EDITORIALS www.jasn.
org
of a randomized trial? How do we define subgroups at the time
of diagnosis who really benefit or who are unresponsive to rit-
uximab? Is rituximab only useful in multimodal combination
therapy? What evidence do we have that rituximab (what opti-
mal dose?) really contributes to the success of the multimodal
combination therapy? (4) Is ABMR really the leading cause of
graft loss given the fact that the vast majority of patients in Paris
and Vienna do not develop DSA or ABMR and that only 30% of
those experience graft loss after 6 years? What about causes of
graft loss in patients who are DSA/ABMR negative?
In summary, both manuscripts have set a new reference
point, which will help us to systematically improve our out-
comes step by step in future clinical trials. Given the low pro-
portion of patients with DSA and the even lower proportion of
patients with active ABMR in both large transplant centers, it is
obvious that multicenter trials are needed to adequately
address novel therapies. Inclusion and exclusion criteria can be
on the basis of the lessons learned from both studies. Ideally, future
models may also predict toxicity and help us to better balance
benefits and risks to develop individualized treatment strategies.
However, at the end, models can only assist in the design of more
successful future prospective trials, which have to investigate new
treatment strategies to improve outcomes for patients with ABMR.
DISCLOSURES
K.B. received honoraria and/or grants from Abbvie, Alexion, Astellas,
Bristol-Myers Squibb, Chiesi, CSL Behring, Fresenius, Genentech, Hexal,
Novartis, Otsuka, Pfizer, Roche, Shire, Siemens, and Veloxis Pharma. M.D.
received honoraria and/or research funds from Bristol-Myers Squibb, Shire,
Alexion, and Novartis. M.D. has received travel grants from Roche and Astellas.
REFERENCES
1. Davis S, Cooper JE: Acute antibody-mediated rejection in kidney
transplant recipients. Transplant Rev (Orlando) 31: 47–54, 2017
2. Archdeacon P, Chan M, Neuland C, Velidedeoglu E, Meyer J, Tracy L,
et al.: Summary of FDA antibody-mediated rejection workshop.
Am J Transplant 11: 896–906, 2011
3. Sautenet B, Blancho G, Büchler M, Morelon E, Toupance O, Barrou B,
et al.: One-year results of the effects of rituximab on acute antibody-
mediated rejection in renal transplantation: RITUX ERAH, a multicenter
double-blind randomized placebo-controlled trial. Transplantation
100: 391–399, 2016
4. Haas M, Loupy A, Lefaucheur C, Roufosse C, Glotz D, Seron D, et al.:
The Banff 2017 kidney meeting report: Revised diagnostic criteria for chronic
active T cell-mediated rejection, antibody-mediated rejection, and pros-
pects for integrative endpoints for next-generation clinical trials [published
online ahead of print December 15, 2017]. Am J Transplant
5. Garg N, Samaniego MD, Clark D, Djamali A: Defining the phenotype of
antibody-mediated rejection in kidney transplantation: Advances in di-
agnosis of antibody injury. Transplant Rev (Orlando) 31: 257–267, 2017
6. Roberts DM, Jiang SH, Chadban SJ: The treatment of acute antibody-
mediated rejection in kidney transplant recipients-a systematic review.
Transplantation 94: 775–783, 2012
7. Viglietti D, Loupy A, Aubert O, Bestard O, Van Huyen JD, Taupin JL,
et al.: Dynamic prognostic score to predict kidney allograft survival in
patients with antibody-mediated rejection. J Am Soc Nephrol 29:
606–619, 2018
352 Journal of the American Society of Nephrology
8. Eskandary F, Regele H, Baumann L, Bond G, Kozakowski N, Wahrmann
M, et al.: A randomized trial of Bortezomib in late antibody-mediated
kidney transplant rejection. J Am Soc Nephrol 29: 591–605, 2018
9. Requião-Moura LR, de Sandes-Freitas TV, Marcelo-Gomes G, Rangel
EB: Bortezomib in kidney transplant: Current use and perspectives
[published online ahead of print November 20, 2017]. Curr Drug Metab
10. OʼConnell PJ, Kuypers DR, Mannon RB, Abecassis M, Chadban SJ, Gill
JS, et al.: Clinical trials for immunosuppression in transplantation:
The case for reform and change in direction. Transplantation 101:
1527–1534, 2017
See related article, “Dynamic Prognostic Score to Predict Kidney Allograft
Survival in Patients with Antibody-mediated Rejection,” and “A Randomized
Trial of Bortezomib in Late Antibody-mediated Kidney Transplant Rejection,”
on pages 606–619 and 591–605 respectively.
