Prevention and Management of AKI

Prevention and Management of
Acute Kidney Injury
&
BIOMARKERS OF AKI
BY DR MONIKA
RESIDENT DM NEPHROLOGY – SAVEETHA MEDICAL COLLEGE

DEFINITION
• A heterogenous syndrome defined by a rapid (over hours to days)
decline in GFR resulting in the retention of metabolic waste products,
including urea and creatinine, and dysregulation of fluid, electrolyte,
and acid-base homeostasis

• AKI is defined as any of the following (Not Graded):
• Increase in SCr by X0.3 mg/dl (X26.5 lmol/l) within 48 hours; or
• Increase in SCr toX1.5 times baseline, which is known or presumed to have
occurred within the prior 7 days; or
• Urine volume o0.5 ml/kg/h for 6 hours

• Specific t/t is not available for the majority of forms of AKI.
• M/M focuses on interventions to prevent development of AKI when
possible and on provision of supportive therapy to ameliorate
derangements of fluid and electrolyte homeostasis and prevent
uremic complications.
• In advanced AKI, RRT is often required.
• The ultimate goals of M/M - to prevent death, facilitate recovery of
kidney function, and minimize the risk of CKD

Prevention of AKI
• Primary – Avoid the disease
• Secondary – Limit damage/Complications
• Tertiary – Improve outcomes with established disease

PRIMARY PREVENTION
Risk Assessment
1st step in preventing AKI - an adequate risk assessment.
• Identification and, if possible, reversal of the risk factors.

Primary Preventive Measures
• Optimizing Volume and Hemodynamic Status
• To prevent AKI, adequate renal perfusion is required.
• optimizing volume status and maintaining hemodynamic status and cardiac output.
• Common reasons for fluid administration and/or vasopressors to prevent AKI include hypovolemia,
hypotension, and sepsis.
• Assessment of volume status can be challenging, particularly in patients in ICU.
• In addition, studies in ICU patients or patients undergoing surgery have shown that only about half of
hemodynamically unstable pts respond to fluid administration.
• However, dynamic measures such as the passive leg raising maneuver and the fluid bolus test coupled with
real-time stroke volume monitoring can determine fluid responsiveness accurately.
• Volume status assessment and response to fluid administration most often relies on BP, HR, oxygen
saturation, CVP & UOP.
• not specific or sensitive
• In emergency settings, point of care ultrasound useful, a collapsing IVC at the end of expiration is s/o
hypovolemia.

• 4 phases of fluid therapy - rescue, optimization, stabilization, and deescalation.
• Rescue -“administration of fluid for immediate m/m of life-threatening conditions a/w impaired tissue perfusion.”
• Fluid boluses are used during the rescue phase, in an adult typically 500 ml of isotonic fluids over 15 minutes or less without close monitoring
• Optimization - “adjustment of fluid type, rate, and amount based upon context to achieve optimization of tissue perfusion.”
• fluid challenges are administered during the optimization phase, 250 ml or 3 ml/kg of isotonic fluids over 5 to 10 minutes with stroke volume (SV)
reassessment.
• Some studies have defined fluid responders as an increase of 10% to 15% of SV or CO after fluid challenge.
• These two phases are essential in preventing AKI secondary to hypoperfusion.
• Stabilization - aims for achieving a neutral or slightly negative fluid balance to favor organ suppor
• Deescalation - “minimization of fluid administration; mobilization of extra fluid to optimize fluid balance.”
• In the stabilization and deescalation phases, clinicians should target a neutral and then a negative fluid balance if fluid overload is present.
• To obtain a neutral or negative fluid balance, fluid administration should be minimized and oral or intravenous diuretics or even ultrafiltration may
be required depending on the clinical scenario and underlying kidney and cardiac function.
• Adverse outcomes associated with fluid overload include cardiopulmonary complications, delayed wound healing and kidney function recovery,
and increased mortality
• A retrospective study has shown that elevated CVP within the first 24 hours of ICU admission was associated with AKI, suggesting a role of venous
congestion in the development of AKI

• optimal fluid to use for resuscitation.
• In the absence of hemorrhagic shock 2012 KDIGO AKI guidelines suggest isotonic crystalloids ,instead of synthetic (hydroxyethyl starch
[HES]) and nonsynthetic (albumin) colloids for intracellular volume expansion in patients at risk or presenting with AKI
• HES solutions increase the risk for AKI.
• A RCT in 7000 ICU pts has shown that even solutions with lower molecular weight such as 6% HES 130/0.4 increased the need for RRT
compared with 0.9% sodium chloride (normal saline)
• Another large RCT including 804 pts with severe sepsis has shown that 6% HES 130/0.4 is detrimental to kidney function and also survival
compared with Ringer acetate.
• The mechanism of HES-induced AKI may be due to proximal renal epithelial cell uptake of HES causing an acquired lysosomal storage
disease. Therefore HES should be avoided in patients at risk for and with AKI.
• Saline Versus Albumin Fluid Evaluation (SAFE) trial of 6997 critically ill pts found that fluid resuscitation with saline or albumin resulted in
similar relative risks for death.
• In addition, no significant differences were found in new single-organ and multiple-organ failure or days on RRT.
• Two subgroup analyses from this study showed that use of albumin may be deleterious in patients with traumatic brain injury and
potentially beneficial in sepsis.

• Albumin can be considered when substantial amounts of crystalloids (e.g., 2 liters) are required to maintain adequate MAP, especially in
septic pts.
• It is possibly deleterious in pts with trauma and has low potential for transmission of infectious diseases.
• A study comparing renal artery flow velocity and renal cortical tissue perfusion showed a significant reduction in renal artery flow and
cortical tissue perfusion with saline but not with the use of chloride-restrictive fluids.
• Indeed, greater chloride delivery to the macula densa may activate tubuloglomerular feedback, triggering renal vasoconstriction and
reduced GFR.
• A large retrospective study showed that chloride-restrictive fluids (lactated solution with balanced buffer–chloride concentration of
98 mmol/l or chloride-poor 20% albumin-chloride concentration of 19 mmol/l) compared with chloride-rich intravenous fluids (0.9%
saline, 4% succinylated gelatin solution, or 4% albumin solution) were associated with a significant decrease in AKI and RRT requirement
• A meta-analysis confirmed that high-chloride fluids significantly increased the risk for AKI.
• SPLIT trial, a large RCT ( 2278 pts), failed to show differences in renal outcomes with the use of the same buffered crystalloid than the
aforementioned study compared with 0.9% saline.
• In this study, AKI was defined as a rise in serum creatinine level of at least twofold. Critiques of this study included the low severity of
disease at baseline and low volume of fluid administered (2.6 liters ± 2.1 to 3.0 liters in each group).
• In addition, the solution used contained acetate (which may cause myocardial toxicity) and gluconate (which may have other metabolic
effects).
• In conclusion, the use of low-chloride solutions does not improve renal outcomes compared with NS in pts at low-moderate risk for AKI.

• vasopressors to prevent AKI
• guidelines for sepsis management - after initial 30 ml/kg of crystalloids and addition of albumin in
pts requiring substantial amounts of crystalloids to maintain adequate MAP, vasopressors (MAP >
65 mm Hg)
• In sepsis, norepinephrine 1st-choice
• A recent RCT showed vasopressin equivalent or may be better than norepinephrine to improve
kidney outcomes in pts with septic shock.
• RRT (25% vasopressin group vs 35% norepinephrine group); however, rates of RRT were
comparable among survivors from each group, and the overall mortality rate was also similar
between groups.
• dobutamine - if myocardial dysfunction or ongoing signs of hypoperfusion
• Hypertensive pts with septic shock - targeting MAP 80-85 mm Hg instead of 65-70 mm Hg
reduced the risk for AKI and RRT, whereas the risk for AF seemed to be heightened.
• Target need to be individualized depending on age, hypertension status, and degree of peripheral
artery and renovascular disease.

Prevention of Contrast-Induced Acute Kidney Injury
• The concept of CI-AKI recently questioned
• Hydration with NS superior to 0.45% NS.
• RCT compared NS with isotonic sodium bicarbonate (150 meq sodium bicarbonate added to
850 ml of 5% dextrose) at 3 ml/kg/h X 1 hour before the procedure followed by 1 ml/kg/h for the 6
hours after the procedure. CI-AKI was significantly lower in the bicarbonate compared with the
saline group (2% vs. 14%).
• Bicarbonate capable of scavenging ROS, and the increased pH in PT & renal medulla a/w
bicarbonate administration could reduce generation of superoxide.
• Most hydration studies with isotonic bicarbonate used shorter infusion protocols (7 hours) than
those with isotonic saline (usually 12 to 24 hours), which is attractive for emergency procedures.
However, there are risks for compounding errors with sodium bicarbonate that can lead to
electrolyte disorders.
• KDIGO AKI guidelines – NS or sodium bicarbonate solutions in pts at risk for CI-AKI unless there
are contraindications to volume expansion.
• PRESERVE trial- 2 × 2 factorial design ,compare effectiveness of sodium bicarbonate vs NS and oral
NAC with placebo in 8680 high-risk patients scheduled to undergo coronary or noncoronary
angiography , no difference in AKI or mortality between the use of sodium bicarbonate and
isotonic sodium chloride.

