Admission systolic blood pressure has emerged as a predictor of postdischarge outcomes of patients with acute decompensated heart failure; however, its validity in varied clinical conditions of this patient subset is unclear. The aim of this study was to further explore the prognostic value of admission systolic blood pressure in patients with acute decompensated heart failure.The Kyoto Congestive Heart Failure (KCHF) registry is a prospective, observational, multicenter cohort study enrolling consecutive patients with acute decompensated heart failure from 19 participating hospitals in Japan. Clinical characteristics at baseline and prognosis were examined by the following value range of admission systolic blood pressure: <100, 100–139, and ≥140 mmHg. The primary outcome measure was defined as all-cause death after discharge. Subgroup analyses were done for prior hospitalization for heart failure, hypertension, left ventricular ejection fraction, and medications at discharge. We excluded patients with acute coronary syndrome or insufficient data.We analyzed 3564 patients discharged alive out of 3804 patients hospitalized for acute decompensated heart failure. In the entire cohort, lower admission systolic blood pressure was associated with poor outcomes . The magnitude of the effect of lower admission systolic blood pressure for postdischarge all-cause death was greater in patients with prior hospitalization for heart failure, heart failure with reduced left ventricular ejection fraction, and β-blocker use at discharge than in those without.Admission systolic blood pressure is useful for postdischarge risk stratification in patients with acute decompensated heart failure. Its magnitude of the effect as a prognostic predictor may differ across clinical conditions of patients. Acute decompensated heart failure (ADHF) is globally one of the most common causes of hospitalization with high rates of in-hospital and postdischarge mortality and rehospitalization. Low admission systolic blood pressure (SBP) is a well-known prognostic predictor of in-hospital outcomes in ADHF patients. In the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry and the Acute Decompensated Heart Failure National Registry (ADHERE), low admission SBP was identified as a predictor of in-hospital mortality in HF patients , 2. In tThe Kyoto Congestive Heart Failure (KCHF) registry is a physician-initiated, prospective, observational, multicenter cohort study enrolling consecutive ADHF patients from 19 participating hospitals between October 1, 2014 and March 31, 2016. The 19 hospitals were either secondary or tertiary hospitals, including both rural and urban as well as large and small ones in Japan. One-year clinical follow-up data with an allowance of 1 month were collected in October 2017. The attending physicians or research assistants at each hospital collected clinical event data after the index hospitalization from medical records or from patients, their family members, or their referring physicians under patient consent. Follow-up was commenced on the day of hospital discharge. The details of the KCHF registry have been described previously –7. BriefThe investigation conformed to the principles outlined in the Declaration of Helsinki. The study was approved by the institutional review boards of Kyoto University Graduate School of Medicine ; Shiga General Hospital ; Tenri Hospital ; Kobe City Medical Center General Hospital ; Hyogo Prefectural Amagasaki General Medical Center ; National Hospital Organization Kyoto Medical Center ; Mitsubishi Kyoto Hospital (approved 11/12/2014); Okamoto Memorial Hospital ; Japanese Red Cross Otsu Hospital ; Hikone Municipal Hospital ; Japanese Red Cross Osaka Hospital ; Shimabara Hospital ; Kishiwada City Hospital ; Kansai Electric Power Hospital ; Shizuoka General Hospital ; Kurashiki Central Hospital ; Kokura Memorial Hospital ; Kitano Hospital ; and Japanese Red Cross Wakayama Medical Center . The study protocol met the conditions of the Japanese Ethical Guidelines for Epidemiological Studies 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: YesReviewer #2: Yes**********2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: YesReviewer #2: 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: YesReviewer #2: 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: YesReviewer #2: 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 paper of Kato and coll is aimed to evaluate the prognostic role of systolic arterial pressure in acute decompensated heart failure.Some points should be considered by the authors:- In the manuscript, it is evaluated the impact of a low systolic arterial pressure on long-term prognosis. However, the role of systolic arterial pressure at the admission is well known. Although this study evaluated the long term prognosis, this is the main limitation of the study.- The association between low systolic pressure and worse outcome was greater in patients in beta-blockers. This is not in line with previous studies and it should be better discussedn.- Analogously, it should be clarified the relationship between greater hospitalization for heart failure in patients with CCB.- Is there any relationship between changes in arterial pressure at admission and pre-discharge and prognosis? This could be an analysis providing data useful for daily clinical practice- The relationship among arterial systolic pressure and HFrEF, HFpEF and HFmrEF should be discussed- Authors included in the multivariate model 19 clinically relevant variables. The method used to select these variables should be described.Reviewer #2: In the present paper, Kawase and colleagues aimed to explore the prognostic value of admission Systolic Blood Pressure (SBP) in Acute Decompensate Heart Failure (ADHF) patients. The study is a prospective, observational, multicenter cohort study involving 19 hospitals in Japan.The paper is rather focused and provides further insight on the value of admission SBP in the prognosis of ADHF. The large number of patients enrolled in the study is undoubtedly an element of strength. Furthermore the statistical analysis is well described and performed. Still, the paper sufferes from some major methodological limitations, as listed below.Major points- Lee and colleagues  found that the initial blood pressure at the time of acute HF presentation was only weakly associated with discharge blood pressure. Why did you choose the admission SBP and not the discharge SBP to explore the post-discharge clinical outcomes?