Making the Right Decision: Do
Clinical Decision Support
Systems for AKI Improve
Patient Outcomes?
1,2
Nicholas M. Selby and Richard J. Fluck2
1
Centre for Kidney Research and Innovation, Division of Medical
Sciences and Graduate Entry Medicine, School of Medicine,
University of Nottingham, Nottingham, United Kingdom and
2
Department of Renal Medicine, Royal Derby Hospital, Derby,
United Kingdom
J Am Soc Nephrol 29: 352–354, 2018.
doi: https://doi.org/10.1681/ASN.2017121284
The path toward new, effective treatments for AKI has been
difficult, with a frustrating lack of progress and a litany of
negative clinical trials.1–4 Faced with large numbers of patients
with AKI who display startlingly poor outcomes, it is not sur-
prising that clinicians and professional organizations have
sought parallel ways to address this, including the Interna-
tional Society of Nephrology “0by25” campaign and the
“Think Kidneys” national program in England. Current
guidelines recommend various elements of supportive AKI
care, but reports spanning different health care systems tell
us that the delivery of these relatively simple measures in “real-
life” clinical settings is often suboptimal.5 A number of factors
may contribute to this: the silent nature of AKI coupled to
competing priorities of coexisting conditions; time pressures
of busy clinical staff; or a lack of awareness, training, or knowl-
edge of AKI outside of specialty nephrology or critical care
Published online ahead of print. Publication date available at www.jasn.org.
Correspondence: Dr. Nicholas M. Selby, Centre for Kidney Research and In-
novation, Division of Medical Sciences and Graduate Entry Medicine, Medical
School, Royal Derby Hospital Campus, Uttoxeter Road, DE22 3DT Derby,
United Kingdom. Email: nicholas.selby@nottingham.ac.uk
Copyright © 2018 by the American Society of Nephrology
J Am Soc Nephrol 29: 349–356, 2018

Figure 1. An electronic alert or computer decision support for AKI
must not only alert the health care provider to the presence of AKI
but also result in a clinical response if it is to be effective in changing
patient outcomes. In many cases, the response to an alert should
be prompt review of the patient, which includes making a clinical
diagnosis of AKI and determining its etiology. Evaluation of this
type of intervention should ideally assess its effect on care
processes in tandem with an assessment of patient outcomes
and report on how the intervention is implemented.
areas where the majority of cases occur. Conceptually, there is
an obvious appeal to technologic solutions to improve AKI
recognition (Figure 1), with increasing interest in this area
over the last few years.6 This has been tempered by valid con-
cerns around “technology overload” arising from poorly de-
signed clinical decision support (CDS) that may detract
from the intended aim, or examples of ineffective alerts that
do not alter processes of care.7 There are also complexities in
evaluating such strategies for AKI. To be effective, proposed
interventions must change the behavior of care providers
across the hospital, the effect must be sustained, and the effect
must translate into improved patient outcomes. Moreover, an
effective intervention in one hospital may not work so well
elsewhere. Studies should take account of these different
elements.
In this issue of the Journal of the American Society of
Nephrology, Al-Jaghbeer et al.8 report an important study
that examines the effect of a CDS system for AKI on patient
outcomes. The study is notable for its large sample size
(.64,000 patients with AKI), its multicenter approach (14
hospitals in Pennsylvania), and its inclusion of a comparator
group (463,000 patients without AKI), all of which differen-
tiate this from previous work. CDS consisted of an AKI alert
message within the electronic medical record that was auto-
matically triggered when a serum creatinine measurement was
50% higher than a baseline value. The alert message was ac-
companied by instructions to clinically evaluate the patient,
information about AKI staging, and contact details for specialist
referral. Outcomes, assessed before and after CDS introduction in
patients with a coded diagnosis for AKI, showed reductions in
mortality, hospital length of stay, and rates of dialysis. These find-
ings held true in sensitivity analyses, did not occur in the non-AKI
group, and were sustained over 24 months. Although the observed
reductions in mortality and length of stay may be considered rel-
atively modest at a patient level, they become of much greater
significance when considering the high incidence of AKI in hos-
pitalized patients. With an estimated annual incidence of 1 million
cases of AKI in patients in the United States,9 a reduction in
mortality from 10.2% to 9.4% could translate into 8000 lives saved
per year, and potentially significant health economic benefits may
J Am Soc Nephrol 29: 349–356, 2018
www.jasn.org EDITORIALS
result from saved hospital bed days and lower dialysis costs. Al-
though such estimates are overly simplistic and probably overop-
timistic (for example, ignoring potential attenuation of effect that
comes with wider dissemination), they serve to emphasize the
potential impact of the study’s findings.
