Evaluation of placental growth factor and soluble Fms-like tyrosine kinase 1 as predictors of all-cause and cardiovascular mortality in patients with Type 1 diabetes with and without diabetic nephropathy

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Abstract

Aims

Placental growth factor is a vascular endothelial growth factor involved in angiogenesis, vascular inflammation and plaque formation. Soluble Fms-like tyrosine kinase 1 is a decoy receptor for placental growth factor, reducing its activity. The aim of this study is to evaluate the predictive value of placental growth factor and soluble Fms-like tyrosine kinase 1 in relation to all-cause and cardiovascular mortality and decline in kidney function in Type 1 diabetes.

Methods

This was a prospective, observational follow-up study with 8 (0–13) years [median (range)] of follow-up, including patients with Type 1 diabetes, of whom 458 had diabetic nephropathy [278 men; age 42 ± 11 years (mean ± SD), diabetes duration 28 ± 9 years, glomerular filtration rate 76 ± 33 ml min−1 1.73 m−2] and 442 had long-standing normoalbuminuria (234 men; age 45 ± 12 years, diabetes duration 28 ± 10 years).

Results

Placental growth factor and soluble Fms-like tyrosine kinase 1 levels measured at baseline were higher in patients with diabetic nephropathy compared with patients with long-standing normoalbuminuria [median (range)] 15 (4–131) vs. 11 (7–64) ng/l, (P < 0.001) and 86 (42–3462) vs. 77 (43–1557) ng/l (P < 0.001), respectively. In patients with diabetic nephropathy, high levels of placental growth factor predicted all-cause and cardiovascular mortality [hazard ratio 1.94 (1.16–3.24) and hazard ratio 2.91 (1.45–5.85)] after adjustment for sex, age, smoking, systolic blood pressure, HbA1c, cholesterol, glomerular filtration rate and previous cardiovascular disease. High levels of placental growth factor predicted increased risk of end-stage renal disease [hazard ratio 2.77 (1.47–5.14)], but covariate adjustments attenuated the association [hazard ratio 1.89 (0.91–3.95)]. Among patients with long-standing normoalbuminuria, placental growth factor levels predicted fatal and non-fatal cardiovascular events [hazard ratio 1.97 (1.03–3.76)], but not all-cause mortality. Baseline soluble Fms-like tyrosine kinase 1 levels did not predict outcome in either group after adjustment.

Conclusion

Placental growth factor is elevated in patients with Type 1 diabetes and diabetic nephropathy and predicts all-cause and cardiovascular mortality, but not deterioration of kidney function.

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