busy and exciting year in the world of nephrology in 2012. Thanks to all of the contributors and readers for keeping the site fun, interesting and educational.
Thanks for supporting RFN and happy holidays.