Renal Protection:
All that Glitters is not Gold
A major concern
in my anesthesia and critical care practices is the risk of perioperative
renal compromise. Postoperative renal insufficiency develops secondary
to pre-, intra-, and/or post-renal factors. Acute renal failure (ARF)
is commonly multifactorial with acute tubular necrosis (ATN) secondary
to hypoperfusion and ischemia as the major cause of perioperative compromise
[1]. ARF evolves over hours to days after surgery and results in increased
patient morbidity, mortality, and cost of care. Therefore, perioperative
preservation of renal function is a crucial priority for anesthesia
care providers. The maintenance of renal viability depends on an adequate
renal blood flow and delivery of substrate. Conversely, it can also
depend on a decrease in substrate demands, particularly if flow is compromised,
and limitation and/or elimination of nephro- and tubulotoxins (drugs,
myoglobin, hemoglobin, contrast dye, others)
Patients undergoing
certain surgical procedures such as cardiac, vascular, hepatobiliary,
GU, and complicated obstetrical are more likely to develop ARF. Preoperative
renal insufficiency (causing an increase in creatinine) is the most
common precursor of postoperative renal failure. In addition, co-morbid
pathologies such as increasing age, diabetes, cirrhosis, hypertension,
congestive heart failure and low ejection fraction, and acute clinical
scenarios such as hypovolemia, drug use (non-steroidal anti-inflammatories,
aminoglycosides, or cis-platin), radiocontrast dye exposure, hemolysis
or rhabdomyolysis are also associated with an increased risk of perioperative
renal dysfunction. In particular, the risk for postoperative renal insufficiency
in patients undergoing cardiopulmonary bypass surgery doubles for one
risk (see reference [2] for definitions of risk factors from their multicenter
study). However, in a small recent study, a relatively low risk group
of patients underwent off pump cardiac revascularization with a much
lower incidence of postoperative renal compromise when compared to bypass
patients [3].
Despite advances
in critical care, dialytic support and renal replacement therapy, the
mortality associated with postoperative ARF remains high, in excess
of 20-60%. Since renal insufficiency is usually silent, pre-emptive
evaluation, identification of renal insufficiency, and intervention
are crucial. In an attempt to correct hypoperfusion and to optimize
transtubular exchange and concentrating function, intravascular volume,
electrolyte, and acid-base deficits should be corrected prior to surgery
or radiographic intervention. Adequate fluid replacement and maintenance
of cardiac output are crucial, to limit, for example, decreases in renal
perfusion secondary to anesthesia, hypotension, hypovolemia, or cross
clamping of the aorta.
A host of medications
have been proposed as potential renal "protectants." However, there
is limited data to substantiate such claims in humans. Atrial natriuretic
factor, calcium channel blockers, angiotensin-converting enzyme inhibitors,
and endothelin antagonists have not been shown prospectively to be effective
in acutely limiting the development of or altering the history of ARF.
Loop (lasix) and osmotic (mannitol) diuretics are still routinely used
by some as renal protectants. Although they may increase urine output,
they have not been shown to be effective and should be used with care
in patients who have intravascular depletion.
"Renal" dose dopamine
(DA) at 1 — 3 microg/kg/min is probably the most widely used and
studied potential protectant. DA is a non-selective agonist, which has
activity at DA-1 (vasodilation) and DA-2 (vasoconstriction) receptors
as well as alpha and beta-adrenergic receptors. Lower plasma levels
of DA result in natriuresis and renal vasodilation of afferent and efferent
arterioles, and may also increase cardiac in a somewhat unpredictable
manner. Although DA increases renal blood flow at low plasma levels,
the glomerular filtration rate (GFR) does not increase consistently.
Furthermore, higher plasma levels of DA are associated with DA-2 and
alpha-receptor agonism, which may decrease renal blood.
MacGregor and colleagues
reported marked pharmacokinetic variability and unpredictability of
plasma DA levels in a study of nine healthy male volunteers. After placement
of venous and arterial catheters, the subjects received a continuous
infusion of DA at 10 microg/kg/min for ten minutes followed by a 30
minute washout period. They then received 3 microg/kg/min for 90 minutes.
Timed plasma samples of DA were obtained throughout the study period.
There was marked variability in baseline DA levels and a 10 — 75
fold intersubject variation in levels of plasma DA during infusion with
some low dose patients having high DA levels and some high dose infusions
resulting in low plasma levels. The data reflected marked intra-individual
and interindividual variability in DA distribution and/or metabolism
with profoundly different plasma DA levels in patients who received
the same DA infusion dose. In his accompanying editorial, Bailey reviewed
the data on renal dose DA and its lack of efficacy. He also queried
whether the unpredictable DA levels may have been affected in part by
the dosing regime and study design, but nonetheless felt that "renal"
or low dose DA is not the same for all patients anymore than a fixed
dose of thiopental is uniformly appropriate for all. For more information
on fenoldopam, see Dr.
Lubarsky's article.
Fenoldopam, initially
marketed as an I.V. antihypertensive drug, is a pure DA-1 agonist that
increases renal blood flow. It is undergoing evaluation at lower doses
(0.05microg/kg to limit secondary hypotension and cost) as a potential
renal protectant in high-risk cardiac and vascular surgical patients
as well as those receiving intravenous radiocontrast material. Whether
fenoldopam is beneficial remains open to discovery
In a recent NEJM
article, Tepel and colleagues treated 42 high risk patients undergoing
radiocontrast computerized tomographic procedures with 600 mg of oral
n-acetylcysteine (mucomyst™), a thiol containing compound, bid
starting 24 h prior to the procedure and continued through the day of
procedure. They compared the post-procedure renal function in treated
patients with 41 placebo control patients undergoing radiocontrast procedures.
Both groups received periprocedural fluid loading and infusion with
0.45 normal saline as well as a nonionic, low osmolarity contrast agent,
which is known to be associated with a lower incidence of associated
renal injury. The two groups were well matched with regards to baseline
serum creatinine (˜2.3mg/dL), demographics and associated pathology
(1/3 were diabetics). The authors defined post-procedure exacerbation
of renal function as a > 0.5 mg/dl rise in serum creatinine. One of
42 treated patients developed progressive renal dysfunction while 8/41
controls did (P<0.0 1). None of the patients in either group required
dialytic therapy.
NAC has been shown
previously to be effective clinically in blunting ischemia-reperfusion
syndromes in the heart, lung, kidney, and liver. Free radical production
is increased in renal tubular cells exposed to contrast dye. Since NAC
is a free radical scavenger, it may reduce the production of oxygen
free radicals as well as modulate nitric oxide metabolism and limit
the generation of the deleterious peroxynitrite radical. Finally, NAC
has been hypothesized to limit cell apoptosis by limiting cell signal
transduction leading to programmed cell death.
What are the clinical
ramifications of these studies? MacGregor's study helps explain the
variability in response reported in so many previous studies with DA.
Since we can't accurately predict plasma DA levels based on body weight
and kinetics, and since DA is a non-selective agent, we may want to
more aggressively explore alternative agents. NAC appears to be simple,
non-toxic, safe and inexpensive. Hopefully, we will see additional data
on administration of NAC in other perioperative and critically ill patients.
Would it benefit high-risk patients undergoing higher risk surgeries
as outlined above and should we consider administering it routinely?
How about the use of NAC in patients receiving I.V. contrast for procedures
such as coronary angiography, angioplasty or stenting?
Time will tell.
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