Kidney News

20 Pages·2015·7.81 MB·English

June 2015 | Vol. 7, Number 6
Microarrays Extend Promise of Precision
Inside
Medicine to Pediatric Nephrology
Testing for CNVs Refines Diagnosis of CKD in Children Findings
Diabetes in early pregnancy
tied to incleased risk
By Timothy O’Brien
of congenital kidney
rodevelopmental syndromes. A new Chromosomal microarrays in abnormalities
study finds that many unsuspected pediatric nephrology
genetic diagnoses can be made using
The researchers analyzed the genetic
chromosomal microarrays to identify Policy
findings of patients enrolled in the
copy number variants (CNVs)—a Kidney Health Advocacy
Chronic Kidney Disease in Children
“precision medicine” approach Day visits expected to yield
(CKiD) study—an ongoing, long-
with major ramifications for dividends over time
term follow-up study of risk factors
treatment selection, family
and outcomes in children with kidney
counseling, and long-term pa-
disease. Using patient DNA derived
tient management. Workforce
from stored samples, the investigators
The prospective study by a
Why are international medical
assessed CNVs using high-density mi-
team of pediatric nephrologists
graduates not choosing
and other specialists from seven croarrays.
nephrology as a career?
centers found diagnostic copy “Chromosomal DNA microarray
number disorders in more than 7 is a relatively new technology, which
percent of a large cohort of children essentially looks at the entire genome
Clinical Trials
with chronic kidney disease (CKD). of an individual and tries to identify
“Detection of pathogenic imbalances gain or loss of DNA material that may Opportunities and obstacles
has practical implications for personal- cause a genetic disease,” Gharavi said. for clinical trials in diabetic
ized diagnosis and health monitoring in Microarrays represent a major advance kidney disease
this population,” according to the report over the microscopic technique of kar-
M in the May issue of The Journal of Clinical yotyping—classicially used to diagnose
Industry Spotlight
any children with kidney Investigation (Verbitsky M, et al: J Clin major chromosomal abnormalities
disease have rare “genomic Invest 2015; 125:2171–2178). The sen- such as Down syndrome. Low-potassium lettuce for CKD
imbalances” as the cause of their kid- ior author was Ali G. Gharavi, MD, of “With karyotyping, we could only patients in Asia
ney dysfunction, often as part of neu- Columbia University). Continued on page 3
Dialysis Patients’ Increased Risk of Cardiac Arrest
May Owe in Part to Genetics
Patients on dialysis have a higher found no significant difference in the New research published in the Jour-
risk of dying from cardiac arrest prevalence of coronary artery disease, nal of the American Society of Nephrolo-
compared with individuals in decreased left ventricular ejection gy now shows that the increased risk of
the general population, but the fac- fraction, valvular heart disease, or left cardiac arrest experienced by patients
tors involved are unknown. Coronary ventricular hypertrophy between dial- with kidney failure may, in part, be
artery disease is often at play in the ysis patients who died of cardiac death inherited. Uncovering the genes that
general population, but investigators vs. those who died of other causes. are involved may point to the mecha-
nisms underlying this risk and suggest
new prevention and treatment strate-
gies.
“It is important to stratify sudden
death risk in end stage renal disease
patients. The study offers a new and
Continued on page 5
Early Programs: November 3–4
Annual Meeting: November 5–8
Registration and Housing Open Soon
www.asn-online.org/KidneyWeek
Early registration
deadline:
Wednesday,
September 16
KW Reg Housing 2015_KN.indd 1 6/1/15 8:52 PM
June 2015 | ASN Kidney News | 3
Microarrays Higher rate of CNV cohort overall, and 30 times higher
with our classical classification.”
abnormalities in children with in those with RHD, as compared
He cited the example of a patient
Continued from page 1 CKD to controls. Even after exclusion of
with clinically diagnosed glomerular
known disorders (19 cases), a number
The analysis included 419 unrelated disorder to discuss the deeper insights
look at deletions or duplications larger of “large, rare gene-disrupting CNVs”
children from CKiD. The patients were offered by genetic diagnosis. “We
than 1 to 2 million base pairs. Whereas were found in the CKiD cohort—in-
being followed up for a wide range of think of glomerular diseases as some-
with [chromosomal microarrays], we cluding 35 cases with CNVs larger
clinical diagnoses, including RHD, ob- thing that affects just the kidney, and
are able to detect much smaller gain than 500 kb.
structive uropathy, reflux nephropathy, they’re usually due to an inflammatory
or loss of DNA material—as small as Close to one-fourth of patients
and focal segmental glomerulosclerosis or an immune-mediated disease. These
100,000 base pairs,” Gharavi said. “As with known or likely pathogenic copy
(FSGS), among others. types of classifications are important,
a result of this, we are able to make di- number disorders also had rare, gene-
Even though CNVs account for a because if we think somebody has an
agnoses that we weren’t able to make by
disrupting second-site CNVs. That
large part of overall variation in the immune-mediated disease, they may
karyotyping.”
was consistent with reported series of
genome, the population frequency of be treated for it by immunosuppressive
That’s important, because small
patients with developmental delay.
genomic disorders is very low. To be medication.
variations in copy number make up a
Most baseline clinical and demo-
able to tell apart those low frequency “Whereas if they have a develop-
large part of genomic variation. Even
graphic characteristics were similar for
genomic disorders from likely benign mental disorder, then we know those
in healthy individuals, up to 10 per-
children with and without pathogenic
common variants, the researchers as- medications are not going to help and
cent of the genome may be subject to
CNVs. There were “nominal” differ-
sembled a multiethnic database of will only result in side effects. So by
this type of variation. Previous stud-
ences in estimated glomerular filtra-
21,575 children and adults undergoing making a precise diagnosis, we can
ies using microarray techniques have
tion rate and proteinuria, consistent
microarray genotyping for research— at least try to come up with the right
identified CNV disorders associated
with an impact of the genetic changes
either healthy controls or individuals therapy and the right course of action.”
