Background: The management of chronic kidney disease-mineral and bone disorder requires the assessment of bone turnover, which most often is based on parathyroid hormone (PTH) concentration, the utility of which remains controversial.Study Design: Cross-sectional retrospective diagnostic test study. Setting & Participants: 492 dialysis patients from Brazil, Portugal, Turkey, and Venezuela with prior bone biopsy and stored (220 C) serum.Index Tests: Samples were analyzed for PTH (intact [iPTH] and whole PTH), bone-specific alkaline phosphatase (bALP), and amino-terminal propeptide of type 1 procollagen (P1NP).Reference Test: Bone histomorphometric assessment of turnover (bone formation rate/bone surface [BFR/ BS]) and receiver operating characteristic curves for discriminating diagnostic ability.Results: The biomarkers iPTH and bALP or combinations thereof allowed discrimination of low from nonlow and high from nonhigh BFR/BS, with an area under the receiver operating characteristic curve . 0.70 but , 0.80. Using iPTH level, the best cutoff to discriminate low from nonlow BFR/BS was ,103.8 pg/mL, and to discriminate high from nonhigh BFR/BS was .323.0 pg/mL. The best cutoff for bALP to discriminate low from nonlow BFR/BS was ,33.1 U/L, and for high from nonhigh BFR/BS, 42.1 U/L. Using the KDIGO practice guideline PTH values of greater than 2 but less than 9 times the upper limit of normal, sensitivity and specificity of iPTH level to discriminate low from nonlow turnover bone disease were 65.7% and 65.3%, and to discriminate high from nonhigh were 37.0% and 85.8%, respectively.Limitations: Cross-sectional design without consideration of therapy. Potential limited generalizability with samples from 4 countries.Conclusions: The serum biomarkers iPTH, whole PTH, and bALP were able to discriminate low from nonlow BFR/BS, whereas iPTH and bALP were able to discriminate high from nonhigh BFR/BS. Prospective studies are required to determine whether evaluating trends in biomarker concentrations could guide therapeutic decisions. Am J Kidney Dis. 67(4):559-566. ª 2016 by the National Kidney Foundation, Inc.

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Disturbances in mineral metabolism play a central role in the development of renal bone disease. In a 54-wk, randomized, open-label study, 119 hemodialysis patients were enrolled to compare the effects of sevelamer hydrochloride and calcium carbonate on bone. Biopsy-proven adynamic bone disease was the most frequent bone abnormality at baseline (59%). Serum phosphorus, calcium, and intact parathyroid hormone were well controlled in both groups, although calcium was consistently lower and intact parathyroid hormone higher among patients who were randomly assigned to sevelamer. Compared with baseline values, there were no changes in mineralization lag time or measures of bone turnover (e.g., activation frequency) after 1 yr in either group. Osteoid thickness significantly increased in both groups, but there was no significant difference between them. Bone formation rate per bone surface, however, significantly increased from baseline only in the sevelamer group (P ϭ 0.019). In addition, of those with abnormal microarchitecture at baseline (i.e., trabecular separation), seven of 10 in the sevelamer group normalized after 1 yr compared with zero of three in the calcium group. In summary, sevelamer resulted in no statistically significant changes in bone turnover or mineralization compared with calcium carbonate, but bone formation increased and trabecular architecture improved with sevelamer. Further studies are required to assess whether these changes affect clinical outcomes, such as rates of fracture. 19: 405-412, 200819: 405-412, . doi: 10.1681 Patients with chronic kidney disease (CKD) typically have abnormal bone histology. Alterations in bone turnover, mineralization, and volume in renal patients depend on several factors. In particular, disturbances in calcium-phosphate, parathyroid hormone (PTH), and vitamin D metabolism are important in the development of renal osteodystrophy (ROD). J Am Soc NephrolThe pattern of ROD observed in patients with stage 5 CKD has changed in recent years. Previously, observed bone conditions in renal patients in order of prevalence were mixed uremic osteodystrophy (MUO), predominant hyperparathyroid bone disease (HPBD), and aluminum-related os-

COSMOS provides evidence of the association of serum phosphorus, calcium and PTH and mortality, and suggests survival benefits of controlling chronic kidney disease-mineral and bone disorder biochemical parameters in CKD5D patients.

