End-stage renal disease (ESRD) strongly associates with cardiovascular disease (CVD) risk. This risk is not completely mitigated by renal replacement therapy. Endothelial dysfunction (ED) and low-grade inflammation (LGI) may contribute to the increased CVD risk. However, data on serum biomarkers of ED and LGI during the transition to renal replacement therapy  are scarce.We compared serum biomarkers of ED and LGI between 36 controls, 43 participants with chronic kidney disease (CKD) stage 5 non-dialysis (CKD5-ND), 20 participants with CKD stage 5 hemodialysis (CKD5-HD) and 14 participants with CKD stage 5 peritoneal dialysis (CKD5-PD). Further, in 34 and 15 participants repeated measurements were available during the first six months following dialysis initiation and kidney transplantation, respectively. Serum biomarkers of ED  and LGI  were measured with a single- or multiplex array detection system based on electro-chemiluminescence technology.In linear regression analyses adjusted for potential confounders, participants with ESRD had higher levels of most serum biomarkers of ED and LGI than controls. In addition, in CKD5-HD levels of serum biomarkers of ED and LGI were largely similar to those in CKD5-ND. In contrast, in CKD5-PD levels of biomarkers of ED were higher than in CKD5-ND and CKD5-HD. Similarly, in linear mixed model analyses sVCAM-1, thrombomodulin, sICAM-1 and sICAM-3 increased after PD initiation. In contrast, incident HD patients showed an increase in sVCAM-1, P-selectin and TNF-α, but a decline of hs-CRP, SAA and IL-6. Further, following kidney transplantation sVCAM-1, thrombomodulin, sICAM-3 and TNF-α were lower at three months post-transplantation and remained stable in the three months thereafter.per se. In contrast to dialysis, several serum biomarkers of ED and LGI markedly declined following kidney transplantation.Levels of serum biomarkers of ED and LGI were higher in ESRD as compared with controls. In addition, PD initiation and, less convincingly, HD initiation may increase levels of selected serum biomarkers of ED and LGI on top of uremia  Individuals with end-stage renal disease (ESRD) are at high risk of cardiovascular disease (CVD) mortality,2. RenalEndothelial dysfunction (ED) and low-grade inflammation (LGI) have both been implicated in the adverse CVD risk associated with ESRD–10. Indei.e., including assessment of ED and LGI prior and following exposure to dialysis)Reviewers' comments:Reviewer's Responses to QuestionsComments to the Author1. Is the manuscript technically sound, and do the data support the conclusions?The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: NoReviewer #2: PartlyReviewer #3: Yes**********2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't KnowReviewer #2: I Don't KnowReviewer #3: Yes**********3. Have the authors made all data underlying the findings in their manuscript fully available?PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.The Reviewer #1: NoReviewer #2: YesReviewer #3: Yes**********4. Is the manuscript presented in an intelligible fashion and written in standard English?PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: NoReviewer #2: YesReviewer #3: Yes**********5. Review Comments to the AuthorPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1: The manuscript is of interest providing some interesting data on the evolution of biomarkers of endothelial function and inflammation, but many concerns are present.General comments: The manuscript is very difficult to read with a tendency to be confused. Statistical analysis must be reviewed by a specialist.The abstract must be reviewed. The methods and results are not clear and the conclusion I is not really conclusive. Word  you have 3 with monotherapy with tacrolimus, 5 with tacro and MMF and 7 with Tacro MMF and corticoids. It is not clear for me for patients with everolimus if they are still with everolimus or not.Pour les dilyser penser à discuter les différentes membranes.In results,In table 1, the authors must separate HD and PD patients. In controls and CKD5-ND it is not residual urine outpout but diuresis. In this table, in the 18% of patient with CKD have a history of Ktx, did they have an immunosuppressive drugs? This must be stated and clear in the characteristics of the patients. It is very different to study endothelial dysfunction to have or not IS drugs.Important clinical data are missing: tobacco, alcool, lipids concentration, calcium phosphore bicarbonate potassium, hb etc. Medications used, mainly immunosuppressive drugs and corticoids, antihypertensive drugs, HMG CoA inhibitors, anticoagulants, aspirin etc. All this drugs could play an important role on endothelial function and inflammation.For the table 2, supplementary analysis separating HD and PD must be done. Adjustment with blood pressure could be of interest mainly regarding endothelial dysfunction.For the longitudinal analysis we must have separation of PD and HD patients. In addition, in my opinion for dialysis patient regarding the boxplot there is no real differences in all the biomarkers, the test used for statistical significance must be provide explicitly in the results. More interesting than a box blot the authors must provide individual courses of the biomarkers separating HD and PD.We must have comparisons with other biological values, like calcium phosphore, bicarbonate urea, creatininemia etc.For transplantation patients same remarks regarding the representation of data. It could be of interest to indicate the course of values for the 4 patients undergoing dialysis then transplantation the data.The additional analysis section is a non sense. All this analysis must be included with main analysis or not discusses. The patients with cyst infection must be definitively excluded.The discussion will be analyzed after the modification asked for the methods and results.Reviewer #2: In the present study, the authors compared biomarkers of endothelium dysfunction and low-grade inflammation in controls and in different groups of CKD patients. They show that most biomarkers are higher in CKD patients than in controls, higher in dialysis patients than in non-dialyzed patients and decline after kidney transplantation. Higher levels of serum biomarkers of ED and LGI in CKD patients have been previously shown in the literature. In addition, the data on serum biomarkers after kidney transplantation do not provide new informations and only confirm previous studies.1) The design of the study is complex. It mixes the data of three separate observational studies, but the number of subjects per group is quite low. The characteristics of CKD5-ND and CKD5-D patients are different in terms of origin of end stage renal disease, and presence of diabetes mellitus.2) Patients on PD are different from patients on HD , and additional analysis demonstrated differences in biomarkers in these two groups of patients. Therefore,the authors should not include these patients in the same CKD5D group.3) The choice of statistical analyses is not clear. Why do the authors compare the data of biomarkers between groups with linear regression analysis and not with tests for group comparison like ANOVA or Mann Whitney? In addition, why do the authors use a natural log transformation to perform statistical test on the levels of serum biomarkers? How is the distribution of the data ?4) Identical data are presented several times, in different figures/tables. For example, Figure 2 and Table 3 provides the same informations, data in Table 3 are also in S1 Table etc…5) For a better understanding, the authors should add the symbols of p values on figures and tables. In particular, the p values between CKD5-ND and CKD5D should be mentioned in Table 1.6) In table 3, an entire column is NA, please remove the column. In S1 Table, dialysis vintage and KT/V are NA, please remove the lines.Reviewer #3: Manuscript is well written. Only minor suggestions to improve the manuscript.Please try to avoid the use of  in the descriptive sentences in academic writing “This risk is not (completely) mitigated by renal replacement therapy”“Only data of their first study was analyzed” “of” should be “from”Also, I suggest the investigators to may improve the introduction/discussion by going over very nice review on this topic PMID: 30607032 Nat Rev Nephrol. 2019 Feb;15(2):87-108. doi: 10.1038/s41581-018-0098-z**********what does this mean?). If published, this will include your full peer review and any attached files.6. PLOS authors have the option to publish the peer review history of their article  digital diagnostic tool,  8 Aug 2019van Gennip et al., PLOS ONEManuscript ID: PONE-D-19-18004August 8, 2019Dear editor, dear reviewers,Thank you for providing us an opportunity to revise our manuscript. We thank the editor and the reviewers for their thoughtful comments and suggestions which have helped us to improve our manuscript. For your convenience, please find below, in bold, our point-by-point rebuttal. All changes made in the manuscript are highlighted with ‘tracked changes’. The page numbers of the manuscript are used below to indicate where the changes have been made. On behalf of all authors,Yours sincerely,April van Gennip, MD Remy Martens, MD, PhD Response to the Reviewer #1The manuscript is of interest providing some interesting data on the evolution of biomarkers of endothelial function and inflammation, but many concerns are present.General comments: The manuscript is very difficult to read with a tendency to be confused. Statistical analysis must be reviewed by a specialist. We thank the reviewer for the time spend to review the manuscript.1) The abstract must be reviewed. The methods and results are not clear and the conclusion I is not really conclusive. We have reviewed and updated the abstracts within the constraints of the word limits :“Introduction: End-stage renal disease (ESRD) strongly associates with cardiovascular disease (CVD) risk. This risk is not completely mitigated by renal replacement therapy. Endothelial dysfunction (ED) and low-grade inflammation (LGI) may contribute to the increased CVD risk. However, data on serum biomarkers of ED and LGI during the transition to renal replacement therapy  are scarce. Methods: We compared serum biomarkers of ED and LGI between 36 controls, 43 participants with chronic kidney disease (CKD) stage 5 non-dialysis (CKD5-ND), 20 participants with CKD stage 5 hemodialysis (CKD5-HD) and 14 participants with CKD stage 5 peritoneal dialysis (CKD5-PD). Further, in 34 and 15 participants repeated measurements were available during the first six months following dialysis initiation and kidney transplantation, respectively. Serum biomarkers of ED  and LGI  were measured with a single- or multiplex array detection system based on electro-chemiluminescence technology.Results: In linear