may allow access to the Article.

The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is
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MINERVA MEDICA COPYRIGHT®

REVIEW

Chronic kidney disease:

implications for the perioperative period
H. EILERS 1, K. D. LIU 2, A. GRUBER 1, C. U. NIEMANN 1, 3

1Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA; 2Department of
Medicine, Division of Nephrology, University of California, San Francisco, CA, USA; 3Division of Transplantation,
Department of Surgery, University of California, San Francisco, CA, USA

ABSTRACT
End-stage renal disease (ESRD) and chronic kidney disease (CKD) are increasing health problems worldwide. In the
US alone, an estimated 26 million people suffer from some form of CKD. In countries such as India and Pakistan, the
prevalence of CKD is also rapidly rising. The presence of CKD is associated with increased perioperative morbidity
and mortality, even when adjusted for other variables such as hypertension or diabetes. Frequently, CKD is under
diagnosed, so patients and physicians are often unaware of the impaired renal function. Renal dysfunction as a predic-
tor of perioperative outcomes is discussed together with therapeutic interventions aimed at the protection of renal
function. Better interventions and diagnostic tools, such as cystatin C, are needed to further improve perioperative mor-
bidity and mortality in patients with CKD. (Minerva Anestesiol 2010;76:725-36)
Key words: Kidney failure, chronic - Early diagnosis - Morbidity - Mortality.

T he incidence of end-stage renal disease

(ESRD), sometimes referred to as chronic
renal failure, is increasing around the world. In
the United States, the prevalence of ESRD more
than doubled between 1990 and 2001 1, and, with
it, the incidence of pre-dialysis chronic kidney dis-
ease (CKD) is also on the rise. Approximately 26
million Americans have some form of CKD, yet
many patients remain undiagnosed.2 Given the
tremendous health and cost burden of ESRD, pre-
venting or avoiding the progression of CKD to
ESRD is critical.
While the perioperative challenges of patients
with ESRD are well appreciated, patients with
CKD are also at increased risk for perioperative
renal adverse outcomes.3 This patient population
tion of the Publisher.
injury” paradigm because they have some stable
chronic baseline organ dysfunction that is dispro-
portionately aggravated when exposed to acute
physiologic stresses, such as hypotension, hypov-
olemia, or drug toxicity.
Definition of CKD
The 2002 National Kidney Foundation Kidney
Disease Outcomes Quality Initiative (K/DOQI)
guidelines proposed a five-stage classification for
CKD based on the glomerular filtration rate
(GFR) 4 (Table I). CKD is defined as either (A) a
GFR of less than 60 mL/min/1.73 m2 for more
than three months, whether there is evidence of
kidney damage, or (B) evidence of kidney damage

perfectly fits the commonly used “second hit for more than three months based on abnormalities

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EILERS CHRONIC KIDNEY DISEASE IN THE PERIOPERATIVE PERIOD
may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is
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sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which

not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary

TABLE I.—National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI): Stages of chronic kidney disease
(CKD).
Stage of CKD Description GFR (mL/min/1.73 m2)

I Kidney damage with normal or increased GFR(e.g., early diabetic nephropathy) ≥90 mL/min
II Mildly reduced GFR 60-89
III Moderately reduced GFR 30-59
IV Severely reduced GFR 15-29
V End stage renal disease <15 or need for dialysis

Renal Distal tubule Proximal tubule

artery
& vein
Collecting
duct

Glomerulus

Ureter From
Cortex renal
artery
Medulla

Loop of
henie

To renal pelvis

A B
Figure 1. A) Blood supply to the kidney and the medulla and cortex. Most patients have a single arterial supply; however, anatom-
ical variations may include two or three arteries; B) anatomy of the proximal and distal tubules and the collecting ducts.

