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ABSTRACTIntroductionSecondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease (CKD). It begins as an adaptive increase in parathyroid hormone levels to prevent calcium and phosphate derangements. Over time, this condition becomes maladaptive and is associated with increased morbidity and mortality. Current therapies encompass phosphate-lowering strategies, vitamin D analogues, calcimimetics and parathyroidectomy. These approaches harbor inherent limitations, stimulating interest in the development of new drugs for SHPT to overcome these limitations and improve survival and quality of life among CKD patients.Areas coveredThis review delves into the main pathophysiological mechanisms involved in SHPT, alongside the treatment options that are currently available and under active investigation. Data presented herein stem from a comprehensive search conducted across PubMed, Web of Science, ClinicalTrials.gov and International Clinical Trials Registry Platform (ICTRP) spanning from 2000 onwards.Expert OpinionThe advancements in investigational drugs for SHPT hold significant promise for enhancing treatment efficacy while minimizing side effects associated with conventional therapies. Although several challenges still hinder their adoption in clinical practice, ongoing research will likely continue to expand the available therapeutic options, refine treatment strategies, and tailor them to individual patient profiles.

Background: Ambulatory blood pressure monitoring is essential for understanding blood pressure patterns beyond clinical visits, aiding in risk assessment, treatment evaluation, and managing hypertension. This retrospective cohort study aimed to identify risk factors for all-cause mortality and major cardiovascular events in patients who underwent ambulatory blood pressure monitoring. Methodology: Eligible participants aged 18 or older, with an estimated glomerular filtration rate (eGFR) > 60 ml/min/1.73 m2, who underwent ambulatory blood pressure monitoring for various reasons, were included in the study. Data were gathered through telephone interviews, electronic health records, and the national health record system. Descriptive analysis and classification and regression tree modeling were used to uncover significant risk factors related to all-cause mortality and cardiovascular events, and to assess the model’s performance compared to traditional Cox survival analysis. Results: The study included 1291 patients, primarily male (51.8%) with a mean age of 61.1 ± 15.2 years. During a mean follow-up of 46.9 months, 76 (5.9%) patients died of any cause, and 195 (15.1%) had a cardiovascular event. The highest survival rates were observed in patients with a diastolic blood pressure (BP) dipping percentage between − 2% and 29%, nighttime systolic BP variability below 32 mmHg, and age below 72. Conversely, smokers with a diastolic BP dipping percentage below − 10% showed the lowest survival rates. The best cardiovascular outcomes were observed in patients with diastolic BP dipping above − 11%, nighttime mean systolic BP < 144 mmHg, no statin use, normotensive status, and daytime mean heart rate ≥ 60 bpm. Conversely, the worst outcomes were seen in patients with diastolic BP dipping below − 11% and a morning surge ≥ 14 mmHg. In all-cause mortality and cardiovascular event analysis, the combined model demonstrated excellent calibration and predictive power, like the classification and regression tree model and traditional analysis. Conclusion: These findings highlight the potential of a combined model for assessing mortality and cardiovascular event risk in patients who have undergone ambulatory blood pressure monitoring. Graphical abstract:

ABSTRACTIntroductionCardiovascular disease (CVD) is one of the global leading causes of morbidity and mortality in chronic kidney disease (CKD) patients. Vascular calcification (VC) is a major cause of CVD in this population and is the consequence of complex interactions between inhibitor and promoter factors leading to pathological deposition of calcium and phosphate in soft tissues. Different pathological landscapes are associated with the development of VC, such as endothelial dysfunction, oxidative stress, chronic inflammation, loss of mineralization inhibitors, release of calcifying extracellular vesicles (cEVs) and circulating calcifying cells.Areas coveredIn this review, we examined the literature and summarized the pathophysiology, biomarkers and focused on the treatments of VC.Expert opinionEven though there is no consensus regarding specific treatment options, we provide the currently available treatment strategies that focus on phosphate balance, correction of vitamin D and vitamin K deficiencies, avoidance of both extremes of bone turnover, normalizing calcium levels and reduction of inflammatory response and the potential and promising therapeutic approaches liketargeting cellular mechanisms of calcification (e.g. SNF472, TNAP inhibitors).Creating novel scores to detect in advance VC and implementing targeted therapies is crucial to treat them and improve the future management of these patients.