• Iodinated contrast –
• high-osmolar contrast medium (approx 2000 mOsm/kg)
• low-osmolar contrast medium (600-800 mOsm/kg)
• Iso-osmolar contrast medium (290 mOsm/kg)
• Risk for nephrotoxicity increases with increasing osmolarity but higher cost
• KDIGO AKI guidelines recommend either iso-osmolar or low-osmolar
iodinated contrast
• volume of contrast - V/CrCl ratio above 3.7 independently predicts CI-AKI.
• Administration of iodinated contrast more than once over 48 to 72 hours
should be avoided

Prevention of Drug-Induced and Nephrotoxin-Induced Acute Kidney Injury
• patient-related factors -older age >60 yrs, CKD, diabetes, heart failure, volume depletion, and sepsis.
• Preventive measures –
• correctly estimating the GFR before initiation of therapy
• adjusting the dosage
• monitoring renal function and drug dosage during therapy
• administration of IV saline before exposure if possible
• Alternative non-nephrotoxic drugs
• nephrotoxic drug combinations should be avoided
• Amphotericin
• 30% of treated pts, risk for AKI increases with higher cumulative doses.
• Lipid formulations less nephrotoxic
• Amphotericin deoxycholate preferred over conventional amphotericin;
• alternative antifungal agents such as itraconazole, voriconazole, and caspofungin
• ACEi & ARBs
• vasodilation of the efferent glomerular arteriole, reducing intraglomerular pressure already compromised by the BP–lowering effect of these agents. After
the initiation of an ACE inhibitor or ARB, if creatinine increases by >30%
• bilateral renal artery stenosis
• stenosis of the renal artery in a solitary kidney
• diffuse intrarenal small-vessel disease
• generalized volume depletion should be suspected
• drugs discontinued. It remains unclear whether withdrawing an ACE inhibitor or ARB before iodinated contrast administration is beneficial.

• NSAIDs
• should be avoided in CKD and intravascular volume depletion
• inhibit COX, which blocks prostaglandin-induced vasodilation of the afferent arteriole,
potentially reducing GFR and RBF.
• In critically ill pts, renal hypoperfusion (decreased effective circulating volume ),
inhibition of prostaglandin-induced vasodilation may further compromise RBF &
exacerbate ischemic injury.
• Aminoglycosides
• usually occurs 5-10 days after initiation of t/t
• Typically nonoliguric & a/w decreased urine concentrating ability & urinary Mg wasting.
• KDIGO guidelines –not to use in pt at risk for AKI (unless no other alternative available)
• aminoglycoside uptake by PT cells is saturable, OD administration can decrease tubular
cell toxicity.
• In the general population, extended intervals between doses maintains the target dose
while decreasing the risk for nephrotoxicity compared with multiple daily doses

• Tumor Lysis Syndrome
• uric acid & calcium-phosphate precipitation in the tubules
• High risk - hematologic malignancies (aggressive lymphomas and ALL)
• patient (age, baseline renal function) and tumor characteristics (cell turnover rate, growth rate, extensive BM
involvement, tumor bulk, and chemosensitivity).
• Baseline UA >7.5 mg/dl, LDH >1500 U/l and WBC >25 × 109/l are also risk factors.
• Diagnosis - 2 simultaneous lab abnormalities within 3 days before or 7 days after chemotherapy:
• UA >8 mg/dl
• K+ > 6 mEq/l
• Pi >4.5 mg/dl
• Ca <7 mg/dl or any symptomatic hypocalcemia.
• M/M –
• In low risk pts - hydration and close monitoring of volume status and renal function.
• urine alkalinization to promote elimination of urate not recommended (can induce calcium phosphate deposition
and aggravate TLS)
• In intermediate and high risk pt - aggressive hydration with isotonic saline 2-3 l/m2 /day aiming for UOP 80-
100 ml/m2/h
• In patients at intermediate risk with UA <8 mg/dl, a XOI , Allopurinol also should be started 2 days before
chemotherapy, whereas rasburicase should be used in patients with UA >8 mg/dl.
• Rasburicase contraindicated in G6PD deficiency.
• For high-risk patients - Rasburicase (up to 0.2 mg/kg, although a lower dose is usually prescribed) stat, f/b close
monitoring of UA If uric acid normalizes, allopurinol treatment can be started.
• If urine output decreases despite adequate fluid administration, a loop diuretic should be added, and RRT will be
required if oliguria persists.

Secondary prevention
• After the renal insult has occurred, secondary preventive measures
should be directed to avoid further injury, facilitate repair and
recovery, and prevent complications.

Traumatic and Nontraumatic Rhabdomyolysis
early and aggressive fluid therapy.
• Intravenous isotonic saline should be initiated even before the crushed limb is relieved to prevent precipitation of
the pigment in the tubular lumen.
• Fluid to target UOP 200-300 ml/h.
• sodium bicarbonate intend to maintain alkaline urine and decrease precipitation of myoglobin and arteriolar
vasoconstriction.
• However, sodium bicarbonate also can precipitate calcium phosphate deposition and worsen hypocalcemia and
should be avoided in severe hypocalcemia or metabolic alkalosis.
• large volumes of NS can cause hyperchloremic metabolic acidosis.
• If urine pH is <6.5, each liter of NS can be alternated with 850 ml of 5% dextrose plus 150 mmol of sodium
bicarbonate.
• Mannitol -beneficial because of its diuretic, antioxidant, and vasodilatory properties.
• could prevent renal tubular cast deposition,
• expand extracellular volume
• Reduce intracompartmental pressure, muscle edema, and pain.
• mannitol may exacerbate HF & nephrotoxicity, requires close monitoring, and is contraindicated in oliguria,
hypervolemia, hypertension, and heart failure.
• Mannitol can be considered if urine flow is higher than 20 ml/h @5 g/h/liter of infusate not to exceed 1-
2 g/kg/day.

• Muscle damage induces stretch-activated ion channels, allowing for influx of Ca into cells after reperfusion.
• The resultant hypocalcemia is usually asymptomatic but can lead to cardiac dysrhythmias.
• Hence, care must be taken to avoid sodium bicarbonate–induced hypocalcemia, which can trigger tetany,
seizures, and cardiotoxicity and worsen muscle damage.
• During AKI recovery, hypercalcemia is frequent, mainly in patients who received calcium infusion, as a result
of the mobilization of previously precipitated Ca, hypocalcemia should be treated only if symptomatic.
• In treating patients with rhabdomyolysis, it is important to consider when to stop fluid resuscitation.
• A general recommendation is to stop when creatine kinase <5000 U/l and myoglobinuria disappears, as
shown by a negative urine dipstick for blood.
• However, the risk for fluid accumulation and compartmental expansion always should be evaluated.
• RRT should be considered in resistant hyperkalemia or metabolic acidosis, rapidly rising serum potassium,
oliguria, anuria, or volume overload

• Hyperglycemia
• RCT in ICU pts, intensive glucose control (glucose of 81 to 108 mg/dl [4.5 to 6.0 mmol/l]) increased the risk for
death at 90 days compared with conventional glucose control (<180 mg/dl [<10 mmol/l]).
• Intensive glucose control also increased the risk for severe hypoglycemia.
• There was no change in the incidence of AKI or use of RRT.
• Other studies have not found an increase in mortality with intensive glucose control.
• In summary, intensive glucose control in ICU patients increased the incidence of severe hypoglycemia and either
increased or had no effect on mortality compared with blood glucose ranges of 140 to 180 mg/dl (7.8 to
10 mmol/l) and 180 to 200 mg/dl (10 to 11 mmol/l).
• Recommended - glucose concentration 110 -149 mg/dl (6.1 to 8.3 mmol/l).
• Remote Ischemic Preconditioning
• Applying inflation of a BP cuff for 4-5 short cycles in the upper or lower limb.
• aims to create brief ischemia and reperfusion in the arm or leg to provide protection in distant organs, such as
heart, kidney, lung, and brain.
• The underlying mechanisms include activation of humoral factors, including adenosine, bradykinin,
cannabinoids, in addition to subcellular modulators, nuclear factor-B and NO
• Two recent large RCTs in cardiac surgery found that RIPC does not confer a benefit over sham conditioning
(placebo).
• RCT, the combined outcome of MACE (major adverse cardiovascular events: death from cardiovascular causes,
nonfatal MI, coronary revascularization, or stroke) 12 months after randomization was similar in RPIC compared
with sham procedure. In the other, no difference was found in death, MI, stroke, or AKI at hospital discharge.
• Currently, the use of RIPC for preventing cardiac surgery and contrast-induced AKI is controversial because its
beneficial effects may be conditioned by the use of propofol as an anesthetic.

• Pharmacologic approaches
• Inhibition of inflammatory mediators
• Enhancement of renal perfusion by blocking vasoconstrictor
mechanisms and intensifying vasodilator mechanisms
• Attenuation of leukocyte infiltration
• Inhibition of the coagulation cascade
• Administration of growth factors to accelerate renal recovery.

• N-Acetylcysteine
• A tripeptide analogous to glutathione and is able to cross cellular membranes.
• may reduce vasoconstriction and oxygen free radical generation after the administration of contrast material.
• Because an increased production of free radicals by the kidneys is partly responsible for their cellular damage in
postischemic and nephrotoxic AKI, several clinical studies have attempted to use NAC to prevent AKI, mainly in CI-AKI and
during cardiac surgery.
• In the initial study, NAC at a dose of 600 mg orally BD, the day before and the day of the procedure prevented AKI after
iodinated contrast administration. However, numerous subsequent studies have shown conflicting results. The recent
PRESERVE trial has shown that the use of NAC does not provide any benefit to prevent CI-AKI. Therefore, we no longer
recommend using NAC to prevent CI-AKI.
• Loop Diuretics and Natriuretics
• Ineffective in prevention of AKI or for improving outcomes once AKI occurs.
• should be avoided in prerenal AKI
• Meta-analyses have confirmed that the use of diuretics to prevent AKI did not reduce in-hospital mortality or need for RRT
• An RCT including 94 patients undergoing high-risk cardiac surgery showed that prophylactic nesiritide (β-type natriuretic
peptide) did not reduce RRT requirement or lengths of stay, although AKI rates were lower with nesiritide.
• In opposition, a Japanese RCT including 303 patients with CKD who underwent CABG surgery showed that human atrial
natriuretic peptide (hANP, carperitide) decreased postoperative serum creatinine and need for dialysis, although other
studies using the same medication have shown increased mortality in patients with acute heart failure. Further studies are
required.

