A current challenge in the fight against the SARS-CoV-2 virus is the assessment of the long-term effectiveness of vaccination, in particular against the variants of concern and in vulnerable populations. One of the key questions is whether biomarkers of humoral and cellular immunities are reliable surrogates for the clinical effectiveness of vaccination, that is, protection against SARS-CoV-2 infection, COVID-19, and mortality. In the general population, a significant waning of antibody levels within 6 months of vaccination was observed.1Levin E.G. Lustig Y. Cohen C. et al.Waning immune humoral response to BNT162b2 COVID-19 vaccine over 6 months.N Engl J Med. 2021; 385: e84https://doi.org/10.1056/NEJMoa2114583Crossref PubMed Scopus (362) Google Scholar Protection against SARS-CoV-2 infection decreased rapidly within 6 months of vaccination, but protection against hospitalization and death persisted at robust levels.2Chemaitelly H. Tang P. Hasan M.R. et al.Waning of BNT162b2 vaccine protection against SARS-CoV-2 infection in Qatar.N Engl J Med. 2021; 385: e83https://doi.org/10.1056/NEJMoa2114114Crossref PubMed Scopus (205) Google Scholar The latter data were generated in Qatar from January 2021 to September 2021 when the B.1.351 (beta) and B.1.617.2 (delta) variants were dominant. A study in health care workers revealed lower peak and peri-infection neutralizing antibody titers in individuals with breakthrough infections, 85% of which were caused by the B.1.1.7 (alpha) variant, as compared with noninfected matched controls.3Bergwerk M. Gonen T. Lustig Y. et al.COVID-19 breakthrough infections in vaccinated health care workers.N Engl J Med. 2021; 385: 1474-1484https://doi.org/10.1056/NEJMoa2109072Crossref PubMed Scopus (459) Google Scholar In the dialysis population, data are currently limited. A gradual waning of antibody levels was observed 2 to 3 months4Angel-Korman A. Peres E. Bryk G. et al.Diminished and waning immunity to COVID-19 vaccination among hemodialysis patients in Israel: the case for a third vaccine dose.Clin Kidney J. 2021; 15: 226-234https://doi.org/10.1093/ckj/sfab206Crossref Google Scholar and 6 months5Davidovic T. Schimpf J. Abbassi-Nik A. et al.Waning humoral response 6 months after SARS-CoV-2 vaccination with the mRNA-BNT162b2 vaccine in hemodialysis patients: time for a boost.Kidney Int. 2021; 100: 1334-1335https://doi.org/10.1016/j.kint.2021.10.006Abstract Full Text Full Text PDF Scopus (23) Google Scholar after vaccination, but direct comparisons with the decay trajectory in healthy volunteers have not been made. In addition, immunologic characteristics that may predict breakthrough infections in dialysis patients have not been identified. In this prospective multicenter study, we assessed the longevity of the humoral and cellular immune responses to BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) vaccination in a large cohort of hemodialysis patients and in COVID-19–naive healthy volunteers and analyzed predictors of breakthrough infections. The short methods are described in the Supplementary Methods.6Van Praet J. Reynders M. De Bacquer D. et al.Predictors and dynamics of the humoral and cellular immune response to SARS-CoV-2 mRNA vaccines in hemodialysis patients: a multicenter observational study.J Am Soc Nephrol. 2021; 32: 3208-3220Crossref Scopus (22) Google Scholar,S1–S3 A total of 569 hemodialysis patients and 76 healthy volunteers were included (Supplementary Figure S1). After exclusion of dropouts, missing samples, and breakthrough infections, the final analysis of the humoral and cellular immune responses at 24 weeks was conducted in 492 hemodialysis patients, of whom 436 were COVID-19 naive, and in 75 COVID-19–naive healthy volunteers (Supplementary Table S1). At 24 weeks after vaccination, antibody geometric mean titer and QuantiFERON geometric mean concentration were substantially lower in COVID-19–naive hemodialysis patients than in COVID-19–naive healthy volunteers. The geometric mean titer and geometric mean concentration were markedly higher in COVID-19–experienced than in COVID-19–naive hemodialysis patients at all time points (Table 1, Supplementary Table S2, and Supplementary Figure S2).Table 1Humoral and cellular immune responses at 24 weeksHemodialysis n = 492)Healthy volunteers (n = 75)BNT162b2 recipients (n = 289)mRNA-1273 recipients (n = 203)PBNT162b2 recipients (n = 37)mRNA-1273 recipients (n = 38)PHumoral responseGMT (95% CI), AU/ml Overall323 (262–399)906 (719–1141)<0.0011521 (1241–1863)4046 (3167–5168)<0.001 COVID-19 naive226 (190–268)702 (565–871)<0.0011521 (1241–1863)4046 (3167–5168)<0.001 COVID-19 experienced5220 (2339–11,649)6671 (3183–13,982)0.676———%>3560 AU Overall, %9.020.20.000510.860.5<0.001 COVID-19 naïve, %2.013.3<0.00110.860.5<0.001 COVID-19 experienced, %63.673.90.563———Cellular response (Ag2aResults for Ag1 are similar.)GMC (95% CI), IU/mlaResults for Ag1 are similar. Overall0.126 (0.101–0.156)0.157 (0.124–0.198)0.1810.134 (0.097–0.185)0.301 (0.197–0.459)0.0041 COVID-19 naive0.106 (0.085–0.133)0.136 (0.107–0.172)0.1470.134 (0.097–0.185)0.301 (0.197–0.459)0.0041 COVID-19 experienced0.447 (0.224–0.893)0.464 (0.207–1.038)0.947———% ≥0.15 IU/ml Overall, %47.249.80.64343.271.10.020 COVID-19 naive, %43.547.70.42943.271.10.020 COVID-19 experienced, %75.865.20.549———AU, Abbott unit; GMC, geometric mean concentration; GMT, geometric mean titer.a Results for Ag1 are similar. Open table in a new tab AU, Abbott unit; GMC, geometric mean concentration; GMT, geometric mean titer. The serologic responses elicited by the mRNA-1273 vaccine were significantly greater than those induced by the BNT162b2 vaccine in hemodialysis patients and healthy volunteers at all time points (Figure 1a and Table 1). Similarly, the cellular response was greater in mRNA-1273 recipients than in BNT162b2 recipients from the control group at all time points. However, the superior effect of the mRNA-1273 vaccine on the cellular response was lost at 24 weeks in hemodialysis patients (Figure 1b and Table 1). In a separate analysis of the COVID-19–experienced hemodialysis patients, the immunogenicity of the BNT162b2 and mRNA-1273 vaccines was not significantly different (Table 1 and Supplementary Figure S2). A multivariate analysis revealed COVID-19 experience, use of immunosuppressive drugs, serum albumin level, hepatitis B nonresponder status, and lymphocyte count as independent predictors of humoral and cellular responses at 24 weeks, while vaccine type was an independent predictor of the humoral response only (Supplementary Table S3). The decay trajectory of the humoral response was similar in all groups, with a decline in antibody levels of around 80% between 8/9 weeks and 24 weeks. In contrast, the decline of the QuantiFERON levels was around 20% in BNT162b2 recipients on hemodialysis versus approximately 50% in the other groups (Supplementary Table S2). In hemodialysis patients, 7 breakthrough infections were identified, 5 of which were documented by polymerase chain reaction (80% alpha, 20% delta) and 2 by appearance of anti-N antibodies at 24 weeks. All breakthrough infections occurred in COVID-19–naive BNT162b2 recipients. Furthermore, 3 patients had severe disease requiring hospitalization and 2 patients died. As compared with the