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14 Diagnosis and Management of Acute Kidney Injury
151
While these defi nitions of AKI show consistent associations
with hard end points such as mortality and hospital or ICU
length of stay, the role of these defi nitions in the clinical management of AKI has not been established. Recently published
observational data in critically ill patients suggest that using a
combination of both serum creatinine and urine output criteria may provide the best prognostic information about AKI
patients both with respect to requirement for dialysis and
mortality [
13 ]. Several novel biomarkers for acute kidney
injury have been identifi ed in recent years, including NGAL
and cystatin C, kidney injury molecule-1 (KIM-1), and interleukin-18 (IL-18). While attractive, these tests are not yet
widely used in clinical practice and remain the focus of ongoing studies to determine their appropriate role in guiding
management of patients at risk of, or impacted by, AKI.
Investigations
Once acute kidney injury has been identifi ed, the etiology
should be determined through further clinical assessment,
investigations, and interventions as necessary. A thorough
history and examination aids in identifying potential causes
of AKI. In particular, a search for indicators of prerenal and
postrenal causes should be performed as their correction can
lead to rapid recovery of kidney function. A number of urine
studies have been described that supplement data from the
history and physical examination including the urine sodium
concentration, fractional excretion of sodium, and fractional
excretion of urea. Unfortunately, all of these tests have limitations in their diagnostic performance and interpretation is
dependent on the clinical context.
Clinical examination to determine volume status may benefi t from more precise assessments of volume status especially in those with preexisting cardiopulmonary dysfunction
such as reduced ejection fraction, COPD, and pulmonary
hypertension, for example. Rapid assessment may be augmented using bedside complete or limited echocardiography
evaluating chamber size, chamber and IVC collapsibility during the phases of respiration, as well as ejection fraction.
AKI due to hypovolemia may be rapidly reversible by
plasma volume expansion. However, not all episodes of AKI
due to hypovolemia (i.e., hemorrhagic shock) respond to restoration of plasma volume. This may be especially true
where plasma volume is expanded using media that provide
little free water leading to hyperoncoticity which is strongly
associated with AKI [ 14 ]. Fluids known to cause hyperon-
coticity when used in large quantity for plasma volume
expansion as the sole volume expander include hyperoncotic
albumin, hyperoncotic starch, and hypertonic saline.
A host of toxins have been identifi ed including a broad
range of renally cleared medications such as aminoglycosides, vancomycin, angiotensin converting enzyme inhibitors,
angiotension receptor blockers, statins, and nonsteroidal
anti-infl ammatory agents. Hydroxyethyl starch in limited volume appears at least in observational studies to not impact
renal function, but in a key trial using an appropriate comparator fl uid, HES demonstrated a defi nitive negative infl uence on renal function in those with severe sepsis or septic
shock [ 15 ]. Why this effect is so clearly pronounced in those
with infection remains unclear but may relate to the subcellular cascade of events that occurs with AKI (see Subcellular
Events below). Radiocontrast (iodinated compounds) have
been associated with AKI (contrast-induced AKI (CI-AKI))
but there is confl icting data, even in the elderly [ 16 ]. In gen-
eral, dehydration and diabetes are believed to render one
more susceptible to CI-AKI; the only well-described effective
mitigation strategy is restoration of a plasma volume defi cit
prior to contrast exposure. Naturally occurring toxins such as
that found in concentrated cherry juice behave similarly to
NSAIDs [ 17 ]. Exposure to bioartifi cial membranes also
appear to impact renal function, principally through their
impact on hepatocyte growth factor [ 18 ]. Perhaps the best
model for endogenous toxin-mediated AKI is hepatorenal
syndrome where hepatic failure compromises renal function
in the absence of structural renal abnormalities. The clinician
should be aware that hyperchloremia and hyperchloremic
metabolic acidosis is also associated with reduced GFR; chloride intake management should be considered. Such efforts
are associated with reduced time to pH normalization,
reduced fl uid administration, reduced ICU length of stay, and
reduced cost although the effects of such strategies on clinically relevant outcomes remains under investigation [ 19 ].
Mechanical causes of AKI should also be considered and
take one of three general forms. The most commonly identifi ed is lower urinary tract obstruction with bladder distension
with or without concomitant ureteral dilatation. Common
etiologies include benign prostatic hypertrophy, clot after
bladder or ureteral instrumentation or renal trauma, and
indwelling bladder catheter obstruction. Detection strategy
includes physical examination, bladder scan, and fl ushing or
removal and/or replacement of an existing indwelling bladder catheter. Selected use of renal ultrasound is useful for
identifying hydroureter and/or hydronephrosis indicative of
a postrenal cause and may be of particular use in the postoperative setting after procedures where there is the potential
for ureteral injury and obstruction although it is important to
note that hydronephrosis may not be universally present in
the setting of acute obstruction. CT scanning may be required
as a complementary tool when there is no hydronephrosis to
evaluate for ureteral laceration (as opposed to obstruction)
with a surrounding urinoma. Bladder catheterization can
effectively relieve lower urinary tract obstruction, while
nephrostomy tubes or ureteric stents can be used to treat
upper urinary tract obstruction. Reconstruction of a lacerated
ureter is beyond the scope of this chapter.