with a broad range of congenital and
on kidney function. These differences
without kidney-related conditions. Making the correct genetic diag-
neurodevelopmental defects. Genomic
will need to be validated in longitudi-
“By comparing the DNA of children nosis is also essential for understand-
imbalances can affect neurologic, car-
nal studies or independent cohorts.
who had chronic kidney disease to ing the long-term clinical course and
diac, and skeletal development (an ef-
the results from these other individu- management. “For example, we found
fect called “pleiotropy”), suggesting Major effects on diagnosis and
als, we were able to detect rare events patients who have deletions of a gene
that common developmental pathways clinical management
that could be disease-causing,” Gharavi called HNF-1 beta, which is diagnos-
are involved.
said. “If you can diagnose a patient with a tic of a disorder called renal cysts and
The new study applied chromosom-
Overall, chromosomal microarrays known genomic disorder, that might diabetes syndrome,” Gharavi said. “As
al microarrays to understanding the
found diagnostic copy number disor- help the treatment of their kidney dis- the name [implies], the kidneys devel-
role of CNVs in a well-characterized
ders in 31 of the children—represent- ease,” Sampson said. “But it also may op cysts, and there are problems with
group of children with clinically diag-
ing 7.4 percent of the study cohort. allow us to provide additional medical kidney function. In addition, these in-
nosed kidney disease. A previous report
The CKiD cases also had a high preva- care—whether it’s screening for neu- dividuals are prone to developing dia-
found “pathogenic genomic imbalanc-
lence of large, gene-disrupting autoso- rodevelopmental problems, diabetes, betes later on in life.”
es” in about 10.5 percent of children
mal CNVs: 37.7 percent, compared to or other congenital anomalies. It really Children with renal cysts and dia-
and young adults with kidney malfor-
23.4 percent of the reference cohort. provides the opportunity at an early betes syndrome may also have other
mations (Sanna-Cherchi S, et al: Am J
“These data suggest that potentially up stage, presymptomatically, to provide a metabolic disorders, such as low mag-
Hum Genet 2012; 91:987–997).
to 14.3 percent of the pediatric CKD genetic diagnosis—which may help to nesium or high uric acid levels, with a
These imbalances were clinically
cases might be attributable to a CNV reduce the risk of long-term complica- risk of developing gout. “The issue is
unsuspected and “overlapped signifi-
of 100 kb or larger,” the researchers tions or optimize the care of a patient that many of these complications won’t
cantly with CNV disorders implicated
wrote. across their lifespan.” happen all at once,” Gharavi said. “The
in neurodevelopmental disorders.” In
In an analysis focusing on a list of In the CKiD sample, of eight chil- kidney cysts are evident earlier on in
the previous study, most known CNV
131 known genomic disorders, 4.5 per- dren clinically diagnosed with cystino- life, sometimes at birth, [while] the
disorders in patients with renal hypo-
cent of the CKiD population had a de- sis, three were homozygous for a known diabetes often occurs around the age
dysplasia (RHD) had previously been
letion or duplication that was “clearly deletion of the cystinosin lysosomal of 25. Because these individuals are at
linked to developmental delay or neu-
diagnostic.” These patients had a dele- cystine transporter gene (CTNS). For risk for diabetes, they should receive
ropsychiatric diagnoses.
tion or duplication with a known asso- this group, CNV testing pinpointed targeted health monitoring to make
Matthew Sampson, MD, a pediatric
ciation with a specific syndrome. The the cause of cystinosis and provided sure that their serum glucose levels are
nephrologist and genetic epidemiolo-
rate of known genomic disorders rose information on the exact mutation for monitored regularly.”
gist at the University of Michigan, was
to 10.5 percent in children clinically family counseling. Patients need ongoing lifestyle ad-
one of the investigators in the previous
diagnosed with RHD. In the remaining 28 patients with a vice to reduce their risk of diabetes,
study. “Understanding the underly-
Further annotation identified an- diagnostic copy number disorder, the and should avoid medications that can
ing mechanism always helps in terms
other 12 patients with a “likely path- final genomic diagnosis was clinically potentially increase blood glucose, in-
of explaining to parents why their
ogenic imbalance,” representing 2.9 unsuspected. In these cases, the CNV cluding immunosuppressive therapy
child is ill,” he said. “From a clinical
percent of the CKiD group. These findings “either resulted in reclassifi- with steroids. Other issues may arise
perspective it often can help in terms
children had very large, very rare cation of the disease or provided ad- later in life—for example, female pa-
of providing more precise prognoses
chromosomal abnormalities that were ditional information that would have tients should be advised that they are at
or suggesting to us the optimal thera-
predicted to be pathogenic. “These warranted genetic counseling, targeted risk of uterine abnormalities and prob-
peutic regimen or further diagnostic
lesions fulfilled very strict criteria for workup, or surveillance.” lems with conception.
tests. And, particularly important in
pathogenicity and would be considered Identical genetic abnormalities
children, it can help in terms of family
Precision medicine in
reportable in a clinical setting,” the re- were found across different clinical
counseling.”
pediatric CKD
searchers wrote. categories. Diagnoses of 1q211.1 re-
While “personalized medicine”
doesn’t always mean genetic testing, Many of the detected CNVs in- current microduplication were made By providing this type of information,
Sampson pointed out, “Genomic in- volved genes thought to be involved in children with a clinical diagnosis CNV testing in children with kidney
quiry reveals more molecularly based, in kidney development and thus may of FSGS, hemolytic uremic syndrome, disease may be a prime example of the
fundamental information about the be “novel candidate genes” for human and chronic glomerulonephritis, while NIH’s Precision Medicine Initiative. As
pathogenesis of a child’s condition.” kidney disease. Although previously XXX syndrome was diagnosed in pa- President Obama stated when announc-
In regard to the new work by Verbit- unknown, these abnormalities are con- tients classified as having recessive ing the initiative, precision medicine
sky et al., he added, “This study is tak- sidered likely to be disease-causing polycystic kidney disease, reflux ne- carries the promise of “delivering the
ing an approach that has really only because of their large size and low fre- phropathy, and RHD. right treatments, at the right time, every
recently been actualized on a clinical quency in the population and because “Our ability to clinically differen- time to the right person.”
