Serum Anion Gap Predicts All-Cause Mortality in Patients with Advanced Chronic Kidney Disease: A Retrospective Analysis of a Randomized Controlled Study

Sung Woo Lee, Sejoong Kim, Ki Young Na, Ran-Hui Cha, Shin Wook Kang, Cheol Whee Park, Dae Ryong Cha, Sung Gyun Kim, Sun Ae Yoon, Sang Youb Han, Jung Hwan Park, Jae Hyun Chang, Chun Soo Lim, Yon Su Kim, Sung Woo Lee, Sejoong Kim, Ki Young Na, Ran-Hui Cha, Shin Wook Kang, Cheol Whee Park, Dae Ryong Cha, Sung Gyun Kim, Sun Ae Yoon, Sang Youb Han, Jung Hwan Park, Jae Hyun Chang, Chun Soo Lim, Yon Su Kim

Abstract

Background and objectives: Cardiovascular outcomes and mortality rates are poor in advanced chronic kidney disease (CKD) patients. Novel risk factors related to clinical outcomes should be identified.

Methods: A retrospective analysis of data from a randomized controlled study was performed in 440 CKD patients aged > 18 years, with estimated glomerular filtration rate 15-60 mL/min/1.73m2. Clinical data were available, and the albumin-adjusted serum anion gap (A-SAG) could be calculated. The outcome analyzed was all-cause mortality.

Results: Of 440 participants, the median (interquartile range, IQR) follow-up duration was 5.1 (3.0-5.5) years. During the follow-up duration, 29 participants died (all-cause mortality 6.6%). The area under the receiver operating characteristic curve of A-SAG for all-cause mortality was 0.616 (95% CI 0.520-0.712, P = 0.037). The best threshold of A-SAG for all-cause mortality was 9.48 mmol/L, with sensitivity 0.793 and specificity 0.431. After adjusting for confounders, A-SAG above 9.48 mmol/L was independently associated with increased risk of all-cause mortality, with hazard ratio 2.968 (95% CI 1.143-7.708, P = 0.025). In our study, serum levels of beta-2 microglobulin and blood urea nitrogen (BUN) were positively associated with A-SAG.

Conclusions: A-SAG is an independent risk factor for all-cause mortality in advanced CKD patients. The positive correlation between A-SAG and serum beta-2 microglobulin or BUN might be a potential reason. Future study is needed.

Trial registration: Clinicaltrials.gov NCT 00860431.

Trial registration: ClinicalTrials.gov NCT00860431.

Conflict of interest statement

Competing Interests: The authors of this manuscript have read the journal's policy and have the following competing interests: The authors received funding from CJ HealthCare Corporation and Kureha Corporation, both commercial companies, for this study. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Patient selection algorithm.
Fig 1. Patient selection algorithm.
ITT, intention to treat; PP, per protocol.
Fig 2. Restricted cubic spline curve of…
Fig 2. Restricted cubic spline curve of albumin-adjusted serum anion gap (A-SAG) for all-cause mortality.
As A-SAG increased, the log hazard of all-cause mortality increased, but nonlinearly.
Fig 3. Kaplan-Meier survival curve according to…
Fig 3. Kaplan-Meier survival curve according to the albumin-adjusted serum anion gap (A-SAG) status.
Mean (95% CI) survivals of

Fig 4. Associations between albumin-adjusted serum anion…

Fig 4. Associations between albumin-adjusted serum anion gap (A-SAG) and uremic toxins.

A, B, and…

Fig 4. Associations between albumin-adjusted serum anion gap (A-SAG) and uremic toxins.
A, B, and C designated serum total indoxyl sulfate (IS), serum beta-2 microglobulin (B2MG) and blood urea nitrogen (BUN), respectively.
Fig 4. Associations between albumin-adjusted serum anion…
Fig 4. Associations between albumin-adjusted serum anion gap (A-SAG) and uremic toxins.
A, B, and C designated serum total indoxyl sulfate (IS), serum beta-2 microglobulin (B2MG) and blood urea nitrogen (BUN), respectively.

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