EDITORIAL
Chronic Kidney Disease: The Silent Enemy?
Robert N. Sladen, MBChB, MRCP(UK), FRCP(C), FCCM
C hronic kidney disease (CKD) has become increas-
ingly prevalent in our aging patient population,
especially because glomerular filtration rate (GFR)
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and renal reserve decline progressively as we grow older.1
The presence of CKD has important implications for our
patients undergoing surgery and anesthesia. These may
range from impaired handling of anesthetic agents to
multiorgan dysfunction and general debility, and specific
problems associated with renal replacement therapy (RRT)
and transplantation.
Our ability to evaluate renal function and diagnose CKD
is largely dependent on measurement of the serum creati-
nine (SCr), which reflects the steady-state equilibrium
between creatinine production from muscle and creatinine
excretion by glomerular filtration.2 However, the SCr is a
poor indicator of acute changes in the GFR because it may
take hours to days before abrupt declines in GFR are
matched by a commensurate increase in SCr. Even in
steady-state situations, the SCr may be a misleading indi-
cator of GFR because SCr may not increase above normal
laboratory limits until the GFR declines below 50 mL/min.
Thus, a 20-year-old patient, a 60-year-old patient, and an
80-year-old patient may all have an SCr in the normal range
even though the average GFR for these age groups is 125
mL/min, 80 mL/min, and 60 mL/min, respectively. In a
sense, the creeping decline in renal reserve is a silent
enemy, because it is not diagnosed or even appraised by
standard laboratory screening of renal function. Indeed,
patients with malnutrition or cachexia produce so little
creatinine from their depleted muscle mass that their SCr
may remain in the normal range even when GFR declines
to as low as 30 mL/min.3
A more meaningful assessment of renal function and
reserve is obtained by an estimation of GFR using clearance
techniques (creatinine, inulin), or by measuring plasma
decay of isotopic markers. However, these are time con-
suming, involve a varying degree of complexity, and are
From the Department of Anesthesiology, College of Physicians & Surgeons
of Columbia University, New York, New York.
Accepted for publication February 23, 2011.
Funding: None.
The author declares no conflict of interest.
Reprints will not be available from the authors.
Address correspondence to Robert N. Sladen, MBChB, MRCP(UK),
FRCP(C), FCCM, Professor and Executive Vice-Chair, Chief, Division of
Critical Care, Department of Anesthesiology, PH 527-B, College of Physi-
cians & Surgeons of Columbia University, 630 West 168th St., New York, NY
10027. Address e-mail to rs543@columbia.edu.
Copyright © 2011 International Anesthesia Research Society
DOI: 10.1213/ANE.0b013e318217f828
June 2011 • Volume 112 • Number 6
themselves subject to error. In steady-state situations, neph-
rologists have long relied on a simple nomogram such as
the Cockcroft–Gault equation to calculate an estimated GFR
(eGFR), which is based upon patient gender, age, weight,
and SCr.4 The Cockcroft–Gault equation has subsequently
been displaced by the Modification of Diet in Renal Disease
(MDRD) nomogram, which is independent of body weight,
and is expressed per 1.73 M2 body surface area5:
eGFR ⫽ 186 ⫻ (Scr)ⴚ1.154 ⫻ (Age)ⴚ0.203
The eGFR is modified by a factor of 0.742 for female
patients and 1.212 for African-American patients.
Although the MDRD is a convenient and relatively
reliable indicator of the severity of CKD, it has some
inherent limitations. It is generally accepted that the MDRD
provides accurate GFR assessment between 20 and 60
mL/min/1.73 M2 only. In general, there is so much vari-
ability in normal GFR that any eGFR calculated ⬎60
mL/min/1.73 M2 is referred to as a “normal” GFR. Al-
though it is weighted for age, the MDRD is still largely
dependent on the SCr and does not consider acute changes
in GFR or depleted muscle mass, as detailed above. None-
theless, it has become established as the “gold standard” of
estimation of GFR in stable patients with CKD.