basis, or a research basis—to uncover they involve genes important for nor- tiate some causes of kidney disease is In the case of pediatric CKD, chro-
some potentially causative genetic mal development. probably more limited than we’d like to mosomal microarrays allow nephrolo-
changes that could be responsible for a On adjusted analysis, the odds of think,” Gharavi said. “Different kidney gists to define the exact genetic diagnosis,
small but substantial percentage of the known genomic disorders were more disorders can present in the same way make a profile for specific complica-
than 10 times higher in the CKiD or in many different ways that overlap
cases we see.” Continued on page 5
4 | ASN Kidney News | June 2015

ASN LEADING THE FIGHT
AGAINST KIDNEY DISEASE
Corporate Supporters
The ASN Corporate Support Program recognizes supporters year
round for their generous contributions to the Society. Through
this program, supporters help ASN lead the fight against kidney
disease. ASN gratefully acknowledges the following companies
for their contributions in 2014.
Editorial Staff
Editor-in-Chief: Richard Lafayette, MD, FACP
Executive Editor: Dawn McCoy
Content and Media Analyst: Kurtis Pivert
Design: Lisa Cain Design
Communications Assistant: Sara Leeds Diamond Level
Editorial Board:
Joseph Mattana, Winthrop University Hospital, New York, NY
Linda McCann, RD, RCN, Satellite Dialysis, San Jose, CA
Andrew King, MD, Scripps, San Diego, CA
Pascale Lane, MD, FASN, University of Oklahoma Health Sciences
Edgar V. Lerma, MD, FASN, University of Illinois – Chicago /Associates in Nephrology, SC
Glenda Payne, MS, RN, CNN, Nephrology Clinical Solutions
Jeffrey Petersen, MD, Amgen
Amy Williams, MD, Mayo Clinic, Rochester, MN
Advertising Sales:
The Walchli Tauber Group
2225 Old Emmorton Road, Suite 201, Bel Air, MD 21015
443-252-0571 Mobile
443-512-8899 *115 Phone
[email protected]
ASN Council:
President: Jonathan Himmelfarb, MD, FASN
President-elect: Raymond C. Harris, MD, FASN
Past-President: Sharon M. Moe, MD, FASN
Secretary-Treasurer: John R. Sedor, MD, FASN
Communications Committee Chair: Eleanor D. Lederer, MD, FASN
Councilors: Eleanor D. Lederer, MD, FASN, Mark D. Okusa, MD, FASN,
Mark E. Rosenberg, MD, FASN, Anupam Agarwal, MD, FASN
Executive Director: Tod Ibrahim
Director of Communications: Robert Henkel
ASN Kidney News is published by the American Society of Nephrology
1510 H Street NW, Suite 800, Washington, DC 20005. Phone: [phone]
www.asn-online.org
ASN Kidney News is the authoritative source for analysis of trends in medicine, industry, and policy
affecting all practitioners in nephrology. The statements and opinions expressed in ASN Kidney News
are solely those of the authors and not of the American Society of Nephrology (ASN) or the editorial
policy of the editors. The appearance of advertisements in ASN Kidney News is not a warranty,
endorsement, or approval of the products or services advertised or of their effectiveness, quality, or
safety. The American Society of Nephrology disclaims responsibility for any injury to persons or
property resulting from any ideas or products referred to in the articles or advertisements.
The American Society of Nephrology is organized and operated exclusively for scientific and
educational purposes, including enhancing the field of nephrology by advancing the scientific
knowledge and clinical practice of that discipline through stimulation of basic and clinical
Platinum Level
investigation, providing access to new knowledge through the publication of journals and the
holding of scientific meetings, advocating for the development of national health policies to improve
the quality of care for renal patients, cooperating with other national and international societies and
organizations involved in the field of nephrology, and using other means as directed
by the Council of the Society.
Postmaster: Please send address changes to ASN Kidney News, c/o Customer Service,
American Society of Nephrology 1510 H Street NW, Suite 800, Washington, DC 20005.
Publications mail agreement No. 40624074. Return undeliverable Canadian addresses to
PO Box 503, RPO West Beaver Creek, Richmond Hill ON L4B 4R6
ASN Kidney News (ISSN print 1943-8044 and online 1943-8052) is an official publication of
the American Society of Nephrology, 1510 H Street NW #800, Washington DC 20005, and
is published monthly. Periodicals postage paid at Washington, DC and at additional mailing offices.
Subscription rates: $12 per year. To order, please email [email protected]. Subscription prices
subject to change. Annual ASN membership dues include $12 for ASN Kidney News subscription.
Copyright© 2015 All rights reserved
June 2015 | ASN Kidney News | 5
Microarrays sues, educational interventions, and “likely” pathogenic variants. “It’s really For now, Gharavi said RHD is the
appropriate behavioral therapy. difficult to interpret what’s causal, and main indication for chromosomal mi-
Continued from page 3 Behavioral issues can also affect what’s not, and so you need a lot more croarrays in pediatric nephrology. “We
compliance and adherence to treat- studies,” he said. Building a national think that children who have congeni-
tions—in some cases, unrelated to the ment for renal dysfunction. “You can research cohort of a million or more tal kidney malformations are really the
patient’s kidney dysfunction—and plan choose also your therapy for kidney dis- volunteers is a key component of the ones at highest risk for having chromo-
clinical care accordingly. ease better knowing that maybe some Precision Medicine Initiative. somal disorders. So there is pretty good
Many of the children in the CKiD medications will affect neurocognitive Sampson emphasized the impor- evidence now that [DNA microarrays]
cohort had pathogenic genomic imbal- function,” Gharavi said. “You can get tance of saving patient specimens, should be applied to this subset of in-
ances associated with neuropsychiatric a much better appreciation of the spec- linked to clinical data, for future re- dividuals.”
