las dos caras de la cretinina sérica · bagshaw et al: nephrol dial transplant 24: 2739-2744, 2009...

©2013 MFMER | 3322132-1©2013 MFMER | 3322132-1

Las dos caras de la cretinina séricaThe two sides of serum creatinine

Kianoush B. Kashani, MD, MSc, FASN, FCCP

ASOCIACION COSTARRICENSE DE MEDICINA INTERNA

San José, Costa Rica

June 2017

©2013 MFMER | 3322132-2

Disclosure

• I have no COI regarding this activity

©2013 MFMER | 3322132-3

Outlines

• AKI definitions

• Bad side

• Limitations

• Clinical impact

• Good side

• Sarcopenia index

• Outcome prediction

©2013 MFMER | 3322132-4

RIFLE Criteria

Bellomo et al; Critical Care 2004, 8:R204-R212

GFR criteria Urine output criteria

Risk

Injury

Failure

Loss

ESRD

High sensitivity

High specificity

Persistent ARF = complete loss of renal function >4 weeks

End-stage renal disease

Increased creatinine x3 or GFR decrease >75%

or creatinine 4 mg/100 mL (acute rise of 0.5 mg/100 mL dL)

Increased creatinine x2 or GFR decrease >50%

Increased creatinine x1.5 or GFR decrease >25%

UO <0.5 mL kg-1

h-1 x6 hr

UO <0.5 mL kg-1

h-1 x12 hr

UO <0.3 mL kg-1

h-1 x24 hr or anuriax12 hr

©2013 MFMER | 3322132-5

AKIN Definition for AKI

Stage I

Stage II

Stage III

• Inc Scr 0.3 mg/dL or >150-200% from baseline

• Inc Scr >200-300% from baseline

• Inc Scr >300%

• Scr >4 with acute min rise of 0.5 mg/dL

• Need for RRT

• <0.3 mL/kg/hr for 24 hr

• Anuria for 12 hr

<0.5 mL/kg/hr for >12 hr


Mehta et al; Critical Care 2007, 11:R31

©2013 MFMER | 3322132-6

KDIGO Definition for AKI

Kidney International Supplements (2012) 2, 19–36

Stage I

Stage II

Stage III

• ↑ Scr 0.3 mg/dL

OR

• 1.5–1.9 times baseline

• 2.0–2.9 times baseline

• 3.0 times baseline OR

• Scr > 4 mg/dL OR

• Initiation of RRT OR

• <18 yrs ↓ in eGFR to <35 ml/min per 1.73 m2

• <0.3 mL/kg/hr for 24 hr

• Anuria for 12 hr



©2013 MFMER | 3322132-10

Siew at al: Clin J Am Soc Nephrol 7:712–719, 2012

ICC (95% CI) per Days Before Admission

Estimated Method 7-365 days 7-730 days 1-730 days

Most recent

outpatient

0.84

(0.80-0.88)a

0.83

(0.78-0.86)b

0.74

(0.68-0.79)c

Mean outpatient0.91

(0.88-0.92)a

0.81

(0.77-0.84)b

0.71

(0.65-0.76)c

Nadir outpatient0.83

(0.76-0.87)a

0.64

(0.46-0.75)b

0.68

(0.31-0.83)c

Most recent

inpatient or

outpatient

0.88

(0.85-0.91)d

0.88

(0.85-0.91)d

0.80

(0.76-0.84)e

©2013 MFMER | 3322132-11

Intraclass correlations based on CKD Status

ICC (95% CI)

Estimation Method

eGFR <60 mL/min per 1.73 m2

(n=259)

eGFR 60 mL/min per 1.73 m2

(n=120)

Most recent outpatient0.80

(0.74-0.85)0.58

(0.42-0.70)

Mean outpatient0.87

(0.83-0.90)0.75

(0.65-0.83)

Nadir outpatient0.76

(0.66-0.83)0.65

(0.48-0.76)

Most recent inpatient or outpatient

0.85(0.81-0.88)

