Rank11
Idea#69
At the current time, we only have RAAS blockade and hypertension control to slow progression to ESRD. What mechanisms should be targeted to slow progression (loss of GFR) in diabetic nephropathy?
Tags: raas ckd esrd progression
Is there a reason to narrow this to diabetes? I think that overall we need to deveop an enhanced understanding of why RAAS blockade seems so effective in delaying progression of all proteinuric renal disease, starting wiht a better understandiogn of how the flter works and malfunctions.
The mechanism of glomerular damage in diabetes and glomerular disease may not be the same. So, for next steps in stopping progression, would you look for a disease specific agent or one that addresses final common pathways?
A related question might be is whether proteinuria should be a target in and of itself?
Fibrosis is a key pathologic feature of diabetic nephropathy. It would certainly be a good idea to target one common pathway leading to fibrosis . Hence more work is needed to identify such pathways and mechanisms. Examining signaling pathways and novel nuclear mechanisms, including epigenetic factors would be worthwhile
It is critical to identify good biomarkers to detect early stages of diabetic nephropathy in order to commence aggressive therapy to prevent progression to ESRD. Some of the areas that are worth paying more attention include the study of urinary prodocyte markers, fibrotic growth factors, exosome components (including proteins and RNA) and microRNAs. Recent technological advances (proteomics, microRNA deep sequencing, exosome isolation) can assist in these ventures.
I think we need ab infrastructure that allows rapid assessment of novel agents to determine futility vs larger trials. Oncologists have set up these networks. Patients are stratified by risk, new agents are added to standard of-care and small cohorts of patients are used to expeditiously determine if further trials are needed. For nephrology to do this, we need to be comfortable with are prediction algorithms and surrogate markers. Waiting longer for these issues to be resolved seems imprudent. We should rapidly testing new agents chosen on the basis of know mechanisms and risk-benefit ratio of the candidate drug.
Linda: Diabetic glomerular disease may be "different", but RAAS blockade strategies are universal. Narrowing this topic unnecessarily weakens it, scientifically and vote-wise.
Therefore, William Fissel's suggestion to broaden the scope still seems valid. ("What next after RAAS blockade" is JUST as much a looming question for other forms of CKD, and underscores the dire need for NEW strategies, (after milking RAAS for modest incremental gains for 2+ decades.
It is time begin seriously developing alternatives, (and explore them far more rapidly as John Sedor suggests.) However, it is not really "fair" to alter an idea people have already voted for, so probably stuck with how it is currently worded.
I actually think it is ok to look at the mechanisms of RAAS blockade in different etiologies of CKD. The mechanisms of progression are clearly only partly shared and the mechanisms of protection by such pleiotrophic agents are also likely to be only partly shared. I do believe that concerted systems biological approaches will help identify the next set of pathways that can be best modulated, possibly by agents that are already extant. But I agree 100% with Rama that the bugaboo, even with the approach that John Sedor has articulated, is the lack of validated predictive biomarkers. Its pretty hard to get high throughput when your primary endpoint is doubling of serum creatinine. I think systems approaches may help us here as well, and I actually think that urinary metabolomics will get us there first. We'll see.
RAAS and BP control may be "all we have" but some researchers are already reporting higher success through more intensive therapy. While we do need to ask "what next?", meanwhile should not neglect to determine whether RAAS can be used more effectively.
As to whether proteinuria should be its own target, is exactly the premise these groups are pursuing, with seemingly remarkable results at slowing and even halting CKD progression for far more patients than would normally be expected on standard therapy.
Reviews of various strategies include: http://www.ncbi.nlm.nih.gov/pubmed/17700639
More recent:
http://www.nature.com/nrneph/journal/v5/n7/full/nrneph.2009.76.html
Several agents (e.g., tranilast/Rizaben) now have a very well established human safety profile, so at the very least these can now be brought forward to human trials for CKD applications.
It is time to move beyond treating just the symptoms of CKD, and target the root causes of progression pathways.
Trustworthy biomarkers will be key, as creatinine-doubling and similar endpoints present an excessive barrier to more rapid assesment of such a wide array of potential new therapies. Accomplishing the goals of this topic will require investigating many of these.
Also, direct renin inhibition (e.g., Aliskiren) might accomplish similar goals, but needs to be tested through direct head to head testing specifically for CKD protection vs. ACE/ARB.
(Whether DRI's will represent "superiority" remains an open question, but there are plausible reasons to believe they may be so.)