• Vasoactive Agents
• Renal-dose dopamine 0.5 to 3 mcg/kg/min given as a renal vasodilator increases urine output,
but several studies have confirmed that this drug does not affect AKI outcome or mortality
• Dopexamine, a synthetic dopamine analogue, is a dopamine type-1 and less potent dopamine
type-2 receptor agonist. Small studies performed in patients undergoing liver transplant surgery
have not found a beneficial effect.
• An RCT in 409 patients with septic shock showed that norepinephrine is equivalent to vasopressin
in terms of kidney failure–free days.
• Fenoldopam -pure dopamine type-1 receptor agonist with hemodynamic renal effects similar to
those of low-dose dopamine, without systemic α- or β-adrenergic stimulation.
• In a meta-analysis, reduce the risk for AKI in postoperative or critically ill patients
• Intrarenal administration of fenoldopam allows the use of a substantial dose of fenoldopam
mesylate while avoiding systemic adverse effects, such as hypotension.
• In a registry of 268 patients treated with intrarenal fenoldopam infused for at least 1 hour, the
incidence of CI-AKI was <1%, compared with 27% based on historic rates in that population.
• Data from experimental models suggest that fenoldopam may have additional antiinflammatory
effects. Currently, we do not recommend use of fenoldopam to prevent AKI because no high-
quality data support use of this agent

• Statins
• Induce downregulation of angiotensin receptors, decrease endothelin synthesis, decrease inflammation,
improve endothelial function by inhibiting NF-κB, decrease expression of endothelial adhesion molecules,
increase NO bioavailability, attenuate production of ROS, and protect against complement-mediated injury.
• most commonly studied Rosuvastatin, 10-40 mg/day X 1 - 7 days after the procedure.
• continue in pts who are already receiving a statin, and those who need statins for another indication such as
MI may receive statins before angiography.
• currently unclear whether statins should be specifically initiated to prevent CI-AKI.
• may reduce the risk for AKI after elective surgery.
• In a large retrospective study of 213,347 patients who underwent surgery, 32% received a statin before
surgery.
• AKI occurred in 1.9% of these pts.
• statin use was a/w decreased risk for AKI, need for RRT, and 30-day mortality.
• There was no difference between groups in dialysis requirement 90 to 120 days after surgery.
• Calcium Channel Blockers
• shown to reverse the afferent arteriolar vasoconstriction induced by a variety of stimuli and also have an
independent natriuretic effect.
• evaluated in the prevention of DGF.
• A large multicenter RCT did not find any benefit on the incidence and severity of DGF.
• A systematic review did not find strong evidence for the routine use of CCBs to reduce the incidence of DGF
after transplantation.

• Adenosine Antagonists
• Theophylline - a nonselective adenosine receptor antagonist, prevents
adenosine-mediated vasoconstriction of the afferent arteriole.
• Adenosine is released in response to increased luminal Cl- in DT as part of the
tubuloglomerular feedback.
• A recent RCT adding theophylline to NAC showed reduced incidence of CI-AKI.
• A large meta-analysis found a significant reduction in CI-AKI with theophylline;
however, beneficial effects were not observed in pts with baseline creat
>1.5 mg/dl (132 µmol/l).
• Insufficient evidence to recommend theophylline as a solo agent
• KDIGO AKI guidelines do not suggest using theophylline to prevent CI-AKI.
• Selective adenosine blocking agents, such as Rolofylline, used in trials for
prevention and t/t of CRS.
• In a small double-blind RCT in dHF -AKI, the coadministration of adenosine A1
antagonist with furosemide increased diuresis and prevented further decrease
in GFR.

• Outcomes after AKI
• A meta-analysis of 13 cohort studies that assessed renal and non-renal outcomes reported higher risks
for CKD (pooled adjusted hazard ratio 8.8, 95% CI 3.1 to 25.5), ESKD (pooled adjusted HR 3.1, 95% CI 1.9
to 5.0) and death (pooled adjusted HR 2.0, 95% CI 1.3–3.1) in pts who had an episode of AKI vs those
without AKI.
• In a limited number of studies AKI was also a/w a higher risk of CVD & CCF but not hospitalisation or
stroke.
• This study confirms the findings of individual studies that AKI is associated with significant renal and
non-renal sequelae.
• References -1SG Coca , S Singanamala , CR Parikh , et al.: Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis. Kidney Int. 81 :442-448
2012 22113526

Prerenal Acute Kidney Injury
• Restoration of normal circulating blood volume.
• optimal composition of administered fluids depends on the source of
fluid loss and associated electrolyte and acid-base disturbances.
• Initial management usually consists of volume resuscitation with an
isotonic electrolyte solution such as 0.9% saline.
• RBC transfusion -hemorrhagic hypovolemia (ongoing bleeding), if pt is
in hemodynamically unstable condition, or if Hb dangerously low

• colloid vs crystalloid – in nonhemorrhagic renal, extrarenal, and 3rd-space fluid losses
controversial
• colloids more effective at restoring circulating blood volume due to greater retention in the IV
compartment.
• RCT and meta-analyses comparing crystalloid with colloid replacement for resuscitation in critically
ill pts -not confirmed this theoretical benefit and have suggested an increased risk of adverse
outcomes with the use of some colloid formulations.
• In a meta-analysis of 55 trials involving 3504 patients randomly assigned to t/t with albumin or
crystalloid- no evidence of either improved outcomes or increased mortality or other
complications associated with albumin administration.
• Albumin vs Saline.
• multicenter RCT involving 7000 pts , fluid resuscitation in hypovolemic medical and surgical ICU
pts; 28-day survival, development of single- or multiple-organ failure, and duration of
hospitalization were similar
• Although specific data on the development of AKI were not provided, need for RRT was similar
• A post hoc analysis of the data for pts with traumatic brain injury, albumin resuscitation was
associated with increased mortality risk.

• synthetic colloid solutions
• alternative to albumin
• Hydroxyethyl starch preparations
• Increased risk of AKI
• Hydroxyethyl starch Vs 3% Gelatin solution
• In a multicenter RCT in 129 pts with sepsis, use of hydroxyethyl starch was associated with a >2 fold increased risk of AKI.
• A subsequent meta-analysis confirmed the increased risk of AKI associated with hydroxyethyl starch across 34 studies that
encompassed 2604 individuals.
• Based on these data demonstrating no benefit and a potential increased risk of AKI with colloid use, along with the greater cost of
these solutions, their routine use for volume resuscitation in pts with hypovolemia and sepsis is not advisable.
• In particular, hydroxyethyl starch solutions should be used only sparingly, with regular monitoring of renal function, and the risk of
hyperoncotic renal failure should be minimized by the concomitant use of appropriate crystalloid solutions

• After initial volume resuscitation, replacement of ongoing urine and GI
fluid losses should generally be accomplished using hypotonic crystalloid
solutions (e.g., 0.45% saline); even though urinary and GI losses may vary
greatly in composition, they are usually hypotonic to plasma.
• The volume and electrolyte content of replacement solutions, as well as pt
Sr electrolyte levels and acid-base status, should be closely monitored to
guide adjustments in the composition of the replacement fluids.
• Although K+ content of gastric juices tends to be low, concomitant urinary
potassium losses may be quite high as the result of metabolic alkalosis.

• Heart Failure
• depends on the clinical setting and cause of the heart failure.
• In patients with congestive heart failure in whom AKI has developed as a result of excessive diuresis, withholding of
diuretics and cautious volume replacement may be sufficient to restore kidney function.
• In ADHF, AKI may develop despite worsening volume overload; intensification of diuretic therapy is often required
for t/t of pulmonary vascular congestion.
• Although diuretic therapy may exacerbate prerenal AKI, it can also result in improvement in kidney function via
several postulated mechanisms:
• (1) by decreasing ventricular distension, which results in a shift from the descending limb to the ascending limb of
the Starling curve and improvement in myocardial contractility
• (2) by decreasing venous congestion
• (3) by diminishing intraabdominal pressure.
• Additional therapies for ADHF in the setting of AKI include inotropic support, administration of vasodilators for
afterload reduction, and mechanical support, including intraaortic balloon pumps and ventricular assist devices.
• The use of invasive hemodynamic monitoring in ADHF has been controversial; although it is often employed to
guide pharmacologic management, clinical data have not demonstrated improved renal outcomes when treatment
is based on readings from pulmonary artery catheters.
• The role of isolated ultrafiltration in ADHF is also controversial.
• Although negative fluid balance can be achieved more readily using extracorporeal ultrafiltration than conventional
diuretic therapy, studies have not demonstrated differences in kidney function or survival

• Liver Failure and Hepatorenal Syndrome
• typically have total-body sodium overload, with peripheral edema and ascites
• however, true hypovolemia or reduced effective systemic arterial blood volume is
often an important contributory factor in the development AKI.
• The underlying pathophysiology of salt and water retention in cirrhosis
• Portal hypertension leads directly to ascites formation
• splanchnic and peripheral vasodilatation result in a state of relative arterial underfilling, which
activates neurohumoral vasoconstrictors that produce intrarenal vasoconstriction, salt and water
retention, and decreased GFR.
• Volume-responsive AKI may develop in the setting of excessive diuresis, increased GI
losses (often as a result of therapy for hepatic encephalopathy), rapid drainage of
ascites, or SBP.
• Worsening hepatic function is often associated with diuretic resistance and
progressive or precipitous worsening of kidney function.
• Inadequate increase in CO in response to the fall in PVR may be central to the
development of HRS.