ABSTRACTIntroduction:Secondary hyperparathyroidism (SHPT) represents a complication of chronic kidney disease (CKD). Vitamin D system is altered since early CKD, and vitamin D deficiency is an established trigger of SHPT. Although untreated SHPT may degenerate into tertiary hyperparathyroidism with detrimental consequences in advanced CKD, best treatments for counteracting SHPT from stage 3 CKD are still debated. Enthusiasm on prescription of vitamin D receptor activators (VDRA) in non-dialysis renal patients, has been mitigated by the risk of low bone turnover and positive calcium-phosphate balance. Nutritional vitamin D is now suggested as first-line therapy to treat SHPT with low 25(OH)D insufficiency. However, no high-grade evidence supports the best choice between ergocalciferol, cholecalciferol, and calcifediol (in its immediate or extended-release formulation).Areas covered:The review discusses available data on safety and efficacy of nutritional vitamin D, VDRA and nutritional therapy in replenishing 25(OH)D deficiency and counteracting SHPT in non-dialysis CKD patients.Expert opinion:Best treatment for low 25(OH)D and SHPT remains unknown, due to incomplete understanding of the best homeostatic, as mutable, adaptation of mineral metabolism to CKD progression. Nutritional vitamin D and nutritional therapy appear safest interventions, whenever contextualized with single-patient characteristics. VDRA should be restricted to uncontrolled SHPT by first-line therapy.

Vascular calcification (VC) is common in advanced chronic kidney disease (CKD), contributes to cardiovascular disease (CVD), and associates with increased mortality. Major risk factors for VC in CKD are increasing age, dialysis vintage, and positive net calcium-phosphate balance. To date, no specific therapy that prevents progression or facilitates regression of VC beyond careful attention to calcium and phosphate balance exists. Accumulating evidence demonstrates that CKD patients may incur subclinical vitamin K deficiency. This deficiency may be induced by exhaustion of vitamin K due to its high requirement by vitamin K-dependent proteins to inhibit VC. This review analyzes the pathophysiological mechanisms and clinical consequences of vitamin K deficiency with emphasis on its involvement on vascular calcification in CKD and end-stage renal disease and its relationship to the bone-vascular axis.

Osteoporosis and chronic kidney disease (CKD) have both independently important potential impact on bone health. A significant number of patients with CKD stages 3a–5D have been shown to have low bone mineral density (BMD), leading to a strikingly elevated risk of fractures (mainly hip fractures) and higher associated morbidity and mortality. Mechanical properties of bone beyond age and menopausal status are additionally affected by intrinsic uremic factors. Therefore, we review in this article not only general concepts of osteoporosis and related consequences, but also the diagnostic and therapeutic implications of low BMD and bone fractures in CKD, beyond increased vascular calcification. Antiresorptive agents (mainly bisphosphonates) were not previously recommended when the estimated glomerular filtration rate (GFR) was lower than 30 ml/min/1.73 m2. However, post-hoc analysis of large randomized clinical trials found that these drugs (i.e. alendronate, ribandronate, denosumab) had comparable efficacy in improving BMD and reducing fracture risk in individuals (mainly women) with moderate reductions of GFR (mostly CKD stages 3–4). Therefore, at least in the absence of clear abnormalities of CKD-related mineral metabolism disturbances, bone antiresorptive agents (and maybe anabolic agents) that are or will be approved for general osteoporosis may be appropriate for CKD. Nephrologists should probably not ignore any longer fracture risk assessment, especially in patients with additional risk factors for osteoporosis if results will impact treatment decisions. However, although different therapeutic agents have been shown to reduce the risk of fracture in CKD patients with low BMD, specific prospective studies, with or without bone biopsies, in CKD are urgently needed.

