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.
Is it a
syndrome? An article in NDT addresses this entity as a possible syndrome in
When one looks at nephrotic syndrome or metabolic
syndrome, those entities usually fulfill the criteria for calling it a “syndrome”
as most patients would fit that criteria and prognosis and treatment would be
resulted. In CKD-MBD, this article
argues against it being a potential syndrome in CKD but perhaps might be. CKD-MBD represents a synopsis of three
closely related disease conditions: laboratory abnormalities indicative of
disturbed bone and mineral metabolism; renal osteodystrophy summarizing the
variety of bone lesion subtypes occurring in CKD; cardiovascular disease
representing accelerated arteriosclerosis, left ventricular hypertrophy and a
variety of additional pathologies in the vasculature and the heart in patients
But do all patients with CKD have all the bone parameters
abnormal; and if they do, what is the CVD risk and prognosis? But it’s worth some thought of this
potentially being a syndrome.
The first ever international society specifically for onconephrology has been created. It's called the C-KIN( Caner and Kidney International Network). Check out the their twitter feed at https://twitter.com/CKINnews and their annual conference schedule and abstract details as well. C-KIN aims at improving patient care through better knowledge, education and awareness on cancer and the kidney related issues and research.
ESRD patient with anemia, Fe sats of
12%, Ferritin 450 needs IV iron. Patient has bacteremia.
A. Proceed to give IV iron as anemia
and low Fe sats demands it. (2%)
B. Given active infection, do not
give IV iron till 2 weeks after infection resolved (73%)
C. Given active infection, do not
give IV iron till 4 weeks after infection resolves. (24%)
There have been no clinical trials of
adequate sample size and duration to provide us sufficient understanding of the
safety of intravenous iron. Is bolus iron better or continuous form? Is iron
infusion pose an infection risk?
et al. retrospectively studied patients on dialysis treated at Davita Inc. dialysis
facilities and found that patients receiving 200mg intravenous iron per month
had an increased risk for hospitalization or death because of infection. They
also found that bolus dosing was more associated with infection. More recently,
A CJASN study by Miskulin
et al. found a increased risk for infection-related mortality when
cumulative iron dose exceeded 1050 mg over 3 months or 2100 mg over 6 months(
not statistical but a trend). In an accompanying editorial to the Miskulin
et al (must read) discuss what the USRDS data suggests. As the mean serum ferritin
of United States patients on dialysis approximately doubled from 1993 to 2001,
the rate of bacteremia/sepsis increased approximately by 40%. From 2001 to 2010,
serum ferritin stabilized, and soon enough the bacteremia/sepsis rate also
stabilized. In light of these above findings, it is advisable to hold iron
infusions in setting of active bacteremia.
What about other active infections such as cellulitis or pneumonias? No
data exists for those at this point. How long do we wait is a good question.
Most likely choice is 2 weeks but data for that is not clear. Some of you chose
4 weeks: might also be a reasonable choice.
Another concern might be catheter use.
Infection risk as stated by the Brookhart study that risks are largest
among patients with a catheter and the ones with a recent infection.
Ebola is a RNA virus that has a high rate
of transmission. As we have now noted
the world’s largest outbreak of this virus to date, the cure for this entity
remains a mystery. Ebola hemorrhagic fever is a severe infection. It can
have a mortality rate of up to 70-90%. The infection can occur in humans and
animals. The virus family is Filoviridae and genus Ebolavirus. It was
first discovered in 1970s near Ebola river in Congo. Since then most of the outbreaks have been in
Africa. While the natural reservoir host
of Ebola remains unknown, some believe it might be bats.
How does the kidney get involved? Severe
volume depletion from this hemorrhagic disease leads to acute kidney
injury. Electrolyte abnormalities such
as hyponatremia, hypokalemia and so forth can be noted as well. Renal
failure was described in this entity in early 1980s. DIC ensues and
a shock state leads to AKI. Prior animal studies
have shown that there is some necrosis and calcification in tubules and glomerular
tufts of kidney. The first victim in the US
in Texas was on dialysis
While some treatments and preventions are
being considered, there is only supportive therapy that can be offered at this
time. However, survival is improved by early supportive care with rehydration
and symptomatic treatment.Early
intensive care therapy might be necessary.
