Risk Factors for Chronic Kidney Disease Evident Decades Before

20 Pages·2014·16.06 MB·English

July 2014 | Vol. 6, Number 7
Risk Factors for Chronic Kidney Disease
Inside
Evident Decades Before Diagnosis
(CKD), but most studies have evaluated ticipants who did and did not develop Glomerular disease
such risk factors at or near the time of kidney disease.
Primary glomerular diseases
diagnosis. Earlier identification may “One of the benefits of the Framing-
account for about 10 percent
allow for risk factor modification ham Heart Study is that we have a very of CKD in the U.S. and
and disease prevention. long duration of follow-up,” Fox said. up to 50 percent in other
Researchers have now found “As a result, we are able to look far back countries. Our special section
that certain factors are present in time prior to when individuals develop looks at recent advances in
and identifiable 30 years or a disease to examine their risk factors.” understanding the diseases
more before a diagnosis of The researchers identified 441 new plus collaborative efforts for
CKD. The findings, which cases of CKD among participants of patient care and research.
are published in the Jour- the Framingham Heart Study, and they
matched them with 882 controls who
nal of the American Society of
did not develop CKD. Those who ulti-
Nephrology, suggest that obe- Policy Update
mately developed CKD were 76 percent
sity, high blood pressure, high
more likely to have had hypertension, 71 FDA proposes revisions to
triglycerides, and diabetes are
percent more likely to have been obese, nutrition and supplement
key signs of potential kidney prob-
and 43 percent more likely to have had labels; ASN, others respond.
lems in the future.
higher triglycerides 30 years before CKD
diagnosis.
Lifetime risks revealed Training the Trainers
They were also 38 percent more likely
Communication workshop for
To look at risk factors for CKD that may to have had hypertension, 35 percent
nephrology educators planned
Risk factors for many chronic appear well in advance of kidney dis- more likely to have had higher triglyc-
for spring 2015
diseases are present well before ease, Caroline S. Fox, MD, MPH, and eride levels, and nearly three times more
any signs of a problem. Age, Gearoid McMahon, MB, BCh, of the likely to have had diabetes 20 years be-
hypertension, ethnicity, diabetes, smok- National Heart Lung and Blood Insti- fore CKD diagnosis. There was a graded Practice Pointers
ing, low HDL cholesterol, proteinuria, tute’s Framingham Heart Study and the increase in CKD risk with each addi-
Drug Dosing in CKD and
and obesity all have been identified as Center for Population Studies led a team tional risk factor in any combination, Dialysis
risk factors for chronic kidney disease that examined risk factors in study par- Continued on page 3
Journal View
Kidney transplant recipients
Medicaid Expansion May Reduce Access Gaps in Kidney-
are at high risk of cancer-
related death. The risk may
Related Care, Study Suggests be even higher in recipients of
organs from deceased donors.
While Medicaid is designed aid coverage have lower incidences of source of rising health care expendi-
to provide health insurance kidney failure and smaller insurance- tures, and access to care for uninsured
for low-income Americans, related gaps in access to kidney disease individuals with a chronic disease has
states have flexibility within federal care. The Journal of the American Society eroded over the last decade. This may
guidelines to design their programs. of Nephrology findings point to the po- change for many patients with the im-
There is limited information on how tential benefits of Medicaid expansion plementation of the Affordable Care
differences in Medicaid coverage influ- on the prevention and management of Act, which expands Medicaid coverage
ence chronic disease care. Now a study a chronic disease. to adults with incomes below 133% of
shows that states with broader Medic- Chronic disease care is a major the federal poverty level; however, not
all states are expected to participate in
this expansion.
Examining the care of patients ap-
proaching end stage renal disease
(ESRD) may provide insights into the
potential effect of Medicaid expan-
Continued on page 3
HeRO (Hemodialysis Reliable OutFlow)
Graft is the ONLY fully subcutaneous
AV access solution clinically proven
to maintain long-term access for
hemodialysis patients with central
venous stenosis.
• Fewer Infections: 69% reduced
infection rate compared with
catheters1
• Superior Dialysis Adequacy: 1.7 Kt/V,
HeRO Graft bypasses
a 16% to 32% improvement compared
central venous stenosis
with catheters1
• High Patency Rates: Up to 87%
cumulative patency at 2 years1, 2
• Cost Savings: A 23% average savings
per year compared with catheters3
Reducing Catheter Dependency
HeRO Graft Candidates Treatment Algorithm
• Catheter-dependent or
Failing AVF or AVG due to central venous stenosis
approaching catheter-
dependency
• Failing AVF or AVG due to
central venous stenosis
Catheter-dependent patients
AVF AVG HeRO Graft Catheter
Learn more at www.herograft.com
1. Download the App
Order at: 888.427.9654
2. Scan the code with
your mobile device
References: to watch video
1) Katzman et al., J Vasc Surg 2009. 2) Gage et al., EJVES 2012. 3) Dageforde et al., JSR 2012.
Indications for Use: The HeRO Graft is indicated for end stage renal disease patients on hemodialysis
who have exhausted all other access options. See Instructions for Use for full indication,
contraindication and caution statements. Rx only.
HeRO Graft is classified by the FDA as a vascular graft prosthesis.
1655 Roberts Boulevard, NW • Kennesaw, Georgia 30144 • Phone [phone] • [phone]
All trademarks are owned by CryoLife, Inc. or its subsidiaries. HeRO Graft is a Hemosphere, Inc. product distributed
by CryoLife, Inc. and Hemosphere, Inc. © 2012 CryoLife, Inc. All rights reserved.
Advertiser: CryoLife
Ad Title: HeRo Graft
Job #:
Ad Size: 10.5 x 14.5
Agency: Boyd Communications
Agency Contact: Chris Mullen [phone]
Publication: ASn Kidney News
Date:
Material Deadline:
July 2014 | ASN Kidney News | 3
Early Risk
studies have pointed to histopathological of uncovering early indications of CKD to 15 percent of the adult population and
changes of obesity-related glomerulopa- decades before disease onset. because of the relative ineffectiveness of
Continued from page 1
thy in obese patients with no evidence of “This is an important study because it currently available therapies to ameliorate
renal disease. Also, weight loss in patients provides further evidence that CKD is a the associated risks of progressive kidney
indicating that the more risk factors an with obesity-related kidney disease has life course illness that often develops over damage and cardiovascular disease.”