In 2002 the National Kidney Foundation (NKF) used the
MDRD to categorize CKD into 5 stages of increasing
severity (Table 1); the criteria must have been present for
longer than 3 months.6,7 Stage 1 CKD includes patients who
have a normal eGFR (⬎90 mL/min/1.73 M2) but are found
to have kidney damage defined by the presence of abnor-
mal markers such as albuminuria. Stage 2 CKD is defined
as the presence of kidney damage with an eGFR between 60
and 89 mL/min/1.73 M2. (Again, from a practical stand-
point it should be recognized that any MDRD eGFR ⬎60
mL/min/1.73 M2 is referred to as a “normal” GFR.) Stages
3 and 4 are characterized by diminishing eGFR, to 30 to 59
and 15 to 29 mL/min/1.73 M2, respectively. Stage 5 pa-
tients have an eGFR ⬍15 mL/min/1.73 M2 or have become
dependent on dialysis.
Some notes on terminology are warranted. RRT encom-
passes the gamut of dialysis (hemodialysis, peritoneal
dialysis, continuous venovenous hemodialysis) as well
as renal transplantation. End-stage renal disease is a
Medicare-defined term that refers to CKD treated with
RRT; it is not applied to stage 4 or 5 CKD patients not
receiving these treatments.
Using the above definitions, it has been estimated that
almost 20 million individuals (about 7% of the population)
in the United States suffer from CKD.8 Of these, about 7.5
www.anesthesia-analgesia.org 1277
 EDITORIAL
Table 1. Stages of CKD (National Kidney
Foundation Kidney Disease Outcomes Quality
Initiative Classification)
CKD eGFR
stage mL/min/1.73 M2 Description
1 ⬎90 Kidney damage with normal GFR
2 60–89 Kidney damage with mildly decreased GFR
3 30–59 Moderately decreased GFR
4 15–29 Severely decreased GFR
5 ⬍15 or RRT Kidney failure
CKD ⫽ chronic kidney disease; eGFR is estimated glomerular filtration rate
calculated by the Modification of Diet in Renal Disease (MDRD) nomogram;
RRT ⫽ renal replacement therapy.
million have stage 3 CKD, and about three-quarters of a
million have stages 4 and 5 CKD.
What are the implications? There is substantial evidence
that preexisting CKD increases perioperative risk.9 Most of
the data have been obtained in patients undergoing major
surgery, notably high-risk vascular surgery or cardiac
surgery with cardiopulmonary bypass. For example, in a
large study on 37,735 patients undergoing coronary artery
bypass graft surgery, Yeo et al. found that operative
mortality increased exponentially with increasing stages of
CKD.10 In comparison with patients who had an eGFR
⬎60 mL/min/1.73 M2, mortality was increased by 18%,
223%, and 439% in patients with stages 3, 4, and 5 CKD,
respectively.
In this edition of Anesthesia & Analgesia, Ackland et al.11
have used the MDRD equation to calculate preoperative
eGFR in 526 patients aged 50 years or older undergoing
elective major joint replacement procedures. They observed
postoperative morbidity prospectively using a validated
survey, the Postoperative Morbidity Survey (POMS).12 In
comparison with patients with preoperative eGFR ⱖ60
mL/min/1.73 M2, patients with eGFR ⬍50 mL/min/
1.73/M2, which comprised more than one quarter of their
population, had significantly increased postoperative pain
and morbidity, and longer recovery times and hospital
length of stay. Significant postoperative morbidity in-
volved the pulmonary, cardiovascular, renal, and nervous
systems as well as postoperative sepsis.
Given the relatively large literature on the impact of
CKD on postoperative morbidity and mortality that al-
ready exists,9 what new information does the Ackland et al.
study provide us? First, it addresses an orthopedic surgical
population in which the connection between preexisting
CKD and postoperative morbidity has not previously been
characterized. It does this prospectively using a validated
tool (the POMS) that provides us with a means of evaluat-
ing the risk of CKD in a wide variety of other noncardiac
surgical procedures. Second, it increases our awareness
that as our surgical population ages, we should expect a
higher incidence of CKD. It is noteworthy that in the
Ackland et al. study, the mean age of patients with eGFR
⬎60 mL/min/1.73 M2 was 66 years, in comparison with a
mean age of 74 years in patients with eGFR ⬍60
mL/min/1.73 M2.