What might be of interest to us as nephrologists is the
use of dialysis modalities to help clear the virus. Hemopurifier, a device fromAethlon Medical(San Diego, CA) that’s capable of
filtering blood of impurities like viruses is available. Apparently
it is being used currently ( per their report) for filtering the blood of an
infected doctor with the virus in Germany. The device can be used with standard
dialysis and continuous renal replacement therapy (CRRT) machines and doesn’t
require any special hardware upgrades.
More information regarding this can be found at the
New York Society of Nephrology 2014-2015 lecture series for this upcoming academic calender.
If you are around, come join this amazing group of speakers( basic science and clinical). This happens at the Faculty Club at Weill Cornell Medical Center
What is the significance of findings of FSGS in biopsies
that are predominately IgA nephropathy?
Two studies have looked into this matter in 2009 and 2011.
NDT study in 2009 looked at 75 patients ( split into IGA with FSGS, IGA without
FSGS). In the multivariate model, the
FSGS+ group showed a worse GFR decline.
It is no surprise that when there is sclerotic lesions, the prognosis is
going to be worse. The question arises if this is part of IGA progression or it
is two processes happening independently? Would steroids be indicated in such
The KI study from 2011 looked at over 100 patients and used
the Oxford classification for IgA and Columbia classification
for FSGS to evaluate the two seen in the same biopsy. Collapsing FSGS with IgA had worse
outcomes. Overall, worse outcomes were
noted with any form of FSGS was present when compared to IgA alone. In addition, when FSGS was present with any
other glomerular findings( mesangial hypercellularity, necrosis, deposits),
outcomes were worse compared to “pure” FSGS.
Staining studies they performed showed that the changes related to the
podocytopathy were present even with mild IgA disease suggesting that the two
processes might be independent and not just an end pathway for any glomerular
IgA can present with preserved renal function and MCD like
podocytopathy. Presenting with FSGS is
more challenging and treatment may be difficult to decide upon. If there is good preservation of IFTA on
biopsy and if there is >1gm of proteinuria, perhaps it’s worth treating with
steroids or at least a trial of steroids.
potential culprit might have been found for the recurrence of FSGS post
transplant. A recent article evaluated pathogenic antibodies in
141 serum samples over 64 patients and looked at many potential culprits such
as CD40, PTPRO, CGB5.etc and pre transplant elevation of anti CD40 alone was
the best predictor of FSGS recurrence after transplantation. Another study
highlight is the observation that patient-derived antibodies against CD40
functionally cooperate with a previously identified culprit of FSGS called
soluble urokinase plasminogen activator receptor (suPAR). Co-injection of
patient-derived CD40 anti-autobodies and suPAR caused enhanced kidney filter
failure more than each component did by itself.
fascinating as can anti CD40 therapies then lead to preventing FSGS in kidney
Abatacept or belatacept
may have some role in FSGS treatment. A recent study showed
the success of using such agents in minimal change disease. It is interesting
to note that in presence of cd40 auto antibody, the wild type suPAR becomes pathogenic
to the podocyte. There seems to be an
on/off switch for suPAR perhaps with Cd40 and a trial of belatacept in FSGS
might be warranted.
Would co stimulating blockade agents be sufficient as their interaction as an anti CD40 is possible?-
as we use those in transplant anyway? Perhaps, looking at the recurrence of
FSGS in patients on belatacept might be a good start. Or are we specifically going to look at ant
CD40 agents( some of which are being studied as anti cancer agents in colon
cancer and others)
Fenoldopam has been advocated in prior studies to prevent
AKI following surgery: specially studied the most in cardiac surgery. The most recent issue of JAMA gives us the
first randomized multi center placebo controlled trial on use of fenoldopam in
CT surgery patients for prevention of AKI.
This study assigned >600 patients to placebo or
fenoldopam that were admitted to CT ICU following cardiac surgery with early AKI. 30 day follow up was done.
