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.

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. 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). 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, HbA(1c) , 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. 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.

Theilade S ，Lajer M ，Jorsal A ，Tarnow L ，Parving HH ，Rossing P ... -  《-》

Soluble CD40 ligand is elevated in type 1 diabetic nephropathy but not predictive of mortality, cardiovascular events or kidney function.

Lajer M ，Tarnow I ，Michelson AD ，Jorsal A ，Frelinger AL ，Parving HH ，Rossing P ，Tarnow L ... -  《-》

Arterial stiffness and endothelial dysfunction independently and synergistically predict cardiovascular and renal outcome in patients with type 1 diabetes.

To evaluate whether pulse pressure alone or with placental growth factor as estimates of arterial stiffness and endothelial dysfunction, predicts mortality, cardiovascular disease and progression to end-stage renal disease in patients with Type 1 diabetes. Prospective, observational study, median (range) follow-up 8 (0-13) years, 900 patients with Type 1 diabetes, 458 with diabetic nephropathy, mean ± SD age 44 ± 11 years. During follow-up, we recorded 178 (20%) all-cause deaths, 109 (12%) cardiovascular deaths, 213 (24%) cardiovascular events and 73 (16%) progressed to end-stage renal disease. Elevated pulse pressure predicted all-cause and cardiovascular mortality and cardiovascular events [Hazard Ratio (HR) (95% CI) per 10 mmHg increase]: HR 1.2 (1.1-1.3), 1.3 (1.2-1.5) and 1.2 (1.1-1.3), P<0.001 (adjusted for sex, age, HbA(1c) , cholesterol, diastolic blood pressure, creatinine, smoking, previous cardiovascular disease and nephropathy status). Furthermore, pulse pressure predicted the development of end-stage renal disease in patients with diabetic nephropathy: HR 1.2 (1.1-1.4), P=0.011 (adjusted for sex, age, HbA(1c) , cholesterol, diastolic blood pressure, previous cardiovascular disease and glomerular filtration rate). In a two-hit model, patients with pulse pressure and placental growth factor levels above the median vs. below the median had increased risk of all-cause and cardiovascular mortality, cardiovascular events and progression to end-stage renal disease: adjusted HRs 2.3 (1.2-4.2), 4.2 (1.6-11.0), 2.3 (1.3-4.1) and 3.5 (1.0-11.8),P<0.05. Elevated pulse pressure independently predicts mortality, cardiovascular events and progression to end-stage renal disease in patients with Type 1 diabetes. Placental growth factor adds to the predictive value of pulse pressure on cardiovascular and renal outcome.

Theilade S ，Lajer M ，Jorsal A ，Tarnow L ，Parving HH ，Rossing P ... -  《-》

Plasma high-sensitivity troponin T predicts end-stage renal disease and cardiovascular and all-cause mortality in patients with type 1 diabetes and diabetic nephropathy.

High-sensitivity troponin T (hsTnT) is a marker of cardiovascular disease (CVD) and in type 2 diabetes also a marker of renal events, but has not been evaluated in type 1 diabetics. We therefore reviewed a type 1 diabetes cohort of 442 without and 458 with diabetic nephropathy. Baseline samples were analyzed for hsTnT levels. Cox regression analyses assessed predictive value in relation to the development of end-stage renal disease (ESRD) in 99 patients, all-cause mortality in 178, and CVD events in 134 after up to 12 years of follow-up. To assess if hsTnT improved risk prediction beyond traditional clinical risk markers, we calculated c statistics and relative integrated discrimination improvement. HsTnT was significantly higher in patients with diabetic nephropathy compared to normoalbuminuria (median 8.9 vs 3.1 ng/L). For a doubling in hsTnT levels, and after adjustment for well-known risk factors, including NT-proBNP and hsCRP, the hazard ratio for ESRD at 1.26 was not significant in the diabetic nephropathy group, but there was a significant association with GFR decline after adjustment during follow-up (2.9 ml/min/1.73 m2 annual decline per doubling in hsTnT). The unadjusted and adjusted hazard ratios for mortality (1.64 and 1.32, respectively) were significant in patients with, but not for patients without, nephropathy. Adjusted hazard ratios for fatal and non-fatal CVD events were significant for the whole cohort (1.13), and those with nephropathy (1.14), but not significant for normoalbuminuria (1.06). Addition of hsTNT to traditional risk factors significantly increased the area under the curve by 0.01 in a receiver-operating characteristic curve for mortality. The relative integrated discrimination improvement was increased 15.7% for mortality, 6.3% for CVD, and 1.9% for ESRD (all significant). Thus, higher hsTnT is an independent predictor of renal decline and cardiovascular events in patients with type 1 diabetes and diabetic nephropathy.

Galsgaard J ，Persson F ，Hansen TW ，Jorsal A ，Tarnow L ，Parving HH ，Rossing P ... -  《-》

Elevated placental growth factor (PlGF) predicts cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy.

Tarnow L ，Astrup AS ，Parving HH 《-》