Interestingly, the expected increase in specialty referrals
after CDS introduction was not seen. This suggests that any
effect on outcomes resulted from better care delivered by the
parent medical team rather than from nephrology or inten-
sivist input. Although a reduction in iodinated contrast use
after CDS introduction may hint at this, other prescribing
(e.g., renin-angiotensin-aldosterone system blockers) did
not change. One weakness of the study is that processes of
care were not studied with granularity, and therefore, mech-
anisms to explain effects of CDS on patient outcomes could
not be established. Other minor limitations include omission
of other relevant outcome measures, such as renal recovery,
and that it was not clear if activities to support the interven-
tion were performed (e.g., education or publicity). Most im-
portant, however, is that the findings are interpreted within
the context of a nonrandomized time series design as ac-
knowledged appropriately by the authors. This means that
confounding effects on outcomes, in particular, temporal
trends, cannot be excluded. Convention would dictate that
the next step would be to suggest a randomized, controlled
trial (RCT), but this point is worthy of debate. The authors
correctly state that an appropriately powered RCT to detect a
similar effect size is unlikely to be feasible. In addition, there
are coherent arguments that the traditional RCT is not the opti-
mal design to evaluate complex interventions targeted at chang-
ing behavior of health care professionals.10 Instead, future work
should consider study methodologies that are able to evaluate
interventions accounting for their context, content, and applica-
tion as well as their effect on outcomes; the Tackling AKI Study,
which is due to report in 2018, is one example of this.11
In summary, the work by Al-Jaghbeer et al.8 provides some
much needed optimism for the use of CDS as a pragmatic tool
to help improve short-term outcomes for patients with AKI.
Whilst this is not a panacea, it does give a message that in
parallel to vital research that pursues novel pharmacothera-
peutics, quality improvement strategies focusing on care
processes for AKI should not be overlooked.
DISCLOSURES
None.
REFERENCES
1. McCullough PA, Bennett-Guerrero E, Chawla LS, Beaver T, Mehta RL,
Molitoris BA, et al.: ABT-719 for the prevention of acute kidney injury in
patients undergoing high-risk cardiac surgery: A randomized phase 2b
clinical trial. J Am Heart Assoc 5: e003549, 2016
2. Mitaka C, Ohnuma T, Murayama T, Kunimoto F, Nagashima M, Takei
T, et al.; JAPAN Investigators: Effects of low-dose atrial natriuretic
Editorials 353
 EDITORIALS www.jasn.org
peptide infusion on cardiac surgery-associated acute kidney injury: A
multicenter randomized controlled trial. J Crit Care 38: 253–258,
2017
3. Bellomo R, Chapman M, Finfer S, Hickling K, Myburgh J; Australian and
New Zealand Intensive Care Society (ANZICS) Clinical Trials Group:
Low-dose dopamine in patients with early renal dysfunction: A placebo-
controlled randomised trial. Lancet 356: 2139–2143, 2000
4. Gillies MA, Kakar V, Parker RJ, Honoré PM, Ostermann M: Fenoldopam
to prevent acute kidney injury after major surgery-a systematic review
and meta-analysis. Crit Care 19: 449, 2015
5. Aitken E, Carruthers C, Gall L, Kerr L, Geddes C, Kingsmore D: Acute
kidney injury: Outcomes and quality of care. QJM 106: 323–332, 2013
6. Horne KL, Selby NM: Recent developments in electronic alerts for acute
kidney injury. Curr Opin Crit Care 21: 479–484, 2015
7. Wilson FP, Shashaty M, Testani J, Aqeel I, Borovskiy Y, Ellenberg SS, et al.:
Automated, electronic alerts for acute kidney injury: A single-blind, paral-
lel-group, randomised controlled trial. Lancet 385: 1966–1974, 2015
8. Al-Jaghbeer M, Dealmeida D, Bilderback A, Ambrosino R, Kellum JA:
Clinical decision support for in-hospital AKI. J Am Soc Nephrol, 29:
654–660, 2018
9. Goldstein SL, Jaber BL, Faubel S, Chawla LS; Acute Kidney Injury Ad-
visory Group of American Society of Nephrology: AKI transition of care:
A potential opportunity to detect and prevent CKD. Clin J Am Soc
Nephrol 8: 476–483, 2013
10. Walshe K: Understanding what works–and why–in quality improvement: The
need for theory-driven evaluation. Int J Qual Health Care 19: 57–59, 2007
11. Selby NM, Casula A, Lamming L, Mohammed M, Caskey F; Tackling
AKI Investigators: Design and rationale of ‘Tackling Acute Kidney
Injury,’ a Multicentre Quality Improvement Study. Nephron 134:
200–204, 2016
See related article, “Clinical Decision Support for In-hospital AKI,” on pages
654–660.