regression analyses adjusted for potential confounders, participants with ESRD had higher levels of most serum biomarkers of ED and LGI than controls. In addition, in CKD5-HD levels of serum biomarkers of ED and LGI were largely similar to those in CKD5-ND. In contrast, in CKD5-PD levels of biomarkers of ED were higher than in CKD5-ND and CKD5-HD. Similarly, in linear mixed model analyses sVCAM-1, thrombomodulin, sICAM-1 and sICAM-3 increased after PD initiation. In contrast, incident HD patients showed an increase in sVCAM-1, P-selectin and TNF-α, but a decline of hs-CRP, SAA and IL-6. Further, following kidney transplantation sVCAM-1, thrombomodulin, sICAM-3 and TNF-α were lower at three months post-transplantation and remained stable in the three months thereafter.Conclusions: Levels of serum biomarkers of ED and LGI were higher in ESRD as compared with controls. In addition, PD initiation and, less convincingly, HD initiation may increase levels of selected serum biomarkers of ED and LGI on top of uremia per se. In contrast to dialysis, several serum biomarkers of ED and LGI markedly declined following kidney transplantation.”2) Word : “This risk is not (completely) mitigated by renal replacement therapy.”3) Ref 3 is of no interest and must be removed.We agree. This reference was inserted erroneously and we have now removed this reference.4) In methods part, the timing of blood samples collection must be more precise. First the vintage of collection must be given for all the patients. It is not entirely clear what the reviewer means with ‘vintage of collection’. All samples were collected during the period the study was conducted. This is described in the methods section in the paragraph study population and design. The studies included were conducted between February 2012 and July 2017, between October 2013 and January 2018, and between June 2012 and December 2017, respectively. 5) Second, the timing of collection regarding the dialysis séance must be precise, first, second or third dialysis of the week.In the group of prevalent dialysis patients samples were collected prior to each patients’ mid-week dialysis session. In the group of incident dialysis patients the timing of blood sampling relative to the dialysis session was not standardized . The same held true for kidney transplant patients who were on dialysis prior to KTx. We have added this information to the Methods section : “In participants on HD, study measurements and blood sampling were performed prior to one of their dialysis sessions .”6) Third, for the biomarkers, how the sample were conserved? All the measurements were done at the same time? Did the authors have data on the effects of blood conservation on the concentration of the biomarkers?Blood was collected in sterile 5 ml BD vacutainer SST II Advance tubes. After centrifugation, serum was aspirated and stored at -80°C until analysis. Before analysis, serum samples where thawed and mixed thoroughly. We have added this information to the Methods :” Blood was collected in sterile 5 ml BD vacutainer SST II Advance tubes. After centrifugation, serum was aspirated and stored at -80°C until analysis. Before analysis, serum samples where thawed and mixed thoroughly.”All measurements were done at the same time. Biomarkers were analyzed with 6 multiplex assays. Per assay, analyses were performed within the same batch to avoid batch effects. In addition, combining the analyses of two assays reduced the number of freeze-thaw cycles to three in total. Unfortunately, data on long-term stability of the serum biomarkers are lacking, except for hs-CRP, which is stable up to 11 years if stored at -80°C [1].7) For others biological value the technique of dosage must be provide. It is not clear to us what the reviewer means with ‘technique of dosage’. 8) Finally, the kidney transplantation protocol is very different with three patient included in a randomized trial. I think these patients must be excluded.All patients received standard protocol patient care during the kidney transplant period. The only difference is the use of different immunosuppressive protocols. However, the immunosuppressive medication as described in the manuscript and used in the RCT (TRANSFORM) and the observational study are already part of standard patient care. Therefore, we chose to include these patients into the analyses since our study has an observational nature and as such therapy cannot be fully standardized. 9) The values, especially for inflammation markers are very difficult to interpret when one a small sample of patients (15) you have 3 with monotherapy with tacrolimus, 5 with tacro and MMF and 7 with Tacro MMF and corticoids. It is not clear for me for patients with everolimus if they are still with everolimus or not.The immunosuppressive regimen, albeit protocolized, is tailored towards the individual patient’s clinical response, leading to some variation in immunosuppressive medication. This is inherent to clinical practice and the observational nature of this study.However, we have mentioned this as a study limitation in the Discussion : “Fifth, in this observational study, the immunosuppressive regimen was protocolized but not fully standardized, which may hamper the interpretation of results in kidney transplant recipients.Two patients started with everolimus. One patient was lossed-to-follow-up, the other patient used everolimus throughout the entire study period. Which is now stated more clearly in the S1 methods: “Three patients included in this study were simultaneously enrolled in a different study (TRANSFORM) (NCT01950819). Two of these three patients were randomized to receive tacrolimus, everolimus and prednisolone as triple therapy from time of kidney transplant. One of these two patients withdrew informed consent for further follow-up in our study in the first week after kidney transplantation for personal reasons. The other received everolimus throughout the entire study period. The third patient was randomized to receive tacrolimus (prograft), MMF and prednisolone as triple therapy from time of kidney transplant. This patient switched to the local immunosuppressive protocol of our centre after the 6 month follow up visit.”10) Pour les dilyser penser à discuter les différentes membranes. It is not entirely clear what the reviewer means with this. An overview of the dialysis membranes used for the patients in this study is provided in S1 Methods .11) In results, In table 1, the authors must separate HD and PD patients. In controls and CKD5-ND it is not residual urine outpout but diuresis. Thank you for noticing. We have changed ‘residual urine output’ into ‘diuresis/ residual urine output’ in Table 1 and S1 Table. In addition, we now present characteristics in Table 1 stratified according to controls, CKD5-ND, CKD5-HD and CKD5-PD. Similarly, we now present characteristics in S2 Table stratified according to incident HD, incident PD and kidney transplant recipients.The description of the cross-sectional population characteristics in the Results  has been adapted as well: “Thirty-six controls, 43 participants with CKD5-ND, 20 participants with CKD5-HD and 14 participants with CKD5-PD comprised the cross-sectional study population . In general, participants with CKD5-ND, CKD5-HD and CKD5-PD were more often men and had a worse CVD risk profile than controls.Participants with CKD5-HD and CKD5-D more often had diabetes mellitus than those with CKD5-ND. All participants with CKD5-ND and most with CKD5-D had residual urine output. Participants with CKD5-PD slightly younger, less often men, less often had a history of CVD, and had higher residual GFR , slightly more fluid overload and shorter dialysis vintage than participants with CKD5-HD, although not all differences were statistically significant in this relatively small study population.”Similarly for the description of the longitudinal population characteristics : “As compared with kidney transplant recipients, incident HD and PD patients were older (65.1 ±12.0 and 57.1 ±12.1 years vs. 51.6 ±12.8 years) and more often had a history of CVD (38.9% and 31.2% vs. 13.3%). In addition, incident HD patients were more often men (83.3% vs. 60.0%). Estimated GFRCKD-EPI was similar and all participants had residual urine output. Incident dialysis patients on PD were younger (57.1 ±12.1 vs. 65.1 ±12.0 years) and less often men (56.2% vs. 83.3%), and had lower BMI (23.5 ±3.0 vs. 26.6 ±3.8 kg/m2), higher diastolic blood pressure (87.3 ±16.0 vs. 77.4 ±9.2 mmHg), and less fluid overload (0.8 ±1.4 vs. 1.9 ±2.4 L), although not all differences were statistically significant. One PD patient switched to HD during follow-up.”12) In this table, in the 18% of patient with CKD have a history of Ktx, did they have an immunosuppressive drugs? This must be stated and clear in the characteristics of the patients. It is very different to study endothelial dysfunction to have or not IS drugs.We agree that this information is relevant. Therefore, we have added data on immunosuppressive medication use in participants with a history of KTx in both cross-sectional and longitudinal analyses, where available, in Table and S2 Table. In addition, we have added more detailed information to S1 Methods.S1 Methods:“For the 14 participants who were included in the cross-sectional analyses and had a history of kidney transplantation, data on their immunosuppressive regimen were retrospectively collected from the electronic patient health record. Of the 8 participants with CKD5-ND and a history of kidney transplantation, 7 participants were on immunosuppressive therapy of whom the therapeutic regimen could be retrieved for 6 participants: 1 prednisolone monotherapy, 4 TAC monotherapy, 1 either TAC or MMF monotherapy . Of the 3 participants with CKD5-HD and a history of kidney transplantation, 1 was on TAC monotherapy, 1 on MMF monotherapy and 1 did not use immunosuppressive therapy. Similarly, of the 3 participants with CKD5-PD and a history of kidney transplantation, 1 was one TAC monotherapy, 1 on MMF monotherapy and 1 did not use immunosuppressive therapy.All incident HD patients with a history of kidney transplantation were on immunosuppressive medication: 2 TAC monotherapy from baseline throughout follow-up, 1 either TAC or MMF monotherapy  from baseline up to and including the six month follow-up measurement, and for 1 of these participants the exact immunosuppressive regimen could not be retrieved.Similarly, all incident PD patients with a history of kidney transplantation were on immunosuppressive medication: 1 prednisolone from baseline throughout follow-up and 1 TAC monotherapy from baseline up to and including the six months follow-up measurement.All kidney transplant recipients with a history of kidney transplantation were on immunosuppressive therapy: 1 TAC monotherapy and 2 MMF monotherapy.”Further, we have performed sensitivity analyses excluding participants with prior KTx to explore confounding effects of immunosuppressive use and the presence of a KTx transplant. For cross-sectional analyses, results were similar. In addition, for longitudinal analyses, results were similar for incident HD and PD patients. Further, for kidney transplant recipients, results were largely similar, except for the decline in hs-CRP, SAA and IL-6, which was more pronounced.We have reported these results as follows in the additional analyses section of the Results :“Third, results of cross-sectional analyses were similar after exclusion of participants with a history of KTx (results not shown).Fourth, results of longitudinal analyses were similar for incident HD and PD patients after exclusion of participants with a history of KTx (results not shown). In addition, for kidney transplant recipients, results were largely similar, except for the decline in hs-CRP, SAA and IL-6 which was more pronounced after exclusion of participants with prior KTx (S8 Table).” 