A recent review on risk factors, treatment and prevention of acute kidney injury in cardiac surgery unit.

1. Acute Kidney Injury
Associated With Cardiac
Surgery
Kenar D. Jhaveri, MD
2015 Update
Hofstra NSLIJ School of Medicine

2. What’s the connection?

3. CASE
SP is a 57 year old male with DMII, HTN and
hyperlipidemia. He has a routine stress test
and is referred to get a cardiac cath. After
demonstration of triple vessel disease,
patient is offered to get a CABG.
The patient is a nephrologist. All he cares
about is the risk to the kidneys. His pre-op
serum creatinine is 1.6mg/dl. His serum
creatinine prior to cardiac cath was 1.2mg/dl.
He has two questions?
Is this CABG urgent, can we
wait till the crt is back to
1.2mg/dl ?
What is the percent chance
that I will require dialysis
following the CABG?

4. Agenda
 Introduction
 Risk Factors
 Treatment
 Prevention

5. Etiology of AKI among Inpatients
ATN (45%)
Prerenal (21%)
ARF on CKD (13%)
Obstruction (10%)
GN/vasc (4%)
AIN (2%)
Atheroemboli (1%)
Kidney Int: 1996

6. Natural History of AKI
 48% ICU patients require dialysis
 58% inpatient mortality among patients who develop AKI in
the ICU
 36% mortality among all inpatients with AKI
 20% of survivors received dialysis
Crit Care Med 1996
JASN 1998

7. RIFLE Criteria for AKI

8. Surgical procedures
 Highest risk of post operative AKI
 Cardiac surgery
 AAA repair
 Surgery to correct obstructive jaundice

9. The Pre-post and intra-renal kidney
injury concept

10. 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%
Dardhasti A J Thorac Cardiovasc Surg 2014
Mangano et al Ann Intern Med 1998
Gailiunas P et al. J Thorac Card Surg 1980

11. 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.
Chertow G. AJM 1998
Thakar CV KI 2005
Lassnigg A et al JASN 2004

12. 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.
Brown JR. Ann T Surg 2010

13. Implications
 AKI associated with prolonged ICU stay
 Higher risk of chronic kidney disease
 For those that require dialysis in CTICU, 64%
require HD permanently.
Zanardo G et al J Thorac Cardi Surg 1994
Ishani A et al. Arch Intern Med 2011
Leacche M et al. Am J Cardiol 2004

14. Risk Factors
Rosner M et al. CJASN 2006

15. Pre-operative Risk Factors
 Patient related risk factors
 Nephrotoxins( NSAIDS, ACEI, ARBS, Diuretics, Contrast)
 Inflammatory environment

16. Patient related factors
(usually known prior to surgery)
 Chronic Kidney Disease (CKD)
 LVEF
 COPD
 DM
 Older Age
 Women
 Emergent surgery
Anderson T Cardi Surg 1993
Chertow G Circulation 1997

17. 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
Thakar CV JASN 2005
Huang TM, JASN 2011

18. Bottom Line
 Most predictive factor is pre operative serum creatinine.
2-4mg/dl ( risk of dialysis prone AKI is 10-20%)
>4mg/dl ( risk of dialysis prone AKI is 25-28%)
 All of the defined risk factors – somehow lead to decrease
renal perfusion or decreased renal reserve.

19. Pre-operative Risk Factors
 Patient related risk factors
 Nephrotoxins( NSAIDS, ACEI, ARBS, Diuretics, Contrast)
 Inflammatory environment

20. Nephrotoxins
 Nephrotoxins ( NSAIDS, ACEI/ARB)
 Contrast
 IV fluids Choices( Normal Saline, Lactate Ringers, Hetastarch)

21. SP Calls
SP was glad you waited till the creatinine came
back to1.2mg/dl. The CABG is now planned in 3
days. He calls your office cell phone and asks you a
question again?
I am on losartan. Should we
hold it few days prior to
surgery?

22. 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.
Raja SG et al. Interact Cardisvasc Thorac Surg 2008
Coca S et al. NDT 2013

23. Heta-Starch Story
Myburgh JA, NEJM 2012

24. Fluids
 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)
Perner A et al NEJM 2012

25. Which Crystalloid?
Balanced Solutions vs Saline based
 Normal Saline
 Lactate Ringers( balanced solutions)
Yunos NM JAMA 2012

26. Pre-operative Risk Factors
 Patient related risk factors
 Nephrotoxins( NSAIDS, ACEI, ARBS, Diuretics, Contrast)
 Inflammatory environment

27. SP texts
 SP texts you one day prior to surgery. His text reads…
Off PUMP or ON PUMP?

28. 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

29. 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 .
Mackay JH et al Crt Care Med 1995
Urzua J et al. J Cardio Vasc Anes 1992
Kanji et al. J Cardio Thora Surg 2010

