The Intricate Role of Non-Coding RNAs in Sepsis-Associated Disseminated Intravascular Coagulation.

Disseminated Intravascular Coagulation (DIC) is a type of tissue and organ dysregulation in sepsis, due mainly to the effect of the inflammation on the coagulation system. Unfortunately, the underlying molecular mechanisms that lead to this disorder are not fully understood. Moreover, current biomarkers for DIC, including biological and clinical parameters, generally provide a poor diagnosis and prognosis. In recent years, non-coding RNAs have been studied as promising and robust biomarkers for a variety of diseases. Thus, their potential in the diagnosis and prognosis of DIC should be further studied. Specifically, the relationship between the coagulation cascade and non-coding RNAs should be established. In this review, microRNAs, long non-coding RNAs, and circular RNAs are studied in relation to DIC. Specifically, the axis between these non-coding RNAs and the corresponding affected pathway has been identified, including inflammation, alteration of the coagulation cascade, and endothelial damage. The main affected pathway identified is PI3K/AKT/mTOR axis, where several ncRNAs participate in its regulation, including miR-122-5p which is sponged by circ_0005963, ciRS-122, and circPTN, and miR-19a-3p which is modulated by circ_0000096 and circ_0063425. Additionally, both miR-223 and miR-24 were found to affect the PI3K/AKT pathway and were regulated by lncGAS5 and lncKCNQ1OT1, respectively. Thus, this work provides a useful pipeline of inter-connected ncRNAs that future research on their impact on DIC can further explore.

Calcimimetics in the chronic kidney disease-mineral and bone disorder.

Mineral and bone disorders (MBD) are both an early and very common complication of chronic kidney disease (CKD). It is now accepted that they represent a significant risk factor, explaining the high cardiovascular morbidity and mortality in CKD patients. During the last decade, we have been witnessing many advances in the nomenclature, classification, pathophysiology, diagnosis, and treatment of CKD and some of its complications, such as CKD-MBD. The identification of the calcium-sensing receptor (CaSR) involvement in the pathogenesis of primary and secondary hyperparathyroidism (SHPT) and the availability of a new class of drugs called calcimimetics are two outstanding examples. Cinacalcet, the only available calcimimetic, has been shown to be a very effective therapeutic tool in CKD-MBD. Many clinical trials with cinacalcet in hemodialysis patients with SHPT have shown a reduction in parathyroid hormone, calcium (Ca), phosphate (P) and Ca x P product levels, allowing far greater success in reaching therapeutic goals as recommended by international guidelines. Additionally, some studies have shown that the use of cinacalcet may improve other aspects of CKD-MBD, reducing the risk of vascular calcification and parathyroidectomy, among others. Prospective studies on dialysis patients, with hard endpoint data, are currently underway. This review summarizes the most significant aspects of calcimimimetics based on both experimental and clinical results, underlining their possibilities not only for the treatment of isolated SHPT but also for other CKD-MBD related conditions.

Update on the treatment of chronic kidney disease-mineral and bone disorder.

Chronic kidney disease (CKD) is associated with increased morbidity and mortality. Mineral metabolism disturbances appear to contribute to the high mortality rate. A CKD-mineral bone disorder (CKD-MBD) has recently been defined as a systemic disorder manifested by one or a combination of abnormalities in bone biopsy, laboratory parameters and/or vascular or other soft-tissue calcifications. New available treatments have contributed to move from the former treatment paradigm of renal osteodystrophy to CKD-MBD management, beyond mere control of parathyroid hormone (PTH) and trying to improve cardiovascular or survival outcomes. Thus, the recommended multidisciplinary approach among nurses, dieticians and clinicians, helping not only through dietary assessment but also through education, behaviour control and by increasing the patient's personal motivation, may have additional important benefits. This article will review the current therapeutic approach with phosphate binders including the latest developments, vitamin D derivatives and selective vitamin D receptor activators as well as the new calcimimetics, all used in the treatment of this systemic disease.

Endothelial nitric oxide synthase gene polymorphism in dialysis patients.

Nitric oxide is an important factor in the regulation of vasodilator tone. In vascular cells, NO is synthesized by endothelial nitric oxide synthase, a key enzyme of the endogenous vasodilator system. Some studies have described the interaction between NO and the other factors that promote vasodilatation in vascular smooth muscular cells. Some of those factors are angiotensin-converting enzyme (ACE), transforming growth factor beta (TGF beta), and endothelial oxide nitric synthase (eNOS). Polymorphism that can alter the expression or the function of the eNOS protein has been identified in the eNOS gene in the promoter and codification zones. We studied the Glu298Asp variant of the eNOS gene in 52 hemodialysis (HD) patients, 22 peritoneal dialysis (PD) patients, and 93 healthy controls. Identification of the Glu298Asp variant in exon 7 was performed by enzymatic amplification and restriction fragment length polymorphism (RFLP) analysis. The frequencies of eNOS genotypes in the control group were GG, 39.8%; GT, 43%; and TT, 17.2%. In HD patients, the frequencies were GG, 40.3%; GT, 38.7%; and TT, 21.7%. In PD patients, they were GG, 41.6%; GT, 50%; and TT, 8.6%. No significant differences were seen between the control group and the dialysis patients, or between the HD and the PD patients.

Protein oxidative stress in dialysis patients.

Inflammatory status is observed in patients with chronic renal failure (CRF). The relationship between oxygen free radical production and dialysis could play an important role in protein oxidation. Carbonyl protein plasma level is an important tool in the study of protein stress, and it is related to the arterial intima thickness in the atherosclerosis process. We studied protein oxidative stress in 21 peritoneal dialysis (PD) patients and 42 hemodialysis (HD) patients as compared with 32 undialyzed patients with CRF. Carbonyl protein plasma levels were measured in nanomoles per milligram protein by the ELISA method (Winterbourn et al). Dialysis patients had a higher protein carbonyl content than did CRF patients (0.1265 +/- 0.04 nmol/mg vs. 0.1594 +/- 0.03 nmol/mg, p < 0.0002). Patients on PD had a lower level than patients on HD (0.1452 +/- 0.03 nmol/mg vs. 0.1665 +/- 0.04, p < 0.004). Glucose administration in PD is known to be able to increase glucose degradation products (GDPs) and advanced glycosylation end-products (AGEs) with high carboxylic and oxidative stress. In our study, the carbonyl protein level was higher in HD patients than in PD patients, perhaps because more protein oxidative stress is associated with hemodialysis technique or because the PD patients had greater residual renal function.