individual had in the past, the more likely been linked with reduced glomerular hy- several decades. The observation that risk Taal noted that the risk factors identi-
they were to develop kidney disease. perfiltration and albuminuria. factors such as hypertension, obesity, dys- fied are equally important for cardiovas-
The authors stressed that their obser- lipidemia, and diabetes may be present cular disease prevention, so programs fo-
Mechanisms and implications
vational study does not show whether two to three decades before the detection cused on cardiovascular risk reduction in
Fox and her colleagues explored the po- altering these risk factors will definitely of CKD implies that early intervention to the general population should also reduce
tential mechanisms behind the links they prevent future disease. Therefore, future abrogate these risk factors may be effective kidney-related risks.
found. For example, regarding dyslipi- studies should focus on whether early risk in reducing the prevalence of CKD,” said ––––––––––––––––––––––––––––––
demia, research indicates that the accu- factor modification will decrease the inci- Maarten Taal, MD, FCP(SA), FRCP, a Study co-authors include Sarah Preis, ScD,
mulation of both triglycerides and the dence of CKD. Another important limi- professor of medicine at the University of PhD, and Shih-Jen Hwang, PhD.
tation is that the population studied was Nottingham and an honorary consultant Disclosures: The authors reported no
breakdown products of lipid metabolism
exclusively European-American, which nephrologist and lead clinician within the financial disclosures.
in the blood have atherogenic and pro-in-
indicates that the results may not be gen- renal unit at the Royal Derby Hospital, in The article, entitled “Mid-Adulthood
flammatory effects on the vasculature in
eralizable to the entire population. the UK. “This is important because of the Risk Factor Profiles for CKD,” is online
the kidney. Obesity is also known to have
Others in the field noted the value high prevalence of CKD that affects up at http://jasn.asnjournals.org/.
detrimental effects on the kidneys, and
Medicaid “We also wanted to determine whether aid coverage was associated with some treatment for diabetes and hyperten-
broad state Medicaid coverage ben- spillover benefits for uninsured adults sion, which are the most common
Expansion
efited uninsured adults in addition to with ESRD, but these were small and underlying causes of ESRD, may have
those receiving Medicaid.” not consistently observed. considerable impacts on the association
Continued from page 1
The researchers identified 408,535 “Our study suggests that Medicaid of more generous state Medicaid cover-
sion on chronic disease care. Affecting adults aged 20 to 64 years who devel- expansion among low-income nonelder- age with lower incidences of ESRD.
more than 350,000 nonelderly Ameri- oped ESRD from 2001 through 2008. ly adults could support efforts to prevent Because a 2012 Supreme Court judg-
cans, ESRD comes with a cost of $10 Medicaid coverage among low-income kidney failure and improve access to kid- ment made the Affordable Care Act’s
billion per year. While all Americans nonelderly adults living in different ney disease care,” Tamura said. Medicaid expansion optional for states,
with ESRD can qualify for Medicare states ranged from 12.2% to 66.0%. The findings are consistent with the current period of differential Med-
coverage, those who are younger than Broader Medicaid coverage among low- other recent studies that found lower icaid coverage will allow researchers to
65 years must rely on other sources of income nonelderly adults was associ- rates of adult mortality and delayed study a variety of questions related to ac-
insurance or pay out of pocket to cover ated with a lower incidence of ESRD: care in states that expanded Medicaid cess to care and health gains for the most
pre-ESRD care. Research indicates that for each additional 10% of the low-in- coverage, and improvements in mental vulnerable segments of the population.
an estimated 10% of adults with nondi- come nonelderly population covered by health among newly enrolled Medicaid “In the case of ESRD, we strongly
alysis-dependent chronic kidney disease Medicaid, there was a 1.8% decrease in beneficiaries. recommend that detailed data also be
are uninsured. ESRD incidence. In an accompanying editorial, Raj- collected concerning the intermediate
Using national data, Manjula Ta- Low-income nonelderly adults with nish Mehrotra, MD, and Larry Kessler, markers or indicators, such as diabetes
mura, MD, MPH, of the VA Palo Alto ESRD who were on Medicaid had bet- ScD, of the University of Washington, and hypertension control, to under-
Health Care System and Stanford Uni- ter access to care in states with broader Seattle, stated that the researchers’ work stand the nature of the impact of the
versity, led a team that assessed the rela- Medicaid coverage: For a 50-year-old “highlights the intricate web of health provision of expanded coverage,” wrote
tion between the extent of state Medic- white woman, the access gap to being insurance, access to care, and ESRD. Mehrotra and Kessler.
aid coverage and access to care among put on the kidney transplant waiting Their study is timely as a social experi-
nonelderly adults approaching ESRD list between Medicaid and private in- ment is unfolding in this country that The article, entitled “State Medicaid Cover-
and whether that relationship differed surance decreased by 7.7 percentage will allow us to further examine the as- age, ESRD Incidence, and Access to Care,”
based on patients’ insurance status. points in high vs. low Medicaid cover- sociation between Medicaid coverage is online at http://jasn.asnjournals.org/.
“We wanted to determine whether age states. Similarly, the access gap to and health care outcomes.” They noted
states with broader Medicaid coverage transplantation decreased by 4.0 per- that such a population-level analysis The editorial, entitled “Health Insurance,
of low-income non-elderly adults had centage points and the access gap to needs corroborative evidence to iden- Access to Care, and ESRD: An Intricate
a lower incidence of ESRD and better peritoneal dialysis decreased by 3.8 per- tify the causes for the links that were Web,” is online at http://jasn.asnjour-
access to pre-ESRD care,” Tamura said. centage points. Finally, broader Medic- found, though. For example, improved nals.org/.
Maintaining your certification with ASN’s
Dialysis Practice Improvement Module
ASN provides the best learning opportunities in kidney care. The Dialysis Practice Improvement
Module (DPIM) guides physicians through a review of patient data and supports the
implementation of a quality-improvement (QI) plan for their practice.
· Evaluate and improve care for dialysis patients
· Implement an individual or practice-wide improvement plan
· Earn 20 MOC points from ABIM
Available Now
Online Learning | The ASN Advantage
www.asn-online.org/learningcenter
4 | ASN Kidney News | July 2014

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
Editorial Staff
for their contributions in 2013.
Editor-in-Chief: Pascale H. Lane, MD, FASN
Executive Editor: Dawn McCoy
Content and Media Analyst: Kurtis Pivert
Design: Lisa Cain Design
Communications Assistant: Sara Leeds
Diamond Level
Editorial Board:
Matthew D. Breyer, MD, FASN, Eli Lilly and Company
Wendy Weinstock Brown, MD, Jesse Brown VA Medical Center, Northwestern University Feinberg
School of Medicine, University of Illinois at Chicago
Teri Browne, PhD, MSW, University of South Carolina
Stephen Darrow, MD, University of Minnesota Medical Center
Ira Davis, MD, Baxter Healthcare Corp.
