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Routine systems for monitoring vascular access (VA) performance are lacking. We developed a vascular access triage system to evaluate the monthly performance of the access, developed a specific score and assessed the association between score improvement and clinical outcomes. Vascular access was triaged (Green, Yellow or Red) according to a score generated by dialytic and clinical parameters in all patients who, from 1/1/2014 to 31/03/2014, had been receiving haemodialysis treatment for at least 3 consecutive months in our Unit and who were then followed up for 4 years. We enrolled 130 patients, 78 with arteriovenous fistula (AVF) and 52 with tunnelled central venous catheter (CVC). During a median of 29 ± 11 months of follow up (range 3–46 months), 28 deaths and 303 hospitalizations (lasting 16 ± 30 days) were recorded. Vascular access triage scores improved over time (2014 vs 2015 vs 2016 vs 2017) in the population with an AVF (Green from 25% to 58% to 77% to 79%, Yellow from 65% to 39% to 18% to 20% and Red from 10% to 3% to 5% to 1%, respectively; χ2 p

In Italy, starting from 2015, the date of publication of the guidelines on the 2014-2020 Digital Growth Strategy, technological evolution in medicine has provided encouraging results. The term telemedicine is now in common use, and it is also indicated at an encyclopedic level as “the set of technical and health care monitoring tools, created through systems designed to provide quick access to both medical specialists and patients, regardless of the place where they are respectively located”. Nowadays, in the COVID era, the need for social distancing has highlighted the contribution of digital technology to healthcare in terms of access to care and healthcare spending. With regard to chronic kidney disease, telemedicine has always proved essential in improving patients’ quality of life, as in the case of peritoneal dialysis. The remote management and monitoring of patients undergoing peritoneal dialysis has not only proved to radically change and improve patients’ quality of life in replacement therapy, but has also reduced costs. There are some situations in which telemonitoring can guarantee the maintenance of an adequate quality of life for patients in the different stages of the disease. Thanks to the constant commitment of some groups of professionals where the largest part is represented by the “pink quota”, it was possible to experiment and implement evaluation protocols for the renal patient in conservative and replacement treatment in some of the most central aspects of care: medical and dietary therapy.

Intradialytic hypotension (IDH) is a hemodynamic phenomenon recently associated with decreased blood oxygen saturation (SO2). The ratio between peripheral oxygen saturation (SpO2) and central venous SO2 (ScvO2) or Oxygen Extraction Ratio (OER), which represents a roughly estimate of the amount of oxygen claimed by peripheral tissues, might be used to estimate haemodialysis (HD) related hypoxic stress. Aim of this pilot study was to evaluate the relationship between OER increments during dialysis sessions (ΔOER) and episodes of IDH. We enrolled chronic HD patients with permanent central venous catheter (CVC) and no fistula, in whom ScvO2 measurement is at hand. OER ([(SpO2 − ScvO2)/SpO2] × 100) was measured in three consecutive HD sessions (HD OER sessions) before HD, after 15′, 30′ and 60′ min and at the end of HD. Then, a one-year follow-up was planned to record the number of IDH episodes. In the 28 enrolled patients (age 74 ± 2.6 years), during 12 ± 1.2 months of follow up, incidence of IDH was 3.6%. We divided patients into two groups, above or below the median value of ΔOER at the end of HD, which was 36%. In these groups, the average incidence of IDH was 7% and 2% respectively (p 19% after only 15′ of HD treatment or > 36% at the end of the session characterize patients with higher rates of hypotension. Intradialytic ∆OER, a parameter of tissue hypoxic stress, identifies more fragile patients at greater risk of IDH.

The impressive estimated number of chronic kidney disease (CKD) patients in the world justifies any possible effort at implementing preventive measures of disease progression. Renal insufficiency is associated with significant changes in the electrolyte handling and body balance of sodium, potassium, phosphate, magnesium, and calcium, all of which are biologically vital molecules. Dietary habits could contribute significantly to the optimal management of possible derangements. In this review, we examined the available evidence recommending dietary prescriptions for these five elements aiming at reducing CKD progression. Clear evidence that specific dietary prescriptions may halt or reduce CKD progression is lacking. However, some practical recommendations are possible to prescribe the best possible therapy to the individual CKD patient.

