Vitamin K plasma levels determination in human health.

Vitamin K (phylloquinone or vitamin K1 and menaquinones or vitamin K2) plays an important role as a cofactor in the synthesis of hepatic blood coagulation proteins, but recently has also aroused an increasing interest for its action in extra-hepatic tissues, in particular in the regulation of bone and vascular metabolism. The accurate measurement of vitamin K status in humans is still a critical issue. Along with indirect assays, such as the undercarboxylated fractions of vitamin K-dependent proteins [prothrombin, osteocalcin (OC), and matrix gla protein], the direct analysis of blood levels of phylloquinone and menaquinones forms might be considered a more informative and direct method for assessing vitamin K status. Different methods for direct quantification of vitamin K serum levels are available. High-performance liquid chromatography (HPLC) methods coupled with post-column reduction procedures and fluorimetric or electrochemical detection are commonly used for food and blood analysis of phylloquinone, but they show some limitations when applied to the analysis of serum menaquinones because of interferences from triglycerides. Recent advancements include liquid chromatography tandem mass spectrometry (LCMS/MS) detection, which assures higher specificity. The optimization and standardization of these methods requires specialized laboratories. The variability of results observed in the available studies suggests the need for further investigations to obtain more accurate analytical results.

Osteocalcin (bone GLA protein) levels, vascular calcifications, vertebral fractures and mortality in hemodialysis patients with diabetes mellitus.

BACKGROUND AND AIMS: Diabetes mellitus is recognized as one of the major causes of end stage kidney disease. Bone Gla protein (BGP) is a vitamin K-dependent protein involved in bone mineralization and vascular calcifications (VC). Our goal was to characterize BGP and undercarboxylated BGP (ucBGP) in DM patients on HD, compared to HD patients without DM, and their association with vascular and bone disease. METHODS: 387 HD patients from 18 dialysis centers in Italy. Associations of DM, levels of BGP, vitamin D and VC were evaluated. Time-to-event analysis for all-cause mortality was performed by the Kaplan-Meier. RESULTS: Patients with DM had lower levels of total BGP (139.00 vs. 202.50 mcg/L, p < 0.001), 25(OH)D (23.4 vs. 30.2 ng/ml, p < 0.001), and ucBGP (9.24 vs. 11.32 mcg/L, p = 0.022). In regression models, the geometric means of total BGP and ucBGP were 19% (p = 0.009) and 26% (p = 0.034) lower in diabetic patients. In univariate Cox regression analysis, DM patients had a higher risk of all-cause mortality (HR:1.83, 95% CI 1.13-2.96, p = 0.014). Adjustment for confounders confirmed the significant DM-mortality link. We included VC and warfarin into the Cox model, the DM-mortality link was no longer significant, suggesting a role of these risk factors as causal mediators leading to increased mortality in dialysis patients. CONCLUSIONS: HD patients have an increased mortality risk associated with DM. Furthermore, we found an association between DM and decreased BGP levels. Although our study does not support the notion that BGP levels act as mediator in the DM-mortality link, to our knowledge this is the first study in HD patients suggesting a potential protective role of BGP in the bone, endocrine and vascular pathway.

Atrial fibrillation and low vitamin D levels are associated with severe vascular calcifications in hemodialysis patients.

BACKGROUND/AIMS: Vascular calcifications (VCs) and fractures are major complications of chronic kidney disease. Hemodialysis patients have a high prevalence of atrial fibrillation (AF) and an increased risk of thromboembolism, which should be prevented with warfarin, a drug potentially causing increased risk of VCs and fractures. Aim of this study is evaluating, in hemodialysis patients with and without AF, the prevalence of VCs and fractures, as well as identifying the associated risk factors. METHODS: A total of 314 hemodialysis patients were recruited, 101 with documented AF and 213 without AF. Comorbidities, chronic kidney disease mineral and bone disorder blood tests and therapies were collected. Vertebral quantitative morphometry was carried out centrally for the detection of fractures, defined as vertebral body reduction by ≥20 %. In the same radiograph, the length of aortic calcification was also measured. Logistic regression models were applied for evaluating the independent predictors of presence of VCs and vertebral fractures. RESULTS: In our population VCs were very common (>85 %). Severe VCs (>10 cm) were more common in patients with AF (76 %) than in patients without (33 %). Vertebral fractures were present in 54 % of patients. Multivariable analysis showed that AF (OR 5.41, 95 % CI 2.30-12.73) and 25(OH) vitamin D <20 ng/mL (OR 2.05, 95 % CI 1.10-3.83) were independent predictors of VCs. Age (OR 1.04/year, 95 % CI 1.01-1.07) and male gender (OR 1.76, 95 % CI 1.07-2.90) predicted vertebral fractures. CONCLUSIONS: Hemodialysis patients had an elevated prevalence of severe VCs, especially when affected by AF. Low vitamin D levels were strongly associated with severe VCs. Prevalence of vertebral fractures was also remarkably high and associated with older age and male gender.