0.65(0.53-0.75)

Siew at al: Clin J Am Soc Nephrol 7: 712–719, 2012

©2013 MFMER | 3322132-12

Fluid Balance Impact on SCr(n=7696)

5,7

16,4

30,3

37,6

5,4

15,9

28,3

40,1

0

20

40

60

80

100

0 Stage 1 Stage 2 Stage 3

No fluid correction

Fluid correction

60-d

ay m

ort

alit

y (

%)

No AKI before and after adjustment

AKI before but No AKI after adjustment

No AKI before but AKI after

adjustment

AKI before andafter adjustment

Odds ratio for 60-day mortality0 1 2 3 4 5

1.19

2.00

3.38

Thongprayoon et al: J Nephrol 29(2): 221-227

©2013 MFMER | 3322132-14

Observed vs. estimated (MDRD GFR=75)Scr67% had pre-admission creatinine; (n=1314; 46% CKD)

Bagshaw et al: Nephrol Dial Transplant 24: 2739-2744, 2009

Diffe

rence

Average

-25

-10

0

10

25

.1 5 10 15 20

Average

-25

-10

0

10

25

.1 5 10 15 20

r = 0.49 r = 0.39

ICU admission At study enrollment

©2013 MFMER | 3322132-15

Observed vs. estimated (MDRD GFR=75)ScrCKD excluded

Bagshaw et al: Nephrol Dial Transplant 24: 2739-2744, 2009

Diffe

rence

Average

ICU admission At study enrollment

-25

-10

0

10

25

.1 5 10 15 20

Average

-25

-10

0

10

25

.1 5 10 15 20

r = 0.84r = 0.9

©2013 MFMER | 3322132-16

Scr at Admission vs. MDRD75When Baseline SCr unavailable (n=3504; 45% of whole cohort)

5,1

11,7

22,725,1

6,0

18,0

32,129,9

0

10

20

30

40

50

0 Stage 1 Stage 2 Stage 3

Thongprayoon et al: BMC Nephrology 17:6, 2016

MDRD75

60

-Day m

ort

alit

y (

%)

Admission SCr

©2013 MFMER | 3322132-18

Discrimination vs. CalibrationA

KI risk

Time

AKI

No AKIEarly AKI(Stage 1, risk)

Pre-disease state

Pre-diseaseAKI signal

ADQI XV

©2013 MFMER | 3322132-19

Therapeutic Window

Himmelfarb et al: Clin J Am Soc Nephrol 3:962, 2008

High Risk

Volume ResponsiveAKI

Volume UnresponsiveAKI

Therapeutic Window

Kidney FunctionMortality

BiomarkersSensitive Traditional

Hypervolemia

Euvolemia

Hypovolemia

©2013 MFMER | 3322132-20

Time Course of Development of Increasing Serum Creatinine in Hospitalized HF Patients

0

20

40

60

80

100

0 3 6 9 12 15

%

Days

Gottlieb et al: J Card Fail 8:136, 2002

0.5

0.4

0.3

0.2

0.1

©2016 MFMER | 3572290-21

MELD Equation

• MELD =(0.957 log(creatinine) + 0.378 x log(bilirubin) +1.12 log(INR) +0.643) x 10

• http://www.mayoclinic.org/gi-rst/mayomodel6.html

©2016 MFMER | 3572290-22

MELD Equation

• MELD =(0.957 log(creatinine) + 0.378 x log(bilirubin) +1.12 log(INR) +0.643) x 10