Bone is not only a mineralized and apparently non-vital structure that provides support for locomotion and protection to inner organs. An increasing number of studies are unveiling new biologic functions and connections to other systems, giving the rise to new fields of research, such as osteoimmunology. The bone marrow niche, a new entity in bone physiology, seems to represent the site where a complex crosstalk between bone and immune/inflammatory responses takes place. An impressive interplay with the immune system is realized in bone marrow, with reciprocal influences between bone cells and haematopoietic cells. In this way, systemic chronic inflammatory diseases realize a crosstalk with bone, resulting in bone disease. Thus, pathogenetic links between chronic kidney disease-mineral bone disorders and osteoporosis, cardiovascular disease, and ageing are common. The aim of this narrative review is to provide a general view of the progresses in the field of bone research and their potential clinical implications, with emphasis on the links with inflammation and the connections to osteoimmunology and chemokines.

Background and Aims Assuming that FGF23 levels correlate with phosphate excretion per nephron, nephron number can be estimated by measuring FGF23 levels and urinary phosphate excretion (FEP). Kuro-O proposed that the ratio of FEP to serum FGF23 levels should correlate with nephron number and is defined as the Nephron Index (NI). The aim of the study is calculating NI as nephron number estimation in patients affected by various degree of chronic kidney disease, both transplanted and not. Method In 147 CRF patients kidney function, mineral metabolism biomarkers and NI were evaluated. Nephron Index was calculated following Kuro-o’s equation (kuro-o 2019): NI=FEP·Ps·eGFRFGF23 Observed patients were divided into two groups: patients with CKD (noTX) and transplanted ones (TX). Results noTX group was made up of 67 patients (40 males and 27 females) affected by CKD stages from G1 to G5. TX group was composed by 80 patient (49 males and 31 females) with various degree of CKD (G1T-G4T) showing mean graft age of 83,2 ± 54,8 months (range: 10,3-268,0). The two groups differed for age (mean age 59 ± 15,6 years in CKD, 55± 10,3years in TX). Mean eGFR did not differ between TX and noTX but NI was higher in TX since FEP was higher despite lower FGF23 levels in TX. The difference in FGF23 levels does not appear to depend on Klotho and PTH whose serum levels were no different between Tx and noTx. (Table1). As far as correlations are concerned, NI correlated with eGFR, FGF23, PTH and 1,25D in both group, while NI correlated with FEP only in the TX group. It's interesting that no correlation existed between FGF23 and sP, FEP, eGFR and sKlotho in TX differently from noTX (Table2). Discussion. NI could not be properly defined as nephron number estimation in TX pts. However it may represent higher function of residual nephrons, since higher FEP did not correlate to FGF23 and could be determined by compensatory hyperfiltration (increased single nephron GFR) in transplanted patients. Conclusion After kidney transplantation, high NI value could have a functional meaning rather than represent residual number of nephrons.

Background and Aims DMT2 and its complications such as chronic kidney disease (CKD) lead to increase vascular stiffness, measurable with CAVI, and biochemical alterations in substances implicated in vascular damage like Klotho, FGF23, and Sclerostin. The aim of the study was to evaluate the role of CKD stage 1-2 and possible alterations of 25 (OH)Vitamin-D, FGF23, Klotho, and Sclerostin on early vascular damage in DMT2 patients Method Patients included: DMT2 from Results We enrolled 40 women and 60 men, average age 56 years (IQR: 52-59), 5-year DMT2 (IQR: 2.7-7), HbA1c 6.3% (5.8-6.7), eGFR of 95 ml/min/1.73m2. FGF23 (42±10 vs controls 29.8±11 pmol/l, p Conclusion In our DMT2 population, borderline and pathological CAVI is associated with increased ACR, elevated DBP and reduced 25(OH)Vitamin-D. Furthermore the alterations of FGF23, Sclerostin and Klotho, secondary to CKD, are an early sign of possible vascular damage. ACR, 25(OH)Vitamin-D and DBP can be modifiable risk factors for early vascular damage in DMT2