Nishank Jain, MD MPH (fellow), University of Texas Southwestern Medical Center
Caroline Jennette Poulton, MSW, University of North Carolina Kidney Center
Richard Lafayette, MD, Stanford University Medical Center
Edgar V. Lerma, MD, FASN, University of Illinois – Chicago /Associates in Nephrology, SC
Teri J. Mauch, MD, FASN, University of Utah
Victoria F. Norwood, MD, FASN, University of Virginia
Matthew A. Sparks, MD, Duke University Hospital
Titte R. Srinivas, MD, Medical University of South Carolina
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: Sharon M. Moe, MD, FASN
President-elect: Jonathan Himmelfarb, MD, FASN
Past-President: Bruce A. Molitoris, MD, FASN
Secretary-Treasurer: John R. Sedor, MD, FASN
Communications Committee Chair: Eleanor D. Lederer, MD, FASN
Councilors: Raymond C. Harris, MD, FASN, Eleanor D. Lederer, MD, FASN,
Mark D. Okusa, MD, FASN, Mark E. Rosenberg, MD, FASN
Executive Director: Tod Ibrahim
Associate Director of Publishing: 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 Platinum Level
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
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© 2014 All rights reserved
July 2014 | ASN Kidney News | 5
Glomerular Disease
Advancing Understanding and Treatment of
Glomerular Disease
By Richard A. Lafayette
Primary glomerular disease is an (9). Specific antibodies have been linked to certain
important cause of chronic and end disease states, such as antibodies to galactose-defi-
stage renal disease cient IgA1 in IgAN and antibodies to the M-type
phospholipase A2 in MN (10,11). Increased levels
Chronic kidney disease (CKD) is increasingly rec-
of circulating factors such as soluble urokinase-
ognized as a growing global challenge, affecting up
type plasminogen activator receptor have been re-
to 16 percent of the adult population (1,2). Al-
ported in FSGS and initially appeared to be related
though the veritable explosion in type II diabetes
to the degree of impaired kidney function (12).
is largely responsible for this growth in developed
These selected examples demonstrate that distinct
and many developing countries, primary glomeru-
pathways may be examined in these patients to
lar disease continues to contribute meaningfully to
help define the mechanisms of disease, and these
the CKD epidemic (2). These diseases account for
approaches may result in the discovery of biomark-
roughly 10 percent of CKD cases in the United
ers of the specific disease, prognostic indicators, or
States and up to 50 percent in other countries (3,
novel targets for therapy.
4). Primary glomerular diseases contribute to con-
siderable morbidity, cost, and mortality. As part
Insights into advances in glomerular
of this, they contribute importantly to ESRD in
disease
the United States (Figure 1). More than 80,000
patients with ESRD report glomerulonephritis as Building on these findings, this issue of Kidney
their primary cause of ESRD, and 9000 patients News presents some insights and opinions regard-
with primary glomerular disease begin undergoing ing glomerular diseases, ranging from specific
receptor as target antigen in idiopathic mem-
dialysis each year (2). In addition to the burden discoveries through mechanisms of collaborative
branous nephropathy. N Engl J Med 2009;
of glomerular disease in adults, it is noteworthy studies and proceeding to suggestions about how
361:11−21.
that roughly one in four cases of pediatric ESRD is to further improve the care of patients with glo-
11. Clement LC, et al. Podocyte secreted angi-
related to primary glomerular disease (2). merular disease, whether primary or secondary to
opoietin-like 4 mediates proteinuria in gluco-
systemic disease. It is hoped that these efforts will
corticoid sensitive nephrotic syndrome. Nat
Recent discoveries have focused usher in more interest, resources, and effort in the
Med 2011; 17:117−123.
attention on primary glomerular area to ultimately benefit the patients we serve.
12. Wei C, et al. Circulating urokinase receptor as
disease
a cause of focal segmental glomerulosclerosis.
References
Whereas many speak of limited progress in the Nat Med 2011; 17:952−960.
field of glomerulonephritis, and being stuck with 1. US Renal Data System. USRDS 2012 Annual
treatments similar to those we used decades ago, Data Report. Bethesda, MD: National Insti- Richard A. Lafayette, MD, FACP, is associate pro-
tutes of Health, National Institute of Diabetes
recent discoveries and trials suggest that advances fessor of medicine in the Division of Nephrology at
and Digestive and Kidney Diseases, 2012.
are indeed being made and are likely to be ex- Stanford University School of Medicine in Palo Alto,
2. El-Nahas AM, Bello AK. Chronic kidney
tended. Minimal change disease (MCD), focal CA. Dr. Lafayette edited this special section for ASN
disease: the global challenge. Lancet 2005;
segmental glomerular sclerosis (FSGS), membra- Kidney News.
365:331−340.
nous nephropathy (MN), and IgA nephropathy
3. Couser WG. Mediation of glomerulonephri-
(IgAN) cause proteinuria by means of glomerular Figure 1. US Renal Data System data for
tis: basic and translational concepts. J Am Soc
podocyte injury, most likely related to immune prevalence of glomerulonephritis as a cause
Nephrol 2012; 23:381–399.
dysregulation, although the exact mechanisms are of ESRD.
4. Rovin BH, Schreiner GF. Cell mediated im-
still unknown (3,4). For populations at risk, the
muity in glomerular disease. Ann Rev Med
mechanisms of podocyte-related and non−podo-
1991; 42:25−33.
cyte-related injury, clinical manifestations (includ-
5. Pollak MR. The genetic basis of FSGS and ster-
ing impaired renal function, hematuria, proteinu-
oid-resistant nephrosis. Semin Nephrol 2003;
ria, and hypertension), response to corticosteroids
23:141−146.
and other anti-inflammatory and immunosuppres-
6. Liu Z, et. al. Alpha-actinin-4 and CLP36 pro-
sive therapies, and rates of progression to ESRD
tein deficiencies contribute to podocyte defects
differ widely among these diseases. Still, all these
in multiple human glomerulopathies. J Biol
conditions have common features that link them Chem 2011; 286:30795−30801.
together. New insights into their mechanisms 7. Gharavi AG, et al. Genome-wide association
are most likely to lead to inroads into prevention study identifies susceptibility loci for IgA ne-
and therapy. Genetic mutations that lead to syn- phropathy. Nat Genet 2011; 43:321−327.
