Reduced hip bone mineral density is associated with high levels of calciprotein particles in patients with Fabry disease.

Calciprotein particles (CPP) are nanoscale mineralo-protein aggregates that help stabilize excess mineral in the circulation. We examined the relationship between CPP and bone mineral density in Fabry disease patients. We found an inverse correlation with total hip and femoral neck density, but none with lumbar spine. PURPOSE: Calciprotein particles (CPP) are colloidal mineral-protein complexes made up primarily of the circulating glycoprotein fetuin-A, calcium, and phosphate. They form in extracellular fluid and facilitate the stabilization, transport, and clearance of excess minerals from the circulation. While most are monomers, they also exist in larger primary (CPP-I) and secondary (CPP-II) form, both of which are reported to be raised in pathological states. This study sought to investigate CPP levels in the serum of patients with Fabry disease, an X-linked systemic lysosomal storage disorder that is associated with generalized inflammation and low bone mineral density (BMD). METHODS: We compared serum CPP-I and CPP-II levels in 59 patients with Fabry disease (37 female) with levels in an age-matched healthy adult cohort (n=28) and evaluated their association with BMD and biochemical data obtained from routine clinical review. RESULTS: CPP-I and CPP-II levels were higher in male Fabry disease patients than female sufferers as well as their corresponding sex- and age-matched controls. CPP-II levels were inversely correlated with BMD at the total hip and femoral neck, but not the lumbar spine. Regression analyses revealed that these associations were independent of common determinants of BMD, but at the femoral neck, a significant association was only found in female patients. CONCLUSION: Low hip BMD was associated with high CPP-II in patients with Fabry disease, but further work is needed to investigate the relevance of sex-related differences and to establish whether CPP measurement may aid assessment of bone disease in this setting.

Epidemiology of infections and antimicrobial use in Australian haemodialysis outpatients: findings from a Victorian surveillance network, 2008-2015.

BACKGROUND: Patients with chronic renal failure who require haemodialysis are at high risk for infections. AIM: To determine the burden of bloodstream and local access-related infections and the prescribing patterns for intravenous antibiotics in Australian haemodialysis outpatients. METHODS: A surveillance network was established following stakeholder consultation, with voluntary participation by haemodialysis centres and data collation by the Victorian Healthcare Associated Infection Surveillance System Coordinating Centre. Definitions for infection and intravenous antimicrobial starts were based upon methods employed by the Centers for Disease Control and Prevention. Longitudinal mixed-effects Poisson regression was used to model time-trends for the period 2008-2015. FINDINGS: Forty-eight of 78 Victorian dialysis centres participated in the network, with 3449 events reported over 78,826 patient-months. Rates of bloodstream infection, local infection and intravenous antimicrobial starts were much higher for patients with tunnelled central lines (2.60, 1.41, and 3.37 per 100 patient-months, respectively), compared to those with arteriovenous fistulae (0.27, 0.23, and 0.73 per 100 patient-months, respectively) and arteriovenous grafts (0.76, 1.08, 1.50 per 100 patient-months, respectively). Staphylococcus aureus was the most frequent pathogen, with meticillin-resistant isolates (MRSA) responsible for 14.0%. Access-related infections diminished significantly across all vascular-access modalities over time. Vancomycin contributed nearly half of all antimicrobial starts consistently throughout the study period. CONCLUSION: Risk for bloodstream and local access-related infections is highest in Australian haemodialysis patients with tunnelled central lines. S. aureus is the most frequent cause of infection, with a low incidence of MRSA. Future programmes should evaluate infection prevention practices and appropriateness of antibiotic prescribing in this population.

Parenteral iron polymaltose changes i:c-terminal FGF23 ratios in iron deficiency, but not in dialysis patients.

BACKGROUND/OBJECTIVES: Iron and phosphate are both vital to many biological cellular processes with central roles in energy metabolism, cellular proliferation and nucleic acid synthesis. Regulatory pathways in some of these metabolic pathways may intersect at fibroblast growth factor 23 (FGF23), a major phosphate regulatory hormone. Iron is reported to induce hypophosphataemia in rare cases, and recent reports suggest that iron deficiency may upregulate FGF23 synthesis by mechanisms involving hypoxia-inducible factor 1α (HIF1α). Our objective was to evaluate the effect of administration of intravenous iron polymaltose on intact and c-terminal FGF23 (i:cFGF23) ratios in two independent cohorts of patients, iron-deficient but non-inflamed patients and haemodialysis (HD)-dependent patients, and to examine the balance of synthesis and degradation. SUBJECTS/METHODS: We studied biochemical effects of intravenous iron polymaltose on both iFGF23 and cFGF23 fragments and their ratios in two patient groups: iron-deficient patients with normal renal function (ID-norm) and HD patients receiving iron supplementation (HD-ESKD) at a single institution. Patients were tested at baseline, day 4 and day 12 post iron administration. RESULTS: Parenteral iron polymaltose resulted in increased i:cFGF23 ratios in ID-norm patients where circulating cFGF23 levels decreased with no appreciable effect on iFGF23, whereas no significant changes in i:cFGF23 ratios were observed in HD-ESKD patients following intravenous administration of 100mg iron polymaltose. CONCLUSIONS: Dysregulation of intracellular FGF23-processing mechanisms may be related to iron deficiency per se rather than iron repletion with iron polymaltose. In ID-norm, i:cFGF23 ratios altered with iron administration without significant clinical alterations in mineral parameters, implying that other regulatory mechanisms may be important. Finally, iron supplementation in HD-ESKD patients does not appear to significantly affect i:cFGF23 ratios already disturbed by a chronic inflammatory or functionally iron-deficient state.

