Bone Mineral Density and Vascular Calcification in Children and Young Adults With CKD 4 to 5 or on Dialysis.

Introduction: Older adults with chronic kidney disease (CKD) can have low bone mineral density (BMD) with concurrent vascular calcification. Mineral accrual by the growing skeleton may protect young people with CKD from extraosseous calcification. Our hypothesis was that children and young adults with increasing BMD do not develop vascular calcification. Methods: This was a multicenter longitudinal study in children and young people (5-30 years) with CKD stages 4 to 5 or on dialysis. BMD was assessed by tibial peripheral quantitative computed tomography (pQCT) and lumbar spine dual-energy X-ray absorptiometry (DXA). The following cardiovascular imaging tests were undertaken: cardiac computed tomography for coronary artery calcification (CAC), ultrasound for carotid intima media thickness z-score (cIMTz), pulse wave velocity z-score (PWVz), and carotid distensibility for arterial stiffness. All measures are presented as age-adjusted and sex-adjusted z-scores. Results: One hundred participants (median age 13.82 years) were assessed at baseline and 57 followed up after a median of 1.45 years. Trabecular BMD z-score (TrabBMDz) decreased (P = 0.01), and there was a nonsignificant decrease in cortical BMD z-score (CortBMDz) (P = 0.09). Median cIMTz and PWVz showed nonsignificant increase (P = 0.23 and P = 0.19, respectively). The annualized increase in TrabBMDz (ΔTrabBMDz) was an independent predictor of cIMTz increase (R 2 = 0.48, ß = 0.40, P = 0.03). Young people who demonstrated statural growth (n = 33) had lower ΔTrabBMDz and also attenuated vascular changes compared with those with static growth (n = 24). Conclusion: This hypothesis-generating study suggests that children and young adults with CKD or on dialysis may develop vascular calcification even as their BMD increases. A presumed buffering capacity of the growing skeleton may offer some protection against extraosseous calcification.

Predictors of iron versus erythropoietin responsiveness in anemic hemodialysis patients.

Anemia protocols for hemodialysis patients usually titrate erythropoietin (ESA) according to hemoglobin and iron according to a threshold of ferritin, with variable response seen. A universally optimum threshold for ferritin may be incorrect, and another view is that ESA and iron are alternative anemia treatments, which should be selected based on the likely response to each. Hemodialysis patients developing moderate anemia were randomised to treatment with either an increase in ESA or a course of intravenous iron. Over 2423 patient-months in 197 patients, there were 133 anemia episodes with randomized treatment. Treatment failure was seen in 20/66 patients treated with ESA and 20/67 patients treated with iron (30.3 vs. 29.9%, p = 1.0). Successful ESA treatment was associated with lower C-reactive protein (13.5 vs. 28.6 mg/L, p = 0.038) and lower previous ESA dose (6621 vs. 9273 µg/week, p = 0.097). Successful iron treatment was associated with lower reticulocyte hemoglobin (33.8 vs. 35.5 pg, p = 0.047), lower hepcidin (91.4 vs. 131.0 µg/ml, p = 0.021), and higher C-reactive protein (29.5 vs. 12.6 mg/L, p = 0.085). A four-variable iron preference score was developed to indicate the more favorable treatment, which in a retrospective analysis reduced treatment failure to 17%. Increased ESA and iron are equally effective, though treatment failure occurs in almost 30%. Baseline variables including hepcidin can predict treatment response, and a four-variable score shows promise in allowing directed treatment with improved response rates.

The burden of subclinical cardiovascular disease in children and young adults with chronic kidney disease and on dialysis.