Banff Classification of Polyomavirus
Nephropathy: A New Tool for
Research and Clinical Practice
Jeffrey B. Kopp
Kidney Disease Section, National Institute of Diabetes and Digestive
and Kidney Diseases, National Institutes of Health, Bethesda,
Maryland
J Am Soc Nephrol 29: 354–355, 2018.
doi: https://doi.org/10.1681/ASN.2017121328
Over the past two decades, various transplant nephrologists
and renal pathologists have worked together under the banner
of the Banff Working Group to define aspects of renal disease
and renal pathology in the setting of kidney transplantation.
Polyomavirus pathology has been a particular area of interest.1,2
Published online ahead of print. Publication date available at www.jasn.org.
Correspondence: Dr. Jeffrey Kopp, National Institutes of Health, 10 Center
Drive, Bethesda, MD 20892. Email: jbkopp@nih.gov
Copyright © 2018 by the American Society of Nephrology
354 Journal of the American Society of Nephrology
In this issue of the Journal of the American Society of Nephrology,
Nickeleit et al.3 put forward a classification of polyomavirus
nephropathy (PVN) that combines clinical and pathologic fea-
tures to generate a working definition of “definitive polyomavi-
rus nephropathy.” More importantly, they have shown that,
across the three severity classes of PVN, there is a progressively
worse renal prognosis at 12 and 24 months.3
The number of known human polyomaviruses has now
reached 15, of which only four are known to be pathogenic
to humans: BKV (BKPyV), JCV (JCPyV), Merkel cell PyV, and
trichodysplasia-spinulosa–associated PyV.4,5 Primary infec-
tion with BKV and JCV occurs in childhood, and these viruses
commonly establish latency in the urinary tract, emerging under
immunosuppression.6–8 After kidney transplant, there com-
monly occurs activation of latent polyomavirus, chiefly BKV
but to a much lesser extent, JCV,9 in the kidney and lower urinary
tract, particularly in association with higher levels of immuno-
suppression. A recent report of the virome in patients with kidney
transplants suggests considerable complexity among PV ge-
nomes as well as reports the finding of the genome of torque
teno virus, a widely distributed virus of uncertain pathogenicity.8
At present, overt PVN occurs in about one third of kidney trans-
plant recipients. The diagnosis of PVN may be made on clinical
grounds, as presumptive PVN, with falling renal function and
high or rising BKV virus titers, or by kidney biopsy.
The Banff classification of PVN, proposed in this issue by
Nickeleit et al.,3 was developed using 192 kidney biopsies
available to the working group, all from subjects with
biopsy-proven PVN. In the majority of patients, the clinical di-
agnosis made at the time of the renal biopsy was acute allograft
rejection. The presence of BKV was shown by intranuclear
inclusions on electron microscopy (81%) or immunostaining
for the T antigen (19%). The objective was to identify factors
that would predict loss of allograft function over the ensuing
24 months.
The authors used a mixed effect model repeated measure-
ment approach, applying forward selection to identify factors
associated with allograft function. The two variables in the final
model included (1) polyomavirus replication/load level deter-
mined in a semiquantitative fashion from zero to three on the
basis of determining the fraction of tubules with morphologic
evidence of polyomavirus replication (particularly as shown
by SV40 antibody staining) and (2) the Banff interstitial fibro-
sis (chronic injury) scores from zero to three, representing
no, mild, moderate, and severe fibrosis, respectively.10 The
six groups thus defined were collapsed into three classes on
the basis of clinical outcomes and excluding patients with
acute rejection. The authors contend, plausibly, that class
1 likely represents early stages of viral reactivation, with
low chronic injury scores, whereas class 2 and class 3 occur
somewhat later and represent more advanced disease. The
choice of fibrosis rather than inflammation was made on
the basis of analyses showing that fibrosis was the more
powerful predictor of outcome. One weakness of reducing
from six to three categories was that it was carried out on
J Am Soc Nephrol 29: 349–356, 2018