disorders, such as autism, schizophre- trum of problems that may be going search and analysis. “For all us clini- “And then for the rest of the chil-
nia, intellectual disability, and seizure on with that individual and tailor the cians who are sending patients with dren with CKD, I think we need to
disorders, Gharavi noted. “That’s therapy directly to their problem.” kidney anomalies or CKD for chromo- expand the study and see what is the
important to be aware of, because Of course, much work remains to somal microarays, I think there needs impact,” he added. The question to be
we know that children with CKD in realize the full impact of precision or to be a way to store that information answered is, “Does it make a difference
general have impaired neurocognitive personalized medicine for children or store that DNA at the same time,” to make [a genetic] diagnosis in the
function and behavioral issues.” Chil- with CKD. But Gharavi emphasized he said. “[Verbitsky et al] showed that care of these patients?”
dren may have problems at school and that DNA microarray studies are clini- there’s an excess burden of large genom- Sampson agreed with the recom-
at home, or may not meet developmen- cally available now and are recom- ic imbalances in cases versus controls, mendation to test children with kidney
tal landmarks. mended as the first-line diagnostic test and we don’t know what those mean.” malformations. “With the caveat that
“And many times that’s been attrib- for children with intellectual disabil- Building patient databases will docu- [testing] has to be done in conjunction
uted to the sequelae of kidney dysfunc- ity, neurocognitive disorders, or major ment the growing experience with chil- with the appropriate specialist who can
tion and being chronically ill, being on congenital abnormalities. dren who do, or do not have contributing interpret the results. Any patient who
medications, [and] being in the hos- As these tests come into use for di- genomic imbalances. With a growing [is] sent for microarray, there should
pital,” he added. “We attribute this to agnosis of children with kidney abnor- body of saved data, Sampson said, “We be a plan in place to also send that pa-
kidney disease.” malities, Gharavi said the main chal- can go back to the medical record and tient to a genetic counselor or geneti-
Instead, this group of children has a lenges will be related to test indications then say over time, ‘OK, this is actually cist for evaluation. Being able to prop-
“fundamental neurodevelopmental dis- and interpretation. While many chil- a harmless [finding], because we actually erly counsel patients in terms of their
order,” requiring a different approach. dren will have a clear-cut genetic diag- see it in quite a few controls.’ Or, ‘Now, genomic disorder, in terms of their risk
In addition to treatment for kidney nosis, the situation will be less clear for we’ve seen 10 patients with this same for developing future problems or the
disease, the clinical plan needs to con- the significant number of patients with disorder and we’re starting to make infer- problems they already have is nuanced
sider treatment for neurocognitive is- other abnormal findings, including ences on their long-term care.” and really needs help from experts.”
Increased Risk of
vironment, did not have an increased but studies suggest that ICDs would population, which has a much lower
Cardiac Arrest risk. not provide as great a survival ben- risk of sudden cardiac death compared
“These findings advance the sci- efit to patients on dialysis compared with newly incident patients. “In this
ence because they suggest that genetic with the general population. Genetic group, I think a strong case can al-
Continued from page 1
factors—or differences in DNA se- analyses may help distinguish which ready be made for attempting primary
quence—contribute to the high risk patients may sufficiently benefit from prevention of sudden cardiac death,
very interesting idea for addressing this
of sudden death among patients on ICDs. which is the rationale for the WED-
problem: assessing, as already done for
dialysis,” said Chan. “It paves the way “The study is particularly well HED, or Wearable External Defibril-
patients with heart disease, if some
for more detailed genetic studies in done, despite limitations related to the lator in Hemodialysis patients, trial,”
hemodialysis patients possess inher-
the dialysis population to find specific retrospective nature and the inability he said.
ited genetic factors that increase their
genes that could explain the high risk to do an analysis of genetic variants The findings come at a time when
risk of sudden death,” said Simonetta
of cardiac arrest and potentially new that may be associated with sudden the annual mortality rate for US pa-
Genovesi, MD, who was not involved
treatments for these patients.” Multi- death,” Genovesi said. She noted that tients on dialysis is approximately 18
in the study and is a clinician and
ple genetic variants have been identi- it is likely that a large proportion of per 100 patient-years. Cardiac arrest
scientist at San Gerardo Hospital, in
fied that are linked with an increased the risk of sudden death in hemodialy- has been reported as the largest cause,
Monza, Italy. Genovesi has published
risk of cardiac arrest in the general sis patients is linked to problems relat- at 5 events per 100 patient-years.
many research articles related to heart
population. It will be important to ed to the dialysis session itself (such as Chan noted that his study’s find-
health in patients with kidney disease.
see if these changes are also involved hyper- and hypokalemia and acidosis) ings are associative and only provide
For the study, Kevin Chan, MD,
in cardiac arrest in the dialysis popula- as well as comorbid conditions such as a promising hypothesis. Detailed ge-
MSc, of Massachusetts General Hos-
tion, or whether novel variants specific diabetes. netic studies are needed to come to a
pital and Fresenius Medical Care
to patients with end stage renal disease “I would not like to see this new definitive conclusion about the role of
North America, led a team that ana-
may explain the excess cardiovascular attention on genetics reduce the effort genetics and cardiac events among di-
lyzed information on a population of
mortality. made to identify the modifiable risk alysis patients.
647,457 patients on chronic dialysis.
