Journal - Assignment Essays

(1)Read “Acute kidney injury: Challenges and opportunities” article then the two additional article files (Challenges Acute Kidney Injury and Acute Kidney Injury Cancer Patients.)

(2)After you’ve read the 3 articles (attached) provide an unplagiarized summation of at least 500 words. Include all 3 references. Use APA format throughout the document.

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Acute kidney injury:
Challenges and
opportunities

BY NHAN L.A. DINH, MSN, CNP, AGACNP-BC, CCRN

Abstract: Acute kidney injury (AKI) can be a devastating diagnosis for any patient and can
increase mortality during hospitalization. There can be long-term consequences for those who
survive the initial insult. This article discusses AKI and its implications for nurses.

Keywords: acute kidney injury, Acute Kidney Injury Network, AKI, chronic kidney disease,
CKD, community-acquired acute kidney injury, hospital-acquired acute kidney injury, KDIGO,
Kidney Disease Improving Global Outcomes, Nephrotoxic Injury Negated by Just-in-time
Action, sick day rule

ACUTE KIDNEY INJURY (AKI) is a
heterogeneous kidney disorder that
increases in-hospital morbidity and
mortality. In 2016 data, the inci-
dence of AKI was 20% for Medicare
patients with both chronic kidney
disease (CKD) and diabetes.1 Based
on Veterans Affairs (VA) 2016 data,
AKI occurred in more than 25% of
hospitalized veterans over age 22,
but less than 50% of those with
lab-documented AKI were coded as
such.1 The chief concern here is a
missed opportunity for intervention.
AKI increases long-term risk of CKD,
but if clinicians do not recognize
the diagnosis, they cannot follow up
or intervene. An AKI diagnosis also
increases the chance of another AKI
episode, with a 30% risk of a recur-
rent AKI episode within 1 year.

Mortality is increased with an AKI
episode. Medicare data from 2016

shows in-hospital mortality of 8.2%,
but this increases to over 13% when
including patients who were dis-
charged to hospice.1 The in- hospital
mortality for patients without AKI
was only 1.8% (3.8% if including
patients discharged to hospice).1 Pa-
tients with AKI also were more likely
to be referred to a long-term-care
facility. (See Hospital discharge status of
first hospitalization for Medicare patients
ages 66+, 2016.)

AKI defined
AKI was previously known as acute
renal failure.

However, many pa-
tients with kidney injury did not
progress to renal failure, yet still had
significant, often permanent, loss of
kidney function. Researchers worked
to better define AKI and noted that
it is a potential but often reversible
rapid deterioration of kidney func-

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tion, with or without kidney dam-
age. It may or may not be associated
with oliguria.

Numerous groups attempted to
define AKI from both a clinical and
physiologic point of view to allow for
epidemiologic studies. A consensus
group developed the first criteria
with a definition relying on changes
in the serum creatinine (SCr), glo-
merular filtration rate (GFR), and/or
urine output, known as Risk of renal
dysfunction, Injury to the kidney,
Failure of kidney function, Loss of
kidney function, and End-stage kid-
ney disease (RIFLE).3 The Acute Kid-
ney Injury Network (AKIN) believed
RIFLE mixed outcomes with severity
classes and developed another classi-
fication, the AKIN criteria.4 In 2012,
Kidney Disease: Improving Global
Outcomes (KDIGO), an international
organization, standardized the com-
peting definitions of AKI (RIFLE and
AKIN) into one coherent classifica-
tion.2 (See Classifications of AKI.)

Using this chart and per interna-
tional KDIGO consensus criteria,
AKI is diagnosed when there is an
increase in SCr from baseline by
at least 0.3 mg/dL within 48 hours

or an increase in SCr to at least 1.5
times from baseline known or pre-
sumed to have occurred within the
7 days before AKI diagnosis.2 The
guidelines also specify that the di-
agnosis can be made when there is
a urine volume of less than 0.5 mL/
kg/h for 6 hours.2

AKI can be divided into two cat-
egories: community-acquired AKI
(CA-AKI) and hospital-acquired AKI
(HA-AKI). Patients who present to
a hospital meeting criteria for AKI
as listed above are defined as having
CA-AKI.5 HA-AKI has been the focus
of research over the last 2 decades as
rates of AKI have steadily increased
and continue to do so.6 However,
CA-AKI has gained more attention
recently because of its prevalence; it
was recently stated that nearly 50%
of AKI incidents begin in the com-
munity setting.7,8,10 This statistic is
concerning and healthcare providers
need to be alert to patients in their
practice who are at risk. In 2013, the
International Society of Nephrology
launched the “0by25” initiative as
a global target to ensure zero death
of patients with preventable and
treatable AKI by 2025 while raising

awareness to change incidence and
prognosis worldwide.9 One difficulty
with tracking CA-AKI is that it is
easier to obtain records and statistics
on hospitalized patients, but CA-AKI
is often treated outpatient. CA-AKI
can be prevented and treated.10 It is
crucial for healthcare professionals to
promptly identify patients with CA-
AKI as well as those who are at risk
for developing CA-AKI.

Etiology of AKI and risk
factors for CA-AKI
AKI is caused by endogenous and/
or exogenous conditions, including
but not limited to severe ischemia or
sepsis, dehydration, gastrointestinal
(GI) bleeding, anemia, and/or use of
nephrotoxic agents.11-13 These causes
are often multifactorial. For example,
patients with sepsis are given renal-
toxic doses of antibiotics.

