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The oto-renal axis describes the relationship between hearing loss and chronic nephropathy. Several clinical studies have investigated the incidence of hypoacusia in patients affected by chronic renal failure, but the etiopathogenic mechanism is not fully understood. In this context, there is a general agreement that hypoacusia is usually neurosensorial and the cochlea is the main site of lesion. Inner ear and kidney present an interesting similarity in terms of structure and function. In particular, the presence of pericytes and podocytes in inner ear and in glomeruli, respectively, evidence common characteristics of microcirculation. Defects in microcirculation in the inner ear mainly cause an electrolytic imbalance with the consequent impairment of endocochlear potential and sensorial transduction. In kidney, microvessels and podocytes contribute to glomerular stability and function. Microcirculation dysfunction often occurs during the inflammatory status, frequently reported both in chronic nephropathy and in cardiovascular disease. Clinical studies aimed to describe the hypoacusia in nephropathy patients are summarized. Then, in order to speculate the etiopathogenic mechanism of hearing loss in chronic nephropathy, we report the similarities between pericytes and podocytes in inner ear and glomeruli microcirculation in terms of structure and function. Finally, we propose a model in which inflammation plays an important role in oto-renal dysfunction. Our model proposes the inflammation, as an etiopathogenic mechanism of hypoacusia in chronic nephropathy and the defective cross-talk between pericytes/podocytes and vascular endothelium, as the initial event of the degenerative process.

This is an update of incidence and mortality cancer data provided by the Italian Network of Cancer Registry (AIRTUM) relative to the period 2003-2005.AIRTUM is a network of general and specialized population-based cancer registries that covers about 1/3 of the Italian resident population (www.registri-tumori.it). Incidence and mortality data for the period 2003-2005 are based on 20 Registries. The five most frequently diagnosed cancers were: - prostate (18.5%), non melanoma skin (15.8%), lung (13.1%), colorectal (12.0%), bladder (5.7%) among males; - breast (24.9%), non melanoma skin (15.1%), colorectal (11.9%), lung (5.0%) and stomach (4.1%) among females. In the same period the most frequent causes of cancer death were: - cancer of the lung (27.6%), colorectal (10.7%), prostate (8.5%), stomach (7.3%) and liver (6.1%) among males; - breast cancer (16.3%), colorectal (11.9%), lung (10.3%), stomach (7.2%) and pancreas (6.5%) among females. According to the age-specific incidence rates one man and one woman every two will receive a cancer diagnosis during his/hers life (from birth to the age of 84 years). From 1993-1995 to 2003-2005, overall crude cancer incidence rate (males and females together) increased from 555.4 to 654.8 x 100,000. Standardization showed that 63% of this increase was due to ageing of the population. Moreover, most of the residual increase was among those cancer sites (breast, prostate, colorectal, thyroid and melanoma) for which early detection may have played a relevant role in anticipating (and therefore increasing) the number of diagnoses. Due to population ageing also overall cancer mortality did not show any decrease when crude rates were compared. On the contrary, standardized mortality rates (all cancers together) showed a strong decrease (311.4 vs. 266.5 x 100.000). The risk of receiving a diagnosis or dying because of cancer is still lower in residents in the regions of the South of Italy than in those of Central and Northern Italy, but they are becoming more and more similar. In Italy cancer incidence and mortality rates are similar to those in northern European countries and in USA among males, but they are still lower for women.

Fractures and vascular calcifications (VCs) are common in patients with chronic kidney disease (CKD). They are related to abnormalities in vitamin D metabolism, calcium, phosphorus, parathyroid hormone, and fibroblast growth factor 23 (FGF23)/Klotho that occur with CKD. Impaired vitamin D metabolism and abnormal levels of calcium, phosphate, parathyroid hormone (PTH), and FGF23/Klotho drive bone and vascular changes in CKD. It is unclear if oral calcitriol safely mitigates fracture risk without increasing the burden of calcifications. Therefore, we investigated whether treatment with calcitriol affected the prevalence of fractures and VC progression in hemodialysis (HD) patients. This report is a secondary analysis of the Vitamin K Italian (VIKI) study, a cross-sectional study involving 387 HD patients. We assessed vitamin 25(OH)D, alkaline phosphatase, PTH, calcium, phosphate, osteocalcin or bone Gla protein, matrix Gla protein, and vitamin K levels. Vertebral fractures (VFs) and VCs were determined by spine radiograph. A reduction of >20% of vertebral body height was considered a VF. VCs were quantified by the length of calcific lesions along the arteries. The patients treated with oral calcitriol were 177 of 387 patients (45.7%). The prevalence of VF was lower in patients receiving oral calcitriol than in those untreated (48.6% versus 61.0%, p=0.015), whereas the presence of aortic and iliac calcifications was similar (aortic: 81.9% versus 79.5%, respectively, p=0.552; iliac: 52.0% and 59.5%, respectively, p=0.167). In multivariable logistic regression analysis, oral calcitriol was associated with a 40.2% reduced odds of fracture (OR 0.598; 95% confidence interval [CI], 0.363–0.985; p=0.043). In conclusion, we found a significant association between oral calcitriol and lower VF in HD patients without an increase in the burden of VC. Further prospective and interventional studies are needed to confirm these findings. © 2021 American Society for Bone and Mineral Research (ASBMR).