13) Important clinical data are missing: tobacco, alcool, lipids concentration, calcium phosphore bicarbonate potassium, hb etc. Medications used, mainly immunosuppressive drugs and corticoids, antihypertensive drugs, HMG CoA inhibitors, anticoagulants, aspirin etc. All this drugs could play an important role on endothelial function and inflammation.We agree with the reviewer that addition of these data would improve the manuscript. Therefore, we have added smoking status, use of renin-angiotensin-aldosterone system inhibitors and HMG CoA inhibitors to Table 1 and S1 Table. The use of immunosuppressive medication is already described in detail for kidney transplant recipients in S1 Methods. Unfortunately, data on the suggested laboratory values, which may provide explanatory information for the associations reported, as well as data on anticoagulant and aspirin use have not been collected for the present study. Methods : “Current smoking was based on self-report.”In addition, in line with the comment, we explored whether additional adjustment for systolic blood pressure, diastolic blood pressure, use of renin-angiotensin-aldosterone system inhibitors, use of HMG CoA inhibitors, current smoking and bmi would change results: results were similar.Results : “The above results were not materially changed after additional adjustment for systolic or diastolic blood pressure, use of renin-angiotensin-aldosterone system inhibitors, use of HMG-CoA inhibitors, current smoking or BMI (results not shown). “14) For the table 2, supplementary analysis separating HD and PD must be done. Adjustment with blood pressure could be of interest mainly regarding endothelial dysfunction.We now present the analyses in Table 2 stratified for CKD5-HD and CKD5-PD.Accordingly, the Results section  has been adapted as well:“Table S1 and Figure 1 shows the distributions of serum biomarkers of ED and LGI stratified by participant group.As compared with controls and after adjustment for age, sex and diabetes mellitus (Table 2), sVCAM-1, E-selectin, thrombomodulin, hs-CRP, SAA, IL-6, and TNF-α were higher in CKD5-ND, CKD5-HD and CKD5-PD. In addition, sICAM-1 was higher in CKD5-ND and CKD5-PD, and sICAM-3 was higher in CKD5-PD only.These results of individual serum biomarkers were also reflected by higher Z-scores for ED and LGI in CKD5-ND, CKD5-HD and CKD5-PD.As compared with CKD5-ND and after adjustment for age, sex and diabetes mellitus (Table 2), biomarkers of ED and LGI were in general similar in CKD5-HD. In addition, as compared with both CKD5-ND and CKD5-HD, sVCAM-1, E-selectin, thrombomodulin, sICAM-3 were higher in CKD5-PD. Further, as compared with CKD5-HD, sICAM-1 was higher in CKD5-PD. These results of individual serum biomarkers were also reflected by a higher Z-score for ED, but not LGI, in CKD5-PD as compared with CKD5-ND and CKD5-HD.”In addition, we have adjusted the first paragraph of the Discussion :“First, participants ESRD had higher levels of most serum biomarkers of ED and LGI than controls. Second, in participants with CKD5-HD, levels of serum biomarkers of ED and LGI were largely similar to those in CKD5-ND. In contrast, participants with CKD5-PD had higher levels of biomarkers of ED than participants with CKD5-ND and CKD5-HD.”Additional analyses with adjustment for systolic or diastolic blood pressure as well as renin-angiotensin-aldosterone system inhibitor use, HMG CoA use, current smoking and BMI, other import risk factors for ED, were similar. We have added this the Results section : “The above results were not materially changed after additional adjustment for systolic or diastolic blood pressure, use of renin-angiotensin-aldosterone system inhibitors, use of HMG-CoA inhibitors, current smoking or BMI (results not shown).”15) For the longitudinal analysis we must have separation of PD and HD patients. In addition, in my opinion for dialysis patient regarding the boxplot there is no real differences in all the biomarkers, the test used for statistical significance must be provide explicitly in the results. More interesting than a box blot the authors must provide individual courses of the biomarkers separating HD and PD.Longitudinal analyses stratified by dialysis modality were in the supplementary analyses. We have now moved these analyses to the main manuscript (Table 2). In addition, we have added individual trajectories to the box plots as requested, both for incident HD patients  and incident PD patients .Accordingly, the Results section  has been adapted as well: “Figure 2, Figure 3 and S3 Table show the distributions of serum biomarkers of ED and LGI in incident HD and incident PD patients from baseline up to six months after dialysis initiation.In linear mixed model analyses (Table 3), incident HD patients showed an increase in sVCAM-1, P-selectin and TNF-α from baseline to six months after dialysis initiation, although this change was only borderline statistically significantly for sVCAM-1. In addition, hs-CRP, SAA and IL-6 were lower after six months of follow-up.In linear mixed model analyses (Table 3), incident PD patients showed a statistically significant increase in sVCAM-1, thrombomodulin, sICAM-1 and sICAM-3 from baseline to six months after dialysis initiation. In these analyses, statistically significant interaction terms suggested that the courses of P-selectin, sICAM-1, sICAM-3, hs-CRP, SAA and IL-6 were different between incident HD and incident PD patients (Pinteraction < 0.10).”Please note that we have reanalyzed the data with the more modern linear mixed model technique. In contrast to repeated measures ANOVA, linear mixed model analysis provides an effect size  in addition to a test of statistical significance, which is presented in the Tables as well. Further, it allows selecting outliers based in regression diagnostics to assess the robustness of results (see below).This is addressed in the Methods section :“Longitudinal analyses were conducted stratified for incident HD and PD patients, and for kidney transplant recipients. Courses of natural log transformed serum biomarkers of ED and LGI over time following dialysis initiation and kidney transplantation were analyzed with linear mixed models to account for within-person correlations between repeated measurements and missing data. The fixed-effects part contained time as categorical variable (baseline served as reference), and the random-effects parts included a random intercept. The models for incident HD and PD patients also contained an interaction term between time and dialysis modality to test whether courses differ between HD and PD. Models were fitted by restricted maximum likelihood. Regression coefficients were exponentiated to obtain the ratio of (geometric mean) biomarker levels relative to baseline levels.”In addition, we have adjusted the first paragraph of the Discussion :“Third, incident PD patients showed an increase in several serum biomarkers of ED as well, but no convincing change in serum biomarkers of LGI. In contrast, results for incident HD patients were mixed, with an increase in some serum biomarkers of ED and LGI, but a decrease in other biomarkers of LGI.”16) We must have comparisons with other biological values, like calcium phosphore, bicarbonate urea, creatininemia etc.We agree that these data would improve the manuscript. Unfortunately, however, these data were not available for the present study, except for serum creatinine, which we have added to Table 1 and S2 Table .17) For transplantation patients same remarks regarding the representation of data. It could be of interest to indicate the course of values for the 4 patients undergoing dialysis then transplantation the data.Similar to the presentation of data of dialysis patients, we now provide boxplots with individual trajectories for kidney transplant recipients . In addition, we have reanalyzed the data with linear mixed model analyses as well.This has been adapted in the Results section :“In linear mixed model analyses (Table 4), kidney transplant recipients showed a statistically significant reduction in sVCAM-1, thrombomodulin, sICAM-3, and TNF-α at three months post-transplantation, which was still present after six months of follow-up. In addition, E-selectin, hs-CRP, SAA and IL-6 were lower at three and six months post-transplantation with similar or even larger magnitudes of effect , albeit not statistically significantly and with wide 95% confidence intervals.In addition, we have adjusted the first paragraph of the Discussion :“Fourth, following kidney transplantation levels of several serum biomarkers of ED and LGI were lower at three months post-transplantation and remained stable at three months thereafter.”Although we agree that a comparison of preemptively and non-preemptively transplanted patients would be interesting, the statistical power of the present study is too low to perform such an analyses and risk of chance findings is high. Instead, we have mentioned this as study limitation : “First, statistical power was limited, in particular for the comparison of HD and PD, and for the follow-up of kidney transplant recipients. In addition, the limited number of kidney transplant recipients precluded further stratification, for example to compare participants with preemptive and non-preemptive kidney transplantation.”18) The additional analysis section is a non sense. All this analysis must be included with main analysis or not discusses. The patients with cyst infection must be definitively excluded.The correlation plots  and stratified analyses for HD vs. PD have now been included in the main analyses . In addition, the explorative analyses on associations of eGFRCKD-EPI, eGFRresidual, residual urine output and dialysis vintage have been removed, as