POST CARDIAC

SURGERY AKI
DR MEHDI BAKHSHI
MSN
PhD
The Glomerulus (Renal Corpuscle)

► The
glomerulus
consists of
five
distinct
components:
▪ capillary
endothelium
▪ glomerular basement
membrane
▪ visceral epithelium
▪ parietal epithelium
( Bowman's
capsule),
▪ mesangium
Glomerular ultrafiltration is governed by
the balance of Starling forces

GFR=Kuf [(Pgc -Pbs )-(Πgc-

Πbs )]
Anatomic relationshipsof the
nephron and the renal
vasculature
 Renal Autoregulation

► Autoregulation
enables the kidney
to maintain solute
and water
regulation
independently of
wide fluctuations of
arterial blood
pressure

(Based on the original work of Shipley and Study. From Pitts RF: Physiology of the Kidney and Body Fluids.
Chicago, Year Book Medical Publishers, 1974.)
 Renal Autoregulation

► Two major mechanisms for renal

autoregulation.
▪ As mean arterial pressure decreases, renal vascular
resistance decreases and renal blood flow (RBF) is
maintained.
▪ Tubuloglomerular feedback via the juxtaglomerular
apparatus also plays a role

Gong R, Dworkin LD, Brenner BM, et al: The renal circulations and glomerular ultrafiltration. In: Brenner BM,
ed. Brenner & Rector's The Kidney, 8th ed. Philadelphia: In; 2008:91-129.
 Autoregulation is impaired
by
► calcium channel blockade
► chronic hypertension
► diabetic kidney
► acute renal failure
► cardiopulmonary bypass (CPB)
► severe sepsis
How do we diagnose & stage
AKI?
 The grim reality of real world
AKI
In 222 non-ICU AKI patients requiring RRT…

29% of patients died within 30 days

37.6% died within 90 days
51.4% died within one year
34.9% of survivors RRT dependent at 1 year
55% of survivors off RRT by 90d had eGFR < 60
 Scoring Perioperative AKI
Risk
• Age > 56 years Risk factors Hazard ratio
• Male gender 0-2 1
3 3.1
• Active CHF
4 8.5
• Ascites
5 15.4
• Hypertension 6 46.2
• Mild to moderate CKD
• Diabetes treated with OHA or insulin
• Emergency surgery
• Intra-peritoneal surgery
Incidence - emergency surgery
 Incidence – elective surgery
Study Population AKI definition AKI incidence

Thakar 1
Retrospective
504 patients – gastric bypass
> 50% rise in creatinine or
need for HD 8.5%
Prospective, observational major Creatinine clearance < 50
Kheterpal 2 non-cardiac surgery 15,102 patients
creatinine clearance > 80 ml/min
ml/min within 7 days of
surgery
0.8%
Retrospective, 1,166 patients
Abelha 3 baseline creatinine < 140 major non-
cardiac surgery
AKIN stage 1 7.5%

Kheterpal 4 Retrospective US national dataset

75,952 general surgery patients
creatinine rise of > 167
mol/L from baseline or
1%
need for HD (6+ risk factors: 9%)

Retrospective database cohort

Molnar 5
Major elective surgery including cardiac Database coding as AKI 1.9%
in 213,347 over 65’s
 Renal biomarker candidates

Neutrophil gelatinase-associated lipocalin (NGAL)

• Kidney injury molecule 1 (KIM-1)

• Cystatin C
• Interleukin 18 (IL-18)
• And others…
 NGAL - what is
it?
• 25kDa protein up-regulated in renal injury
• Present in urine and plasma in AKI
• Level rises as early as 2 hours after cell injury
• Falls with successful therapy (animal models)

Predicts AKI
Predicts poor outcomes (RRT/death)
Allows monitoring of therapy
 Biomarker time-course
  Therapeutic window 

Creatinine

Cystatin C

KIM - 1

NGAL
0 3-6 24 48 Time (hours)
AKI Triggers &
Perpetuators
AKI hurts other organ systems
 Surgical procedures
⚫ Highest risk of post operative AKI