on pathologic specimen, imaging or laboratory tests
(for example, proteinuria), irrespective of GFR.
Etiology of CKD
CKD may primarily affect either the blood ves-
sels or the interstitium of the kidney (Figure 1A);
diseases of the nephron can be divided into
glomerular and tubular diseases (Figure 1B). Table
II lists some of the most common causes of CKD.
CKD during hospitalization and the
perioperative period
Patients with pre-existing CKD are particular-
ly susceptible to further renal impairment during
hospitalizations or surgical interventions because
tion of the Publisher.
Acute kidney injury occurs in 5-7% of all hospi-
talized patients to varying degrees.5 Unfortunately,
changes in the serum creatinine as small as 0.3
mg/dL are associated with increased morbidity,
length of hospital stay and mortality, whereas an
increase in the serum creatinine of >0.5 mg/dL is
associated with an adjusted 6.5-fold increase in
the odds of death.6
In a recent cohort study of all patients admitted
to a single US center and followed prospectively to
detect worsening renal function,5 7.2% of all
patients experienced at least one episode of renal
insufficiency, as assessed by increased serum crea-
tinine, during their hospitalization. The vast major-
ity of renal insufficiency acquired during a patient’s
hospitalization was attributed to decreased renal
perfusion, medications, radiographic contrast,

CKD is a known risk factor for acute kidney injury. postoperative status, and sepsis. Only 38.6% expe-

726 MINERVA ANESTESIOLOGICA September 2010

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CHRONIC KIDNEY DISEASE IN THE PERIOPERATIVE PERIOD EILERS

may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either
sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which

not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary

TABLE II.—Etiology of chronic kidney disease.

Diabetic nephropathy
Hypertensive nephrosclerosis
Glomerular disease
Interstitial diseases of the kidney
Vascular diseases of the kidney
Inherited kidney diseases
Most common cause in the United States, accounting for approximately 45% of disease burden.1
Disease of the glomerulus.100-102
Bidirectional relationship between blood pressure and renal disease: hypertension as a result of renal
failure hypertension or cause of renal dysfunction.
Divided into "nephrotic" and "nephritic" diseases.103 Membranous glomerulopathy most common
cause of nephrotic syndrome in Caucasian adults.104 Secondary membranous glomerulopathy with
autoimmune diseases (lupus) or malignancy. Focal segmental glomerulosclerosis (FSGS) most com-
mon in African American adults.105 Secondary FSGS associated with obesity, HIV (collapsing variant
of FSGS).106 Amyloidosis in elderly.
Idiosyncratic allergic reaction to medications.107-108 Antibiotics, non-steroidal anti-inflammatory
medications, and heavy metal toxicity (lead and cadmium).
ANCA diseases, lupus (small vessel disease). Adults giant cell arteritis and polyarteritis nodosa
(medium and large size vessels).109
Autosomal dominant and recessive forms of polycystic kidney disease. Less common Alport's syndro-
me (mutation in the type IV collagen molecule).

