Undetectable haptoglobin is associated with major adverse kidney events in critically ill burn patients

We conducted a single-centre cohort study in the burn unit of St. Louis Hospital (Assistance Publique - Hôpitaux de Paris), Paris, France. The study was approved by our local ethics committee (PRONOBURN study, comité de protection des personnes IV, St-Louis Hospital; Institutional Review Board 00003835, protocol 2013/17NICB). All medical records of the patients admitted to our intensive care burn unit between January 2012 and April 2017 were screened. All burn patients meeting the following criteria were included in the study: total body surface area (TBSA) burned > 20%, and/or mechanical ventilation at admission, and/or catecholamine infusion at admission, and a measurement of haptoglobin upon admission.

The primary endpoint of the study was MAKE at day 90. The secondary endpoints were AKI and death within 90 days. MAKE was defined as a composite of the following criteria: death within 90 days, new renal replacement therapy (RRT) during ICU stay, and/or no renal recovery (defined as a ratio of serum creatinine at ICU discharge to serum creatinine at admission > 125%) [17]. AKI was defined and staged according to the Kidney Disease: Improving Global Outcomes criteria [17]. Serum creatinine (Screat) at hospital admission was used to define the baseline Screat.

We collected the following data: age, sex, body mass index, TBSA, full-thickness body surface area burned, mechanism of injury and patient characteristics, Simplified Acute Physiology Score II (SAPS II), Abbreviated Burn Severity Index (ABSI) [18], Unit Burn Standard [19], treatments administered during the first 7 days after admission (hydroxocobalamin, aminoglycosides, vasopressors), and 28- and 90-day mortality. Haptoglobin measurement was performed using a haptoglobin assay (Hitachi modular P analyser; Roche, Paris, France) that is based on the principle of immunological agglutination. Anti-haptoglobin antibodies react with antigen in the sample to form antigen-antibody complexes, which, after agglutination, can be determined turbidimetrically. The reference values of haptoglobin are from 0.3 g/L to 2 g/L; the detection limit is 0.1 g/L; and the linearity limit is 5.2 g/L.

Patients were resuscitated according to the St. Louis Hospital Intensive Care Burn Unit resuscitation protocol with the following haemodynamic targets: mean arterial blood pressure > 65 mmHg, 0.5 ml/kg/h less than urine output < 1 ml/kg/h, 2.5 L/minute/m² less than cardiac index < 3 L/minute/m² and central venous oxygen saturation > 70%. Norepinephrine was administered when required (diastolic arterial blood pressure < 50 mmHg and/or systemic vascular resistance index < 1250 dyn/second/cm⁻⁵/m²). Patients received initial fluid resuscitation using an intravenous bolus of Ringer’s lactate 0.25 ml/kg/%TBSA/h (which corresponds to the 2 ml/kg/%TBSA in the first 8 h of the Parkland formula) with fluid infusion adjusted to reach pre-defined haemodynamic targets. Cardiac function was systematically assessed on admission by echocardiography. Cardiac index was measured by transpulmonary thermodilution using a PiCCO2 monitor (Pulsion Medical Systems AG, Munich, Germany). The PiCCO monitor was calibrated every 2 h during the first 48 h.

Albumin 20% was administered to patients with TBSA > 30% after the sixth hour after thermal injury to reach a serum albumin concentration of 30–35 g/L. When mechanical ventilation was initiated, tidal volume was limited to 6–7 ml/kg to maintain an inspiratory plateau pressure < 30 cmH₂O and a transpulmonary driving pressure < 15 cmH₂O. Early enteral nutrition was initiated within 24 h of admission. Glycaemic control was adjusted to maintain glucose levels between 5 and 9 mmol/L. Surgical treatment included escharotomy or fasciotomy as needed and early coverage of excised burn wounds with autografts and/or allografts within the first 7 days after admission.

Continuous variables are reported as mean and SD or median (25th–75th percentile range) as appropriate. Categorical variables are expressed as count (percent). Categorical variables were compared using the chi-square test or Fisher’s exact test as appropriate. Continuous variables were compared using Student’s t test or the Mann- Whitney U test as appropriate.

Variables associated with MAKE and AKI in univariate analysis were entered in a multivariable logistic regression model with Lasso penalization [20] to identify the factors independently associated with the outcome. Inference was obtained using the post-selection inference method for L ₁-penalized models described by Taylor and Tibshirani [21]. Considering the rule of thumb suggesting at least five to ten events for each predictor variable included in the model [22], only the most clinically relevant were included in the multivariate model: creatinine at admission, SAPS II, ABSI, undetectable haptoglobin, need for catecholamine during the first 7 days, and administration of hydroxocobalamin. Model performance was estimated using the cross-validated (tenfold) AUC. Mortality during the first 90 days was described using the Kaplan-Meier estimate and modelled using a Cox proportional hazards model. Survival curves were compared using the log-rank test. In all comparisons, a p value < 0.05 was considered statistically significant. All analyses were performed using R software version 3.3.3 for Mac (R Foundation for Statistical Computing, Vienna, Austria).

Between January 2012 and April 2017, 1029 patients were admitted (Fig. 1). Of these, 899 did not meet the inclusion criteria. The characteristics of the 130 patients included in the study are summarised in Table 1.

Forty-one patients developed MAKE, including 33 (80.5%) patients who died within 90 days. Twenty-six patients required RRT, and 25 patients had no renal recovery. Seventy-three patients developed AKI during the first 7 days, including 29 (39.7%) patients with stage 1 AKI, 17 (23.3%) with stage 2 and 27 (37%) with stage 3 AKI (Table 2). Only one patient developed AKI after 7 days. Among the 73 patients who developed AKI during the first 7 days, 32 (44%) died during their ICU stay.