Predicting the requirement for renal replacement therapy in intensive care patients with sepsis

Sepsis is one of the most frequent causes of acute kidney injury (AKI) in critically ill patients, with initial organ impairment often followed by dysfunction in other systems. Renal dysfunction may therefore represent one facet in the evolution towards multiple organ dysfunction syndrome (MODS) or, alternatively, may be indicative of system-wide endothelial damage caused by hyperinflammation and a positive fluid balance. Whilst numerous biomarkers have been investigated to predict renal replacement therapy (RRT) requirement, including NGAL, TIMP-2 and IGFBP-7, mid-regional proadrenomedullin (MR-proADM) may also be of interest due to its involvement in capillary leakage, endothelial dysfunction and the initial stages of multiple organ failure development. ...

Sepsis is one of the most frequent causes of acute kidney injury (AKI) in critically ill patients, with initial organ impairment often followed by dysfunction in other systems [1]. Renal dysfunction may therefore represent one facet in the evolution towards multiple organ dysfunction syndrome (MODS) or, alternatively, may be indicative of system-wide endothelial damage caused by hyperinflammation and a positive fluid balance. Whilst numerous biomarkers have been investigated to predict renal replacement therapy (RRT) requirement, including NGAL, TIMP-2 and IGFBP-7 [2], mid-regional proadrenomedullin (MR-proADM) may also be of interest due to its involvement in capillary leakage, endothelial dysfunction and the initial stages of multiple organ failure development [3,4].
Biomarker (PCT, MR-proADM, CRP and lactate) and standard clinical and laboratory parameters (creatinine, urea and 24-h urine output) were subsequently compared to identify RRT requirement at baseline (day 0), and predict requirement between days 1 and 7 in patients where no RRT was previously initiated. AUROC and logistic regression analysis found that urine output, MR-proADM and creatinine performed similarly in identifying RRT requirement at baseline, whereas MR-proADM more accurately predicted requirement between days 1 and 7 (Fig. 1 in patients where no RRT was initiated at baseline resulted in a high likelihood of subsequent RRT requirement. Conversely, few cases of RRT over the first 21 days of ICU therapy were initiated in patients with continuously low (N = 3; 1.3%) or decreasing (moderate to low: N = 1; 1.3%) MR-proADM concentrations.
Results suggest that increasing or continuously elevated MR-proADM concentrations, indicative of increased capillary leak, may be a useful predictor of RRT requirement during ICU therapy. Further studies are required to investigate the relationship between MR-proADM, positive fluid balance and renal replacement therapy in critically ill patients with sepsis.

Funding
The SISPCT trial infrastructure was partially funded by grant 01 KI 0106 from the German Federal Ministry of Education and Research. Biosyn (Germany) and Thermo Fisher (Germany) provided study medication and financial support via unrestricted grants. For the purpose of this letter, no specific funding was received. Neither for the original SISPCT trial nor this letter did the funding organizations have any role in the design and conduct of the trial; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript and decision to submit the manuscript for publication.

Availability of data and materials
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
Authors' contributions AN was the primary author and editor of the manuscript. FB was the principal investigator for the SISPCT trial. AN, FB, DCW, GE and PM collected the study data and contributed to the evaluation and interpretation of data as well as the writing and editing of the manuscript. AN, FB, DCW, GE and PM performed the statistical analysis of data. All authors critically reviewed and approved the final manuscript. Fig. 1 Identification of patients requiring renal replacement therapy (RRT) upon sepsis diagnosis and over the first week of ICU treatment. Logistic regression and AUROC analysis for the requirement of RRT in all patients at baseline (a) and during the first 7 days of ICU therapy in patients with no prior RRT (b). Multivariate Cox regression analysis was corrected for age and the presence of comorbidities. AUROC area under the receiver operating characteristic curve, CI confidence interval, CRP C-reactive protein, IQR interquartile range, LR likelihood ratio, MR-proADM mid-regional proadrenomedullin, N number, OR odds ratio, PCT procalcitonin, RRT renal replacement therapy