matched COVID-19–naive hemodialysis patients without breakthrough infection, peak humoral response was numerically but not significantly lower in breakthrough cases (Table 2). However, cellular responses at 8/9 weeks were significantly lower in the patients with breakthrough infections than in matched noninfected patients (Table 2).Table 2Immunologic responses in breakthrough infections and matched controlsBreakthrough cases n = 7Matched controls n = 21SignificanceaAccording to Fisher exact test, Mann-Whitney U test, or exact conditional logistic regression analysis (mid-P value).Age, yr76.4 (49.1–79.2)aAccording to Fisher exact test, Mann-Whitney U test, or exact conditional logistic regression analysis (mid-P value).76.4 (51.8–79.1)aAccording to Fisher exact test, Mann-Whitney U test, or exact conditional logistic regression analysis (mid-P value).P = 0.937Male, %71.4% (5)71.4% (15)P = 0.999mRNA-1273 recipient, %0.0% (0)33.3% (7)P = 0.141Dialysis vintage, yr2.62 (0.87–2.88)bMedian (interquartile range).3.54 (1.59–5.91)bMedian (interquartile range).P = 0.160Immunosuppressive drugs, %0.0% (0)19.1% (4)P = 0.545Hepatitis B vaccine nonresponder, %14.3% (1)10.0% (2)P = 0.999Serum albumin, g/l40.2 (39.6–41.4)bMedian (interquartile range).39.8 (38.4–41.0)bMedian (interquartile range).P = 0.448Ln (lymphocyte count), n/μl1000 (900–1300)bMedian (interquartile range).1200 (1000–1650)bMedian (interquartile range).P = 0.577Humoral response at 8/9 wkGMT (95% CI), AU/ml1097 (309–3892)1888 (756–4715)P = 0.564% >3560 AU/ml28.6% (2)33.3% (7)P = 0.816Cellular response (Ag2) at 8/9 wkcResults for Ag1 are similar.GMC (95% CI), IU/ml0.052 (0.034–0.081)0.261 (0.124–0.552)P = 0.014% ≥0.15 IU/ml0.0% (0)57.1% (12)P = 0.013AU, Abbott unit; GMC, geometric mean concentration; GMT, geometric mean titer.a According to Fisher exact test, Mann-Whitney U test, or exact conditional logistic regression analysis (mid-P value).b Median (interquartile range).c Results for Ag1 are similar. Open table in a new tab AU, Abbott unit; GMC, geometric mean concentration; GMT, geometric mean titer. A large body of evidence has documented impaired short-term immune responses to SARS-CoV-2 vaccination in hemodialysis patients.7El Karoui K. De Vriese A.S. COVID-19 in dialysis: clinical impact, immune response, prevention and treatment.Kidney Int. 2022; (, pii: S0085-2538(22)00099-0. https://doi.org/10.1016/j.kint.2022.01.022)Abstract Full Text Full Text PDF Scopus (6) Google Scholar Emerging data reveal waning antibody levels in hemodialysis patients,4Angel-Korman A. Peres E. Bryk G. et al.Diminished and waning immunity to COVID-19 vaccination among hemodialysis patients in Israel: the case for a third vaccine dose.Clin Kidney J. 2021; 15: 226-234https://doi.org/10.1093/ckj/sfab206Crossref Google Scholar,5Davidovic T. Schimpf J. Abbassi-Nik A. et al.Waning humoral response 6 months after SARS-CoV-2 vaccination with the mRNA-BNT162b2 vaccine in hemodialysis patients: time for a boost.Kidney Int. 2021; 100: 1334-1335https://doi.org/10.1016/j.kint.2021.10.006Abstract Full Text Full Text PDF Scopus (23) Google Scholar but comparisons with healthy volunteers were not made. In a large cohort of hemodialysis patients, we demonstrate that hemodialysis patients maintain suboptimal humoral and cellular immunities 24 weeks after vaccination as compared with healthy volunteers. The superior immunogenicity of the mRNA-1273 vaccine versus the BNT162b2 vaccine is well preserved in healthy volunteers, but gradually disappears in hemodialysis patients, such that there is no longer a difference in cellular response between mRNA-1273 and BNT162b2 recipients at 24 weeks. COVID-19 experience results in strikingly better vaccine-induced immune responses, overruling the effect of vaccine type. Other independent predictors of the immune responses were similar as those reported at 8/9 weeks6Van Praet J. Reynders M. De Bacquer D. et al.Predictors and dynamics of the humoral and cellular immune response to SARS-CoV-2 mRNA vaccines in hemodialysis patients: a multicenter observational study.J Am Soc Nephrol. 2021; 32: 3208-3220Crossref Scopus (22) Google Scholar: use of immunosuppressive drugs, serum albumin level, lymphocyte count, and hepatitis B nonresponder status. Despite these impaired immune responses, only few breakthrough infections (0.01%, 7/569) were recorded in our hemodialysis population. However, these favorable results need to be interpreted against the background of extremely high vaccination coverage among hemodialysis patients (98%) and health care workers (nearing 100%) in the participating dialysis centers, including in the general population in Flanders (80% of the entire population), resulting in low circulation of the virus among close patient contacts. In addition, data were collected between April 2021 and October, 2021, when the epidemic was slowing down, and the delta variant only became the dominant strain in early July. The risk of breakthrough infections in the dialysis population may increase substantially with greater circulation of the virus resulting from general waning of immunity, dominance of the highly contagious delta and omicron variants, and indoor activities during the winter months. The identification of immunologic predictors of breakthrough infections is therefore critical to optimize the vaccination strategy. The cellular immune responses at week 8/9 were remarkably different between breakthrough cases and matched controls. In contrast, peak antibody levels were numerically but not significantly different, most likely because of low patient numbers. Taken together, humoral and cellular immunities to SARS-CoV-2 vaccination remain significantly lower in hemodialysis patients than in healthy volunteers 6 months after vaccination, although the overall pattern of decay is similar. Robust cellular immunity appears paramount to prevent breakthrough infections. All the authors declared no competing interests. The authors are indebted to Tessa Acke, Manuela Caster, Evelyne Deglorie, Mirjam Demesmaecker, Suzanne Driessens, Inne Hoebrekx, Annelien Leunen, Carine Lowis, Isabel Moyaert, Danny Pauwels, Joris Penders, Melissa Renders, Carmen Reynders, Sofie Tombeur, Katrien Uyttersprot, Femke Van Den Berg, Kristel Van Varenbergh, Tine Verheyen, Manon Verhulst, and Sophie Vleeschouwers for their invaluable help in the collection of the patient data and analysis of the samples. This research was supported by a grant of Amgen (DONATION-331036). The funding source had no role in the design, conduct, or analysis of the study or the decision to submit the manuscript for publication. Download .pdf (.42 MB) Help with pdf files Supplementary File (PDF) Table S1. Demographic and clinical characteristics at baseline. Table S2. (A) Changes in humoral response between 8/9 and 24 weeks. (B) Changes in cellular response (Ag 2∗∗) between 8/9 and 24 weeks. Table S3. (A) Multivariate analysis of factors associated with humoral immune response at 24 weeks. (B) Multivariate analysis of factors associated with cellular immune response at 24 weeks. Figure S1. Study flowchart. Figure S2. Humoral and cellular responses in hemodialysis patients. Download .docx (.01 MB) Help with docx files Supplementary File (WORD) Supplementary Reference.