- In the “Discussion”, you did not explain if the findings could have clinical implications or suggestions on how to manage HF therapies. Please, add a paragraph in the “Discussion”. It would strengthen the value of the whole paper.- The whole in-hospital outcomes section seems to be not included neither in primary outcomes nor in secondary ones, why? Please motivate your choice if not modifiable.- The three groups have wide range of SBP values. More narrow limits between different groups would have provided a more accurate statistical analysis. What is your opinion and why did you choose those threshold?Minor points- Do you have any data of compliance to the therapy for the three different groups of admission SBP?- Some syntax errors are present in the paper, please revise the global English form**********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,  26 May 2021Respose to Reviewer 1:Thank you for your review of our paper. We have answered each of your points below.Reviewer #1: The paper of Kato and coll is aimed to evaluate the prognostic role of systolic arterial pressure in acute decompensated heart failure.Some points should be considered by the authors:- In the manuscript, it is evaluated the impact of a low systolic arterial pressure on long-term prognosis. However, the role of systolic arterial pressure at the admission is well known. Although this study evaluated the long term prognosis, this is the main limitation of the study.We agree with you and have incorporated this suggestion into our paper. In this study, we examined whether the validity of low admission SBP in predicting clinical outcomes is consistent across various clinical subtypes of ADHF patients, and whether the impact of admission SBP on long-term prognosis tended to be similar to that reported by previous studies in modern medical care for ADHF.We have rewritten the text  as “The aim of this study was to determine whether the impact of admission SBP on long-term prognosis in modern medical care for ADHF tended to be similar to that reported by previous studies by exploring the prognostic value of low admission SBP using the data from a large Japanese observational database of ADHF patients.”.- The association between low systolic pressure and worse outcome was greater in patients in beta-blockers. This is not in line with previous studies and it should be better discussed.We agree with your assessment. We added the following sentence to the text .“In the patients with β-blocker, all-cause death occurred more frequently in the low admission SBP group, and that occurred less frequently in other groups. Sympathetic nervous system may be more activated in ADHF patients with high admission SBP. It may be possible to improve the prognosis by β-blocker in those patients. In contrast, β-blockers are drugs that improve prognosis in HFrEF patients, but in the low admission SBP group, hypotension as an adverse event may be more likely to occur, which may lead to an increase in the incidence of all-cause death. Otherwise, B-blocker may have different class effect in the low admission SBP group.”- Analogously, it should be clarified the relationship between greater hospitalization for heart failure in patients with CCB.We agree with your assessment. We added the following sentence to the text .“In patients taking CCB, hospitalization for HF occurred less frequently in the low admission SBP group. In patients taking CCB at discharge in the low admission SBP group, even if their blood pressure values were low on admission, it is probable that the values increased at the time of discharge and the patients were discharged after controlling blood pressure with CCB. The control of blood pressure with CCB might be effective to prevent the next surge of sympathetic tone which leads to hospitalization for HF.”- Is there any relationship between changes in arterial pressure at admission and pre-discharge and prognosis? This could be an analysis providing data useful for daily clinical practiceYou have raised an important point; however, we explored the prognostic value of admission systolic blood pressure in ADHF patients in this study. Blood pressure is determined by cardiac output and systemic resistance. In ADHF settings, the prompt adaptation of cardiac output and elasticity of arteries and vascular bed was decompensated. Therefore, we could consider a few plausible mechanisms explaining the inverse association between admission SBP and poor prognosis of HF patients. We could not assessed changes in arterial pressure at admission and pre-discharge and prognosis.We added the following sentence to Study limitaions .“Third, we did not assess the sequential change of SBP, low SBP during hospitalization, and predischarge SBP.”- The relationship among arterial systolic pressure and HFrEF, HFpEF and HFmrEF should be discussedWe agree with your assessment. We added the following sentence to the text .“There are a few plausible mechanisms of the inverse association between admission SBP and poor prognosis of HF patients. Blood pressure is determined by cardiac output and systemic resistance. In ADHF settings, the prompt adaptation of cardiac output and elasticity of arteries and vascular bed was decompensated. In HFrEF patients, low cardiac output was related to low admission SBP; thus, low admission SBP was related to both high in-hospital mortality and poor postdischarge outcomes. In contrast, when cardiac output is normal or slightly reduced, a hypertensive response is expected, particularly in hypertensive patients, as a result of sympathetic and neurohormonal activation. Thus, at the time of discharge when they were under drug therapy, admission SBP may have had smaller effects on HFmrEF and HFpEF patients. In this study, we examined whether admission SBP was a predictor of long-term prognosis, assuming that the response of blood pressure during acute exacerbation of HF was due to the mechanism described above.”