The goal of the World Kidney Day 2020 (WKD) is “the promotion of public health by ensuring universal, equitable and sustainable access to care, making access to health for all people and social categories equitable”. Chronic Kidney Disease (CKD) is a complex and “demanding” health problem for patients and professionals, particularly in the more advanced stages of the disease. In addition to factors such as the so-called systemic conditions and risk factors, sex-related factors intervene in women, which can further complicate the CKD trend. For these reasons, one of the objectives of the World Kidney Day is that prevention and early treatment are included in the Universal Health Coverage (UHC) and that common strategies are implemented to promote awareness of this pathology. The woman has always played a central role in the “coordination” of family life and “taking care”, a role transversal to the different ethnic groups, as evidenced also by the data relating to living kidney donation. This article gives a reflection on some issues related to prevention and treatment of CKD from a female perspective, such as what strategies to identify to implement prevention in the family starting from nutrition, such as the advice for the preparation of a diet plan respectful of the traditions of the country of origin, the identification and treatment of risk factors in order to implement strategies aimed at prevention dedicated to the female world and which style distinguishes the female approach to care | (Gender_nephrology)

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.

Chronic Kidney Disease (CKD) associates with disturbed modulation of hormones involved in calcium and phosphate homeostasis, with development of secondary hyperparathyroidism (SHPT). SHPT includes not only divalent ions derangements, but also renal bone disease (high turnover, low turnover and/or osteomalacia) and accelerated vascular and ectopic calcifications. In this way, SHPT resembles a true clinical syndrome named CKD-MBD, which is a recognized risk factor of all-cause and cardiovascular death. Long lasting stimulation of parathyroid hormone synthesis and secretion, as observed in CKD, causes specific and progressive histological changes responsible for the development of nodular hyperplastic glands unresponsive to physiologic inhibitors and thus characterized by hypercalcemia, elevated PTH levels and resistance to the available medical therapies. In these cases, surgical parathyroidectomy (PTX) becomes the only therapeutic option. In this chapter we review current evidence on indications, types and clinical outcomes of PTX from a practical and clinical point of view.

Increasing knowledge on inflammatory mediators and bone metabolism highlights the relationship between inflammation and bone disease. During acute illness, inflammatory cells and cytokines modulate bone cells activity so as to mobilize calcium seemingly to supply the metabolic requirements for immune response. In case of long lasting, chronic inflammatory states a condition of maladaptive, smouldering inflammation is realized and negatively affects calcium bone balance. Aging, now nicknamed inflammaging, is regarded as a chronic inflammatory condition, characterized by increased circulating inflammatory cytokines, that contributes to the development of osteoporosis, cardiovascular diseases and chronic kidney disease. In patients with renal insufficiency, the development of bone and mineral disorders (so called CKD-MBD "syndrome") is now a recognized pathogenic factor for the seemingly accelerated process of aging and for the increased risk of cardiovascular death in these patients. The adaptive changes in mineral and bone metabolism developing in the early stages of chronic kidney disease could represent a hypothetical model of accelerated aging, osteoporosis and cardiovascular disease.

Background and Aim: Chitotriosidase (Chit), a mammalian chitinases secreted by monocytes and epithelial cells, is increased in both cardiovascular disease (CVD) and type 2 diabetes (T2D). Arterial stiffness rises early in T2D and increases the risk of CVD. Aim of the study was to evaluate Chit activity as a precocious biomarker of arterial stiffness in T2D patients without overt vascular complications. Methods: Arterial stiffness was measured by Cardio-Ankle Vascular Index (CAVI) in 174 T2D patients (mean±SD age=55±4 years, 103 men) without established diabetic complications. For this cross-sectional study, we measured Chit activity by electrochemiluminescent assay in the sera from the 41 patients with the lowest (L_CAVI) and the 42 patients with the highest (H_CAVI) CAVI values. Results: Compared with L_CAVI, H_CAVI patients were older (57±4years vs. 52±4years, p Conclusion: Arterial stiffness raises with age, metabolic control, DBP and impaired kidney function. Chit is also associated with DBP, metabolic control and kidney damage but did not result as a direct marker of arterial stiffness in T2D patients without established complications. Disclosure L. D'Onofrio: None. C. Luordi: None. C. Mignogna: None. A. Carlone: None. C. Moretti: None. L. Tartaglione: None. E. Maddaloni: Speaker's Bureau; Self; Merck & Co., Inc., Pikdare. G. Leto: None. S. Mazzaferro: None. R. Buzzetti: None. Funding Sapienza University of Rome (“Avvio alla ricerca 2016”)

Chronic renal failure has an average prevalence of 10% in the general population and carries a significant burden of morbidity and mortality. Moreover, the recently appreciated cross-talk between b...

