Dabigatran overload in acute kidney injury: haemodialysis or idarucizumab? A case report and proposal for a decisional algorithm.

Dabigatran overload has been reported in acute kidney injury (AKI), leading to occasional major bleeding. Haemodialysis (HD) was the method used for reversing dabigatran anticoagulant effects before the approval of idarucizumab, which is now indicated for dabigatran reversal in major bleeding or surgical emergencies. There have been reports of rebound of dabigatran levels following idarucizumab administration in AKI, requiring HD to achieve effective dabigatran clearance. However, a decisional algorithm to individualize treatments for dabigatran overload seems lacking. We present a case of dabigatran accumulation in obstructive AKI with minor bleeding that was successfully treated with HD and tranexamic acid without using idarucizumab, and propose a decision-making algorithm including different pathways in the management of suspected dabigatran overload in AKI.

Forced diuresis oriented by point-of-care ultrasound in cardiorenal syndrome type 5 due to light chain myeloma-The role of hepatic venogram: A case report.

Monitoring venous congestion by ultrasound assessment of hepatic venogram allowed individualized fluid management in severe cardiorenal syndrome type 5 due to light chain myeloma, preserving residual renal function and avoiding heart failure.

Current treatment options for secondary hyperparathyroidism in patients with stage 3 to 4 chronic kidney disease and vitamin D deficiency.

Introduction: Secondary hyperparathyroidism (SHPT) represents a complication of chronic kidney disease (CKD). Vitamin D system is altered since early CKD, and vitamin D deficiency is an established trigger of SHPT. Although untreated SHPT may degenerate into tertiary hyperparathyroidism with detrimental consequences in advanced CKD, best treatments for counteracting SHPT from stage 3 CKD are still debated. Enthusiasm on prescription of vitamin D receptor activators (VDRA) in non-dialysis renal patients, has been mitigated by the risk of low bone turnover and positive calcium-phosphate balance. Nutritional vitamin D is now suggested as first-line therapy to treat SHPT with low 25(OH)D insufficiency. However, no high-grade evidence supports the best choice between ergocalciferol, cholecalciferol, and calcifediol (in its immediate or extended-release formulation).Areas covered: The review discusses available data on safety and efficacy of nutritional vitamin D, VDRA and nutritional therapy in replenishing 25(OH)D deficiency and counteracting SHPT in non-dialysis CKD patients.Expert opinion: Best treatment for low 25(OH)D and SHPT remains unknown, due to incomplete understanding of the best homeostatic, as mutable, adaptation of mineral metabolism to CKD progression. Nutritional vitamin D and nutritional therapy appear safest interventions, whenever contextualized with single-patient characteristics. VDRA should be restricted to uncontrolled SHPT by first-line therapy.

SARS-CoV-2-related ARDS in a maintenance hemodialysis patient: case report on tailored approach by daily hemodialysis, noninvasive ventilation, tocilizumab, anxiolytics, and point-of-care ultrasound.

Without rescue drugs approved, holistic approach by daily hemodialysis, noninvasive ventilation, anti-inflammatory medications, fluid assessment by bedside ultrasound, and anxiolytics improved outcomes of a maintenance hemodialysis patient affected by severe COVID-19.

Cardiovascular disease in dialysis patients.

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

Cigarette Smoking is Associated with Decreased Bone Gla-protein (BGP) Levels in Hemodialysis Patients.

BACKGROUND: Bone Gamma-carboxyglutamic acid (Gla)-protein (BGP or osteocalcin) is a vitamin K-dependent protein involved in the regulation of bone mineralization. Smoking is a risk factor for osteoporosis. METHODS: We carried out a secondary analysis of the Vitamin K Italian (VIKI) study to investigate the association between cigarette smoking and BGP levels in patients with end stage renal disease. Data were collected in 370 haemodialysis patients, 37% (136) smokers (or ex-smokers) and 63% (234) nonsmokers. Vascular calcifications and vertebral fractures (quantitative morphometry) were identified on spine radiographs. RESULTS: Smokers had significantly lower BGP levels (152 vs. 204 µg/L, p=0.003). Smokers had lower plasma phosphate levels (4.2 vs. 4.7 mg/dl, p<0.01). Lower BGP levels were associated with aortic calcification (p<0.001), iliac calcification (p=0.042) and vertebral fractures (p=0.023). In addition, the regression model showed that smoking is associated with a significant reduction of total BGP levels by about 18% (p=0.01). CONCLUSION: This is the first clinical study in a haemodialysis population, which identifies cigarette smoking as a potential factor that can lower BGP levels, a protective agent in bone and vascular health.