152
N. Pannu and M.T. James
Postrenal obstruction also occurs with intra-abdominal
hypertension. In this setting, the postrenal component is relative, and increasing extrinsic renal vein compression leads to
reduced fl ux of blood across the renal vasculature.
Experimental data creating renal vein hypertension by external compression demonstrates reproducible decreases in
renal blood fl ow, urine fl ow, and GFR, as well as increases in
aldosterone and renin and the development of proteinuria.
Moreover, in the experimental setting, these fi ndings are
reversible with relief of renal vein hypertension [
20 ]. In a
related fashion, raising intra-abdominal pressure to 20 mmHg
with induced pneumoperitoneum creates physiology that
mimics the abdominal compartment syndrome with concomitant decreases in RBF, urine fl ow, and Scr [ 21 ]. However,
unlike relief of renal vein compression, relief of intraabdominal hypertension does not lead to reversed physiology but instead has only partial recovery of urine fl ow and a
further increase in Scr. Interestingly, this model also demonstrated systemic impact on pulmonary and GI mucosal histology consistent with ischemia and reperfusion as well.
These data also support a toxic effect of functional hypovolemia that may be explained in part by induced changes in
mitochondrial function and the elaboration of damage or
pathogen-associated molecular patterns [ 22 ].
The third setting in which postrenal obstruction may
occur is with intracapsular hypertension – a less common
condition after injury where there is renal parenchymal
injury but intact Gerota’s fascia. Extravasated blood that cannot escape the capsule creates intrarenal hypertension and
leads to renal venous compression in advance of renal arteriolar compression. Renal recovery has been described in an
experimental model with Gerota’s fascia incision [ 23 ].
Intrinsic etiologies are diverse but may impact the vasculature, parenchyma, or collecting system and span the gamut of
infectious, infl ammatory, immune-mediated, malignant,
thrombotic, and embolic events. Regardless of etiology,
investigation benefi ts from a combination of imaging to
determine the presence of structural and fl ow abnormalities –
generally as an ultrasound often complemented by a CT scan
with IV contrast as appropriate based on the patient’s intrinsic
renal function. Urinalysis and urine microscopy provide
important information about intrinsic renal causes of acute
kidney injury, although may be of limited value in catheterized and critically patients. The fi ndings of granular casts or
renal tubular epithelial cells are associated with an increase in
the likelihood of tubular injury and help to predict patients at
highest risk of worsening renal function, the requirement for
renal replacement therapy, or death. The fi ndings of hematuria and proteinuria in the absence of risk factors for ATN
should prompt further investigations for causes of glomerulonephritis, while white blood cell casts should prompt a careful assessment for causes of interstitial nephritis, including a
review of medication exposures. Acute interstitial nephritis is
likely underdiagnosed and can be associated with urine eosinophils as an allergic manifestation.
Subcellular Events: Current Theories
It is increasingly clear that our knowledge of clinical conditions is rapidly expanding as we come to understand the
molecular underpinnings of the host response to injury or
illness; similar events have occurred for AKI. Since septic
AKI predominates in high acuity ICUs, it provides an excellent platform from which to develop insights into commonalities between the different etiologies of AKI at the
subcellular level. Central to AKI are the interwoven effects
of altered microcirculation, infl ammatory mediators, and
their downstream effects, as well as energy metabolism
impacting mitochondrial alterations in productivity or survival. Interweaving these three domains into a coherent
whole has crafted a unifying theory of AKI triggers and the
functional consequences as the cellular and subcellular levels
[ 24 ]. Key to sepsis is the circulation of pathogens, pathogen
products (pathogen-associated molecular patterns (PAMPs),
e.g., lipopolysaccharide), and cellular response elements to
cellular injury (damage-associated molecular patterns
(DAMPs), e.g., nuclear protein high-mobility group box 1)
[ 25 ]. These various triggers initiate a variety of host responses
including the well-described cytokine cascades associated
with the host response to injury or infl ammation.