The Ackland et al. study adds measurably to our under-
standing of the perioperative risk of CKD, but it does have
one unfortunate limitation. Instead of using the NKF stages
1278 www.anesthesia-analgesia.org
of CKD as outlined in Table 1 (an eGFR of 30 to 59, 15 to 29,
and ⬍15 mL/min/1.73 M2 for stages 3, 4, and 5 CKD), the
authors chose to divide their population into subgroups on
the basis of an eGFR of 50 to 59, 40 to 49, and 20 to 39
mL/min/1.73 M2, and excluded patients with eGFR ⬍20
mL/min/1.73 M2 or those on dialysis. Thus, one cannot
draw conclusions from their study that directly relate to the
NKF stage of CKD. In fact, the authors found a “cut-off”
eGFR of ⬍50 mL/min/1.73 M2, below which morbidity
and mortality increased considerably. Patients with an
eGFR of 50 to 59 mL/min/1.73 M2 had morbidity and
mortality that differed little from patients with “normal”
eGFR ⬎60 mL/min/1.73 M2. Although the study was
likely underpowered to detect differences in outcome
among stages 3, 4, and 5 CKD, this would be useful
information. Nonetheless, it does alert us to the signifi-
cantly increased risk represented by an eGFR ⬍50
mL/min/1.73 M2 in this population.
Notably, this study cannot begin to address the question
of why patients with CKD have such an increased morbid-
ity or mortality. It is clear that CKD must be considered a
multisystem disease and that no organ system emerges
unscathed. What is the common factor? It is very unlikely
that it is urea itself. We know that although RRT controls
very well the acute manifestations of uremia (hyperkale-
mia, acidosis, fluid overload, encephalopathy, enteropathy,
and serositis), many others—such as anemia, thrombocy-
topathy, osteodystrophy, delayed wound healing, and
increased susceptibility to sepsis—are incompletely con-
trolled, if at all. We are beginning to understand that there
is a multiplicity of unmeasured toxins besides urea that
accumulate in CKD and that may play a role in organ
dysfunction. More than 90 such toxins have already
been identified,13 and include compounds such as ␤2-
microglobulin, advanced glycation end products, advanced
oxidation protein products, granulocyte inhibitory pro-
teins, and homocysteine, among others.14 It is understood
that small molecules (⬍500 Da) that are not protein bound,
and which include urea and creatinine, are very easily
dialyzed by all forms of RRT.15 However, larger, so-called
“middle molecules” (⬎500 Da), or those that are protein
bound, are poorly cleared by dialysis. These include in-
flammatory cytokines such as interleukins, tumor necrosis
factor, and complement. Could a low-grade chronic inflam-
matory state exist in CKD that predisposes patients to
multiorgan morbidity after major surgery? In patients with
CKD who are not dialysis dependent, it is likely that these
toxins accumulate pari passu with diminishing GFR, which
may account for the exponential relationship of postopera-
tive morbidity to advancing stages of CKD. For example, a
small molecule, asymmetric dimethylarginine (ADMA),
accumulates in patients with CKD well before they require
RRT. ADMA inhibits nitric oxide synthase and appears to
contribute to arterial stiffness, which is characteristic of
vascular comorbidity in patients with CKD.13,16 Clearly,
this is an avenue that bears fruitful ongoing exploration.
Meanwhile, the Ackland et al. study provides a practi-
cal, take-home message that is pertinent to all anesthesiolo-
gists in clinical practice. We should assess postoperative
risk in patients with elevated SCr or advanced age by
utilizing the MDRD nomogram to define the CKD stage.
ANESTHESIA & ANALGESIA
Chronic Kidney Disease: The Silent Enemy?
This can be readily accessed on the Internet on the Website
of the National Kidney Disease Education Program at
http://www.nkdep.nih.gov. All one has to do is insert the
patient’s age and SCr and the eGFR will be calculated,
which allows CKD stage classification. Although some
have cautioned against untargeted screening for CKD in
the general population,17 and risk may vary with the nature
of the surgical procedure, in this author’s opinion this
simple and rapid assessment of perioperative risk should
be incorporated into routine preoperative anesthetic assess-
ment. And we need more studies like those of Ackland et
al. to further define outcomes in all realms of surgery.
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