Significance Statement Patients on hemodialysis characteristically have an impaired response to vaccination. This large multicenter cohort study found an incomplete and delayed humoral and a blunted cellular immune response to SARS-CoV-2 vaccination in patients on hemodialysis. Recipients of the mRNA-1273 vaccine had mean responses that were substantially larger than responses of BNT162b2 vaccine recipients, and were significantly more likely to achieve the higher antibody thresholds thought to be required for preventing infection. A multivariate analysis identified COVID-19 experience, vaccine type, use of immunosuppressive drugs, serum albumin, lymphocyte count, hepatitis B vaccine nonresponder status, and dialysis vintage as independent predictors of humoral and cellular responses. The strikingly better responses in mRNA-1273 recipients may be related to the vaccine’s higher mRNA content, suggesting that a high-dose vaccine may help improve SARS-CoV-2 vaccine effectiveness in patients on hemodialysis. Background Preliminary evidence suggests patients on hemodialysis have a blunted early serological response to SARS-CoV-2 vaccination. Optimizing the vaccination strategy in this population requires a thorough understanding of predictors and dynamics of humoral and cellular immune responses to different SARS-CoV-2 vaccines. Methods This prospective multicenter study of 543 patients on hemodialysis and 75 healthy volunteers evaluated the immune responses at 4 or 5 weeks and 8 or 9 weeks after administration of the BNT162b2 or mRNA-1273 vaccine, respectively. We assessed anti–SARS-CoV-2 spike antibodies and T cell responses by IFN-γ secretion of peripheral blood lymphocytes upon SARS-CoV-2 glycoprotein stimulation (QuantiFERON assay) and evaluated potential predictors of the responses. Results Compared with healthy volunteers, patients on hemodialysis had an incomplete, delayed humoral immune response and a blunted cellular immune response. Geometric mean antibody titers at both time points were significantly greater in patients vaccinated with mRNA-1273 versus BNT162b2, and a larger proportion of them achieved the threshold of 4160 AU/ml, corresponding with high neutralizing antibody titers in vitro (53.6% versus 31.8% at 8 or 9 weeks, P <0.0001). Patients vaccinated with mRNA-1273 versus BNT162b2 exhibited significantly greater median QuantiFERON responses at both time points, and a larger proportion achieved the threshold of 0.15 IU/ml (64.4% versus 46.9% at 8 or 9 weeks, P <0.0001). Multivariate analysis identified COVID-19 experience, vaccine type, use of immunosuppressive drugs, serum albumin, lymphocyte count, hepatitis B vaccine nonresponder status, and dialysis vintage as independent predictors of the humoral and cellular responses. Conclusions The mRNA-1273 vaccine’s greater immunogenicity may be related to its higher mRNA dose. This suggests a high-dose vaccine might improve the impaired immune response to SARS-CoV-2 vaccination in patients on hemodialysis.