• Differentiation between volume-responsive prerenal AKI and HRS is based on the clinical
response to volume loading.
• Hyperoncotic (20% or 25%) albumin 1 g/kg/day
• however, there are no rigorously collected data supporting this regimen compared with
volume expansion with isotonic crystalloid solutions.
• More data are available regarding the use of albumin infusion to prevent renal dysfunction
in patients undergoing large-volume (>5 L) paracentesis and in the t/t of SBP.
• In a RCT pts who received infusion of 10 g of albumin per liter of drained ascites
experienced less activation of RAS and a significantly lower rate of worsening of kidney
function than patients who did not receive albumin infusion.
• In a subsequent study, albumin infusion was superior to administration of either dextran or
gelatin solutions in preventing renal dysfunction after large-volume paracentesis.
• Current recommendations are to infuse 6 to 8 g of albumin per liter of ascites drained
when paracentesis volume exceeds 5 L.
• In a RCT comparing antibiotics alone with antibiotics plus albumin in pts with SBP, infusion
of 1.5 g/kg of albumin at initiation of t/t and an additional 1 g/kg on the 3rd day of t/t was
a/w reduced rates of both AKI and mortality,although the benefit appears to be restricted
to pts in whom the S creat is >1 mg/dL, the BUN is >30 mg/dL, or T Bil >4 mg/dL

• Definitive t/t of HRS - liver transplantation.
• The role of peritoneovenous shunting (e.g., LeVeen and Denver shunts) in
HRS inadequately studied.
• In a subset of 33 pts with HRS included in a randomized trial comparing
placement of peritoneovenous shunts with medical therapy, shunting was
not a/w improved survival
• These data need to be interpreted with caution because of the small sample
size and because data on improvement in kidney function were not reported.
• In addition, due to poor long-term patency rates and high rates of
complications, particularly encephalopathy, peritoneovenous shunts have
largely been supplanted by transjugular portosystemic shunts.
• Transjugular portosystemic shunts have been demonstrated to provide better
control of ascites than sequential paracentesis and, in one series, lower rates
of HRS, albeit with a higher risk of encephalopathy
• In a small case series, transjugular portosystemic shunting has been reported
to be effective as primary therapy for HRS, but it has not been evaluated in a
randomized trial

• Pharmacologic therapy with vasoconstrictors, when combined with
albumin infusion, has been a/w improvement in kidney function in
patients with HRS
• Norepinephrine
• combination of octreotide and midodrine
• V1 vasopressin receptor agonist terlipressin
• although only terlipressin has been evaluated in RCT.
• In a meta-analysis of 5 published randomized trials, t/t with
terlipressin was a/w an OR for reversal of HRS of 8.1 (95% CI= 3.5 to
18.6) compared with t/t with albumin infusion alone, but did not
significantly improve survival.

Intrinsic Acute Kidney Injury
• General Principles
• vary based on the specific cause of kidney injury.
• Optimization of cardiovascular function and restoration of IV volume status are key interventions to minimize the risk that prerenal AKI will
evolve into ischemic ATN.
• There is compelling evidence that aggressive intravascular volume expansion dramatically reduces the incidence of ATN after major surgery
or trauma, in burns, and in cholera.
• AKI due to sepsis is common and is associated with mortality rates as high as 80%.
• Recent studies have emphasized two salient features of successful m/m of sepsis that may be of importance in the prevention of AKI.
• early goal-directed resuscitation to defined hemodynamic targets (MAP >65 mm Hg, CVP 10 to 12 mm Hg, UOP >0.5 mL/kg/hr, CVO2 >70%) using a
combination of crystalloid solutions, RBC transfusion, and vasopressors resulted in a significant reduction in organ dysfunction and mortality in patients
with sepsis syndrome.
• early and aggressive volume resuscitation and hemodynamic stabilization
• Second, in another study of critically ill patients, intensive insulin therapy to maintain a glucose level of 80 to 110 mg/dL, compared with
conventional management to maintain the glucose concentration between 180 and 220 mg/dL, resulted in decreases in AKI, defined based
on either the change in serum creatinine concentration or the need for RRT
• Although these strategies have been incorporated into the Surviving Sepsis Campaign, it should be recognized that the data supporting both
early goal-directed therapy and intensive glycemic control are derived primarily from single-center clinical trials.
• Early goal-directed therapy has not been evaluated in a multicenter trial; the benefit of tight glycemic control was not confirmed in a
multicenter trial of intensive therapy to achieve a target glucose level of approximately 80 to 110 mg/dL compared with more conventional
therapy designed to maintain the blood glucose level below 180 mg/dL.

• Intravascular volume depletion has been identified as a risk factor for
ATN resulting from exposure to iodinated contrast material,
rhabdomyolysis, hemolysis, cisplatin, amphotericin B, multiple
myeloma, aminoglycosides, and other nephrotoxins; crystal-
associated AKI related to acyclovir and acute urate nephropathy; and
AKI stemming from hypercalcemia.
• Restoration of intravascular volume status prevents the development
of experimental and human ATN in many of these clinical settings.

• Avoidance of potentially nephrotoxic medications
• Diuretics, NSAIDs (including selective COX-2 inhibitors), ACE
inhibitors, ARBs, and other inhibitors of the renin-angiotensin-
aldosterone system should be used with caution in patients with
suspected absolute or effective hypovolemia or in patients with
renovascular disease, because they may convert reversible prerenal
AKI to intrinsic ischemic ATN.
• The combined use of agents that block the renin-angiotensin-
aldosterone system, diuretics, and NSAIDs has been identified as a
risk factor for AKI, particularly in patients with heart failure, liver
failure, or other causes of reduced baseline renal perfusion.

• Careful monitoring of circulating drug levels appears to reduce the
incidence of AKI associated with aminoglycoside antibiotics and CNI.
• The observation that the antimicrobial efficacy of aminoglycosides persists
in tissues even after the drug has been cleared from the circulation
(postantibiotic killing) has led to the use of once-daily dosing with these
agents.
• Dosing regimens that provide higher peak drug levels but less-frequent
administration appear to produce comparable antimicrobial activity and
less nephrotoxicity than older conventional dosing regimens.
• Nephrotoxicity of drugs may also be reduced through changes in
formulation.
• For example, the use of lipid-encapsulated formulations of amphotericin B
may decrease the risk of amphotericin-induced AKI.

• Prevention of Other Forms of Intrinsic Acute Kidney Injury
• Allopurinol (10 mg/kg/day in three divided doses, to a maximum of 800 mg/day) is useful for
limiting uric acid generation in patients at high risk for acute urate nephropathy; however, AKI can
develop despite the use of allopurinol, probably through the toxic actions of hypoxanthine
crystals on tubule function.
• In settings in which rates of uric acid generation are high, such as tumor lysis syndrome, the use
of recombinant urate oxidase (rasburicase, 0.05 to 0.2 mg/kg) may be more effective.
• Rasburicase catalyzes the degradation of uric acid to allantoin ,effective both as prophylaxis and
as treatment & prevent for acute uric acid–mediated tumor lysis syndrome
• In oligoanuric patients, prophylactic hemodialysis may be used for short-term reduction of uric
acid levels.
• Amifostine, an organic thiophosphate, ameliorate cisplatin nephrotoxicity in patients with solid
organ or hematologic malignancies.
• N-Acetylcysteine limits acetaminophen-induced renal injury if given within 24 hours of ingestion,
• Dimercaprol, a chelating agent, may prevent heavy metal nephrotoxicity.
• Ethanol inhibits the metabolism of ethylene glycol to oxalic acid and other toxic metabolites, but
it has been largely replaced by fomepizole, an inhibitor of alcohol dehydrogenase that decreases
production of ethylene glycol metabolites and prevents the development of AKI.

• Pharmacologic Therapy for Acute Tubular Necrosis
• Over the past decade, several serum and urinary biomarkers have been investigated for their ability to
identify AKI in its earliest stages and differentiate ATN from volume-responsive AKI.
• Work in this area may facilitate the identification of those pts most likely to respond to t/t that have been
found to be effective in animal models.
• Dopamine
• Low-dose dopamine (1-3 mg/kg/min) had been widely advocated for the management of oliguric AKI.
• In experimental animals and healthy human volunteers, low-dose dopamine increases RBF and, to a lesser
extent, GFR.
• not been demonstrated to prevent or alter the course of ischemic or nephrotoxic ATN in prospective clinical
trials.
• This absence of clinical benefit may relate to differences in the hemodynamic response to low-dose
dopamine in patients with renal disease compared with healthy individuals.
• In contrast to the reduction in renal resistive index associated with low-dose dopamine in critically ill
patients without kidney disease, dopamine infusion is associated with an increase in renal resistance in
patients with AKI.
• Moreover, dopamine, even at low dosages, is potentially toxic in critically ill patients and can induce
tachyarrhythmias, myocardial ischemia, and extravasation necrosis.
• Thus, the routine administration of low-dose dopamine to ameliorate or reverse the course of AKI is not
justified based on the balance of experimental and clinical evidence.