dromes of podocyte dysfunction and injury have 8. Stanescu HC, et al. Risk HLA-DQA1 and
yielded conditions indistinguishable from classic PLA(2)R1 alleles in idiopathic membranous ne-
MCD and FSGS (5,6). New findings derived from phropathy. N Engl J Med 2011; 364:616−626.
linkage analyses may elucidate other glomerular 9. Berthoux F, et al. Autoantibodies targeting
diseases such as MN, FSGS, or IgAN (7,8). De- galactose-deficient IgA1 associate with progres-
fects in specific proteins, such as angiopoetin-like sion of IgA nephropathy. J Am Soc Nephrol
4 protein, may also lead to MCD, and these de- 2012; 9:1579−1587.
fective proteins may be specific targets of therapy 10. Beck LH Jr., et al. M-type phospholipase A2
Glomerular Disease
The Nephrotic Syndrome Study Network: A Rare Disease
Network for Precision Medicine in Nephrotic Syndrome
By Joh n Sedor, Matthias Kretzler, and Denise L. Taylor-Moon
The main goal of the Nephrotic Syndrome ease definitions to be informed by a comprehen- thy Trial of Rituximab] and DUET, clinical trials
Study Network, NEPTUNE, is to build sive, multilayered analysis of the disease course in No. NCT01180036 and No. NCT01613118).
a translational research infrastructure for observational cohort studies. NEPTUNE is re- Over the past 4.5 years, NEPTUNE has de-
diseases manifesting as nephrotic syndrome (NS), cruiting a core cohort of patients with NS and has veloped an investigative infrastructure that has
which includes focal and segmental glomerulo- generated datasets, which define the underlying established an observational longitudinal cohort
sclerosis (FSGS), minimal change disease (MCD), genetic architecture and capture environmental of more than 450 incident adult and pediatric
and membranous nephropathy (MN) (1). The exposures, unique molecular phenotypes, histopa- patients, allowing for standardized collection of
network of investigators from 21 academic cent- thology, and prospective clinical outcomes. This renal biopsy tissues, blood and urine, comprehen-
ers across the United States and Canada, and two disease knowledge along the genotype–phenotype sive patient history, associated clinical data, and
patient interest groups, the NephCure Founda- continuum is used by basic and clinical scientists standardized measures of psychosocial well-being.
tion and the Halpin Foundation, have worked to develop a knowledge network of NS that defines Ongoing recruitment will further grow this unique
closely together to study these rare glomerular the diseases from molecular pathogenesis rather cohort, and interested patients can be referred to
diseases. Despite their rarity, these diseases gener- than from histopathologic patterns. The molecular NEPTUNE centers (see https://rarediseasesnet-
ate enormous individual, societal, and economic disease definition (i.e., taxonomy) will allow more work.epi.usf.edu/NEPTUNE/centers/index.htm
burdens. The current classification of NS fails to accurate diagnosis, which is a prerequisite for tar- for recruitment centers and investigators). This
capture the molecular bases of these diseases and geted treatments that improve health outcomes in resource is available to all interested research in-
consequently does not adequately predict either NS (Figure 1). vestigators through ancillary studies to benefit
their natural history or their response to thera- The NEPTUNE cohort studies were designed the advancement of care of patients with FSGS,
py. Given our limited understanding of MCD, to generate multilayered data on the disease course MCD, and MN. It is already used in more than 30
FSGS, and MN biology and our inadequate clas-
encompassing the genotype–phenotype continu- approved ancillary studies ranging from methods
sification system, it is not surprising that our
um and generating a NS informational commons development to phase II clinical trials. For further
therapeutic approach to these diseases is also
as requested by the national academies (1). NEP- information on available datasets and access, see
imperfect. No new therapeutic targets have been
TUNE has assembled to date more than 450 NS http://www.neptune-study.org/.
validated by clinical trials for two decades, and
participants with biosamples for the generation With the joint support and participation of pa-
current therapies rely almost exclusively on im-
of individual catalogues of genomewide variation tients, the patient interest group NephCure, cli-
munosuppression, which is used without a clear
based on whole genome sequences, renal biopsy nicians, clinician scientists, and bench researchers
biological basis, is often not beneficial, and is fre-
sample–derived tissue transcriptomes, and urine from academia and industry, therapeutic targets
quently complicated by significant toxicities (2).
and plasma proteomes. These datasets are aug- are now identified and can effectively be moved
Given these shortcomings, basic science,
mented with digital histopathologic information through a translational research pipeline for evalu-
translational, and clinical studies are needed that
from renal biopsy specimens (4), longitudinal clin- ation in NS patients.
address the serious obstacles to providing effec-
ical phenotypes, and patient-reported outcomes, Please contact the NEPTUNE investigators at
tive care for the MCD, FSGS, or MN patient.
which in aggregate will be used to develop the [email protected] if you are interested in us-
NEPTUNE was funded in 2009 as part of the
framework for discovering disease mechanisms, ing or contributing to NEPTUNE.
Rare Disease Clinical Research Networks with
testing biomarkers, and designing trials that inte-
support from the National Institutes of Health
grate outcomes important to patients. In parallel, John Sedor, MD, is affiliated with the Kidney Disease
and the NephCure Foundation to overcome the
NEPTUNE is developing innovative tools for col- Research Center, Case Western Reserve University,
major barriers impeding the design of NS clinical
laborations in molecular medicine. A web-based Cleveland, Ohio. Matthias Kretzler, MD, and Den-
trials. NEPTUNE is implementing the concept
data sharing and analysis platform (Nephromine, ise L. Taylor-Moon are affiliated with the division
of precision medicine proposed by the Institute
www.nephromine.org) will allow the scientific of nephrology at the University of Michigan Health
of Medicine in 2011 (3) (Figure 1). Precision
community to link biopsy sample–derived gene System in Ann Arbor, Michigan.
medicine aims for the development of new dis-
expression datasets with predefined clinical pa-
rameters. Additional approaches for collaborative References
data mining and analysis are developed with the 1. Gadegbeku CA, et al. Design of the Nephrotic
Figure 1. Precision medicine in nephrotic aim to establish the informational commons in NS Syndrome Study Network (NEPTUNE) to
syndrome (mod. National Research Council, research around the comprehensive clinical and evaluate primary glomerular nephropathy by a
2011).
molecular information. multidisciplinary approach. Kidney Int 2013;
NEPTUNE has extensive pilot, ancillary, and 83:750–756.