Vitamin K acts as a coenzyme of carboxylase, catalyzing the carboxylation of several vitamin K dependent proteins. Beyond its well-known effects on blood coagulation, it also exerts relevant effects on bone and the vascular system. In this review, we point out the relevance of an adequate vitamin K intake to obtain sufficient levels of carboxylated (active form) vitamin K dependent proteins (such as Osteocalcin and matrix Gla protein) to prevent bone health. Another bone-related action of Vitamin K is being a ligand of the nuclear steroid and xenobiotic receptor (SXR). We also discuss the recommended intake, deficiency, and assessment of vitamin K. Furthermore, we review the few available studies that have as pre-specified outcome bone fractures, indicating that we need more clinical studies to confirm that vitamin K is a potential therapeutic agent for bone fractures.

Recent improvements in our understanding of physiology have altered the way in which bone is perceived: no longer is it considered as simply the repository of divalent ions, but rather as a sophisticated endocrine organ with potential extraskeletal effects. Indeed, a number of pathologic conditions involving bone in different ways can now be reconsidered from a bone-centred perspective. For example, in metabolic bone diseases like osteoporosis (OP) and renal osteodystrophy (ROD), the association with a worse cardiovascular outcome can be tentatively explained by the possible derangements of three recently discovered bone hormones (osteocalcin, fibroblast growth factor 23 and sclerostin) and a bone-specific enzyme (alkaline phosphatase). Further, in recent years the close link between bone and inflammation has been better appreciated and a wide range of chronic inflammatory states (from rheumatoid arthritis to ageing) are being explored to discover the biochemical changes that ultimately lead to bone loss and OP. Also, it has been acknowledged that the concept of the bone-vascular axis may explain, for example, the relationship between bone metabolism and vessel wall diseases like atherosclerosis and arteriosclerosis, with potential involvement of a number of cytokines and metabolic pathways. A very important discovery in bone physiology is the bone marrow (BM) niche, the functional unit where stem cells interact, exchanging signals that impact on their fate as bone-forming cells or immune-competent haematopoietic elements. This new element of bone physiology has been recognized to be dysfunctional in diabetes (so-called diabetic mobilopathy), with possible clinical implications. In our opinion, ROD, the metabolic bone disease of renal patients, will in the future probably be identified as a cause of BM niche dysfunction. An integrated view of bone, which includes the BM niche, now seems necessary in order to understand the complex clinical entity of chronic kidney disease-mineral and bone disorders and its cardiovascular burden. Bone is thus becoming a recurrently considered paradigm for different inter-organ communications that needs to be considered in patients with complex diseases.

Gene polymorphisms involved in homocysteine-methionine pathway result in hyperhomocysteinemia, a predisposing condition to several diseases. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate and homocysteine metabolism. The two known functional polymorphisms of MTHFR gene, 677C>T and 1298A>C have been implicated in a variety of multifactorial diseases: cardio-cerebrovascular and neurodegenerative disorders, autoimmune diseases, birth defects, diabetes, neuropsychiatric disorders, cancer and renal disease. C667T, and to a lesser extent A1298C polymorphisms, have been also reported to have a pharmacogenetic role in predicting drug toxicity in cancer and rheumatoid arthritis treatment. We review here the principal effects of the MTHFR gene variations in different clinical conditions.