What every doctor should know about drug safety in patients with chronic kidney disease.

Drug safety is a very relevant issue when dealing with patients with chronic kidney disease (CKD) who need vascular access procedures and interventions. Drug dosage adjustments are needed for patients with acute or chronic kidney disease. In CKD patients, the estimated glomerular filtration rate is used to guide dose adjustments. Determining the influence of renal replacement therapies on drug dosage adjustment is also very important. Safety issues for the following drugs used for situations related to vascular access are reported: anticoagulants and antiplatelet agents, antibiotics, antimicrobials for catheter lock therapy, thrombolytics, local anesthetics, and painkillers. General principles of the interactions of drugs in CKD are also reported.

[Strongyloidiasis in nephrologic patients]. / Strongiloidosi: la cenerentola delle parassitosi. due casi emblematici in pazienti nefrologici.

Strongyloides stercoralis is a nematode causing strongyloidiasis, more frequent in immigrants and in travelers coming from tropical and subtropical areas. Infection is usually asymptomatic, frequently associated with eosinophilia. Immunocompromised patients are at high risk of developing hyperinfection syndrome (HI) or dissemination (SD), life threatening complications. Diagnosis of strongyloidiasis is firstly based on larvae isolation in stool samples; specific therapy involves the use of ivermectin as first choice and albendazole as second choice. We describe two cases of strongyloidiasis. The first one is a disseminated strongyloidiasis occurred in an Ecuadorian male on corticosteroid therapy for nephrotic syndrome due to focal segmental glomerulosclerosis, successfully treated with ivermectin; the second one involves another Ecuadorian male affected by acute kidney failure and nephrotic syndrome in IgA nephropathy with a diagnosis of chronic strongyloidiasis performed before starting the immunosuppressive treatment. The timing of treatment with ivermectin has allowed the complete eradication of the parasite before starting steroid and mycophenolate mofetil therapy, preventing the occurrence of a disseminated infection. Epidemiological data show us how strongyloidiasis is rising at our latitude because of increased number of migrants and travelers coming from endemic areas. So we must always exclude asymptomatic strongyloidiasis before prescribing a steroid or immunosuppressive therapy, in order to avoid developement of disseminated and often fatal disease.

Prevalence of vertebral fractures, vascular calcifications, and mortality in warfarin treated hemodialysis patients.

Warfarin inhibits vitamin-K dependent proteins involved in bone mineralization and the prevention of vascular calcification (bone Gla protein BGP, matrix Gla protein MGP). In this multicenter, cross-sectional study with 3-year follow-up, data from 387 patients on hemodialysis for ≥1 year at 18 dialysis units were analyzed. Patients on warfarin treatment for > 1 year (11.9% of the population) were compared with the remaining cohort for vertebral fractures, vascular calcifications and mortality. Vertebral fractures and vascular calcifications were sought in L-L vertebral X-rays (D5 to L4). Compared with controls, warfarin-treated male patients had more vertebral fractures (77.8 vs. 57.7%, p<0.04), but not females (42.1% vs. 48.4%, p=0.6); total BGP was significantly reduced (82.35 vs. 202 µg/L, p<0.0001), with lower levels in treated men (69.5 vs. women 117.0 µg/L, p=0.03). In multivariate logistic regression analyses, the use of warfarin was associated with increased odds of aortic (OR 2.58, p<0.001) and iliac calcifications (OR 2.86, p<0.001); identified confounders were age, atrial fibrillation, angina, PPI use and total BGP. Seventy-seven patients died during a 2.7±0.5 year follow-up. In univariate Cox regression analysis, patients on warfarin had a higher risk of all-cause mortality (HR 2.42, 95% CI 1.42-4.16, p=0.001) when compared with those untreated and data adjustment for confounders attenuated but confirmed the significant warfarin-mortality link (HR: 1.97, 95% CI: 1.02-3.84, P=0.046). In hemodialysis patients, additional studies are warranted to verify the risk/benefit ratio of warfarin, which appears to be associated with significant morbidity and increased mortality.

Hemodialysis tunneled central venous catheters: five-year outcome analysis.