Calciphylaxis is a rare disease characterized by ectopic calcification of skin arterioles resulting in ischemia, thrombosis and necrosis. Since end stage renal disease patients are those mainly affected, the term calcific uremic arteriolopathy (CUA) is also suggested. Early clinical manifestations are subtle, while overt necrotic ulcers may quickly spread and become infected so as to result in ominous outcome. Diagnosis might not be easy due to the number of other ischemic and non-ischemic skin lesions observed in uraemia. Skin biopsy, has been proposed as the diagnostic test and is often considered, but not systematically performed due to the hypothetical risk of further spreading of the lesions. Such ambiguity could be responsible for misdiagnosis or underdiagnosis. We review here five consecutive cases recorded in our Unit, all submitted to skin biopsy but with inconsistent results which generated some clinical frustration. Thus, we decided to carefully re-evaluate all of them together with pathologists and dermatologists. However, even after this ex-post discussion, we could not reach a complete agreement on the final diagnosis. In the meanwhile, papers were published in the literature that started to shed some light on the role of skin biopsy in the diagnosis of CUA.

Background Doppler ultrasound (DU) monitoring early after arteriovenous fistula (AVF) creation allows the identification of low blood flow (Qa) requiring prompt revision, but it is costly (needs skilled operators and technical instruments) and is not available in all dialysis units. Therefore alternative first-line methods to measure Qa would be welcomed. We reasoned that once an AVF is created, an increment in central venous oxygen saturation (ScvO2) is predictable and proportional to Qa. Methods Accordingly, in patients receiving dialysis through a central venous catheter (CVC) in whom an AVF was created, we measured, by means of blood gas analysis, the ScvO2 increment before and after manual compression of the arteriovenous shunt and verified its correlation with DU-measured Qa. Results We sampled blood gas in 18 patients with CVC and AVF before and after 30 s manual compression of the AVF. ScvO2 averaged 70.5 ± 3% before and 65.2 ± 3% after AVF closure, with an average drop of 5.1 ± 3% (range 1–12). AVF Qa, which was measured within 24 h by means of DU, averaged 635 ± 349 mL/min (range 50–1300) and was strictly and positively correlated with ΔScvO2 (r = 0.954, P Conclusions Therefore we suggest that in patients with CVC and a newly created AVF, it is possible to monitor AVF Qa without DU by simply measuring blood gas and ΔScvO2. This technique is simple, cheap, repeatable, non-invasive and operator independent and represents a new useful screening test to detect delayed AVF access maturation deserving prompt DU measurement and surgical revision. It helps to quickly identify patients in urgent need of DU verification and possible surgical revision. Regrettably, it is applicable only in patients with CVC.

Rationale & Objective Hyperphosphatemia is associated with increased risk for chronic kidney disease (CKD) progression and reduced antiproteinuric effects of renin-angiotensin system (RAS) blockers. We investigated whether the phosphate binder sevelamer carbonate may enhance the antiproteinuric effect of RAS inhibitors in patients with CKD. Study Design Phase 2, randomized, controlled, open-label, crossover trial. Setting & Participants Between November 2013 and December 2014, we enrolled 53 patients with CKD with estimated glomerular filtration rates (eGFRs)>15mL/min/1.73m2 and residual proteinuria with protein excretion≥0.5g/24h despite maximal tolerated ramipril and/or irbesartan therapy from 2 nephrology units in Italy. Intervention After stratification by serum phosphate level, ≤4 or>4mg/dL, patients were randomly assigned to 3 months of sevelamer (1,600mg thrice daily) treatment followed by 3 months without sevelamer separated by a 1-month washout period or 3 months without sevelamer followed by 3 months with sevelamer, also separated by a 1-month washout period. Outcomes The primary outcome was 24-hour proteinuria (n=49patients). Secondary outcomes included measured GFR (using iohexol plasma clearance), office blood pressure (BP), serum lipid levels, levels of inflammation and bone metabolism biomarkers, urinary electrolyte levels, and arterial stiffness. Results Changes in proteinuria during the 3-month treatment with (from 1.36 [IQR, 0.77-2.51] to 1.36 [IQR, 0.77-2.60] g/24h) or without (from 1.36 [IQR, 0.99-2.38] to 1.48 [IQR, 0.81-2.77] g/24h) sevelamer were similar (P=0.1). Sevelamer reduced urinary phosphate excretion without affecting serum phosphate levels. Sevelamer reduced C-reactive protein (CRP), glycated hemoglobin, and total and low-density lipoprotein cholesterol levels and increased high-density lipoprotein cholesterol levels without affecting levels of office BP, measured GFR, fibroblast growth factor 23, klotho, intact parathyroid hormone, serum vitamin D, or other urinary electrolytes. Results were similar in the low- and high-phosphate groups. Sevelamer was well tolerated. Adverse events were comparable between treatment periods. One case of transient hypophosphatemia was observed during treatment with sevelamer. Limitations Short treatment duration, lower pretreatment proteinuria than expected. Conclusions 3-month sevelamer treatment did not reduce proteinuria in patients with CKD on maximal RAS blockade. Amelioration of inflammation and dyslipidemia with sevelamer treatment raises the possibility that it may confer benefit in patients with CKD beyond reduction of proteinuria. Funding Sanofi (Milan, Italy). Trial Registration Registered at ClinicalTrials.gov with study number NCT01968759.

