Chronic kidney disease (CKD) presents a major public health problem, with approximately 14% of the population diagnosed with CKD, with many progressing to end-stage kidney disease (ESKD) requiring initiation of dialysis or kidney transplantation. Among patients with CKD, the mortality rate is more than double that of the general population.
Patients with advanced CKD commonly develop metabolic acidosis due to a combination of dietary and metabolic acid load and diminished net acid excretion. Patients with CKD and metabolic acidosis are at risk for adverse outcomes, including progressive CKD, cardiovascular events, impaired immune response, bone and muscle loss, and death.
Studies designed to examine the association of metabolic acidosis with adverse renal outcomes have had conflicting results. In some observational studies there was an association between serum bicarbonate and progression of CKD (defined as ESKD requiring dialysis or transplant), a reduction of 50% in estimated glomerular filtration rate (eGFR), or reaching an eGFR of <15 mL/min/1.73 m2. However, in other studies there was no association following adjustment for baseline eGFR.
Navdeep Tangri, MD, and colleagues conducted an observational, longitudinal, retrospective cohort study to determine whether metabolic acidosis is an independent risk factor for adverse renal outcomes and death, and to quantify the magnitude of its effect. Results were reported online in BMC Nephrology [doi.org/10.1186.s12882-021-02385z].
The cohort included more than 51,000 patients with CKD with or without metabolic acidosis derived from a real-world, validated, electronic medical record dataset with a follow-up period of up to 10 years. Patients in the United States with CKD and available serum bicarbonate measurements who either had at least 2 years of longitudinal follow-up or died during the 2-year period were included. Data from 2007 through 2017 were extracted from Optum’s deidentified integrated electronic health record (ehR) database.
Eligible patients had at least 1 year of EHR activity with at least three eGFR results of <60 mL/min/1.73 m2 and at least three serum bicarbonate results with at least one value between 12 and 29 mEq/L. Patients had to have two consecutive valid serum bicarbonate values 28 and 365 days apart that were either between 12 and <22 mEq/L (metabolic acidosis) or between 22 and 29 mEq/L (range of normal serum bicarbonate). Inclusion also required a baseline eGFR value between >10 and <60 mL/min/1.73 m2.
The primary outcome of interest was the composite end point of a decline in eGFR ≥40%, renal replacement therapy (RRT), defined as chronic dialysis or kidney transplant, or all-cause mortality (DD40). Each component of the primary outcome was examined as a secondary outcome; other secondary outcomes were a kidney-specific composite outcome of RRT or a decline in eGFR ≥40% (RRT40), and RRT alone.
Of the 81 million patient records in the Optum database, 319,126 met inclusion criteria for database extraction. Of those patients, 51,558 met data sufficiency requirements, had stage 3-5 CKD with no indication of dialysis or transplant, and qualified for inclusion in the metabolic group (n=17,350) or the normal serum bicarbonate group (n=34,208).
Patients in the metabolic acidosis group had lower levels of serum bicarbonate (mean 19.7 vs 26.1 mEq/L), were younger (mean age 70.3 vs 74.3 years), were more likely to be Black (15% vs 7%), had more advanced CKD (baseline eGFR 37.2 vs 43.2 mL/min/1.73 m2), had a greater burden of comorbidities (coronary artery disease, diabetes, hypertension, heart failure, peripheral vascular disease, and a higher comorbidity burden as measured by the Charlson Comorbidity Index [CCI]), and had higher mean urine albumin-to-creatinine ratio (ACR) (277 mg/g vs 127 mg/g), P<.001 for all comparisons.
At 2 years, the incidence of the composite outcome increased with CKD severity in both the metabolic acidosis group and the group with normal serum bicarbonate. Within each subgroup of CKD, the rates of the composite outcome were significantly higher among patients with metabolic acidosis compared with patients with normal serum bicarbonate: CKD stage 3a, 39% vs 12%, P<.001; CKD stage 3b, 43% vs 16%, P<.001; CKD stage 4, 59% vs 33%, P<.001; CKD stage 5, 87% vs 82%, P=.03.
The effects of selected covariates on the risk of the composite outcome were evaluated using Cox proportional hazards models over <10 years, and effects on the odds of the composite outcome were evaluated using a logistic regression model over ≤2 years.
In all models, serum bicarbonate was a significant predictor of the composite outcome. Over a 10-year period, each 1-mEq/L increase in serum bicarbonate was associated with a 7.4% decrease in the risk of the composite outcome (hazard ratio [HR], 0.926; 95% confidence interval [CI], 0.922-0.930; P<.001) after controlling for age, sex, race, eGFR, pre-existing diabetes, hypertension, heart failure, CCI score, and log ACR. There was also an independent association between serum bicarbonate and the 2-year composite outcome.
Over a ≤2-year period, there was an association between each 1-mEq/L increase in serum bicarbonate and a 13% decrease in the odds of the composite outcome (odds ratio [OR], 0.873; 95% CI, 0.866-0.879; P<.001) following adjustment for age, sex, race, eGFR, pre-existing diabetes, hypertension, heart failure, CCI score, and log ACR.
Each 1-mEq/l increase in baseline serum bicarbonate was associated with a 4.7% decrease in the risk of the kidney-specific composite outcome of RRT or a decline in eGFR ≥40% (HR, 0.953; 95% CI, 0.947-0.958; P<.001), a 4.5% decrease in the risk of RRT (HR, 0.955; 95% CI, 0.948-0.963), and a 9.3% decrease in the risk of all-cause mortality (HR, 0.907; 95% CI, 0.902-0.911; P<.001) over ≤10 years.
The significance of serum bicarbonate as a predictor of the composite outcome was sustained in subgroups analyzed by age. In the extended cohort that included patients who had missing values for urine ACR, serum bicarbonate remained a significant predictor of the composite outcome, the kidney-specific composite outcome of RRT or a decline in eGFR ≥40%, RRT, and all-cause mortality.
Limitations cited by the authors included the retrospective observational study design resulting in possible residual confounding, the lack of data from specialized providers of most dialysis care, and only considering laboratory values at baseline.
In conclusion, the researchers said, “Among patients with non-dialysis-dependent stage 3-5 CKD, low levels of serum bicarbonate within the range of metabolic acidosis are independently associated with increased risk of DD40 (reduction in eGFR >40%, RRT, or all-cause mortality), RRT40 (RRT or reduction in eGFR ≥40%), and the individual outcomes of RRT and all-cause mortality. These findings are consistent with findings from recent clinical trials. Taken together, our study, combined with evidence from randomized, controlled trials, indicate that a low serum bicarbonate level may be an important modifiable risk factor for CKD progression and mortality. Efforts to improve disease awareness and treatment of metabolic acidosis in patients with CKD are urgently needed.”
- Researchers conducted an observational, longitudinal, retrospective cohort study to examine the association between metabolic acidosis and progression of CKD and mortality in a large US community-based cohort.
- The primary outcome was a composite of a decline in estimated glomerular filtration rate of ≥40%, renal replacement therapy, or all-cause mortality. There was an association between low levels of serum bicarbonate within the range of metabolic acidosis and increased risk of the primary outcome.
- There was also an association between low levels of serum bicarbonate and the kidney-specific composite outcome of RRT or a decline in eGFR ≥40%.