rienced complete recovery of renal function, while
almost 20% were discharged with an increased
creatinine or on chronic dialysis. Of particular
note is the observation that all but one patient
who subsequently developed acute renal insuffi-
ciency had some degree of renal dysfunction at
the time of admission to the hospital.5 Almost
20% of patients died, and this mortality rate is
similar for most of the common causes of the renal
insufficiency except for sepsis, which carries a
much higher mortality (76%).5 In patients hos-
pitalized in the intensive care unit, the mortality
rate of patients with acute kidney injury has been
reported to be as high as 50-60%.7-9 In a large
semi-quantitative analysis, based on a review of
26 studies including more than 10000 surgical
patients, Novis et al. identified increased serum
creatinine, blood urea nitrogen and preoperative
renal dysfunction as the three most common risk
factors associated with postoperative renal fail-
ure.10 Preoperative efforts should focus on identi-
fying patients with risk factors for CKD to risk
stratify them according to 1) degree of impair-
ment and 2) type of surgery proposed.
Furthermore, the possibility of slowing the decline
of renal function and preoperative optimization
of renal function should be assessed.
Hypertension and cardiovascular disease
Arterial hypertension can either be a cause or
tion of the Publisher.
progression. Under normal conditions, renal blood
flow (RBF) is autoregulated over a broad range of
systemic mean arterial pressure (MAP); however,
arterial hypertension and renal disease will disturb
the autoregulatory mechanisms, and RBF will be
more directly proportional to MAP.11 Chronic
hypertension and renal disease, diabetes, or high
protein intake all disturb the autoregulatory mech-
anisms 12 and increase the pressure load on the
renal vasculature, possibly resulting in glomeru-
losclerosis. Proteinuria, which can further exacer-
bate these mechanisms, is an independent pro-
moter of the progression of renal disease.13
In the Multiple Risk Factor Intervention Trial,
a strong relationship was observed between both
systolic and diastolic blood pressures and ESRD,
regardless of other known risk factors. The rela-
tive risk for ESRD was >20-fold higher for patients
with stage 4 hypertension (SBP>210 or diastolic
blood pressure DBP>120 mmHg) than for patients
with optimum blood pressure levels (SBP<120
and DBP<80 mmHg).14, 15
A recent meta-analysis of 11 randomized con-
trolled trials in non-diabetic patients found that
well controlled systolic blood pressure (SBP 110-
129 mmHg) was associated with a lower risk for
disease progression than a SBP outside of this range
(lower and higher).16 Similarly, a meta-analysis of
nine longitudinal studies of type 1 diabetics showed
a four-fold reduction in the decline of GFR for
MAP<99 mmHg, regardless of the type of treat-

consequence of CKD and is associated with its ment.17 Consistent with these studies, data from

