Cardiovascular disease (CVD) is a highly common complication and the first cause of death in patients with end-stage renal disease (ESRD) on haemodialysis (HD). In this population, mortality due to CVD is 20 times higher than in the general population and the majority of maintenance HD patients have CVD. This is likely due to ventricular hypertrophy as well as non-traditional risk factors, such as chronic volume overload, anaemia, inflammation, oxidative stress, chronic kidney disease–mineral bone disorder and other aspects of the ‘uraemic milieu’. Better understanding the impact of these numerous factors on CVD would be an important step for prevention and treatment. In this review we focus non-traditional CVD risk factors in HD patients.

A high prevalence of vascular calcification (VC) and a high incidence of cardiovascular events are two key complications of chronic kidney disease. Since most observational studies found a positive association between these two complications, a causal relationship has been assumed. If so, this would render VC a target of therapy. Recent studies, however, suggested this assumption might be an oversimplification. The fundamental aspects of these recent studies are two-fold. The first novel insight is that VC is not a single entity. VC can be the consequence of a wide range of different biological processes, but also of pharmacological interventions. Sometimes it is the underlying process that carries the additional risk, and sometimes it is tissue calcification itself. Both calcium-containing phosphate binders and statin therapy are associated with an increase in VC, but with divergent effects on cardiovascular risk. Moreover, VC can have different anatomical and histological locations. The second novel insight is that the assumption of a straightforward linear association between the amount of VC and risk for clinical events can be challenged. In this review we summarize recent literature that should lead to reconsidering the implications of VC in CKD. This includes an overview of the many different pathways underlying the ultimate occurrence of VC. Finally, we present a nuanced view concerning the pathophysiologic and therapeutic implications of the different types of calcification in patients with chronic kidney disease.

Pathogenesis of vascular calcification in chronic kidney disease. Background. Hyperphosphatemia and hypercalcemia are independent risk factors for higher incidence of cardiovascular events in patients with chronic kidney disease. In addition to increased calcium-phosphate product, hyperphosphatemia accelerates the progression of secondary hyperparathyroidism with the concomitant bone loss, possibly linked to vascular calcium-phosphate precipitation. Results. The control of serum phosphate levels reduces vascular calcification not only by decreasing the degree of secondary hyperparathyroidism and calcium-phosphate product, but also by reducing the expression of proteins responsible for active bone mineral deposition in cells of the vasculature. The calcium and aluminum-free phosphate-binders provide a new and effective therapeutic tool in preventing vascular calcifications in chronic kidney disease in animal models and in hemodialysis patients. Conclusion. Additional investigations are necessary to examine the benefits of different phosphate-binders in reducing mortality from cardiovascular disease.

Diabetes, hypertension and cardiovascular disease have been listed as risk factors for severe coronavirus disease 2019 (COVID-19) since the first report of the disease in January 2020. However, this report did not mention chronic kidney disease (CKD) nor did it provide information on the relevance of estimated glomerular filtration rate (eGFR) or albuminuria. As the disease spread across the globe, information on larger populations with greater granularity on risk factors emerged. The recently published OpenSAFELY project analysed factors associated with COVID-19 death in 17 million patients. The picture that arose differs significantly from initial reports. For example, hypertension is not an independent risk factor for COVID-19 death [adjusted hazard ratio (aHR) 0.89], but renal disease very much is. Dialysis (aHR 3.69), organ transplantation (aHR 3.53) and CKD (aHR 2.52 for patients with eGFR <30 mL/min/1.73 m2) represent three of the four comorbidities associated with the highest mortality risk from COVID-19. The risk associated with CKD Stages 4 and 5 is higher than the risk associated with diabetes mellitus (aHR range 1.31–1.95, depending upon glycaemic control) or chronic heart disease (aHR 1.17). In another recent publication, the Global Burden of Disease collaboration identified that worldwide, CKD is the most prevalent risk factor for severe COVID-19. Moreover, the distribution of risk factors for COVID-19 mortality appears to be different in patients with CKD when compared with the general population. The high prevalence of CKD in combination with the elevated risk of mortality from COVID-19 in CKD necessitates urgent action for this group of patients. This article defines essential action points (summarized in Box 1), among which is advocating the inclusion of CKD patients in clinical trials testing the efficacy of drugs and vaccines to prevent severe COVID-19.

