Tuesday, December 16, 2014

Concept Map: Herbal Remedies and Kidney Diseases

Herbal agents are used on a daily basis by many. Risks to the kidney have been identified with some of these agents. Here is a brief concept map of few of the agents have had strong associations with CKD, glomerular disease and electrolyte disorders. Dr Warren Kupin from Miami recently spoke to us about these and I summarize these from his discussion to us.

NKF has a summary as well on this concept.  V Jha has a nice review as well.
Click on image below for larger view of the concept map.

Monday, December 8, 2014

Nephrology at crossroads in 2014-2015

Looking back at the year 2014, where do we stand in terms of Nephrology?

                Compared to last year, this year bought a spectrum of kidney diseases to light and the number of articles published in high impact journals was astounding. NEJM and JAMA had great articles from amazing clinical research done this year in Nephrology.  There has been no research done in hyperkalemia in decades, but of recent, 3 top tier articles with 2 new agents in NEJM and JAMA.  And if you look by category- nephrology in NEJM, this year had 13 original articles, up from 10 in 2013. There was significant review articles as well in NEJM this year on various topics.  Simplicity 3 and CORAL trial being some of the major Hypertension highlights but the JNCVIII also made way to affect the world of Nephrology. The science of nephrology is clearly advancing.  Even though some of the trials were negative trials, we know what DOES NOT work and keep trying rather than doing something based on observational data and then finding out it caused harm.  The renal fellow network has a top 10 nephrology story countdown. Go and vote for your top study.  The new allocation system for transplantation is a positive step for clinical patient care in nephrology.
                In the realm of education, Nephmadness 2014 ( brainchild of Topf and Sparks) was well received with much more participation then 2013 version.  Watch out for the upcoming Nephmadness 2015 this upcoming year.
                The NRMP Nephrology match was met with a debacle and many spots going unfilled. ASN has a special report on this.  While this might be a setback for our field, this should not stop us from continuing what we do best – be passionate of nephrology and continue to shower enthusiasm and knowledge about renal disorders for our trainees.  Trainees ultimately have the right to choose the field that they desire to be happy with.  The last thing we want is “just filling the spots” and unhappy fellows in making.  The ASN is planning to create a match Taskforce to help in this matter.  Tejas Desai, creator of NOD has come up with a creative solution that suggests a short term solution of fixing the match process- decreasing the number of fellowship spots. Which programs should do this and which should not is the question and he address that in his proposal… have a look and comment on what you think?
                So as we look into 2015, think positive and let’s create the same magic as we did in 2014 for science in nephrology. Every field has their bumps and so does nephrology. We shall overcome this barrier as a community as well.  Collectively, we need to inspire students, residents at ground level and every institution needs to light this candle. No large society can make this happen. Even if one person at each institution can inspire students and resident, we will make it happen.  This is a collectively call for all academic, and private practice nephrologists who love what they do to shed their experience and passion to trainees.  For those who don’t like what they do- I have no comments but to ask yourself why you went into it for the first place?

Thursday, December 4, 2014

Concept Map: APOL1 Nephropathy

APOL1 gene nephropathy has now emerged as a potential new entity given the linkage to African American ancestry and having these alleles that were protective against sleeping sickness and then leading to more HTN proteinuric and non proteinuric renal disease in AA.  Below is a summary concept map on this topic and how having these alleles and then a SECOND HIT concept might be necessary for disease phenotype.  There are likely two disease phenotypes- FSGS variants and then the tubular non proteinuric variants. African Americans with arterionephrosclerosis who possess two APOL1 risk variants more often lack obsolescent glomerulosclerosis and have greater degrees of (solidified and disappearing) glomerulosclerosis, thyroidization-type tubular atrophy, and microcystic tubular dilation than patients with fewer than two risk variants in the non proteinuric patient lists.  
Also, there is some emerging data that JC and BK virus might be protective for the kidney relatives of patients with APOL1 nephropathy.


Pathology of Non proteinuric Renal diseases in APOL1 nephropathy
Second hit concept
Protective viruses for APOL1 nephropathy

Saturday, November 29, 2014

Sickle Cell Trait and Renal disease

Are there any association of sickle cell trait( SCT) and renal disease? Sickle cell disease and renal disease has been well established, but SCT and renal disease is an area understudied. A recent JAMA study showed association using a registry data.  Primary outcomes were CKD , incident CKD, albuminuria and decline in eGFR. The study concluded that among African Americans in these cohorts, the presence of SCT was associated with an increased risk of CKD, decline in eGFR, and albuminuria, compared with noncarriers.
What type of diseases do we see with SCT in the kidney? In SCT, injection radiographs demonstrate renal medullary vascular disruption, though to a lesser extent than seen in sickle cell disease, suggesting that sickle hemoglobin may have a dose-dependent relationship with kidney injury.  Our finding that SCT was related to both CKD and albuminuria is consistent with these proposed mechanisms. SCT is 4-5 times more common than sickle cell disease.  Hematuria by far is the most common complication of SCT especially seen in African Americans.  Admission rate in one study with patients with SCT and hematuria was 4%.  