• http://www.mayoclinic.org/gi-rst/mayomodel6.html

©2016 MFMER | 3572290-23

Sample MELD Scores

INR Bilirubin Creatinine MELD

1 1 1 6

2 1 1 19

1 3 1 11

1 1 3 17

3 3 3 33

©2016 MFMER | 3572290-24

Transplant Benefit by MELD Score

1

10

100

1000

10000Waitlist

Transplant

Mort

alit

y r

ate

per

10

00 p

atie

nts

6-11 12-14 15-17 17-20 21-23 24-26 27-29 30-39 40+

MELD

HR=3.64

P<0.001

HR=2.35

P<0.001

HR=1.21

P=0.41

HR=0.62

P<0.01

HR=0.38

P<0.001

HR=0.22

P<0.001

HR=0.18

P<0.001

HR=0.07

P<0.001

HR=0.04

P<0.001

©2016 MFMER | 3572290-25

GFR and Waitlist Survival

Lim: J Hep 52:523, 2010

660 LTx candidates at Mayo (90-99)

Years

Surv

ival

0.0 0.5 1.0 1.5 2.0

0.0

0.2

0.4

0.6

0.8

1.0

60 (n=482)

30-59 (n=134)

<30 (n=44)

P<0.001

©2016 MFMER | 3572290-26

Waitlisted ♀ 20% Less Likely Than ♂ to Undergo Liver Transplantation

0

20

40

60

80

100

0 2 4 6 8 10

Allen AM. Tall, Male, and What Else? Disparities in Liver Transplantation Based On Gender and Height

Transplantation 2014 (98) S-725

Years since activation

Male

Female

Pro

ba

bili

ty (

%)

Transplant

Death

UNOS 2002-2011

©2016 MFMER | 3572290-27

Factors That Disadvantage Women

Shorter

Small body

Less muscle mass

Lower creatinine =

lower MELD

More hepatocellular

carcinoma =

MELD exception points

Women Men

MELD

exceptionsHeight

?

©2016 MFMER | 3572290-28

Women Receive Fewer Creatinine-Meld Points Than Men With Similar Renal Function

0

2

4

6

8

Measured GFR (mL/min/BSA)

Male

Female

Cre

atin

ine M

ELD

poin

ts

1.74

2.37

1.15

1.34

1.54

80 70 60 50 40 30 20

©2016 MFMER | 3572290-31

Sensitivity

Specificity

Availability

Serumcreatinine

Urine outputBL serum creatinine

Contextual data, comorbidities, medications, organ failure, biomarkers

ADQI 15th

©2016 MFMER | 3572290-32

Koyner et al: Clin J Am Soc Nephrol 11, 2016

1

1

1

1

2

2

2

4

4

5

5

6

7

8

9

9

10

11

14

14

16

18

23

24

26

49

52

66

100

0 20 40 60 80 100

AST

DBP

Hb

AVPU

SVP

Platelets

Bilirubin

Prior ICU

Sodium

Age

Potassium

Glucose

BUN/Cr

HR

Creatinine

Variable importance

©2013 MFMER | 3322132-33

Complementary to injury biomarkers

10th ADQI Consensus Conference. Adapted from Murray PT et al. Kidney International 2013

“Subclinical AKI”

No functional changes or damage

Damage without loss of function

Loss of function without damage

Damage with loss of function

BiomarkerNegative

BiomarkerPositive

CreatinineNegative

CreatininePositive

“Prerenal AKI”

“True AKI”

©2013 MFMER | 3322132-36

• Observational cohort study in Dutch 154,308 ICU patients

• Hospital mortality, increasing for BMI <18.5 kg/m2

• BMI 30-39.9 kg/m2

had the lowest risk of death with an adjusted OR of 0.86 (0.83-0.90)

Relative risk

Absolute mortality rate (%)20

10

5

2.5

1.0

0.5

0.25

30

25

20

15

5040302010

Body-mass index (kg/m2)

©2013 MFMER | 3322132-37

• A retrospective cohort study of 11,291 adult patients

• Mayo Clinic Hospital –Rochester ICUs

• Between 2003 and 2006

Creatinine concentration in mg/dL

Mort

alit

y (

%)

50

0.4 0.4-0.6 0.6-0.8 0.8-1.0 1.0-1.4 1.4-1.6 1.91.6-1.9

25 350 665 2558 4545 941 1443764n=

40

30

20

10

0

3

0

1

2

LO

S in IC

U (

Days)