30. 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)
Beauford RB et al Heart Surg Forum 2004
Stallwood MI et al. Ann Thorac Surg 2004

31. Off pump versus On pump
 The complications of on-pump CABG, especially stroke and
decrease in higher mental function, spurred the development of
the Off pump technique
 Largest meta-analysis showed: “Eighty-six trials (10,716
participants) were included. Pooled analysis of all trials showed
that off-pump CABG increased all-cause mortality compared with
on-pump CABG (189/5,180 (3.7%) versus 160/5144 (3.1%); RR
1.24, 95% CI 1.01 to 1.53; P =.04). No significant differences in
myocardial infarction, stroke, renal insufficiency, or coronary re-
intervention were observed.
 No circulatory support of CPB, hypotension, vasopressor requirements-
Perhaps the AKI risk stays the same
Puskas JD et al JAMA 2004
Moller CH et al Cochrane Database Sys Rev 2012

32. CORONARY TRIAL
Lamy A, NEJM 2012

33. 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.
Lamy A, CORONARY, NEJM 2012
Garg A, CORONARY AKI update, JAMA 2014

34. 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??
Swaminathan M. Ann Thorac Surg 2003
Karkouti K J Thorac Cardiovasc Surg 2005
Carson JL. NEJM 2011

35. 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
Karkouti K. Br J Anesth 2012
Nuis RJ. Circ Cardiovasc Interv 2012
Khan UA. J Thorac Cardiovasc Surg 2014
Koch CG. NEJM 2008
Yu PJ. J Cardiothor And Vasc Anes 2014

36. Post operative Risk factors
 Nephrotoxins
 Sepsis
 Volume depletion
 Hemodynamic instability
 Proteinuria
 Vaso-active agent choices

37. Proteinuria
Higher levels of proteinuria after cardiac surgery identify
patients at increased risk for AKI during their hospital stay
Molnar AO CJASN 2012

38. 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
Morelli A Shock 2008
Morelli A Crit Care 2008
Russell JA NEJM 2008

39. Rosner M et al. CJASN 2006
Summary of Risk Factors

40.   
Contrast, NSAIDS,
CKD, ACEI/ARB, NPO
CPB, clamp, inflammation
hypotension
Sepsis, reduced LV,
Nephrotoxins

41. Can we predict the risk via a calculator?
• CICSS (Continuing Improvement in Cardiac Surgery Study)
• Cleveland Clinic
• STS Bedside Risk
• MCSPI (Multicenter study of perioperative ischemia)
• AKICS (AKI after Cardiac Surgery)
• NNECDSG (Northern New England Cardiovascular Disease
Study Group)

42. Predictions?
Thakar CV et al
JASN 2005

43. Your response
 Dr. SP, your risk of needing dialysis after CABG is only 1.8%
given your risk factors. I think we can proceed with on-
pump CABG… And let’s hold your losartan now.

45. Post Op Day 1
 SP is hypotensive and you decide to start IV fluids. His
baseline serum creatinine is 1.2mg/dl pre op. His creatinine
post op has been stable and urine output is starting to
diminish… What fluids would you consider starting now?
 A. 0.9% normal saline
 B. Lactate Ringers
 C. Hetastarch (HES)
 D. 25% Salt poor albumin

46. Supportive
 Maintenance of hemodynamic status
 Assessment of etiology for any acute cause for AKI
 Fluids management ( avoid HES)
 Start renal replacement therapy ( CRRT or HD ) for severe
AKI and when indicated

47. Diuretics
 Make patients non oliguric from oliguric/anuric
 Does it help?- increases urine output
 Two randomized trials have been conducted and no
improvement in renal outcomes or mortality benefit.
 Suggest against the use of it as long term therapy and use
should not postpone need for initiation of dialysis
 Short term use of it is preferred for volume management
Cantarovich F et al AJKD 2004
van der Voort PH et al Crit Care Med 2009

48. Anti Inflammatory agents
 N-acetylcysteine (N-AC , mucomyst)
 Steroids
 Statins – harm??
Wang G. J Cardiothorac Vasc Aneth 2011
Morariu AM Chest 2005
Loef BG Br J Anaesth 2004

49. Bove T JAMA 2014

50. Fenoldopam
Bove T JAMA 2014

51. Atrial Natriuretic Peptide(ANP)

52. ANP
 Re combinant ANP(rhANP) used in AKI post cardiac surgery
for heart failure
 Patients who received it had a significant reduction in
incidence of dialysis at day 21 after start of treatment
 ANP was infused at lower rate in the above study compared
to prior studies
Sward K Crit Care Med 2004

