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.
Looking back at the year 2014, where do we stand in terms of
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.
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.
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.
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?
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.
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%.
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
third trial titled HARMONIZE was a phase 3, multicenter,
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.
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.