Etiology of AKI can be divided into
three categories: prerenal, intrarenal/
intrinsic kidney disease, and postrenal.
(See AKI etiologies.) Prerenal causes,
such as volume depletion from de-
hydration, GI losses (vomiting, diar-
rhea, bleeding), excessive diuresis,
hemorrhage from trauma, and/or

Hospital discharge status of first hospitalization for Medicare patients
ages 66+, 20161

49.1

8.2

7.6

30.1

5.0

68.8 1.8

4.7

22.7

2.0

Home

Death

Other

Institution

Hospice

With AKI diagnosis Without AKI diagnosis

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changes in vascular resistance occur-
ring from disease processes or certain
drug use, cause hypoperfusion to the
kidneys.11-13 These changes, in turn,
lead to a lower GFR.

Intrarenal AKI can result from
a prolonged prerenal state with
or without toxic insults related to
toxins, drugs, or any underlying
systemic process such as sepsis.
Inflammation and ischemia of the
kidneys can be sequelae of those
insults.12,13 Over-the-counter (OTC)
and prescribed medications are a
common intrarenal cause of CA-
AKI. Examples include nonsteroidal
anti-inflammatory drugs (NSAIDs)
for pain management, angiotensin-
converting enzyme (ACE) inhibitors
or angiotensin II receptor blockers
(ARBs) for hypertension and CKD
with diabetes, proton pump inhibi-
tors for gastric reflux, and cyclospo-
rine and/or tacrolimus for antirejec-
tion management.12,13

Intrarenal AKI

can be categorized by the compo-
nents of the kidney that are primarily
affected: tubular, glomerular, intersti-
tial, and vascular.12,13

Postrenal AKI, the least common
etiology, is usually caused by an
obstruction in urinary flow out of
either a single kidney or both kid-
neys. In postrenal AKI, kidneys still
produce urine, but the urine cannot
be excreted via the urethra due to
blockage. Therefore, the urine backs

Classifications of AKI2-4

Stage Urine Output RIFLE*

Intrarenal AKI can
result from a prolonged
prerenal state with or
without toxic insults
related to drugs or

an underlying systemic
process.

up into the kidneys (retrograde
flow), impairing renal functions.
Obstruction of urinary flow can
result from obstructing stones or
blood clots in the ureters or renal
pelvises, an enlarged prostate, dys-

AKIN

function or obstruction of the blad-
der, and/or strictures in the urinary
system.12,13

Volume depletion is more com-
monly the cause of CA-AKI than
HA-AKI.14 Incidence of AKI increas-
es during summer months, when
the risk of dehydration is greater.
Two studies found that pre-renal
causes relating to AKI are almost
two-fold higher than all other causes
together.5,14

Patients are at the highest risk for
CA-AKI when they have significant
comorbidities along with polyphar-
macy.15 Diuretics are associated with
a higher incidence of CA-AKI than
ACE inhibitors and ARBs.6 A combi-
nation of these medications puts pa-
tients at a greater risk for developing
CA-AKI than diuretics alone.

Even though risk factors for CA-
AKI and HA-AKI are similar, CA-AKI
is common in older adult males with
comorbidities including diabetes
mellitus, hypertension, heart disease,
CKD, cancer, and/or dementia.1,6,14

Gender also plays a role in CA-AKI
development. Men across all age
groups are at higher risk for CA-AKI
compared with their female coun-
terparts. This factor is thought to be
mediated in part by testosterone.16,17

According to a Vanderbilt University
study, testosterone has been found to
increase renal GFR expression, which
is associated with the likelihood of

KDIGO

<0.5 mL/kg/h Risk: Increase in SCr of 1.5x Increase in SCr 1.5–2x Increase in SCr of 1.5–1.9x for 6 h or decrease in GFR >25% baseline or ≥0.3 mg/dL baseline or ≥0.3 mg/dL

<0.5 mL/kg/h Injury: Increase in SCr 2x Increase in SCr 2–3x baseline Increase in SCr of 2–2.9x for 12 h or decrease in GFR >50% baseline

3 <0.3 mL/kg/h Failure: Increase in SCr 3x Increase in SCr 3x baseline or Increase in SCr of >3x base-
for 24 h or or decrease in GFR >75% SCr of ≥4 mg/dL (with acute line or increase in SCr ≥ 4.0
anuria for 12 h rise of ≥0.5 mg/dL) mg/dL or initiation of renal

replacement therapy

* Loss and ESRD of the RIFLE criteria are not included in this staging chart, as they are considered outcome variables.

Used with permission from Erica Davis, PA-C: AAPA presentation. 2017. New Orleans, La.

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https://1.5�1.9x

https://HA-AKI.14

progressive kidney injury.17 The exact
mechanism remains unclear and is
currently being investigated. Further,
Black, Hispanic, and hospitalized
patients with a previous diagnosis
of AKI are more likely to develop
AKI than those from different ethnic
groups or those without risk fac-
tors.1,6,14,16,18

As noted previously, patients with
diabetes mellitus and CKD tend to
have more incidents of AKI than
those without comorbidities.1 Al-
though CKD has consistently been
shown to increase risk for the devel-
opment of AKI, one study found that
it does not pose any significant dif-
ferences in the severity of AKI.14

Signs and symptoms of AKI
Although the kidneys are responsible
for regulating extracellular and in-
travascular fluid volume, osmolality,
electrolyte concentrations, pH, and
excretion of wastes and toxins in
the body, AKI does not manifest any
specific signs and symptoms until

AKI etiologies
Prerenal AKI

other organs or systems are affected.
Patients with AKI can present with
either oliguria or nonoliguria. Signs
and symptoms of AKI also depend
on the causes that dictate how rapid
and severe the decline of kidney
function is.11-13 Most patients pre-
senting to a hospital with AKI are not
aware that they have this condition.
Patients often present with signs and
symptoms that later cause AKI (such
as hemorrhage or severe nausea and
vomiting) or signs and symptoms
related to complications of AKI (in-
cluding altered mental status, severe
edema, shortness of breath, malaise/
lethargy, hemodynamic instability,
and dysrhythmias). These signs and
symptoms are often related to uremia
or its underlying causes.11-13

