Comment

neoangiogenesis in general. Interestingly, 1 year of postoperative adjuvant treatment with the TKI imatinib
was found to improve disease-free survival signicantly
in a dierent type of tumour, gastrointestinal stromal
tumours (GIST).10 In the context of this rare but
instructive tumour type, TKI treatment has been shown
to induce cellular quiescence in tumour cells, hence
providing a survival benet to the patient by slowing
down tumour cell growth kinetics.11 This appears not to
be the case in renal-cell carcinoma. Instead, we believe
that the results of Haas and colleagues study might well
be in line with the angiogenic switch model proposed by
Judah Folkman in the 1990s.12 The underlying idea is that
tumours are independent of blood vessel formation up
to a certain size and that neoangiogenesis permits the
growth of larger tumours. Hence, only larger tumour
nodules will contain topological areas that are critically
dependent on neoangiogenesis and therefore sensitive
to VEGF-targeting agents. Why sunitinib or sorafenib
did not prevent this switch is unknown. However, other
mechanisms of neoangiogenesis that can compensate
for VEGF deprivation have been reported.12 Although
outside the scope of the present study, it will be
important to establish whether TKI-treated and placebotreated patients show dierences in their responses
when re-challenged with TKIs after disease recurrence.
Although VEGF-targeted TKIs haven been shown to
be ineective in the adjuvant setting in high-risk renalcell carcinoma in the present study,6 future approaches
might focus on pathways to eliminate hidden tumour
cells. Harnessing the immune system would be an
attractive opportunity, together with eorts to nd cell
surface markers that can be used to trace and target
dormant renal-cell carcinoma cells.
As much as we hoped for a more positive outcome
for the use of adjuvant VEGF-targeted TKIs in renal-cell

carcinoma, the benet for patients that will result from

this study by Haas and team is that unnecessary toxic
eects and impaired quality of life associated with
these drugs can now, and should, be safely avoided.
Additional studies, especially in node-positive patients,
appear to be warranted.
*Stefan Duensing, Markus Hohenfellner
Section of Molecular Urooncology (SD), Department of Urology
(SD, MH), University of Heidelberg, Medical Faculty Heidelberg,
D-69120 Heidelberg, Germany
stefan.duensing@med.uni-heidelberg.de
We declare no competing interests.
1

2
3

4
5
6

8
9

10

11

12

Znaor A, Lortet-Tieulent J, Laversanne M, Jemal A, Bray F. International

variations and trends in renal cell carcinoma incidence and mortality.
Eur Urol 2015; 67: 51930.
Chin AI, Lam JS, Figlin RA, Belldegrun AS. Surveillance strategies for renal
cell carcinoma patients following nephrectomy. Rev Urol 2006; 8: 17.
Rosenberg SA, Lotze MT, Yang JC, et al. Combination therapy with
interleukin-2 and alpha-interferon for the treatment of patients with
advanced cancer. J Clin Oncol 1989; 7: 186374.
Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in
metastatic renal-cell carcinoma. N Engl J Med 2007; 356: 11524.
Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell
renal-cell carcinoma. N Engl J Med 2007; 356: 12534.
Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk,
nonmetastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind,
placebo-controlled, randomised, phase 3 trial. Lancet 2016; published online
March 8. http://dx.doi.org/10.1016/S0140-6736(16)00559-6.
Capitanio U, Jeldres C, Patard J-J, et al. Stage-specic eect of nodal
metastases on survival in patients with non-metastatic renal cell
carcinoma. BJU Int 2009; 103: 3337.
Johnsen JA, Hellsten S. Lymphatogenous spread of renal cell carcinoma:
an autopsy study. J Urol 1997; 157: 45053.
Grioen AW, Mans LA, de Graaf AMA, et al. Rapid angiogenesis onset after
discontinuation of sunitinib treatment of renal cell carcinoma patients.
Clin Cancer Res 2012; 18: 396171.
Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate
after resection of localised, primary gastrointestinal stromal tumour:
a randomised, double-blind, placebo-controlled trial. Lancet 2009;
373: 1097104.
DeCaprio JA, Duensing A. The DREAM complex in antitumor activity of
imatinib mesylate in gastrointestinal stromal tumors. Curr Opin Oncol
2014; 26: 41521.
Hanahan D, Folkman J. Patterns and emerging mechanisms of the
angiogenic switch during tumorigenesis. Cell 1996; 86: 353364.