Different arterial wall properties can significantly increase the risk of blood turbulent fluxes leading to complications such as atherosclerosis. Since the mechanical properties of arterial vessels are influenced by age, we investigated, in a retrospective study, the effects on renal artery stenosis of an age difference >15 years between donor and recipient in a cohort of 164 patients undergoing renal transplantation between 1981 and 1991. The age difference between donor and recipient was ≤15 years in 87 patients (53.0%) (Group A) and >15 years in 77 patients (47.0%) (Group B,p=ns). None of the Group A patients developed an anastomotic arterial stenosis, whereas 8/77 Group B patients (10.4%) had an anastomotic arterial stenosis (p<0.001). This study shows that an age difference >15 years is significantly linked to the risk of developing arterial stenosis after renal transplantation. Indeed, different wall properties can significantly increase the risk of generation of blood turbulent fluxes and involve, in the arterial vessels, the development of complications such as atherosclerosis.

Background: Hyperhomocysteinemia (Hhcy) occurs in about 85% of chronic kidney disease (CKD) patients because of impaired renal metabolism and reduced renal excretion. Folic acid (FA), the synthetic form of vitamin B9, is critical in the conversion of homocysteine (Hcy) to methionine. If there is not enough intake of FA, there is not enough conversion, and Hcy levels are raised. Summary: Hhcy is regarded as an independent predictor of cardiovascular morbidity and mortality in end-stage renal disease. Hhcy exerts its pathogenic action on the main processes involved in the progression of vascular damage. Research has shown Hhcy suggests enhanced risks for inflammation and endothelial injury which lead to cardiovascular disease (CVD), stroke, and CKD. FA has also been shown to improve endothelial function without lowering Hcy, suggesting an alternative explanation for the effect of FA on endothelial function. Recently, the role of FA and Hhcy in CVD and in CKD progression was renewed in some randomized trials. Key Messages: In the general population and in CKD patients, it remains a topic of discussion whether any beneficial effects of FA therapy are to be referred to its direct effect or to a reduction of Hhcy. While waiting for the results of confirmatory trials, it is reasonable to consider FA with or without methylcobalamin supplementation as appropriate adjunctive therapy in patients with CKD.

Background/Aim: Clinical and subclinical hypothyroidism is more common in patients with end-stage renal disease (ESRD) than in the general population. Patients with ESRD with hypothyroidism are more susceptible to cardiovascular disease, with an increased risk of mortality than those with normal thyroid function. Moreover, these patients have higher incidence of benign and malignant nodules. Patients and Methods: This was a retrospective study on 2,147 patients with ESRD on the renal transplant waiting list between 2000 and 2015 aimed at identifying the presence of hypothyroidism and associated variables. Results: Hypothyroidism was detected in 437/2,147 (20.3%) patients, 289 of them having the subclinical form. Cardiovascular disease and older age were significantly associated with hypothyroidism, and autosomal polycystic kidney disease was correlated to goiter (p

Background Patients affected by Chronic Kidney Disease and Mineral Bone Disorder (CKD-MBD) have a high risk of cardiovascular (CV) mortality that is poorly explained by traditional risk factors. The newest medical treatments for CKD-MBD have been associated with encouraging, but still inconsistent, improvement in CV disease complications and patient survival. A better understanding of the biomarkers and mechanisms of left ventricular hypertrophy (LVH), atherosclerosis, and vascular calcification (VC) may help with diagnosis and treatment of the organ damage that occurs secondary to CKD-MBD, thus improving survival. Recent insights about fibroblast growth factor-23 (FGF23) and its co-receptor, Klotho, have led to marked advancement in interpreting data on vascular aging and CKDMBD. Conclusion This review will discuss the current experimental and clinical evidence regarding FGF23 and Klotho, with a particular focus on their roles in LVH, atherosclerosis, and VC.

