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1 Supplemental Digital Content

At-risk drinking is independently associated with acute kidney injury in critically ill patients

Arnaud Gacouin, MD, Mathieu Lesouhaitier, MD, Aurelien Frérou, MD, Benoit Painvin MD, Florian Reizine, MD, Sonia Rafi, MD, Adel Maamar, MD, Yves Le Tulzo, MD, PhD and Jean Marc Tadié, MD, PhD

Corresponding Author:

Arnaud Gacouin, Service des Maladies Infectieuses et Réanimation Médicale, CHU Rennes, F-35033 Rennes, France.

Email: [email protected]

Telephone: +33-2-99284248, Fax: + 33-2-99284164

Assessment of alcohol consumption and definition of at-risk drinking

The patients and/or their closest relative were interviewed about the patients’ dietary and lifestyle habits. Whenever possible, patients and relatives were interviewed separately. We aimed to systematically determine the onset, duration and daily consumption of alcohol.

Previous medical records were systematically reviewed for the diagnosis of chronic alcohol abuse or prior hospital stay for alcohol withdrawal. The main predictor variable was At-risk drinking, which was defined by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) criteria for the unhealthy use of alcohol in the United States (1,2). At-risk drinking was defined as consuming more than 14 drinks per week or more than four drinks per occasion for healthy men between 18 and 64 years of age and as consuming more than seven drinks per week or more than three drinks per occasion for women and healthy men aged 65 years or older. Non-at-risk drinkers comprised abstainers and moderate drinkers. Moderate

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2 drinking was defined as consuming two or fewer drinks per day for men ≤65 years of age and one or zero drinks per day for women and men aged 65 years or older

AKI staging for severity

Stage 2 or greater AKI was defined according to Kidney Disease Improving Global Outcomes (KDIGO) creatinine criteria (3). In patients with a bladder catheter, stage 2 was defined as an increase in the serum creatinine (SCr) level to 2.0-2.9 times baseline (i.e., a double in serum creatinine) and/or a urine output <0.5 ml/kg/h for more than 12 h; stage 3 was defined as an increase to 3.0 times baseline (i.e., a trebling in serum creatinine) and/or a urine output <0.3 ml/kg/h for more than 24 h or anuria for 12 h. When patients had no bladder catheter, urine output was estimated based on urine volume recorded over a 24 h period.

Baseline creatinine

Baseline SCr for the study was defined as the lowest plasma creatinine measured in the 12 months prior to hospital admission, if available. If it was not available, the lower SCr between the hospital admission and ICU admission was used (4, 5). A true baseline SCr was unknown in many patients included in the study. For patients with an unknown baseline SCr, the baseline SCr was estimated by using the Modification of Diet in Renal Disease (MDRD) formula (6).

Definitions

Known CKD was defined as a GFR < 60 mL/min/1.73 m², which was estimated based on the known baseline SCr (7). For the other patients, we assumed that they had no documented CKD. Patients 65 years or older were classified as having advanced age. Chronic heart disease was considered in patients with previous coronary artery and/or valvular disease with treatment (e.g., diuretic, antiarrhythmic, and antihypertensive medications). Chronic

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3 respiratory disease included obstructive and restrictive diseases, including chronic obstructive pulmonary disease, kyphoscoliosis, and obesity-hypoventilation syndrome. Diabetes mellitus was defined as a history of diabetes requiring chronic therapy with insulin and/or hypoglycemic agents. Solid tumor and hematologic disease were considered when actively treated or diagnosed within the year before admission. Patients considered as cured or in remission were not considered as having exposure. Anemia was defined by a blood hemoglobin concentration lower than 13.7 g/dL for white men, lower than 12.2 g/dL for white women, lower than 12.9 g/dL for black men, and lower than 11.5 g/dL for black women (8).

Volume depletion was considered in patients with a history of hemorrhagic shock, diarrhea, or heatstroke. Patients with suspected or documented infection with a SOFA score ≥ 2 on admission to the ICU were diagnosed as having sepsis, and circulatory shock was considered in patients with a MBP ≤ 65 mmHg after volume expansion and/or after receiving vasopressors (9).