New Accurate Targeted Improved training programs open to the international scien- 2. Meyers CM, Geanacopoulos M, Holzman LB,
NS- tific community to leverage its samples and core Salant DJ. Glomerular Disease Workshop. J Am
Health
Taxonomy Diagnosis Treatment Outcomes data for additional projects that will expand the Soc Nephrol 2005; 16:3472–3476.
knowledge base in the NS informational com- 3. The Committee on a Framework for Develop-
mons. NEPTUNE has supported and is closely ing a New Taxonomy of Disease, Board on Life
Knowledge Network Clinical Medicine linked with parallel efforts in Europe, China, In- Sciences, Division on Earth and Life Studies,
dia, and sub-Saharan Africa. Together with its in- National Research Council of the National
• Phenome ternational partners, NEPTUNE has established a Academies. Toward Precision Medicine: Build-
• Morphology
• Metabolome joint systems biology core for analyses across disci- ing a Knowledge Network for Biomedical Research
• Proteome
• mRna plines and continents. Additionally, NEPTUNE is and a NewTaxonomy of Disease. Washington,
• Transcriptome
• Epigenome Observational Studies facilitating investigator- and industry-led clinical DC: 2011.
• Rare variants during clinical care
• Genome trials of targeted treatments in NS from trial design 4. Barisoni L, et al. Digital pathology evolution
Biomedical
to implementation, using its clinical research net- in the multicenter Nephrotic Syndrome Study
Informational Commons Research
work for effective recruitment of rare glomerular Network (NEPTUNE) Clin J Am Soc Nephrol
disease (i.e., MENTOR [Membranous Nephropa- 2013; 8:1449–1459.
Glomerular Disease
JJuullyy 22001144 || AASSNN KKiiddnneeyy NNeewwss || 77
Understanding MPGN In the Native and
Transplanted Kidney
By Sanjeev Sethi and Fernando C. Fervenza
Membranoproliferative glomerulonephritis capillary walls and occasionally the intramembranous graft failure in up to 50 percent of patients, with graft
(MPGN), also termed mesangiocapillary and subepithelial regions of the capillary walls as well. loss occurring within 2.5 years of transplantation.
glomerulonephritis, is a diagnosis based on a By contrast, in DDD the deposits are large, extremely To summarize, the new Mayo classification of MPGN
glomerular injury pattern common to a heterogeneous dense (osmiophilic), and intramembranous, often re- is easy to understand, is based on the underlying patho-
group of diseases (1). MPGN is characterized by both an sulting in marked thickening of the glomerular base- physiology, and divides MPGN into immune complex−
inflammatory (proliferative) and resolving (membrane) ment membranes. mediated MPGN and complement-mediated MPGN for
phase. Histologically, the proliferative phase is character- It can be appreciated that the new Mayo classifica- further pathologic subheadings. The classification facili-
ized by an increase in mesangial and endocapillary cel- tion attempts to elucidate the underlying causes of tates appropriate laboratory evaluation, leading to identi-
lularity, and the resolving phase is characterized by an MPGN by dividing it into immune complex−medi- fication of the underlying cause of MPGN and the hope
increase in mesangial matrix and capillary wall remod- ated and complement-mediated disease. The classi- of better guidance for management.
eling with basement membrane material forming a wall, fication facilitates appropriate evaluation, leading to
resulting in double contour formation. identification of the correct cause. Treatment should Sanjeev Sethi and Fernando C. Fervenza are affiliated
Previously, MPGN was classified into MPGN then be based on the underlying pathogenesis of with the Mayo Clinic, Rochester, MN.
types I, II, and III, based on the ultrastructural MPGN. Recent retrospective studies have tried to
location of the electron-dense deposits along the compare the course and prognosis between the two References
capillary walls. This classification did not take groups of MPGN. However, in fairness, one cannot 1. Sethi S, Fervenza FC. Membranoproliferative glo-
into account the underlying pathophysiology and adequately compare the two groups in retrospective merulonephritis: a new look at an old entity. N
was based purely on electron microscopic findings. studies because the underlying causes were poorly un- Engl J Med 2012; 366:1119−1131.
However, a new Mayo classification of MPGN has derstood at the time, and none of the groups received 2. Sethi S, Fervenza FC. Membranoproliferative glo-
specific treatment aimed at the cause. merulonephritis: pathogenetic heterogeneity and
recently been proposed that is based on the patho-
The new Mayo classification of MPGN bears on proposal for a new classification. Semin Nephrol
physiology of MPGN (1,2). Immunofluorescence
the understanding of recurrence of MPGN after kid- 2011; 31:341−348.
(IF) studies are the key to this classification, which
ney transplantation. MPGN recurs in up to 50 to 70 3. Sethi S, et al. Membranoproliferative glomerulo-
now classifies MPGN into immune complex−me-
percent of transplant recipients. Among the immune- nephritis secondary to monoclonal gammopathy.
diated MPGN or complement-mediated MPGN
complex MPGNs, recurrence rates are very high for Clin J Am Soc Nephrol 2010; 5:770−782.
(Figure 1). The basis of immune complex−mediated
MPGN resulting from monotypic Ig deposition from 4. Zand L, et al. Membranoproliferative glomerulo-
MPGN is the IF finding of mesangial and capillary
an underlying monoclonal gammopathy. Current rec- nephritis associated with autoimmune diseases. J
wall Ig deposits with or without C3. Deposition of
ommendations include treatment of the monoclonal Nephrol 2014; 27:165−171.
Ig activates the classic pathway of complement. As gammopathy before transplantation. By contrast, the 5. Sethi S, et al. C3 glomerulonephritis: clinicopatho-
a result, C3 is often noted on IF studies along with recurrence rates of MPGN from infections and au- logical findings, complement abnormalities, glo-
the immune deposits. Furthermore, the type of im- toimmune disease are relatively low. With regard to merular proteomic profile, treatment, and follow-
mune deposits indicates the underlying cause. For complement-mediated MPGN, C3 glomerulonephri- up. Kidney Int 2012; 82:465−473.
example, deposition of monotypic Ig such as IgG-κ tis recurs in almost two thirds of patients, with graft 6. Zand L, et al. Clinical findings, pathology, and
or IgM-λ indicates an underlying monoclonal gam- failure resulting in half of the patients within 6 to 7 outcomes of C3GN after kidney transplantation.
mopathy/dysproteinemia (3). By contrast, IgM years of recurrence (6). DDD also has a high rate of J Am Soc Nephrol 2013 Dec 19 [Epub ahead of
deposits are often noted in chronic viral infections recurrence after kidney transplantation and results in print].
such as hepatitis C, whereas IgM-predominant de-
posits with smaller amounts of IgG are often noted Figure 1. Proposed classification scheme for MPGN into immune complex–mediated and comple-
in autoimmune diseases (4). Thus, immune com-
ment-mediated MPGN, based on immunofluorescence microscopy (IF) findings. Immune complex–medi-
plex−mediated MPGN typically results from one of
ated MPGN is characterized by the presence of immunoglobulins (Ig) and/or C3, while complement-
three underlying disease mechanisms: monoclonal
mediated MPGN is characterized by the presence of bright C3 and absent/scant Ig. Evaluation of
gammopathy/dysproteinemias, infections, or auto-
immune complex–mediated MPGN should include work-up for monoclonal gammopathy, autoimmune
immune diseases.
diseases, and infections. On the other hand, evaluation of complement-mediated MPGN should include
By contrast, complement-mediated MPGN re-
work-up for functional, acquired, and inherited abnormalities of the alternative pathway of complement.
sults from glomerular deposition of C3 and other
complement factors and degradation products (5).
