Kidney Function and Fracture Risk: The Atherosclerosis Risk in Communities (ARIC) Study

Abstract

Background: People with end-stage renal disease are at high risk for bone fracture. Less is known about fracture risk in milder chronic kidney disease and whether chronic kidney disease-associated fracture risk varies by sex or assessment with alternative kidney markers.

Study design: Prospective cohort study.

Setting & participants: 10,955 participants from the Atherosclerosis Risk in Communities (ARIC) Study followed up from 1996 to 2011.

Predictor: Kidney function as assessed by creatinine-based estimated glomerular filtration rate (eGFRcr), urine albumin-creatinine ratio, and alternative filtration markers.

Outcomes: Fracture-related hospitalizations determined by diagnostic code.

Measurements: Baseline kidney markers; hospitalizations identified by self-report during annual telephone contact and active surveillance of local hospital discharge lists.

Results: Mean age of participants was 63 years, 56% were women, and 22% were black. During a median follow-up of 13 years, there were 722 incident fracture-related hospitalizations. Older age, female sex, and white race were associated with higher risk for fracture (P<0.001). The relationship between eGFRcr and fracture risk was nonlinear: <60mL/min/1.73m(2), lower eGFRcr was associated with higher fracture risk (adjusted HR per 10mL/min/1.73m(2) lower, 1.24; 95% CI, 1.05-1.47); there was no statistically significant association for ≥60mL/min/1.73m(2) in the primary analysis. In contrast, there was a graded association between other markers of kidney function and subsequent fracture, including albumin-creatinine ratio (HR per doubling, 1.10; 95% CI, 1.06-1.14), cystatin C-based eGFR (HR per 1-SD decrease, 1.15; 95% CI, 1.06-1.25), and 1/β2-microglobulin (HR per 1-SD decrease, 1.26, 95% CI, 1.15-1.37).

Limitations: No bone mineral density assessment; one-time measurement of kidney function.

Conclusions: Both low eGFR and higher albuminuria were significant risk factors for fracture in this community-based population. The shape of the association in the upper ranges of eGFR varied by the filtration marker used in estimation.

Keywords: Bone fracture; albumin-creatinine ratio (ACR); albuminuria; chronic kidney disease (CKD); estimated glomerular filtration rate (eGFR); fracture risk; hospitalization; hospitalized fracture; kidney filtration markers; renal function.

Figure 1

A. Unadjusted incidence rates (per 1,000 person years) of fracture-related hospitalization by eGFR_Cr and albuminuria category at baseline (1996–1998). * n=number of fractures/number of participants. Colors reflect ranking of risk of fracture-related hospitalization. Green: low risk; Yellow: moderately increased risk; Orange: high risk; Red: very high risk. B. Adjusted incidence rate ratios^† of fracture-related hospitalization by eGFR_Cr and albuminuria category at baseline (1996–1998). * Colors reflect ranking of risk of fracture-related hospitalization. Green: low risk; Yellow: moderately increased risk; Orange: high risk; Red: very high risk. ^†Adjusted for age, gender, race-center, BMI, diabetes status, cigarette smoking, prevalent coronary heart disease, bisphosphonate use, proton pump inhibitor use and glucocorticoid use. *p≤0.05, ** p≤0.01, *** p≤0.001

Figure 2

Adjusted hazard ratio* (95% confidence interval) of fracture-related hospitalization by level of eGFR_Cr (A) and albuminuria (B) at baseline (1996–1998), with histogram of eGFR_Cr and albuminuria values. *The solid lines in A and B are the predicted values from the Cox proportional hazards model; the dashed lines represent the corresponding 95% confidence intervals. eGFR_Cr is represented using linear splines (A), with a knot at 60 ml/min/1.73 m².

Figure 3

Adjusted hazard ratio* (95% confidence interval) of fracture-related hospitalization by level of eGFR_Cr and albuminuria at baseline (1996–1998), by sex. *The solid lines are the predicted values from the Cox proportional hazards model; the corresponding 95% confidence intervals are included. eGFR_Cr is represented using linear splines, with a knot at 60 ml/min/1.73 m².