AKI management
AKI management depends on the
underlying etiology and the severity
of kidney injury. Because mortal-
ity is high in patients with AKI, the
most important goal of therapy is

Intrarenal AKI

preventing life-threatening compli-
cations.11-13 However, current AKI
interventions are limited to support-
ive care and prevention of causative
factors. Any possible causes of AKI
and its contributing factors should
be prevented, treated, or removed as
soon as possible.11,12

Prevention and early detection
are the keys to improving outcomes
for patients with AKI. For example,
ACE inhibitors and ARBs should be
held temporarily in patients with
decreased oral intake and in those
who present with prerenal AKI that
may have started in the community
setting, because these drugs may
exacerbate a prerenal state. While
waiting for the kidneys to recover
on their own, restricting or avoid-
ing substances and medications that
are known to impair kidney func-
tion is vital. In the event of signifi-
cant electrolyte derangement and/
or fluid overload, emergent dialysis
can be performed to prevent further
complications related to cardiac dys-

Postrenal AKI

↓ Intravascular volume Acute tubular necrosis Upper urinary tract obstruction
• Dehydration/hemorrhage • Ischemic: • Intrinsic
• GI, cutaneous, or renal losses – Sepsis – Stone
• Third spacing – Hypotension – Papillary necrosis

• Nephrotoxic: – Blood clot
↓ Effective blood volume – Drugs – Tumor
• Heart failure – Heme pigments • Extrinsic
• Cirrhosis – Retroperitoneal fibrosis
• Nephrotic syndrome Acute interstitial nephritis – Malignancy
• Sepsis • Drug-induced – Ligation
• Anesthesia • Infection-related – Pelvic mass

• Systemic diseases
Altered renal hemodynamics • Malignancy Lower urinary tract tract obstruction
• Preglomerular constriction • Urethral stricture
• Postglomerular vasodilation Acute glomerulonephritis • Benign prostatic hyperplasia
• Medications: ACE inhibitors, NSAIDs • Prostate cancer
• Hepatorenal syndrome, surgery Acute vascular syndrome • Bladder cancer

• Renal artery dissection • Bladder stones
Renal vascular obstruction • Renal artery thromboembolism • Neurogenic bladder

• Renal vein thrombosis • Malpositioned indwelling urinary
Abdominal compartment syndrome • Atheroembolic disease catheter

Used with permission from Catherine Wells, DNP: NKF presentation. 2013. Orlando, Fla.

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rhythmias, heart failure, or respira-
tory failure during hospitalization.
Collaboration among the interdisci-
plinary team, including primary care
physicians, hospitalists, nephrolo-
gists, nurses, and advanced practice
providers, is crucial in optimizing
AKI management.

CA-AKI outcomes
CA-AKI has been identified as the
most common type of AKI.14 CA-
AKI accounted for almost 80% of the
patients with a discharge diagnosis
of AKI at a single VA hospital, and its
severity was found to be as significant
as HA-AKI.14 If present at admission,
CA-AKI has a significant impact on
hospital length of stay and is associ-
ated with a substantially higher risk
of death and CKD progression.14,19

The rate of rehospitalization in pa-
tients with CA-AKI versus HA-AKI
did not differ, and early temporary
dialysis may improve the outcome
of CA-AKI.10,18 However, those who
initially present with CA-AKI exhibit
the highest incidence of CKD at their
5-year follow-up.19 Two studies found
that 40.2% of patients developed
CKD stage 3 (GFR 30 to 60 mL/min)
or higher, and nearly 27% progressed
to either CKD stage 5 (GFR less than
15 mL/min) or end-stage renal dis-
ease (ESRD) requiring dialysis.19

CA-AKI is often underappreciated
as a clinic or office-based issue.14,20

In patients presenting with upper re-
spiratory or GI complaints, clinicians
may focus on the presenting condition
and may not consider dehydration
and the need to adjust certain medica-
tions. In addition, many patients pres-
ent to urgent care and are treated for
the problem and labs are not checked
for existing kidney disease.

Some patients self-medicate with
OTC combination or multisymptom
medications containing NSAIDs,
such as naproxen or ibuprofen. This
compounds the chance of develop-
ing AKI. The National Kidney Foun-
dation has a patient website that

An AKI diagnosis
increases the chance

of another AKI episode,
with a 30% risk of

recurrence within 1 year.

highlights medication dosing for the
at-risk patient.21

Prevention
Multiple studies have shown an im-
provement of outcomes in patients
with AKI with early detection as well
as preventive measures when AKI is
diagnosed.8,10,14,16,22 Stress to patients
in the community setting the im-
portance of optimization of volume
status as well as avoiding exposures
to any nephrotoxic agents.10 When
primary prevention fails to prevent
AKI from occurring, the Recognition-
Action-Result framework can act as
a secondary prevention by properly
diagnosing and evaluating AKI with a
goal of limiting duration and severity
to prevent complications.10

A multidisciplinary approach has
been recommended for tertiary pre-
vention of AKI. This includes close

monitoring, medication review, and
reassessment of patients, especially
those with a history of AKI.2,10,12

Outpatient preventive measures after
the first episode of AKI are vital in
improving quality of life, alleviating
long-term complications, and limit-
ing recurrences.