53. “Cocktail “
 Mannitol + Furosemide+ Dopamine
 Postoperative oliguric/anuric patients randomly assigned to
above regimen or intermittent doses of loop diuretics
 90% vs. 6.7% requirement of dialysis
 Early restoration of renal function.
Sirivella S et al. Ann Thor Surg 2003

54. Mesenchymal Stem Cells
 Pre clinical studies have shown that mesenchymal stem cells (MSC) both
prevent and facilitate recovery of renal failure.
 Allogenic human MSC was used in a phase 2 trial that was RCT in CABG
patients who developed AKI. ( intra arterial dose of MSC or placebo)
 21 centers in north America, 156 patients randomized
 This phase 2 trial with early AKI following CABG, treatment with MSC did
not improve the time to complete kidney recovery, need for dialysis or
mortality within 30 and 90 days.
Swaminathan M. ASN Oral Abstract, Philadelphia, 2014

55. Dialysis
 Intermittent
hemodialysis(IHD)
 CRRT (CVVHD, CVVHDF,
CVVH)
 Sustained low efficiency
dialysis (SLED)
 Peritoneal Dialysis(PD)

56. Indications
 AEIOU
 Acidosis, refractory metabolic
 Electrolyte disorders, mainly hyperkalemia
 Intoxication ( unusual for CT surgery case)
 Overload( fluid related, totally possible)
 Uremia( very possible)

59. IDEAL STUDY

60. Indications for and timing of initiation of RRT in
the ICU
 Bagshaw et al showed that early initiation of
dialysis by creatinine criteria was associated
with an increased risk of death.
 Shiao et al showed that early initiation of
dialysis by BUN criteria was associated with
decreased risk of death.
Bagshaw M et al J Crt Care 2009
Shiao CC et al Crit Care 2009

61. Cardiac surgery patients?
 CVVHDF was performed on Group 1 when creatinine level exceeded
5 mg/dL, or potassium level exceeded 5.5 mEq/L irrespective of the
urine output. CVVHDF was performed on Group 2 when urine output
was less than 100 mL within consecutive 8 hours, with no response to
50 mg furosemide with the supplementary criterion that urine sodium
concentration should be >40 mEq/L before the administration of
furosemide.
 The mean intensive care unit (ICU) stay for Group 1 was 12 ± 3.44
days and 7.85 ± 1.26 days for Group 2 (p = 0.0001). ICU mortality
rate was 48.1% for Group 1 and 17.6% for Group 2 (p = 0.014). The
overall hospital mortality rate was 55.5% for Group 1 and 23.5% for
Group 2 (p = 0.016).
 Conclusion: Recognition of ARF and early beginning of the
CVVHDF are extremely important. The sooner the ARF after
surgery is recognized and CVVHDF is performed, the higher the
likelihood of the reduction of the hospital mortality.
Demirkiliç et al. J Card Surg 2004

62. Early and aggressive CRRT is
associated with better predicted
survival.
Early starters had increased survival
benefit.
Hospital mortality 43% in late starters and 22% in
early starters
Elahi et al. Eur J of cardio thora surg 2009

63. International survey of Nephrologists
 Analysis of survey of nephrologists found that severity of illness in
ICU patients with AKI influences the timing of dialysis initiation.
So, survey respondents were more likely to initiate early dialysis in
case scenarios portraying higher severity of illness.
Also, the study found that decision to initiate dialysis in ICU
patients with AKI is still largely driven by imminent indications of
dialysis (e.g. hyperkalemia, or hypoxemia) rather than a proactive
decision based on degree of severity of kidney injury.
 Until we have prospective clinical trials, timing of dialysis will
remain a subjective decision, one that is dependent on several
factors including severity of illness.
Thakar CV , Crit Care 2012

64. But here comes a meta analysis in CT
ICU patients
 Early initiation of RRT for patients with AKI after cardiac
surgery revealed a lower 28 days mortality and shorter ICU
stay.
 Based on 11 studies with various qualities and very high
heterogeneity of results.
Liu Y. J Cardiothorac Vasc Anesth 2014

65. Liu Y. J Cardiothorac Vasc Anesth 2014

66. Modality of choice
 CRRT versus Intermittent hemodialysis: A paucity of evidence
exists that have examined these issues.
However, current data suggest that survival and recovery of
renal function are similar with both CRRT and IHD.

