Fibrosis is a process characterized by an excessive accumulation of the extracellular matrix as a response to different types of tissue injuries, which leads to organ dysfunction. The process can be initiated by multiple and different stimuli and pathogenic factors which trigger the cascade of reparation converging in molecular signals responsible of initiating and driving fibrosis. Though fibrosis can play a defensive role, in several circumstances at a certain stage, it can progressively become an uncontrolled irreversible and self-maintained process, named pathological fibrosis. Several systems, molecules and responses involved in the pathogenesis of the pathological fibrosis of chronic kidney disease (CKD) will be discussed in this review, putting special attention on inflammation, renin-angiotensin system (RAS), parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), Klotho, microRNAs (miRs), and the vitamin D hormonal system. All of them are key factors of the core and regulatory pathways which drive fibrosis, having a great negative kidney and cardiac impact in CKD.

The predisposition to vascular calcifications in patients with chronic kidney disease (CKD) has gained great interest in recent years as many studies have described its likely impact on morbidity and mortality. The mechanism by which the process of vascular calcification is produced is complex, and it does not consist in a simple precipitation of calcium and phosphate but is instead an active and modifiable process. Several “modifiable and nonmodifiable” factors that are able to promote vascular calcification are extremely frequent in patients with CKD. Most of the present strategies to decrease vascular calcifications are based in the control of the more prevalent modifiable risk factors. Unfortunately, the extremely important nonmodifiable risk factors, which are highly prevalent, such as older age, time on dialysis, and diabetes, are not under one’s control. Recent studies also have shown that vascular calcifications in some localizations were associated with increased osteoporotic fractures not only in dialysis patients but also in the general population, and interestingly, mortality also was associated significantly and positively with vascular calcifications and nontraumatic bone fractures. Despite that new strategies may improve the management of vascular diseases and specifically have a positive impact on the high prevalence of vascular calcifications, still the best possible control of the bone metabolic and inflammatory parameters are in the primary line. The horizon of the coming decade looks promising, but solid clinical and epidemiologic data are needed to manage better the bone- and cardiovascular-related disorders in patients with CKD.

The mechanisms by which estrogens modulate PTH are controversial, including whether or not estrogen receptors (ERs) are present in the parathyroid glands. To explore these mechanisms, we combined a rat model of CKD with ovariectomy and exogenous administration of estrogens. We found that estrogen treatment significantly decreased PTH mRNA and serum levels. We did not observe ERα or ERβ mRNA or protein in the parathyroids, suggesting an indirect action of estrogens on PTH regulation. Estrogen treatment significantly decreased serum 1,25(OH)₂ vitamin D₃ and phosphorus levels. In addition, estrogens significantly increased fibroblast growth factor 23 (FGF23) mRNA and serum levels. In vitro, estrogens led to transcriptional and translational upregulation of FGF23 in osteoblast-like cells in a time- and concentration-dependent manner. These results suggest that estrogens regulate PTH indirectly, possibly through FGF23.