Significance Statement Direct oral anticoagulants (DOACs) have a superior risk-benefit profile compared with vitamin K antagonists (VKAs) in patients with normal renal function or early stage CKD, but whether this can be extended to the hemodialysis population is unknown. The authors report the first randomized controlled trial of thromboembolic and bleeding risk in patients on hemodialysis with atrial fibrillation on long-term treatment with a VKA or DOAC therapy. After a median follow-up of 1.88 years, the VKA and DOAC groups had a similar risk of stroke. However, the composite outcome of fatal and nonfatal cardiovascular events occurred more frequently with a VKA than with a DOAC, as did major bleeding complications. These findings support a superior risk-benefit profile of DOACs versus VKAs and suggest that VKAs should be avoided in patients on hemodialysis. Background In patients with normal renal function or early stage CKD, the risk-benefit profile of direct oral anticoagulants (DOACs) is superior to that of vitamin K antagonists (VKAs). In patients on hemodialysis, the comparative efficacy and safety of DOACs versus VKAs are unknown. Methods In the Valkyrie study, 132 patients on hemodialysis with atrial fibrillation were randomized to a VKA with a target INR of 2–3, 10 mg rivaroxaban daily, or rivaroxaban and vitamin K2 for 18 months. Patients continued the originally assigned treatment and follow-up was extended for at least an additional 18 months. The primary efficacy end point was a composite of fatal and nonfatal cardiovascular events. Secondary efficacy end points were individual components of the composite outcome and all-cause death. Safety end points were life-threatening, major, and minor bleeding. Results Median (IQR) follow-up was 1.88 (1.01–3.38) years. Premature, permanent discontinuation of anticoagulation occurred in 25% of patients. The primary end point occurred at a rate of 63.8 per 100 person-years in the VKA group, 26.2 per 100 person-years in the rivaroxaban group, and 21.4 per 100 person-years in the rivaroxaban and vitamin K2 group. The estimated competing risk–adjusted hazard ratio for the primary end point was 0.41 (95% CI, 0.25 to 0.68; P=0.0006) in the rivaroxaban group and 0.34 (95% CI, 0.19 to 0.61; P=0.0003) in the rivaroxaban and vitamin K2 group, compared with the VKA group. Death from any cause, cardiac death, and risk of stroke were not different between the treatment arms, but symptomatic limb ischemia occurred significantly less frequently with rivaroxaban than with VKA. After adjustment for competing risk of death, the hazard ratio for life-threatening and major bleeding compared with the VKA group was 0.39 (95% CI, 0.17 to 0.90; P=0.03) in the rivaroxaban group, 0.48 (95% CI, 0.22 to 1.08; P=0.08) in the rivaroxaban and vitamin K2 group and 0.44 (95% CI, 0.23 to 0.85; P=0.02) in the pooled rivaroxaban groups. Conclusions In patients on hemodialysis with atrial fibrillation, a reduced dose of rivaroxaban significantly decreased the composite outcome of fatal and nonfatal cardiovascular events and major bleeding complications compared with VKA. Clinical Trial registry name and registration number: Oral Anticoagulation in Hemodialysis, NCT03799822