When medical therapy is unable to achieve biochemical control of secondary hyperparathyroidism, parathyroidectomy (PTX) is indicated, fortunately in a minority of patients. Thus, data on PTX prevalence and biochemical control are limited and, in particular in Italy, date back to 1999. We designed a prospective, observational and multicenter study to collect data from dialysis units distributed throughout the Italian regions. Clinical data were collected with a dedicated data sheet. From January to December 2010, 149 Centers serving a total of 12,515 patients provided data on 528 living PTX cases (PTX prevalence = 4.2%). Prevalence was higher in hemo- than in peritoneal dialysis (4.5 vs. 1.9%, X2 = 21.52; p

Recent clinical observations underline the link between bone disease and disturbances of mineral metabolism with increased morbidity and mortality of Chronic Renal Failure (CRF). Indeed, in patients with Chronic Kidney Disease (CKD), bone disease may occur either with normal glomerular filtration rate (renal tubular disorders involving pH, Calcium or Phosphate metabolism) or with reduced glomerular filtration rate (the complex endocrine disorder of secondary hyperparathyroidism of CRF). Recently, to underline the clinical burden of this type of secondary hyperparathyroidism, a new clinical term has been introduced: CKD-MBD (chronic kidney disease-mineral and bone disorder). Besides bone disease, the endocrine derangements of mineral metabolism and the accelerated calcification processes of vessel walls are considered together in this syndrome, to highlight the pathogenetic link with cardiovascular disease and the eventual morbidity and mortality. The gold standard technique to diagnose renal osteodystrophy still remains the invasive bone biopsy. The less invasive biomarkers and radiologic techniques are less reliable to evaluate bone histology but are necessary to study the hormonal condition and the mechanical performance of the skeleton, respectively. As for therapy, it has been mostly focused on the control of secondary hyperparathyroidism, but this does not impact significantly the high fracture rate of renal patients. New drugs employed for osteoporosis and targeting specific functions of bone cells promise to open new therapeutic frontiers for renal osteodystrophy and CKD-MBD.

Renal osteodystrophy (ROD), the histologic bone lesions of chronic kidney disease (CKD), is now included in a wider syndrome with laboratory abnormalities of mineral metabolism and extra-skeletal calcifications or CKD-mineral and bone disorders (CKD-MBD), to highlight the increased burden of mortality. Aging people, frequently identified as early CKD, could suffer from either the classical age-related osteoporosis (OP) or ROD. Distinguishing between these two bone diseases may not be easy without bone biopsy. In any case, besides classical therapies for ROD, nephrologists are now challenged by the possibility of using new drugs developed for OP. Importantly, while therapies for ROD mostly aim at controlling parathyroid secretion with bone effects regarded as indirect, new drugs for OP directly modulate bone cells activity. Thus, their action could be useful in specific types of ROD. Parathyroid hormone therapy, which is anabolic in OP, could be useful in renal patients with low turnover bone disease. Denosumab, the monoclonal antibody against receptor activator of NF-κB ligand (RANK-L) that inhibits osteoclast activity and proliferation, could be beneficial in cases with high turnover bone. Use of romosozumab, the monoclonal antibody against sclerostin, which both stimulates osteoblasts and inhibits osteoclasts, could allow both anabolic and anti-resorptive effects. However, we should not forget the systemic role now attributed to CKD-MBD. In fact, therapies targeting bone cells activity could also result in unpredicted extra-bone effects and affect cardiovascular outcomes. In conclusion, the new biologicals established for OP could be useful in renal patients with either OP or ROD. In addition, their potential non-bone effects warrant investigation.