Prostaglandin E2(PGE2) is the major prostaglandin produced both centrally and in the periphery in models of acute and chronic inflammation, and its formation in both locations is blocked by cyclooxygenase-2 (COX-2) inhibitors such as celecoxib. In animal models of inflammation, PGE2inhibition in the brain may occur secondarily to a peripheral action by inhibiting local PG formation that elicits increased firing of pain fibers and consequent activation of PG synthesis in the central nervous system (CNS). Celecoxib was studied in the kainate-induced seizure model in the rat, a model of direct central prostaglandin induction, to determine whether it can act directly in the CNS. In the kainate-treated rat brain there was increased PGE2, PGF2α, and PGD2production, with COX activity and PGE2formation increased about 7-fold over normal. We quantitated mRNA levels for enzymes involved in the prostaglandin biosynthetic pathways and found that both COX-2 and PGE synthase (PGEs) mRNA levels were increased in the brain; no changes were found for expression of COX-1 or PGD synthase mRNA. By Western blot analysis, COX-2 and PGEs were induced in total brain, hippocampus, and cortex, but not in the spinal cord. Immunohistological studies showed that COX-2 protein expression was enhanced in neurons. Dexamethasone treatment reduced the expression of both COX-2 and PGEs in kainate-treated animals. Celecoxib reduced the elevated PGE2levels in brain of kainate-treated rats and inhibited induced COX activity, demonstrating the ability of this compound to act on COX-2 in CNS. Doses of celecoxib that inhibited brain COX-2 were lower than those needed for anti-inflammatory activity in adjuvant arthritis, demonstrating a potent direct central action of the compound.

The aim of this work was to evaluate the role of leukotrienes in brain damage in vivoin a model of focal cerebral ischaemia in the rat, obtained by permanent occlusion of middle cerebral artery.A significant (P<0.01) elevation of LTC4, LTD4and LTE4(cysteinyl‐leukotrienes) levels occurred 4 h after ischaemia induction in the ipsilateral cortices of ischaemic compared to sham‐operated animals (3998±475 and 897±170 fmol g−1tissue, respectively, P<0.01).The NMDA receptor antagonist MK‐801 and the adenosine A2Areceptor antagonist SCH 58261 were administered in vivoat doses known to reduce infarct size and compared with the leukotriene biosynthesis inhibitor MK‐886.MK‐886 (0.3 and 2 mg kg−1i.v.) and MK‐801 (3 mg kg−1i.p.) decreased cysteinyl‐leukotriene levels (−78%, P<0.05; −100%, P<0.01; −92%, P<0.01, respectively) 4 h after permanent occlusion of the middle cerebral artery, whereas SCH 58261 (0.01 mg kg−1i.v.) had no significant effects.MK‐886 (2 mg kg−1i.v.) was also able to significantly reduce the cortical infarct size by 30% (P<0.05).We conclude that cysteinyl‐leukotriene formation is associated with NMDA receptor activation, and that it represents a neurotoxic event, the inhibition of which is able to reduce brain infarct area in a focal ischaemic event.

Vitamin D in CKDImportant mineral homeostasis disorders occur from the early stages of chronic kidney disease (CKD), despite patients may be completely asymptomatic. These disorders, affecting the serum levels of calcium, phosphorus, parathyroid hormone, and vitamin D, have a striking impact on the patient's prognosis as they affect the cardiovascular system. The new term “Chronic Kidney Disease-Mineral Bone Disease” (CKD-MBD) was created to define bone disease during CKD as a systemic disorder tightly linked to cardiovascular calcifications and disabilities. Vitamin D deficiency has a main role in the pathogenesis of CKD-MBD through the pleiotropic actions of this hormone. Vitamin D receptors (VDRs) are ubiquitarious, and their activation has shown protective effects against the development of secondary hyperparathyroidism as well as anti-hypertensive, anti-inflammatory, anti-fibrotic, immunomodulating, anti-proliferative, anti-diabetic, and anti-proteinuric properties. These mechanisms can explain, at least in part, the influence of vitamin D status for avoiding and delaying cardiovascular disease and CKD progression. These findings strongly support the importance of an early diagnosis of mineral homeostasis disorders in CKD and the need for a correction of vitamin D deficiency to prevent the disabilities and major events related to it.

Reaction of the Wieland-Miescher ketone 1 in ethylene glycol at room temperature using one equivalentof p- toluenesulphonicacid gives the 9-ethylene ketal 2in ≥90% yield and 92% selectivity.