Deposition of C3 and complement factors results
from dysregulation and overactivation of the al-
ternative pathway of complement. The alternative
pathway of complement is usually tightly regulated;
however, dysregulation of the alternative pathway
of complement can occur as a result of mutations/
polymorphism (inherited) or autoantibodies (ac-
quired) to complement regulating proteins, such as
factor H, B, or I. In complement-mediated MPGN,
the IF findings are characterized by dominant C3
staining with absent or scant Ig. The term C3 glo-
merulopathy is also used to define complement-
mediated MPGN, inasmuch as other patterns in
addition to the MPGN pattern, such as mesangial
or diffuse proliferative glomerulonephritis, may be
present. Electron microscopy further subdivides C3
glomerulopathy into C3 glomerulonephritis and
dense deposit disease (DDD). In C3 glomerulo-
nephritis, the deposits are discrete and are present
in the mesangium and subendothelial region of the
Glomerular Disease
Progress in IgA Nephropathy and Its Clinical
Implications
By Pietro A. Canetta
In the past several years, major progress has of IgAN in 2009, involving four easily identified clear that a substantial portion of disease risk is
been made in understanding the mechanisms variables that were shown to predict clinical out- conferred genetically.
underlying the development and progres- come in the inception cohort and to be repro- Within the past 5 years, a series of genomewide
sion of IgA nephropathy (IgAN). These advances ducible among pathologists: mesangial cellularity association studies have identified at least seven
have contributed to the generation of an ever- (M), endocapillary proliferation (E), segmental susceptibility loci for IgAN (5). Furthermore, in
expanding catalog of measurable variables that sclerosis (S), and tubular atrophy/interstitial fi- an elegant example of congruity between genet-
provide diagnostic or prognostic information brosis (T) (3). Subsequent to the publication of ics and epidemiology, a comprehensive geospatial
about IgAN. Such measures span the gamut from the Oxford classification, many reports have evalu- analysis of genetic risk led by colleagues at Co-
immune mediators and metabolites detectable in ated it in various cohorts. The largest was the re- lumbia University demonstrated that changes in
serum or urine, to genetic and epigenetic traits, cent publication from the pan-European VALIGA genetic risk closely paralleled disease prevalence
to histologic features both traditional and novel. study, which confirms and generalizes the value of across 85 populations worldwide (5). The genetic
IgAN has a complex multistep pathogenesis in- Oxford across a widely diverse group of patients loci identified thus far comprise genes associated
volving essentially every branch of the immune representing the entire (European) spectrum of with innate immunity, adaptive immunity (with
system, and this progress in measurable variables IgAN patients undergoing biopsy (4). VALIGA the strongest signals consistently seen in the MHC
holds great promise for better characterizing the and several other studies have identified the “E” region), and the complement system. This last lo-
disease and, in turn, allowing for a more nuanced component as the least predictive of prognosis, cus is particularly interesting, involving genes en-
approach to prognosis and therapy. but this interpretation is confounded because of coding complement factor H and its five related
The modern understanding of IgAN pathogen- the diffusion (expanded use) of immunosuppres- proteins (CFHR1-5), which regulate the alterna-
esis centers on the creation and deposition of IgA- sive treatment for IgAN, whereby “E” may indicate tive complement pathway. Mutations in the CFH/
containing immune complexes in the glomerular disease amenable to therapy rather than irrevers- CFHR gene region have been associated with C3
mesangium (Figure 1) (1).The earliest step appears ible damage like fibrosis. Beyond traditional bi- glomerulopathy, raising the intriguing possibility
to be the development of elevated circulating lev- opsy techniques, studies continue to identify novel of overlapping pathogenic mechanisms with this
els of poorly glycosylated immunoglobulin A1, histopathologic markers of prognosis in IgAN, in- much rarer form of proliferative glomerulonephri-
known as galactose-deficient IgA (Gd-IgA1). This cluding specific immune cells, complement com- tis. Although complement activation is well rec-
alone is insufficient to cause disease because el- ponents, and markers of inflammation or fibrosis. ognized in IgAN, the relative importance of the
evated Gd-IgA1 levels are also found in healthy Although the majority are unlikely to become rou- different initiating pathways—classic, alternative,
relatives of IgAN patients. Next, either IgA or IgG tine in practice, they inform our understanding of and lectin—remains unclear. A series of reports has
antibodies are formed that bind to Gd-IgA1, lead- disease pathogenesis, and they identify potential demonstrated the prognostic significance of vari-
ing to the development of immune complexes. therapeutic targets. ous complement components on biopsy, including
There are many hypothesized triggers for this au- Among the most illuminating developments in mannose-binding lectin, C1q, C4d, C3a, and C5a,
toantibody production, but a common theme is IgAN is the increasingly thorough characteriza- and both mesangial and serum C3. These indicate
activation of mucosal immunity, especially in the tion of the genetic contributions to both disease that complement activation in IgAN may be a
tonsillar or intestinal lymphoid tissue. As immune establishment and severity. Although geographic promising target for therapy.
complexes form or are deposited in the renal me- and racial differences in disease prevalence have What developments in IgAN can we expect in
sangium they activate local inflammatory cascades long been recognized, until recently it was still de- the near future? First, the number of genetic loci
whose final common pathway is cell proliferation, bated to what degree these were due to differences associated with the disease will undoubtedly ex-
matrix production, and eventually glomerular in disease ascertainment (e.g., due to diverse lo- pand as results from larger and higher-resolution
sclerosis and interstitial fibrosis. In this final stage cal biopsy practices) rather than biology. It is now genomewide studies are published. Large-scale,
of pathogenesis, IgAN becomes clinically appar-
ent, with hematuria, proteinuria, and eventual
loss of glomerular filtration. Figure 1. Left, stepwise schematic of the pathogenesis of IgAN. Adjacent to each step are
Two key measurable elements of the patho- listed relevant opportunities for diagnosis or therapy. RAAS, renin-angiotensin aldosterone system.