Each of these elements is in turn fi ltered by the glomerulus leading to exposure to vascular and tubular elements of
the renal parenchyma and predictably leads to a local infl ammatory response that alters microcirculation, reduced net
fl ow, and enhances the exposure time of the vascular endothelium to these modulators. Endothelial activation and
WBC recruitment follows in the wake of endothelial triggering. These events lead in turn to the elaboration of alarmins,
DAMPs that are released by dying cells that drive further
infl ammation, perhaps most notably at the distal tubule, and
may act in concert with mediators such as TNF-α in reducing
tubular function. As a result, cell homeostasis is distorted;
toxic O 2 mediators are created establishing cell lipid bilayer
and molecular machinery oxidant damage, triggering
mitophagy as a bioenergetic adaptive response. Mitophagy
then leads to cell cycle arrest, reducing energy utilization and
perhaps providing time for host defense recovery and then in
turn renal recovery. Supporting that AKI may be functional
and not structural is the series of observations in one experimental E. coli sepsis model using sheep, where net renal
blood fl ow increased during the period of peak AKI (as
judged by peak Scr) but was unaccompanied by signifi cant
histopathological changes despite intense cortical immune
responses such as nitric oxide synthase isoforms and hypoxia
inducible factor-1 expression during the peak period of AKI
14 Diagnosis and Management of Acute Kidney Injury
153
[ 26 ]. At present, it remains unclear how to modify these
recently articulated host responses to mitigate against the
AKI phenotype outlined above.
Supportive Care and Medical Management of Complications
Once acute kidney injury is established, management focuses
on preventing further extension of kidney injury and providing supportive care while awaiting potential renal recovery.
Attempts are usually made to avoid further exposure to nephrotoxic agents to the greatest extent possible without compromising management of other comorbidities. Doses of
renally cleared medications should be adjusted for the level
of kidney function. This can be particularly important for
antimicrobial agents in order to maintain appropriate therapeutic levels in patients with sepsis while avoiding further
nephrotoxicity. The involvement of a PharmD focused on
critical care may be helpful.
Supportive care in patients with established acute kidney
injury requires continued interventions to maintain fl uid,
electrolyte, and acid-base balance. Disorders of sodium and
water handling, metabolic acidosis, and hyperkalemia are
common complications of acute kidney injury. Hyponatremia
may result from impaired free water excretion in excess of
sodium or solute intake, while hypernatremia is common in
patients with impaired free water intake, hypotonic fl uid
losses, or in those who have received large volumes of intravenous saline for resuscitation. These abnormalities may be
corrected by modifying free water intake or the composition
of intravenous fl uids. It is appropriate to also evaluate the
water content of supplemental medications such as antibiotics and vasoactive infusions as water intake may be substantial, especially with vasoactive agents prepared in low
concentration solutions.
Acid generation can be reduced by dietary protein
restriction as is common for those with CKD in the
outpatient setting, although this is undesirable in hypercatabolic patients such as those after septic shock, severe
sepsis, or severe injury, especially traumatic brain injury.
Often overlooked acid sources such as chloride intake are
also appropriate to evaluate be it in the form of intravenous
fl uids for maintenance or oral or IV nutritional support formulae [ 19 ]. In particular, those with AKI who also need
mechanical ventilation benefi t from having a reduced need
for minute ventilation to buffer iatrogenically induced acidosis. Multiple correction strategies have been articulated
including the administration of alkalinizing intravenous
fl uids such as those supplemented with sodium bicarbonate (or sodium acetate) may be provided to correct metabolic acidosis. Of course, when physiologic limitations
prevent the administration of additional IV fl uid, renal
replacement techniques can also restore acid- base
balance.
Hyperkalemia is a common complication of AKI and has
multiple etiologies spanning excess administration in oral or
IV form, infusion of aged blood in large quantity, rhabdomyolysis, and a host of others. Hyperkalemia therapy has three
goals: (1) elimination of potassium intake, (2) preservation
of myocardial conduction, and (3) potassium elimination
[ 27 ]. For those with preserved renal function, forced diuresis
using IVF and furosemide generally is suffi cient to repair
hyperkalemia. Preservation of myocardial conduction in the
presence of ECG changes such as peaked T-waves is
supported by calcium chloride (CaCl 2 ) infusion instead of
calcium gluconate as the calcium in CaCl 2 is immediately
bioavailable as Ca 2+ , and Cl - are strong ions and remain
dissociated from one another at physiologic pH in an aqueous
milieu; Ca gluconate needs to undergo degluconation via
hepatic processing and has a therefore less rapid
bioavailability. Supplemental therapy may also include betaagonists, insulin, and glucose; these agents help to shift K
from the extracellular space in to the intracellular one principally relying on the ability of insulin to drive this process.
Glucose administration is required to avoid iatrogenic
hypoglycemia.