Acute kidney disease and the community

Published Online
April 13, 2016
http://dx.doi.org/10.1016/
S0140-6736(16)30239-2
See Articles page 2017

1974

One simple fact has hindered progress in the ght

against kidney disease more than any otherunless
complete renal failure occurs, kidney disease is almost
asymptomatic. Fatal complications such as cardiovascular
disease can occur in patients whose kidney disease is
completely unknown to them. Not only is kidney disease
silent to the patient, the general public knows little about

the problem, and health-care providers might also have

insucient knowledge.1 In 2012, we estimated that 3
million deaths would occur from acute kidney injury
worldwide, and called for increased public awareness and
research investment.2 Based on the most recent periodprevalence studies in critically ill patients,3 our estimates
are probably low since more than half of patients
www.thelancet.com Vol 387 May 14, 2016

admitted to intensive care develop acute kidney injury,

and 27% die before hospital discharge (a rate nearly four
times that of patients without acute kidney injury). More
disturbing still is that these statistics are likely to be only
the tip of the iceberg.
Infections such as community-acquired pneumonia
result in acute kidney injury at an alarming rate. A
third of patients admitted to hospital with pneumonia
developed acute kidney injury,4 and how often it occurs
in patients sent home from the emergency department,
seen in physicians oces or clinics, or in patients
who receive no medical attention at all, is unknown.
Pneumonia is not even thought to be a common cause
of acute kidney injury, with malaria and diarrhoeal
illnesses being much more typical causes. Furthermore,
drugs are thought to be major causes of acute kidney
injury, with nearly 25% of cases involving at least one
nephrotoxic drug.5 Together, the many millions of
people exposed to infectious diseases, nephrotoxic
drugs, and other exposures make acute kidney injury
one of the most common medical disorders in the
worldhowever, it is mostly unknown.
Although chronic kidney disease is said to exist when
abnormalities in kidney function or damage markers
persist for 90 days or more, acute kidney disease6
is present until 90 days. Although the most severe
form of acute kidney disease is acute kidney injury,
an emergency disorder treated mainly by acute care
physicians, other forms of acute kidney disease might
develop that do not meet criteria for acute kidney injury.
Additionally, acute kidney injury that does not resolve
in 12 weeks is, by denition, acute kidney disease. Like
chronic kidney disease, acute kidney disease is mainly
managed by primary care physicians. A global strategy
to address acute kidney injury should also address
acute kidney disease, and these eorts should involve
all levels of health care and include input from primary
care providers and subspecialists. Hospital systems will
need to mobilise organisational eorts to identify highrisk patients even before they present with advanced
disease, and acute kidney disease clinics might provide
follow-up.
In The Lancet, Ravindra L Mehta and colleagues7 report
on the epidemiology of acute kidney injury across
72 countries, with an emphasis on developing countries.7
Data were collected from 4018 patients, 2337 (58%) of
whom developed community-acquired acute kidney
www.thelancet.com Vol 387 May 14, 2016

Mohammed Huwais

Comment

injury, with 889 (80%) of 1118 patients in low-income

and lower-middle-income countries (LLMICs), 815 (51%)
of 1594 in upper-middle-income countries (UMICs),
and 663 (51%) of 1241 in high-income countries
(HICs; for HICs vs UMICs p=033; p<00001 for all other
comparisons). Their ndings are similar to those of other
studies3 in that 60% of acute kidney injury is community
acquired, and most is already fully developed at the time
of recognition. 50% of cases were already at Kidney
Disease: Improving Global Outcomes (KDIGO) stage 3 at
presentation and of unknown duration before medical
attention. Similar ndings were reported for patients
with septic shock in North America,8 and together, these
studies highlight the need to develop strategies to treat
acute kidney injury, because prevention will often be
impossible. Importantly, Mehta and colleagues identied
common aetiological factors across all countries, and
many of these might be amenable to a standardised
approach to treatment.
We agree with Mehta and colleagues that additional
strategies are needed to raise awareness in community
health-care settings, especially in lower-income
countries. However, early recognition alone might
not be enough,9 since standard measures such as
creatinine levels already lag behind injury. Recently
discovered biomarkers of acute kidney injury, such as
TIMP2 and IGFBP7, might have important roles in risk
stratication,10,11 especially since they increase before
damage occurs. A health-care-community eort will be
needed to stem the tide of this pandemic. The excellent
work of the 0by25 initiative, which seeks to reduce
1975

Comment

to zero the number of deaths from preventable acute

kidney injury by 2025, has highlighted the need for
global coordination and integration, not just across
providers but also across whole health-care delivery
systems. Nearly 30% of patients had indications for
renal replacement therapy, but only 79% of these
patients received dialysis. Absence of resources and
inability to aord therapy were identied as reasons to
withhold dialysis in 46% of patients in LLMICs, but in
less than 3% in HICs.
One limitation of the study by Mehta and colleagues
was that it relied on volunteer doctors to screen for cases
of acute kidney injury, so the study might underestimate
the true burden of disease. Conversely, use of a small
decrease in serum creatinine to conrm acute kidney
injury is also problematic since such changes routinely
occur with uid resuscitation-related dilution, even in
the absence of acute kidney injury. Such factors should
therefore not be used as the sole criterion to diagnose
acute kidney injury. Alternatively, health-care systems
need to establish baseline creatinine values for patients
so that diagnosis and staging can be accurate. A better
alternative might be to focus on raising public awareness
of kidney health status as an important component of
an individuals general health inventory.
Nevertheless, thanks to global eorts such as 0by25,7
and others,3,12,13 we now have a clearer picture of the
burden of acute kidney injury. The picture is grim, but
now that we see it, we can begin the arduous task of
making it better. The study by Mehta and colleagues is
an excellent rst step.

