Bioimpedance Indices of Fluid Overload and Cardiorenal Outcomes in Heart Failure and Chronic Kidney Disease: a Systematic Review

Background Bioimpedance-based estimates of fluid overload have been widely studied and systematically reviewed in populations of those undergoing dialysis, but data from populations with heart failure or nondialysis chronic kidney disease (CKD) have not. Methods and Results We conducted a systematic review of studies using whole-body bioimpedance from populations with heart failure and nondialysis CKD that reported associations with mortality, cardiovascular outcomes and/or CKD progression. We searched MEDLINE, Embase databases and the Cochrane CENTRAL registry from inception to March 14, 2022. We identified 31 eligible studies: 20 heart failure and 11 CKD cohorts, with 2 studies including over 1000 participants. A wide range of various bioimpedance methods were used across the studies (heart failure: 8 parameters; CKD: 6). Studies generally reported positive associations, but between-study differences in bioimpedance methods, fluid overload exposure definitions and modeling approaches precluded meta-analysis. The largest identified study was in nondialysis CKD (Chronic Renal Insufficiency Cohort, 3751 participants), which reported adjusted hazard ratios (95% confidence intervals) for phase angle < 5.59 vs ≥ 6.4 of 2.02 (1.67–2.43) for all-cause mortality; 1.80 (1.46–2.23) for heart failure events; and 1.78 (1.56–2.04) for CKD progression. Conclusions Bioimpedance indices of fluid overload are associated with risk of important cardiorenal outcomes in heart failure and CKD. Facilitation of more widespread use of bioimpedance requires consensus on the optimum device, standardized analytical methods and larger studies, including more detailed characterization of cardiac and renal phenotypes. (J Cardiac Fail 2022;00:1 – 14)


Revised protocol
The original protocol included kidney failure populations however this decision was revised based upon the number of studies retrieved. Associations in dialysis (kidney failure) populations have been established by existing reviews therefore we focused this review on non-dialysis CKD and heart failure populations. The initial title/abstract screening was performed in two stages: firstly screening all studies and then secondly removing all retained studies which clearly studied only dialysis (kidney failure) populations. Records of these studies were retained for review of fluid overload definitions and threshold values in existing studies across all CKD (non-dialysis and dialysis) and heart failure populations.

Search strategy
Studies of potential relevance not identified by the systematic search (through hand searching of references of relevant studies) were added prior to screening. The database search was not restricted by language however all studies were available in English. Conference abstracts were excluded. Studies were only included once and the approach to selection of the report used for extraction was based upon the following factors: maximal outcome data, maximal followup time and largest population. Where different fluid overload parameters were used, this was considered alongside the aforementioned factors and parameters most synonymous with other studies were favored.

Supplementary Table S6: Studies with multiple reports identified
The selected report from which data were extracted is highlighted in bold. Approach to selection as follows: maximal outcome data, maximal follow-up time, largest population. Where different fluid overload parameters were used, this was considered alongside the aforementioned factors and parameters most synonymous with other studies were favoured. 1 Multivariable survival analysis not reported by fluid overload (diuretic status only), author confirmed by email therefore 2017 report favoured. 2 Author confirmed all studies represent the same cohort and recruitment dates 2002-2011 provided by email; 2012 study favoured based upon population size and fluid overload measurement more synonymous with other studies. 3 2017 paper states no association between fluid overload and KRT or CV events however not quantified. Several other included studies share authors but report upon distinct cohorts.     Quality in Prognostic Studies (QUIPS) tool for risk of bias 1. Study Participation: The study sample adequately represents the population of interest Consider the following: a) The source population or population of interest is adequately described for key characteristics (CKD/HF history/eGFR, proteinuria, diabetes, CVD). b) The sampling frame and recruitment are adequately described, including methods to identify the sample sufficient to limit potential bias (number and type used, e.g., referral patterns in health care) c) Period of recruitment is adequately described d) Place of recruitment (setting and geographic location) are adequately described e) "Inclusion and exclusion criteria are adequately described (e.g., including explicit diagnostic criteria or "zero time" description)." f) There is adequate participation in the study by eligible individuals g) The baseline study sample (i.e., individuals entering the study) is adequately described for key characteristics (CKD/HF history/eGFR, proteinuria, diabetes, CVD).

High risk of bias:
The relationship between fluid overload and outcome is very likely to be different for participants and eligible nonparticipants Moderate risk of bias: The relationship between fluid overload and outcome may be different for participants and eligible nonparticipants Low risk of bias: The relationship between fluid overload and outcome is unlikely to be different for participants and eligible nonparticipants

Study Attrition:
The study data available (i.e., participants not lost to follow-up) adequately represent the study sample Consider the following: a) Response rate (i.e., proportion of study sample completing the study and providing outcome data) is adequate. b) Attempts to collect information on participants who dropped out of the study are described. c) Reasons for loss to follow-up are provided. d) Participants lost to follow-up are adequately described for key characteristics (CKD/HF history/eGFR, proteinuria, diabetes, CVD). e) There are no important differences between key characteristics (CKD/HF history/eGFR, proteinuria, diabetes, CVD) and outcomes in participants who completed the study and those who did not.

High risk of bias:
The relationship between fluid overload and outcome is very likely to be different for completing and noncompleting participants Moderate risk of bias: The relationship between fluid overload and outcome may be different for completing and noncompleting participants Low risk of bias: The relationship between fluid overload and outcome is unlikely to be different for completing and noncompleting participants b) The method of outcome measurement used is adequately valid and reliable to limit misclassification bias c) The method and setting of outcome measurement is the same for all study participants.

High risk of bias:
The measurement of the outcome is very likely to be different by the baseline level of fluid overload Moderate risk of bias: The measurement of the outcome may be different by the baseline level of fluid overload Low risk of bias: The measurement of the outcome is unlikely to be different by the baseline level of fluid overload 5. Study Confounding: Important potential confounding factors are appropriately accounted for Consider the following: a) All important confounders (eGFR/CKD stage, HF type/EF, diabetes, proteinuria, BP etc), are measured. b) Clear definitions of the important confounders measured are provided c) Measurement of all important confounders is adequately valid and reliable d) The method and setting of confounding measurement are the same for all study participants. e) Appropriate methods are used if imputation is used for missing confounder data. f) Important potential confounders are accounted for in the study design (e.g., matching for key variables, stratification, or initial assembly of comparable groups). g) Important potential confounders are accounted for in the analysis (i.e., appropriate adjustment).

High risk of bias:
The observed effect of fluid overload on the outcome is very likely to be distorted by another factor related to fluid overload and outcome Moderate risk of bias: The observed effect of fluid overload on outcome may be distorted by another factor related to fluid overload and outcome Low risk of bias: The observed effect of fluid overload on outcome is unlikely to be distorted by another factor related to fluid overload and outcome

Statistical Analysis and Reporting:
The statistical analysis is appropriate, and all primary outcomes are reported a) There is sufficient presentation of data to assess the adequacy of the analysis. b) The strategy for model building (i.e., inclusion of variables in the statistical model) is appropriate and is based on a conceptual framework or model. c) The selected statistical model is adequate for the design of the study. d) There is no selective reporting of results.
High risk of bias: The reported results are very likely to be spurious or biased related to analysis or reporting Moderate risk of bias: The reported results may be spurious or biased related to analysis or reporting Low risk of bias: The reported results are unlikely to be spurious or biased related to analysis or reporting