Elevated Plasma Levels of Endostatin Are Associated with Chronic Kidney Disease

Abstract

Background/Aims: Angiogenesis may play an important role in the renal repair process after injury. We investigated the association between plasma endostatin, an endothelial-specific antiangiogenic factor, and chronic kidney disease (CKD). Methods: We compared plasma endostatin levels in 201 CKD patients and 201 controls. CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m² or presence of albuminuria (≥30 mg/24 h). Results: After adjustment for established CKD risk factors, the median (interquartile range) of plasma endostatin was 276.7 ng/dl (199.3–357.5) in patients with CKD and 119.4 ng/dl (103.7–134.6) in controls without CKD (p < 0.0001 for group difference). log-transformed plasma endostatin was significantly and inversely correlated with eGFR (r = –0.83, p < 0.0001) and positively correlated with log-transformed urine albumin (r = 0.66, p < 0.0001) in the study participants. In addition, one standard deviation increase in log-transformed plasma endostatin (0.55 ng/dl) was associated with a decline in eGFR of –26.2 ml/min and an increase in urine albumin of 3.26 mg/ 24 h after adjusting for multiple covariables. Furthermore, the multivariable-adjusted odds ratio for CKD comparing the highest tertile (≥131.4 ng/dl) to the two lower tertiles of plasma endostatin was 21.6 (95% CI: 10.2–45.5; p < 0.0001). Conclusion: These data indicate that elevated plasma endostatin is strongly and independently associated with CKD. Prospective cohort studies and clinical trials are warranted to further examine the causal relationship between endostatin and risk of CKD and to develop novel interventions targeting circulating endostatin aimed at reducing CKD risk.

Association Between Circulating Endostatin, Hypertension Duration, and Hypertensive Target-Organ Damage

“…Moreover, experimental studies show that damages to the vasculature, 24 the myocardium, 25 and the kidneys 26 lead to increased expression of endostatin in these tissues, and that circulating concentrations of endostatin are elevated in patients with prevalent cardiovascular diseases 20,[27][28][29][30] or chronic kidney disease. 13 Thus, the fact that endostatin was both associated with the duration of hypertension and indices of vascular, myocardial, and renal hypertensive target-organ damage in the present study may indicate that higher circulating levels of endostatin mirror an increased extracellular remodeling that originates from these tissues. Still, based on the present observational study, no firm conclusions about from what tissue the elevated levels of endostatin originate should be drawn, nor can we establish the underlying mechanism that leads to higher circulating endostatin levels.…”

“…Thus, a possible explanation could be that increased endostatin mirrors a systemic elevated angiogenic activity, reflecting increased neovascularization induced by vascular, myocardial, or renal ischemia, similar as the role suggested for vascular endothelial growth factor. 4,13,14,[36][37][38] Endostatin has also been shown to exert acute reductions in blood pressure via a release of NO, 39 and individuals with Down Syndrome have significantly higher circulating levels of endostatin and exhibit lower blood pressure compared with control subjects. 40,41 This may indicate that endostatin, per se, may exert a blood pressure lowering effect.…”

“…4,13,14 Meanwhile, extracellular matrix proteinases also increase in those tissues. 4,15,16 Thus, endostatin, a cleaved product of collagen XVIII, could be an indicator of adverse extracellular remodeling in hypertension.…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Keratin 18, an epithelial-specific cytoskeletal protein released into urine or serum upon tubular cell death, might also be a novel marker of CKD (395). Several other molecules are under investigation as biomarkers in CKD, including asymmetric dimethylarginine, an endogenous inhibitor of NO synthase (396), Creactive protein (CRP), tumor necrosis factor receptor (TNF-R) II, pentraxin-3, adiponectin and apolipoprotein A-IV, as metabolic factors involved in the regulation of kidney metabolism, or endostatin as an anti-angiogenic factor (396,397). In kidney allografts, increased urinary CCL-2 was associated with renal fibrosis (317).…”

Predictive Value of Endostatin in Chronic Heart Failure Patients with Poor Kidney Function

“…Experimental studies showed that endostatin may lead to endothelial dysfunction and abnormalities in the renal microvasculature [4], and in patients with chronic kidney disease, elevated circulating endostatin levels correlated with clinical severity [5,6]. To our knowledge, there are no studies in large HF populations investigating the interaction between endostatin and renal function on adverse outcomes.…”