• Fenoldopam
• selective postsynaptic dopamine agonist that acts on dopamine D1
receptors and mediates more potent renal vasodilatation and natriuresis
than dopamine.
• However, fenoldopam is a potent antihypertensive agent and causes
hypotension by decreasing peripheral vascular resistance.
• Randomized trial comparing fenoldopam with standard hydration in pts
undergoing invasive angiographic procedures found no benefit with regard
to decreasing the incidence of CI - AKI.
• In another large randomized controlled trial, fenoldopam administration
failed to reduce mortality or the need for renal replacement therapy in ICU
patients with early ATN.
• Therefore, there is currently no clinical role for fenoldopam in the
prevention or treatment of AKI.

• Natriuretic Peptides
Atrial natriuretic peptide (ANP) is a 28–amino-acid polypeptide synthesized in cardiac atrial muscle.
• ANP augments GFR by triggering afferent arteriolar vasodilatation and constriction of the efferent arteriole.
• In addition, ANP inhibits sodium transport and lowers oxygen requirements in several nephron segments.
• Synthetic analogs of ANP showed promise in the management of ATN in the laboratory setting; however, these
benefits in animal models of AKI have failed to translate into clinical benefit in humans.
• A large multicenter, prospective, randomized, placebo-controlled trial of anaritide, a synthetic analog of ANP, in
patients with ATN failed to show clinically significant improvement in dialysis-free survival or overall mortality, although
there was an improvement in dialysis-free survival in oliguric patients.
• This benefit in oliguric patients was not confirmed in a subsequent prospective study.
• It has been suggested that the absence of benefit may be related both to the relatively late initiation of therapy and to
the effect of ANP on systemic blood pressure. In a subsequent pilot study, low-dose recombinant ANP administration in
high-risk cardiac surgery patients was associated with a reduction in the requirement for postoperative renal
replacement therapy.
• Until these results are confirmed in a larger multicenter trial, the use of ANP in this setting cannot be recommended.
Trials of ANP for the prevention of contrast medium–induced AKI have generated mixed results.
• Urodilatin (Ularitide) is a natriuretic pro-ANP fragment produced within the kidney. In a small randomized trial,
urodilatin did not reduce the need for dialysis in patients with AKI.
• A recent meta-analysis of studies investigating the use of ANP for the treatment of AKI concluded that the paucity of
high-quality studies precluded a determination of the effects of this therapy.

• Loop Diuretics
• High-dose intravenous diuretics to increase urine output are
commonly prescribed for patient with oliguric AKI
this strategy assists in volume management and minimizes the risk of progressive volume overload, there is no
evidence that diuretic therapy alters the natural history of AKI or improves mortality or dialysis-free survival.
In a retrospective analysis, diuretic therapy was associated with an increased risk of death and nonrecovery of
renal function.
These risks, however, were restricted to patients who did not respond to diuretic administration with increased
urine volume; in diuretic-responsive patients, outcomes were similar to those in untreated patients.
In a prospective randomized trial, high-dose intravenous furosemide augmented urine output but did not alter the
outcome of established AKI.
In a post hoc analysis of data from the Fluid and Catheter Treatment Trial, a positive fluid balance after AKI in
patients with acute lung injury was strongly associated with mortality, whereas diuretic therapy was associated
with improved 60-day patient survival.
Given the risks of loop diuretic use in AKI, including irreversible ototoxicity and exacerbation of prerenal AKI,
these agents should be used solely to facilitate the management of extracellular volume overload.

Mannitol
The osmotic diuretic mannitol, which also has renal vasodilatory and
oxygen free radical–scavenging properties, has been investigated as
a preventive treatment for AKI.
No adequate data exist to support the routine administration of
mannitol to oliguric patients.
Moreover, when administered to severely oliguric or anuric patients,
mannitol may trigger expansion of intravascular volume and
pulmonary edema, as well as severe hyponatremia due to an osmotic
shift of water from the intracellular to the intravascular space.

Management of Other Causes of Intrinsic Acute Kidney Injury
Acute Vasculitis and Acute Glomerular Disease
AKI caused by acute glomerulonephritis or vasculitis may respond to
corticosteroids, alkylating agents, and plasmapheresis depending on the primary
cause of the disease.
Plasma exchange is useful in the treatment of sporadic TTP and possibly sporadic
HUS in adults
The role of plasmapheresis in treatment of the drug-induced thrombotic
microangiopathies is less certain, and removal of the offending agent is the most
important initial therapeutic maneuver.
Postdiarrheal HUS in children is usually managed conservatively, because
evidence suggests that early antibiotic therapy may actually promote the
development of HUS.
HT and AKI associated with scleroderma may be exquisitely sensitive to treatment
with ACEi.

Acute Kidney Injury in Multiple Myeloma
Early studies suggested that plasmapheresis may be of benefit in AKI
due to myeloma cast nephropathy.
Clearance of circulating light chains with concomitant chemotherapy to
decrease the rate of production had been postulated to reverse renal
injury in patients with circulating light chains, heavy Bence Jones
proteinuria, and AKI.
A recent relatively large randomized controlled trial compared plasma
exchange and standard chemotherapy with chemotherapy alone.
Although the study did not demonstrate improvement with plasma
exchange with regard to a composite outcome of death, dialysis
dependence, or GFR less than 30 mL/min at 6 months, the study was
inadequately powered to definitively exclude a clinical benefit, and there
was a trend toward improved outcomes with plasmapheresis.

Acute Interstitial Nephritis
majority of cases is due to an allergic response to a medication.
The initial therapeutic step - discontinuation of the offending medication or treatment of the probable inciting factor if not drug
induced.
Data on the efficacy of corticosteroids derive from small observational studies (i.e., before significant renal damage and within 7 to
14 days of discontinuation of the offending medication) that have yielded highly discordant results.
If corticosteroid therapy is being considered and no patient-related contraindications exist, one potential regimen is that used in a
recent study consisting of the IV MPS (250 to 500 mg/day) x 3 to 4 days f/b oral prednisone 1 mg/kg/day tapered over 8 to 12
weeks.
However, there are no data supporting the superiority of this specific approach over others.
MMF - In a study of 8 patients with acute interstitial nephritis, 6 experienced improvement in renal function, whereas 2 showed
stabilization of renal function.
Although this small case series suggests a possible role for mycophenolate mofetil in the treatment of acute interstitial nephritis,
additional data are needed to confirm its efficacy for this indication.

Postrenal Acute Kidney Injury
prompt relief of urinary tract obstruction.
Urethral or bladder neck obstruction may be relieved with transurethral or
suprapubic placement of a bladder catheter.
ureteric obstruction may be relieved in the short term by placement of
percutaneous nephrostomy tubes or by cystoscopic placement of ureteral stents.
Following the initial relief of obstruction most pts experience a physiologic
diuresis, caused by the excretion of volume and solutes retained during the
period of renal obstruction, that resolves after several days;
Approx 5% of pts have a more prolonged diuretic phase because of delayed
recovery of tubule function relative to GFR, which results in a salt-wasting
syndrome, and intravenous fluid replacement may be required to maintain BP
Following initial relief of obstruction, urologic evaluation is required for definitive
evaluation and management of the underlying cause of obstruction.

Nondialytic Supportive Management of Acute Kidney Injury
Metabolic complications such as intravascular volume overload,
hyperkalemia, hyperphosphatemia, and metabolic acidosis are
common in oliguric AKI, and preventive measures should be
implemented beginning at initial diagnosis
Adequate nutrition should be provided to meet caloric
requirements and minimize catabolism.
In addition, all medications that are normally excreted by the
kidney need to be adjusted based on the severity of renal
impairment.

TERTIARY PREVENTION
• After correction of intravascular volume deficits, salt and water intake should be adjusted to match ongoing losses (urinary and
gastrointestinal losses, losses from drainage sites, insensible losses).
• Intravascular volume overload can usually be managed by restriction of salt and water intake and by judicious use of diuretics.
• High doses of loop diuretics (e.g., the equivalent of 200 mg of furosemide administered as an intravenous bolus infusion or 20
mg/hr as a continuous infusion) or combination therapy with both thiazide and loop diuretics may be required.
• If an adequate diuresis cannot be attained, further use of diuretics should be discontinued to minimize the risk of complications
such as ototoxicity.
• Fluid administration should be closely monitored to avoid progressive volume overload.
• There is a strong association between progressive fluid overload and mortality risk in patients with AKI, a causal relationship has
not been definitively established, and volume overload may be a surrogate for hemodynamic instability and capillary leak.
• Conservative fluid management has, however, been demonstrated to result in improved outcomes in critically ill patients with lung
failure.
• Ultrafiltration or dialysis may be required for volume management when conservative measures fail.
• Hyponatremia - fall in effective serum osmolality , usually be corrected by restriction of water intake.
• Conversely, hypernatremia is treated by administration of water, hypotonic saline solutions, or hypotonic dextrose-containing
solutions (the latter are effectively hypotonic because dextrose is rapidly metabolized).