The primary outcome was need for RRT and mortality was the secondary
outcome/ rate of hypotension during infusion.
Patient characteristics appeared equal. There seemed to be
more patients with A fib in treatment arm, more pulm HTN and MI in control arm.
Types of surgeries were equal in both( CABG, MVR, AVR, TVR,
aorta surgery, and others)
CKD stages based patients were equal in both. There was 13 CKD IV patients in control and 19 CKD IV patients in fenoldopam arm. But majority of them initially had GFR
Conclusions: Among patients with AKI after CT surgery,
fenoldopam infusion compared to placebo showed no benefit in need for RRT or 30
In addition, the infusion caused some harm and led to
hypotension episodes compared to placebo arm.
A prior study had shown similar findings from AJKD.
Is this the end of fenoldopam in prevention of AKI in CT surgery? Largest study, multi centered and good power
showing harm more than benefit. I think we have our answer.
hemodialysis can increase cerebral water content and lead
to edema. The pressure in the brain or ICP shouldn’t have too many
influences. There is strong buffer
system in the brain but if that fails- then the ICP can increase rapidly. It has been noted that even small subclinical
cerebral edema that occurs in IHD can slowly raise the ICP. Why is that and how does the BP and acidosis
make this possible?
by Davenport on this topic suggests few
in blood pressure or intradialytic hypotension can lead to ICP rises( Figure 1
from the Davenport review)
fluctuations in urea shifting
acidosis in the brain as CO2 is removed in dialysis leads to paradoxical Co2
absorption in the brain and causing imbalance.
substances can enter brain ( albumin) during brain injury as BBB is broken and
lead to worsening edema.
points regarding what should be done then?
1.All standard intermittent therapies, hemofiltration,
hemodialysis, and hemodiafiltration, will lead to increased cerebral swelling,
and if the patient has suffered a severe injury and is unconscious, then most
centers would deem continuous renal replacement or hybrid therapies as the
preferred treatment. ICPs have shown to remain much more preserved and constant
in CRRT forms rather than IHD forms of therapy.
2.Treatment should be designed to both slow down the rate
of change of serum urea and osmolality, and to maintain cardiovascular
stability( so perhaps daily IHD might be needed to minimize BUN shifts and
prevent edema from getting worse)
breakdown of BBB, avoid heparin based dialysis in this setting
doing HD, would do daily and use a lower BFR and cooler dialysate( 35C), smaller
dialyzer and high Na bath(≤10 mEq/L above serum sodium),
bicarb of 30meq/l , higher K and calcium baths).
5.Some might suggest keeping a pre
dialysis BUN low( less osmotic shifts – close to 30 and keep on supplemental
Interestingly, regarding cooled
dialysis- a recent JASN 2014 article sheds some light
on that as well. In total, 73 patients on incident hemodialysis starting
within 6 months were randomized to dialyze with a dialysate temperature of
either 37°C or 0.5°C below the core body temperature and followed up for 1
year. Cooled dialysate improved hemodynamic tolerability, and changes in brain
white matter were associated with hemodynamic instability and patients who
dialyzed at 0.5°C below core body temperature exhibited complete protection
against white matter changes at 1 year.
hypotension and rapid osmotic shifts is essentially what is required.
John Roberts, a nephrology fellow at Duke, recently produced a collection of short (10-15min) videos on renal physiology to simplify nephrology. They are "khan academy" type videos. Medical students, residents and fellows can benefit from this basic physiology review.
induced nephropathy is a known complication of paraproteinemias. A recent review In JASN
focuses on this presentation of kidney damage from paraproteins. Monoclonal proteins can also deposit in
the kidney as crystals and cause tissue damage. This happens in cases of light chain proximal tubulopathy,
crystal-storing histiocytosis, and crystalglobulinemia. Crystalglobulinemia
is a rare complication of multiple myeloma that results from
crystallization of monoclonal proteins in the systemic vasculature, leading to
vascular injury, thrombosis, and occlusion. One can observe diffuse rectangular,
rhomboid and sharp needle shaped hyaline-like crystals depositing in multiple organ systems,
including the kidneys, myocardium, coronary arteries, tricuspid and pulmonary valves, lungs, bone marrow and other
organs. Usually, this is a quick and drastic leading to AKI, and ESRD. The
reason why this happens is unclear. It
is possible that it related to the abnormal
glycosylation of light chains and their interactions with albumin. IgG k and IgG lambda chains both have been
reported to be involved. Heavy chains have also been reported. Both cases of MM and MGRS
have been reported to be present with crystalglobulinemia.