⚫ Cardiac surgery
⚫ AAA repair
⚫ Surgery to correct obstructive jaundice
 Incidence After bypass surgery
⚫ Incidence of AKI ranges from 1-30% in patients with
cardiac surgery ( most recent being 18%)
⚫ Typical CABG 2.5%
⚫ Valvular surgery 2.8%
⚫ Valvular surgery with CABG 4.6%
⚫ Requiring ECMO 80%

⚫ Incidence of AKI requiring dialysis is around

⚫ Typical CABG 1%
⚫ Valvular surgery 1.7%
⚫ Valvular surgery with CABG 3.3%
 Mortality
⚫ 15-30% if there is AKI

⚫ As high as 60% if on dialysis

⚫ Higher risk of infections for
those who develop AKI
and started on dialysis

⚫ Even small rises in serum

creatinine were noted to have 3
fold to 18 fold higher mortality.
 Duration of acute kidney
injury impacts long-term
survival after cardiac
surgery.
⚫ 1 to 2 days
⚫ 3 to 6 days
⚫ ≥7 days
⚫ The duration of AKI after cardiac surgery is directly
proportional to long-term mortality.
 Implication
s
⚫ AKI associated with prolonged ICU stay
⚫ Higher risk of chronic kidney disease
⚫ For those that require dialysis in CTICU, 64%
require HD permanently.
Risk
Factors
 Pre-operative Risk
Factors
⚫ Patient related risk factors
⚫ Nephrotoxins( NSAIDS, ACEI, ARBS, Diuretics, Contrast)
⚫ Inflammatory environment
 Patient related factors
(usually known prior to surgery)
⚫ Chronic Kidney Disease (CKD)
⚫ LVEF
⚫ COPD
⚫ DM
⚫ Older Age
⚫ Women
⚫ Emergent surgery
 Proteinuria??
⚫ Higher levels of proteinuria pre cardiac surgery
identify patients at increased risk for AKI during their
hospital stay.

⚫ Mild and heavy proteinuria each associated with an

increased odds of cardiac surgery associated AKI ,
independent of CKD stage

⚫ Heavy proteinuria also associated with increased odds of

postoperative RRT
 Pre-operative Risk
Factors
⚫ Patient related risk factors
⚫ Nephrotoxins( NSAIDS, ACEI, ARBS, Diuretics, Contrast)
⚫ Inflammatory environment
 Nephrotoxins
⚫ Nephrotoxins ( NSAIDS, ACEI/ARB)
⚫ Contrast
⚫ IV fluids Choices( Normal Saline, Lactate Ringers, Hetastarch)
 ACEI/ARB prior to
surgery?
Systematic review has been performed of 421 articles
concerning use of ACEI/ARB in CT surgery
3 randomized studies, other observational

Low quality evidence supporting holding ACEI/ARB before

surgery

Functional AKI likely but not Structural AKI

Individualize therapy.
 Fluid
s
⚫ Colloid versus Crystalloid battle
⚫ NEJM 2012: randomized controlled trial in sepsis patients
showed that patients with severe sepsis assigned to fluid
resuscitation with HES 130/0.42 had an increased risk of death
at day 90 and were more likely to require renal-replacement
therapy, as compared with those receiving Ringer's acetate.
⚫ In CCU and CTICU, no data to support either way.
⚫ Renal injury is evident with HES more than Ringer’s lactate or
Normal Saline (In the 90-day period, 87 patients (22%)
assigned to HES 130/0.42 were treated with renal-
replacement therapy versus 65 patients (16%) assigned to
Ringer's acetate (relative risk, 1.35; 95% CI, 1.01 to 1.80;
P=0.04)
 Which Crystalloid?
Balanced Solutions vs Saline based
⚫ Normal Saline
⚫ Lactate Ringers( balanced solutions)
 Pre-operative Risk
Factors
⚫ Patient related risk factors
⚫ Nephrotoxins( NSAIDS, ACEI, ARBS, Diuretics, Contrast)
⚫ Inflammatory environment
 Intra-operative Risk
Factors
⚫ Regional Hypoxia
⚫ Atherosclerotic Emboli
⚫ Inflammation( free radicals, cytokines)
⚫ Hemodynamic State
⚫ Mechanical Blood Trauma( centrifugal vs. roller pumps)
⚫ The Cardiopulmonary Bypass
⚫ Hematocrit
⚫ Peri-operative PRBCs transfusions
 Intra operative events
⚫ Systemic Perfusion Pressures
⚫ Animal data supports renal blood flow(RBF) dependence on
renal perfusion pressures(PP) in CPB
⚫ Small clinical studies have shown that increasing MAP and
adding pressors increased renal PP during CPB.
⚫ No head to head higher vs. lower PP has been done for renal
outcomes .
 Surgical
risks
⚫ Cross clamp time ( blood flow to renal vessels)
⚫ Traditional On-pump CABG versus Off -pump CAB surgery(
most controversial topic)
⚫ Non randomized studies showed AKI was less frequent in Off
Pump CABG
⚫ With prior CKD, Off pump CABG might be a better option
⚫ Decrease in inflammatory markers
⚫ No hemolysis
⚫ Hemo-dilution related injury( decrease viscosity)
 Off Pump vs. On
Pump
No difference in new renal injury requiring dialysis