One of the most promising
preventive methods is implement-
ing “sick day rules” developed by
the National Health Service of the
United Kingdom.23 Sick is defined as
vomiting or diarrhea (unless minor),
fevers, sweats, and shaking. When
these symptoms occur, patients are
directed to temporarily stop taking:
• NSAIDs, which can impair re-
nal autoregulation by inhibiting
prostaglandin-mediated vasodilation
of the afferent arterioles and may
increase the risk of AKI.
• ACE inhibitors and ARBs, which
reduce systemic BP and also cause
vasodilation of the efferent arterioles,
further reducing glomerular perfu-
sion pressure.
• Diuretics (including spironolactone
and eplerenone), which can cause
hypovolemia and AKI.
• Other BP-lowering medications.
• Medications that may accumulate
due to decreased kidney function
caused by hypotension, increasing
the risk of adverse reactions. Ex-
amples include metformin (risk of
lactic acidosis), sulfonylureas (risk
of hypoglycemia), and trimethoprim
(risk of hyperkalemia).

Screening for children at risk
Because AKI can be especially dev-
astating in children, researchers at
Cincinnati Children’s Hospital (CCH)
developed an electronic health record
screening and trigger program for the
hospital.24 Enrolling all non-critically
ill hospitalized children between
2011 and 2015, CCH decreased the
exposure rate of nephrotoxic medica-
tions by 38%. More important, CCH
reduced the incidence of AKI by an
impressive 64%.24

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https://hospital.24

https://Kingdom.23

https://complications.10

https://agents.10

https://patient.21

https://dialysis.19

https://follow-up.19

https://HA-AKI.14

CCH reports the most impor-
tant aspect of the program was the
person-person interaction. If the
pharmacist noted three or more
nephrotoxic medications for one
patient, he or she would notify the
healthcare team. The pharmacist
would highlight the risk and discuss
other medications that would be less
nephrotoxic, but leave the final deci-
sion to the healthcare team.24 CCH
offered this software application
and clinical system to all children’s
hospitals nationwide, and more than
14 children’s hospitals have imple-
mented it.25

Implications for nurses
Because CA-AKI and HA-AKI can
both be devastating diagnoses for
any patient, nurses must be familiar
with the pathophysiology of AKI in
order to promptly recognize signs
and symptoms. Early treatment is the
key to preventing further complica-
tions and progression of AKI. For
example, nurses in a primary care
setting should implement the “sick
day rules” to help reduce the risks of
CA-AKI development. In the case of
AKI trajectory, it is important for the
nurse to educate the patient about
the acute condition and supportive
care for kidney recovery. Nephrology
referral is beneficial for follow-up in
the event of worsening of AKI or CKD
development.

Timely intervention is key
AKI is associated with significant
clinical consequences and increased
healthcare costs. It is crucial that all
providers identify patients at risk for
AKI and conduct primary prevention.
Preventive measures are especially im-
portant in high-risk patients, includ-
ing those with previous AKI exposure,
CKD, older age, or other high-risk
comorbidities.

When AKI is present, diagnosis
must be made in a timely manner to
allow for prompt management. The
process of minimizing progression

of AKI, especially with CA-AKI, is
important both at hospital admission
and at the clinic or office visit.

Though awareness of CA-AKI has
increased recently, it is still an under-
appreciated clinical presentation.
Further research should focus more
on comprehensive risk assessment,
biomarkers, and management for
HA-AKI and CA-AKI to ensure high-
quality care.26 Preventive measures
can be provided at the community
level to patients with a previous AKI
diagnosis and patients who may be at
risk for developing AKI.2,10 ■

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Nhan L.A. Dinh is a certified nurse practitioner at
University of New Mexico Hospital in Albuquerque, N.M.

The author has disclosed no financial relationships
related to this article.

This article originally appeared as Dinh NLA. Acute
kidney injury: challenges and opportunities. Nurse
Pract. 2020;45(4):48-54.

DOI-10.1097/01.NURSE.0000694776.10448.97

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www.cincinnatichildrens.org

www.thinkkidneys.nhs.uk/aki/wp

www.kidney.org/atoz/content/5-drugs-you

www.theisn.org/all-articles/616-0by25

Kidney International (2008) 74 257

commentar yhttp://www.kidney-international.org

The compromise of renal microvascular
structure has received considerable atten-
tion as a central and possibly causative
feature of the development of chronic
fibrotic kidney diseases. The reduction
in capillary number has been reported
in a number of chronic diseases and has
been suggested to promote fibrosis in a
variety of different ways, including the
exacerbation of hypoxia.1,2 However, in
the case of chronic kidney disease, the
reduction of renal microvessels repre-
sents a chicken-and-egg dilemma: does
microvessel dropout contribute to renal
fibrosis, or does developing renal fibro-
sis impinge on renal capillary stability?
The answer to this is not known, but data
derived from acute or subtle injury mod-
els (folate, ischemia, nephrotoxin, tran-
sient angiotensin II) demonstrate a loss
of capillaries that typically precedes the
development of prominent fibrosis.3–5

These observations suggest that pres-
ervation or reversal of microvascular loss
in a reversible injury model represents
a sound strategy for ameliorating the

Challenges of targeting vascular
stability in acute kidney injury
David P. Basile1

Acute kidney injury following folate administration is characterized by
a vascular remodeling that is initially proliferative but subsequently
results in vascular endothelial loss. Interventions directed toward
promoting endothelial growth may preserve vascular structure and
therefore renal function. However, angiopoietin-1 therapy in the setting
of folate-induced acute kidney injury resulted in an expanded fibrotic
response despite apparent preservation of the vasculature, indicating
that renal repair responses are complex and vascular-directed therapies
should be approached with caution.
Kidney International (2008) 74, 257–258. doi:10.1038/ki.2008.243

development of renal interstitial fibrosis,
as well as addressing the role of vascular
dropout as an antecedent event in pro-
gressing disease. We and others have dem-
onstrated that a number of factors with
potential to influence vascular growth are
altered in the early course of renal injury
(in our experience using ischemia/reper-
fusion) and have argued that replacement
or enhancement of these factors should
maintain blood vessel structure and influ-
ence long-term outcome.1,6,7

