In this longitudinal observational study, we could show that a high level of circulating ET-1 at baseline was associated with progression to CKD stage 3 or higher at follow-up after ten years in women, but not in men. This association was independent of other common risk factors for the development of CKD. These findings suggest that ET-1 may be a predictor of CKD in women.
It has been established on population basis that circulating ET-1 could help predict chronic heart disease and diabetes, but repeatedly that it lacks a significant association to hypertension . These findings suggest that endothelial dysfunction per se might influence the deterioration of kidney function independently of hypertension. Generally, in CKD we can observe pathological changes where ET-1 has a central and well mapped physiological role, a mechanism that may precede a detectable decrease in eGFR and albuminuria by causing increased glomerular hypertension , cellular hypertrophy and inflammation . Speculatively, discrete endothelial dysfunction in a younger population might precede other observable risk factors such as decreased eGFR or albumin leakage, which are surrogates for disease progression, and ET-1 could act as a risk marker for metabolic disturbances connected to endothelial dysfunction. CKD is a large contributor to health decline in the aging population and is usually detected late in the disease progression. Early detection would be of great benefit to the patient and preventive care could be initiated much sooner if patients at risk could be identified at an early stage. The Vara-Skövde cohort in this study is still considered young and many of the participants are still at an age where the disease has not yet emerged. Our paper may thus add to the understanding of the role of ET-1 in a longitudinal population perspective, but further studies are warranted.
This study also indicates considerable sex differences where women seem to be more vulnerable to the deleterious effect of ET-1. Sex differences are observed in previous studies in the development of cardiovascular disease, possibly due to differences regarding ET-1 and the regulation of vascular tone and receptor response [20,21]. Data also suggest that ET-1 production in the vascular endothelium is attenuated in the presence of estrogens and progesterone . Moreover, to stress the complexity of ET-1, these mechanistic studies focus more on the sensitivity for ET-1 in men and even speculate that ET-1 may be one of the reasons for the higher risk for CVD events in men as compared to premenopausal women , while, in our population-based study, we report levels of ET-1 to be of higher importance in women than in men. A part from the studies from the Skaraborg project there are very few population-based studies and none, to the best of our knowledge, reporting differences between the sexes [24,25]. In addition, previous results from this cohort has shown that serum concentrations of ET-1 can predict development of diabetes, high insulin resistance as well as an increased CHD risk in women but not in men consistent with findings in this study [14,15].
Strengths and limitations
The study has a long follow-up period and a high participation rate. The age distribution of the population has both advantages and disadvantages. A main disadvantage being that the younger age of the studied population and the use of eGFR to define CKD underestimates the presence of damage to the kidneys. The method cannot differentiate between individuals that still have a reasonably high GFR but various levels of structural damage to the glomerular units.
The OR curve is slightly J shaped, however not significant, indicating possible power issues that could be remedied by a larger study population. Anyhow, it might reflect that the association between ET-1 levels and CKD-risk is not linear. It may be that the best levels of ET-1 are those in the middle and both high and low levels suggest a dysfunction in the endothelium and thus increased risk for CKD and CVD events.
One other consideration is that the ET-1 measured in this study is circulating serum concentrations and not the paracrine production in the kidney. However, in pragmatic day to day clinical practice we have no access to the paracrine measurements without advanced and invasive methods. Benefits of studying circulating levels, should they show clinical significance, present a method more readily accessible to clinicians and would be easier to implement in daily clinical routine.