Background: Chronic kidney disease-mineral and bone disorder (CKD-MBD) has been implicated in vascular calcification pathogenesis. CKD-MBD results in alterations in the number and function of circulating endothelial progenitor cells (EPCs), physiological regulators of angiogenesis and vessel repair, commonly defined as proangiogenic progenitor cells (PACs) by the antigen pattern CD34+CD133+KDR+CD45– and putative EPCs by the pattern CD34+CD133−KDR+CD45–. These cells might acquire a calcifying phenotype in CKD-MBD, expressing mineralization biomarkers. We investigated the expression of vitamin D receptor (VDR) and osteocalcin (OC) on EPCs of healthy individuals and haemodialysis patients, and their possible associations with circulating biomarkers of inflammation and vascular calcification. Methods: We compared EPC counts, expressing VDR or OC, in 23 healthy subjects versus 53 haemodialysis patients, 17 of them without vitamin D receptor agonist (VDRA) therapy and 35 treated with calcitriol (n = 17) or paricalcitol (n = 18). The correlations with serum levels of inflammatory and calcification indexes were also analysed. Results: All subsets expressing VDR or OC were significantly higher in haemodialysis patients compared with healthy controls, but PACs were increased only in VDRA treatment subgroup, while putative EPCs showed a similar rise also in untreated patients. In VDRA-untreated patients, OC+ PACs correlated positively with calcium levels, while in VDRA-treated patients, VDR+ PACs correlated positively with interleukin 6 levels, and OC+ PACs correlated positively 25-hydroxyvitamin D levels. Conclusions: Our data suggest that in CKD-MBD, EPCs undergo an endothelial-to-procalcific shift, representing a risk factor for vascular calcification. A link between mineral disorders and vitamin D replacement therapy emerged, with potential adverse effects for CKD patients.

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Background: While chronic renal damage is a condition with low-grade inflammation, the potential role of inflammation in kidney disease as a marker of cardiovascular damage is of current interest. This study analyzed the relationship between renal dysfunction, chronic inflammation, and extension of coronary atherosclerosis in patients with non-ST-segment elevation myocardial infarction (NSTEMI). Methods: This retrospective study was carried out on consecutive patients presenting with NSTEMI to Maggiore Hospital’s emergency department between January 1, 2010 and December 31, 2011. Patients’ electronic charts were reviewed to gather information on patients’ history, clinical and biochemical variables, with a special focus on inflammatory markers, coronary vessel damage, and drug treatments. Results: Of the 320 individuals in the study population, 138 (43.1%) had an admission GFR

INTRODUCTION: Chronic kidney disease (CKD) is a worldwide health problem. Despite remarkable headway in slowing the progression of kidney diseases, the incidence of end-stage renal disease (ESRD) is increasing in all countries with a severe impact on patients and society. The high incidence of diabetes and hypertension, along with the aging population, may partially explain this growth. Currently, the mainstay of pharmacological treatment for CKD, aiming to slow progression to ESRD are ACE inhibitors and angiotensin II receptor blockers for their hemodynamic/antihypertensive and anti-inflammatory/antifibrotic action. However, novel drugs would be highly desirable to effectively slow the progressive renal function loss. AREAS COVERED: Through the search engines, PubMed and ClinicalTrial.gov, the scientific literature was reviewed in search of emerging drugs in Phase II or III trials, which appear to be the most promising for CKD treatment. EXPERT OPINION: The great expectations for new drugs for the management of CKD over the last decade have unfortunately not been met. Encouraging results from preliminary studies with specific agents need to be tempered with caution, given the absence of consistent and adequate data. To date, several agents that showed great promise in animal studies have been less effective in humans.

Background: Kidney transplantation is the treatment of choice for chronic kidney disease (CKD), but in kidney transplant recipients (KTRs) cardiovascular events are the first cause of death with a functioning graft, ranging from 36 to 55%. The impact of vascular calcification (VC) on morbidity and mortality of KTRs is not appreciated enough nowadays. Summary: This review summarizes 13 important studies on VC in KTRs, comparing the results with CKD and dialysis populations. We focused on VC evaluation and use of coronary artery calcification (CAC) and aorta calcification (AoC) scores. We also evaluated the influence of traditional and non-traditional progression risk factors. Key Messages: VC strongly predicts cardiovascular events and all-cause mortality in KTRs. VC assessment is important in KTRs and based essentially on multislice computed tomography or electron beam computed tomography recognition of lesions. Quantitative measurement of CAC and AoC scores is essential for a correct definition of the calcium burden before and after kidney transplant. Progression of CAC slows down but does not halt after kidney transplant. A variable association of both traditional and non-traditional risk factors is shown. There is a strong association between baseline CAC score and CAC progression. A significant improvement in secondary hyperparathyroidism after transplantation favorably affects the progression of CAC. Low 25(OH)D3 levels are an independent determinant of CAC progression. Diabetes is a risk factor for the presence of CAC in KTRs, but has not been independently associated with CAC progression. The data published on the use of immunosuppressive drugs as progression factors are few and inconclusive.