1.    Papillary necrosis ( most common)
2.    Renal infarction
3.    Isosthenuria
4.    Increased risk of exercise induced rhabdomyolysis
5.    Renal medullary carcinoma( very rare)

6.    Earlier onset of ESRD if also have ADPKD

Wednesday, November 26, 2014

Sunday, November 23, 2014

Hyperkalemia meets their new K-busters

      Hyperkalemia is a challenge in CKD and ESRD patients. The treatment agents for this complication have been limited to bowel resins, diuretics and dialysis.  There has been some recent interest in novel agents as some evidence suggesting the efficacy of Kayexalate and side effects leading to colonic necrosis in some settings.

Three articles published this week (2 in NEJM and 1 in JAMA) give us trials of using novel K lowering agents in three different settings.
The first trial looked at patiromer use for hyperkalemia in CKD patients on RAAS inhibitors. The active moiety of patiromer for oral suspension is a nonabsorbed polymer that binds potassium in exchange for calcium in the distal colon leading to highest K excretion possible. Patiromer is a dry powder, primarily a spherical bead that is not absorbed and that binds potassium when mixed in small amounts of water. It exchanges potassium for calcium, which would be of some concern if the drug were absorbed. It appears, however, that the drug is not absorbed and that the amount of calcium absorbed is small. In A RCT with placebo, patiromer treatment was associated with a decrease in serum potassium levels and, as compared with placebo, a reduction in the recurrence of hyperkalemia. Mild-to-moderate constipation was the most common adverse event (in 11% of the patients); hypokalemia occurred in 3%.

The second trial looked at zirconium cyclosilicate (ZS-9), a novel selective cation exchanger, could lower serum potassium levels in patients with hyperkalemia. ZS-9 is a compound with a crystalline structure that traps potassium  10 times as much potassium as kayexalate does. It is insoluble and remains in the intestine during transit. This was in a variety of diagnosis leading to hyperkalemia in over 700 patients. There was an initial phase and then a maintenance phase. Patients with hyperkalemia who received ZS-9, as compared with those who received placebo, had a significant reduction in potassium levels at 48 hours, with normokalemia maintained during 12 days of maintenance therapy per their conclusion

The third trial titled HARMONIZE was a phase 3, multicenter, randomized,
double-blind, placebo-controlled trial evaluating zirconium cyclosilicate in outpatients with hyperkalemia (serum potassium_5.1mEq/L) . Among outpatients with hyperkalemia, sodium zirconium cyclosilicate reduced serum potassium to normal levels within 48 hours; compared with placebo, all 3 doses of zirconium cyclosilicate resulted in lower potassium levels and a higher proportion of patients with normal potassium levels for up to 28 days.

Two accompanying editorials are in NEJM and JAMA as well

Few questions still remain and are a concern:

Since all 3 trials were pharmaceutical company sponsored, placebo was used to compare the agents for efficacy. Why not kayexalate?- it works and it’s cheaper. The authors in one study did state that the agent was not compared to sodium or calcium polystyrene  since prospective studies are lacking in the later and also agents cause bowel necrosis.
But there are significant years of experience and pathophysiology that it works.  Side effects are part and parcel of every agent. The above agents had constipation as side effect, and some might have calcium and magnesium concerns if used long term given how they work. Also all three trials were very short term and long term trials are needed still.  FDA approval is also warranted before any use.
Nevertheless, the patients we have that have CKD and or heart failure and we really want them to be on ACEI, ARB or aldactone but cannot due to K related concerns and or require diuretics with them:- now we may have an alternative option for the situation. 

Tuesday, November 18, 2014

Pause to think about POISE

One of the largest AKI trials was presented at ASN Kidney week 2014 and just published in JAMA as well- POISE 2.  It was a trial to look at a preventive strategy for AKI in non cardiac surgery setting.   An international trial, with 88 centers, 22 countries, from 2011-2013 of over 6000 patients was done to see if ASA or clonidine given prior to surgery prevented AKI post surgery.  Not to my surprise, a mong patients undergoing major noncardiac surgery, neither aspirin nor clonidine administered perioperatively reduced the risk of acute kidney injury. In addition, the ASA group had more risk of bleeding and the clonidine arm had more risk of hypotension. 

The logic behind using this strategy doesn’t make sense to me.  There are few trials in the surgical literature that might have prompted this trial.

The funding was provided by the CIHR, Spanish ministry of health and few other funding pharm agencies.  A multi international trial of AKI that might be one of the largest to date is an amazing ordeal but the concept seemed less likely to have worked.  A drug that causes bleeding and another one that causes hypotension is more likely to cause harm then benefit.  Ischemic re conditioning or sonogram might have been an interesting approach.  

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