Other significant factors associ- factors operating in end stage renal
They identified 5117 pairs of patients
________________________
ated with an increased risk of cardiac disease patients who die of sudden car-
who came from the same family, and
arrest in this study included age (7% diac arrest,” she said. “I also find it a
they matched each of these patients on
26 characteristics to a control patient increased risk per 5 years), African bit risky to suggest ICD implantation Study co-authors include Christopher
from the same population. American race (37% increased risk for primary prevention on the basis of Newton-Cheh, MD, MPH, James Gu-
The researchers found that in 4.3% compared with Caucasian race), serum genetic markers in a population for sella, MD, MPH, and Franklin Mad-
of family pairs, both members died of potassium level (19% increased risk which there still are several doubts on dux, MD.
per mEq/L), erythropoietin dose (3% the actual usefulness of such an inter-
a cardiac arrest compared with 2.6%
in the control pairs. Genetically re- increased risk per 1000 units), and vention, as the underlying pathogenic Disclosures: KC and FWM receive
lated family members who did not documented coronary artery disease mechanism of fatal arrhythmias in this salary support from Fresenius Medical
cohabitate had an 88% increased risk (44% increased risk). Higher albumin population has not been clarified yet.” Care North America.
levels were associated with a decreased Charles Herzog, MD, an investiga-
of dual cardiac arrest compared with
their matched unrelated controls, risk of cardiac arrest. tor at the Hennepin County Medical The article, entitled “Heritabil-
while genetically related family mem- The investigators noted that pa- Center and the University of Minne- ity of Risk for Sudden Cardiac Ar-
bers who lived together in the same tients on dialysis have a similar risk for sota, in Minneapolis, and was also not rest in ESRD,” is available at http://
environment had 66% increased risk. cardiac arrest as patients who fulfill the involved with the study, noted that the jasn.asnjournals.org/content/ear-
Spouses, who were genetically unrelat- criteria for prophylactic implantation approach might make the most sense ly/2015/04/16/ASN.2014090881.ab-
ed but lived together in the same en- of a cardioverter defibrillator (ICD), only in the prevalent hemodialysis stract.
6 | ASN Kidney News | June 2015
Findings
Diabetes in Early
study in the American Journal of Kidney cluding the first 20 weeks’ gestation; and control group. There was no significant
Pregnancy Linked to Diseases. gestational, beyond 20 weeks. The analy- difference in gestational diabetes: 4.2
The population-based study includ- sis was adjusted for a wide range of con- versus 3.3 percent, respectively.
Increased CAKUT Risk
ed 945 patients with CAKUT born in founders, including size for gestational In a multivariable model, the odds ra-
Manitoba, Canada, between 1996 and age as a surrogate for maternal glycemic tio for CAKUT in infants with pregesta-
Pregestational exposure to maternal 2010. They were matched for gestational control. tional diabetes exposure was 1.67. The es-
diabetes—during the first 20 weeks of age, sex, and birth year to 4725 control Pregestational exposure to maternal timated incidence of CAKUT in mothers
pregnancy—is associated with congeni- children. The study focused on the as- diabetes was significantly more com- with pregestational diabetes was 8.3 per
B:15.5”
tal anomalies of the kidney and urinary sociation between CAKUT and timing mon among infants with CAKUT: 4.1 1000 live births, compared to 5 per 1000
tract (CAKUT) in offspring, reports a of diabetes exposure: pregestational, in- percent, compared to 2.3 percent in the in the general population. The presence T:15.5”
S:7”
INDICATION
AURYXIA is a phosphate binder indicated for the Overdose: AURYXIA contains iron. Iron absorption
control of serum phosphorus levels in patients with from AURYXIA may lead to excessive elevations
chronic kidney disease on dialysis. in iron stores, especially when concomitant IV iron
is used.
IMPORTANT SAFETY INFORMATION
Accidental Overdose of Iron: Accidental overdose
Contraindication: AURYXIA is contraindicated in of iron containing products is a leading cause of fatal
patients with iron overload syndromes. poisoning in children under 6 years of age. Keep this
product out of the reach of children.
Iron Overload: Iron absorption from AURYXIA may
Patients with Gastrointestinal Bleeding or
lead to excessive elevations in iron stores. Assess
Infl ammation: Safety has not been established.
iron parameters, serum ferritin and TSAT, prior to
and while on AURYXIA. Patients receiving IV iron may Pregnancy Category B and Nursing Mothers:
require a reduction in dose or discontinuation of IV Overdosing of iron in pregnant women may carry
iron therapy.
June 2015 | ASN Kidney News | 7

Living with Polycystic
of CAKUT was associated with both The link with large size for gestational
according to a qualitative analysis in
large and small size for gestational age: age suggests that poor glycemic control Kidney Disease:
Nephrology Dialysis Transplantation.
odds ratio 1.34 and 1.59, respectively. may increase risk. The authors discuss the
Patients’ Perspective The researchers performed a the-
Previous studies of the association need for optimal glycemic control during
matic analysis of qualitative or mixed-
between maternal diabetes and CAKUT early pregnancy, with consideration of
have not examined potential differences screening for renal anomalies [Dart AB, The unpredictable nature of pain and methods studies of ADPKD, focusing
by the timing of exposure. The new study et al: Maternal diabetes mellitus and the difficulty of establishing long-term on patient perspectives and experi-
finds a significant increase in CAKUT congenital anomalies of the kidney and life goals are major burdens for pa- ences of living with their disease. The
B:15.5” among infants with pregestational, but urinary tract (CAKUT) in the child. Am tients affected by autosomal dominant analysis included 21 studies totaling
T:15.5” not gestational, exposure to diabetes. J Kidney Dis 2015; 65:684–691]. polycystic kidney disease (ADPKD), Continued on page 8
aDlli aabreet eFsi nadnidn gMsetabolism
S:7”
For the control of serum phosphorus levels in patients
with chronic kidney disease on dialysis
AURYXIA™ (ferric citrate) IS THE FIRST AND ONLY
ABSORBABLE-IRON–BASED PHOSPHATE BINDER
CLINICALLY PROVEN TO MANAGE HYPERPHOSPHATEMIA1-6
(cid:127) Proven control of serum phosphorus within
KDOQI guidelines (4.88 mg/dL at Week 56)7,8
(cid:127) Demonstrated safety and tolerability profi le
over 52 weeks
(cid:127) Eeqacuhiv AalUeRntY tXoI A1 tga bfelerrti cc ocnittraaitnes 210 mg ferric iron, S:10” T:10.25 B:10.25
” ”
References:
1. Fosrenol [package insert]. Wayne, PA: Shire US, Inc.; 2014. 2. Phoslyra [package insert]. Waltham, MA: Fresenius Medical Care North America;
2011. 3. PhosLo Gelcaps [package insert]. Waltham, MA: Fresenius Medical Care North America; 2012. 4. Renagel [package insert]. Cambridge,
MA: Genzyme Corporation; 2014. 5. Renvela [package insert]. Cambridge, MA: Genzyme Corporation; 2014. 6. Velphoro [package insert].