requested.We respectfully disagree with the reviewer that the patient with a history of recurring cyst infection should be excluded a priori. Indeed, his most recent episode was six months before study participation and a recent transluminal angioplasty of the patient’s dialysis shunt may be an alternative explanation for the increased inflammatory parameters [2]. Nevertheless, we agree that this was not clear from our formulation in the previous version of the manuscript. In addition, other participants may have had a rise in inflammatory markers due to an intercurrent infection or inflammatory response as well. Therefore, we have now more performed sensitivity analyses after exclusion of outliers . In general, results were largely similar after exclusion of outliers.Results : “First, when we excluded outliers  in the cross-sectional linear regression analyses, results were largely similar (S5 Table). Most notable dissimilarities after exclusion of outliers were a smaller difference between CKD5-HD and CKD5-PD for E-selectin; more pronounced differences in SAA between CKD5-HD/CKD5-PD and CKD5-ND; and more pronounced differences in Z-score for LGI between CKD5-PD and CKD5-ND/CKD5-HD.Second, when we excluded outliers in analyses for the courses of serum biomarkers following dialysis initiation (S6 Table) and kidney transplantation (S7 Table), results were in general similar or somewhat more pronounced.”In addition, we consider the additional adjustments for eGFRresidual, residual urine output, dialysis vintage meaningful: these analyses explore potential explanations for differences between CKD5-HD and CKD5-ND, but may distract from the main message if placed in the main results.Therefore, we have retained these results as part of the additional analyses .In addition, the use of linear mixed model analyses allowed exploring whether the course of eGFRresidual explained the courses of the serum biomarkers following HD or PD initiation. As we think this question naturally follows from the results, we have added it to the additional analyses : “Sixth, additional adjustment for eGFRresidual in linear mixed model analyses attenuated the courses of sVCAM-1 in incident HD and thrombomodulin in incident PD, but did not explain the courses in the other serum biomarkers (S9 Table).”19) The discussion will be analyzed after the modification asked for the methods and results.We have incorporated the results of the stratified analyses of HD and PD throughout the Discussion. Response to the Reviewer #2 In the present study, the authors compared biomarkers of endothelium dysfunction and low-grade inflammation in controls and in different groups of CKD patients. They show that most biomarkers are higher in CKD patients than in controls, higher in dialysis patients than in non-dialyzed patients and decline after kidney transplantation. Higher levels of serum biomarkers of ED and LGI in CKD patients have been previously shown in the literature. In addition, the data on serum biomarkers after kidney transplantation do not provide new informations and only confirm previous studies.We thank the reviewer for the time spend to review the manuscript.1) The design of the study is complex. It mixes the data of three separate observational studies, but the number of subjects per group is quite low. The characteristics of CKD5-ND and CKD5-D patients are different in terms of origin of end stage renal disease, and presence of diabetes mellitus.We agree with the reviewer that the design is complex. To help the reader in appreciating the flow of patients of the respective study groups, we have provided a flow diagram in S1 Fig. The limited study power is addressed as study limitation : “. First, statistical power was limited, in particular for the comparison of HD and PD, and for the follow-up of kidney transplant recipients. In addition, the limited number of kidney transplant recipients precluded further stratification, for example to compare participants with preemptive and non-preemptive kidney transplantation.”We agree that characteristics of CKD5-ND and CKD5-D patients differ in terms to cause of ESRD and prevalence of diabetes mellitus. Therefore, comparisons between CKD5-ND and CKD5-D were adjusted for diabetes mellitus. Unfortunately, the number of participants was too low to stratify by cause of ESRD. We added this to the study limitations : “Third, the distribution of ESRD causes, with varying prognosis, in this study may hamper comparisons between CKD5-ND and CKD5-D patients, and may limit generalizability. For example, the prevalence of polycystic kidney disease was high, whereas that of diabetic nephropathy was low.”2) Patients on PD are different from patients on HD , and additional analysis demonstrated differences in biomarkers in these two groups of patients. Therefore,the authors should not include these patients in the same CKD5D group.We have now provided results stratified by dialysis modality, both for the cross-sectional and longitudinal analyses. The Results section, including Tables and Figures, has been adapted accordingly.Results :“Population characteristics – cross-sectional analysesThirty-six controls, 43 participants with CKD5-ND, 20 participants with CKD5-HD and 14 participants with CKD5-PD comprised the cross-sectional study population . In general, participants with CKD5-ND, CKD5-HD and CKD5-PD were more often men and had a worse CVD risk profile than controls.Participants with CKD5-HD and CKD5-D more often had diabetes mellitus than those with CKD5-ND. All participants with CKD5-ND and most with CKD5-D had residual urine output. Participants with CKD5-PD slightly younger, less often men, less often had a history of CVD, and had higher residual GFR , slightly more fluid overload and shorter dialysis vintage than participants with CKD5-HD, although not all differences were statistically significant in this relatively small study population.” Results :“Associations of end-stage renal disease with serum biomarkers of endothelial dysfunction and low-grade inflammationTable S1 and Figure 1 shows the distributions of serum biomarkers of ED and LGI stratified by participant group.As compared with controls and after adjustment for age, sex and diabetes mellitus (Table 2), sVCAM-1, E-selectin, thrombomodulin, hs-CRP, SAA, IL-6, and TNF-α were higher in CKD5-ND, CKD5-HD and CKD5-PD. In addition, sICAM-1 was higher in CKD5-ND and CKD5-PD, and sICAM-3 was higher in CKD5-PD only.These results of individual serum biomarkers were also reflected by higher Z-scores for ED and LGI in CKD5-ND, CKD5-HD and CKD5-PD.As compared with CKD5-ND and after adjustment for age, sex and diabetes mellitus (Table 2), biomarkers of ED and LGI were in general similar in CKD5-HD. In addition, as compared with both CKD5-ND and CKD5-HD, sVCAM-1, E-selectin, thrombomodulin, sICAM-3 were higher in CKD5-PD. Further, as compared with CKD5-HD, sICAM-1 was higher in CKD5-PD. These results of individual serum biomarkers were also reflected by a higher Z-score for ED, but not LGI, in CKD5-PD as compared with CKD5-ND and CKD5-HD.”Results :“Population characteristics – longitudinal analysesThirty-four participants with CKD5-ND who initiated dialysis , 6 with CKD5-ND who received a kidney transplant, and 5 on chronic dialysis who received a kidney transplant were included in the longitudinal analyses . In addition, 4 participants who initiated dialysis and later received a kidney transplant were included as kidney transplant recipients as well. As compared with kidney transplant recipients, incident HD and PD patients were older (65.1 ±12.0 and 57.1 ±12.1 years vs. 51.6 ±12.8 years) and more often had a history of CVD (38.9% and 31.2% vs. 13.3%). In addition, incident HD patients were more often men (83.3% vs. 60.0%). Estimated GFRCKD-EPI was similar and all participants had residual urine output. Incident dialysis patients on PD were younger (57.1 ±12.1 vs. 65.1 ±12.0 years) and less often men (56.2% vs. 83.3%), and had lower BMI (23.5 ±3.0 vs. 26.6 ±3.8 kg/m2), higher diastolic blood pressure (87.3 ±16.0 vs. 77.4 ±9.2 mmHg), and less fluid overload (0.8 ±1.4 vs. 1.9 ±2.4 L), although not all differences were statistically significant. One PD patient switched to HD during follow-up.”Results :“Courses of serum biomarkers of endothelial dysfunction and low-grade inflammation following dialysis initiationFig 2, Fig 3 and S3 Table provide data on the distributions and individual trajectories of serum biomarkers of ED and LGI in incident HD and incident PD patients from baseline up to six months after dialysis initiation. In linear mixed model analyses (Table 3), incident HD patients showed an increase in sVCAM-1, P-selectin and TNF-α from baseline to six months after dialysis initiation, although this change was only borderline statistically significantly for sVCAM-1. In addition, hs-CRP, SAA and IL-6 were lower after six months of follow-up.In linear mixed model analyses (Table 3), incident PD patients showed a statistically significant increase in sVCAM-1, thrombomodulin, sICAM-1 and sICAM-3 from baseline to six months after dialysis initiation. In these analyses, statistically significant interaction terms suggested that the courses of P-selectin, sICAM-1, sICAM-3, hs-CRP, SAA and IL-6 were different between incident HD and incident PD patients (Pinteraction < 0.10).”In addition, we have adjusted the first paragraph of the Discussion :“This study on ED and LGI on individuals transitioning from untreated ESRD to renal replacement therapy had four main findings. First, participants ESRD had higher levels of most serum biomarkers of ED and LGI than controls. Second, in participants with CKD5-HD, levels of serum biomarkers of ED and LGI were largely similar to those in CKD5-ND. In contrast, participants with CKD5-PD had higher levels of biomarkers of ED than participants with CKD5-ND and CKD5-HD. Third, incident PD patients showed an increase in several serum biomarkers of ED as well, but no convincing change in serum biomarkers of LGI. In contrast, results for incident HD patients were mixed, with an increase in some serum biomarkers of ED and LGI, but a decrease in other biomarkers of LGI. Fourth, following kidney transplantation levels of several serum biomarkers of ED and LGI were lower at three months post-transplantation and remained stable at three months thereafter.”Further, we have incorporated the results of analyses stratified by dialysis modality throughout the Discussion.3) The choice of statistical analyses is not clear. Why do the authors compare the data of biomarkers between groups with linear regression analysis and not with tests for group comparison like ANOVA or Mann Whitney? In addition, why do the authors use a natural log transformation to perform statistical test on the levels of serum biomarkers? How is the distribution