Angiopoietin-1 is a potent angiogenic
factor that interacts with the Tie-2 recep-
tor on endothelial cells. Angiopoietin-1
has little or no proliferative potential but
is a potent inhibitor of endothelial apop-
tosis.8 Angiopoietin-1 has promigratory
effects on endothelial cells, and this may
relate to its important activity facilitat-
ing tube formation during angiogenesis.
Angiopoietin-1 stimulation also tightens
endothelial junctions to reduce vascular
leakiness, and this activity may be related
to its anti-inflammatory effects. In general,
angiopoietin-1 is considered a prominent
vascular stabilizing factor in the develop-
ment of new blood vessels. Although the
effects of angiopoietin-1 are complicated by
the sometimes antagonistic activity of the
related protein angiopoietin-2, the activities
suggest that angiopoietin-1 is ideally suited
as a molecule with potential to preserve
blood vessels therapeutically.8

The regenerating kidney after an acute
insult provides an opportunity to intervene
at a potentially critical window of time in
which remodeling events may influence
vascular integrity and affect long-term
function. Angiopoietin-1 expression is
increased in a model of acute kidney injury
induced by folate administration9 and
recently was also shown to be increased in
a model of ischemic acute kidney injury.7
It is reasonable to hypothesize that such
alterations in expression may represent
an attempt to preserve the renal vascula-
ture undergoing active injury. It could be
suggested that further enhancement of
angiopoietin-1 would enhance vascular
preservation following acute injury. As it
turns out, it also represents an invitation
for unanticipated complications.

Long et al.10 (this issue) have sought to
address the potential therapeutic role of
angiopoietin-1 using adenoviral delivery
of a modified human angiopoietin-1 in a
mouse model of folate-induced acute kid-
ney injury. This model is typically associ-
ated with an early (2–3 days) proliferation
of cortical capillary endothelial cells fol-
lowed by a gradual regression of these cap-
illaries at longer times during recovery.9
It was hypothesized that angiopoietin-1
delivery may prevent the regression of
capillaries in this model. This indeed was
the case. Interestingly, the investigators
also observed the simultaneous enhance-
ment of interstitial fibrosis characterized
by collagen deposition and increased
inflammatory-cell deposition.10

Although the authors may have antici-
pated different results, the implications of
these findings are profound and impactful
among those who are interested in vascu-
lar repair processes and their potential to
affect kidney function. The study should
raise considerable awareness of the com-
plicated nature of renal repair character-
ized by a complex milieu of cell types and
altered chemical signaling. It forces atten-
tion to the fact that although angiogenesis
may be observed in cultures in response
to a given trophic factor, in vivo these
molecules are promiscuous and may be
highly inflammatory depending on the
specific setting. It reminds us that renal
injury has a prominent inflammatory

1Department of Cellular & Integrative Physiology,
Indiana University School of Medicine,
Indianapolis, Indiana, USA
Correspondence: David P. Basile, Department
of Cellular & Integrative Physiology, Indiana
University School of Medicine, 635 Barnhill Drive,
Indianapolis, Indiana 46202, USA.
E-mail: dpbasile@iupui.edu

see original article on page 300

http://www.kidney-international.org

mailto:dpbasile@iupui.edu

258 Kidney International (2008) 74

commentar y

component that cannot be overlooked in
the evaluation of potential interventions.

Importantly, angiopoietin-1 did, appar-
ently, preserve vascular integrity as would
be predicted, but the added inflammatory
activity is contradictory to its generally
observed anti-inflammatory activity. The
reason for this may represent an interesting
area of future investigation. However, there
is evidence that angiopoietin-1 may activate
a cascade of inflammatory cytokines.11

In addition, the results should high-
light that therapy geared toward vascular
preservation or repair may not be ubiqui-
tously applied across pathophysiological
conditions. Clearly, as the authors noted,10
there has already been considerable atten-
tion paid to the potential utility of vascu-
lar endothelial growth factor-A, which is
protective to blood vessels and prevents
further fibrosis in several, but not all,
models investigated.12–14 In the case of
angiopoietins, a novel and potent form,
termed COMP-angiopoietin-1, has been
shown to be effective in limiting fibrosis
in a model of ureteral obstruction.15 How-
ever, as Long et al. point out,10 factors such
as the establishment of an effective dose
and the form of angiopoietin-1 adminis-
tered may also play an important role in
outcome. The point of emphasis is that not
all conditions are alike, and several other
factors may influence vascular stability in
disease models. One molecule is not likely
to represent a panacea promoting vascular
preservation without complications.

Several other questions are brought
to mind in consideration of this area of
investigation. The first question is whether
therapy that targets the vasculature rep-
resents a useful approach at all, and if so,
what is the basis for deciding what path-
ways should be targeted. Although vessel
density is clearly compromised and asso-
ciated with hypoxia,1 vascular rarefaction
does not occur as the sole and isolated event
after injury with the potential to complicate
chronic kidney function. Recent studies
from our laboratory demonstrated that the
manifestation of salt-sensitive hypertension
and profound secondary chronic kidney
disease was essentially nullified by admin-
istration of mycophenolate mofetil after the
establishment of vascular injury induced by
ischemia/reperfusion in rats.16 We interpret
these results to suggest that both hypoxia

occurring secondary to vascular loss and a
complexity of infiltrating cells are required
for the development of fulminant disease
and that any of these may represent useful
therapeutic targets.

