Michel Jadoul

The relation between hypomagnesaemia and vascular stiffness in renal transplant recipients

BACKGROUNDnArterial stiffness is a strong predictor of outcome. Hypomagnesaemia, by its association with arterial hypertension, endothelial dysfunction, dyslipidaemia and inflammation, might affect vascular stiffness. As hypomagnesaemia is common in renal transplant recipients (RTR), we examined its potential association with arterial stiffness.nnnMETHODSnCross-sectional analysis. Evaluation of vascular stiffness in 512 RTR from two university centres at a median of 72 months post-transplantation. Determination of carotid-femoral pulse wave velocity (PWV) (SphygmoCor). A multiple linear regression analysis was used to investigate the independent relationship between magnesium serum level and PWV with the following covariates: age, diabetes, smoking status, body mass index, blood pressure, heart rate (HR), C-reactive protein (CRP), high-density lipoprotein cholesterol, parathyroid hormone and use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, diuretics, calcium channel blockers, statins and calcineurin inhibitors next to their drug levels.nnnRESULTSnLower serum magnesium was independently associated with PWV (P = 0.018) in addition to age, CRP, HR, diabetes and mean arterial pressure (model R(2) = 0.45; P < 0.001). The relationship between magnesium and PWV was attenuated (P = 0.054) after adjustment for the use of sirolimus, which was associated with higher magnesium levels (P<0.001) and lower PWV (P = 0.013). In patients >55 years (median age), however (low), magnesium remained an independent predictor of PWV (P = 0.024) after accounting for the same covariates.nnnCONCLUSIONSnSerum magnesium is an independent predictor of arterial stiffness in RTR, especially in patients >55 years.

Immunogenicity and safety of an investigational AS02v-adjuvanted hepatitis B vaccine in patients with renal insufficiency who failed to respond or to maintain antibody levels after prior vaccination: results of two open, randomized, comparative trials

An investigational AS02(v)-adjuvanted hepatitis B (HB-AS02) was compared with a licensed conventional recombinant hepatitis B vaccine (HBVAXPRO™; Sanofi Pasteur MSD, Lyon, France) in pre-dialysis, peritoneal dialysis and hemodialysis patients aged ≥18 years who had failed either to respond to prior vaccination with a conventional hepatitis B vaccine (Study A; n=251) or to maintain protective antibody concentrations after prior hepatitis B vaccination (Study B; n=181). These were open, randomized, comparative trials. Mean (range) age was 65.9 (31-92) and 64.6 (29-92) years in the two studies, respectively. In Study A, two doses of HB-AS02 given one month apart were found to be superior to two doses of the licensed vaccine in terms of seroprotection rate (76.9% versus 37.6%) and anti-HBs geometric mean antibody concentration (GMC; 139.3 versus 6.9mIU/ml), with antibody concentrations ≥100mIU/ml in 61.1% and 15.4% of subjects in the two groups, respectively. In Study B, one month after administration of a single booster dose, seroprotection rates were 89.0% in the HB-AS02 group and 90.8% in the licensed vaccine group, 81.3% and 60.9% of subjects had antibody concentrations ≥100mIU/ml, and anti-HBs GMCs were 1726.8 and 189.5mIU/ml. HB-AS02 was found to be more reactogenic than the licensed vaccine. In summary, the investigational HB-AS02 vaccine induced higher seroprotection rates and anti-HBs GMCs than a licensed conventional hepatitis B vaccine in uremic patients who had failed to respond or to maintain protective antibody titers after prior hepatitis B vaccination.

Anti-HBs antibody persistence following primary vaccination with an investigational AS02(v)-adjuvanted hepatitis B vaccine in patients with renal insufficiency.

Background: Three doses of the investigational AS02v-adjuvanted hepatitis B virus (HBV) vaccine HB-AS02 have been shown to induce more rapid seroprotection and higher anti-HBs antibody concentrations in patients with renal insufficiency than four doses of FENDrix™ (HB-AS04), an adjuvanted HBV vaccine licensed in Europe for use in this population. This study evaluated persistence of immune response up to 36 months after primary vaccination. Methods: In this open, international, Phase III follow-up study, 151 pre-dialysis, peritoneal dialysis and hemodialysis patients ³15 years of age received HB-AS02 at 0, 1, 6 months and 149 received HB-AS04 at 0, 1, 2, 6 months. Of these, 99 and 80 returned at Month 36, 76 and 62 of whom were eligible for inclusion in the Long-Term According-To-Protocol (LT-ATP) cohort for descriptive analysis of antibody persistence (mean age: 65.6 years). Results: At Month 36, 89.5% of subjects in the HB-AS02 group and 72.6% of those in the HB-AS04 group had anti-HBs antibody concentrations ³10 mIU/ml. Anti-HBs antibody concentrations were ³100 mIU/ml in 82.9% and 35.5% of subjects, respectively. Anti-HBs geometric mean antibody concentrations were higher in the HB-AS02 group over the 36 months of follow-up. An exploratory “time to boost” analysis confirmed that subjects who received HB-AS02 were 2.54 times more likely than those who received HB-AS04 to have anti-HBs antibody concentrations ³10 mIU/ml at Month 36 (p=0.013 [95% CI: 1.22, 5.31]). Conclusion: HB-AS02 candidate vaccine induces high and persistent anti-HBs antibody levels in pre-dialysis, peritoneal dialysis and hemodialysis patients, potentially reducing the need for booster doses in this population.