Vol. 76 - No. 9 MINERVA ANESTESIOLOGICA 727

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may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either
sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which
not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary
the Irbesartan Diabetic Nephropathy Trial (IDNT)
demonstrated that, in type 2 diabetics, the risk for
the progression of renal disease was reduced pro-
gressively and continuously at lower levels of SBP,
with an optimal renoprotective effect occurring
between 120-130 mmHg; there was no further
benefit with a SBP below 120 mmHg.18
The antiproteinuric effect of tight blood pres-
sure control is an important protective mecha-
nism, as indicated by the results of several trials.
While the Modification of Diet in Renal Disease
showed a markedly reduced proteinuria as the
result of BP control, regardless of agent used,13
other studies found ACE inhibitors and ARBs to
be more effective in reducing proteinuria than
other classes of antihypertensives.19, 20 Consistent
with these data, the K/DOQI practice guidelines
recommend a blood pressure goal of <130 mmHg
systolic and <80 mmHg diastolic for all CKD
patients, with blockers of the renin-angiotensin
axis as first-line agents for renoprotection in
patients with both diabetic and non-diabetic
CKD.21
In addition to slowing the progression of renal
disease, lowering of the blood pressure also reduces
the incidence of major cardiovascular events in
patients with hypertension and CKD.22 Based on
the observed improvement in renal function and
patient survival during the Irbesartan Diabetic
Nephropathy Trial (IDNT) in type 2 diabetic
patients, Pohl et al. recommended a systolic blood
pressure target of 120-130 mmHg, achieved
through blockade of the renin-angiotensin sys-
tem.18
Elevated serum creatinine has been identified
as a risk factor for adverse cardiac outcomes in
major non-cardiac surgery.23, 24 Perioperative beta
blockade has been repeatedly shown to reduce
perioperative cardiac morbidity and mortality in
patients with confirmed coronary artery disease
and in patients with multiple cardiac risk factors
25-27; many institutions now have protocols for
perioperative beta-blockade despite recent con-
troversy about the concept, indications, and ben-
efits of such an intervention.28 The concept of
sympathetic overactivity in CKD as a contribu-
tor to arterial hypertension and cardiovascular
tion of the Publisher.
morbidity and mortality raises the question of the
728 MINERVA ANESTESIOLOGICA
CHRONIC KIDNEY DISEASE IN THE PERIOPERATIVE PERIOD
benefit of beta blockers in CKD.29, 30 A surpris-
ingly low percentage of patients with CKD are
being treated with beta-blockers, and prospective
trials examining the impact of both beta-blockers
and centrally acting sympatholytic agents on car-
diovascular mortality in CKD are very much need-
ed.29
Glycemic control
Clinical studies have identified chronic hyper-
glycemia (e.g. DM) as an independent risk factor
for perioperative morbidity and mortality. There
is compelling evidence that perioperative glycemic
control improves early clinical outcomes of dia-
betic patients undergoing coronary artery bypass
surgery.31-33 Furnary et al. evaluated the relation-
ship between the average blood glucose concen-
tration on the day of surgery and during the first
two postoperative days on cardiac- and non–car-
diac-related mortality in 3,554 diabetic patients
undergoing coronary artery bypass grafting.
Hyperglycemia at any time during the study peri-
od was associated with an increased mortality.31
Similarly, Ouattara et al. provided evidence for
the outcomes benefit of tight control of intraop-
erative blood glucose in diabetic patients undergo-
ing coronary artery bypass graft surgeries.32 The
authors demonstrated a more than seven-fold
increase in cardiovascular morbidity in patients
with refractory hyperglycemia (four consecutive
blood glucose levels >200 mg/dL despite insulin
treatment) compared with patients whose blood
glucose concentration was more tightly controlled.
Interestingly, preoperative and postoperative blood
glucose concentrations were similar in patients
with and without postoperative morbidity. In a
very recent study, the overall prevalence of peri-
operative (within 24 hours of surgery) hyper-
glycemia (glucose values >200 mg/dL) in more
than 4,800 non-cardiac patients has been docu-
mented to be 31% and as high as 42% in colorec-
tal patients.34
More recently, the benefit of intensive insulin
therapy has been called into question after the
NICE-SUGAR study found an increase in the
mortality among intensive care patients treated
with intensive insulin therapy; more data are need-
September 2010
 MINERVA MEDICA COPYRIGHT®

CHRONIC KIDNEY DISEASE IN THE PERIOPERATIVE PERIOD EILERS

may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either
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TABLE III.—Determination and calculation of GFR. Novel biomarkers of renal function and injury.

Inulin
Iothalamate, iohexol, 51Cr-ethyl-
enediaminetetraacetic acid,
99mTc-diethylenetriaminepenta-
acetic acid.
Cockcroft-Gault equation 111
Modification of Diet in Renal
Disease (MDRD) equation 112
Cystatin C –Biomarker of
Renal Function
Neutrophil gelatinase-associated
lipocalin (NGAL)- Biomarker
for Renal Injury
Small fructose polysaccharide that is an ideal marker of GFR since freely filtered and not reab-
sorbed.110
Not as good as inulin for GFR measurements. Limited use in clinical practice.
Serum creatinine to estimate creatinine clearance. Derived from homogenous patient population.
Does not include ethnicity for example.
Includes African American and Caucasian men and women with chronic kidney disease. Several
versions of this equation exist.
Small cysteine protease, freely filtered by the glomerulus and subsequently reabsorbed and cata-
bolized by the proximal tubule.37 Cystatin C produced by all tissues, production relatively con-
stant (independent of muscle breakdown)
NGAL, a very early biomarker (within hours) of renal injury in preclinical and clinical studies
during surgery.42, 43, 45-47