BACKGROUND: Cardiovascular disease (CVD) is a common cause of morbidity and mortality even in young people with chronic kidney disease (CKD). We examined structural and functional CV changes in patients ˂30 years of age with CKD Stages 4 and 5 and on dialysis. METHODS: A total of 79 children and 21 young adults underwent cardiac computed tomography for coronary artery calcification (CAC), ultrasound for carotid intima-media thickness (cIMT), carotid-femoral pulse wave velocity (cfPWV) and echocardiography. Differences in structural (CAC, cIMT z-score, left ventricular mass index) and functional (carotid distensibility z-score and cfPWV z-score) measures were examined between CKD Stages 4 and 5 and dialysis patients. RESULTS: Overall, the cIMT z-score was elevated [median 2.17 (interquartile range 1.14-2.86)] and 10 (10%) had CAC. A total of 16/23 (69.5%) patients with CKD Stages 4 and 5 and 68/77 (88.3%) on dialysis had at least one structural or functional CV abnormality. There was no difference in the prevalence of structural abnormalities in CKD or dialysis cohorts, but functional abnormalities were more prevalent in patients on dialysis (P < 0.05). The presence of more than one structural abnormality was associated with a 4.5-fold increased odds of more than one functional abnormality (95% confidence interval 1.3-16.6; P < 0.05). Patients with structural and functional abnormalities [cIMT z-score >2 standard deviation (SD) or distensibility <-2 SD) had less carotid dilatation (lumen:wall cross-sectional area ratio) compared with those with normal cIMT and distensibility. CONCLUSIONS: There is a high burden of subclinical CVD in young CKD patients, with a greater prevalence of functional abnormalities in dialysis compared with CKD patients. Longitudinal studies are required to test these hypothesis-generating data and define the trajectory of CV changes in CKD.

Routine serum biomarkers, but not dual-energy X-ray absorptiometry, correlate with cortical bone mineral density in children and young adults with chronic kidney disease.

BACKGROUND: Biomarkers and dual-energy X-ray absorptiometry (DXA) are thought to be poor predictors of bone mineral density (BMD). The Kidney Disease: Improving Global Outcomes guidelines suggest using DXA if the results will affect patient management, but this has not been studied in children or young adults in whom bone mineral accretion continues to 30 years of age. We studied the clinical utility of DXA and serum biomarkers against tibial cortical BMD (CortBMD) measured by peripheral quantitative computed tomography, expressed as Z-score CortBMD, which predicts fracture risk. METHODS: This was a cross-sectional multicentre study in 26 patients with CKD4 and 5 and 77 on dialysis. RESULTS: Significant bone pain that hindered activities of daily living was present in 58%, and 10% had at least one low-trauma fracture. CortBMD and cortical mineral content Z-scores were lower in dialysis compared with CKD patients (P = 0.004 and P = 0.02). DXA BMD hip and lumbar spine Z-scores did not correlate with CortBMD or biomarkers. CortBMD was negatively associated with parathyroid hormone (PTH; r = -0.44, P < 0.0001) and alkaline phosphatase (ALP; r = -0.22, P = 0.03) and positively with calcium (Ca; r = 0.33, P = 0.001). At PTH <3 times upper limit of normal, none of the patients had a CortBMD below -2 SD (odds ratio 95% confidence interval 7.331 to infinity). On multivariable linear regression PTH (ß = -0.43 , P < 0.0001), ALP (ß = -0.36, P < 0.0001) and Ca (ß = 0.21, P = 0.005) together predicted 57% of variability in CortBMD. DXA measures did not improve this model. CONCLUSIONS: Taken together, routinely used biomarkers, PTH, ALP and Ca, but not DXA, are moderate predictors of cortical BMD. DXA is not clinically useful and should not be routinely performed in children and young adults with CKD 4-5D.

Heterogeneity in the nonplanarity and arterial curvature of arteriovenous fistulas in vivo.