Less risk of mild-moderate AKI, not requiring dialysis in the off-pump

group
Use of off-pump compared to on-pump CABG reduced risk of post
operative AKI by 17%( 95% CI, 5-28%)
There is no change in kidney function 1 year out with off pump CABG
compared to on pump
The absolute risk reduction of acute kidney injury with off-pump vs on-
pump CABG surgery was greater in those with CKD compared with
those without CKD.
In a subgroup analysis, preoperative CKD did not alter overall 1year
kidney function results.
 Hematocrit
⚫ Priming leads to hemodilution
⚫ Relationship noted with lowest hemoglobin during CPB and
AKI

⚫ Is there an optimum hemoglobin that balances risk of

hemodilution( and less release of free hemoglobin) with
risks of inadequate oxygen delivery with CPB?
8.5g/dl??
 Pre and intra-operative PRBCs transfusion
⚫ Anemia and number of PRBCs transfusion are independent risk factors for
development of AKI post CABG
⚫ Catalytic iron can produce oxidative stress
⚫ Surrogate for hypotension and a “sick patient”
⚫ Age of PRBCs maybe the culprit?

⚫ 16% increase risk of mortality post CABG

⚫ Risk of sepsis and pneumonia
⚫ Risk of increased length of intubation
 Post operative Risk factors
⚫ Nephrotoxins
⚫ Sepsis
⚫ Volume depletion
⚫ Hemodynamic instability
⚫ Proteinuria
⚫ Vaso-active agent choices
 Vasopressor selection
⚫ Effect on renal blood flow( vasopressin agonist or a pure
alpha agonists)

⚫ Norepinephrine vs Phenylephrine in septic shock ( more

urine output in norepinephrine arm)

⚫ Vasopressin vs Norepinephrine ( 2 trials)