67. In the hemodynamic unstable patient
Modality CRRT IHD
Mortality Poor Poor
Recovery or renal function Poor Poor
*Hemodynamic stability Better Poor
*Volume management Better Poor
*Inflammatory markers
removal
Better Poor
*Cerebral perfusion Better Poor
*= data is from non randomized trials

68. Prevention strategies

69. SP’s recovery
 SP responded well to LR and his renal function
never got worse. He did not require dialysis and
he is now transferred to step down. You are
making rounds and he asks you?
Is there anything you can
give your patients to prevent
renal failure following
CABG? Mucomyst,
dopamine, lasix, mannitol?

70. Overall prevention
 Identify HIGH risk patients early to prevent AKI
 Optimize renal perfusion and avoid nephrotoxins (NSAIDS
and contrast if possible)
 Delay time between contrast and surgery
 Pharmacologic interventions???- all are failures
 Cardiac surgery induced ATN is too complex
 Too late usually given
 Most studied had been low risk patients.
Del Duca D. Ann Thorac Surg 2007

71. Increase Renal Blood Flow
 Dopamine
 Fenoldopam
 Theophylline
Woo EB et al. Eur J Cardiothor Surg 2002
Stone GW et al. JAMA 2003
Kramer BK et al. NDT 2002

72. Induce natriuresis
 ANP ( Anaritide)
 Diuretics
 Mannitol
Allgren RL et al NEJM 1997
Lewis J et al. AJKD 2000
Lombardi R et al. Ren Fail 2003
Rigden SP et al. Clin Nephrol 1984

73. ANP
 Systematic review ( 19 studies) and another meta-analysis of
11 studies showed no significant benefit. However, low
dosage ANP was associated with significant reduction of
need for dialysis.
 Two randomized trials ( small) each of around 500 patients
to ANP at 0.02ug/kg per min or placebo found that the
incidence of AKI was much lower in ANP arm. No mortality
difference. Post operative complications less in ANP arm. No
patients in ANP arm required dialysis. The second study was
130 patients or so with low EF ( <35%)- similar findings.
Nigwekar U et al. J Cardiothor Vasc Anes 2009
Sezai A et al. JACC 2009
Sezai A et al. JACC 2010

74. Block inflammation
 Steroids
 Pentoxifylline
 N-AC ( mucomyst)
Cagli K et al. Perfusion 2005
Loef BG et al. Br J Anaesth 2004
Kshirsagar AV et al. JASN 2004

75. Steroids in Cardiac Surgery Trial (SiRS)
 Randomized 7000 patients undergoing CABG to steroids vs
placebo
 Methylprednisolone does not reduce death or major
morbidity at 30 days for high-risk patients undergoing
cardiac surgery with the use of cardiopulmonary bypass.
 Methylprednisolone increases the risk of early post-
operative myocardial infarction
 Methylprednisolone did not have any impact on
development of new renal failure in 30 days.
Whitlock R. Am H Journal 2014
http://solaci.org/es/pdfs/acc2014/6_richard_whitlock_slides.pdf

76. No BENEFIT
No BENEFIT
Lack of good
randomization

77. Remote Ischemic
Preconditioning
 Brief ischemia and reperfusion in distant tissues protects a
critical target organ or tissue from lethal ischemia and
reperfusion through neuronal or humoral pathway.
 Results in cardiovascular surgery related use in AKI remain
controversial.
 Meta-analysis showed no evidence in using such strategy in
renal protection. There was no significant difference for
incidence of AKI, renal biomarkers or hemodialysis
requirements and mortality.
Hausenloy DJ Lancet 2007
Li L J of Cardiothorac Surg 2013

78. Sodium Bicarbonate
Did not reduce in the incidence of AKI
Prolonged the duration of ventilation and ICU stay
Increased the risk of alkalemia

79. Dialysis before surgery?
 Durmaz et al looked at prophylactic dialysis for 42 CKD
patients to improve renal outcomes- showed decreased
mortality and ICU stay.
 One arm was prophylactic dialysis pre CABG , other arm was
dialysis as needed post CABG as the control.
 Mortality was higher in control arm of 30.4% compared to
5% in prophylactic arm.
 These results need to be repeated in randomized control
trials before considering it in practice.
Durmaz et al. Ann Thorac Surg 2003

80. Can we pick up renal disease
early?

81. SP had a successful recovery and was
discharged.

82. What works thus far?
 Minimize contrast exposure and time to surgery
 Avoid HES
 Minimize PRBCs transfusions
 Avoiding diuretics unless medical indication
 Reducing the use of alpha adrenergic agents by adding
vasopressin
 Use of ANP?

83. Summary
 AKI occurs in 18% of patients with CABG, with 2-6% needing
dialysis.
 Mortality is high when you have AKI
 There are NO active treatments that work for cardiac
surgery associated AKI
 Prevention strategies are needed.
 Dialysis may be needed in patients with severe AKI
 Early CRRT may improve renal outcomes and mortality