If, as we believe, targeting the vasculature
is important, the choice of molecules to be
tested may require more specific informa-
tion regarding the nature of vascular drop-
out. For example, a more global perspective
on the alterations of vasculotrophic fac-
tors in specific models is required, and
therapies should use combinations of
factors to compensate for alterations in
the angiogenic milieu of the injured kid-
ney. Secondly, and related to the previous
point, additional knowledge of the likely
mechanism by which endothelial cells are
lost would be helpful. Curiously, very little
is known of the cellular events that lead
to the loss of capillary endothelial cells
in the setting of acute injury. Although
an obvious hypothesis is that endothelial
cells undergo apoptosis, aside from a sepsis
model there is little direct evidence to sup-
port this contention.

As a final point of consideration, we
would like to bring attention to the meth-
odology used by Long et al.10 to establish
preserved vessel density in response to
angiopoietin-1 treatment. These investi-
gators used CD31 immunohistochemistry
to beautiful ly demonstrate that
angiopoietin-1- exposed animals have a
preserved or enhanced vasculature. This
technique is well established, and we have
used this approach in our own work. Nev-
ertheless, in light of the interesting, unex-
pected, and paradoxical results, perhaps
further analysis is warranted. Because ves-
sels exist to support the perfusion needs
of the organ, the physiological efficacy of
these preserved vessels should be evaluated
more thoroughly. In addition, given that
there exist several populations of CD31-
positive circulating cells, including many
that also express markers of monocyte
or macrophage lineage, it is possible that
the deposition of such cells, which may be
termed ‘angiogenic macrophages,’17 could
result in an enhanced inflammatory state
masquerading as an angiogenic response.

Regardless, this interesting study high-
lights the promise and limitations of
targeting the vasculature. In so doing, it
defines important obstacles and allows us

to generate new and testable paradigms to
mitigate this perplexing problem.
DISCLOSURE
The authors declared no competing interests.

REfEREnCES
1. Basile DP. The endothelial cell in ischemic acute

kidney injury: implications for acute and chronic
function. Kidney Int 2007; 72: 151–156.

2. Norman J, Fine LG. Intrarenal oxygenation in chronic
renal failure. Clin Exp Pharmacol Physiol 2006; 33:
989–996.

3. Yuan H-T, Li X-Z, Pitera JE et al. Peritubular capillary
loss after mouse acute nephrotoxicity correlates
with down-regulation of vascular endothelial
growth factor-A and hypoxia-inducible factor-1
alpha. Am J Pathol 2003; 163: 2289–2301.

4. Lombardi D, Gordon KL, Polinsky P et al. Salt-
sensitive hypertension develops after short-term
exposure to angiotensin II. Hypertension 1999; 33:
1013–1019.

5. Basile DP, Donohoe DL, Roethe K et al. Renal
ischemic injury results in permanent damage to
peritubular capillaries and influences long-term
function. Am J Physiol 2001; 281: F887–F899.

6. Basile DP, Fredrich K, Chelladurai B et al. Renal
ischemia reperfusion inhibits VEGF expression and
induces ADAMTS-1, a novel VEGF inhibitor. Am J
Physiol Renal Physiol 2008; 294: F928–F936.

7. Horbelt M, Lee S, Mang H et al. Acute and chronic
microvascular alterations in a mouse model of
ischemic acute kidney injury. Am J Physiol Renal
Physiol 2007; 293: F688–F695.

8. Brindle N, Saharinen P, Alitalo K. Signaling and
functions of angiopoietin-1 in vascular protection.
Circ Res 2006; 98: 1014–1023.

9. Long DA, Woolf AS, Suda T, Yuan HT. Increased renal
angiopoietin-1 expression in folic acid-induced
nephrotoxicity in mice. J Am Soc Nephrol 2001; 12:
2721–2731.

10. Long DA, Price KL, Ioffe E et al. Angiopoietin-1
therapy enhances fibrosis and inflammation
following folic acid-induced acute renal injury.
Kidney Int 2008; 74: 300–309.

11. Aplin A, Gelati M, Fogel E et al. Angiopoietin-1
and vascular endothelial growth factor induce
expression of inflammatory cytokines before
angiogenesis. Physiol Genomics 2006; 27: 20–28.

12. Long D, Mu W, Price K et al. Vascular endothelial
growth factor administration does not improve
microvascular disease in the salt-dependent phase
of post angiotensin II hypertension. Am J Physiol
2006; 291: F1248–F1254.

13. Kang DH, Hughes J, Mazzali M et al. Impaired
angiogenesis in the remnant kidney model. II.
Vascular endothelial growth factor administration
reduces renal fibrosis and stabilizes renal function.
J Am Soc Nephrol 2001; 12: 1448–1457.

14. Kang DH, Anderson S, Kim YG et al. Impaired
angiogenesis in the aging kidney: vascular
endothelial growth factor and thrombospondin-1 in
renal disease. Am J Kidney Dis 2001; 37: 601–611.

15. Kim W, Moon S, Lee S. COMP-angiopoietin-1
ameliorates renal fibrosis in a unilateral ureteral
obstruction model. J Am Soc Nephrol 2006; 17:
2474–2483.

16. Pechman KR, Basile DP, Lund H, Mattson DL. Immune
suppression blocks sodium-sensitive hypertension
following recovery from ischemic acute renal failure.
Am J Physiol Regul Integr Comp Physiol 2008; 294:
R1234–R1239.