Longevity and correlation with disease severity of the humoral and cellular response to SARS-CoV-2 infection in haemodialysis patients An S. De Vriese , Jens Van Praet, Marijke Reynders, Line Heylen , Liesbeth Viaene, Rogier Caluwé, Melanie Schoutteten and Dirk De Bacquer 8 Division of Nephrology and Infectious Diseases, AZ Sint-Jan Brugge-Oostende AV, Brugge, Belgium, Division of Medical Microbiology, AZ Sint-Jan Brugge-Oostende AV, Brugge, Belgium, Department of Internal Medicine, Ghent University, Ghent, Belgium, Division of Nephrology, Ziekenhuis Oost-Limburg, Genk, Belgium, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium, Division of Nephrology, AZ Groeninge, Kortrijk, Belgium, Division of Nephrology, OLV Hospital, Aalst, Belgium and Department of Public Health and Primary Care, Ghent University, Ghent, Belgium

BACKGROUND:Vitamin K antagonists (VKAs), although commonly used to reduce thromboembolic risk in atrial fibrillation, have been incriminated as probable cause of accelerated vascular calcification (VC) in patients on hemodialysis. Functional vitamin K deficiency may further contribute to their susceptibility for VC. We investigated the effect of vitamin K status on VC progression in 132 patients on hemodialysis with atrial fibrillation treated with VKAs or qualifying for anticoagulation.METHODS:Patients were randomized to VKAs with target INR 2-3, rivaroxaban 10 mg daily, or rivaroxaban 10 mg daily plus vitamin K2 2000 µg thrice weekly during 18 months. Systemic dp-ucMGP levels were quantified to assess vascular vitamin K status. Cardiac and thoracic aorta calcium scores and pulse wave velocity were measured to evaluate VC progression.RESULTS:Baseline dp-ucMGP was severely elevated in all groups. Initiation or continuation of VKAs further increased dp-ucMGP, whereas levels decreased in the rivaroxaban group and to a larger extent in the rivaroxaban+vitamin K2 group, but remained nevertheless elevated. Changes in coronary artery, thoracic aorta, and cardiac valve calcium scores and pulse wave velocity were not significantly different among the treatment arms. All cause death, stroke, and cardiovascular event rates were similar between the groups. Bleeding outcomes were not significantly different, except for a lower number of life-threatening and major bleeding episodes in the rivaroxaban arms versus the VKA arm.CONCLUSIONS:Withdrawal of VKAs and high-dose vitamin K2 improve vitamin K status in patients on hemodialysis, but have no significant favorable effect on VC progression. Severe bleeding complications may be lower with rivaroxaban than with VKAs.

The cardinal biological role of vitamin K is to act as cofactor for the carboxylation of a number of vitamin K-dependent proteins, some of which are essential for coagulation, bone formation and prevention of vascular calcification. Functional vitamin K deficiency is common and severe among dialysis patients and has garnered attention as a modifiable risk factor in this population. However, no single biochemical parameter can adequately assess vitamin K status. For each biological function of vitamin K, the degree of carboxylation of the relevant vitamin K-dependent protein most accurately reflects vitamin K status. Dephosphorylated uncarboxylated matrix Gla protein (dp-ucMGP) is the best biomarker for vascular vitamin K status when cardiovascular endpoints are studied. Dp-ucMGP levels are severely elevated in haemodialysis patients and correlate with markers of vascular calcification and mortality in some but not all studies. The aetiology of vitamin K deficiency in haemodialysis is multifactorial, including deficient intake, uraemic inhibition of the vitamin K cycle and possibly interference of vitamin K absorption by phosphate binders. The optimal vitamin K species, dose and duration of supplementation to correct vitamin K status in dialysis patients are unknown. Dp-ucMGP levels dose-proportionally decrease with supraphysiological vitamin K2 supplementation, but do not normalize even with the highest doses. In the general population, long-term vitamin K1 or K2 supplementation has beneficial effects on cardiovascular disease, bone density and fracture risk, and insulin resistance, although some studies reported negative results. In haemodialysis patients, several trials on the effects of vitamin K on surrogate markers of vascular calcification are currently ongoing.

Individualized weighing of the risk-benefit of anticoagulation is recommended in patients with atrial fibrillation (AF) that have low established risk scores or, conversely, are at increased risk for bleeding1. Parameters of arterial stiffness and wave reflection could improve risk stratification, but their use has not been validated in arrhythmia2–3. We measured carotid-femoral pulse wave velocity (PWV), central augmentation index (AI) and central pulse pressure (CPP) using the Sphygmo-Cor (AtCor Medical, Sydney, Australia) system in 34 patients (53 to 85 years; 25 males) with AF before and after elective electrical cardioversion. Agreement was assessed using the intraclass correlation coefficient (ICC) and the coefficient of variation, completed with Bland-Altman plots. Following cardioversion, mean arterial blood pressure (MAP) and heart rate (HR) decreased significantly by 7 mmHg and 18 bpm respectively. PWV decreased from 11.8 m/s to 10.7 m/s, AI increased from 24

