Association of mild to moderate chronic kidney disease with venous thromboembolism: pooled analysis of five prospective general population cohorts

Abstract

Background: Recent findings suggest that chronic kidney disease (CKD) may be associated with an increased risk of venous thromboembolism (VTE). Given the high prevalence of mild-to-moderate CKD in the general population, in depth analysis of this association is warranted.

Methods and results: We pooled individual participant data from 5 community-based cohorts from Europe (second Nord-Trøndelag Health Study [HUNT2], Prevention of Renal and Vascular End-stage Disease [PREVEND], and the Tromsø study) and the United States (Atherosclerosis Risks in Communities [ARIC] and Cardiovascular Health Study [CHS]) to assess the association of estimated glomerular filtration rate (eGFR), albuminuria, and CKD with objectively verified VTE. To estimate adjusted hazard ratios for VTE, categorical and continuous spline models were fit by using Cox regression with shared-frailty or random-effect meta-analysis. A total of 1178 VTE events occurred over 599 453 person-years follow-up. Relative to eGFR 100 mL/min per 1.73 m(2), hazard ratios for VTE were 1.29 (95% confidence interval, 1.04-1.59) for eGFR 75, 1.31 (1.00-1.71) for eGFR 60, 1.82 (1.27-2.60) for eGFR 45, and 1.95 (1.26-3.01) for eGFR 30 mL/min per 1.73 m(2). In comparison with an albumin-to-creatinine ratio (ACR) of 5.0 mg/g, the hazard ratios for VTE were 1.34 (1.04-1.72) for ACR 30 mg/g, 1.60 (1.08-2.36) for ACR 300 mg/g, and 1.92 (1.19-3.09) for ACR 1000 mg/g. There was no interaction between clinical categories of eGFR and ACR (P=0.20). The adjusted hazard ratio for CKD, defined as eGFR <60 mL/min per 1.73 m(2) or albuminuria ≥30 mg/g, (versus no CKD) was 1.54 (95% confidence interval, 1.15-2.06). Associations were consistent in subgroups according to age, sex, and comorbidities, and for unprovoked versus provoked VTE, as well.

Conclusions: Both eGFR and ACR are independently associated with increased risk of VTE in the general population, even across the normal eGFR and ACR ranges.

Figure 1

Flow diagram for selection of studies. * Reference included analysis of 2 cohorts.

Figure 2

Pooled hazard ratios and 95% CIs for venous thromboembolism according to spline estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR). Hazard ratios and 95% CIs (error bars) according to eGFR (A) and ACR (B) adjusted for each other, age, sex, body mass index, history of cardiovascular disease, hypertension, diabetes, smoking, and total cholesterol. The reference (diamond) was eGFR 100 mL/min/1.73 m² and ACR 5 mg/g (0.6 mg/mmol), respectively. Red dots represent statistically significance. Num Part and Num VTE denote the number of participants and number of VTE, respectively, in the range between the knots represented by the vertical gray lines. To convert ACR to mg/mmol multiply by 0.113.

Figure 2

Pooled hazard ratios and 95% CIs for venous thromboembolism according to spline estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR). Hazard ratios and 95% CIs (error bars) according to eGFR (A) and ACR (B) adjusted for each other, age, sex, body mass index, history of cardiovascular disease, hypertension, diabetes, smoking, and total cholesterol. The reference (diamond) was eGFR 100 mL/min/1.73 m² and ACR 5 mg/g (0.6 mg/mmol), respectively. Red dots represent statistically significance. Num Part and Num VTE denote the number of participants and number of VTE, respectively, in the range between the knots represented by the vertical gray lines. To convert ACR to mg/mmol multiply by 0.113.

Figure 3

Overall and study-specific hazard ratios for overall, unprovoked and provoked venous thromboembolism in participants with CKD compared to those without CKD. CKD was defined by eGFR of <60 mL/min/1.73m² and/or ACR ≥30 mg/g. Hazard ratios are adjusted for age, sex, body mass index, history of cardiovascular disease, hypertension, diabetes, smoking, and total cholesterol. The slight differences in numbers with Table 1 are due to missing observations for either eGFR or ACR, and because for defining non-CKD both eGFR and ACR were required. For HUNT2 study only measured ACR was considered in this analysis.

Figure 4

Association of CKD with VTE in subgroups according to traditional cardiovascular risk factors. CVD denotes cardiovascular disease. CKD was defined by eGFR of <60 mL/min/1.73m² and/or ACR ≥30 mg/g . Hazard ratios are adjusted for other than the stratified risk factor itself, which included age, sex, body mass index, history of cardiovascular disease, hypertension, diabetes, smoking, and total cholesterol. *Race comparison was limited to ARIC and CHS studies, since the other studies enrolled only whites.