ed to identify the indications and safe targets for
glycemic control during surgery.35, 36
Preoperative assessment of renal function and
identification of patients with chronic kidney
disease
Patients with CKD are often asymptomatic,
and, thus, the recognition of patients with CKD
depends on the identification of sociodemograph-
ic factors (obesity, smoking, and alcohol use) and
common diseases associated with CKD (diabetes,
hypertension, and peripheral vascular disease) and
laboratory testing. In addition to the identifica-
tion of risk factors and diseases associated with
CKD, preoperative assessment often includes an
estimate of GFR using mathematical models based
on preoperative serum creatinine levels. Several
new biomarkers for the progression of CKD have
been identified, including cystatin C, C-reactive
protein (CRP), homocysteine, and asymmetric
dimethyl arginine (ADMA), but they require more
validation in prospective clinical studies in differ-
ent patient populations before their use in preop-
erative assessment can be generally recommended.
It also remains to be established whether some of
these metabolites are true biomarkers of disease
or risk factors. However, several studies have
demonstrated the potential usefulness of some of
these biomarkers. Table III provides an overview
tion of the Publisher.
determine GFR and some recent biomarkers for
CKD.
Cystatin C is a small (13 kilodalton) cysteine
protease that is freely filtered by the glomerulus
and is subsequently reabsorbed and catabolized
by the proximal tubule.37 In contrast to creatinine,
a muscle breakdown product whose production
correlates with muscle mass (with small individu-
als producing less creatinine than large, muscular
individuals), cystatin C is produced by all tissues,
and the production is relatively constant. Serum
cystatin C appears to correlate better with GFR
than creatinine, especially at higher levels of GFR.38
Several studies have demonstrated that cystatin C
is a stronger predictor of the risk of death and car-
diovascular events than creatinine, particularly in
the elderly.39, 40 Cystatin C has also been used suc-
cessfully in the critical care and transplantation
settings as a marker of acute renal dysfunction.41
However, at present, the reference range for cystatin
C has not been standardized across laboratories,
making the clinical use of cystatin C measure-
ments difficult. Standardization of measurement
and the development of equations to estimate GFR
based on cystatin C are likely future developments.
Cystatin C levels may be affected by thyroid dys-
function and steroid therapy, although the effects
of these diseases on serum levels need to be stud-
ied in larger populations.37
Most recently, neutrophil gelatinase-associated

of the tests and mathematical equations used to lipocalin (NGAL) has been shown to be a prom-