A surgical intervention for the body politic: Generation Squeeze applies the Advocacy Coalition Framework to social determinants of health knowledge translation.

SETTING: The World Health Organization Commission on the Social Determinants of Health (SDoH) observes that building political will is central to all its recommendations, because governments respond to those who organize and show up. Since younger Canadians are less likely to vote or to organize in between elections, they are less effective at building political will than their older counterparts. This results in an age gap between SDoH research and government budget priorities. Whereas Global AgeWatch ranks Canada among the top countries for aging, UNICEF ranks Canada among the least generous OECD (Organisation for Economic Co-operation and Development) countries for the generations raising young children. INTERVENTION: A surgical intervention into the body politic. Guided by the "health political science" literature, the intervention builds a non-profit coalition to perform science-based, non-partisan democratic engagement to increase incentives for policy-makers to translate SDoH research about younger generations into government budget investments. OUTCOMES: All four national parties integrated policy recommendations from the intervention into their 2015 election platforms. Three referred to, or consulted with, the intervention during the election. The intervention coincided with all parties committing to the single largest annual increase in spending on families with children in over a decade. IMPLICATIONS: Since many population-level decisions are made in political venues, the concept of population health interventions should be broadened to include activities designed to mobilize SDoH science in the world of politics. Such interventions must engage with the power dynamics, values, interests and institutional factors that mediate the path by which science shapes government budgets.

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.

[Choosing the right medications in elderly patients with chronic kidney disease]. / Appropriatezza della farmacoterapia nel paziente anziano nefropatico.

With the aging of the population, the prevalence of chronic kidney disease (CKD) is increased. Measurement of glomerular filtration rate as a screening tool may over-diagnose CKD, especially when proteinuria is normal, but it can be very useful when considering drug metabolism. Renal dysfunction is a factor predisposing to potential adverse drug reactions, because drug can accumulate to toxic levels. In addition, some drugs are nephrotoxic and can more easily damage the kidneys in the elderly. Limited data are available on the risks of drugs in the elderly population with CKD. Drugs with no clear evidence-based indication, drugs with higher risks of adverse side effects compared to their benefits, and drugs which are not cost-effective, have been defined "potentially inappropriate medications" (PIMs). Even if criteria to evaluate PIMs and adverse drug reactions are available to clinical management, we strongly support the idea that the issue of PIMs in the elderly affected by CKD should be better studied and defined. The Italian website Slow Medicine, based on the US project "Choosing Wisely", opened a new strategy in this field, taking into consideration both economic issues and patients quality of life. The main goal of this initiative is avoiding wasteful or unnecessary medical tests, treatments and procedures.

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.

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.

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.

Role of vitamin d receptor activators in cardio-renal syndromes.

The involvement of vitamin D deficiency in cardiovascular morbidity and mortality is attracting great interest. In patients with chronic kidney disease this association is stronger because vitamin D levels decrease as a result of renal progressive impairment. In chronic kidney disease secondary hyperparathyroidism commonly occurs in response to persistent hypocalcemia and hyperphosphatemia; moreover, parathyroid gland volume increases, vascular calcification is accelerated, and structural and functional modifications of the left ventricle are observed. These alterations entail both cardiac and renal involvement, resulting in cardio-renal syndrome. Recent studies concluded that vitamin D administration seems to have cardioprotective and renoprotective effects and improve peripheral vascular disease, vascular calcification, cardiac outcome, and blood pressure control. In clinical practice, therefore, the use of this hormone may play an important role in cardio-renal syndrome prevention.

Blood pressure loci identified with a gene-centric array.

Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.

The Effect of Paricalcitol on Vascular Calcification and Cardiovascular Disease in Uremia: Beyond PTH Control.

Secondary hyperparathyroidism is a systemic disorder that associates with bone and cardiovascular disease, including arterial calcification. Treatment with calcitriol, the active form of vitamin D, reduces parathyroid hormone levels, but may result in elevations in serum calcium and phosphorus, increasing the risk of vascular calcification in dialysis patients. New vitamin D receptor activators (VDRAs) have been developed and investigated with the rationale to treat high serum PTH levels, with a reduced risk of hypercalcemia and hyperphosphatemia. Paricalcitol is a selective VDRA that suppresses PTH secretion with minimal increases on serum calcium and phosphate. Moreover, paricalcitol prevents vascular calcification in experimental models of renal failure, compared with calcitriol.