ICU LOS

Mortality

©2013 MFMER | 3322132-38

• Multicenter, binational, retrospective cohort study

• ANZICS

• 1.5 million admission

• 175 ICUs

• 2000 – 2013

©2013 MFMER | 3322132-39

Patients’ Flow Chart

All records for the period 2000-2013 in ANZICS

=1,250,449 Admissions

1,045,718 Admissions

Exclusions

62585 – Readmissions (during the same hospital stay)

5904 – Missing vital status at hospital discharge

361 – Post kidney transplant

34902 – Receiving chronic renal replacement therapy

54979 – Missing peak plasma CR concentration in first 24 hrs

©2013 MFMER | 3322132-41

Low Admission Scr

• Observational cohort study in 73,994 patients

• Mayo Clinic Hospital –Rochester ICUs

• Between 2011 and 2013

2,8

1,00,8

1,01,3

2,4

3,6

0

1

2

3

4

0.4 0.5-0.6 0.7-0.8 0.9-1.0 1.1-1.2 1.3-1.4 1.5

Serum creatinine at hospital admission (mg/dl)

In-h

ospital m

ort

alit

y (

%)

Cheungpasitporn W, Thongprayoon C, Kashani K. The American Journal of Medicine (2016)

©2013 MFMER | 3322132-42

Low Admission Scr ↑ Hospital Mortality (Independent of BMI)

• Adjustments:

• Age, sex, race, BMI, principal diagnosis, CCI, CAD, CHF, PVD, CVA, DM, COPD, cirrhosis, hemi/paraplegia

Cheungpasitporn W, Thongprayoon C, Kashani K. The American Journal of Medicine (2016)

0

1

2

3

4

≤0.4 0.5-0.6 0.7-0.8 0.9-1.0 1.1-1.2 1.3-1.4 ≥1.5

OR

of

in-h

os

pit

al m

ort

ali

ty

Serum Creatinine at Hospital Admission (mg/dL)

©2013 MFMER | 3322132-43

Body-mass index (kg/m2)

0.6

0.7

0.8

0.9

1.0

1.2

1.4

1.6

1.8

2.0

All-

cause m

ort

alit

y h

azard

ratio

Unadjusted

Case-mix

Case-mix & MICS

Reference

Recommended

range

Over-

weight

Obesity

Mild

Mo

de

rate

Se

ve

re

Ve

ry s

eve

re

• 121,762 patients receiving HD 3 times/wk

• Years 2001- 2006

• Outpatient dialysis facilities (DaVita)

Kalantar-Zadeh, K., et al. (2010). Mayo Clinic Proceedings 85(11): 991-1001

©2013 MFMER | 3322132-44

Unadjusted

Case-mix

Case-mix & MICS

Serum creatinine (mg/dL)

All-

cause m

ort

alit

y h

azard

ratio

2.0

2.4

1.6

1.2

1.0

ReferenceSmall muscle mass

Moderate muscle mass

Large muscle mass0.8

0.6

0.4

<4 4 to <6 6 to <8 8 to <10 10 to <12 12 to <14 14


©2013 MFMER | 3322132-45

Reference Gained muscle mass

Lost muscle mass

No change in

muscle mass

Unadjusted

Case-mix

Case-mix & MICS

Serum creatinine (mg/dL)

All-

cause m

ort

alit

y h

azard

ratio

0.8

<-2 -2 to -1 -1 to +1 +1 to +2 >+2

0.9

1.0

1.2

1.4

1.6


©2013 MFMER | 3322132-49

ICU cohort

• N=226 high risk ICU patients with no AKI

• 105 had an abdominal CT scan within 4 weeks from ICU admission

• Median (IQR) 0.5 (0.1 to 2.4) days

©2013 MFMER | 3322132-50

SI correlation with CT Muscle mass measurement

SI = (serum creatinine/serum cystatin C) x 100

Muscle surface area (MSA; n=105) and SI

Sarcopenia index = 65 Sarcopenia index = 440,0

0,2

0,4

0,6

0,8

1,0

1,2

1,4

50 100 150 200 250

Muscle surface area (cm2)