⚫ It is reasonable to use either norepinephrine or vasopressin for

hemodynamic support in patients with high risk for AKI post
CABG
Summary of Risk
Factors
 Cardiopulmonary Bypass
Management and Organ Protection
► TheCPB circuit is designed to perform four
major functions:
▪ Oxygenation and carbon dioxide elimination
▪ Circulation of blood
▪ Systemic cooling and rewarming
▪ Diversion of blood from the heart to provide a
bloodless surgical field
 End-organ effectsof
Cardiopulmonary bypass
► Modern cardiac surgery continues to be
challenged by the risk for organ dysfunction
and the morbidity and mortality that
accompany it
 Injurious Common Pathways
Associated With Cardiac
Surgery.
► CPB initiates a whole-body inflammatory
response with the release of various
injurious inflammatory mediators.
► Preexisting patient comorbidities
► Embolization
► Hypoperfusion
 Renal protection during
cardiac surgery
► Impact of acute kidney injury
▪ In a study from the Duke University database
▪ 2672 patients undergoing elective CABG with
CPB
▪ AKI requiring RRT occurred in only 0.7% of
patents but was associated with 28% mortality,
compared with 1% in patients without AKI
 Renal protection during
cardiac surgery
► Impact of acute kidney injury
▪ Prospective cohort study on 4118 patients who
underwent cardiac and thoracic aortic surgery in
Austria
▪ Increase of serum creatinine of more than 0.5
mg/dL at 48 hours after surgery was associated
with a mortality of 32.5%, compared with 2.1%
in patients who had a slight decrease
Perioperative renal risk factors
► Preoperative risk factors
▪ Female gender
▪ Advanced age
▪ Diabetes mellitus
▪ Ventricular dysfunction
▪ left main coronary artery disease
▪ Chronic obstructive pulmonary disease
▪ Preexisting sepsis
▪ Liver disease
▪ Preexisting renal insufficiency
▪ Diastolic hypertension
▪ Genetic predisposition
 Perioperative renal risk factors
► Intraoperative risk factors and pathogenesis
of AKI
▪ Pre CPB
▪ During CPB
▪ Post CPB
Pre-CPB factors contributing to
AKI
► Low MAP below limits of auto-regulation
▪ ASCVD
▪ CKD
▪ Chronic hypertension
▪ Recent MI
▪ Severe valvular disease
▪ Reduced LVF
Pre-CPB factors contributing to
AKI
► Drugs impacting auto-regulation
▪ ACE-inhibitors
▪ ARBs
▪ Radio contrast agents
► Low CO in the pre-CPB period
▪ Cardiogenic shock
▪ Inotropic support
▪ IABP
▪ Hypotensive episodes
 CPB factors contributing to
AKI
► Risk of perioperative AKI appears to be increased
▪ prolonged duration of CPB and aortic cross-
clamping time
▪ complex procedures, such as combined CABG
and valve surgery
▪ hemodilution or anemia on CPB to a hematocrit
of less than 22%
 CPB factors contributing to AKI
► Risk of perioperative AKI appears to be increased
▪ Nonpulsatile flow
▪ contact activation on CPB
► vasoconstrictor hormones (epinephrine, angiotensin)
► inflammatory cytokines (endotoxin, IL-1b, IL-6, IL-8
and TNF-α)
► Activates factor XII to XIIa (intrinsic pathway)
► Activates kallikrein system
► Activates fibrinolytic system
► Activates complement system
▪ Free iron released from heme leads to organic and
inorganic oxygen radical reactions, lipid
peroxidation and formation of hydroxyl radicals
▪ Atheromatous embolism <40 μm
 Aprotinin
► Administration of high doses of the serine
protease inhibitor aprotinin dramatically
decreased blood loss after CPB
► When plasma concentrations of greater
than 150 (KIU) per mL are achieved,
kallikrein, plasmin, and CPB-induced
fibrinolysis are effectively inhibited.
► Platelet activation and thromboxane release
is prevented.
 Aprotinin
► Numerous reports of an association between
aprotinin and elevation in postoperative serum
creatinine
► Effects on kinin pathways that alter intrarenal
hemodynamics
► Canadian BART Trial was halted by the Data
Safety Monitoring Board because of increased 30-
day mortality in patients receiving aprotinin.
► As a consequence, the Food and Drug
Administration (FDA) suspended marketing of
aprotinin in November 2007
 Post CPB factors contributing to
AKI
► Hemodynamic instability
▪ Low CO state
▪ Prolonged or repeated periods of hypotension
▪ Hypovolemia
► Nephrotoxic agents
► Sepsis/SIRS
► Mechanical circulatory support
Interventions to provide perioperative
renal protection
► Hydration
► Tight glycemic control
► Dopaminergic agents
► Furosemide
► Mannitol
► N-acetylcysteine
► Calcium channel blockers
► Natriuretic peptides
 Interventions To Provide Perioperative
Renal Protection
► Hydration
▪ It appears intuitive that judicious volume expansion to
maintain cardiac output and renal blood flow would
provide perioperative renal protection.
▪ The relationship between the volume of perioperative
fluid administered and AKI has not been subjected
to randomized, controlled trials.
▪ No difference in markers of AKI whether 6%
hydroxyethyl starch or 5% albumin was administered to
50 patients undergoing cardiac surgery
 Interventions To Provide Perioperative
Renal Protection
► Tight glycemic control
▪ 1548 patients studied underwent cardiac surgery
▪ demonstrated that tight postoperative glycemic control (bl
sugar 80 to 110 mg/dL) decreased mortality by 50%
▪ 41% reduction in ARF requiring RRT
 Interventions To Provide
Perioperative Renal
Protection
► Tight glycemic control
▪ Intra-operative hyperglycemia (blood sugar
>200 mg/d) is associated with a sevenfold
increase in the incidence of severe
postoperative morbidity
▪ A retrospective analysis of more than 3500
diabetic cardiac surgical patients observed a
decrease in postoperative mortality from 5% to
2.5% when a subcutaneous insulin regimen was
changed to continuous insulin infusion
 Dopaminergic agents
► Dopamine
► Fenoldopam
 Dopaminergic agents
► Dopamine is a naturally occurring catecholamine
that has dose-dependent effects on dopaminergic,
beta1- and alpha-adrenergic receptors
► Its renoprotective role has been questioned and
three systematic reviews found no evidence of
benefit
► Dopamine may still be a useful inotropic agent that
can improve renal perfusion and urine output by
increasing cardiac contractility
 Dopaminergic agents
► Fenoldopam
▪ Fenoldopam, a synthetic phenol derivative of
dopamine, is a selective DA1 receptor agonist
that increases renal blood flow in a
dosedependent manner
▪ In several small prospective studies of cardiac
surgery patients, low-dose fenoldopam infusion
(0.3–0.5 mcg/kg/min) has been associated
with preservation of GFR and serum creatinine
 Dopaminergic agents
► Fenoldopam
▪ However, other studies in high-risk cardiac
surgery or vascular surgery with aortic cross-
clamping were unable to find a benefit of
fenoldopam on renal function compared with
dopamine or sodium nitroprusside
 Dopaminergic agents
► Fenoldopam
▪ Nonetheless, a recent meta-analysis of 16
studies on 1290 patients concluded that
fenoldopam consistently and significantly
reduced the risk for AKI, need for RRT, ICU
length of stay and in-hospital mortality
 Furosemide

