Reprint of: Vitamin D receptor activation and prevention of arterial ageing.

In chronic kidney disease (CKD) patients, cardiovascular (CV) morbidity and mortality rate is higher than in the general population, because of frequently concomitant hypertension, peripheral vascular disease, heart failure, vascular calcification (VC), diabetes and mineral bone disease. Recently, another important factor associated to CV risk in CKD has been deeply investigated: vitamin D deficiency. Vitamin D Receptors (VDRs) are present in several systems and tissues and VDR activation is associated to positive effects, resulting in better blood pressure control and prevention of diabetic nephropathy. Unfortunately, the natural, non-selective vitamin D receptor activator (VDRA), calcitriol, is associated to higher serum calcium and phosphate levels, thus worsening CV risk in CKD. Recent data showed that the selective VDRA paricalcitol might have ameliorative CV effects. The potential positive impact of the use of paricalcitol on diabetic nephropathy, cardiac disease, hypertension, and VC may open new paths in the fight against CV disease in CKD patients.

Vitamin D receptor activation and prevention of arterial ageing.

In chronic kidney disease (CKD) patients, cardiovascular (CV) morbidity and mortality rate is higher than in the general population, because of frequently concomitant hypertension, peripheral vascular disease, heart failure, vascular calcification (VC), diabetes and mineral bone disease. Recently, another important factor associated to CV risk in CKD has been deeply investigated: vitamin D deficiency. Vitamin D Receptors (VDRs) are present in several systems and tissues and VDR activation is associated to positive effects, resulting in better blood pressure control and prevention of diabetic nephropathy. Unfortunately, the natural, non-selective vitamin D receptor activator (VDRA), calcitriol, is associated to higher serum calcium and phosphate levels, thus worsening CV risk in CKD. Recent data showed that the selective VDRA paricalcitol might have ameliorative CV effects. The potential positive impact of the use of paricalcitol on diabetic nephropathy, cardiac disease, hypertension, and VC may open new paths in the fight against CV disease in CKD patients.

Unsuccessful application of taurolidine in the treatment of fungal peritonitis in peritoneal dialysis.

Fungal peritonitis (FP) is a serious complication for peritoneal dialysis (PD) patients, determining hospitalization, technique failure, catheter loss and death. In the 2005 update, treatment recommendations for FP from the International Society of Peritoneal Dialysis (ISPD) advocate catheter removal immediately after fungi are identified by microscopy or culture. The availability of more effective medical treatments could therefore be of great importance. The aim of this report is to describe a case of a 43-year-old, diabetic, HIV positive PD patient with fluconazole resistant Candida peritonitis, who was treated with an i.p. taurolidine solution. Taurolidine is a non-antibiotic antimicrobial, with broad bactericidal and fungicidal properties. It has been used during surgery for lavage of the peritoneum in cases of peritonitis. Its mechanism of action is related to direct toxic action on micro-organisms, through a chemical reaction between active taurolidine derivatives and structures on the cell wall. Treatment failed because the patient had severe burning pain during i.p. administration of the drug, limiting its dose. PD catheter removal allowed complete recovery. It remains undetermined if, with different doses and methodology, taurolidine could be more effective in treating bacterial and/or fungal peritonitis. Currently, catheter removal remains the most effective therapy of fungal peritonitis.

Clinical significance of FGF-23 measurement in dialysis patients.

AIMS: Considering the growing relevance of fibroblast growth factor-23 (FGF-23) in the pathogenesis of chronic kidney disease bone and mineral disorder (CKD-MBD), an analysis was performed to determine the relative importance of C-terminal (cFGF-23) and intact (iFGF-23) assays in assessing CKD-MBD status in the first place and the relationship between FGF-23 and mortality as a secondary aim. METHODS: In 77 patients (15 peritoneal dialysis and 62 hemodialysis), levels of calcium, phosphate, parathyroid hormone (PTH), 25-hydroxyvitamin- D (25D), 1,25D, FGF-23 (C-terminal and intact molecule) were measured and their correlations were analyzed. The relationship between FGF-23 levels and patient survival was also analyzed. RESULTS: A significant correlation was found between cFGF-23 and 1,25D, PTH and 25D while iFGF-23 was significantly correlated with phosphate, 25D and PTH. PTH and 1,25D were independent predictors of cFGF-23, while for iFGF-23 independent predictors were phosphate and 25D. No significant relationship was found between FGF-23 and mortality. CONCLUSIONS: C-terminal or intact FGF-23 levels are weakly correlated and thus not clearly indicative of FGF-23 effects on PTH, P and vitamin D metabolism in dialysis patients. Assays for cFGF-23 and iFGF-23 showed a good correlation, but the intact molecule was not superior in defining interactions with CKD-MBD molecules. Measuring FGF-23 on a regular basis with the current assays in CKD and dialysis patients does not yet seem clinically useful.