References

1. Saitz R: Clinical practice. Unhealthy alcohol use. N Engl J Med 2005; 352:596–607 2. Fiellin DA, Reid MC, O’Connor PG: Screening for alcohol problems in primary care: a

systematic review. Arch Intern Med 2000; 160:1977–1989

3. Kellum JA, Lameire N, Group KAGW: Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1). Crit Care 2013; 17:204

4. Semler MW, Wanderer JP, Ehrenfeld JM, et al.: Balanced Crystalloids versus Saline in the Intensive Care Unit. The SALT Randomized Trial. Am J Respir Crit Care Med 2017; 195:1362–

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5. Thongprayoon C, Cheungpasitporn W, Kittanamongkolchai W, et al.: Optimum methodology for estimating baseline serum creatinine for the acute kidney injury classification. Nephrol Carlton Vic 2015; 20:881–886

6. Bellomo R, Ronco C, Kellum JA, et al.: Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004;

8:R204-12

7. Levey AS, Eckardt K-U, Tsukamoto Y, et al.: Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO).

Kidney Int 2005; 67:2089–2100

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4 8. Beutler E, Waalen J: The definition of anemia: what is the lower limit of normal of the blood

hemoglobin concentration? Blood 2006; 107:1747–1750

9. Singer M, Deutschman CS, Seymour CW, et al.: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315:801

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5 Table 2S1: Unadjusted and adjusted odds ratios for 4-day KDIGO stage 2-3 acute kidney injury (AKI) in the 832 patients without KDIGO stage 2-3 AKI at admission to the ICU

Variables Unadjusted Odds Ratio

(95% CI)

p Value Adjusted Odds Ratio (95% CI)

p Value

Alcohol consumption

At-risk drinking during the 6 months or more before admission to the ICU

1.33 (0.96-1.84) 0.09 1.44 (1.02-2.02) 0.04

At-risk drinking stopped 6 months before admission to the ICU 0.7 (0.41-1.31) 0.29 Severity

SAPS II score (1-point increment) 1.003 (0.995-1.011) 0.40

SOFA score (1-point increment) 1.019 (0.963-1.055) 0.31

Susceptibility

Age ≥ 65 years 0.86 (0.65-1.13) 0.28

Female gender 1.26 (0.94-1.67) 0.10 1.34 (1.01-1.79) 0.04

Anemia at admission to the ICU 0.98 (0.74-1.28) 0.86

Known baseline glomerular filtration rate < 60 ml/mn per 1.73 m² 1.61 (1.03-2.52) 0.04 1.67 (1.06-2.61) 0.03

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Diabetes mellitus 0.98 (0.63-1.51) 0.92

Cancer or hematologic disease 0.86 (0.59-1.26) 0.45

Cardiovascular or respiratory comorbidity 0.93 (0.71-1.22) 0.59

Volume depletion before ICU admission 1.12 (0.62-2.05) 0.70

Cardiac surgery within 7 days before admission to the ICU 1.70 (0.65-4.43) 0.28 Exposure

Cardiac surgery within 7 days before admission to the ICU 1.70 (0.65-4.43) 0.28

Admission to the ICU with sepsis 1.03 (0.77-1.37) 0.83

Circulatory shock within 7 days before admission to the ICU 1.29 (0.93-1.75) 0.13 Intravenous radiocontrast agents within 7 days before admission

to the ICU

0.89 (0.65-1.22) 0.46

Nephrotoxic drugs within 7 days before admission to the ICU 1.37 (0.85-2.21) 0.20 Other

Transfer to the ICU from a hospital ward 0.72 (0.55-0.95) 0.02 0.72 (0.55-0.95) 0.04

Abbreviations: CI, Confident interval; SAPS, Simplified Acute Physiology Score; SOFA, Sequential Organ Failure Assessment; KDIGO, Kidney Disease Improving Global Outcome.