• Mild hyperkalemia (<5.5 mEq/L of potassium) - restriction of dietary potassium intake and elimination of potassium
supplements and potassium-sparing diuretics.
• More severe degrees of hyperkalemia (5.5 to 6.5 mEq/L of potassium) - sodium polystyrene sulfonate, a potassium-
binding resin, to enhance GI potassium losses.
• Although this resin has been widely used for decades, concerns have been raised regarding its safety, particularly
when it is administered in 70% sorbitol, due to reports of bowel necrosis.
• Loop diuretics can also increase potassium excretion in diuretic-responsive patients.
• Emergency measures - severe hyperkalemia and in patients with ECG manifestations of hyperkalemia. Intravenous
insulin (10 to 20 units of regular insulin) promotes potassium entry into cells and lowers extracellular potassium
concentration within 15 to 30 minutes, with an effect that lasts for several hours.
• Concomitant administration of intravenous dextrose (25 to 50 g over 30 to 60 minutes) is required to prevent
hypoglycemia in patients who do not have hyperglycemia.
• Administration of β-adrenergic agonists, such as inhaled albuterol (10 to 20 mg by nebulizer), also promotes rapid
potassium uptake into the intracellular compartment.
• sodium bicarbonate also stimulates potassium uptake into the intracellular compartment, this effect is not
sufficiently rapid for sodium bicarbonate to be clinically useful for the emergent management of hyperkalemia
• In patients with severe hyperkalemia with concomitant electrocardiographic manifestations the intravenous
administration of calcium will antagonize the cardiac and neuromuscular effects of hyperkalemia and is a valuable
emergency temporizing measure.
• Intravenous calcium must be used with caution, however, if there is concomitant severe hyperphosphatemia or
evidence of digitalis toxicity. Emergent dialysis is indicated if hyperkalemia is resistant to these measures.

• metabolic acidosis - does not require t/t unless the serum HCO3 <15 mEq/L or the pH
<7.15 to 7.20.
• either oral or IV bicarbonate administration.
• Initial rates of replacement should be based on estimates of HCO3 deficit and adjusted
thereafter according to serum levels.
• In patients with underlying lactic acidosis, the role of bicarbonate therapy is
controversial, and the primary focus of therapy should be on correction of the underlying
cause.
• Patients treated with intravenous bicarbonate need to be monitored for complications of
therapy, including metabolic alkalosis, hypocalcemia, hypokalemia, hypernatremia, and
volume overload.
• Hyperphosphatemia -restrict dietary phosphate intake and administering GI phosphate
binders (e.g., aluminum hydroxide, calcium salts, sevelamer carbonate, or lanthanum
carbonate).
• Hypocalcemia –t/t in severe cases, rhabdomyolysis or pancreatitis or after
administration of bicarbonate.
• Hyperuricemia is usually mild in acute renal failure (<15 mg/dL) and does not require
specific intervention.
• Severe hyperuricemia secondary to cell lysis may be managed by blocking xanthine
oxidase with allopurinol or by enhancing degradation with recombinant uricase.

• Individualized nutritional management -especially in critically ill patients receiving RRT in whom protein catabolic rates can exceed 1.5
g/kg body weight per day day.
• The objective of nutritional management in AKI is to provide sufficient calories to preserve lean body mass, avoid starvation
ketoacidosis, and promote healing and tissue repair while minimizing production of nitrogenous waste.
• If the duration of renal insufficiency is likely to be short and the patient is not extremely catabolic, then dietary protein should be
restricted to approximately 0.8 g/kg body weight per day.
• Protein intake should not be restricted in patients in whom AKI is likely to be prolonged, who are in a hypercatabolic state, or who are
receiving RRT. Protein intake in these patients should be at least 1.4 to 1.5 g/kg body weight per day
• Total caloric intake should not exceed 35 kcal/kg body weight per day and will typically be in the range of 25 to 30 kcal/kg body weight
per day.
• Vigorous parenteral hyperalimentation has been claimed to improve prognosis in AKI; however, a consistent benefit has yet to be
demonstrated.
• The enteral route of nutrition is preferred, because it avoids the morbidity associated with parenteral nutrition while providing support
to intestinal function.
• Water-soluble vitamins and trace elements should be supplemented in patients receiving RRT.
• Severe anemia is generally managed with blood transfusion.
• The role of ESA in AKI has not been well studied.
• Patients with AKI or other acute illness are relatively resistant to the effect of these agents. In randomized controlled trials involving
critically ill patients, recombinant human erythropoietin decreased transfusion requirement but had no effect on other outcomes.
• Uremic bleeding usually responds to desmopressin, correction of anemia, estrogens, or dialysis.
• Dosages of drugs that are excreted by the kidney must be adjusted for renal impairment and the use of renal replacement therapy.
• Whenever possible pharmacokinetic monitoring should be employed to ensure appropriate drug dosing, especially for agents with
narrow therapeutic windows
• In addition to careful monitoring for toxicity of agents that are normally excreted by the kidney, careful attention must be paid to dosing
of antibiotics and other drugs removed by renal replacement therapy to ensure that therapeutic drug levels are achieved, particularly in
patients receiving renal replacement therapy of augmented intensity.

• Renal Replacement Therapy in Acute Kidney Injury
• does not play a role in the management of AKI given the potential for recovery of kidney function.
• RRT facilitates the management of patients with AKI, allowing correction of acid-base and electrolyte
disturbances, amelioration of volume overload, and removal of uremic waste products.
• Although RRT can forestall or reverse the life-threatening complications of uremia associated with severe
and prolonged AKI, it does not hasten and can potentially delay the recovery of kidney function in patients
with AKI and can be associated with potentially life-threatening complications
• Despite more than 60 years of research and clinical experience, numerous questions regarding the optimal
application of RRT in AKI remain.
• Indications for Renal Replacement Therapy
• volume overload unresponsive to diuretic therapy
• severe metabolic acidosis despite appropriate medical therapy
• hyperkalemia despite appropriate medical therapy
• overt manifestations of uremia, including encephalopathy, pericarditis, or uremic bleeding diathesis
• clinical course marked by progressive azotemia or sustained oliguria.
• Observational series and small clinical trials dating from the 1950s through the 1980s suggested that
initiating RRT when the BUN concentration approached 90 to 100 mg/dL was associated with improved
survival compared with more delayed initiation of therapy.
• More recent observational studies have suggested that initiation of RRT at even less severe degrees of
azotemia may further improve survival.

TABLE 30-14 Indications for Renal Replacement Therapy

• Observational studies have demonstrated a strong association between the degree of volume overload and mortality risk, which suggests that RRT
should be initiated early, before the development of progressive volume overload
• Modalities of Renal Replacement Therapy
• conventional intermittent hemodialysis (IHD), peritoneal dialysis, multiple forms of continuous renal replacement therapy (CRRT), and “hybrid”
therapies such as sustained low-efficiency dialysis (SLED; also known as extended duration dialysis, or EDD).
• Intermittent Hemodialysis
• Short-term IHD has been the mainstay of RRT in AKI for more than five decades.
• Patients typically undergo dialysis treatments for 3 to 5 hours on a thrice-weekly, alternate-day, or daily schedule depending on catabolic demands,
electrolyte disturbances, and volume status.
• As with the timing of initiation of dialysis, the most appropriate dosing strategy for IHD in patients with AKI has been the subject of considerable
investigation.
• The dose of IHD may be adjusted by altering the intensity of each individual dialysis session, usually quantified as the product of urea clearance and
dialysis duration normalized to volume of distribution of urea (Kt/V), or by changing the frequency of the dialysis sessions.
• In an observational study, Paganini and colleagues demonstrated a survival benefit in patients with intermediate severity of illness scores when the
delivered Kt/V was more than 1.0 per treatment compared with a delivered Kt/V of less than 1.0 per treatment.
• However, there have been no prospective clinical trials evaluating the relationship between outcomes and the delivered Kt/V when dialysis is provided
on a constant treatment schedule.
• Schiffl and colleagues reported on a prospective trial of 160 patients with AKI assigned in an alternating fashion to alternate-day or daily IHD.
• The more frequent treatment schedule was associated with a reduction in mortality at 14 days after the last dialysis session from 46% in the
alternate-day dialysis arm to 28% in the daily treatment arm (P = 0.01).
• Duration of renal failure declined from 16 ± 6 days to 9 ± 2 days (P = 0.001). This study has been criticized, however, because the delivered dose of
therapy per session was low in both treatment arms (Kt/V of <0.95), which resulted in a high rate of symptoms in the alternate-day dialysis arm that
may have been associated with overtly inadequate dialysis.

• The impact of frequency of IHD was also evaluated in the Veterans Affairs/National Institutes of Health (VA/NIH) Acute Renal Failure Trial Network study.
• In this study, 1124 critically ill patients were randomly assigned to an intensive or less-intensive strategy for the management of RRT. When patients were in
hemodynamically stable condition, they received IHD, and when they were in hemodynamically unstable condition they were treated with CRRT or SLED, regardless of
treatment arm. Patients randomly assigned to the less-intensive treatment arm received hemodialysis on a thrice-weekly schedule (alternate days except Sunday), whereas
patients randomly assigned to the intensive treatment arm received hemodialysis six times per week (daily except Sunday). Sixty-day all-cause mortality was 53.6% in the
intensive treatment arm compared with 51.5% in the less-intensive arm (P = 0.47).
• The mean delivered Kt/V was 1.3 per treatment after the first IHD session. Although the study was not designed to evaluate outcomes by individual modality of RRT, there
were no differences in mortality between groups when evaluated in terms of percentage of time treated using IHD.
• Based on these results, it does not appear that there is further benefit to routinely increasing the frequency of IHD treatments beyond three times per week as long as the
delivered Kt/V is at least 1.2 per treatment. More frequent treatments may be necessary in patients in whom the target dose per treatment cannot be achieved, in patients in
a hypercatabolic state, in patients with severe hyperkalemia or metabolic acidosis, and in patients with problems related to volume management.
• The selection of IHD dialyzer membrane may also impact clinical outcomes. Exposure to cellulosic membranes results in greater leukocyte and complement activation and
delayed recovery of kidney function in experimental models of AKI compared with exposure to more biocompatible synthetic membranes.
• Clinical trials have yielded conflicting results. Although some studies demonstrated delayed recovery of kidney function with cellulosic membranes, other studies observed no
benefit with synthetic membranes.
• When these data have been aggregated in systematic reviews a benefit of the synthetic membranes is not convincingly demonstrated.
• Although the effect of membrane type on humoral and cellular activation may still influence recovery of kidney function in AKI, the clinical impact of this issue has diminished
as the cost differential between synthetic and cellulosic membranes has narrowed and the use of unsubstituted cellulosic membranes has decreased.
• The major complications associated with acute dialysis are related to the need to access the vasculature, the need for anticoagulation to maintain patency of the
extracorporeal circuit, and intradialytic hypotension primarily resulting from shifts in solute and volume.
• Many of these issues, particularly the need for vascular access and anticoagulation, are similar for IHD, CRRT, and SLED.
• Vascular access is usually obtained through insertion of a double-lumen catheter into a large-caliber central (internal jugular or subclavian) or femoral vein.
• The major complications associated with vascular access include vascular and organ trauma during insertion; bleeding; catheter malfunction and thrombosis; and infection.
• Although femoral catheters are generally associated with a greater risk of infection than catheters in the subclavian or internal jugular veins, an increased risk of infection was
observed only when femoral vein catheters were used in patients with a high body mass index in a randomized controlled trial involving patients undergoing acute RRT.
• The use of tunneled dialysis catheters has been proposed as a means of decreasing the risk of infection in patients undergoing acute dialysis, however, this strategy has not
been rigorously evaluated in prospective clinical trials.