Polycystic kidney disease (PKD) is characterized by urinary tract infections and extrarenal abnormalities such as an increased risk of cancer. As mutations in polycystin-1 and -2 are associated with decreased proliferation of immortalized lymphoblastoid cells in PKD, we investigated whether lymphopenia could be an unrecognized trait of PKD.We studied 700 kidney transplant recipients with (n = 126) or without PKD at the time of kidney transplantation between 1 January 2003 and 31 December 2014 at Ghent University Hospital. We also studied 204 patients with chronic kidney disease (CKD) with PKD and 204 matched CKD patients without PKD across comparable CKD strata with assessment between 1 January 1999 and 1 February 2016 at three renal outpatient clinics. We compared lymphocyte counts with multiple linear regression analysis to adjust for potential confounders. We analysed flow cytometric immunophenotyping data and other haematological parameters.Lymphocyte counts were 264/A mu L [95% confidence interval (CI) 144-384] and 345/A mu L (95% CI 245-445) (both P < 0.001) lower in the end-stage kidney disease (ESKD) and CKD cohort, respectively, after adjustment for age, sex, ln(C-reactive protein) and estimated glomerular filtration rate (in the CKD cohort only). In particular, CD8(+) T and B lymphocytes were significantly lower in transplant recipients with versus without PKD (P < 0.001 for both). Thrombocyte and monocyte counts were lower in patients with versus without PKD in both cohorts (P < 0.001 for all analyses except P = 0.01 for monocytes in the ESKD cohort).PKD is characterized by distinct cytopenias and especially lymphopenia, independent of kidney function. This finding has the potential to alter our therapeutic approach to patients with PKD.

Individualized weighing of the risk benefit of anticoagulation is recommended in patients with atrial fibrillation (AF) who have low established risk scores or, conversely, are at increased risk for bleeding. Parameters of arterial stiffness and wave reflection could improve risk stratification, but their use has not been evaluated in arrhythmia. We measured carotid-femoral pulse wave velocity (PWV), central augmentation index (AI), and central pulse pressure (CPP) using the SphygmoCor system in 34 patients (53 to 85 years; 25 males) with AF before and after elective electrical cardioversion. Agreement was assessed using the intraclass correlation coefficient (ICC) and the coefficient of variation, completed with Bland-Altman plots. After cardioversion, mean arterial blood pressure (MAP) and heart rate (HR) decreased significantly by 8 mmHg and 18 bpm, respectively. PWV decreased from 11.8 m/s to 10.7 m/s, AI increased from 24% to 29%, and CPP rose from 38 mmHg to 43 mmHg. The decrease in PWV was related to the decrease in MAP (beta = 0.57; R-2 = 0.33; P <.001), whereas changes in AI and CPP were related to the decrease in HR (AI: beta = 0.59; R-2 = 0.35; P <.001, CPP: beta = 0.55; R-2 = 0.28; P =.001). After adjustment for changes in MAP and HR, reliability analysis showed an excellent agreement for PWV (ICC = 0.89; 95% confidence interval (CI): 0.79-0.95) but moderate agreement for AI (ICC = 0.59; 95% CI: 0.17-0.80). Excellent agreement was also found for CPP (ICC = 0.89; 95% CI: 0.720.95). Measurement of PWV and CPP is reliable in patients with AF, as they appear unaffected by the presence of arrhythmia. (C) 2018 American Heart Association. All rights reserved.

Objectives: A kidney transplant recipient with recurrent pleuritis underwent an open lung biopsy, the results of which revealed multiple nodular infiltrates. Grocott and periodic acid-Schiff staining were positive. Fungal and Tropheryma whipplei PCR were, however, negative. Further identification was needed. Methods: Formalin-fixed, paraffin-embedded (FFPE) extraction was performed using an FFPE extraction kit. T. whipplei was searched for using a real-time PCR targeting the noncoding repeat specific for T. whipplei. Identification of the bacteria in the extract was done using 16S rDNA and 23S rDNA sequencing and BLAST analysis. Internal transcribed spacer PCR was used for fungal DNA identification. Results: The FFPE extract was negative for fungi and T. whipplei. 16S rDNA sequence analysis of a 1375 bp fragment gave T. whipplei as the best match with 26 mismatches, resulting in only 98% agreement. Sequence analysis of the 23S rDNA gene again gave T. whipplei as the best match, but with only 91% agreement. A pan-Tropheryma 16S rDNA real-time PCR was developed, and both the biopsy sample and a respiratory sample of the patient were strongly positive. The patient received antimicrobial treatment targeting T. whipplei with good clinical outcome. Conclusions: 16S and 23S rDNA sequencing gave T. whipplei as the best hit, although with limited agreement. These findings suggest that a novel Tropheryma species that lacks the noncoding repeat, most frequently used for molecular detection of Whipple disease, might be the cause of the pulmonary disease. Adaptation of current PCR protocols is warranted in order to detect all Tropheryma species. (C) 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Objective: To benchmark the immunogenicity of pneumococcal conjugated vaccine (PCV-13) versus pneumococcal polysaccharide vaccine (PPV-23) in haemodialysis patients pre-vaccinated or not with PPV-23. Methods: The study is a longitudinal quasi-experimental phase IV study in chronic haemodialysis patients aged >= 50 years. Total (ELISA) and functional (opsonophagocytic assay) antibodies after pneumococcal vaccination were quantified at baseline, and after 28 and 365 days. Of 201 eligible patients, 155 were included. Patients were divided in four groups. PPV-23 naive patients were randomized to PPV-23 (40) or PCV-13 (40) vaccination. PPV-23-pre-vaccinated patients were categorized as being vaccinated more (40) or less (35) than 4 years before the study and all received PCV-13. Results: Patients among the four groups had a significant ELISA antibody response for most serotypes that remained significant up to day 365 versus baseline. In PPV-23-naive patients, ELISA antibody titres were significantly higher among PCV-13 versus PPV-23 recipients for six serotypes (1.85-2.34-fold) after 28 days, and remained significantly higher for one serotype (6A, 1.57-fold) after 365 days. Following PCV-13 vaccination, increase in ELISA antibody titres was significantly higher among PPV-23-naive versus PPV-23-pre-vaccinated patients for 12 serotypes after 28 days (1.68-7.74-fold) and remained significantly higher in ten serotypes (1.44-3.29-fold) after 365 days. Conclusion: Immune response after PPV-23 and PCV-13 remains significant for at least 1 year in nonPPV- 23-pre-vaccinated patients. Among vaccine-naive haemodialysis patients PCV-13 seems more immunogenic than PPV-23. Immune response to PCV-13 is weaker in PPV-23-pre-vaccinated compared with vaccine-naive patients. (C) 2017 Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases.