of the data ?We chose to analyze between-group differences with linear regression analyses as this technique allows adjustment for potential confounders .The distribution of serum biomarkers were positively skewed. Therefore, these values were natural log transformed to obtained acceptably normally distributed residuals of the regression analyses.We have now clarified this in the Methods : “Differences in individual serum biomarkers of ED and LGI between CKD5-ND, CKD5-HD, CKD5-PD and controls were evaluated with linear regression analyses to allow adjustment for potential confounders. Levels of serum biomarkers were positively skewed and, therefore, natural log transformed to obtain acceptably normally distributed residuals. The regression coefficients were exponentiated to obtain the ratio of (geometric mean) levels of the serum biomarkers in CKD5-ND, CKD5-HD and CKD5-PD relative to controls and among ESRD groups.”Please note that we have reanalyzed the data with the more modern linear mixed model technique, which in contrast to repeated measures ANOVA, provides an effect size  in addition to a test of statistical significance, which is presented in the Tables as well.This is addressed in the Methods section :“Longitudinal analyses were conducted stratified for incident HD and PD patients, and for kidney transplant recipients. Courses of natural log transformed serum biomarkers of ED and LGI over time following dialysis initiation and kidney transplantation were analyzed with linear mixed models to account for within-person correlations between repeated measurements and missing data. The fixed-effects part contained time as categorical variable (baseline served as reference), and the random-effects parts included a random intercept. The models for incident HD and PD patients also contained an interaction term between time and dialysis modality to test whether courses differ between HD and PD. Models were fitted by restricted maximum likelihood. Regression coefficients were exponentiated to obtain the ratio of (geometric mean) biomarker levels relative to baseline levels.”4) Identical data are presented several times, in different figures/tables. For example, Figure 2 and Table 3 provides the same informations, data in Table 3 are also in S1 Table etc…We have adapted the tables to reduce overlapping information in the main manuscript. However, we think that some readers prefer tabulated data on serum biomarkers over boxplots. Therefore, we have provided such tables as supplementary data .5) For a better understanding, the authors should add the symbols of p values on figures and tables. In particular, the p values between CKD5-ND and CKD5D should be mentioned in Table 1.We have added symbols for P values for comparisons among patient groups to Table 1 as requested and added this to the Methods section as well.Methods :“Unadjusted post-hoc comparisons of characteristics of participant groups were performed with the independent Student t-test for normally distributed data, Dunn’s test for non-normally distributed data and Fisher’s exact test for categorical data if a one-way analysis of variance (ANOVA) test, Kruskal-Wallis test and Fisher’s exact test, respectively, indicated an overall difference between groups.”Legend Table 1 : “† P value < 0.05 vs. controls; ‡ P value < 0.05 vs. CKD5-ND; ¶ P value < 0.05 vs. CKD5-HD. Unadjusted post-hoc comparisons of controls, CKD5-ND, CKD5-HD and CKD5-PD were performed with the independent Student t-test for normally distributed data, Dunn’s test for non-normally distributed data and Fisher’s exact test for categorical data if an ANOVA, Kruskal-Wallis test and Fisher’s exact test, respectively, indicated an overall difference between groups .”Legend S2 Table: “¶ P value < 0.05 vs. CKD5-HD based on Student’s t test for normally distributed data, Wilcoxon rank sum test for non-normally distributed data and Fisher’s exact test for categorical data.”In addition, we have added figures for P values to Fig 1-4, as requested.6) In table 3, an entire column is NA, please remove the column. In S1 Table, dialysis vintage and KT/V are NA, please remove the lines.We have adapted the Tables as requested. Please note that former Table 3 is now S3 Table and S4 Table, and that former S1 Table is now S2 Table. Response to Reviewer #3Manuscript is well written. Only minor suggestions to improve the manuscript.We thank the reviewer for the compliment and the time spend to review the manuscript.1) Please try to avoid the use of  in the descriptive sentences in academic writing “This risk is not (completely) mitigated by renal replacement therapy”We have removed the brackets as requested. Abstract : “This risk is not (completely) mitigated by renal replacement therapy.”Methods : “History of diabetes mellitus and cardiovascular disease, and medication use were based on self-report for healthy controls and the health record for patients.”2) “Only data of their first study was analyzed” “of” should be “from”We have changed this accordingly : “Only data from their first study was analyzed.”3) Also, I suggest the investigators to may improve the introduction/discussion by going over very nice review on this topic PMID: 30607032 Nat Rev Nephrol. 2019 Feb;15(2):87-108. doi: 10.1038/s41581-018-0098-zWe thank the reviewer for the recommended review. As the review is mostly on the effects of ED at the renal level instead of systemic ED, we briefly mention this in the Introduction : “In addition, ED and LGI interact at the renal level and may contribute to the development and progression of renal injury, as elegantly described recently[3].”In addition, we added this review as a reference to our discussion on the causal mechanisms of ED and LGI in ESRD : “The causal mechanisms of ED and LGI in ESRD are likely multifactorial and may include exposure to traditional CVD risk factors, oxidative stress, fluid and sodium overload, gut dysbiosis, accumulation of uremic toxins[3-5], and turbulent flow[6] due to the hyperdynamic circulation after arteriovenous shunt creation[7]. In addition, ED and LGI may be interrelated[8] as illustrated by the correlation matrix.” Journal Requirements:1. When submitting your revision, we need you to address these additional requirements.Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found athttp://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdfWe have adapted the manuscript according to PLOS ONE’s style requirements. The heading of the section listing supporting information was changed to Supporting information . 2. In your Methods section, please provide additional information regarding the source of donated organs received by the patients in the study. Please specify whether the study involved the use of donated tissue/organs from any vulnerable populations, and provide information on the consent given by the donor or their next of kin. Examples of vulnerable populations include prisoners, subjects with reduced mental capacity due to illness or age, and children. If such a population was used, please ensure you have describe the population and justify the decision to use tissue/organ donations from this group. If not, please state in your Ethics Statement, 'None of the transplant donors were from a vulnerable population and all donors or next of kin provided written informed consent that was freely given.We have added this to the Methods section : In addition, none of the transplant donors were from a vulnerable population and all donors or next of kin provided written informed consent that was freely given.Donors are carefully provided information and the screening procedure of a potential donor is essential in living kidney donation. Therefore, potential donors are screened and evaluated according to the national Guideline ‘Evaluation of potential donors for living kidney donation’ of the Dutch Transplant Society and the Dutch Kidney Transplantation Advisory Committee. These guidelines are based on the ‘The United Kingdom Guidelines for Living Donor Kidney Transplantation’ of the British Transplantation Society and the Renal Association (see link) https://bts.org.uk/wp-content/uploads/2018/01/BTS_LDKT_UK_Guidelines_2018.pdf. All donors have been informed about the risks and consequences of kidney donation, and before donation written informed consent is needed. Independent psychosocial evaluation is mandatory to be sure that the potential donor is well informed and understands the risks of donation and a further life with a reduced eGFR.3. 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PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository  and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data.Thank you for noticing. This part has been removed as part of the review process. References1. Doumatey AP, Zhou J, Adeyemo A, Rotimi C. High sensitivity C-reactive protein (Hs-CRP) remains highly stable in long-term archived human serum. Clin Biochem. 2014;47(4-5):315-8. Epub 2014/01/01. doi: 10.1016/j.clinbiochem.2013.12.014.2. Schillinger M, Exner M, Mlekusch W, Haumer M, Ahmadi R, Rumpold H, et al. Balloon angioplasty and stent implantation induce a vascular inflammatory reaction. J Endovasc Ther. 2002;9(1):59-66. Epub 2002/04/18. doi: 10.1177/152660280200900111.3. Jourde-Chiche N, Fakhouri F, Dou L, Bellien J, Burtey S, Frimat M, et al. Endothelium structure and function in kidney health and disease. Nature reviews Nephrology. 2019;15(2):87-108. Epub 2019/01/05. doi: 10.1038/s41581-018-0098-z.4. Cobo G, Lindholm B, Stenvinkel P. Chronic inflammation in end-stage renal disease and dialysis. Nephrol Dial Transplant. 2018;33(suppl_3):iii35-iii40. Epub 2018/10/04. doi: 10.1093/ndt/gfy175.5. Malyszko J. Mechanism of endothelial dysfunction in chronic kidney disease. Clin Chim Acta. 2010;411(19-20):1412-20. Epub 2010/07/06. doi: 10.1016/j.cca.2010.06.019.6. Davies PF. Hemodynamic shear stress and the endothelium in cardiovascular pathophysiology. Nat Clin Pract Cardiovasc Med. 2009;6(1):16-26. Epub 2008/11/26. doi: 10.1038/ncpcardio1397.7. Meeus F, Kourilsky O, Guerin AP, Gaudry C, Marchais SJ, London GM. Pathophysiology of cardiovascular disease in hemodialysis patients. Kidney Int Suppl. 2000;76:S140-7. Epub 2000/08/11.8. Padilla J, Simmons GH, Bender SB, Arce-Esquivel AA, Whyte JJ, Laughlin MH. Vascular effects of exercise: endothelial adaptations beyond active muscle beds. Physiology (Bethesda). 2011;26(3):132-45. Epub 2011/06/15. doi: 10.1152/physiol.00052.2010.AttachmentRespons to Reviewers.docxSubmitted filename: Click here for additional data file. 3 Sep 2019[EXSCINDED]Endothelial dysfunction and low-grade inflammation in the transition to renal replacement therapyPONE-D-19-18004R1Dear Dr. van Gennip,We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. 