Waltham, MA: Fresenius Medical Care North America; 2014. 7. National Kidney Foundation. K/DOQI clinical practice guidelines for bone
metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003;42(4 Suppl 3):S1-S201. 8. Data on File 1, Keryx Biopharmaceuticals, Inc.
a risk for spontaneous abortion, gestational diabetes, Drug Interactions: Doxycycline should be taken at
and fetal malformation. Rat studies have shown least 1 hour before AURYXIA. Consider separation
the transfer of iron into milk. There is possible infant of the timing of the administration of AURYXIA with
exposure when AURYXIA is taken by a nursing woman. drugs where a reduction in their bioavailability would
have a clinically signifi cant effect on safety or effi cacy.
Pediatric: The safety and effi cacy of AURYXIA have
not been established in pediatric patients. Please see Brief Summary on following page.
Adverse Events: The most common adverse events You may report side effects to Keryx at
with AURYXIA were diarrhea (21%), nausea (11%), 1-844-44KERYX (844-445-3799).
constipation (8%), vomiting (7%), and cough (6%).
Gastrointestinal adverse reactions were the most
common reason for discontinuing AURYXIA (14%).
©2015 Keryx Biopharmaceuticals, Inc.
01/15 PP-AUR-US-0075
8 | ASN Kidney News | June 2015
Findings
Polycystic Kidney
guities” included difficulty accepting patients who refused genetic testing, patients with ADPKD. The authors
the diagnosis, feeling unable to con- ‘owning the decision’ to have children discuss the implications for improv-
Disease
trol and monitor their health, unpre- or not, or a need or wish for direc- ing patient-centered care outcomes,
dictable daily disruptions due to pain, tive counseling. Under the theme of including increased engagement in
Continued from page 7
and an uncertain future with inability “defining parental responsibility for pain management, self-care strategies,
to plan ahead. genetic testing and disclosure,” pa- counseling to address “genetic guilt,”
247 patients.
Patients reported “genetic guilt tients talked about trying to preserve and disease-specific decision support
The analysis identified five major
and resentment,” blaming their par- normality for their child, respecting tools for family planning [Tong A,
themes, including “unvalidated pain”
ents and themselves for their disease, the child’s autonomy in deciding to be et al: A painful inheritance—patient
that was not taken seriously by physi-
and guilt about transmitting the risk tested, and confidence in future tech- perspectives on living with polycys-
cians and for which pain management
to their children. The theme of “pre- nologies to cure the disease. tic kidney disease: thematic synthesis
options were inadequate. The theme
cariousness in pursuing parenthood” The analysis lends insights into the of qualitative research. Nephrol Dial
of “persisting uncertainties and ambi-
included prognostic uncertainty in complex factors affecting the lives of Transpl 2015; 30:790–800].
GaDleli anabereetit ceF sid naidsneidna gsMesse toafb koildisnmey
T:7”
BRIEF SUMMARY
AURYXIA™ (ferric citrate) tablets contain 210 mg of ferric iron equivalent to 1 g ferric citrate for oral use.
INDICATIONS AND USAGE
AURYXIA is a phosphate binder indicated for the control of serum phosphorus levels in patients with chronic kidney disease on dialysis.
CONTRAINDICATIONS
AURYXIA is contraindicated in patients with iron overload syndromes (eg, hemochromatosis).
WARNINGS AND PRECAUTIONS
Iron Overload: Iron absorption from AURYXIA may lead to excessive elevations in iron stores. Increases in serum ferritin and transferrin saturation
(TSAT) levels were observed in clinical trials. In a 56-week safety and efficacy trial in which concomitant use of AURYXIA and IV iron was permitted,
55 (19%) patients treated with AURYXIA had a ferritin level >1500 ng/mL as compared with 13 (9%) patients treated with active control.
Assess iron parameters (eg, serum ferritin and TSAT) prior to initiating AURYXIA and monitor iron parameters while on therapy. Patients receiving IV
iron may require a reduction in dose or discontinuation of IV iron therapy.
Accidental Overdose of Iron: Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6 years of age.
Keep this product out of the reach of children. In case of accidental overdose, call a doctor or poison control center immediately.
Patients with Gastrointestinal Bleeding or Inflammation: Patients with inflammatory bowel disease or active, symptomatic gastrointestinal
bleeding were excluded from clinical trials. Safety has not been established in these populations.
ADVERSE REACTIONS
Adverse reactions to a drug are most readily ascertained by comparison with placebo, but there is little placebo-controlled experience with AURYXIA,
so this section describes adverse events with AURYXIA, some of which may be disease-related, rather than treatment-related. A total of 289 patients
were treated with AURYXIA and 149 patients were treated with active control (sevelamer carbonate and/or calcium acetate) during the 52-week,
randomized, open-label, active control phase of a trial in patients on dialysis.
A total of 322 patients were treated with AURYXIA for up to 28 days in three short-term trials. Across these trials, 557 unique patients were treated
with AURYXIA; dosage regimens in these trials ranged from 210 mg to 2,520 mg of ferric iron per day, equivalent to 1 to 12 tablets of AURYXIA. In
these trials, adverse events reported for AURYXIA were similar to those reported for the active control group. Adverse events reported in more than
5% of patients treated with AURYXIA in these trials included diarrhea (21%), nausea (11%), constipation (8%), vomiting (7%), and cough (6%).
During the 52-week active control period, 60 patients (21%) on AURYXIA discontinued study drug because of an adverse event, as compared to
21 patients (14%) in the active control arm. Patients who were previously intolerant to any of the active control treatments (calcium acetate and
sevelamer carbonate) were not eligible to enroll in the study. Gastrointestinal adverse events were the most common reason for discontinuing
AURYXIA (14%).