BACKGROUND:Hypomagnesemia is associated with a disturbed glucose metabolism. Insulin hypo-secretion predicts diabetes in the general population and in transplant recipients. We aimed to assess whether magnesium improves insulin secretion and glycemic control after transplantation in prevalent hypomagnesemic kidney transplant recipients. MATERIAL AND METHODS:We conducted an open-label, randomized, parallel-group study. Eligible participants were adults more than 4 months after kidney transplantation on tacrolimus with persisting serum magnesium concentrations <1.8 mg/dL randomized to magnesium oxide supplementation up to a maximum of 3 times 450 mg daily (N=26) or no supplements (N=26). Insulin secretion was assessed by OGTT-derived, first-phase insulin secretion (FPIR). The primary endpoint was the mean difference in FPIR between baseline and 6 months after randomization. Secondary endpoints were differences in HbA1c and insulin resistance, measured by HOMA. Dietary magnesium was assessed by a food-frequency questionnaire. All analyses were done on an intention-to-treat basis. RESULTS:Magnesium with a mean daily dose of 688±237mg in the treatment group failed to lead to significant differences between the 2 groups in FPIR, fasting glucose, HbA1c, or HOMA-IR. Persisting hypomagnesemia was very common and associated with more insulin hypo-secretion, glucose intolerance, and lower dietary magnesium intake (142±56 versus 202±90 mg; p=0.015) as compared to patients with a rise in serum magnesium over 6 months. CONCLUSIONS:Magnesium supplementation does not improve insulin secretion in stable hypomagnesemic kidney transplant recipients on tacrolimus. Persisting hypomagnesemia is associated with impaired glucose tolerance, insulin hypo-secretion, and dietary factors.

Objectives: Magnesium is a co-factor in natural killer and T cell reactivity and may modify the course of infections. We examined the association between baseline serum magnesium concentration and infections requiring admission the first year after kidney transplantation.Methods: Inclusion of adults transplant recipients between January 2003 and 31 December 2013. Cox piecewise linear regression model estimating the hazard ratio for first admission for infection. Outcomes until one year post-transplantation or up to May 1, 2014.Results: Overall, 371 of 873 persons were admitted at least once the first year after transplantation (65 events per 100 person-years). The infection-specific cumulative incidence increased with lower serum magnesium concentration (P = 0.008). After adjustment for confounders, a low serum magnesium was associated with an increased hazard of infection (P < 0.0001 in type 3 test). With 2 mg/dL as the reference value, every 0.1 mg/dL reduction in serum magnesium at baseline below 2 mg/dL (N = 165) increased the hazard ratio by 15% (HR 1.15, 95% CI 1.05 -1.27; P = 0.002) while every increase of 0.1 mg/dL in those with a serum magnesium between 2 and 3 mg/dL (NZ661) decreased the hazard ratio by 4% (HR 0.96, 95% CI 0.93-1.00; P = 0.08).Conclusion: A lower baseline serum magnesium concentration is associated with an increased risk of infection after kidney transplantation. (C) 2016 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

The burden of atrial fibrillation (AF) and the risk of stroke are high in dialysis patients. The decision to use anticoagulation rests heavily on effective risk stratification. Because both the pathophysiology of the disease and the response to therapy differ in dialysis, data from the general population cannot be extrapolated. The effect of vitamin K antagonists (VKAs) on the risk of stroke in dialysis patients with AF has not been studied in randomized trials. The available observational data provide contradictory results, reflecting differences in the degree of residual confounding, quality of international normalized ratio control, and stroke characterization. Dialysis patients have a high baseline bleeding risk. It remains unclear to what extent VKAs affect the overall bleeding propensity, but they may significantly increase the risk of intracerebral hemorrhage. Vascular calcifications are extremely prevalent in dialysis patients and independently associated with an adverse outcome. Vitamin K antagonists inhibit the activity of key anticalcifying proteins and may thus compound the risk of vascular calcification progression in dialysis. In the absence of evidence-based guidelines for anticoagulation in dialysis patients with AF, we provide recommendations to assist clinicians in individualized risk stratification. We further propose that new oral anticoagulants may have a better benefit-risk profile in dialysis patients than VKA, provided appropriate dose reductions are made. New oral anticoagulant may yield more on-target anticoagulation, reduce the risk of intracerebral bleeding, and not interfere with vascular calcification biology. Clinical trials with new oral anticoagulant in dialysis patients are eagerly awaited, to reveal whether these assumptions can be confirmed.