17. Ingram DA, Caplice NM, Yoder MC. Unresolved
questions, changing definitions, and novel
paradigms for defining endothelial progenitor cells.
Blood 2005; 106: 1525–1531.

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.

Correspondence

n engl j med 377;5 nejm.org August 3, 2017 499

Acute Kidney Injury in Patients with Cancer

To the Editor: Rosner and Perazella (May 4 is-
sue)1 provide an overview of acute kidney injury
in patients with cancer. Acute kidney injury jeop-
ardizes the continuation of effective cancer treat-
ment in a patient and limits the opportunity for
inclusion in clinical trials. The review did not
mention that diuretics are a major and underes-
timated cause of nephrotoxicity.2 Diuretics are
commonly used in daily practice, despite uncer-
tainties about the benefits except in the context
of fluid overload and cardiac dysfunction,3 and
are frequently associated with the presence of the
tumor lysis syndrome, sepsis,4 and hemodynamic
instability.5

We assessed prognostic factors of modified
major adverse kidney events at day 30 (MAKE30
— a composite of death, persistent renal failure,
discontinuation of the most effective cancer treat-
ment, and long-term dialysis) in 133 critically ill
patients with cancer who were transferred to the
intensive care unit and received renal-replace-
ment therapy. A multivariate analysis confirmed
that the usual risk factors for acute kidney injury
— the tumor lysis syndrome (in patients receiv-
ing first-line chemotherapy), use of vasopres-
sors, and hepatic failure — were independently
associated with the MAKE30 outcome, but di-
uretic use was also independently associated
with that combined outcome (Table 1).

Preventing acute kidney injury in critically ill
patients with cancer is important. Weighing the
risks and benefits of diuretic use in these pa-
tients who commonly present with the tumor
lysis syndrome, sepsis, and hemodynamic insta-
bility seems to be crucial for short-term and
long-term outcomes.

Colombe Saillard, M.D.
Institut Paoli-Calmettes
Marseille, France

Michael Darmon, M.D., Ph.D.
Hôpital Nord
Saint-Etienne, France

Djamel Mokart, M.D., Ph.D.
Institut Paoli-Calmettes
Marseille, France
mokartd@ ipc . unicancer . fr

No potential conflict of interest relevant to this letter was re-
ported.

1. Rosner MH, Perazella MA. Acute kidney injury in patients
with cancer. N Engl J Med 2017; 376: 1770-81.
2. Pierson-Marchandise M, Gras V, Moragny J, et al. The drugs
that mostly frequently induce acute kidney injury: a case–non-
case study of a pharmacovigilance database. Br J Clin Pharmacol
2017; 83: 1341-9.
3. Ho KM, Sheridan DJ. Meta-analysis of frusemide to prevent
or treat acute renal failure. BMJ 2006; 333: 420.
4. Honore PM, Jacobs R, Hendrickx I, et al. Prevention and
treatment of sepsis-induced acute kidney injury: an update. Ann
Intensive Care 2015; 5: 51.
5. Prowle JR, Kirwan CJ, Bellomo R. Fluid management for the
prevention and attenuation of acute kidney injury. Nat Rev
Nephrol 2014; 10: 37-47.

DOI: 10.1056/NEJMc1707248

To the Editor: In their review, Rosner and Pera-
zella summarize various mechanisms of acute kid-
ney injury in patients with cancer. As stated by the
authors, some chemotherapeutic agents can pro-
mote the development of thrombotic microangi-
opathy.

Malignant conditions can also be the cause of
secondary microangiopathy.1 The most common
cancers associated with microangiopathies are
gastric, breast, prostate, and lung cancers.2 In the
case of prostate cancer, some patients are prone to
having a presentation similar to that of the atypical
hemolytic–uremic syndrome.3 Furthermore, in pa-
tients who have a predisposition to complement
dysregulation, cancer has been associated with
the occurrence of the atypical hemolytic–uremic
syndrome.4

Thus, acute kidney injury caused by micro-

Prognostic Factor Odds Ratio (95% CI) P Value

Diuretic use 3.2 (1.00–10.13) 0.04

Receiving first-line
chemotherapy

3.7 (1.09–12.73) 0.03

Hepatic failure 3.6 (1.03–12.53) 0.04

Use of vasopressors 5.7 (1.90–17.31) 0.002

* CI denotes confidence interval.

Table 1. Independent Prognostic Factors Associated with Modified Major
Adverse Kidney Events at Day 30 after Discharge from the Intensive Care
Unit.*

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 377;5 nejm.org August 3, 2017500

angiopathy should not be seen only as a poten-
tial complication of treatments in patients with
cancer but also as a specific cancer-related injury.
Although microangiopathy-related acute kidney
injury caused by cancer is uncommon, early diag-
nosis and recognition of this cancer-related injury
is crucial, mainly to avoid immune-modulating
therapies that are inappropriate in this context.
Aliénor Dreyfus, M.D.
Frederic M. Jacobs, M.D.
Hôpital Antoine-Béclère
Clamart, France
frederic . jacobs@ abc . aphp . fr

No potential conflict of interest relevant to this letter was re-
ported.

1. Morton JM, George JN. Microangiopathic hemolytic anemia
and thrombocytopenia in patients with cancer. J Oncol Pract
2016; 12: 523-30.
2. Fakhouri F, Zuber J, Frémeaux-Bacchi V, Loirat C. Haemo-
lytic uraemic syndrome. Lancet 2017 February 25 (Epub ahead of
print).
3. Lechner K, Obermeier HL. Cancer-related microangiopathic
hemolytic anemia: clinical and laboratory features in 168 re-
ported cases. Medicine (Baltimore) 2012; 91: 195-205.
4. Favre GA, Touzot M, Fremeaux-Bacchi V, et al. Malignancy
and thrombotic microangiopathy or atypical haemolytic and
uraemic syndrome? Br J Haematol 2014; 166: 802-5.