• Anticoagulation is used to help maintain patency of the extracorporeal dialysis circuit in IHD, CRRT, and SLED.
• The most commonly used anticoagulant for dialysis is unfractionated heparin, with multiple protocols used to attain sufficient anticoagulation of the dialysis circuit while
minimizing systemic effects.
• Regional heparinization can be used, in which heparin is infused proximal to the dialyzer and protamine is infused into the return line to reverse its effect,but this method
has generally been supplanted by the use of low-dose heparin protocols.
• Low-molecular-weight heparin may be used as an alternative to unfractionated heparin; however, the benefits of this approach are unclear, because low-molecular-weight
heparin is not associated with enhanced efficacy, drug half-life is variably prolonged in renal failure, and monitoring of the anticoagulant effect is more difficult.
• In patients with heparin-induced thrombocytopenia, heparin administration is contraindicated. Alternative anticoagulant agents include regional citrate, the serine protease
inhibitor nafamostat, the direct thrombin inhibitors hirudin lepirudin and argatroban, and, rarely, the prostanoids epoprostenol and iloprost
• In many patients, particularly those with underlying coagulopathy or thrombocytopenia, and in patients with active hemorrhage or recent postoperative status, acute RRT
can be provided in the absence of anticoagulation.Intradialytic hypotension is common in patients undergoing acute IHD.
• Episodes of hypotension may impair solute clearance and the efficiency of dialysis and can further compromise renal perfusion and delay recovery of kidney function.
• Intradialytic hypotension is typically triggered by intercompartmental fluid shifts or excessive fluid removal, which leads to decreased intravascular volume, and may be
exacerbated by altered vascular responsiveness related to the underlying acute process.
• Hypotension may be particularly problematic in critically ill patients, in whom sepsis, cardiac dysfunction, hypoalbuminemia, malnutrition, or large third-space losses may
accompany the development of AKI.
• Prevention of intradialytic hypotension requires careful assessment of intravascular volume; prescription of realistic ultrafiltration targets; extension of treatment time to
minimize the ultrafiltration rate; increase of the dialysate sodium concentration, and reduction of the dialysate temperature.
• Although there is a tendency to reduce the extracorporeal blood flow in patients prone to hypotension, there is little evidence that this provides any benefit.
• Although reducing blood flow decreased the volume of the extracorporeal circuit in the past when parallel plate and coil dialyzers were used, there is little change in the
volume of the extracorporeal circuit in response to changes in blood flow when hollow fiber dialyzers are employed. Reducing blood flow may, however, result in reduction
of the delivered dose of dialysis.

• Continuous Renal Replacement Therapy
• offered technical simplicity, blood flow was dependent upon the gradient between mean arterial and central venous pressure, and
there was an increased risk of complications from prolonged arterial cannulation
• As a result, the continuous arteriovenous therapies have largely been supplanted by pump-driven, venovenous CRRT.
• The modalities of venovenous CRRT vary primarily in their mechanism of solute removal: in continuous venovenous hemofiltration
(CVVH), solute transport occurs by convection; in continuous venovenous hemodialysis (CVVHD), it occurs by diffusion; and in
continuous venovenous hemodiafiltration (CVVHDF), it occurs by a combination of the two.
• Although, at the same level of urea clearance, convective therapies provide enhanced clearance of higher-molecular-weight solutes
than diffusive therapies, no clear clinical benefit has been demonstrated for CVVH or CVVHDF compared with CVVHD.
• The clearance of urea and other small solutes during CRRT is proportional to the total effluent flow rate (the sum of ultrafiltrate and
dialysate flow rates), and dose of therapy is usually expressed as the effluent volume indexed to body weight.
• Several single-center randomized controlled trials demonstrated an improvement in survival when doses of CVVH were increased from
20 to 25 mL/kg/hr to more than 35 to 45 mL/kg/hr
• however, other small studies did not find a similar benefit.
• Two large multicenter randomized controlled trials also failed to find a survival benefit associated with more intensive CRRT.
• As described earlier, in the VA/NIH Acute Renal Failure Trial Network study, 1124 patients were randomly assigned to two intensities of
RRT.
• In both treatment arms, patients received IHD when in hemodynamically stable condition and CVVHDF or SLED when in
hemodynamically unstable condition.
• CVVHDF was provided at an effluent flow rate of 20 mL/kg/hr in the less-intensive treatment arm and at 35 mL/kg/hr in the more-
intensive arm. Sixty-day all-cause mortality was 51.5% in the less-intensive arm and 53.6% in the more-intensive arm (P = 0.47).
• In the Randomized Evaluation of Normal versus Augmented Level (RENAL) Replacement Therapy Study, 1508 patients were randomly
assigned to CVVHDF at either 25 mL/kg/hr or 40 mL/kg/hr.
• Ninety-day all-cause mortality was 44.7% in both treatment arms (P = 0.99).
• Based on these two studies, there does not appear to be a need to establish a routine target dose of CRRT of more than 20 to 25
mL/kg/hr, although a slightly higher dose may have to be prescribed to achieve the target delivered dose to compensate for
interruptions in treatment.

• Given the greater hemodynamic tolerance of CRRT compared with IHD, particularly in patients with underlying hemodynamic instability, it has been
postulated that CRRT should be associated with improved clinical outcomes.
• In a multicenter randomized controlled trial of 166 patients with AKI, Mehta and colleagues observed ICU and hospital mortality rates of 59.5% and
65.5%, respectively, in patients randomly assigned to undergo CRRT compared with 41.5% and 47.6%, respectively, in patients randomly assigned to
receive IHD (P < 0.02).
• As a result of an imbalance in randomization, patients in the CRRT arm had greater severity of illness as measured by Acute Physiology and Chronic
Health Evaluation III (APACHE III) score and a higher rate of liver failure. After adjusting for the imbalanced randomization in a post hoc analysis, the
investigators found no difference in mortality attributable to modality of RRT.
• In a single-center randomized trial involving 80 patients, Augustine and colleagues reported more effective fluid removal and greater hemodynamic
stability with CVVHD than with IHD but observed no difference in survival.
• Similarly, in another single-center randomized controlled trial in Switzerland, Uehlinger and colleagues observed no difference in survival in 70
patients randomly assigned to CVVHDF and in 55 patients assigned to IHD.
• In the Hemodiafe study, a multicenter randomized controlled trial conducted in 21 ICUs in France, Vinsonneau and colleagues reported 60-day
survival rates of 31.5% in 184 patients randomly assigned to receive IHD compared with 32.6% in 175 patients randomly assigned to undergo CVVHDF
(P = 0.98).
• Similarly, Lins and colleagues observed hospital morality rates of 62.5% in 144 patients randomly assigned to receive IHD and 58.1% in 172 patients
randomly assigned undergo to CRRT (P = 0.43).
• Multiple meta-analyses have concluded that there is no association between survival and use of either of these modalities of RRT.
• Although several studies have suggested that CRRT is associated with higher rates of recovery of kidney function than IHD in surviving patients, all of
these studies are notable for having higher morality rates in the CRRT group.
• When data are analyzed across studies in which there were no differences in mortality, rates of recovery of kidney function do not appear to be
impacted by modality of RRT.
• Hybrid Therapies
• The hybrid modalities of RRT represent therapies in which conventional hemodialysis equipment is modified to provide extended-duration dialysis
using lower blood flow rates and dialysate flow rates.
• A variety of terms have been used to describe these therapies, including sustained low-efficiency dialysis (SLED), extended daily dialysis (EDD), and
sustained low-efficiency daily diafiltration (SLEDD-f).
• Because these therapies extend the duration of the dialysis treatment while providing slower ultrafiltration and solute clearance, they are associated
with enhanced hemodynamic tolerability compared with IHD. The degree of metabolic control attained with these treatments is comparable to that
observed with CRRT, however, there has been an absence of studies evaluating clinical outcomes.