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Various studies have examined the effects of perioperative blood transfusion on kidney functions. In this study, we investigated the effects of blood transfusion on the kidney functions of patients undergoing total knee arthroplasty.: This retrospective study was carried out on 216 patients who had undergone total knee arthroplasty between January 2016 and January 2017. The patients were divided into two groups according to the level of blood transfusion used during surgery. Group-1 comprised 157 patients (72.7%) needing a blood transfusion of less than three units, while the 59 (27.3) patients in Group-2 required three or more than three units.No statistical difference was found between the two groups regarding hypertension before surgery, diabetes mellitus, chronic kidney failure, smoking habits or lung disease (p> 0.05). Likewise, there was no significant difference related to pulmonary and other complications or mortality (p> 0.05). When the groups were compared according to their blood parameters, no statistical differences in postoperative renal or other system functions were found (p> 0.05).Blood transfusion does not have a negative effect on postoperative blood urea nitrogen (BUN) and creatinine levels, or glomerular filtration rate in total knee arthroplasty. In USA 3.9% of all blood transfusions used during orthopedic surgery are during knee arthroplasty.3Complications that may develop perioperatively in patients having blood transfusions include hemolytic and allergic reactions during surgery, transfusion-associated acute lung damage, transfusion-associated circulatory overload, graft versus host disease and infection.8During our literature search, we found many studies looking at the effects of perioperative blood transfusions. However, there were no studies in the field of orthopedic surgery that specifically examined these effects during total knee prosthesis surgery. Therefore, our study focuses on the effects of perioperative blood transfusion on the kidney functions of patients undergoing total knee arthroplasty.A series of 216 patients who had undergone total knee arthroplasty between January 2016 and January 2017 was reviewed retrospectively. For this purpose, ethical approval was obtained .Patients’ age, gender and smoking habits; any history of hypertension, diabetes mellitus, chronic obstructive lung disease and chronic kidney disease were noted. Duration of hospital stay, the type of anesthesia used, preoperative and postoperative blood glucose levels, perioperative blood transfusion amounts, postoperative pulmonary complications, other postoperative complications and postoperative morbidity and mortality were also recorded, as well as preoperative and postoperative urea, creatinine, aspartate aminotransferase(AST), alanine aminotransferase (ALT) and glomerular filtration rates. Glomerular filtration rates were calculated using MDRD formula .One hundred and fifty-seven patients  who received a blood transfusion of less than three units were categorized as Group-1; 59 (27.3%)patients receiving 3 or more units comprised Group-2. Comparison of the two groups focused primarily on preoperative and postoperative renal functions. Hematocrit (hct) levels of patients receiving a transfusion were under 24% and hemodialysis was not required for any of the patients. Any patients with a preoperative creatinine level of 2mg /dl or over were excluded from the study.Data analysis was carried out using SPSS 15.0 for Windows software with 95% confidence interval. Continuous variables were categorized and compared according to chi-square test and fisher’s exact chi square test. T-test was used for group comparison of variables. The level of significance was set at p-value less than 0.05.No difference was found between the preoperative data of both groups regarding age, gender, hypertension, diabetes mellitus, chronic lung disease, chronic kidney failure or smoking habit (p> 0.05) . The preWhen length of postoperative hospital stay was compared between the two groups, the duration was seen to be longer in Group-2 (p<0.05). Since most patients had elective surgery, spinal anesthesia was used most frequently (92.1%). There was no significant difference between the groups regarding the anesthesia type applied (p>0.05) .The groups did not differ significantly with regard to preoperative and postoperative pulmonary complications or mortality (p> 0.05) . When thWhen blood parameter changes were reviewed between the groups, preoperatively and postoperatively, no significant difference was found statistically regarding levels of urea or creatinine; AST (aspartate aminotransferase); ALT ; or glomerular filtration rates (GFR)(p> 0.05) .As the number of orthopedic surgical procedures rises, there is a corresponding increase in the incidence of perioperative blood transfusions. Patients undergoing total knee arthroplasty frequently receive blood transfusions. Along with an escalation in the financial burden, many studies have reported blood transfusion-associated medical complications.11Whitlock EL et al. found that in a large retrospective cohort of patients undergoing a diverse variety of surgeries, perioperative transfusion of a single unit of red blood cells is associated with an increased risk of perioperative ischemic stroke or myocardial infarction.According to a study by Ponnusamy KE et al., the effects of blood transfusion in orthopedic surgery include allergic reactions 21%), and transfusion-associated acute lung injury (27%). Amongst these complications, the most common causes of mortality are graft versus host disease 85-100%), transfusion-associated circulatory overload 2-15%), and transfusion-associated acute lung injury (5-10%).1%, and t5-100%, t%, and trOur findings were not in consistent with the literature. We found no significant statistical difference between the groups regarding lung complication rates. Although very few in number, there were complications of a comparable nature such as minor allergic and hemolytic reactions which were not recorded in our database.Some researchers have investigated the relationship between perioperative blood transfusion and delirium among older people undergoing elective orthopedic surgery. They found that blood transfusion during surgery was an independent risk factor for post-operative delirium.16Another complication of perioperative blood transfusion is the postoperative deterioration in kidney function. Cardiovascular surgery reports are commonly referred to in orthopedic literature.Another study reviewed the correlation between the use of blood products and acute kidney failure. According to this study, the incidence of kidney failure in a group receiving transfusion was 8%, compared to 1.8% in the non-transfused group; this was considered statistically significant.18Satoglu IS et al. compared two groups for blood parameters showing postoperative renal and other system functions and detected no statistical differences. In this study, we evaluated GFR for renal functions in addition to the other values. No statistically significant difference was found between the groups regarding kidney functions.1Our study examines the effects of perioperative blood transfusion on kidney functions. In cardiovascular surgery literature, studies indicate that blood transfusions affect kidney functions adversely; however, there are very few studies focusing on this topic in the field of orthopedic surgery. Despite the understanding that kidney functions are affected in a negative way in cardiovascular surgery, our study showed no negative effect on kidney functions of transfusion during total knee arthroplasty.It is a retrospective study, and the patient population is small.There is no doubt that postoperative complication rates increase with perioperative blood transfusion. However, contrary to other surgical disciplines, our orthopedic surgery study did not show any negative effect of blood transfusions on kidney functions in total knee arthroplasty. In order to confirm these findings larger prospective patient series and more parameters are required.BS conceived, designed and did statistical analysis & editing of manuscript.BS & RO did data collection and manuscript writing.RO did review and final approval of manuscript.


Hypertension is a major contributor to the global disease burden and mortality. Evidence suggests increasing hypertension prevalence in Ghana but there is limited public awareness and information on the characteristics of those with the disease. To describe the baseline characteristics of adults with hypertension who were randomized to receive either hypertension related nutrition education plus hospital-based standard of care or only the standard of care (control group) in Asesewa, a semi-rural community in the Eastern Region of Ghana. Only baseline data were used in the present analysis. A cross-sectional baseline survey was completed for 63 adults with confirmed hypertension diagnosis. Data on sociodemographic characteristics and diet were obtained through interviews and participants' body mass index (BMI) was computed. Pearson chi-square statistic was used to assess differences between those with both elevated diastolic blood pressure (DBP) and systolic blood pressure (SBP) and those with only elevated SBP. Mean ± SD age of participants was 54.5±13.8 years. Approximately 71% of participants had both elevated SBP (>140 mmHg) and DBP (>90 mmHg) while the remaining 29% had only elevated SBP. The median number of times the food groups beneficial to hypertension management were consumed in the preceding week to the interview was 1 for green leafy vegetables, 1 for dairy products, 2 for fruits, and 4 for legumes. The median number of times for consuming harmful food groups was 3 for salted fish and 7 times for fats and oils. Signifcantly more participants in the age group above 50 than the younger participants had elevated SBP (83.3 vs. 16.7:P=0.027) and those with BMI equal to or greater than 25 were more likely to have both elevated SBP and DBP (P=0.047). Findings from this study have implications for the prevention and management of hypertension in this semi-rural population. Control your blood pressure” as the theme for 2013 World Health Day signified increasing recognition that elevated blood pressure (EBP) or hypertension is an important global public health concern [The decision to render the phrase “ concern . While m concern .Despite the increasing burden of hypertension in Ghana, there is limited context specific information on the sociodemographic and lifestyle risk factors of those affected. Identifying such risk factors is important for intervention planning, especially in a low resource context where lifestyle related preventive actions may be important in averting progression of mildly hypertensive or prehypertensive individuals to a more serious