Vitamin K, bone fractures, and vascular calcifications in chronic kidney disease: an important but poorly studied relationship.

Vitamin K denotes a group of lipophilic vitamins determining post-translational modification of proteins. There are 2 main forms of vitamin K: vitamin K1 (phylloquinone, found in vegetables); vitamin K2 (menaquinone, produced by bacteria in the intestine and in fermented foods). Vitamin K stores are limited in humans, but it can be recycled. Vitamin K1 is principally transported to the liver, regulating the production of coagulation factors. Vitamin K2, instead, is also transported to extra-hepatic tissues, such as bone and arteries, regulating the activity of matrix Gla-protein (MGP) and osteocalcin [bone Gla-protein (BGP)]. In patients with chronic kidney disease (CKD), cardiovascular mortality is the first cause of death. Some pathogenetic mechanisms of vascular calcification (such as hyperparathyroidism, hyperphosphatemia, hypercalcemia, role of vitamin D) have been widely investigated, but the potential role of vitamin K is still uncertain. Vitamin K could play a key role, as it transforms glutamic acid residues into γ-carboxyglutamic acid, through a carboxylation process, makings both MGP (cMGP) and BGP (cBGP) biologically active. cMGP inhibits vascular calcifications (VC), while cBGP has an important role for a proper mineralization process. Uncarboxylated MGP and BGP (ucMGP and ucBGP) concentrations are indirect markers of vitamin K2 deficiency. The purpose of this review is to analyze the current literature to understand the relationship between vitamin K2 status, fragility fractures and VC in CKD patients. This analysis could be of help in planning investigations of Vitamin K status and its possible supplementation in CKD patients to avert fragility fractures and VC.

Vertebral fractures in dialysis: Endocrinological disruption of the bone-kidney axis.

The occurrence of metabolic bone disease in patients with renal dysfunction is due to the key role played by the kidney in regulating calcium-phosphate metabolism. The incidence of hip fractures in end-stage renal disease is 3- to 4-fold higher than the general population, while poor data about vertebral fractures show similar prevalence. Bone health has been mainly evaluated in the general population through bone mass density (BMD) measurements, while in Chronic Kidney Disease (CKD) patients, bone turnover (low or high turnover) has been considered the most relevant parameter. Indeed, in CKD patients, the association between BMD and fractures is unclear, and even studies on established risk factors (body mass index, PTH, and vitamin D) for fractures have contrasting outcomes. Recently, an important association has been found between bone disorders and vascular calcifications in CKD patients that has changed the denomination of renal osteodystrophy in CKD mineral and bone disorder. In this article, a poorly investigated subject, vertebral fractures in CKD patients, is addressed, as it is underestimated despite its remarkable clinical relevance.

Metabolic consequences of peritoneal dialysis treatment.

Energy and protein metabolism are both altered in chronic kidney disease (CKD) from its early stages. Patients undergoing peritoneal dialysis (PD) use peritoneal solutions with glucose as osmotic agent, which exposes them to an increased glucose load (40-80 g/day) and during PD there is a net loss of proteins through the peritoneum (4-8 g/day). Insulin resistance may lead to a reduction of the anabolic effects of insulin, while its proliferative effects on adipose tissue are potentially enhanced. Insulin resistance is also an important factor in the development of hypertriglyceridemia in PD patients: it increases free fatty acid availability, which then stimulates the release of large triglyceride-rich VLDL. Moreover, inhibitors of lipolytic enzymes (apoC-III, inflammation, oxidative modification and carbamoylation of apolipoproteins) may reduce lipid clearance, contributing to the development of dyslipidemia. Inflammatory molecules also play an important role in regulating glucose metabolism, and the excessive activation of inflammatory pathways may represent a fundamental step in the development of insulin resistance, including an over-expression of cytokines. Frequently, protein intake is reduced in PD because of under-dialysis, glucose load, abdominal discomfort and abnormal hormones levels, leading to a complex "protein-energy malnutrition". Optimization of dialysis dose, correction of acidosis and anemia and nutritional counseling, together with "non-traditional" management strategies, such as the use of PD solutions without glucose, like icodextrin and amino acid based solutions, represent the best strategies to prevent and correct malnutrition in PD patients. The mainstay of therapy is a reduction of glucose-based PD solutions and a correct dietary prescription.