Potassium elimination for those with AKI or CKD may
be ineffective via the urine and, therefore, alternative methods are required. One common method is to use Na-K cation
exchange resin administration via the upper or lower GI
tract. Mixed in sorbitol to draw potassium-rich fl uid into the
GI tract to interact with the resin, dosing is guided by the
initiation of diarrhea and has a relatively slow onset. Usage
of these exchange resins has been associated with intestinal
necrosis or perforation in certain circumstances [ 28 ]; there-
fore, this approach is generally supplemental in nature rather
than stand-alone therapy and is unlikely to be adequate in
patients with severe hyperkalemia associated with lifethreatening dysrhythmia. When medical management of
these abnormalities is unsuccessful or medical interventions
cannot be tolerated by the patient, renal replacement therapy
is usually necessary. In those with anuria and dialysis requiring CKD at baseline who have life-threatening hyperkalemia, dialysis is a fi rst-line therapy. While marshaling the
appropriate resources for either IHD or CRRT, volume loading to dilute the potassium concentration, administration of
potassium displacing agents, and CaCl 2 may require concomitant airway control and mechanical ventilation to preserve oxygenation and manage work of breathing from the
induced extravascular lung water.
Other common complications include volume overload,
hyperphosphatemia, and increased work of breathing related
to acidosis. Each of these is manageable using some form of
RRT to reduce total body water, adjust electrolytes, and
reduce metabolic acid load.
154
N. Pannu and M.T. James
Intravenous Fluids and Hemodynamic Support
Hypotension is a common contributor to the initiation of
acute kidney injury and renal perfusion may be further
diminished once acute kidney injury is established because
autoregulation is impaired and unable to maintain constant
blood fl ow with changes in systemic blood pressure, in particular, mean arterial pressure. Early correction of hypovolemia and hypotension cannot only reverse many prerenal
causes of acute kidney injury but is likely also important to
avoid extension of an existing injury. Strategies to maintain
hemodynamic stability include the use of intravenous fl uids,
vasopressors/inotropic medications, as well as protocols that
involve hemodynamic monitoring to guide use of these therapies. While more aggressive use of intravenous fl uids early
in the initial phase of illness may be benefi cial when acute
kidney injury is volume responsive, excessive fl uid repletion
in oliguric patients with established AKI may have adverse
effects, including prolonged mechanical ventilation, initiation of secondary abdominal compartment syndrome, anastomotic leak, and mortality in a variety of studies [
Isotonic crystalloids are the principal intravenous fl uid
used for plasma volume expansion of patients with AKI with
0.9 % NSS predominating globally. Observational data suggest that buffered crystalloids may be associated with a
decreased risk of AKI and of death as compared to saline
[ 32 – 34 ]. The presumed toxicity of saline is attributed to the
high chloride content of the solution, which may decrease
glomerular fi ltration rate due to tubuloglomerular feedback
from excessive chloride delivery to the distal tubule. A recent
systematic review and meta-analysis of high vs low chloride
content fl uids in perioperative and critical care fl uid resuscitation found no association between fl uid chloride content
and mortality but a weak association of high chloride solutions with AKI – primarily identifi ed in the observational
studies [ 35 ]. In contrast, a recent randomized controlled trial
of high vs. low chloride solutions in a heterogeneous group
of critically ill patients found no difference between groups
with respect to mortality or acute kidney injury although the
total fl uid volume received in each group over the course of
the study was 2 L, perhaps insuffi cient to defi nitively determine an effect. Further study in patients with or at high risk
of AKI is warranted.
Colloid solutions such as albumin and starches are theoretically attractive alternative fl uids for intravenous volume
expansion given their oncotic properties; however, their
appropriate use remains controversial. No differences in the
incidence or duration of renal replacement therapy were
observed in a randomized trial of critically ill patients comparing treatment with 4 % albumin in 0.9 % saline with isotonic saline alone [ 36 ]. However, a recent systematic review
of randomized trials concluded that the use of hyperoncotic
29 – 31 ].
albumin solutions reduced the risk of acute kidney injury and
may be appropriate for some patients including those with
ascites, spontaneous bacterial peritonitis, burns, or following
surgery but not as the sole resuscitant given concerns of
hyperoncoticity [
colloid solution; however, when compared to crystalloids,
hyperoncotic hydroxyethyl starch has been associated with a
higher incidence of acute kidney injury [ 38 , 39 ] and features
of renal tubular injury (termed osmotic nephrosis) on kidney
biopsy, suggesting these solutions may be harmful. As colloids have not been shown to consistently reduce mortality
when compared with crystalloids across all populations who
are at high risk of acute kidney injury, these solutions are
usually reserved for selected patients or in those with continuing large fl uid requirements. In light of the 6S trial that
identifi ed an increase in AKI frequency with starch resuscitation, starch solutions are generally avoided in those with
severe sepsis or septic shock [ 15 ].