Chronic kidney disease (CKD) is a
common medical condition, affecting approximately 26 million adults in the U.S.
Parallel to the increasing prevalence of CKD, a record number of patients now
have end stage renal disease (ESRD). In 2007, 368 544 patients were on
dialysis—a striking 54% increase from one decade earlier. Meanwhile, mortality
rates for dialysis patients have declined, and approximately 775 000 people are
expected to be alive with ESRD in the year 2020.
Telemedicine is the practice of
medicine using modern communication technologies when the physician and the
patient are separated by distance. The modern communication technologies
involved are nothing more intimidating than the telephone, e-mail and
videoconferencing. Formally defined by the American Telemedicine Association,
telemedicine is the use of medical information exchanged from one site to
another via electronic communications to improve a patient’s clinical health
status. It has been applied to other specialties, particularly neurology,
radiology, psychiatry, ophthalmology, and high-risk obstetrics but nephrology
has been a slow starter. Indeed, as a specialty, nephrology may be very
suitable for this type of medicine.
Nephrology is a visual and auditory rather
than tactile subject – the skill is in recognizing diseases principally from a
history, backed up by demonstrating basic physical signs in an examination and
established by laboratory tests. So, if nephrologists based in urban centers
can deal with renal patients in distant parts of the country, or even different
countries, by means of communication technology, then the problem of reduced
access to specialist care may be lessened, if not solved.
observational trials had shown that there is much more benefit in daily
dialysis (improved phos control, better HTN control, anemia), the FHN trial in NEJM proved some of the hunch
that more dialysis was better in terms of cardiac remodeling and quality of
life. This study compared in center patients to standard HD vs daily
dialysis. These were prevalent patients
and not incident patients with some residual renal function.
A recent editorial in AJKD sheds some light on
residual renal function as an important predictor of renal survival. The authors suggest that thrice weekly might
rapidly decline renal function compared to perhaps twice a weekly dialysis
sessions. But does that matter compared to cardiac outcomes. The second FHN trial in Kidney international showed that the more
intensive nocturnal HD group failed to show benefit compared to the three times
a week dialysis. Interestingly, this was
in all incident patients with residual renal function. The study found that the more intensive HD
group lost residual renal function faster and in addition no difference in
cardiac remodeling and quality of life. More vascular interventions were also
performed in the more intensive arm.
the most recent AJN article published this week, a single
center study from China shows that twice a week HD preserves residual renal
examined 85 HD patients; 30 of them were initiated with twice-weekly HD for 6
months or longer and 55 patients were started and maintained on thrice-weekly
HD treatment. Then a subcohort study in 48 incident HD patients was implemented
to assess the independent risk factors responsible for RKF decline during the
first year of HD therapy. Clinical outcomes were the same in both
groups. The multivariate analysis showed that factors such as the male gender,
HD frequency, URR and intradialytic hypotension episode were associated with
residual renal function loss. This study’s main outcome was residual
renal function and not mortality. It
will be interesting to see and follow these patients to see the mortality data
What does this lead us to believe? One size DOES NOT fit all. Perhaps
initially, HD should be catered to preserving residual renal function and start
slowly. Some patients might require twice a week HD, some three times a week
and some perhaps more such as 4-6 times a week.
Should we be doing HD just as we do PD? When we calculate PD related
CRCL, we use the residual renal function clearance and then the peritoneal
clearance and add them to get to our expected/desired kt/v. Why shouldn’t we do that in HD as well? Incident patients might benefit from less
intensive HD and prevalent patients who have lost residual renal function,
might benefit from more intensive HD.
More studies are needed to answer these questions that the FHN and other
studies have raise.