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* See text for definition of variables

Table 2S2: Unadjusted and adjusted odds ratios for day-4 KDIGO stage 2-3 acute kidney in the 971 study patients without known chronic kidney disease

(95% CI)

p Value

Alcohol consumption

2.0 (1.49-2.69) <0.0001 1.92 (1.41-2.61) <0.0001

SAPS II score (1-point increment) 1.011 (1.004-1.018) 0.002 1.002 (0.933-1.011) 0.63

SOFA score (1-point increment) 1.072 (1.035-1.112) 0.0001 1.016 (0.975-1.060) 0.44

Susceptibility*

Age ≥ 65 years 1.09 (0.84-1.41) 0.54

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Female gender 0.87 (0.67-1.14) 0.32

Diabetes mellitus 1.51 (0.98-2.32) 0.06 1.45 (0.93-2.33) 0.10

Cardiovascular or respiratory comorbidity 0.80 (0.62-1.04) 0.10 0.94 (0.71-1.24) 0.65

Volume depletion before ICU admission 2.08 (1.27-3.41) 0.003 2.11 (1.25-3.56) 0.005

Cardiac surgery within 7 days before admission to the ICU 1.79 (0.63-5.07) 0.27 Exposure*

Admission to the ICU with sepsis 1.34 (1.03-1.75) 0.03 1.16 (0.87-1.54) 0.32

Circulatory shock within 7 days before admission to the ICU 1.82 (1.36-2.43) <0.0001 1.55 (1.11-2.17) 0.01 Intravenous radiocontrast agents within 7 days before admission to

the ICU

0.83 (0.62-1.12) 0.22

Nephrotoxic drugs within 7 days before admission to the ICU 1.67 (1.07-2.62) 0.02 1.65 (1.02-2.67) 0.04 Other

Transfer to the ICU from a hospital ward 0.73 (0.56-0.94) 0.02 0.73 (0.56-0.9) 0.02

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9 Abbreviations: CI, Confident interval; SAPS, Simplified Acute Physiology Score; SOFA, Sequential Organ Failure Assessment; KDIGO,

Kidney Disease Improving Global Outcome.

Table 2S3: Unadjusted and adjusted odds ratios for 4-day KDIGO stage 2-3 acute kidney injury in the 866 study patients present in the ICU on the fourth day from admission

(95% CI)

p Value

Alcohol consumption

2.52 (1.86-3.42) <0.0001 2.60 (1.87-3.61) <0.0001

SAPS II score (1-point increment) 1.021 (1.013-1.018) <0.0001 1.005 (0.999-1.015) 0.38

SOFA score (1-point increment) 1.154 (1.110-1.203) <0.0001 1.079 (1.020-1.243) 0.008

Susceptibility*

Age ≥ 65 years 1.25 (0.96-1.64) 0.10 1.10 (0.81-1.50) 0.54

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Female gender 1.18 (0.90-1.55) 0.29

Known baseline glomerular filtration rate < 60 ml/mn per 1.73 m² 1.22 (1.46-3.73) 0.0002 2.11 (1.40-3.50) 0.0007

Diabetes mellitus 1.59 (1.07-2.37) 0.0.02 1.23 (0.80-1.91) 0.35

Cardiovascular or respiratory comorbidity 0.85 (0.65-1.12) 0.22

Volume depletion before ICU admission 1.95 (1.15-3.29) 0.01 2.24 (1.27-3.96) 0.0006

Cardiac surgery within 7 days before admission to the ICU 1.72 (0.67-4.40) 0.26 Exposure*

Admission to the ICU with sepsis 1.73 (1.31-2.78) <0.0001 1.41 (1.04-1.91) 0.03

Circulatory shock within 7 days before admission to the ICU 2.04 (1.52-2.75) <0.0001 1.48 (1.04-2.12) 0.03 Intravenous radio contrast agents within 7 days before admission

to the ICU

0.88 (0.65-1.20) 0.43

Nephrotoxic drugs within 7 days before admission to the ICU 2.04 (1.31-3.18) 0.002 1.71 (1.05-2.78) 0.03 Other

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Transfer to the ICU from a hospital ward 0.90 (0.67-1.18) 0.44

Abbreviations: CI, Confident interval; SAPS, Simplified Acute Physiology Score; SOFA, Sequential Organ Failure Assessment; KDIGO, Kidney Disease Improving Global Outcome; MV: mechanical ventilation.