DOI: 10.1056/NEJMc1707248

The authors reply: We thank Saillard et al. for
their observations on the risk of diuretics in crit-
ically ill patients with cancer who either have or
are at risk for acute kidney injury. Their observa-
tions are in line with those from observational
studies that caution about the risk of adverse out-
comes with the use of diuretics in patients with
acute kidney injury.1 In the few prospective trials
that have examined the use of diuretics in pa-
tients with acute kidney injury, these agents were
shown to be either ineffective or detrimental in
the prevention and treatment of the condition, with
no effect on the duration of acute kidney injury or
prevention of the need for dialysis.1 However, di-
uretics have an important role in the manage-
ment of volume overload in patients with or with-
out acute kidney injury. For instance, a higher
positive fluid balance was associated with worse
outcomes, and diuretic use was associated with a
higher rate of survival.2 Furthermore, in a second-
ary analysis of data from patients with acute kid-
ney injury in the Fluid and Catheter Treatment
Trial, furosemide dose administered after the de-
velopment of acute kidney injury improved fluid

balance, and this improvement was associated
with a lower mortality.3 Thus, diuretics should be
used cautiously in patients with acute kidney in-
jury who have clear indications for reduction of
volume overload. For the specific group of pa-
tients with both cancer and acute kidney injury,
individualized therapeutic decisions should be
made that weigh the risks and benefits of diuret-
ics, with clear goals of the therapy and cessation
of the diuretic if these goals are not being met.

Dreyfus and Jacobs raise the point that vari-
ous cancers are associated with the development
of thrombotic microangiopathy in the absence
of exposure to chemotherapeutic drugs. We
agree that certain malignant conditions, in par-
ticular mucin-producing adenocarcinomas, are a
more common cause of this form of acute kid-
ney injury.4 However, cancer as a direct cause of
thrombotic microangiopathy is less common
than thrombotic microangiopathy induced by
chemotherapy.4 A feature of this less-common
cause of thrombotic microangiopathy is that
90% of patients in whom cancer-related throm-
botic microangiopathy develops have metastatic
disease, whereas chemotherapeutic agents often
cause thrombotic microangiopathy despite mini-
mally detectable or no detectable cancer.4 Fur-
thermore, up to 15% of patients with metastatic
cancer–related thrombotic microangiopathy fre-
quently have disseminated intravascular coagu-
lation,5 which is absent in patients with the
drug-induced form. Another distinguishing fea-
ture is that patients with cancer-related throm-
botic microangiopathy have a leukoerythroblastic
blood smear and higher serum lactate dehydroge-
nase levels than patients who have chemotherapy-
associated thrombotic microangiopathy.4,5 It has
been speculated that direct vascular endothelial
injury (with release of large von Willebrand fac-
tor multimers) from the mucin produced by
these malignant conditions, as well as circulat-
ing tumor cells and tumor emboli, cause throm-
botic microangiopathy in this context.4,5

Mitchell H. Rosner, M.D.
University of Virginia Health System
Charlottesville, VA
mhr9r@ virginia . edu

Mark A. Perazella, M.D.
Yale University School of Medicine
New Haven, CT

Since publication of their article, the authors report no fur-
ther potential conflict of interest.

n engl j med 377;5 nejm.org August 3, 2017 501

notices

1. Ho KM, Sheridan DJ. Meta-analysis of frusemide to prevent
or treat acute renal failure. BMJ 2006; 333: 420-5.
2. Teixeira C, Garzotto F, Piccinni P, et al. Fluid balance and
urine volume are independent predictors of mortality in acute
kidney injury. Crit Care 2013; 17: R14.
3. Grams ME, Estrella MM, Coresh J, Brower RG, Liu KD. Fluid
balance, diuretic use, and mortality in acute kidney injury. Clin
J Am Soc Nephrol 2011; 6: 966-73.
4. Izzedine H, Perazella MA. Thrombotic microangiopathy,
cancer, and cancer drugs. Am J Kidney Dis 2015; 66: 857-68.
5. Lechner K, Obermeier HL. Cancer-related microangiopathic
hemolytic anemia: clinical and laboratory features in 168 re-
ported cases. Medicine (Baltimore) 2012; 91: 195-205.
DOI: 10.1056/NEJMc1707248
Correspondence Copyright © 2017 Massachusetts Medical Society.

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MEDICAL MUSICAL GROUP
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symphony orchestra and chorale. The group will perform con-
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THE LANDSCAPE OF GENETIC VARIANTS IN ASIAN
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6TH GLOBAL CONGRESS FOR CONSENSUS
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UPDATE IN INTERNAL MEDICINE 2017
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Contact the Department of Continuing Education, Harvard
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AMERICAN SOCIETY OF TROPICAL MEDICINE
AND HYGIENE

The “ASTMH 66th Annual Meeting” will be held in Baltimore,
Nov. 5–9. The following pre-meeting courses will be offered:
“Migrant Health: Addressing Health Disparities — A Guide for
the Practitioner” (Nov. 4 and 5); “Clinical Presentation and
Management of Arboviral Diseases: Lesson from the Bedside
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tologists” (Nov. 5).

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26TH WORLD CONGRESS OF LYMPHOLOGY
The biennial congress of the International Society of Lym-

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The meeting, entitled “Emerging Trends in Clinical Pharma-
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Contact Krista Levy, American College of Clinical Pharmacol-
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prohibited without permission.

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