*John A Kellum, Claudio Ronco, Rinaldo Bellomo

Center for Critical Care Nephrology, Department of Critical Care
Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
(JAK); Department of Nephrology, Dialysis and Transplantation,
International Renal Research Institute (IRRIV), San Bortolo
Hospital, Vicenza, Italy (CR); and Departments of Intensive Care
and Medicine, Austin Hospital and Melbourne University,
Melbourne, VIC, Australia (RB)
kellumja@ccm.upmc.edu
We declare no competing interests.
1
2
3

5
6
7

10

11
12
13

Macleod A. NCEPOD report on acute kidney injurymust do better. Lancet

2009; 374: 140506.
Kellum JA, Bellomo R, Ronco C. Kidney attack. JAMA 2012; 307: 226566.
Hoste EAJ, Bagshaw SM, Bellomo R, et al. Epidemiology of acute kidney
injury in critically ill patients: the multinational AKI-EPI study.
Intensive Care Med 2015; 41: 141123.
Murugan R, Karajala-Subramanyam V, Lee M, et al. Acute kidney injury in
non-severe pneumonia is associated with an increased immune response
and lower survival. Kidney Int 2010; 77: 52735.
Mehta RL, Pascual MT, Soroko S, et al. Spectrum of acute renal failure in the
intensive care unit: the PICARD experience. Kidney Int 2004; 66: 161321.
KDIGO AKIWG. Kidney Disease: Improving Global Outcomes (KDIGO) Clinical
Practice Guideline for Acute Kidney Injury. Kidney Int Suppl 2012; 2: 1138.
Mehta RL, Burdmann EA, Cerd J, et al. Recognition and management of
acute kidney injury in the International Society of Nephrology 0by25
Global Snapshot Study: a multinational cross-sectional study. Lancet 2016;
published online April 13. http://dx.doi.org/10.1016/S01406736(16)30240-9.
Kellum JA, Chawla LS, Keener C, et al. The eects of alternative resuscitation
strategies on acute kidney injury in patients with septic shock.
Am J Respir Crit Care Med 2015; published online Sept 23. DOI:10.1164/
rccm.201505-0995OC.
Wilson FP, Shashaty M, Testani J, et al. Automated, electronic alerts for
acute kidney injury: a single-blind, parallel-group, randomised controlled
trial. Lancet 2015; 385: 196674.
Bihorac A, Chawla LS, Shaw AD, et al. Validation of cell-cycle arrest
biomarkers for acute kidney injury using clinical adjudication.
Am J Respir Crit Care Med 2014; 189: 93239.
Ronco C. Cell cycle arrest biomarkers: new weapons for a new battle.
Blood Purif 2014; 38: IIII.
Uchino S, Kellum JA, Bellomo R, et al. Acute renal failure in critically ill
patients: a multinational, multicenter study. JAMA 2005; 294: 81318.
Bouchard J, Acharya A, Cerda J, et al. A prospective international multicenter
study of AKI in the intensive care unit. Clin J Am Soc Nephrol 2015; 10: 132431.

Bioengineered vascular grafts o the shelf

See Articles page 2026

1976

The management of end-stage renal disease is a

worldwide health-care challenge. In the USA alone, more
than 650 000 patients have end-stage renal disease and
the number of cases is expected to rise in the coming
years.1 For haemodialysis treatment of these patients,
autologous arteriovenous stulas are the preferred
approach for vascular access.2 If this fails, expanded
polytetrauoroethylene (ePTFE) grafts are often used as a
synthetic alternative.3 However, ePTFE graft implantation
bears a considerable risk of infection, intimal hyperplasia,
and thrombosis.4,5 Progress in tissue engineering means
that these problems might be overcome in the near future.

In The Lancet, Jerey Lawson and colleagues6 report

the results of two single-arm phase 2 trials including
60 patients from six centres in Poland and the USA.
These patients were implanted with bioengineered
human acellular vessels for haemodialysis access and were
followed up for at least 12 months. The primary endpoints
were safety and ecacy as assessed by primary patency,
primary assisted patency, and secondary graft patency.
The vessels were fabricated in vitro by cultivation of
human vascular smooth muscle cells from deceased organ
and tissue donors on tubular polyglycolic acid polymer
scaolds.7 Decellularisation of the constructs after 8 weeks
www.thelancet.com Vol 387 May 14, 2016