Bariatric surgery represents the elective treatment of severe obesity (BMI≥40Kg/m2) since it results in better control of cardiovascular risk factors and comorbidities typically associated with obesity, like diabetes, hypertension and dyslipidemia. Obesity is a recognized independent risk factor for chronic kidney disease and for progression of renal insufficiency. Pathomechanisms are still incompletely known. Obesity is associated with hyper-filtration, microalbuminuria and proteinuria all of which favor renal disease and its progression. This narrative review reports on the available evidence linking bariatric surgery and renal function since this surgery may affect proteinuria, hyper-filtration and glomerular filtration rate. Although available data are limited in particular in cases with more advanced stages of renal failure, bariatric surgery associates with improved filtration and lower proteinuria in patients with mild to moderate renal insufficiency. In patients with more advanced stages of renal failure, surgery should be considered if obesity represents a relative contraindication to transplantation. Surgery seems to improve graft survival. Further, nephrologists should be informed on the metabolic and nutritional changes associated with bariatric surgery, which could be responsible for untoward effects requiring early identification and treatment. Bariatric surgery could be a valid therapeutic option in renal patients to improve the negative clinical outcomes of obese subjects.

INTRODUCTION Vitamin D insufficiency contributes to calcitriol (1,25D) reduction in chronic kidney disease (CKD). Since CKD patients on conservative therapy (CRF) mostly develop, whereas transplant (TX) patients possibly recover from, secondary hyperparathyroidism (SH), we hypothesized a different efficiency of vitamin D hydroxylation in these 2 clinical conditions. METHODS We compared the impact of reduced 25-hydroxyvitamin D (25D) on circulating 1,25D in 111 CRF (mean age 63 ± 15 years; estimated glomerular filtration rate [eGFR] 36.4 ± 22.0 ml/min) and in 136 TX patients (mean age 50 ± 11 years; eGFR 47 ± 19.0 ml/min). RESULTS Vitamin D insufficient patients (69.1% in TX vs. 82% in CRF; p

For many years vitamin D has been the only available drug to suppress parathyroid hormone (PTH) hypersecretion in patients with renal insufficiency. This effect is accomplished directly through activation of the vitamin D receptor (VDR) on parathyroid cells. However, vitamin D also stimulates intestinal absorption of calcium and phosphate, thus often resulting in hypercalcemia and hyperphosphatemia, both undesirable in renal patients. For this reason vitamin D analogs with less calcemic effects have been developed, with some improvement of this problematic effect. The discovery of calcium sensing receptor (CaSR) and the subsequent production of drugs capable of stimulating it, has allowed the introduction of calcimimetics as an alternative therapy to vitamin D. Cinacalcet, the first to be available for clinical uses, has been successfully employed to reduce serum PTH levels in patients with end stage renal disease. At variance with vitamin D, calcimimetics, while decreasing PTH, also decrease serum levels of calcium and phosphate. The effect on serum calcium is of such entity that symptomatic hypocalcemia may occur. As a consequence, vitamin D is frequently associated and instead of becoming an alternative, cinacalcet is mostly prescribed together with vitamin D. Importantly, we have clear experimental evidence that vitamin D administration increases the expression of CaSR on target cells and that, reciprocally, calcimimetics increase VDR expression. This interaction allows presuming potential clinical advantages to control secondary hyperparathyroidism. Further, since both VDR and CaSR are expressed also in tissues not involved with mineral metabolism, other still unpredicted clinical effects are possible.