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 MINERVA MEDICA COPYRIGHT®
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This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either
sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which
not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary
ising biomarker of acute renal failure. Several pre-
clinical 42, 43 and clinical studies in cardiac surgery
patients and transplant patients demonstrated that
NGAL is a very early biomarker (within hours)
of renal injury.44-47 However, the value of NGAL
in CKD remains to be investigated.48
In summary, screening for and diagnosing CKD
in the perioperative setting remains challenging.
Today’s clinician mainly relies on insensitive mark-
ers of renal function (i.e., serum creatinine) and
a detailed medical history. Unfortunately, even
when abnormal serum creatinine values are noted,
further evaluation and/or interventions are often
not initiated. If the ultimate goal of preoperative
evaluation is a reduction of intra- and postopera-
tive renal adverse events, the mechanisms of iden-
tifying patients at risk for adverse renal outcomes
need to be improved. The development of newer,
more specific and sensitive biomarkers may allow
for a more accurate estimate of GFR in the near
future.
Risk stratification for surgery
As for any other patient, the type and extent of
surgery is naturally a significant factor in predict-
ing the perioperative morbidity and mortality for
patients with presumed CKD. Reports on the inci-
dence of renal failure after CABG surgery vary
between 1% and 11%,49, 50 likely reflecting variabil-
ity in co-existing disease. Even mild preoperative
renal dysfunction has been identified as a power-
ful predictor of perioperative morbidity and mor-
tality.51-55 In patients undergoing CABG surgery,
CKD and acute renal failure have been linked to
an increase in the length of stay in the ICU and
hospital and an increased incidence of respiratory
infections, sepsis and gastrointestinal or postop-
erative surgical bleeding.56 Interestingly, the
decreased long-term survival associated with acute
postoperative renal failure is independent of
whether renal function is recovered at the time of
discharge from the hospital.57
It is unclear at this time if recent advances in
surgical techniques, resulting in a higher percent-
age of off-pump cases, will have a beneficial effect
on the incidence of perioperative renal dysfunc-
tion of the Publisher.
tion, and various studies have reported conflict-
730 MINERVA ANESTESIOLOGICA
CHRONIC KIDNEY DISEASE IN THE PERIOPERATIVE PERIOD
ing results.58-60 The need for preoperative renal
risk stratification has recently been emphasized
and probably needs to be improved 61, although
several protocols have been published primarily
for the cardiac patient population.62, 63
Similarly, high-risk vascular procedures, such
as thoracic aneurysm repair or supra-renal abdom-
inal aortic aneurysm (AAA) repair, are associat-
ed with a high risk of renal dysfunction. However,
most studies were performed in patients under-
going open surgical repair, which is increasingly
being replaced by endovascular techniques.
Overall, postoperative renal dysfunction appears
to be less frequent in patients undergoing
endovascular AAA repair when compared to con-
ventional repair 64, 65, and perioperative mortal-
ity is also lower in patients after endovascular
repair.66 However, other studies have found no
benefit in the long-term survival between the two
approaches.67, 68 Endovasular techniques and an
increasing number of other interventions require
the use of radiographic contrast, which has been
associated with acute kidney injury. A recent sys-
tematic evaluation of studies examining contrast-
induced nephropathy identified important
patient-related (diabetes mellitus, heart failure,
older age, anemia, and CKD) and non-patient-
related risk factors (high-osmolar contrast agents,
ionic contrast agents, contrast viscosity, and con-
trast volume).69
There is also emerging evidence that even com-
mon surgeries, such as laparoscopic procedures,
may be implicated in transient renal dysfunction.70
It is, therefore, surprising that there remains a lack
of perioperative studies involving patients with
CKD undergoing non-cardiac or vascular surger-
ies.
Perioperative interventions for renal
protection for patients with CKD
While adequate control of hypertension in the
perioperative setting is important both to maintain
renal function and to avoid other perioperative
complications, overzealous correction of blood
pressure may result in relative renal hypoperfu-
sion and worsening renal function. Indeed, the
most common cause of perioperative ATN is hypo-
September 2010
 MINERVA MEDICA COPYRIGHT®
CHRONIC KIDNEY DISEASE IN THE PERIOPERATIVE PERIOD
may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either
sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which
not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary
volemia and hypotension leading to hypoxic injury
in the medullary region (Figure 1).71
Common toxic insults encountered in the peri-
operative period include radiocontrast dye,
aminoglycoside antibiotics, and NSAIDs (includ-
ing COX-2 inhibitors), and a careful risk-bene-
fit assessment should be done before potential