BACKGROUND: Tunneled central venous catheters (tCVCs) are considered inferior to arteriovenous fistulas (AVFs) and grafts in all nephrology guidelines. However, they are being increasingly used as hemodialysis vascular access. The purpose of this study was to document the natural history of tCVCs and determine the rate and type of catheter replacement. METHODS: This was a prospective study of 141 patients who underwent hemodialysis with tCVCs between January 2008 and December 2012. The patients used 154 tCVCs. Standard protocols about management of tCVCs, according to European Renal Best Practice, were well established. All catheters were inserted in the internal jugular vein. Criteria for catheter removal were persistent bloodstream infection, detection of an outbreak of catheter-related bloodstream (CRBS) infections, or catheter dysfunction. Event rates were calculated per 1,000 catheter days; tCVC cumulative survival was estimated by Kaplan-Meier analysis. RESULTS: Catheter replacement occurred in 15 patients (0.29 per 1,000 days); catheter dysfunction was the main cause of replacement (0.18 per 1,000 days), typically within 12 months of surgical insertion. A total of 53 CRBS events in 36 patients were identified (0.82 per 1,000 days); 17 organisms, most commonly Gram-positive pathogens, were isolated; 87% of CVC infections were treated by systemic antibiotics associated with lock therapy. tCVC cumulative survival was 91% at 1 year, 88% at 2 years and 85% at 4 years. CONCLUSIONS: Our data show a high survival rate of tCVCs in hemodialysis patients, with low incidence of catheter dysfunction and CRBS events. These data justify tCVC use for hemodialysis vascular access, also as first choice, especially in patients with exhausted peripheral access and limited life expectancy.

Phosphate control in dialysis.

Prevention and correction of hyperphosphatemia is a major goal of chronic kidney disease-mineral and bone disorder (CKD-MBD) management, achievable through avoidance of a positive phosphate balance. To this aim, optimal dialysis removal, careful use of phosphate binders, and dietary phosphate control are needed to optimize the control of phosphate balance in well-nourished patients on a standard three-times-a-week hemodialysis schedule. Using a mixed diffusive-convective hemodialysis tecniques, and increasing the number and/or the duration of dialysis tecniques are all measures able to enhance phosphorus (P) mass removal through dialysis. However, dialytic removal does not equal the high P intake linked to the high dietary protein requirement of dialysis patients; hence, the use of intestinal P binders is mandatory to reduce P net intestinal absorption. Unfortunately, even a large dose of P binders is able to bind approximately 200-300 mg of P on a daily basis, so it is evident that their efficacy is limited in the case of an uncontrolled dietary P load. Hence, limitation of dietary P intake is needed to reach the goal of neutral phosphate balance in dialysis, coupled to an adequate protein intake. To this aim, patients should be informed and educated to avoid foods that are naturally rich in phosphate and also processed food with P-containing preservatives. In addition, patients should preferentially choose food with a low P-to-protein ratio. For example, patients could choose egg white or protein from a vegetable source. Finally, boiling should be the preferred cooking procedure, because it induces food demineralization, including phosphate loss. The integrated approach outlined in this article should be actively adapted as a therapeutic alliance by clinicians, dieticians, and patients for an effective control of phosphate balance in dialysis patients.

Sevelamer for hyperphosphataemia in kidney failure: controversy and perspective.

The term 'chronic kidney disease-mineral and bone disorder' (CKD-MBD), coined in 2006, was introduced in a position statement by the Kidney Disease: Improving Global Outcomes (KDIGO) organization. According to the KDIGO guidelines, CKD-MBD is a systemic disorder and patients with vascular or valvular calcifications should be included in the group with the greatest cardiovascular risk. Therefore, the presence or absence of calcification is a key factor in strategy decisions for such patients. In particular, it is recommended that the use of calcium-based phosphate binders should be restricted in patients with hypercalcaemia, vascular calcification, low levels of parathyroid hormone (PTH) or adynamic bone disease. In this respect, it should be underscored that treatment with phosphate-binding agents can normalise the levels of phosphate and PTH, but the use of calcium carbonate can favour the progression of vascular calcifications. There is evidence of reduced progression of vascular calcification in patients treated with sevelamer compared with high doses of calcium-based binders, but there is as yet no strong evidence regarding hard outcomes, such as mortality or hospitalization, to support the use of one treatment over another. Nevertheless, a number of experimental and observational findings seem to suggest that sevelamer should be preferred over calcium-based binders, in as much as these can increase cardiovascular mortality when used in high doses. A threshold dose below which calcium-based binders can be used safely in CKD patients with hyperphosphatemia has yet to be established.

Neurological complications of hemodialysis: state of the art.

Neurological complications frequently affect chronic kidney disease patients. They are important causes of morbidity and mortality. We present a review of neurological complications affecting hemodialysis patients, focusing on classical and new aspects. Neurological complications can be classified as central or peripheral, but they also include other conditions such as muscle and autonomic disorders. Neurological complications in hemodialysis patients are often underdiagnosed and undertreated. Dialysis treatment can modify the clinical pattern and the course of neurological complications, but it may also directly induce some specific, dialysis-related complications. A strict collaboration between nephrologists, neurologists and other specialists can potentially improve prevention and management of these disorders and improve quality of life for hemodialysis patients.

Phosphate control in peritoneal dialysis.

