Outcomes associated with microalbuminuria: effect modification by chronic kidney disease

Abstract

Objectives: This study sought to compare the association of microalbuminuria with outcomes in patients with different comorbidities.

Background: The risk of adverse outcomes associated with lower levels proteinuria has been found to be linearly decreasing with even low-normal levels of microalbuminuria. It is unclear whether comorbid conditions change these associations.

Methods: We examined the association of urine microalbumin-creatinine ratio (UACR) with mortality and the slopes of estimated glomerular filtration rate (eGFR) in a nationally representative cohort of 298,875 U.S. veterans. Associations of UACR with all-cause mortality overall and in subgroups of patients with and without diabetes mellitus, hypertension, cardiovascular disease, congestive heart failure, and advanced chronic kidney disease (CKD) were examined in Cox models, and with the slopes of eGFR in linear and logistic regression models.

Results: Very low levels of UACR were linearly associated with decreased mortality and less progression of CKD overall: adjusted mortality hazard ratio and estimated glomerular filtration rate slope (95% confidence interval [CI]) associated with UACR ≥200 μg/mg, compared to <5 μg/mg were 1.53 (95% CI: 1.38 to 1.69, p < 0.001) and -1.59 (95% CI: -1.83 to -1.35, p < 0.001). Similar linearity was present in all examined subgroups, except in patients with CKD in whom a U-shaped association was present and in whom a UACR of 10 to 19 was associated with the best outcomes.

Conclusions: The association of UACR with mortality and with progressive CKD is modified in patients with CKD, who experience higher mortality and worse progression of CKD with the lowest levels of UACR. Proteinuria-lowering interventions in patients with advanced CKD should be implemented cautiously, considering the potential for adverse outcomes.

Figure 1. Unadjusted and multivariable adjusted hazard ratios (95% confidence intervals) of all-cause mortality associated with various levels of urine microalbumin-creatinine ratio in 298,875 patients (time-dependent Cox models)

The groups with urine microalbumin-creatinine ratio <5 mcg/mg served as referent. Models represent unadjusted association (Model 1) and associations after adjustment for age, gender and race (Model 2), Model 2 variables + diabetes mellitus, cardiovascular disease, congestive heart failure and the Charlson comorbidity index (Model 3) and Model 3 variables + blood pressure, ACEI/ARB use, estimated glomerular filtration rate, serum albumin, blood hemoglobin, white blood cell count and serum alkaline phosphatase (Model 4). *p<0.001, ^#p<0.01, ^§p<0.05

Figure 2. Hazard ratios (95%CI) of mortality associated with urine microalbumin-creatinine ratio categories of 5–9, 10–19, 20–199 and ≥200 mcg/mg, compared to <5 mcg/mg in different subgroups of patients

Results were obtained from Cox models adjusted for age, gender, race, diabetes mellitus, cardiovascular disease, congestive heart failure, the Charlson comorbidity index, blood pressure, ACEI/ARB use, estimated glomerular filtration rate, serum albumin, blood hemoglobin, white blood cell count and serum alkaline phosphatase. P values represent significance levels for interaction terms.

Figure 3. Unadjusted and multivariable adjusted odds ratios (95% confidence intervals) of progressive CKD associated with various levels of urine microalbumin-creatinine ratio in logistic regression models

The groups with urine microalbumin-creatinine ratio <5 mcg/mg served as referent. Models represent unadjusted association (Model 1) and associations after adjustment for age, gender and race (Model 2), Model 2 variables + diabetes mellitus, cardiovascular disease, congestive heart failure and the Charlson comorbidity index (Model 3) and Model 3 variables + blood pressure, ACEI/ARB use, serum albumin, blood hemoglobin, white blood cell count and serum alkaline phosphatase (Model 4). *p<0.001, ^#p<0.01, ^§p<0.05

Figure 4. Odds ratios (95% confidence intervals) of progressive CKD associated with urine microalbumin-creatinine ratio categories of 5–9, 10–19, 20–199 and ≥200 mcg/mg, compared to <5 mcg/mg in different subgroups of patients

Results were obtained from logistic regression models adjusted for age, gender, race, diabetes mellitus, cardiovascular disease, congestive heart failure, the Charlson comorbidity index, blood pressure, ACEI/ARB use, serum albumin, blood hemoglobin, white blood cell count and serum alkaline phosphatase. P values represent significance levels for interaction terms.