genic mechanism are circulating Gd-IgA1 and
the antiglycan autoantibodies. Studies have sepa-
rately demonstrated that both elevated Gd-IgA1
levels and elevated antiglycan levels predict an
increased risk for kidney failure, and at least one
study of longitudinal measurements has directly
correlated the level of these biomarkers with dis-
ease activity (2). Validation of these findings and
the development of reliable, affordable, and com-
mercially available assays could provide a much
needed biomarker of immune activity, perhaps
akin (and hopefully superior) to DNA antibodies
in systemic lupus erythematosus or ANCA levels
in pauci-immune glomerulonephritis. This would
represent a major advance in the clinical approach
to IgAN, supplementing the current time-tested
but entirely nonspecific standards of disease ac-
tivity, proteinuria, and serum creatinine.
,
Because kidney biopsy remains the gold stand-
ard for IgAN diagnosis and an invaluable source
of prognostic information, efforts continue to re-
fine and augment the information gleaned from
histopathology. A major advance was the develop-
ment and publication of the Oxford classification
Glomerular Disease
JJuullyy 22001144 || AASSNN KKiiddnneeyy NNeewwss || 99
longitudinal cohort studies are needed to validate sis (Figure 1). Given the progress achieved thus far, Jan 30 [Epub ahead of print].
proposed biomarkers and discover new ones; one both nephrologists and their patients have ample 3. Cattran DC, et al. The Oxford classification of
notable example is the CureGN study, recently reason to be excited. IgA nephropathy: rationale, clinicopathologi-
funded by the National Institutes of Health, an am- cal correlations, and classification. Kidney Int
Pietro A. Canetta, MD, is assistant professor of medi-
bitious undertaking that will enroll patients with 2009; 76:534−545.
cine, division of nephrology, Columbia University
various glomerular diseases, including 600 patients 4. Coppo R, et al. Validation of the Oxford clas-
College of Physicians and Surgeons, New York.
with IgAN. The results from ongoing randomized sification of IgA nephropathy in cohorts with
controlled treatment trials are eagerly awaited, in different presentations and treatments. Kidney
References
particular the nearly completed German STOP- Int 2014 Apr 2 [Epub ahead of print].
IgAN study, which examines the effects of immu- 1. Mestecky J, et al. IgA nephropathy: molecular 5. Kiryluk K, et al. Pathogenesis of immunoglobu-
nosuppression versus supportive care, stratified by mechanisms of the disease. Annu Rev Pathol lin A nephropathy: recent insight from genetic
estimated GFR. Finally, we can expect to see novel 2013; 8:217−240. studies. Annu Rev Med 2013; 64:339−356.
immunosuppressive approaches tested in patients, 2. Suzuki Y, et al. Serum levels of galactose-defi- 6. Kiryluk K, et al. Geographic differences in ge-
targeting pathways across the disease pathogenesis cient immunoglobulin (Ig) A1 and related im- netic susceptibility to IgA nephropathy: GWAS
including B-cell immunity, antibody generation, mune complex are associated with disease activ- replication study and geospatial risk analysis.
complement activation, inflammation, and fibro- ity of IgA nephropathy. Clin Exp Nephrol 2014 PLoS Genet 2012; 8:e1002765.
Kick off

ASN Kidney Week 2014
with Early Programs
The following 1- or 2-day courses (November 11–12) require separate
registration from the ASN Annual Meeting (November 13–16).
• Advances in Research Conference— • Innovation in Kidney Disease, Dialysis, and Vascular Access
Building a Kidney: From Stem Cells to Function
• In-Service Exam
• Coming to a Unit near You: Cluster-Randomized Trials in
• Kidney Transplantation
Hemodialysis
• Maintenance Dialysis
• Critical Care Nephrology: 2014 Update
• Maintenance of Certification: NephSAP Review and ABIM
• Diagnosis and Management of Disorders of Acid-Base, Fluid,
Modules
and Electrolyte Balance: Challenging Issues for the Clinician
• Nephro-Pharmacology across the Spectrum of Kidney
• Fundamentals of Renal Pathology
Diseases
• Glomerulonephritis Update: Diagnosis and Therapy 2014
• Professional Development Seminar
• Human Genetics in Nephrology: Clinical Fundamentals and
Research Advances
Register online at www.asn-online.org/KidneyWeek
KW EP_KN.indd 1 6/30/14 10:29 AM
Glomerular Disease
New Treatments for Idiopathic Membranous
Nephropathy
By Claudio Ponticelli
The treatment of idiopathic membranous ne- Adrenocorticotropic hormone calcineurin inhibitors have been tested by RCTs, meta-
phropathy (IMN) has been a matter of discus- analyses, and retrospective clinical studies to assess their
Berg et al. (8) first showed that prolonged administra-
sion for many years. Given the variable clinical effectiveness and safety profile. It is more difficult to
tion of synthetic ACTH (Synacthen) could obtain re-
course and potential toxicity of current regimens, the determine the role of new treatments in IMN in the
mission in patients with IMN and NS. A small RCT
main issue nephrologists face at the moment are who absence of rigorous studies and long-term follow-up
compared a 12-month course of Synacthen, 1 mg twice
to treat and with what regimen. Conservative man- times.
a week for 1 year, with a 6-month regimen based on
agement is justified for patients with subnephrotic MMF associated with corticosteroids might be an
steroids alternated with a cytotoxic drug every month.
proteinuria, inasmuch as spontaneous remission oc- alternative therapy in patients with contraindications
After a mean follow-up time of 23 months, no differ-
curs more frequently in these patients, and their long- or poor response to cytotoxic therapy. However, solid
ence in the rate of remission or in the mean decline
term prognosis is usually excellent. studies are required to confirm the efficacy of this asso-
in proteinuria was seen between the groups (9). In an
By contrast, patients with nephrotic syndrome ciation and to indicate the optimal dosage and duration
observational study, natural ACTH (Acthar gel), given
(NS) may show a progression to ESRD and are of therapy.
at a dose of 80 units subcutaneously twice a week for
more frequently affected by any of several extrarenal The mechanism of action of ACTH is completely
6 months, was used in 11 patients with IMN and NS.
complications. Thus, initiation of specific therapy is different from that of immunosuppressive agents. Only
Three complete remissions and six partial remissions
indicated for patients with declining renal function a few small studies have been conducted with ACTH.