Chronic kidney disease (CKD) is characterized by phosphorus retention and, in more advanced stages, by high serum phosphorus (P) levels. During the last decade, it has been elucidated the central role of P in the pathogenesis of CKD mineral bone disorder (CKD-MBD), determining both renal osteodystrophy and cardiovascular disease. Unfortunately, at least one third of patients on chronic dialysis have high serum P levels, with a consequent higher serum PTH levels, commonly associated with vitamin D deficiency, increased vascular calcification and the highest ratios of morbidity and mortality. In patients with CKD stage 5 on dialysis, therapeutic approaches to reduce serum P levels should include restriction of dietary phosphate intake, optimal dialysis treatment, and use of P binders. In this context, the use of P binders appears to be an essential treatment to control P overload in CKD patients. In this review, we analyzed the use of calcium-based and calcium-free P binders in peritoneal dialysis patients.

Vitamin d receptor activators and clinical outcomes in chronic kidney disease.

Vitamin D deficiency appears to be an underestimated risk factor for cardiovascular disease in patients with chronic kidney disease. Evidence from both basic science and clinical studies supports the possible protective role of vitamin D beyond its effect on mineral metabolism. Toxicity of pharmacologic doses of active vitamin D metabolites, in particular calcitriol, is mainly due to the possibility of positive calcium and phosphorus balance. Therefore, vitamin D analogs have been developed, which suppress PTH secretion and synthesis with reduced calcemic and phosphatemic effects. Observational studies suggest that in hemodialysis patients the use of a vitamin D receptor (VDR) activator, such as calcitriol, doxercalciferol, paricalcitol, or alfacalcidol, is associated with a reduced mortality when compared with nonusers of any VDR activator. In this article the existing literature on the topic is reviewed, although a more robust answer to the question of whether or not VDR activators have beneficial effects in hemodialysis patients will hopefully come from a randomized controlled trial.

Central venous catheters: legal issues.

In dialysis patients, both central venous catheter (CVC) insertion and CVC use during the dialysis procedure pose important legal issues, because of potentially severe, even fatal, complications. The first issue is the decision of the kind of vascular access that should be proposed to patients: an arteriovenous (AV) fistula, a graft, or a CVC. The second issue, when choosing the CVC option, is the choice of CVC: nontunneled versus tunneled. Leaving a temporary nontunneled CVC for a prolonged time increases the risk of complications and could raise a liability issue. Even when choosing a long-term tunneled CVC, nephrologists should systematically explain its potential harms, presenting them as "unsafe for long-term use" unless there is a clear contraindication to an AV native or prosthetic access. Another critical issue is the preparation of a complete, informative, and easy-to-understand consent form. The CVC insertion procedure has many aspects of legal interest, including the choice of CVC, the use of ECG monitoring, the use of ultrasound guidance for cannulation, and the use of fluoroscopy for checking the position of the metal guidewire during the procedure as well as the CVC tip before the end of the procedure. Use of insertion devices and techniques that can prevent complications should obviously be encouraged. Complications of CVC use are mainly thrombosis and infection. These are theoretically expected as pure complications (and not as malpractice effects), but legal issues might relate to inappropriate catheter care (in both the inpatient and outpatient settings) rather than to the event per se. Thus, in the individual case it is indeed very difficult to establish malpractice and liability with a catheter-related infection or thrombosis. In conclusion, we cannot avoid complications completely when using CVCs, but reducing them to a minimum and adopting safe approaches to their insertion and use will reduce legal liability.

Should the myometrial free margin still be considered a limiting factor for hysteroscopic resection of submucous fibroids? A possible answer to an old question.

OBJECTIVE: To evaluate the feasibility of the hysteroscopic resection of type II submucous fibroids regardless of the myometrial free margin separating them from the serosa and to report the dynamic changes the margin undergoes after the various phases of resection. DESIGN: A prospective observational study. SETTING: A tertiary-level university hospital. PATIENT(S): Thirteen women with single type II submucous fibroids of ≤ 5 cm in diameter regardless of the myometrial free margin. INTERVENTION(S): Hysteroscopic myomectomy and ultrasound evaluation of myometrial free margin before and after each phase of the procedure. MAIN OUTCOME MEASURE(S): The possibility of a complete one-step resection, the incidence of intraoperative or postoperative complications, and the analysis of the dynamic changes occurring in myometrial free margin. RESULT(S): Complete resection was performed successfully in all patients. No complications were registered. The myometrial free margin decreased on the distension of the uterine cavity and then increased progressively and significantly after the various phases of resection. CONCLUSION(S): In selected cases and in experienced hands, hysteroscopic myomectomy of type II submucous fibroids may be performed successfully and safely regardless of the myometrial free margin. Myometrial free margin increases progressively with each step of the procedure probably leading to an increasing margin of safety.