AURYXIA is associated with discolored feces (dark stools) related to the iron content, but this staining is not clinically relevant and does not affect
laboratory tests for occult bleeding, which detect heme rather than non-heme iron in the stool.
DRUG INTERACTIONS
Doxycycline is an oral drug that has to be taken at least 1 hour before AURYXIA. Oral drugs that can be administered concomitantly with AURYXIA
T
are: amlodipine, aspirin, atorvastatin, calcitriol, clopidogrel, digoxin, doxercalciferol, enalapril, fluvastatin, levofloxacin, metoprolol, pravastatin, :1
0
propranolol, sitagliptin, and warfarin. There are no empirical data on avoiding drug interactions between AURYXIA and most concomitant oral drugs. ”
For oral medications where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy,
consider separation of the timing of the administration of the two drugs. The duration of separation depends upon the absorption characteristics
of the medication concomitantly administered, such as the time to reach peak systemic levels and whether the drug is an immediate release or an
extended release product. Consider monitoring clinical responses or blood levels of concomitant medications that have a narrow therapeutic range.
USE IN SPECIFIC POPULATIONS
Pregnancy: Pregnancy Category B: There are no adequate and well-controlled studies in pregnant women. It is not known whether AURYXIA can
cause fetal harm when administered to a pregnant woman. Animal reproduction studies have not been conducted.
The effect of AURYXIA on the absorption of vitamins and other nutrients has not been studied in pregnant women. Requirements for vitamins and
other nutrients are increased in pregnancy. An overdose of iron in pregnant women may carry a risk for spontaneous abortion, gestational diabetes,
and fetal malformation.
Labor and Delivery: The effects of AURYXIA on labor and delivery are unknown.
Nursing Mothers: Data from rat studies have shown the transfer of iron into milk by divalent metal transporter-1 (DMT-1) and ferroportin-1 (FPN-1).
Hence, there is a possibility of infant exposure when AURYXIA is administered to a nursing woman.
Pediatric Use: The safety and efficacy of AURYXIA have not been established in pediatric patients.
Geriatric Use: Clinical studies of AURYXIA included 106 subjects aged 65 years and older (33 subjects aged 75 years and older). Overall, the
clinical study experience has not identified any obvious differences in responses between the elderly and younger patients in the tolerability or
efficacy of AURYXIA.
OVERDOSAGE
No data are available regarding overdose of AURYXIA in patients. In patients with chronic kidney disease on dialysis, the maximum dose studied was
2,520 mg ferric iron (12 tablets of AURYXIA) per day. Iron absorption from AURYXIA may lead to excessive elevations in iron stores, especially when
concomitant IV iron is used.
In clinical trials, one case of elevated iron in the liver as confirmed by biopsy was reported in a patient administered IV iron and AURYXIA.
PATIENT COUNSELING INFORMATION
Dosing Recommendations: Inform patients to take AURYXIA as directed with meals and adhere to their prescribed diets. Instruct patients on
concomitant medications that should be dosed apart from AURYXIA.
Adverse Reactions: Advise patients that AURYXIA may cause discolored (dark) stools, but this staining of the stool is considered normal with oral
medications containing iron.
AURYXIA may cause diarrhea, nausea, constipation, and vomiting. Advise patients to report severe or persistent gastrointestinal symptoms to
their physician.
Keryx Biopharmaceuticals, Inc.
©2015 Keryx Biopharmaceuticals, Inc.
Printed in USA PP-AUR-US-0075 01/15
June 2015 | ASN Kidney News | 9
Many Kids with Type 1 Diabetes Have Ketoacidosis at Diagnosis
In recent years, close to half of young that serves more than 80 percent of dia- 2007 to 37.5 percent in 2012. consistent with diagnosis and treatment.
patients with type 1 diabetes in Colo- betic youth in Colorado. Rates, trends, Incidence of DKA at diagnosis was The authors note the incidence is simi-
rado have had diabetic ketoacidosis and risk factors for DKA at diagnosis higher for younger and African Ameri- lar to that reported in countries with
(DKA) when their diabetes was diag- were assessed. can patients, and lower for those with poor health care access, and much high-
nosed, according to a research letter in Overall, 38.9 percent of patients had private insurance or with a first-degree er than in Canada or the United King-
The Journal of the American Medical As- DKA at the time of diabetes diagnosis. relative affected by type 1 diabetes. In dom. The recent trends may be related
sociation. Incidence of DKA at diagnosis increased recent years, incidence increased to a to a rising prevalence of child poverty
The researchers analyzed 3439 pa- from 29.9 percent in 1998, to 35.0 per- larger extent among children with pri- [Rewers A, et al: Incidence of diabetic
tients diagnosed with type 1 diabetes cent in 2007, to 46.2 percent in 2012. vate insurance. ketoacidosis at diagnosis of type 1 dia-
before age 18 between 1998 and 2012. The percentage of patients on public in- The study suggests rising rates of betes in Colorado youth, 1998–2012.
All were followed up at a Denver center surance increased from 17.1 percent in DKA at diagnosis of type 1 diabetes, JAMA 2015; 313:1570–1572].