Distributive shock is a common contributor to acute kidney injury in patients with sepsis, anaphylaxis, liver failure,
and burns. Aggressive fl uid resuscitation remains of paramount importance in these patients; however, once intravascular volume has been repleted, vasopressors such as
norepinephrine and vasopressin may be required to maintain
hemodynamic stability. On the basis of a single-center trial,
protocol-based fl uid, vasopressor, and blood component
transfusion strategies for the resuscitation of those with
severe sepsis or septic shock gained widespread prominence
[ 40 ]. However, three separate randomized multicenter and
multinational trials (ProCESS, ARISE, ProMISe) comparing
protocolized versus non-protocolized care in that patient
population demonstrated no benefi t to the protocolized
approach [ 41 – 43 ]. Certain key features were evident from
the trials including early recognition of those with septic
shock and rapid fl uid resuscitation. Both of these aspects
were believed to be key elements in management common to
both protocolized and non-protocolized management.
37 ]. Hydroxyethyl starch is an alternative
Diuretics
Total body salt and water excess is one of the major complications of AKI and diuretics are often prescribed to control
fl uid balance. The use of loop diuretics may also aid in the
management of hyperkalemia and hypercalcemia accompanying acute kidney injury. However, diuretics can cause
hypovolemia exacerbating AKI, and their use has been associated with mortality and failure to recover renal function in
observational studies [ 44 ]. Some small randomized trials of
furosemide reported higher risks of AKI when used as a prophylactic agent at the time of imaging and surgical procedures, while a systematic review of trials that included
patients with or at risk of AKI found no signifi cant impact on
14 Diagnosis and Management of Acute Kidney Injury
155
risk of death, requirement for renal replacement therapy, or
number of dialysis sessions [
effectively to improve fl uid balance, thereby facilitating
mechanical ventilation (or liberation from mechanical ventilation) in volume overloaded patients. Although furosemide
has been shown to facilitate diuresis, this approach does not
appear to improve renal recovery among patients receiving
dialysis regardless of modality for AKI.
45 , 46 ]. Diuretics can be used
Vasodilators and Other Pharmacologic Agents
Several pharmacological agents with renal vasodilatory
properties have been studied with the aim of increasing renal
blood fl ow and ameliorating ischemic damage in acute kidney injury. However, none of these agents have been proven
to improve the clinical outcomes of acute kidney injury. A
systematic review of trials including patients with or at risk
of AKI found that low-dose dopamine had no signifi cant
impact on survival, need for dialysis, or adverse clinical
events [ 47 ]. Dopamine has been associated with arrhythmias
and intestinal ischemia and is not currently recommended to
prevent or treat AKI. Fenoldopam is a dopamine type-1
receptor that also increases renal blood fl ow, although it
decreases systemic vascular resistance. A meta-analysis suggested promising results with the use of fenoldopam in critically ill patients, including a reduction in AKI, need for renal
replacement therapy, and in-hospital mortality [ 48 ]. However,
given its risk of hypotension along with limitations of the
existing published trials, further trials remain necessary to
support the use of fenoldopam for this indication. Atrial
natriuretic peptide has favorable renovascular effects that
have been shown to increase glomerular fi ltration rate in animals. Large trials of atrial natriuretic peptide (0.2 μg/kg/min)
in critically ill patients with AKI showed no impact on mortality or dialysis-free survival but a higher incidence of hypotension with atrial natriuretic treatment [
systematic review has suggested that low-dose atrial natriuretic peptide (0.1 μg/kg/min) is not associated with hypotension and may lead to a reduction in the requirement for
renal replacement therapy [
of low-dose atrial natriuretic peptide will be required before
this agent can be recommended for prevention or treatment
of AKI.
There is inadequate effi cacy and safety data to support the
use of growth factors for acute kidney injury. Although
insulin- like growth factor-1 showed promising results on
recovery of renal function in animals, small trials have failed
to demonstrate benefi cial results on kidney function in
humans. A small trial of erythropoietin for the prevention of
AKI following cardiac surgery reported a reduction in incidence of AKI in treated patients; however, a subsequent trial
51 ]. Yet again, further large trials
49 , 50 ]. One
in the ICU detected no impact on the incidence of
AKI. N-acetylcysteine gained widespread use for prevention
of radiocontrast-associated nephropathy. However, the
effects of N-acetylcysteine for prevention of acute kidney
injury has been heterogeneous across studies, and the results
from the most rigorously performed trials demonstrate no
effect on the incidence of AKI, requirement for dialysis, or
mortality.