disease state requiring costly medical intervention.Hypertension related deaths in low- and middle-income settings could potentially be reduced substantially by applying lessons learnt in high-income countries. One diet-based intervention that has been efficacious in reducing blood pressure among those with hypertension as well as preventing hypertension is the Dietary Approaches to Stop Hypertension (DASH) diet pattern developed in the United States and successfully adapted elsewhere including South Africa , 7. The In 2015, a randomized controlled trial to test the impact of a nutrition education intervention based on the DASH diet principles on blood pressure was implemented among adults with blood pressure in Asesewa, a semi-rural township in the Eastern Region of Ghana. Baseline data collection on the study population (to facilitate pre- and postintervention comparisons of outcomes of interest) permitted the current analysis, which was aimed at describing the sociodemographic characteristics, dietary habits, and nutritional status of adults with hypertension enrolled in the nutrition education intervention study.The survey was carried out in Asesewa in the Upper Manya Krobo District in the Eastern Region of Ghana. Asesewa has a youthful population (50.9%) representing a broad-based pyramid with an elderly population of about 6%. Most people in the area (73.0%) are employed in the agricultural sector .This was a cross-sectional, baseline study of adults enrolled in the DASH-based nutrition education intervention study between February and July 2015. Potential participants were adults (>25 years old) who responded to announcements at places such as the main market, selected local churches, and the Asesewa Government Hospital at Asesewa for free blood pressure screening as well as adults attending outpatient services at the Asesewa Hospital, who had elevated BP.Those screened with elevated blood pressure (systolic blood pressure (SBP) ≥ 140 mmHg and/or diastolic blood pressure (DBP) ≥ 90 mmHg) and those with EBP who were identified from the hospital OPD were asked to complete two consecutive follow-up measurements at the Asesewa Government Hospital to confirm the diagnosis. Persons with a confirmed diagnosis who agreed and signed the informed consent document after the study procedures had been explained to them were recruited into the study. Ethical approval for the study was granted by the Institutional Review Board of the University of Ghana Noguchi Memorial Institute for Medical Research. All participants signed or thumb-printed (if illiterate) a written informed document before being recruited.Blood pressure (BP) screening was done by trained project personnel using the digital Omron Blood Pressure Monitors , while the BP measurements to confirm hypertension diagnosis were completed by the nursing staff at the Asesewa Hospital. At enrolment, a pretested questionnaire was used to collect information on background sociodemographic characteristics, personal and family history of chronic diseases, and history of alcohol consumption and cigarette smoking. A 7-day food frequency questionnaire (FFQ) was used to obtain information about the number of times different food groups were consumed in the past 7 days. The FFQ was based on foods typically consumed in the locality and grouped in such a way to enable assessment of whether study participants' intake is in accordance with the DASH dietary pattern. Salted fish was added as a separate food group because it is a regular ingredient in Ghanaian cuisine which contributes significantly to salt intake with potential implications for hypertension. Additionally, participants' weights were taken to the nearest one kilogram with an Omron Body Composition Analyzer and Scale . Participants' heights were taken with a Stadiometer to the nearest 0.1 centimetre. Anthropometric measurements were taken in duplicate and the averages computed.We performed statistical analysis by using Stata package 12 . Body mass index (BMI) was computed from weight and height measurements and participants were categorized as underweight (BMI: < 18.5), normal weight (BMI: 18.5–24.9), overweight (BMI: 25.0–29.9), and obese (BMI: > 30.0). Descriptive statistics, mean ± SD for continuous variables and frequencies (%) for categorical variables, were used to summarize the data. The data on consumption of different food groups in the past week were skewed with some of the food groups having outliers; therefore median values were also computed. Bivariate analyses using Pearson Chi-Square Statistic were used to assess whether there were significant differences in sociodemographic characteristics, dietary intakes, and nutritional status between study participants with both elevated SBP and DBP and those with isolated only SBP.Sample. A total of 1165 adults were screened for hypertension and about 24% (n=282) had elevated systolic blood pressure. Only sixty-three adults with confirmed elevated systolic and diastolic blood pressure completed the baseline survey. Of these approximately 29% (16) had systolic hypertension only, while the remainder had both elevated systolic and diastolic blood pressure. Mean ± SD systolic and diastolic blood pressure of study participants were 151.9 ± 7.4 and 92.5 ± 7.7, respectively.Sociodemographic Characteristics of Respondents. About 56% of the respondents were female, with a mean ± SD age of 54.5±13.8 years (.8 years . The majReported monthly household income was less than 200 Ghana Cedis (1 Ghana Cedi is approximately 0.23 US dollars) for the majority of participants and only 13% of households had incomes higher than 600 Ghana Cedis per month.The mean ± SD BMI of the respondents was 27.1 ± 5.3 with 38.1% and 25.4% of the respondents being overweight and obese, respectively. About one-fifth of study participants reported having at least one family member being overweight or obese. A family history of hypertension (55%) was the most common followed by stroke (23.8%). About 16% of the respondents reported a family history of diabetes and 8% had relatives that have suffered a heart attack.Non-green leafy vegetables, roots and tubers, and cereals were the most frequently consumed foods by the respondents in the past week . The medFish and seafood were the most consumed animal source of foods. Salted fish and fats/oils were consumed a median of 3 and 7 times, respectively, in the past week. p=0.027) and a greater proportion of obese/overweight individuals had both elevated systolic and diastolic pressure compared to individuals within the normal body size   .Other sociodemographic factors such as family history of hypertension, income, and dietary intakes showed no significant difference among the various categories.This study contributes to our current knowledge of the characteristics and potential predictors of hypertension among adults living in semi-rural communities in Ghana. It is important to note that less than 50% of those screened with elevated BP returned for the necessary confirmatory tests to determine their hypertension status. This apathy to follow-up on screening results may reflect lack of awareness about hypertension and its consequences which have been noted among socioeconomically disadvantaged individuals and communities . Using dIn this study, the age of the respondents was found to be significantly associated with either having both elevated systolic and diastolic blood pressure or having isolated elevated systolic blood pressure. Older adults (50 years and above) had elevated isolated systolic consistent with other findings; older respondents had elevated isolated systolic blood pressure. This was consistent with similar studies in rural and urban India . ContrarThese findings also buttress the need for the increased call for routine checks for high blood pressure among young adults as advocated for older adults. This is because, notably, young adults with elevated systolic and diastolic pressure are likely to have a slower rate of receiving an initial diagnosis than middle-aged and older adults in their study . This caAlso, more than half (55%) of the respondents in this study reported that they had a family history of hypertension. This is much higher than the 35.7 % reported in a study on the frequency of hypertension and prehypertension among adults in Hohoe, a municipality in the Volta region of Ghana . A revieThe predominant occupation of the respondents in this study was trading. This is likely to predispose them to hypertension due to the job-related stress and inappropriate food consumption and meal patterns. Concerning the level of income of the respondents, the majority of them were earning GHS200.00 or less. This low-income level may influence the dietary habits of the respondents and their ability to purchase foods beneficial for hypertension prevention and control , 24. HowOur study found significant differences in nutritional status (BMI) between participants with both elevated systolic and diastolic blood pressure and those with isolated SBP. The association between BMI and blood pressure is well established with several studies reporting higher likelihood of elevated BP among overweight and obese individuals –27. A stThe frequency of consuming food from various food groups was also found to be a contributory factor to having either an isolated elevated SBP or both elevated SBP and DBP. This research found out that respondents consumed fewer green leafy vegetables and fruits, which generally tend to be higher in potassium needed in the management of hypertension and had increased intake of fats and oils. A cross-sectional study on the prevalence and correlates of hypertension among rural populations in Sub-Saharan African revealed that frequent intake of fruit and vegetables was associated with lower blood pressure measures . AdditioGenerally, although the restriction of salted foods is considered an appropriate strategy for the control of high blood pressure adherence to this recommendation is often a challenge . In the Food groups such as legumes and green leafy vegetables that have potential benefits for hypertension management , 39 wereThe intake of dairy foods, which are good sources of calcium and potassium, was very low among the study participants. A systematic review and meta-analysis of elevated blood pressure and consumption of dairy foods showed that consumption of low-fat dairy foods was associated with a 13% reduction in risk of high blood pressure . HoweverThe findings of this study provide useful information on dietary habits of people with hypertension in a low-income rural community which may inform hypertension management services. The study also points to the need for education and awareness among the general populace to foster better health-seeking behaviours for hypertension screening and management. Furthermore, lessons from this study will assist in developing programs for healthy ageing consistent with the World Health Organizations global strategy on ageing and health .