[Pathogenesis and treatment of vascular calcification in CKD]. / Invecchiamento cardiovascolare nel soggetto uremico: nuove acquisizioni.

Increased vascular calcification is a major cause of cardiovascular events in patients with chronic kidney disease (CKD). It is the result of an active ossification process counteracted by ''bone'' proteins such as osteopontin, alkaline phosphatase, osteoprotegerin, and osteocalcin. Chronic kidney disease - mineral and bone disorder (CKD-MBD) is a systemic disorder of mineral and bone metabolism that occurs in CKD. In addition to abnormalities in the serum calcium and phosphate profile, CKD-MBD is characterized by abnormalities of bone turnover, mineralization, volume and growth as well as vascular calcification. Considering that the presence and extent of vascular calcification in CKD portend a poor prognosis, many efforts have been made to shed light on this complicated phenomenon to prevent vascular calcium deposition and its progression. Indeed, careful control of calcium load, serum phosphate and parathyroid hormone along with the use of calcium-free phosphate binders and vitamin D receptor activators represent a new therapeutic armamentarium to improve quality of life and reduce mortality in CKD.

The mechanisms of hyperphosphatemia-induced vascular calcification.

Extensive calcification of the arterial wall and soft tissues is a frequent feature of patients with end-stage chronic kidney disease (CKD stage 5). Hyperphosphatemia and secondary hyperparathyroidism have been extensively investigated as inducing factors in cardiovascular calcification. In fact, cardiovascular disease in renal failure is associated with bone metabolism alterations. Together with passive deposition of calcium-phosphate in extraskeletal tissues, it has recently been demonstrated that inorganic phosphate induces arterial calcification directly through a real "ossification" of the tunica media in the vasculature of CKD patients. Therefore, control of serum phosphate in CKD patients becomes crucial in preventing increases in calcium x phosphate product, secondary hyperparathyroidism, and ultimately vascular calcification.

Impaired brachial artery endothelial flow-mediated dilation and orthostatic stress in hemodialysis patients.

PURPOSE: Chronic kidney disease (CKD) is associated with an impaired endothelial function, which may contribute to cardiovascular events. Whether impairment in endothelial function is involved in the circulatory response to orthostatic stress is unknown. We assessed endothelial function via brachial artery flow-mediated dilation (BAFMD), an index of endothelial-dependent vasodilation. METHODS: We measured changes in brachial artery diameter (BAD) and blood flow by Doppler ultrasound in 35 CKD patients on hemodialysis, 37 young healthy controls (HC) and 50 non-uremic matched controls (MC), in the supine position and after 60 degrees head-up tilting (HUT). RESULTS: In the supine position, endothelial flow-mediated BAD was significantly increased in HC (p<0.001) and MC (p<0.01) while no significant changes were detected in CKD. Mean percent blood flow changes were HC+323.5%, MC+195.1% and CKD+158.8% (HC vs. CKD p<0.001; HC vs. MC p<0.001; MC vs. CKD p=0.04). Similarly, during HUT mean BAD and blood flow increases were significantly impaired in CKD patients. CONCLUSION: In CKD patients, an impaired response in the physiologic vascular reactivity, suggesting endothelial dysfunction, was found in the supine position and after orthostasis by BAFMD. Our results are in favor of a possible adjunctive role of uremia in the abnormal brachial artery response.

Duplex ultrasound evaluation for dialysis access selection and maintenance: a practical guide.

Detailed case directed history and examination is the mainstay of dialysis access modality selection, ie site and type of access, as well as for maintenance of dialysis access for longevity. As a logical step following history and physical examination, duplex ultrasound evaluation (DUE) is the most cost effective and non-invasive screening tool for evaluation for access placement and for assessment of an established access. Pre-operative vascular mapping allows selection of the optimal dialysis access modality and site. In established accesses, duplex ultrasound testing will diagnose the majority of vascular access complications and direct proper surgical or interventional radiology management. This review outlines a practical decision-making algorithm using DUE for choosing and managing the dialysis access.

Understanding the dialysis access steal syndrome. A review of the etiologies, diagnosis, prevention and treatment strategies.