Proton-pump inhibitors do not influence serum magnesium levels in renal transplant recipients.

Severe hypomagnesemia has been reported with use of proton-pump inhibitors (PPIs). We assessed the effect, if any, of PPI use on serum magnesium level in a cross-sectional analysis of a large published cohort of renal transplant recipients (RTRs). Between February 2004 and February 2006, 512 consecutive prevalent RTRs were enrolled at two university hospitals in Belgium (Brussels and Ghent). Serum creatinine was 1.5xa0±xa00.7xa0mg/dl, and estimated glomerular filtration rate (eGFR) 53xa0±xa019xa0ml/min/1.73xa0m2. Mean (and median) magnesium level was 1.91xa0±xa00.23xa0mg/dl. PPIs were prescribed in 20xa0% (nxa0=xa0101) of cases. At multivariable analysis, PPI use was not an independent predictor of serum magnesium level or hypomagnesemia. The independent predictors of a lower serum magnesium level were the use of tacrolimus, cyclosporin and sirolimus, the absence of use of mycophenolate mofetil, lower levels of parathyroid hormone and higher eGFR. This study is the first to analyze the potential impact of PPIs on magnesium level in a large, representative cohort of RTR patients. Our results suggest that PPIs may be used without particular fear of favoring hypomagnesemia-related side effects in RTRs, an important finding in a population at high risk of hypomagnesemia.

The fate of triaged and rejected manuscripts.

In 2011, Nephrology Dialysis and Transplantation (NDT) established a more restrictive selection process for manuscripts submitted to the journal, reducing the acceptance rate from 25% (2008-2009) to currently about 12-15%. To achieve this goal, we decided to score the priority of manuscripts submitted to NDT and to reject more papers at triage than in the past. This new scoring system allows a rapid decision for the authors without external review. However, the risk of such a restrictive policy may be that the journal might fail to capture important studies that are eventually published in higher-ranked journals. To look into this problem, we analysed random samples of papers (∼10%) rejected by NDT in 2012. Of the papers rejected at triage and those rejected after regular peer review, 59 and 61%, respectively, were accepted in other journals. A detailed analysis of these papers showed that only 4 out of 104 and 7 out of 93 of the triaged and rejected papers, respectively, were published in journals with an impact factor higher than that of NDT. Furthermore, for all these papers, independent assessors confirmed the evaluation made by the original reviewers. The number of citations of these papers was similar to that typically obtained by publications in the corresponding journals. Even though the analyses seem reassuring, previous observations made by leading journals warn that the risk of big misses, resulting from selective editorial policies, remains a real possibility. We will therefore continue to maintain a high degree of alertness and will periodically track the history of manuscripts rejected by NDT, particularly papers that are rejected at triage by our journal.

Cinacalcet for managing secondary hyperparathyroidism in dialysis patients in clinical practice in Belgium: a 16-month observational study (ECHO-B).

Abstract In Belgium, the calcimimetic cinacalcet is initially reimbursed for ≤ 4 months in dialysis patients with secondary hyperparathyroidism (SHPT) and intact parathyroid hormone (iPTH) ≥ 800 pg/mL, or iPTH 300-800 pg/mL and Ca × P > 55 mg2/dL2 despite ≥ 6 months’ optimal treatment with vitamin D sterols and/or phosphate binders. The Belgian, multicentre, observational study ECHO-B evaluated cinacalcet in such patients. Patients who began cinacalcet treatment after March 1, 2007 were eligible. Data were collected retro/prospectively from 6 months before until 16 months after starting cinacalcet (whether or not cinacalcet was continued). Median iPTH was markedly elevated (816 [IQR 551-991] pg/mL) at baseline (the time of starting cinacalcet), but decreased continuously over the course of the study, reaching a value of 414 pg/mL (IQR 240-641; median change -41%) at 4 months, 335 pg/mL (IQR 159-616; -60%) at 12 months and 250 pg/mL (IQR 172-436; -64%) at 16 months. Reductions in serum calcium (-7%) and phosphorus (-13%) were already (near) maximal at 4 months. The primary outcome (iPTH 150-300 pg/mL and/or a ≥ 30% reduction within 4 months of tarting cinacalcet; criterion for continued reimbursement in Belgium) was achieved in 65/81 patients (80%; 95% CI 72-89%). Results show that in dialysis patients with SHPT in real-life clinical practice, mineral metabolism improves after starting cinacalcet: our study findings suggest that PTH levels may continue decreasing after 12 months’ treatment in this setting.