Nutritional Support
Combined protein-calorie malnutrition is common in patients
with AKI and has been consistently associated with mortality. Although clinical trials assessing the impact of nutrition
on clinical end points are lacking, it is broadly accepted that
appropriate nutritional support should be provided to meet
the metabolic requirements of patients with AKI. Total
energy consumption is not increased in AKI and only mildly
increased above resting energy expenditure even in patients
with critical illness. A total (not only nonprotein calories)
energy intake of 20–30 kcal/kg/day is recommended to provide nutritional support in patients with acute kidney injury,
while avoiding hyperglycemia, hypertriglyceridemia, and
the net excess fl uid load that is frequently observed with
higher calorie regimens [ 52 ].
The optimal protein intake in AKI is not known. Given
the association between protein-calorie malnutrition and
mortality in patients with AKI, dietary restriction of protein
is not considered appropriate in attempts to delay or prevent
the initiation of renal replacement therapy for azotemia or
acidosis. Protein wasting and negative nitrogen balance may
occur in patients with AKI due to the infl ammatory and
physiological stresses of accompanying acute illnesses, particularly those occurring in critical illness. Nutritional protein administration is therefore usually increased to meet the
greater metabolic demands of hypercatabolic patients.
Furthermore, additional losses of amino acids and protein
occur in the fi ltrate on continuous renal replacement therapy
and via peritoneal dialysis resulting in additional nutritional
requirements for patients receiving of these forms of renal
replacement therapy; similar losses occur in those managed
with an open abdomen and such losses should be addressed
in the nutritional prescription. It is common to aim for a protein intake of 0.8–1.0 g/kg/day in non-catabolic patients not
requiring renal replacement therapy, with increases of 2.0 g/
kg/day as a common protein goal for hypercatabolic patients.
Higher doses may be required for those receiving renal
replacement therapy especially in the setting of septic shock,
major injury, traumatic brain injury, or severe burn injury.
Clinical guidelines are available to aid in this process including specifi c applications to those with clinically severe obesity, hyperglycemia, and those with AKI or CKD [
53 , 54 ].
156
N. Pannu and M.T. James
Consultation with a registered dietician is valuable to estimate the appropriate energy and protein requirements for an
individual patient given the multiple approaches that are
available to provide guidance. Since net nitrogen balance
analysis often relies on determining urinary nitrogen losses
(i.e.,, UUN assay), the oliguric or anuric patient represents a
unique challenge in this respect. Prealbumin has a shorter
half-life than albumin but varies inversely with C-reactive
protein leading to the recommendation that they should be
concomitantly assessed to determine the fi delity of the prealbumin concentration. Serial assessments generally have limited value when obtained more frequently than once per
week. Novel assessment strategies such as ultrasound assessment of muscle thickness may ultimately prove useful, but
data are limited and no recommendation regarding this
parameter may be made at present.
Long-Term Follow-Up
AKI is associated with an increased risk of progressive
chronic kidney disease and ESRD after hospital discharge
with 2.1 % of survivors in a regional study progressing to
AKI [ 55 ]. Post-discharge follow-up of renal function is rec-
ommended for survivors of AKI [ 12 ]. Subsequent long-
term management of patients with CKD after AKI usually
proceeds according to the principles of CKD management
[ 12 , 56 ] .
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Renal Replacement Therapy in the Critically Ill Surgical Patient
Kevin K. Chung and Ian J. Stewart
1 5
Introduction
The diagnosis of clinically signifi cant acute kidney injury
(AKI) among the critically ill surgical population occurs in
approximately one in four admissions [
patients admitted to the intensive care unit (ICU), or 1 out of
every 20 admissions, require some form of renal replacement
therapy (RRT) [ 1 ]. Among all critically ill patients who
require RRT, the mortality has consistently been around
60 % [ 2 ]. Practically speaking, RRT refers to the clearance of
excessive electrolytes, toxic solutes, and volume that accumulates in the intravascular and extravascular space in the
setting of AKI. Most often, this type of therapy is delivered
via a venovenous extracorporeal circuit with a blood pump
that drives venous blood through an artifi cial “kidney” membrane. Less commonly, the peritoneal cavity could be used to
exchange electrolytes and solutes in the form of peritoneal
dialysis. We will focus our discussion in this chapter mainly
on extracorporeal RRT with only a brief section on peritoneal dialysis.
1 ]. About 5 % of all
Overview of Modalities
There are a number of RRT “modes” that can be used in the
ICU. The various modes are typically divided into continuous RRT (CRRT) or intermittent hemodialysis (IHD) based
The opinions or assertions contained herein are the private views of the
author and are not to be construed as offi cial or as refl ecting the views
of the Department of the Army or the Department of Defense.