• Peritoneal Dialysis
• Access for short-term PD can be obtained either by percutaneous placement of an uncuffed
temporary peritoneal catheter or through surgical placement of a tunneled cuffed catheter.
• advantage of avoiding the need for vascular access or anticoagulation.
• Solute clearance and control of metabolic parameters may be inferior to that achieved with
other modalities of RRT.
• Although systemic hypotension is less of an issue than with other modalities of RRT,
ultrafiltration cannot be as tightly controlled.
• Other limitations include the relative contraindication in patients with acute abdominal
processes or recent abdominal surgery, the risk of visceral organ injury during catheter
placement, the risk of peritoneal dialysis–associated peritonitis, and an increased tendency
toward hyperglycemia, which is associated with adverse outcomes in acute illness, due to
the high glucose concentrations in peritoneal dialysate.
• In a study of 70 patients with infection-associated AKI in Vietnam, 58 of whom had severe
Plasmodium falciparum malaria, peritoneal dialysis was associated with less adequate
metabolic control and higher mortality than continuous hemofiltration.
• In contrast, in a study of 120 patients in Brazil who were randomly assigned to undergo
high-volume peritoneal dialysis or daily hemodialysis, indices of metabolic control, recovery
of kidney function, and survival were similar for both modalities of therapy.

Glomerular Injury Markers
• Serum Glomerular Filtration Markers
• Serum creatinine and BUN
• GFR can be determined using exogenous and endogenous markers of
filtration.
• exogenous markers sucrose iothalamate or iohexol provides reliable
results and represents the gold standard
• however, the process is time consuming and expensive, and can be
performed only in specialized settings.
• Once the GFR level falls below 60 mL/min/1.73 m2, renal functional
impairment can be estimated adequately by serum creatinine using
various equations to calculate the eGFR. These equations are less
accurate at higher GFRs.

• generation of creatinine from muscle is reduced in sepsis-induced AKI, and serum
creatinine concentrations may not increase proportionally to GFR decline.
• A window of time exists in which kidney injury goes undetected until serum
creatinine concentrations rise (8 to 48 hours)
• Novel serum and urine biomarkers with potential as early indicators of AKI
include
• tissue inhibitor of metalloproteinase 2 (TIMP-2)
• insulin-like growth factor–binding protein 7 (IGFBP7)
• Hepcidin
• kidney injury molecule 1 (KIM-1)
• neutrophil gelatinase–associated lipocalin (NGAL)
• cystatin C
• interleukin-18 (IL-8)

• The combination of urinary levels or IGFBP7 and TIMP-outperforms all other biomarkers in the early detection of AKI in critically ill patients.
• Both proteins are expressed in tubular cells and have autocrine and paracrine effects that lead to G1 cell cycle arrest for short periods. In AKI, preventing or delaying tubular cell division
may be a protective response to injury.
• The risk for stage 2 or 3 AKI correlated well with logarithmic values of [IGFBP7]*[TIMP-2] measured from a urine sample obtained within 12 hours of the diagnosis of AKI, and their
combined urinary levels correlated to clinician-adjudicated AKI better than KDIGO criteria.
• Assessing kidney function with a loop diuretic challenge (furosemide stress test) improves prediction of kidney outcomes compared with biomarker measurement.
• In patients with early AKI in the ICU, urinary responses to intravenous furosemide predicted the need for dialysis better than biomarker measurement alone.
• Failure to produce more than 200 ml of urine within 2 hours of intravenous furosemide dosed at 1 to 1.5 mg/kg strongly predicted both the need for dialysis and progression to AKI
stage 3
• KIM-1, a cell membrane glycoprotein upregulated in injured proximal tubular cells, can act as a nonmyeloid phosphatidylserine receptor that transforms epithelial cells into
semiprofessional phagocytes.
• The ectodomain of this membrane-associated molecule is shed into the urine of injured but not healthy kidneys.
• KIM-1 messenger ribonucleic acid (mRNA) levels may rise more than any other gene after kidney injury, and urinary levels are increased specifically with AKI resulting from ischemia or
toxin exposure.
• NGAL, a protein produced by neutrophils, binds and traffics free iron
• It also mediates the tubular response to epidermal growth factor and is thereby involved in the progression of kidney disease.
• Urinary NGAL levels are increased in the setting of tubular stress or injury, but not in prerenal disease
• A large number of studies correlated urinary NGAL levels to early detection of AKI.
• IL-18 is an inflammatory cytokine found in macrophages, monocytes, and proximal tubule cells. Urinary levels are upregulated in renal ischemic injury in multiple clinical settings.
Biomarkers have the potential for detecting AKI early, identifying minor kidney injuries that do not raise serum creatinine concentrations, monitoring therapeutic benefits of novel
treatment interventions, and specifying the cause of AKI.
• However, AKI frequently occurs unobserved in the community or is present at the time of recognition. Approximately 50% of patients admitted from the emergency department with
septic shock have AKI on arrival to the ICU
• Even with early recognition of AKI, health care providers have not been able to alter its trajectory. The composite outcome of maximum change in serum creatinine level, need for
dialysis, or death at 7 days did not change when primary providers were notified of AKI by an electronic alert system.
• Nevertheless, biomarkers have potential to further understanding of AKI and remain an exciting tool on the horizon of clinical use for diagnosing, identifying a cause of, and predicting
outcomes of AKI.

Prophylactic hydration to protect renal function from intravascular iodinated contrast material in patients at high risk of contrast-induced
nephropathy (AMACING): a prospective, randomised, phase 3, controlled, open-label, non-inferiority trial
• Summary
• Background
• Intravenous saline is recommended in clinical practice guidelines as the cornerstone for preventing contrast-induced nephropathy in patients with
compromised renal function. However, clinical-effectiveness and cost-effectiveness of this prophylactic hydration treatment in protecting renal
function has not been adequately studied in the population targeted by the guidelines, against a group receiving no prophylaxis. This was the aim of
the AMACING trial.
• Methods
• AMACING is a prospective, randomised, phase 3, parallel-group, open-label, non-inferiority trial of patients at risk of contrast-induced nephropathy
according to current guidelines. High-risk patients (with an estimated glomerular filtration rate [eGFR] of 30–59 mL per min/1·73 m2) aged 18 years
and older, undergoing an elective procedure requiring iodinated contrast material administration at Maastricht University Medical Centre, the
Netherlands, were randomly assigned (1:1) to receive intravenous 0·9% NaCl or no prophylaxis. We excluded patients with eGFR lower than 30 mL per
min/1·73 m2, previous dialysis, or no referral for intravenous hydration. Randomisation was stratified by predefined risk factors. The primary outcome
was incidence of contrast-induced nephropathy, defined as an increase in serum creatinine from baseline of more than 25% or 44 μmol/L within 2–6
days of contrast exposure, and cost-effectiveness of no prophylaxis compared with intravenous hydration in the prevention of contrast-induced
nephropathy. We measured serum creatinine immediately before, 2–6 days, and 26–35 days after contrast-material exposure. Laboratory personnel
were masked to treatment allocation. Adverse events and use of resources were systematically recorded. The non-inferiority margin was set at 2·1%.
Both intention-to-treat and per-protocol analyses were done. This trial is registered with ClinicalTrials.gov, number NCT02106234.
• Findings
• Between June 17, 2014, and July 17, 2016, 660 consecutive patients were randomly assigned to receive no prophylaxis (n=332) or intravenous
hydration (n=328). 2–6 day serum creatinine was available for 307 (92%) of 332 patients in the no prophylaxis group and 296 (90%) of 328 patients in
the intravenous hydration group. Contrast-induced nephropathy was recorded in eight (2·6%) of 307 non-hydrated patients and in eight (2·7%) of 296
hydrated patients. The absolute difference (no hydration vs hydration) was −0·10% (one-sided 95% CI −2·25 to 2·06; one-tailed p=0·4710). No
hydration was cost-saving relative to hydration. No haemodialysis or related deaths occurred within 35 days. 18 (5·5%) of 328 patients had
complications associated with intravenous hydration.
• Interpretation
• We found no prophylaxis to be non-inferior and cost-saving in preventing contrast-induced nephropathy compared with intravenous hydration
according to current clinical practice guidelines.

[Meta-analysis on Efficacy of Salvianolate in Prevention of Contrast-Induced Nephropathy]
• A total of 9 RCTs with 2 186 participants were included.
• RESULTS:: of Meta-analysis showed that the incidence of contrast-induced nephropathy of trial group was
significantly higher than that of control group( RR = 0. 46,95% CI[0. 35,0. 59],P<0. 001). Subgroup analysis
showed that the incidences of CIN in patients with acute coronary syndrome( ACS) undergoing PCI,in
patients with the average age≥65 years,in patients who received mean contrast volume ≥200 m L,in patients
with serum creatinine( Scr) ≥ 80 μmol,or in patients who received intraoperative administration of
salvianolate or PCI were higher than those in control group,with statistically significant differences( P<0. 05).
The experimental group was superior to the control group in improving the indexes of renal function after
operation,and the difference was statistically significant( P<0. 05). No study reported the incidence of
adverse reactions( ADRs). The funnel plots of the incidence of CIN showed potential publication bias. The
results of Egger's linear regression showed that there was certain publication bias. Sensitivity analysis,funnel
plot,and " trim and fill" showed that the results of this study were stable and reliable.
• Salvianolate combined with routine hydration showed definite clinical efficacy in the prevention of contrast-
induced nephropathy.
• However,exact conclusion should be further verified by additional high-quality,multi-centre,and large-scale
RCT studies.
• Xi YT, Yuan LY, Xu ST, Liu XY, Wu W. Zhongguo Zhong Yao Za Zhi. 2019;44(12):2616‐2626 doi:10.19540/j.cnki.cjcmm.20190220.002

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