The seated posture resulted in a significantly greater AIx than supine . Fasting state had significant main effects on AIx and AIx75 .Acceptable short-term reproducibility (ICC >0.75) was reported for all peripheral and central variables in all conditions (ICC = 0.77–0.90) and for AIx and AIx75 in both fasted postures (ICC = 0.78–0.81). Food consumption significantly lowered all blood pressures (Oscillometric estimates of central blood pressure have high short-term reproducibility in different postures and fasting states but markers of systolic load should be assessed whilst fasted. Fasting state has a large effect on central and peripheral blood pressures and on measures of systolic loading. It is important for clinicians to be aware of optimal assessment conditions without this impacting on patient wellbeing.Clinical trial registry name: NCT02537652. Hypertension is the most common disease seen in primary care . This coThe assessment of blood pressure is traditionally completed through occlusion of the brachial artery , but central blood pressure (cBP) measures  may be more closely related to cardiovascular risk . The invIdentifying the optimal operating conditions of devices able to non-invasively calculate central haemodynamic variables in terms of both posture and fasting state is an important step in their introduction to research and clinical use. Posture –17 and fThis study examined the effect of posture and fasting state on the short-term reproducibility of peripheral and central blood pressures and central systolic loading in an acute stroke population using a non-invasive, oscillometric device (SphygmoCor XCEL). It was hypothesised that posture and fasting state would have a significant effect on peripheral and central blood pressures and markers of central systolic loading and that oscillometric PWA would report high between-day reproducibility in an acute stroke population. These findings will be of importance to those considering the use of the non-invasive oscillometric devices to estimate central blood pressures in research and clinical settings.The methods of this study are reported in accordance with the Helsinki Declaration of 1975 and STROBE  guidelines .https://clinicaltrials.gov/ct2/show/NCT02537652).Twenty-two stroke patients  provided written consent whilst they were in-patients at a hospital in Hampshire, UK. Recruitment is outlined in Participants were tested on three consecutive mornings, having consumed only water in the 12 hours prior to data collection. After random allocation to a supine-first or seated-first condition using a computerised random number generator, participants assumed this posture in a fasted state for twenty minutes. A minimum of two PWA measurements were completed using the SphygmoCor XCEL  with a three minute interval. Measures of PWA consisted of a peripheral blood pressure measure followed by a 10-second sub-systolic recording. The merging points of the forward and reflected waves were identified on the aortic pressure waveform . AugmentA priori sample size calculations were based on central systolic blood pressure measures as the primary outcome and assumed a typical error of 6.4 mmHg adopted from a previous reliability study with healthy participants . The max-1 [AIx75]). An independent samples t-test was run to ensure that gender had no significant effect on measures of blood pressure, AIx or AIx75 (p > .05). Effect sizes were reported using partial eta squared . All presented data are means . Statistical significance was set at p < 0.05 (two tailed). Analysis of variance for repeated measures with two within-participant factors (posture and fasting state) examined differences in central and peripheral pressures  and central systolic loading; AIx standardised to HR of 75 b·min effects .The short-term reproducibility of the device was measured by calculating the intra-class correlation coefficient (ICC), standard error of measurement (SEM) and smallest detectable change .Data was successfully collected from all participants in each condition. There were no gender differences in measures of blood pressure, AIx or AIx75 , with DBP and cDBP both significantly increasing in a seated posture relative to supine. Fasted state had a significant main effect on central and peripheral haemodynamics, with significant decreases in SBP, DBP, pPP, cSBP, cDBP and cPP observed  but not in AIx75; suggesting that these differences were mainly due to the significant changes in heart rate observed in this study. Fasting state had a significant main effect on both AIx and AIx75 with significant decreases reported after food consumption  and moderate reproducibility in both non-fasted postures (ICC = 0.66–0.74 ). PosturThe SphygmoCor XCEL exhibits high short-term reproducibility in different fasting states and postures when assessing peripheral and central blood pressure measures, but central systolic loads were more reproducible in a fasted than non-fasted state. Fasting state was demonstrated to have a large influence on both peripheral and central blood pressure and central systolic load measures, whereas posture significantly influenced peripheral and central diastolic measures and AIx, but no other variables recorded. The lack of statistical differences in AIx75 between postures suggests that differences in AIx are caused by fluctuations in heart rate caused by postural change. This is in line with previous research showing that AIx is confounded by the timing of the reflected wave . When meHigh short-term reproducibility was reported when assessing central and peripheral blood pressure measures, with ICCs exceeding the 0.75 criterion of excellence in all conditions. These ICCs (0.77–0.90) are consistent with, but slightly better than, previous work examining the short-term reproducibility of the SphygmoCor XCEL in a younger, healthy population which reported ICCs of 0.68–0.90 for peripheral and central measures . To our No significant interaction effects were reported. Significant main effects were observed for both posture and fasting state on peripheral and central blood pressures. Due to technological advances, the measurement of these variables non-invasively may become widespread. As a result, research into factors influencing central measures is of great importance. It is possible that medications may induce different responses between peripheral and central blood pressure measures . The siget al [Fasting state was demonstrated to cause statistical decreases in SBP, DBP, pPP, cSBP, cDBP and cPP. A post-prandial decrease of ~10 mmHg was reported in SBP and ~12 mmHg in cSBP. A smaller decrease in DBP (8–9 mmHg) and cDBP (8 mmHg) caused a large change in pPP and cPP to occur. Significant decreases in central blood pressure after food consumption have been observed in a non-clinical population over the age of 50  but not et al  who repoet al  suggest et al . It shouet al .p = 0.08), whilst wide ranges in the reported 95% confidence intervals were reported (see Supplementary Table). This may be due to a potential lack of statistical power to detect an association of this magnitude in this sample of 22 stroke patients. The finding that fasting state had a significant main effect on AIx and AIx75 with post-prandial reductions observed in both measures aligns with previous research and may be a result of increased arterial compliance due to tone alterations in the small vessel beds, large artery function and large artery geometry [This study reports that the SphygmoCor XCEL has high short-term reproducibility when reporting AIx and AIx75, particularly in fasted participants. ICCs of 0.78–0.81 were observed when recording AIx and AIx75 in a fasted state, whereas this lowered to 0.66–0.73 and 0.70–0.74 for AIx and AIx75, respectively, when participants were non-fasted. The digestive process causes alterations in vasodilation which may vary on a day-to-day or meal-to-meal basis depending on extraneous factors . This may cause the assessment of AIx and AIx75 to become less stable when the body is not truly at rest as it would be more likely to be in a fasted state. The significant main effect observed for posture in AIx but not in AIx75 may add credence to the concept that AIx and HR may not be entirely linearly related; a suggestion which reduces the propriety of AIx75 being reported without AIx alongside . Signifigeometry .This study suggests that non-invasive central blood pressure assessments provide reproducible measurements of peripheral and central haemodynamics. Significant decreases in peripheral and central blood pressures were observed after food consumption. During hospitalisation after stroke, assessments of central and peripheral blood pressures should therefore be assessed in a fasted state to reduce the variability caused by food intake. This is particularly true when medication prescription is at least partially based on these routine blood pressure measures. The combined effect of post-stroke medication and fasting state should also be considered when monitoring patient health, as both variables cause a decrease in peripheral and central blood pressure measures.With regards to central systolic loading, increased arterial stiffness is reported to be significantly associated with reduced cognitive function in stroke patients . ReportiIt is important to contextualise the study through the recognition of strengths and weaknesses. Firstly, we did not recruit a unisex sample, a fact which may influence results due to potential differences in responses to postural changes in peripheral blood pressure between sexes . SecondlIn conclusion, this study demonstrates that the SphygmoCor XCEL, a non-invasive oscillometric PWA device, possesses high short-term reproducibility in assessing both central and peripheral blood pressure measures in both fasted and non-fasted states, and good short-term reproducibility when assessing markers of central systolic loading, particularly in a fasted state. The current study demonstrates that posture has a significant effect on DBP, cDBP and AIx, whereas, fasting state significantly influences all peripheral and central variables, as well as both AIx and AIx75, in acute stroke patients. The findings of this study are pertinent to researchers and clinicians, although consideration around the practicalities of implementing these measures within practice (e.g. optimising conditions for BP assessment whilst minimising adverse events associated with fasting state) is necessary.S1 CONSORT Checklist(DOC)Click here for additional data file.S1 Dataset(XLSX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S1 File(DOCX)Click here for additional data file.