were observed (10). No relevant side effects have been
or full-blown NS (1). The guidelines of Kidney Dis- The results are interesting, but Synacthen has been re-
reported in patients treated with synthetic or natural
ease: Improving Global Outcome (KDIGO) recom- tired, and the exceedingly high cost of gel ACTH may
ACTH, but it should be taken into account that pro-
mend a 6-month course of alternating monthly cy- impede further development of this treatment in IMN.
longed treatment may be complicated by diabetes, os-
cles of oral and intravenous corticosteroids, and oral The results with rituximab are impressive. However,
teoporosis, or hypertension.
alkylating agents. The continuous use of alkylating as discussed above, more answers are needed. Trials
The available small studies suggest a potential role
agents may also be effective but is associated with a comparing the efficacy and toxicity of rituximab with
for ACTH in IMN. Yet, synthetic ACTH is no long-
greater risk of severe adverse events. Cyclosporine or regimens based on cytotoxic/steroid administration
er commercially available, whereas natural ACTH
tacrolimus have been suggested as alternative options will be welcome. The decision on whom, when, and
is burdened by an excessively high cost. Given that
in nonresponders or in patients who do not tolerate how to treat is completely up to each clinician. How-
the mechanism of action of ACTH is related to the
treatment with steroids and cytotoxic drugs (2). ever, it should be kept in mind that whatever the treat-
stimulation of melanocortin receptors (11), it is pos-
In the past few years, the discovery that most pa- ment, an early response is seldom observed. In many
sible that less expensive and more specific synthetic
tients with IMN have circulating antibodies directed cases, remission can develop months or even years after
melanocortin receptor agonists will be developed in
against the M-type phospholipase A2 receptor pro- the therapy has been completed.
the near future.
vided important insights into the mechanistic inter-
Claudio Ponticelli is associated with the Humanitas Clini-
pretation of IMN (3). Further studies confirmed that
Rituximab cal and Research Center, Milano, Italy.
this receptor represents the main antigen involved,
although other podocyte antigens may also play a role Recently, Ruggenenti et al. (12) reported their cumu-
References
in the pathogenesis of this disease. lative experience with rituximab in 100 patients with
In the same period of time, new drugs have been MN. After a mean follow-up time of 29 months, 27 1. Ponticelli C, Glassock RJ. Glomerular diseases:
used for IMN, three of which show a potential bene- patients showed complete remission and 38 partial membranous nephro pa th y —a modern view. Clin
ficial effect: mycophenolate mofetil (MMF), adreno- remission, the median time to response being around J Am Soc Nephrol 2014; 9:609–616.
corticotropic hormone (ACTH), and rituximab. 7 months. The response to treatment did not change 2. Radhakrishnan J, Cattran DC. The KDIGO
clinical practice guideline on glomerulonephritis:
whether rituximab was used in treatment-naïve pa-
Mycophenolate mofetil tients or in patients previously treated with ineffective reading (guide)lines—application to the individu-
al patient. Kidney Int 2012; 82(2):840–856.
regimens. No severe side effects were reported. How-
Retrospective studies and three small randomized con-
3. Beck LH Jr, et al. M-type phospholipase A2 recep-
ever, 4 patients died, cancer developed in 3, and pro-
trolled trials (RCTs) evaluated the effects of MMF in
tor as target antigen in idiopathic membranous
gression to ESRD occurred in 4. The authors attributed
IMN. Only a small rate of remission was reported by
nephropathy. N Engl J Med 2009; 361:11–21.
these events to previous treatment, but a direct or indi-
observational studies when MMF was used as mono-
4. Dussol B, et al. Mycophenolate mofetil mono-
rect role of rituximab cannot be excluded. Good results
therapy, and negative results were reported by a French
therapy in membranous nephropathy: a 1-year
have also been reported in other observational studies.
trial. That trial randomized 36 patients to either MMF
randomized controlled trial. Am J Kidney Dis
In a multicenter study of 20 patients treated with four
alone (2 g per day for 12 months) or symptomatic
2008; 52:699–705.
weekly courses of rituximab repeated after 6 months,
therapy, and the rates of remission were similar (4).
5. Branten AJ, et al. Mycophenolate mofetil in
2 patients did not respond, 4 entered complete remis-
Still, a response in about two-thirds of patients (pre-
idiopathic membranous nephropathy: a clinical
sion, 12 underwent partial remission, 1 patient had
dominantly partial remission) was reported by a retro-
trial with comparison to a historic control group
limited response, and 1 experienced relapse. No severe
spective study in which MMF was combined with oral
treated with cyclophosphamide. Am J Kidney Dis
adverse events were reported (13).
prednisone and methylprednisolone pulses. However,
2007; 50:248–256.
From the available reports it can be extrapolated
patients with NS frequently experienced relapse after
6. Chan TM, et al. Prospective controlled study
that 65 percent to 80 percent of patients may have a
treatment was interrupted (5). Two small RCTs with
on mycophenolate mofetil and prednisolone in
complete or partial (more frequent) response to rituxi-
short-term follow-up reported remissions in about 70
the treatment of membranous nephropathy with
mab. However, apart from the high cost, the optimal
percent of patients treated with MMF and steroids—a
nephrotic syndrome. Nephrology (Carlton) 2007;
dose, timing, and duration of re-treatment and the
rate similar to that observed in patients assigned to a
12:576–581.
long-term benefit-to-harm ratio of rituximab remain
steroid/cytotoxic drug regimen (6, 7).
7. Senthil Nayagam L, et al. Mycophenolate mofetil
incompletely explored. It is also unclear whether pa-
These data are insufficient to enable any firm con-
or standard therapy for membranous nephropa-
tients with renal dysfunction, tubulointerstitial lesions,
clusion to be drawn. Trials with adequate sample size
thy and focal segmental glomerulosclerosis: a pilot
or both will be sensitive or resistant to such treatment.
and follow-up are needed to better clarify the efficacy
study. Nephrol Dial Transplant 2008; 23:1926–
and safety of MMF with corticosteroids in IMN. At
Summary and conclusions 1930.
present, this therapy may be considered for patients
8. Berg AL, et al. Beneficial effects of ACTH on the
who do not respond to other treatments. To prevent At present, there are at least five different options for
serum lipoprotein profile and glomerular function
relapses, this therapy should be given for at least 1 year treating nephrotic patients with IMN. Therapies based
in patients with membranous nephropathy. Kid-
if well tolerated. on cycling cytotoxic agents/steroid administration or
ney Int 1999; 56:1534–1543.