K. K. Chung , MD (*)
Burn Center , US Army Institute of Surgical Research ,
Fort Sam Houston , TX 78258 , USA
kevin.k.chung.mil@mail.mil
e-mail:
I. J. Stewart , MD
Department of Medicine , David Grant Medical Center ,
Travis AFB , CA 94535 , USA
ian.stewart@us.af.mil
e-mail:
on how long the therapy is applied and what type of machine
is used. Regardless of the length of therapy, it is important to
differentiate the two different ways that solutes can be
cleared through a hemofi lter within the context of an extracorporeal circuit. The two modes of clearance are “diffusive
clearance” (a.k.a. hemodialysis) and “convective clearance”
(a.k.a. hemofi ltration). Before being able to understand this
difference, we must understand the anatomy of a hemofi lter,
which does not differ signifi cantly regardless of “mode.”
Hemofi lter Anatomy
Standard hemofi lters that are utilized for the purposes of
RRT are comprised of thousands of parallel hollow fi bers
encased in a cylindrical casing through which blood can fl ow
(Fig. 15.1 ). These hollow fi bers are analogous to tiny garden
hoses with semipermeable walls, allowing small solutes and
fl uid to leak through the walls while blood is contained and
passes through the middle portion of the fi bers. In between
the individual fi bers naturally exists the “interstitial space”
where leaked solutes can then escape through an opening in
the cylindrical casing through the generation of a steady negative pressure or hydrostatic pressure alone.
Hemodialysis (Diffusive Clearance)
As blood fl ows through the fi bers of a standard hemofi lter, a
port exists on one end of the outer cylindrical casing through
which an electrolyte balanced solution (dialysate) can be
infused to bathe the “interstitial space” and exit through
another port on the other end of the outer casing. The steady
fl ow of dialysate through this space creates a gradient
between the concentration of any given electrolyte or solute
in the blood contained in the hollow fi bers and the concentration of the electrolyte or solute contained in the dialysate in
the interstitial space. This concentration gradient allows solutes to passively move across the semipermeable membrane,
from the space of high concentration, in the blood, to the
space of low concentration, in the dialysate (Fig.
15.2 ). To
© Springer International Publishing Switzerland 2016
N.D. Martin, L.J. Kaplan (eds.), Principles of Adult Surgical Critical Care, DOI 10.1007/978-3-319-33341-0_15
159
160
←
→
Fig. 15.1 ( a ) Schematic of a
hemofi lter used in this case
for hemodialysis. The
patient’s blood enters the
device at the top and is
distributed into a multitude of
semipermeable hollow fi bers,
demonstrated by the
cross-sectional view ( b ). The
patient’s blood exists the
fi lter at the bottom and is
returned. Dialysate fl ows in a
countercurrent fashion (i.e.,
the opposite direction of
blood fl ow) to optimize the
concentration gradient across
the entire length of the
hemofi lter
K.K. Chung and I.J. Stewart
ab
Blood in
Dialysate out
Hemofilter
Dialysate in
Blood out
Cross sectional view of hemofilter
Fig. 15.2 Schematic representation of diffuse clearance in the
setting of hemodialysis. Large particles (such as cells or albumin) are
represented by the red circles . As these particles are too large to fi t
through the pores of the semipermeable membrane, they pass through
the hemofi lter and are returned to the patients. Small molecules (such
as potassium and urea) are represented by the black circles . These
molecules fl ow down their concentration gradient across the
semipermeable membrane from the blood space to the interstitial
space. To optimize the concentration gradient across the length of the
hemofi lter, the blood and dialysate go in opposite directions
(countercurrent)
Blood
Dialysate
optimize the gradient between the two compartments, the
dialysate is run in a countercurrent fashion (i.e., the blood
and dialysate fl ow in opposite directions). This movement of
solutes across a membrane down the concentration gradient
is described as “diffusive clearance.” Simply, dialysis
removes various excess solutes from the bloodstream by
maintaining a gradient to optimize “diffusion.” Although
highly effi cient, this mode of clearance targets mostly solutes
and molecules that are of low molecular weight in size
(i.e., ≤10 kDal). Potassium and urea are examples of
molecules that are in this range. Depending on the type
of machine utilized, dialysate can be generated through the
machine (IHD machines), come in premixed bags, or mixed
by the hospital pharmacy.