In intact cells, HIV-PIs markedly suppress the activities of 25- and 1alpha-hydroxylase, which are critical in 1,25(OH) D synthesis, while exerting mild inhibition of 24-hydroxylase, responsible for 1,25(OH) D catabolism. If PIs elicit a similar potency in inhibiting these critical steps for 1,25(OH) D homeostasis, defective 1,25(OH) D production could contribute to the bone demineralization in HIV patients.

In early uremia, vitamin D suppression of high P-induced PT hyperplasia and high dietary Ca arrest of PT growth involve induction of PT p21 and prevention of increases in TGF-alpha.

The importance of phosphate homeostasis in chronic kidney disease (CKD) has been recognized for decades, but novel insights - which are frequently relevant to everyday clinical practice - continue to emerge. Epidemiological data consistently indicate an association between hyperphosphataemia and poor clinical outcomes. Moreover, compelling evidence suggests direct toxicity of increased phosphate concentrations. Importantly, serum phosphate concentration has a circadian rhythm that must be considered when interpreting patient phosphate levels. Detailed understanding of dietary sources of phosphate, including food additives, can enable phosphate restriction without risking protein malnutrition. Dietary counselling provides an often underestimated opportunity to target the increasing exposure to dietary phosphate of both the general population and patients with CKD. In patients with secondary hyperparathyroidism, bone can be an important source of serum phosphate, and adequate appreciation of this fact should impact treatment. Dietary and pharmotherapeutic interventions are efficacious strategies to lower phosphate intake and serum concentration. However, strong evidence that targeting serum phosphate improves patient outcomes is currently lacking. Future studies are, therefore, required to investigate the effects of modern dietary and pharmacological interventions on clinically meaningful end points.

Resistance to erythropoiesis-stimulating agents (ESAs) has been observed in a considerable proportion of patients with chronic kidney disease (CKD) and it is reportedly associated with adverse outcomes, such as increased cardiovascular morbidity, faster progression to end-stage renal disease (ESRD) and all-cause mortality. The major causes of ESA resistance include chronic inflammation producing suppressive cytokines of early erythroid progenitor proliferation. In addition, pro-inflammatory cytokines stimulate hepcidin synthesis thus reducing iron availability for late erythropoiesis. Recent studies showing an association in deficiencies of the vitamin D axis with low haemoglobin (Hb) levels and ESA resistance suggest a new pathophysiological co-factor of renal anaemia. The administration of either native or active vitamin D has been associated with an improvement of anaemia and reduction in ESA requirements. Notably, these effects are not related to parathyroid hormone (PTH) values and seem to be independent on PTH suppression. Another possible explanation may be that calcitriol directly stimulates erythroid progenitors; however, this proliferative effect by extra-renal activation of 1α-hydroxylase enzyme is only a hypothesis. The majority of studies concerning vitamin D deficiency or supplementation, and degree of renal anaemia, point out the prevalent role of inflammation in the mechanism underlying these associations. Immune cells express the vitamin D receptor (VDR) which in turn is involved in the modulation of innate and adaptive immunity. VDR activation inhibits the expression of inflammatory cytokines in stromal and accessory cells and up-regulates the lymphocytic release of interleukin-10 (IL-10) exerting both anti-inflammatory activity and proliferative effects on erythroid progenitors. In CKD patients, vitamin D deficiency may stimulate immune cells within the bone marrow micro-environment to produce cytokines, inducing impaired erythropoiesis. Immune activation involves the reticuloendothelial system, increasing hepcidin synthesis and functional iron deficiency. Consequences of this inflammatory cascade are erythropoietin (EPO) resistance and anaemia. Given the key role of inflammation in the response to EPO, the therapeutic use of agents with anti-cytokines properties, such as vitamin D and paricalcitol, may provide benefit in the prevention/treatment of ESA hyporesponsiveness.