Large vessel calcification in Takayasu arteritis.

We report the novel case of a young woman with Takayasu arteritis, with extensive large vessel disease. The case demonstrates that while mechanisms of vascular calcification are poorly understood, inflammation per se might be sufficient to mediate increased mineral stress leading to vessel calcification, even in the absence of renal impairment.

Review article: vitamin D and inflammatory bowel disease--established concepts and future directions.

BACKGROUND: Understanding of the role of vitamin D in health and disease has increased markedly in the past decade, with its involvement extending well beyond traditional roles in calcium and phosphate homeostasis and musculoskeletal health. This conceptual expansion has been underpinned by identification and exploration of components of this axis including vitamin D-binding protein, key enzymes and receptors in multiple cell types, and a greater recognition of nonclassical autocrine and paracrine effects. Its influence in IBD remains uncertain. AIM: To review the role of vitamin D in bone health, immune regulation and cancer prevention in IBD, and to outline practical issues and limitations of its use. METHODS: An extensive online literature review including PubMed and Medline. RESULTS: In patients with IBD, the vitamin D axis provides an important and often underutilised pathway to preserving bone health. Furthermore, an exciting body of clinical and basic science research demonstrates that these pathways may have an integral part to play in regulation of the immune response in IBD, through effects on the intestinal barrier, antigen presenting cells and adaptive T cells. The possibility of chemoprevention requires further study. The optimal target level of 25-hydroxy vitamin D in patients with IBD is currently uncertain, as is the best therapeutic modality. CONCLUSIONS: Study of vitamin D pathways may result in the development of relatively inexpensive therapeutic options to optimise patient outcomes. Further prospective clinical research is required to address efficacy and long-term safety.

Simultaneous measurement of urinary albumin and total protein may facilitate decision-making in HIV-infected patients with proteinuria.

OBJECTIVE: We recently showed that a urine albumin/total protein ratio (uAPR) <0.4 identifies tubular pathology in proteinuric patients. In tubular disorders, proteinuria is usually of low molecular weight and contains relatively little albumin. We tested the hypothesis that uAPR is useful in identifying tubular pathology related to antiretroviral use in HIV-infected patients. METHODS: We retrospectively identified urine protein/creatinine ratios (uPCRs) in HIV-infected patients. A subset of samples had uPCR and urine albumin/creatinie ratio (uACR) measured simultaneously. We classified proteinuric patients (uPCR >30 mg/mmol) into two groups: those with predominantly 'tubular' proteinuria (TP) (uAPR <0.4) and those with predominantly 'glomerular' proteinuria (GP) (uAPR ≥ 0.4). RESULTS: A total of 618 of 5244 samples from 1378 patients had uPCR ≥ 30 mg/mmol. uAPRs were available in 144 patients: 46 patients (32%) had TP and 21 (15%) GP; the remainder had uPCR <30 mg/mmol. The TP group had a higher fractional excretion of phosphate compared with the GP group (mean 27% vs. 16%, respectively; P<0.01). Patients with TP were more likely to be on tenofovir and/or a boosted protease inhibitor compared with those with GP. In 18 patients with heavy proteinuria (uPCR >100 mg/mmol), a renal assessment was made; eight had a kidney biopsy. In all cases, the uAPR results correlated with the nephrological diagnosis. CONCLUSIONS: In HIV-infected patients, measuring uAPR may help to identify patients in whom a renal biopsy is indicated, and those in whom tubular dysfunction might be an important cause of proteinuria and which may be related to antiretroviral toxicity. We suggest that this would be useful as a routine screening procedure in patients with proteinuria.

Spectrum of chronic kidney disease in HIV-infected patients.