Hemofi ltration (Convective Clearance)
Hemofi ltration, on the other hand, is a mode of solute
removal that utilizes “convective clearance.” In this mode, a
negative pressure is generated in the interstitial space of the
hemofi lter, actively pulling solutes across the semipermeable membrane while an electrolyte balanced solution is
introduced simultaneously either into the extracorporeal circuit or into the venous system of the body at the same rate
(Fig. 15.3 ). This fl uid is appropriately designated as
“replacement fl uid.” Replacement fl uid solutions are typically premade and commercially available in sterile packaging from various CRRT vendors. Alternatively, balanced
crystalloid solutions, such as PlasmaLyte A
®
(Baxter
Healthcare Corporation, Deerfi eld, IL), can be utilized as
replacement solution. Of note, dialysate that is generated by
IHD machines, typically through a reverse osmosis system
15 Renal Replacement Therapy in the Critically Ill Surgical Patient
161
Fig. 15.3 Schematic representation of convective clearance in the set-
ting of hemofi ltration. With hemofi ltration, there is no dialysate in the
interstitial space. Negative pressure in the interstitial space pulls both
solvent and fl uid across the semipermeable membrane. Replacement
fl uid is infused either proximal to the hemofi lter (pre-dilution) or distal
to the hemofi lter (post-dilution)
Blood
Effluent
utilizing tap water, cannot be utilized as replacement solution as it is not considered “sterile.”
Convective clearance, due to its active nature, can target
solutes and molecules of higher molecular weight generally
described as “middle molecules” (i.e., – 10–50 kDal).
Examples of such molecules include beta2-microglobulin,
most drugs such as antimicrobials, and pro- and antiinfl ammatory mediators such as interleukin-1, interleukin-6,
and interleukin-8. The ability of hemofi ltration (convection)
to remove such molecules has direct implications in the way
electrolytes are managed, how drugs are dosed, and may
impart extrarenal benefi ts.
Intermittent Hemodialysis
IHD describes a mode of extracorporeal therapy that is based
on diffusive clearance and applied for a fi xed period of time.
Generally, IHD utilizes the same machines, personnel (dialysis technicians), and principles as chronic outpatient hemodialysis. In IHD, clearance is dependent on the blood fl ow rate
and the dialysate rate. Treatments in the ICU, lasting 2–4 h in
length, are prescribed three to fi ve times weekly.
Compared to CRRT, IHD results in much greater clearances because of higher dialysate fl ow rates. This may be
advantageous in patients that require high clearance (such as
severe crush injury with rhabdomyolysis and resultant hyperkalemia). However, IHD may not be the preferred modality
in critically ill surgical patients, because it can result in more
hemodynamic instability than CRRT via two mechanisms.
The fi rst mechanism is due to the high clearance of IHD with
resultant decrease in plasma osmolality [ 3 ]. When solute is
removed from the intravascular space, equilibration from the
extravascular space is not immediate. This establishes a gradient between these two compartments. Via oncotic pressure, water will fl ow out of the intravascular space leading to
decreased blood volume. The second mechanism is due to
the short treatment time during which volume can be
removed. Similar to solute, equilibration of volume from the
extravascular to the intravascular space is not immediate, and
ultrafi ltration can result in decreased blood volume. The rate
at which volume is removed is therefore a key determinant in
how a treatment is hemodynamically tolerated. For example,
if 2 L of volume needs to be removed, the rate at which this
occurs during a 4 h IHD treatment is 500 ml/h. This is much
greater than the rate of ~83 ml/h that could be achieved using
a continuous modality (2 L removed over 24 h). Therefore,
IHD should only be used on hemodynamically stable
patients, unless high clearances are required, for example,
severe rhabdomyolysis with hyperkalemia that cannot be
maintained at a safe level with a continuous modality.
Decreasing the rate at which fl uid is removed, by either
increasing time or frequency, has been shown to decrease
intradialytic hypotension in outpatient IHD [ 4 ] and can be
considered in the critical care setting to minimize hemodynamic instability.
Continuous Modalities
Continuous modalities are typically delivered via machines
that are specifi cally designed and marketed for inpatient use
as CRRT machines. Unlike IHD, these machines typically do
not utilize a water source (tap water) as they do not generate
dialysate real time. Instead, the machines rely on premade
sterile solutions that can be utilized for the purposes of both
hemodialysis and hemofi ltration. In fact, the exact same bag
of solution can be labeled as “dialysate” or “replacement
fl uid” based entirely on how the solution is employed. The
four modes described below are all commonly grouped
under the term “CRRT.” See Table 15.1 for suggested initial
prescriptions.
Slow Continuous Ultrafi ltration (SCUF)
In SCUF mode, a steady negative pressure is applied to the
interstitial space pulling solutes and water across the semipermeable membrane and discarded through an opening in
the outer fi lter casing through a tube that leads to an empty