Metabolic acidosis is associated with increased risk of adverse kidney outcomes and mortality in patients with non-dialysis dependent chronic kidney disease: an observational cohort study

Abstract

Background: Management of chronic kidney disease (CKD) requires the management of risk factors, such as hypertension and albuminuria, that affect CKD progression. Identification of additional modifiable risk factors is necessary to develop new treatment strategies for CKD. We sought to quantify the association of metabolic acidosis with CKD progression and mortality in a large U.S. community-based cohort.

Methods: In this longitudinal, retrospective cohort study we identified non-dialysis-dependent patients with stage 3‒5 CKD from Optum's de-identified integrated electronic health records. We selected cohorts of patients with confirmed metabolic acidosis or normal serum bicarbonate levels based on 2 consecutive serum bicarbonate values: 12 to < 22 mEq/L or 22-29 mEq/L, respectively, 28‒365 days apart. The primary composite outcome was ≥ 40 % decline in estimated glomerular filtration rate (eGFR), renal replacement therapy (chronic dialysis or kidney transplant), or all-cause mortality (DD40). Secondary outcomes included each component of the composite outcome. Cox proportional hazards models were used for the DD40 outcome and secondary outcomes, while logistic regression models were used for the DD40 outcome at 2 years.

Results: A total of 51,558 patients qualified for the study. The unadjusted 2-year incidence of adverse renal and fatal outcomes was significantly worse among patients in the metabolic acidosis group vs. those who had normal serum bicarbonate levels: 48 % vs. 17 % for DD40, 10 % vs. 4 % for ≥ 40 % decline in eGFR, 20 % vs. 6 % for renal replacement therapy, and 31 % vs. 10 % for all-cause mortality (all P < 0.001). Over a ≤ 10-year period, for each 1-mEq/L increase in serum bicarbonate, the adjusted hazard ratio for DD40 was 0.926 (95 % confidence interval [CI], 0.922-0.930; P < 0.001); over a ≤ 2-year period, the adjusted odds ratio for DD40 was 0.873 (95 % CI, 0.866-0.879; P < 0.001).

Conclusions: In this large community cohort of patients with stage 3‒5 CKD, the presence of metabolic acidosis was a significant, independent risk factor for the composite adverse outcome of CKD progression, renal replacement therapy, and all-cause mortality (DD40).

Keywords: CKD progression; Chronic kidney disease; dialysis; metabolic acidosis; mortality; observational study; renal replacement therapy; serum bicarbonate; transplantation.

Fig. 1

Patient selection flow diagram. Investigators had full access to the database extract but no direct access to the Optum database. Abbreviations: AKI, Acute Kidney Injury; CKD, chronic kidney disease; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate; EHR, Electronic Health Records

Fig. 2

Two-year adverse renal and fatal outcomes among patients with chronic kidney disease with or without baseline metabolic acidosis (unadjusted analysis). The analysis included patients from the extended cohort: metabolic acidosis group, N = 17,350; normal serum bicarbonate group, N = 34,208). Abbreviation: DD40, ≥ 40 % eGFR decline, renal replacement therapy, or all-cause mortality; eGFR, estimated glomerular filtration rate. *P < 0.001: metabolic acidosis group vs. normal serum bicarbonate group

Fig. 3

Two-year incidence of the composite outcome of DD40 by CKD stage (unadjusted analysis). The analysis included patients from the extended cohort: metabolic acidosis group, N = 17,350; normal serum bicarbonate group, N = 34,208). Abbreviations: CKD, chronic kidney disease; DD40, ≥ 40 % eGFR decline, renal replacement therapy, or all-cause mortality. *P < 0.001, **P < 0.05, metabolic acidosis group vs. normal serum bicarbonate group

Fig. 4

Adjusted risk of all-cause mortality and CKD progression per 1 mEq/L increase in serum bicarbonate. a Cox proportional hazards ratios for DD40 in the extended cohort (patients with no missing ACR data), with subgroup analysis by age group (< 65 and ≥ 65 years of age). b Cox proportional hazards ratios for secondary outcomes (RRT40, RRT, and all-cause mortality) and sensitivity analyses (DD40 and RRT40 by the first single outpatient eGFR value representing a decline of ≥ 40 % from baseline eGFR). c Cox proportional hazards ratios for primary and secondary outcomes in the primary analysis cohort (no missing ACR data). All analyses were adjusted for all covariates other than the analysis omitting ACR in Panel b, and all analyses in Panel c, which included all covariates other than ACR. Abbreviations: ACR, albumin-creatinine ratio; DD40, all-cause mortality, renal replacement therapy, or a ≥ 40 % decline in eGFR; HR, hazard ratio; LCL, lower confidence limit; RRT, renal replacement therapy; RRT40 = renal replacement therapy or a ≥ 40 % decline in eGFR; single OP eGFR, analysis in which the component of a ≥ 40 % decline in eGFR is established by a single outpatient eGFR measurement rather than an average eGFR during a 90-day period; UCL, upper confidence limit