nephrotoxic agents are used, especially in patients
with CKD. A recent study showed that periop-
erative administration of paracetamol and pare-
coxib transiently affected glomerular and tubu-
lar function in patients with normal GFR under-
going orthopedic procedures.72 Surprisin-gly,
few studies have been published that concern
CKD and its perioperative management, includ-
ing possible prevention by therapeutic interven-
tions aimed at protecting renal function. A recent
comprehensive literature review by Zacharias et
al.73 identified only 37 studies that addressed
interventions for renal protection that satisfied
the selection criteria, albeit in the majority the
quality of the study design was judged to be poor.
Most of these studies tested interventions for
renal protection in a population with assumed
normal preoperative kidney function. Therefore,
similar to the need for studies that address risk
stratification, there is clearly a need for further
randomized controlled trials to assess the effec-
tiveness of potentially protective therapies aimed
at preserving renal function in patients with
CKD.
Fluid management
Because of the close association of renal and
cardiac disease, one particular problem with the
comorbidity of CKD and heart failure, also
referred to as “cardiorenal syndrome”, is the con-
flict in treatment goals, especially with respect to
fluid management. While diuretics are an inte-
gral component of the pharmacological thera-
py of heart failure, they may also lead to deteri-
oration of renal function. In addition, CKD has
been identified as an independent prognostic
factor in diastolic and systolic dysfunction 74, 75,
and it has been found to be a stronger predictor
of mortality than left ventricular function in
tion of the Publisher.
advanced CHF.76
Vol. 76 - No. 9 MINERVA ANESTESIOLOGICA
EILERS
While intraoperative urine output has repeated-
ly been shown to be a poor predictor of postoper-
ative renal function,77 the lack of adequate mon-
itors of renal function will often trigger generous
fluid administration entirely based on a urine out-
put that is considered inadequate (<0.5 mL/kg/hr).
Surprisingly, little data can be found to determine
the effect of the amount of fluid loading and the
type of fluid used on the postoperative renal func-
tion. Pull ter Gunne et al., comparing “optimal” to
“standard” hydration in patients undergoing sur-
gery for infrarenal aortic aneurysm showed a dif-
ference in heart rate but no difference in hemo-
dynamics and renal function as measured by cre-
atinine clearance.78
Evidence for the renal protective effects of hydra-
tion in the setting of CKD exists for patients under-
going radiographic studies requiring intravenous
contrast agents, which also can cause intense vaso-
constriction. Solomon et al. showed that hydra-
tion with 0.45% saline reduced the incidence of
nephropathy as measured by serum creatinine
when compared to saline in combination with
furosemide or mannitol.79 While subsequent stud-
ies in patients undergoing procedures involving
IV contrast have demonstrated a better protection
from 0.9% saline compared to 0.45%, presum-
ably due to more effective volume expansion,80
the hyperchloremic acidosis that may develop after
administration of the 0.9% ‘normal’ saline may
adversely affect renal function.81
Pharmacological interventions
While a ‘small’ or ‘renal’ doses of a dopamine
infusion may have a benefit in volume manage-
ment by increasing urine output, there is now
increasing evidence that it does not have any renal
protective effects and may even be detrimental in
that respect.82, 83 Recently, a large multicenter ran-
domized trial for the ANZICS Clinical Trials
Group, involving 328 intensive care patients at
23 institutions, examined the use of low-dose
dopamine for renal protection and found no ben-
efit for dopamine when compared to the placebo
group.84 A recent meta-analysis of studies in crit-
ically ill patients concluded that fenoldopam
reduces mortality and the need for renal replace-
731
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This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either
sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which
not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary
ment therapy,85 but its use in the perioperative
setting is still not supported by adequate data.
Loop diuretics, such as furosemide, are frequent-
ly used to preserve intraoperative urine output,
but the only data to support a possible protective
effect against acute renal failure come from a rodent
model.86 While older clinical studies concluded
that the use of high dose furosemide in patients
with ARF reduces the need for dialysis without
improving mortality, more recent evidence shows
no renal protection in cardiac surgery patients.87,
88 The osmotic diuretic mannitol is routinely used
during kidney transplantation 89 and is also fre-
quently administered as an intravenous bolus
before the clamping of large vessels, leading to an
impairment or cessation of renal perfusion with
the goal of renal protection and maintenance of
adequate urine output. These indications are based
on older data showing protective effects in the
treatment of renal ischemia,90, 91 but a more recent
randomized trial has failed to show a protective