Distal hypoperfusion ischemic syndrome (DHIS), commonly referred to as hand ischemia or 'steal' after dialysis access placement, occurs in 5-10% of cases when the brachial artery is used, or 10 times that of wrist arteriovenous fistulas (AVFs) using the radial artery. It is typically seen in elderly women with diabetes, and may carry severe morbidity including tissue or limb loss if not recognized and treated. Three distinct etiologies include (1) blood flow restriction to the hand from arterial occlusive disease either proximal or distal to the AV access anastomosis, (2) excess blood flow through the AV fistula conduit (true steal), and (3) lack of vascular (arterial) adaptation or collateral flow reserve (ie atherosclerosis) to the increased flow demand from the AV conduit. These three causes of steal may occur alone or in concert. The diagnosis of steal is based on an accurate history and physical examination and confirmed with tests including an arteriogram, duplex Doppler ultrasound (DDU) evaluation with finger pressures and waveform analysis. Treatment of steal includes observation of developing symptoms in mild cases. Balloon angioplasty is the appropriate intervention for an arterial stenosis. At least three distinct surgical corrective procedures exist to counteract the pathophysiology of steal. The ultimate treatment strategy depends on severity of symptoms, the extent of patient co-morbidity, and the local dialysis access technical team support and skills available.

A patient centered decision making dialysis access algorithm.

Much controversy surrounds the establishment of proper planning, placement and management (the best practice pattern) of dialysis access. These include the dialysis type and modality selection, timing of access placement and who places the access. The lack of and the difficulty of performing randomized studies with multiple confounding factors, in an extremely heterogeneous and rapidly changing ESRD population demographics, only partly explains the dialysis access conundrum. Add to this the rapidly developing and competing technologies, the wide spectrum of the professional experience, bias and socio-economic forces to make the ESRD problems as multivariate and complex as life itself. This overview describes a dialysis access algorithm approach to the patient needing renal replacement therapy, considering long-term improved patient outcome as the ultimate objective.

How to avoid and manage a pneumothorax.

Pneumothorax is one of the most frequent complications during percutaneous central vascular cannulation. When choosing a site for central vascular access, the internal jugular vein is preferable to other vessels, for the lower frequency of related complications, including pneumothorax. This review intends to summarize the current state of the art on how to avoid and, if it occurs, to manage this rare but relevant complication. In order to prevent pneumothorax, as well as other relevant complications of central vein cannulation, it is advisable to use ultrasound guidance whenever possible. If pneumothorax occurs, it is important to recognize its signs and symptoms. To exclude the presence of asymptomatic pneumothorax, in the normal clinical routine a chest X-ray should be obtained within 4 hours from the procedure of central vein cannulation of subclavian and internal jugular veins. If promptly recognized, pneumothorax can be managed quickly and in a relatively easy way. Depending on its size and symptoms, and in particular when a tension pneumothorax is suspected, treatment can vary from simple observation to a chest tube insertion or, in the latter case, to an emergency thoracentesis needle insertion in the pleural space.

Light chains removal by extracorporeal techniques in acute kidney injury due to multiple myeloma: a position statement of the Onconephrology Work Group of the Italian Society of Nephrology.

Acute kidney injury (AKI) is a frequent complication of multiple myeloma and is associated with increased short-term mortality. Additionally, even a single episode of AKI can eventually lead to end-stage renal disease (ESRD), significantly reducing quality of life and long-term survival. In the setting of multiple myeloma, severe AKI (requiring dialysis) is typically secondary to cast nephropathy (CN). Renal injury in CN is due to intratubular obstruction from precipitation of monoclonal serum free light chains (sFLC) as well as direct tubular toxicity of sFLC via stimulation of nuclear factor (NF)κB inflammatory pathways. Current mainstays of CN treatment are early removal of precipitating factors such as nephrotoxic drugs, acidosis and dehydration, together with rapid reduction of sFLC levels. Introduction of the proteasome inhibitor bortezomib has significantly improved the response rates in multiple myeloma due to its ability to rapidly reduce sFLC levels and has been referred to as "renoprotective" therapy. As an adjunct to chemotherapy, several new extracorporeal techniques have raised interest as a further means to reduce sFLC concentrations in the treatment of CN. Whether addition of extracorporeal therapies to renoprotective therapy can result in better renal recovery is still a matter of debate and there are currently no guidelines in this field. In this positon paper, we offer an overview of the available data and the authors' perspectives on extracorporeal treatments in CN.

Gastric pH, sevelamer hydrochloride and omeprazole.