OBJECTIVE: Native arteriovenous fistulas (AVFs) for hemodialysis are susceptible to nonmaturation. Adverse features of local blood flow have been implicated in the formation of perianastomotic neointimal hyperplasia that may underpin nonmaturation. Whereas computational fluid dynamic simulations of idealized models highlight the importance of geometry on fluid and vessel wall interactions, little is known in vivo about AVF geometry and its role in adverse clinical outcomes. This study set out to examine the three-dimensional geometry of native AVFs and the geometric correlates of AVF failure. METHODS: As part of an observational study between 2013 and 2016, patients underwent creation of an upper limb AVF according to current surgical best practice. Phase-contrast magnetic resonance imaging was performed on the day of surgery to obtain luminal geometry along with ultrasound measurements of flow. Magnetic resonance imaging data sets were segmented and reconstructed for quantitative and qualitative analysis of local geometry. Clinical maturation was evaluated at 6 weeks. RESULTS: There were 60 patients who were successfully imaged on the day of surgery. Radiocephalic (n = 17), brachiocephalic (n = 40), and brachiobasilic (n = 3) fistulas were included in the study. Centerlines extracted from segmented vessel lumen exhibited significant heterogeneity in arterial nonplanarity and curvature. Furthermore, these features are more marked in brachiocephalic than in radiocephalic fistulas. Across the cohort, the projected bifurcation angle was 73 ± 16 degrees (mean ± standard deviation). Geometry was preserved at 2 weeks in 20 patients who underwent repeated imaging. A greater degree of arterial nonplanarity (log odds ratio [logOR], 0.95 per 0.1/vessel diameter; 95% confidence interval [CI], 0.22-1.90; P = .03) and a larger bifurcation angle (logOR, 0.05 per degree; 95% CI, 0.01-0.09; P = .02) are associated with a greater rate of maturation, as is fistula location (upper vs lower arm; logOR, -1.9; 95% CI, -3.2 to 0.7; P = .002). CONCLUSIONS: There is significant heterogeneity in the three-dimensional geometry of AVFs, in particular, arterial nonplanarity and curvature. In this largest cohort of AVF geometry to date, the effect of individual geometric correlates on maturation is uncertain but supports the premise that future modeling studies will need to acknowledge the complex geometry of AVFs.

Early (2008-2010) hospital outbreak of Klebsiella pneumoniae producing OXA-48 carbapenemase in the UK.

OXA-48 ß-lactamase is one of the several emerging carbapenemases. Pre-2007 reports were almost exclusively from Turkey, but subsequently its distribution has expanded. We report an early and prolonged outbreak in the UK of Klebsiella pneumoniae producing OXA-48 carbapenemase affecting a predominantly renal cohort in a West London hospital. Carbapenemase production was detected by the modified Hodge test, with confirmation by PCR for bla(OXA-48). Isolates were typed by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). Risk factors for acquisition were determined. Between January 2008 and April 2010, 20 K. pneumoniae isolates with reduced susceptibility to carbapenems were identified from 13 patients, comprising 12 renal cases and 1 oncology patient; 8 were outpatients and 5 were inpatients; 7 were deemed to be colonised and 6 infected, including 2 with bacteraemia, 1 of whom died. Hodge tests were positive for all isolates and all had bla(OXA-48). PFGE showed strain similarity in isolates from nine patients, whereas four patients' isolates were distinct, representing three further PFGE profiles and suggesting horizontal spread of bla(OXA-48). Most patients had received antibiotics in the preceding 3 months and all had healthcare contact, but none had recent travel to areas with endemic OXA-48 Enterobacteriaceae. The renal cohort was screened and a prevalence rate of 0.17% was found. Interventions that collectively brought the outbreak under control included strict infection control precautions, screening, improved laboratory detection protocols and antibiotic stewardship rounds.

Erythropoietin administration in humans causes a marked and prolonged reduction in circulating hepcidin.

Expression of hepcidin, the key hormone governing iron transport, is reduced by anemia in a manner which appears dependent on increased bone marrow activity. The temporal associations between plasma hepcidin and other iron parameters were examined in healthy humans after erythropoietin administration and venesection. Profound hepcidin suppression appeared abruptly 24 hours after subcutaneous erythropoietin (P=0.003), and was near maximal at onset, with peak (mid-afternoon) levels reduced by 73.2%, gradually recovering over the following two weeks. Minor changes in circulating iron, soluble transferrin receptor and growth differentiation factor-15 were observed after the reduction in hepcidin. Similar but more gradual changes in these parameters were observed after reducing hematocrit by removal of 250 mL blood. These human studies confirm the importance of a rapidly responsive marrow-hepcidin axis in regulating iron supply in vivo, and suggest that this axis is regulated by factors other than circulating iron, soluble transferrin receptor or growth differentiation factor-15.

Bacteremia associated with tunneled hemodialysis catheters: outcome after attempted salvage.