[Cardioprotective effect of vitamin D in nondialyzed patients with stage 3-5 CKD]. / Effetti cardioprotettivi della vitamina D nei pazienti con malattia renale cronica allo stadio 3-5 non in dialisi.

Epidemiological and observational data indicate that there is a close relationship between progressive renal dysfunction in chronic kidney disease (CKD), cardiovascular disease, and mortality. In addition, deficits in vitamin D (25-hydroxyvitamin D) and vitamin D receptor (VDR) activation play a crucial role in adversely affecting cardiovascular health in CKD patients. Even in patients with mild CKD, renal dysfunction is associated with cardiovascular events. Modulation of vitamin D levels results in correlative regulatory effects on mineral homeostasis, hypertension, and vascular calcification. The use of VDR activators such as paricalcitol to treat these and other parameters outside of cardiovascular and renal disease not only results in enhanced patient health but significantly reduces the mortality risk in CKD patients.

Improvement of endothelial function in uraemic patients on peritoneal dialysis: a possible role for 5-MTHF administration.

BACKGROUND: Hyperhomocysteinaemia is an independent risk factor for the development of atherosclerosis. Furthermore, homocysteine induces endothelial dysfunction by an increased inactivation of nitric oxide. In patients with chronic renal failure, the administration of folic acid or its metabolites reduces but does not normalize plasma homocysteine concentrations. METHODS: We examined the effect of oral treatment with 15 mg/daily of 5-methyltetrahydrofolate (5-MTHF) for 12 weeks, on homocysteinaemia and endothelial function in 19 patients undergoing peritoneal dialysis and compared them, for the same period of time, to a control group of patients on peritoneal dialysis. Endothelial function was evaluated by B-mode ultrasonography on the brachial artery. Flow-mediated dilation (FMD) was recorded during reactive hyperaemia produced by the inflation of a pneumatic tourniquet. Nitroglycerine-mediated dilation (NMD) was recorded after sublingual administration of glyceryl trinitrate. Finally, oxidative stress was assessed by evaluating the conjugated dienes plasma levels. RESULTS: Plasma homocysteine concentrations fell by 30% after oral treatment with 5-MTHF. Endothelial function improved significantly after oral 5-MTHF treatment (13.8 +/- 1.2% vs 11.4 +/- 1.4%; P < 0.02) while in the control group we observed a worsening of basal values from 12.1 +/- 2.66% to 8.7 +/- 2.90% (P < 0.02). The conjugated dienes plasma levels did not change either. CONCLUSIONS: Our study demonstrated that 5-MTHF administration improves endothelial dysfunction in patients undergoing peritoneal dialysis. This effect appears to be independent of the reduction in homocysteine plasma levels.

Impaired oxygen extraction in metabolic myopathies: detection and quantification by near-infrared spectroscopy.

Patients with mitochondrial myopathies (MM) or myophosphorylase deficiency (McArdle's disease, McA) show impaired capacity for O(2) extraction, low maximal aerobic power, and reduced exercise tolerance. Non-invasive tools are needed to quantify the metabolic impairment. Six patients with MM, 6 with McA, 25 with symptoms of metabolic myopathy but negative biopsy (patient-controls, P-CTRL) and 20 controls (CTRL) underwent an incremental cycloergometric test. Pulmonary O(2) uptake (VO(2)) and vastus lateralis oxygenation indices (by near-infrared spectroscopy, NIRS) were determined. Concentration changes of deoxygenated hemoglobin and myoglobin (Delta[deoxy(Hb + Mb)]) were considered an index of O(2) extraction. Delta[deoxy(Hb + Mb)] peak (percent limb ischemia) was lower in MM (25.3 +/- 12.0%) and McA (18.7 +/- 7.3) than in P-CTRL (62.4 +/- 3.9) and CTRL (71.3 +/- 3.9) subjects. VO(2) peak and Delta[deoxy(Hb + Mb)] peak were linearly related (r(2) = 0.83). In these patients, NIRS is a tool to detect and quantify non-invasively the metabolic impairment, which may be useful in the follow-up of patients and in the assessment of therapies and interventions.