► Furosemide infusion (0.5 mg/kg/min), and

saline placebo were administered
throughout cardiac surgery and
postoperatively in 126 patients
► Furosemide infusion was associated with an
increase in serum creatinine twice as high
as the other groups
 Mannitol
► Mannitol is an osmotic diuretic and free
radical scavenger
► Can prevent tubular obstruction by sloughed
proximal tubular cells and attenuate
experimental ischemia-reperfusion injury
► Mannitol is routinely added to the priming
solution on CPB but there is little evidence
to support a renoprotective effect
 N-acetylcysteine
► Antioxidant that directly scavenges reactive
oxygen species, and there is considerable
evidence to support its use to prevent
contrast-induced nephropathy
► Similar benefit has not been found in
cardiac surgery
 Calcium channel blockers
► Calcium channel blockers promote renal
vasodilatation and increase renal blood flow
and glomerular filtration rate
► They inhibit angiotensin action in the
glomerulus and decrease
circulating interleukin-2 receptors
► In one study, administration of intravenous
diltiazem was associated with worsened
function
 Natriuretic peptides
► The natriuretic peptides are formed by the
endogenous synthesis of chains of 22 to 32
amino acids of similar structure.
► They specifically oppose the
sympathoadrenal, renin-angiotensin,
aldosterone, and arginine vasopressin
systems via multiple mechanisms
 Natriuretic peptides
► Anaritide
▪ Anaritide is the human recombinant formulation
of ANP
▪ After a 24-hour infusion of anaritide, patients
with oliguric ATN (urine output <400 mL/day)
had significantly improved dialysis- free survival,
but outcome was actually worse in patients with
non-oliguric renal failure (NORF)
 Natriuretic peptides
► Nesiritide
▪ A meta-analysis of the use of nesiritide infusion in
patients with advanced decompensated heart failure
suggested that it is associated with worsening serum
creatinine
▪ In patients with left ventricular dysfunction (ejection
fraction <40%) undergoing coronary revascularization or
mitral valve surgery (n= 279)
► a perioperative nesiritide infusion increased urine output
► attenuated the postoperative increase in serum creatinine
► associated with a 6-month mortality benefit
 Conclusion
► AKI is a common and serious complication
after cardiac surgery
► Perioperative organ hypoperfusion is the
most important factor leading to AKI
► Co-morbid conditions in cardiac patients
place patients at increased risk
► No magic bullet for prevention of AKI with
the exception of