AIMS: Sevelamer hydrochloride is a polymer containing multiple amines (40% amine hydrochloride) separated by one carbon from the polymer backbone, and it is not absorbed by the intestine. These amines are partially protonated and interact with phosphate molecules through ionic and hydrogen bonding, therefore reducing phosphate absorption and lowering serum phosphate concentration. Alterations of gastric pH, in particular excessive alkalinization, could interfere with sevelamer phosphate binding capacity. CASE HISTORY: A 30-year-old dialysis patient affected by secondary hyperparathyroidism started sevelamer treatment, 4.8 g/day, with a basal serum phosphate of 6.9 mg/dl. The patient was also treated with omeprazole (20 mg/day) because of chronic gastritis. Phosphate levels normalized (4.2 mg/dl), but after four months of follow-up serum phosphate unexpectedly increased to 7.2 mg/dl. We found out that in the same period she had autonomously increased the dosage of omeprazole to 80 mg/day, due to worsening of dyspepsia. Gastric pH measurement showed a median level of 4.1, rather than the normal values of 1 - 2, indicating excessive pharmacological alkalinization. When omeprazole was reduced to the correct dose of 20 mg/day, we observed a rapid decrease of phosphate levels. CONCLUSION: This case report highlights the influence of gastric pH on sevelamer phosphate binding capacity. The high dose of omeprazole and the consequent excessive increase in gastric pH was probably responsible for a decreased phosphate binding capacity of sevelamer. When patients taking appropriate doses of sevelamer do not respond to treatment, a potential interaction with drugs determining an increase of gastric pH should be considered.

Facial changes in adult uremic patients on chronic dialysis: possible role of hyperparathyroidism.

BACKGROUND: Uremic patients on regular dialytic treatment (RDT) are often affected by a complex metabolic syndrome leading to osteodystrophy. Bone changes are primarily due to high bone turnover, often combined with a mineralization defect leading to increased bone fractures and bone deformities. Although rarely considered, the craniofacial skeleton represents one of the peculiar targets of this complex metabolic disease whose more dramatic pattern is a form of leontiasis ossea. This complication, although described, has never been evaluated in depth nor quantitatively assessed. In order to assess facial deformities in uremic conditions and to understand the possible relation with hyperparathyroidism, we undertook a quantitative evaluation of soft facial structures in a cohort of uremic patients undergoing RDT. METHODS: The three-dimensional coordinates of 50 soft-tissue facial landmarks were obtained by an electromagnetic digitizer in 10 male and 10 female patients with chronic renal insufficiency aged 53-81 years, and in 34 healthy individuals of the same age, ethnicity and sex. Uremic patients were enrolled according to hyperparathyroid status (PTH < 300 pg/mL and PTH > 500 pg/mL). From the landmarks, facial distances, angles and volumes were calculated according to a geometrical face model. RESULTS: Overall, the uremic patients had significantly larger facial volumes than the reference subjects. The effect was particularly evident in the facial middle third (maxilla), leading to an inversion of the mandibular-maxillary ratio. Facial dimensions were increased in all three spatial directions: width (skull base, mandible, nose), length (nose, mandible), and depth (mid face, mandible). The larger maxilla was accompanied by a tendency to more prominent lips (reduced interlabial angle). Some of the facial modifications (nose, lips, mandible) were significantly related to the clinical characteristics of the patients (age, duration of renal insufficiency and PTH levels). CONCLUSIONS: This report, the first in the literature, shows that facial structures of uremic patients are enlarged in comparison with matched normal subjects and that increased bone turnover could be responsible--at least in part--for facial bone changes.

[Prevention of extraskeletal calcifications in uremia]. / Prevenzione delle calcificazioni extrascheletriche nel paziente uremico.

Secondary hyperparathyroidism (HPTH) is a common feature in end-stage renal disease (ESRD) patients. The three main factors involved in secondary HPTH pathogenesis are high phosphate levels, hypocalcemia and vitamin D deficiency. Recently, many studies demonstrated a strong association between bone disease and cardiovascular events in chronic kidney disease patients. In addition, cardiovascular events are the most frequent cause of death in patients with chronic renal failure. Increased levels of serum phosphorus and calcium-phosphate product are directly involved in the pathogenesis of extraskeletal calcifications (blood vessels, soft tissues, etc) in dialyzed patients compared to the non-uremic population. Recent studies suggested that vascular calcification is due not only to a passive calcium-phosphate deposition on atherosclerotic arteries, but also to active mechanisms regulated by bone-associated genes. In particular, fetuin and matrix Gla-protein are two 'protective' proteins associated with reduced vascular calcification and could be the regulatory keys in preventing this process in renal failure. The limitations of calcium salts as phosphate-binders in patients with advanced renal failure have been thoroughly evaluated in the last 5 yrs. New phosphate binders, which do not contain aluminum or calcium, have been developed to reduce the risk of extraskeletal calcifications in ESRD.