aDlli aabreet eFsi nadnidn gMsetabolism
No Difference in Response to Nitrofurantoin with Reduced Kidney Function
Mild to moderate reductions in kid- women’s median age was 79 years and trofurantoin compared to ciprofloxacin ney function, leading to the suggestion
ney function don’t alter the treatment median estimated glomerular filtration and norfloxacin (but not TMP-SMX). that this antibiotic be avoided when
failure rate of nitrofurantoin in older rate (eGFR) 38 mL/min/1.73 m2. However, analysis of the cohort with the eGFR is less than 40 mL/min/1.73
women with urinary tract infections, Fourteen-day treatment failure rates relatively high eGFR revealed a similar m2. The new analysis finds no increase
concludes a report in the Canadian were examined in terms of need for a pattern of higher treatment failure rates in the nitrofurantoin failure rate in
Medical Association Journal. second antibiotic or hospital encounter with nitrofurantoin. Compared to ni- older women with mild to moderate
Using Ontario health databases, the for urinary tract infection. The same trofurantoin, adjusted odds ratios for a reductions in kidney function. Regard-
researchers identified a cohort of 9223 outcomes were assessed in a cohort of second prescription with ciprofloxacin less of eGFR, treatment failure is more
older women with reduced kidney func- 182,634 women with relatively high were 0.43 for women with lower kid- likely with nitrofurantoin than with
tion receiving one of four oral antibiot- eGFR: median 69 mL/min/1.73 m2. ney function and 0.50 for those with other antibiotic choices [Singh N, et
ics commonly used for reduced urinary Women receiving the four antibiot- higher kidney function. al: Kidney function and the use of ni-
tract infections: nitrofurantoin, cipro- ics had similar baseline characteristics. Previous reports have suggested sub- trofurantoin to treat urinary tract in-
floxacin, norfloxacin, or trimethoprim/ Among those with low eGFR, failure therapeutic concentrations of nitro- fections in older women. CMAJ 2015.
sulfamethoxazole (TMP-SMX). The rates were significantly higher with ni- furantoin in patients with reduced kid- DOI:10.1503/cmaj.150067].
aDlli aabreet eFsi nadnidn gMsetabolism
High CPR Rates, Poor Survival in Dialysis Patients
Hemodialysis patients have a high rate occurring more than 90 days after di- The incidence of in-hospital CPR incidence of in-hospital CPR among he-
of in-hospital cardiopulmonary resus- alysis initiation were assessed, along events per 1000 in-hospital days in- modialysis patients, despite poor surviv-
citation (CPR), with low rates of long- with survival to hospital discharge af- creased from 1.0 in 2000 to 1.6 in al after CPR. The researchers conclude,
term survival after CPR, according to ter the first CPR event. 2011, while the percentage of patients “These findings support the relevance of
a study in JAMA Internal Medicine. In this national cohort, the annual surviving to discharge increased from advance care planning and setting real-
Rates and outcomes of in-hospital incidence of CPR was 1.4 events per 15.2 percent to 28.0 percent. The istic expectations regarding resuscita-
CPR were assessed in 663,734 Medi- 1000 hospital days. Survival to dis- percentage of in-hospital deaths with tion treatment in this population [Wong
care beneficiaries who started main- charge after CPR was 21.9 percent; CPR during the terminal hospitali- SPY, et al: Trends in in-hospital cardio-
tenance dialysis from 2000 through median survival after discharge was zation increased from 9.5 percent to pulmonary resuscitation and survival in
2010, identified from the US Renal 5.0 months. About 15 percent of pa- 19.8 percent. There was no change in adults receiving maintenance dialysis.
Data System registry. All hospital ad- tients who died in the hospital under- postdischarge survival after CPR. JAMA Intern Med 2015; doi: 10.1001/
missions and in-hospital CPR events went CPR during that admission. These national data suggest a rising jamainternmed.2015.0406].
aDlli aabreet eFsi nadnidn gMsetabolism
Minority Patients Have Lower Rates of Fistula Access
African American and Hispanic patients hemodialysis for 18.3 percent of white and 0.86 for Hispanic patients.
are less likely to have an arteriovenous patients, compared to 15.5 percent of The results show persistent racial/
fistula (AVF) in place when starting he- African American and 14.6 percent of ethnic disparities in the presence
modialysis, compared to white patients Hispanic patients. This was so even of an AVF for initial hemodialysis
with similar characteristics, reports a though the minority patients were access in the United States. The
study in JAMA Surgery. younger and had lower rates of comor- lower rates of AVF access among
The analysis included US Renal bid conditions: coronary artery disease, African American and Hispanic
Data System data on 396,075 patients chronic obstructive pulmonary disease, patients are independent of insur-
initiating hemodialysis from 2006 and cancer. ance status, nephrology care, and
through 2010. Multivariable analysis Odds ratios for AVF access were other factors driving fistula place-
and propensity-score matching were 0.90 for uninsured and 0.85 for in- ment. “The sociocultural underpin-
used to compare hemodialysis access sured African American patients, and nings of these disparities deserve in-
rates—including AVF, arteriovenous 0.72 for uninsured and 0.81 for insured vestigation and redress to maximize the
graft, and intravascular hemodialysis Hispanic patients. The difference was benefits of initiating hemodialysis via
catheter—for patients of different ra- significant even among the subgroup of fistula in patients with end-stage renal
cial/ethnic groups but otherwise similar patients who had been under a neph- disease irrespective of race/ethnicity,” sociated with initial hemodialysis ac-
characteristics. rologist’s care for more than one year: the investigators conclude [Zarkowsky cess. JAMA Surg 2015; doi:10.1001/
An AVF was in place at the start of odds ratio 0.81 for African American DS, et al: Racial/ethnic disparities as- jamasurg.2015.0287].
aDlli aabreet eFsi nadnidn gMsetabolism
ASN Board Review Course & Update
July 25–31, 2015 | Chicago, IL
Fairmont Chicago, Millennium Park
Registration
now open
Face the boards with confidence
Maximize your readiness for the ABIM nephrology examination.
ASN’s Board Review Course & Update is designed for fellows and practicing physicians preparing for certification
or recertification in nephrology. Each topic and its time allocation are patterned after the ABIM nephrology
examination, giving you the most efficient preparation. Lectures, interactive case discussions, and panel Q&A
sessions contribute to ASN’s unparalleled review course.
Earn CME credits.
ASN designates this live activity for a maximum of 69 AMA PRA Category 1 Credits™. Physicians should claim
only the credit commensurate with the extent of their participation in the activity.
The best choice for your board preparation.
• Free post-course access to BRCU Online
• 250 practice exam questions
• Exam-focused curricula
• Renowned expert faculty
• Comprehensive syllabus with lecture outlines, explanatory text, and key slides
Learn more and register at www.asn-online.org/brcu.
Education | The ASN Advantage
www.asn-online.org/brcu