benefit in patients undergoing major vascular sur-
gery.92
Several small, underpowered clinical trials test-
ing the administration of ACE inhibitors for renal
protection have failed to conclusively show a ben-
efit. While one small trial showed an improve-
ment in renal perfusion when compared to controls
in patients undergoing CABG,93 Zacharias et al.
concluded, based on their meta-analysis of three
small studies, including the trial by Ryckwaert,93
that RBF was not different than in control
patients.73
Data are also insufficient to support the use of
calcium channel blockers. When analyzing the
data of six studies and using creatinine clearance
as the primary outcome, Zacharias et al. found a
slight advantage for the treatment group at early
time points (first 24 hours to 4 days). However,
no benefit was seen at later time points (5 to 7
days).73
A number of studies have focused on the preven-
tion of contrast nephropathy, which has a high
incidence in patients with CKD. A recent meta-
analysis of 9 randomized controlled trials includ-
ing more than 2,000 patients concluded that
hydration with sodium bicarbonate is superior to
tion of the Publisher.
sodium chloride, although the heterogeneity in
732 MINERVA ANESTESIOLOGICA
CHRONIC KIDNEY DISEASE IN THE PERIOPERATIVE PERIOD
the data was significant, and the findings may have
been confounded by the concomitant use of N-
acetylcysteine.94
As suggested by several small, underpowered
studies and their meta-analysis, N-acetylcysteine
(NAC) may reduce the risk of contrast nephropa-
thy slightly, with limited side effects. Indeed, recent
studies focused on patients with acute coronary
syndromes have suggested that NAC may have a
dose-related impact on contrast-induced nephropa-
thy and also result in reduced mortality 95, although
controversy still exists about whether NAC actu-
ally prevents contrast nephropathy.96 NAC has
failed to show any benefit when used as a reno-
protective agent during major surgery97-98, and
more data are clearly needed to determine its role
and benefit.
Conclusions
The presence of CKD is associated with
increased perioperative mortality, even when
adjusted for other variables, such hypertension
or diabetes. However, the lack of physician aware-
ness of CKD and its associated risks is still wide-
spread.99 It is evident that CKD is frequently
under diagnosed, and, if acknowledged during
acute hospital care or surgery, it is often not includ-
ed in the clinical decision making process.
Questions about whether the patient is hyper-
kalemic or “symptomatic” are no longer sufficient
to determine whether a CKD patient is optimized
for surgery.
Currently, the best available evidence indicates
that successful identification, risk stratification
and intervention should take place in the preop-
erative evaluation phase. Non-emergent proce-
dures should be postponed to evaluate the causes
of preoperative renal dysfunction and initiate the
appropriate treatment, with the goal of optimizing
renal function as much as possible before surgery
and anesthesia. Universal acceptance of preoper-
ative GFR calculations and new markers of CKD,
such as cystatin C, will help to identify and risk
stratify patients for a particular surgical procedure.
At the same time, modification of disease progres-
sion can be achieved by interventions, such as the
optimization of blood pressure and glycemic con-
September 2010
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CHRONIC KIDNEY DISEASE IN THE PERIOPERATIVE PERIOD
may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either
sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which
not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary
trol. Nephrotoxic drugs should be identified and,
if possible, discontinued before a patient with
CKD undergoes elective surgery. During the
17.
immediate perioperative phase, treatment options
appear to be limited. With the exception of con-
trast-induced nephropathy, most interventional 18.
studies have been inconclusive or non-beneficial.
Prospective randomized studies are clearly needed
that specifically enroll patients with established
CKD who are undergoing surgery. 19.
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may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either
sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which
not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary
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may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either
sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which
not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary
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Funding.—Grant support was provided in part by the Foundation of Anesthesia Education and Research (C.U.N.) and NIH Roadmap for
Medical Research 8 K12 RR023262 (K.D.L.)
Received on November 19, 2009; accepted for publication on May 3, 2010.
Corresponding author: H. Eilers, MD, Department of Anesthesia and Perioperative Care, Department of Surgery, Division of Transplantation,
University of California, San Francisco, 521 Parnassus Avenue, P.O. Box 0648, San Francisco, CA 94143-0648, USA. E-mail:
eilersh@anesthesia.ucsf.edu
tion of the Publisher.

736 MINERVA ANESTESIOLOGICA September 2010