Background The extent and the progression of vascular calcification (VC) are independent predictors of cardiovascular risk in the haemodialysis population. Vitamin K is essential for the activation of matrix gla protein (MGP), a powerful inhibitor of tissue calcification. Functional vitamin K deficiency may contribute to the high VC burden in haemodialysis patients. In addition, haemodialysis patients are frequently treated with vitamin K antagonists, mainly to prevent stroke in atrial fibrillation, potentially compounding the cardiovascular risk in these already vulnerable patients. New oral anticoagulants (NOACs) are valuable alternatives to vitamin K antagonists in the general population, but their use in dialysis has been encumbered by substantial renal clearance. However, a recent pharmacokinetic study provided information on how to use rivaroxaban in haemodialysis patients. Methods We conduct a randomized, prospective, multicentre, open-label interventional clinical trial that will include 117 chronic haemodialysis patients with non-valvular atrial fibrillation, treated with or candidates for treatment with vitamin K antagonists. Patients will be randomized to a vitamin K antagonist titrated weekly to an international normalized ratio between 2 and 3, a daily dose of rivaroxaban of 10 mg, or a daily dose of rivaroxaban 10 mg with a thrice weekly supplement of 2000 µg vitamin K2. Cardiac computed tomography, pulse wave velocity (PWV) measurements and MGP sampling will be performed at baseline, 6 months, 12 months and 18 months. Primary endpoints include progression of coronary artery and thoracic aorta calcification and changes in PWV. Secondary endpoints are progression of aortic and mitral valve calcification, all-cause mortality, major adverse cardiovascular events, stroke and bleeding. The ClinicalTrials.gov database was searched to retrieve related trials. Results Seven trials, three of which are performed in the haemodialysis population, evaluate whether pharmacological doses of vitamin K1 or K2 retard progression of VC. Five studies compare the effect of warfarin and NOACs on progression of VC, the present study being the only conducted in the dialysis population. Conclusion Vitamin K deficiency may be a modifiable cardiovascular risk factor in the haemodialysis population. Conversely, vitamin K antagonists may aggravate VC burden in haemodialysis patients. Several ongoing trials may provide an answer to these questions in the near future.

BACKGROUND:Use of vitamin K antagonists for the prevention of stroke and systemic embolism in dialysis patients with nonvalvular atrial fibrillation is controversial. However, no good alternatives presently are available. The anti-factor Xa antagonist rivaroxaban is contraindicated for lack of pharmacokinetic, pharmacodynamic, and clinical data. This study aims to characterize the pharmacokinetics/pharmacodynamics of rivaroxaban in maintenance hemodialysis patients.STUDY DESIGN:Pharmacokinetic and pharmacodynamic study.SETTING & PARTICIPANTS:18 maintenance hemodialysis patients without residual kidney function at 2 centers. DRUG ADMINISTRATION, OUTCOMES, & MEASUREMENTS: (1) A single dose of 10mg of rivaroxaban was administered at the end of each of 3 consecutive dialysis sessions and area under the curve (AUC) and the effect on coagulation parameters were measured for 44 hours thereafter. (2) A single dose of 10mg of rivaroxaban was given 6 to 8 hours before a dialysis session and the effect of dialysis on rivaroxaban concentrations was evaluated. (3) To assess potential accumulation, 10mg of rivaroxaban was given once daily and AUC was measured during 24 hours on days 1 and 7.RESULTS:Mean AUC0-44 of rivaroxaban plasma concentrations after a single dose of 10mg was 2,072μg/L/h, mean maximum concentration was 172.6μg/L, and mean terminal elimination half-life was 8.6 hours. Dialysis had no appreciable effect on rivaroxaban plasma concentrations. Mean trough concentration after multiple daily doses of 10mg was 20.2μg/L.LIMITATIONS:Higher rivaroxaban doses and patients with substantial residual kidney function were not studied.CONCLUSIONS:A 10-mg dose of rivaroxaban in hemodialysis patients without residual kidney function results in drug exposure similar as published for 20mg in healthy volunteers. Rivaroxaban is not eliminated by dialysis. There is no accumulation after multiple daily dosing. The efficacy and safety of rivaroxaban in hemodialysis patients should be the subject of a large randomized trial.

Haemodialysis patients suffer from accelerated vascular calcification. The vitamin K-dependent matrix Gla protein (MGP) is one of the most powerful inhibitors of vascular calcification. Haemodialysis patients have high levels of the inactive form of MGP (desphosphorylated-uncarboxylated-MGP, dp-uc-MGP) and may benefit from pharmacological doses of vitamin K2 (menaquinone) to improve the calcification inhibitory activity of MGP.To determine the optimal dose of menaquinone-7 (MK-7) for MGP activation, 200 chronic haemodialysis patients were recruited to randomly receive 360, 720 or 1080 A mu g of MK-7 thrice weekly for 8 weeks. Dp-uc-MGP was measured at baseline and after 8 weeks. Dietary intake of vitamin K1 (phylloquinone) and menaquinone was estimated based on a detailed questionnaire.At baseline, dp-uc-MGP was not associated with phylloquinone intake (P = 0.92), but correlated inversely with menaquinone intake (P = 0.023). MK-7 supplementation dose dependently reduced dp-uc-MGP. The levels decreased by 17, 33 and 46% in the respective groups. Drop-outs were mainly due to gastrointestinal side-effects related to the unpleasant smell of the tablets.Chronic haemodialysis patients have high levels of inactive MGP, possibly related to a low dietary vitamin K intake. Pharmacological doses of MK-7 dose-dependently reduce dp-uc-MGP. Menaquinone supplementation may be a novel approach to prevent vascular calcifications in chronic haemodialysis patients.