Cytomegalovirus (CMV) is the most common viral infection after transplantation. Valganciclovir (VGC) is established for prophylaxis and treatment of CMV infections, but leukopenia which appears in 10% to 13% (severe in 4.9%) is the principal side effect. We have recently noted an increased incidence of leukopenia and severe neutropenia among our renal transplant patients and thought to identify the associated factors. We conducted a retrospective analysis of all kidney transplantations performed between January 2005 and December 2006. All patients received mycophenolate mofetil (MMF), tacrolimus, and steroids. VGC was used for targeted prophylaxis and preemptive therapy of CMV infection, with doses adjusted to renal function. Of the 64 patients undergoing renal transplantation 13 (20.3%) developed leukopenia within 3 Ϯ 2 months after transplantation with severe neutropenia in 5 (7.8%). All patients were on MMF and VGC (VGC 605 Ϯ 296 mg/d). Leukopenia was significantly associated with simultaneous liver-kidney transplantation and with second kidney transplantations (P Ͻ .01). The incidence of leukopenia was higher among patients under VGC since day 1 of transplantation (P ϭ .008) with maximal incidence observed among patients prescribed 900 mg/d as opposed to those on lower doses (P Ͻ .01). There was no increase in CMV infection among patients with a low dose of VGC. No patient developed clinical CMV disease. In conclusion, VGC prophylaxis was associated with an increased frequency of leukopenia on MMF-tacrolimus treated patients or regimens. Low-dose VGC for CMV prophylaxis appeared to be as effective as high-dose treatment, and associated less frequently with leukopenia and neutropenia. C YTOMEGALOVIRUS (CMV) is a major cause of morbidity and mortality among solid organ transplant recipients.1 Among recipients of kidney transplants, CMV infection and disease are associated with decreased allograft and patient survivals.2 Risk factors for CMV infection and disease include donor (D) and recipient (R) serostatus, with donor-seropositive, recipient-seronegative (Dϩ/RϪ) as well as administration of antilymphocyte antibodies. Valganciclovir (VGC) is an L-valyl ester of ganciclovir with an oral bioavailability 10 times higher than oral ganciclovir, with the convenience of a once-daily oral dosing regimen. 4 It was recently reported that among Dϩ/RϪ patients, 900 mg/d of VGC was as clinically effective as 3 g/d of oral ganciclovir to prevent CMV.5 Several studies have reported that low-dose (450 mg/d) VGC is as effective as oral ganciclovir for CMV prophylaxis.6 -9 Present guidelines recommend 900 mg/d for CMV prophylaxis. 10Leukopenia has been the main side effect of VGC. A recent study showed that full VGC doses are associated with an important risk for neutropenia (12.5%), in conjunction with a cyclosporine (CsA)/tacrolimus-mycophenolate mofetil (MMF)-based regimen.11 In our transplant unit, in the last years we have noticed a higher incidence of leukopenia among our patients, particularly upon the introduct...

Background and objectives: There is increasing evidence that altered bone metabolism is associated with cardiovascular calcifications in patients with stage 5 chronic kidney disease on hemodialysis (HD). This study was conducted to evaluate the association between bone volume, turnover, and coronary calcifications in HD patients.Design, setting, participants, & measurements: In a cross-sectional study, bone biopsies and multislice computed tomography were performed in 38 HD patients. Bone volume/total volume, activation frequency, and bone formation rate/bone surface were determined by histomorphometry and coronary calcifications were quantified by Agatston scores.Results: Prevalence of low bone turnover was 50% and of low bone volume was 16%. Among the studied traditional cardiovascular risk factors, only age was found to be associated with coronary calcifications. Lower bone volume was a significant risk factor for coronary calcifications during early years of HD, whereas this effect was not observed in patients with dialysis duration >6 yr. Histomorphometric parameters of bone turnover were not associated with coronary calcifications.Conclusions: Low bone volume is associated with increased coronary calcifications in patients on HD.

<b><i>Background:</i></b> Hypomagnesaemia is a cardiovascular (CV) risk factor in the general population. The aim of this study was to evaluate the relationship between pre-dialysis magnesium (Mg) and CV risk markers, [including pulse pressure (PP), left ventricular mass index (LVMI) and vascular calcifications (VC)], and mortality in haemodialysis (HD) patients. <b><i>Methods:</i></b> We performed a 48-month prospective study in 206 patients under pre-dilution haemodiafiltration with a dialysate Mg concentration of 1 mmol/l. <b><i>Results:</i></b> Lower Mg concentrations were predictors of an increased PP (≥65 mm Hg) (p = 0.002) and LVMI (≥140 g/m²) (p = 0.03) and of a higher VC score (≥3) (p = 0.01). Patients with Mg <1.15 mmol/l had a lower survival at the end of the study (p = 0.01). Serum Mg <1.15 mmol/l was an independent predictor of all-cause (p = 0.01) and CV mortality (p = 0.02) when adjusted for multiple CV risk factors. <b><i>Conclusions:</i></b> Lower Mg levels seem to be associated with increased CV risk markers, like PP, LVMI and VC, and with higher mortality in HD patients.

Hyperphosphatemia has been associated with higher mortality risk in CKD 5 patients receiving dialysis. Here, we determined the association between the use of single and combined phosphate-binding agents and survival in 6797 patients of the COSMOS study: a 3-year follow-up, multicenter, open-cohort, observational prospective study carried out in 227 dialysis centers from 20 European countries. Patient phosphate-binding agent prescriptions (time-varying) and the case-mix-adjusted facility percentage of phosphate-binding agent prescriptions (instrumental variable) were used as predictors of the relative all-cause and cardiovascular mortality using Cox proportional hazard regression models. Three different multivariate models that included up to 24 variables were used for adjustments. After multivariate analysis, patients prescribed phosphate-binding agents showed a 29 and 22% lower all-cause and cardiovascular mortality risk, respectively. The survival advantage of phosphate-binding agent prescription remained statistically significant after propensity score matching analysis. A decrease of 8% in the relative risk of mortality was found for every 10% increase in the case-mix-adjusted facility prescription of phosphate-binding agents. All single and combined therapies with phosphate-binding agents, except aluminum salts, showed a beneficial association with survival. The findings made in the present association study need to be confirmed by randomized controlled trials to prove the observed beneficial effect of phosphate-binding agents on mortality.