OBJECTIVES: The aim of the study was to investigate the prevalence and aetiology of chronic kidney disease (CKD) and trends in estimated glomerular filtration rate (eGFR) in HIV-infected patients. METHODS: Ascertainment and review of CKD cases among patients attending King's College and Brighton Hospitals, UK were carried out. CKD was defined as eGFR <60 mL/min for > or =3 months. Longitudinal eGFR slopes were produced to examine trends in renal function before, during and after exposure to indinavir (IDV) or tenofovir (TFV). RESULTS: CKD prevalence was 2.4%. While HIV-associated nephropathy accounted for 62% of CKD in black patients, 95% of CKD in white/other patients was associated with diabetes mellitus, hypertension, atherosclerosis and/or drug toxicity. Exposure to IDV or TFV was associated with an accelerated decline in renal function (4.6-fold and 3.7-fold, respectively) in patients with CKD. In patients initiating IDV, age > or =50 years increased the odds of CKD [odds ratio (OR) 4.9], while in patients initiating TFV, age > or =50 years (OR 5.4) and eGFR 60-75 mL/min (OR 17.2) were associated with developing CKD. CONCLUSION: This study highlights the importance of metabolic and vascular disease to the burden of CKD in an ageing HIV-infected cohort. In patients who developed CKD, treatment with IDV or TFV was associated with an accelerated decline in renal function.

Radiotherapy for a pulmonary aspergilloma complicating p-ANCA positive small vessel vasculitis.

Life-threatening haemoptysis may complicate aspergillomas within pre-existing lung cavities. Treatment options have included lung resection, pulmonary or bronchial artery embolisation and antifungal therapy administered either systemically or by endobronchial or percutaneous instillation. We present a case of aspergilloma complicating small vessel vasculitis, and its successful treatment using radiotherapy.

Atrial thrombus and central venous dialysis catheters.

A native arteriovenous fistula is the first choice for hemodialysis access. Despite improved catheter designs and the use of internal jugular veins, thrombotic complications still occur when tunneled central venous catheters are used as an alternative. Although right atrial thrombus (RAT) is a well-characterized complication of long-term central venous cannulation, particularly when used for parenteral nutrition and chemotherapy in pediatric practice, only 9 reported cases previously have been associated with the long-term use of central venous catheters for hemodialysis. We report five cases of RAT seen at our unit between 1994 and 1998 in patients who had been dialyzed using tunneled catheters. In four of five cases, the diagnosis was made during the investigation of hemoptysis or dyspnea. In the fifth case, a screening transthoracic echocardiogram revealed the thrombus. Three of five of the patients suffered pulmonary emboli, and a fourth patient had an unexplained electromechanical dissociation cardiac arrest without definite evidence of pulmonary embolus. Our experience suggests that anticoagulated patients with RAT remain at risk of pulmonary embolism. One of our patients successfully underwent atrial thrombectomy. In four of five of our cases and four of nine cases in the literature, the central venous catheter tip was within the right atrium. Positioning of the central venous catheter tip low down in the superior vena cava or in the right atrium has been advocated to improve dialysis adequacy and to reduce the incidence of catheter thrombosis. However, placement of the catheter tip within the right atrium may be associated with an increased risk of RAT.

Pathogenesis and treatment of renal dysfunction in rhabdomyolysis.

Rhabdomyolysis is a major cause of acute renal failure, and recent experimental data have provided a better understanding of the pathophysiology of the renal dysfunction. Renal failure is due to renal vasoconstriction, tubular damage caused by oxidant injury, and possibly tubular obstruction. Recent studies have provided greater insight into the rationale behind current therapy and potential treatment strategies. This review thus aims to summarise current understanding of the causes, pathogenesis and treatment of renal failure caused by rhabdomyolysis.

A causative role for redox cycling of myoglobin and its inhibition by alkalinization in the pathogenesis and treatment of rhabdomyolysis-induced renal failure.

Muscle injury (rhabdomyolysis) and subsequent deposition of myoglobin in the kidney causes renal vasoconstriction and renal failure. We tested the hypothesis that myoglobin induces oxidant injury to the kidney and the formation of F2-isoprostanes, potent renal vasoconstrictors formed during lipid peroxidation. In low density lipoprotein (LDL), myoglobin induced a 30-fold increase in the formation of F2-isoprostanes by a mechanism involving redox cycling between ferric and ferryl forms of myoglobin. In an animal model of rhabdomyolysis, urinary excretion of F2-isoprostanes increased by 7.3-fold compared with controls. Administration of alkali, a treatment for rhabdomyolysis, improved renal function and significantly reduced the urinary excretion of F2-isoprostanes by approximately 80%. EPR and UV spectroscopy demonstrated that myoglobin was deposited in the kidneys as the redox competent ferric myoglobin and that it's concentration was not decreased by alkalinization. Kinetic studies demonstrated that the reactivity of ferryl myoglobin, which is responsible for inducing lipid peroxidation, is markedly attenuated at alkaline pH. This was further supported by demonstrating that myoglobin-induced oxidation of LDL was inhibited at alkaline pH. These data strongly support a causative role for oxidative injury in the renal failure of rhabdomyolysis and suggest that the protective effect of alkalinization may be attributed to inhibition of myoglobin-induced lipid peroxidation.