Transmembraneα-Klotho (TM-Klotho), expressed in renal tubules, is a cofactor for FGF23-receptor. Circulating soluble-α-Klotho (s-Klotho) results from TM-Klotho shedding and acts on Phosphate (P) and Calcium (Ca) tubular transport. Decreased TM-Klotho, described in experimental chronic kidney disease (CKD), prevents actions of FGF23 and lessens circulating s-Klotho. Thus, levels of s-Klotho could represent a marker of CKD-MBD. To evaluate the clinical significance of s-Klotho in CKD we assayed serum s-Klotho and serum FGF23 in 68 patients (age58±15; eGFR45±21 mL/min). s-Klotho was lower than normal (519±183versus845±330 pg/mL,P<.0001) in renal patients and its reduction was detectable since CKD stage 2 (P<.01). s-Klotho correlated positively with eGFR and serum calcium (Cas) and negatively with serum phosphate (Ps), PTH and FGF23. FGF23 was higher than normal (73±51versus36±11,P<.0002) with significantly increased levels since CKD stage 2 (P<.001). Our data indicate a negative effect of renal disease on circulating s-Klotho starting very early in CKD. Assuming that s-Klotho mirrors TM-Klotho synthesis, low circulating s-Klotho seems to reflect the ensuing of tubular resistance to FGF23, which, accordingly, is increased. We endorse s-Klotho as an early marker of CKD-MBD.

The increased awareness of the potential role played by mineral and bone disorder in the appearance of cardiovascular disease in renal patients has produced research efforts aimed at discovering possible pathogenic links. Accordingly, the diagnostic significance of the classic bone markers of mineral disorders and of the new markers in the setting of chronic kidney disease-mineral and bone disorders (CKD-MBD) needs to be re-evaluated along with increasing information. In this article we include classic markers of bone metabolism and some of the noncollagenous bone proteins that are gaining experimental and clinical significance in CKD-MBD. Among classic markers of secondary hyperparathyroidism and of renal osteodystrophy, we analyzed parathyroid hormone, alkaline phosphatase, tartrate-resistant acid phosphatase, and bone collagen-derived peptides. We underlined, for each, the relevance of parent proteins (peptides or isoforms) that affect assay methods and, eventually, the diagnostic or prognostic significance. Also, we considered their relationship with cardiovascular mortality. Among the numerous noncollagenous bone proteins, we examined matrix Gla protein (MGP), osteocalcin (OC), osteoprotegerin, and the small integrin-binding ligand N-linked glycoprotein family. For MGP and OC we report the relevant involvement with the process of calcification (MGP) and with glucose and energy metabolism (OC). Both of these proteins require vitamin K to become active and this is a specific problem in renal patients who frequently are deficient of this vitamin. Finally, recent acquisitions on the fascinating family of the small integrin-binding ligand N-linked glycoprotein proteins are recapitulated briefly to underline their potential clinical interest and their complex involvement with all aspects of CKD-MBD. Their diagnostic role in clinical practice awaits further studies.

The pathogenesis of vascular calcifications in uremia is not completely understood, but is regarded as multifactorial, involving traditional and nontraditional risk factors. In particular, derangements in divalent ions are considered of outmost importance, but also the role of physiologic inhibitors of calcification is now claimed. The most powerful physiologic inhibitor of calcification is pyrophosphate, but its biochemical instability precludes its clinical use to date. The pharmacologic analogs of pyrophosphate, bisphosphonates, cannot be easily tested for this purpose in renal patients, given their renal clearance. The list of proteins involved in calcification is a growing one, and experimental models point to the potential clinical relevance of matrix Gla protein, fetuin, osteopontin, osteoprotegerin and bone morphogenetic protein-7. Induction of metabolic acidosis, although theoretically useful, is not recommended, while administration of sodium thiosulphate could be beneficial, but its safety awaits confirmation. Actually, the only available therapies for vascular calcifications are those directed toward achievement of the biochemical targets for calcium, phosphate and parathyroid hormone with the hope, but not the certainty, that this will be efficacious. However, to this purpose, selection of the most appropriate strategy in the individual patient seems essential.

Renal tubular diseases may present with osteopenia, osteoporosis or osteomalacia, as a result of significant derangements in body electrolytes. In case of insufficient synthesis of calcitriol, as in renal failure, the more complex picture of renal osteodystrophy may develop. Hypothetically, also disturbed renal production of BMP-7 and Klotho could cause bone disease. However, the acknowledgment that osteocytes are capable of producing FGF23, a phosphaturic hormone at the same time modulating renal synthesis of calcitriol, indicates that it is also bone that can influence renal function. Importantly, a feed-back mechanism exists between FGF23 and calcitriol synthesis, while Klotho, produced by the kidney, determines activity and selectivity of FGF23. Identification of human diseases linked to disturbed production of FGF23 and Klotho underlines the importance of this new bone-kidney axis. Kidney and bone communicate reciprocally to regulate the sophisticated machinery responsible for divalent ions homeostasis and for osseous or extraosseous mineralisation processes.