BACKGROUND AND OBJECTIVES: Treatment without catheter replacement (catheter salvage) has been described for bacteremia associated with tunneled venous catheters in hemodialysis patients, but few data are available on which to base an estimation of the likelihood of treatment success. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a prospective cohort study, all cases of catheter-associated bacteremia that occurred in a large dialysis center were identified during a 12-mo period. Catheter salvage was attempted according to a standard protocol in all cases in which a favorable early response to antibiotic therapy was seen, and patients were followed for at least 6 mo. Bacteremias, catheter changes, and all major clinical events were recorded. RESULTS: During a period covering 252,986 catheter days, 208 episodes were identified involving 133 patients, 74% of which were selected for attempted salvage. Salvage was successful in 66.1% of incident bacteremias with a very low complication risk (0.9%). Some bacteremias, however, recurred as late as 6 mo after the initial infection; salvage was less likely to be successful in treating recurrences. CONCLUSIONS: Appropriately used catheter salvage can be successful in approximately two thirds of cases; however, recurrences continue to occur up to 6 mo later and are unlikely to be cured without catheter replacement.

Plasma hepcidin levels are elevated but responsive to erythropoietin therapy in renal disease.

Hepcidin is a critical inhibitor of iron export from macrophages, enterocytes, and hepatocytes. Given that it is filtered and degraded by the kidney, its elevated levels in renal failure have been suggested to play a role in the disordered iron metabolism of uremia, including erythropoietin resistance. Here, we used a novel radioimmunoassay for hepcidin-25, the active form of the hormone, to measure its levels in renal disease. There was a significant diurnal variation of hepcidin and a strong correlation to ferritin levels in normal volunteers. In 44 patients with mild to moderate kidney disease, hepcidin levels were significantly elevated, positively correlated with ferritin but inversely correlated with the estimated glomerular filtration rate. In 94 stable hemodialysis patients, hepcidin levels were also significantly elevated, but this did not correlate with interleukin-6 levels, suggesting that increased hepcidin was not due to a general inflammatory state. Elevated hepcidin was associated with anemia, but, intriguingly, the erythropoietin dose was negatively correlated with hepcidin, suggesting that erythropoietin suppresses hepcidin levels. This was confirmed in 7 patients when hepcidin levels significantly decreased after initiation of erythropoietin treatment. Our results show that hepcidin is elevated in renal disease and suggest that higher hepcidin levels do not predict increased erythropoietin requirements.

Tesio-Caths provide effective and safe long-term vascular access.

BACKGROUND: Vascular access is judged on its ability to provide good dialysis adequacy, its durability and complication rates. Formation of a functional arteriovenous fistula is desirable but difficult to achieve in a significant proportion of patients. We report the large-scale use of Tesio-Caths, a twin-line single-lumen central venous catheter, to maximize dialysis adequacy where formation of an arteriovenous fistula was not possible. METHODS: All patients who had Tesio-Caths inserted between 1 January 1999 and 1 October 2002 were studied. RESULTS: Six hundred and twenty-three Tesio-Caths were inserted from 1 January 1999 to 1 October 2002 in 435 patients, generating 7464 patient months of follow-up. Five hundred and ninety-four out of 623 (95.3%) Tesio-Caths were immediately functional. Mean dialysis adequacy measured by single-pool Kt/V was 1.5+/-0.3 for all Tesio-Caths for the entire period of study, with 68% of Tesio-Caths delivering a Kt/V >1.4. Cumulative functional Tesio-Cath survival to final failure was 77.8 and 44% at 1 and 3 years, respectively. Cumulative patient survival was 84.7, 71.4 and 63% at 1, 2 and 3 years, respectively. Access-related infection accounted for 0.28 admissions/1000 catheter days, and the death rate from access-related sepsis was 9.6 deaths/1000 patient years at risk. The admission rate for access dysfunction was 0.33/1000 patient years at risk. CONCLUSION: Tesio-Caths provide good dialysis adequacy for patients in whom an arteriovenous fistula cannot be formed. Patient and functional access survival for this group was comparable with current European data irrespective of vascular access type. Complication rates were acceptably low.