Sarc

openia

index

r = 0.62

P<0.0001

Kashani et al: Crit Care Med, 2016

©2013 MFMER | 3322132-51

ICU mortality Hospital

mortality

90-d mortality

Nutritional indicator AUC (p) AUC (p) AUC (p)

Sarcopenia index 0.63 (0.1) 0.67 (0.0007) 0.7 (<0.0001)

Body mass index 0.63 (0.2) 0.56 (0.3) 0.58 (0.1)

Para-spinal muscle

surface area (cm2)

0.72 (0.2) 0.79 (0.01) 0.79 (0.002)

Admission serum creatinine 0.5 (0.9) 0.59 (0.09) 0.53 (0.5)

NUTrition Risk In the

Critically ill score (NUTRIC)

0.67 (0.06) 0.67 (0.006) 0.72 (<0.001)


©2013 MFMER | 3322132-52

Clinical model without SI Clinical models with SI

ICU mortality

Variable OR 95% CI P OR 95% CI P

APACHE III 0.96 0.94-0.98 0.0008 0.96 0.947-0.98 0.0009

SI 1.02 0.99-1.06 NS

C-stat (95% CI 0.72 (0.65-0.77) 0.74 (0.68-0.8)


Hospital mortality

Variable OR 95% CI P OR 95% CI P

APACHE III 0.97 0.95-0.99 0.0003 0.97 0.95-0.99 0.0003

SI 1.04 1.02-1.07 0.001

C-stat (95% CI 0.70 (0.63-0.76) 0.75 (0.69-0.81)

90-d mortality

OR 95% CI P OR 95% CI P

Age 0.97 0.94-0.99 0.01 0.97 0.94-0.99 0.046

APACHE III 0.97 0.95-0.99 0.0002 0.97 0.95-0.98 0.0001

SI 1.05 1.03-1.08 <0.0001

C-stat (95% CI 0.77 (0.7-0.82) 0.8 (0.74-0.85)

©2013 MFMER | 3322132-53

Sarcopenia Index

Odds ratio Lower 95% Upper 95% P

Age 0.97 0.94 0.99 0.05

Body mass index 1.02 0.99 1.1 0.2

Sarcopenia index 1.05 1.03 1.1 0.001

APACHE III 0.97 0.95 0.98 0.0004


• Critically ill patients

• Mayo Clinic Hospital, Rochester ICU

• October 2008- December 2010

Prediction of 90 day mortality

0,0

0,2

0,4

0,6

0,8

1,0

0,0 0,2 0,4 0,6 0,8 1,0

1-specificity false positive

Tu

re p

ositiv

e s

en

sitiv

ity

ROC-AUC = 0.81

©2013 MFMER | 3322132-54

SI correlation with length of Mechanical ventilation

• Patients on mechanical ventilator N= 131

• Duration of mechanical ventilation predicted by sarcopenia index

• –1 d for each 10 unit of sarcopenia index

• 95% CI –1.4 to –0.2; p = 0.006

Sarcopenia index = 65 Sarcopenia index = 44


MV length 2 days shorter

©2013 MFMER | 3322132-55

50

100

150

200

250

300

60 70 80 90 100 110 120 130 140

Pre-Lung Transplant Cohort (n=40)

Sarcopenia index

L2L3 a

rea

r2 = 0.2

p = .03

©2013 MFMER | 3322132-56

Summary

• Creatinine as a marker of kidney function has several limitations

• Knowing these limitations allows its appropriate use

• Heart failure

• Liver disease

• Low admission serum creatinine is as impactful in clinical outcomes as high admission Scr

• Sarcopenia Index could be utilized at bedside to estimate muscle mass/nutritional status

las dos caras de la cretinina sérica · bagshaw et al: nephrol dial transplant 24: 2739-2744, 2009...

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