- Authors included in the multivariate model 19 clinically relevant variables. The method used to select these variables should be described.Thank you for pointing out. We selected them based on the clinical relevance to prognosis and the mean values of the data to ensure consistency with our previous report. We structured the listing in “demographical-HF related-comorbidities-living status-admission vital signs-admission lab values-discharge medications” for clarity.We have rewritten the text  as “We included the following 19 clinically relevant risk-adjusting variables into the model: demographical variables , variables related to heart failure , variables related to comorbidities , living status , vital signs at presentation (admission heart rate <60 bpm), laboratory tests on admission  as well as the three groups based on admission SBP (S1 Table). We selected them based on the clinical relevance to prognosis and the mean values of the data to ensure consistency with our previous report”.We have rewritten the text  as “We included the following 21 clinically relevant risk-adjusting variables into the model: demographical variables , variables related to heart failure , variables related to comorbidities , living status , laboratory tests on admission , and medications at discharge  as well as the three groups based on admission SBP. We selected them on the basis of the clinical relevance to prognosis and the mean values of the data to ensure consistency with our previous report”.Respose to Reviewer 2:Thank you for your review of our paper. We have answered each of your points below.Reviewer #2: In the present paper, Kawase and colleagues aimed to explore the prognostic value of admission Systolic Blood Pressure (SBP) in Acute Decompensate Heart Failure (ADHF) patients. The study is a prospective, observational, multicenter cohort study involving 19 hospitals in Japan.The paper is rather focused and provides further insight on the value of admission SBP in the prognosis of ADHF. The large number of patients enrolled in the study is undoubtedly an element of strength. Furthermore the statistical analysis is well described and performed. Still, the paper sufferes from some major methodological limitations, as listed below.Major points- Lee and colleagues  found that the initial blood pressure at the time of acute HF presentation was only weakly associated with discharge blood pressure. Why did you choose the admission SBP and not the discharge SBP to explore the post-discharge clinical outcomes?You have raised an important point; however, we explored the prognostic value of admission systolic blood pressure in ADHF patients in this study. Blood pressure is determined by cardiac output and systemic resistance. In ADHF settings, the prompt adaptation of cardiac output and elasticity of arteries and vascular bed was decompensated. Therefore, we could consider a few plausible mechanisms explaining the inverse association between admission SBP and poor prognosis of HF patients. We could not assessed changes in arterial pressure at admission and pre-discharge and prognosis.We added the following sentence to Study limitaions .“Third, we did not assess the sequential change of SBP, low SBP during hospitalization, and predischarge SBP.”- In the “Discussion”, you did not explain if the findings could have clinical implications or suggestions on how to manage HF therapies. Please, add a paragraph in the “Discussion”. It would strengthen the value of the whole paper.Thank you for pointing out. We added the following sentence to the text .“Postdischarge risk stratification using admission SBP may contribute to risk management during hospitalization and after discharge. β-blocker use in patients with low blood pressure on admission should be done with caution, and CCB should be added when blood pressure increased by the time of discharge, even if blood pressure on admission is low.”- The whole in-hospital outcomes section seems to be not included neither in primary outcomes nor in secondary ones, why? Please motivate your choice if not modifiable.We agree with you and have incorporated this suggestion throughout the paper. We added in-hospital mortalities to the secondary outcomes.We have rewritten the text  as “The secondary outcome measures included in-hospital all-cause death, in-hospital cardiovascular death, in-hospital noncardiovascular death, cardiovascular death after discharge, noncardiovascular death after discharge, and hospitalization for HF.”.We have rewritten the text  as “Subgroup analyses of the association of admission SBP with primary and secondary outcome measures during hospitalization and after discharge were conducted for prior hospitalization for HF, hypertension, and LVEF. Also, those after discharge alone were conducted for β-blocker use, angiotensin converting enzyme inhibitor or angiotensin II receptor blocker use, and calcium channel blocker (CCB) use at discharge”.We added the following sentence to the text .“The rate of ventricular tachycardia or fibrillation was significantly higher in the low admission SBP group than in the intermediate and high admission SBP groups  (S3 Table). The rate of worsening renal function was significantly lower in the low admission SBP group than in the intermediate and high admission SBP groups  (S3 Table).”We have rewritten the text  as “In the entire cohort, lower admission SBP was associated with higher risk of in-hospital and postdischarge all-cause and cardiovascular death and hospitalization for HF, but not with in-hospital and postdischarge noncardiovascular death”.In addition, Table 1 and Fig 2 have been added.- The three groups have wide range of SBP values. More narrow limits between different groups would have provided a more accurate statistical analysis. What is your opinion and why did you choose those threshold?Thank you for pointing out. In this study, we divided into three categories according to the clinical scenario classification. We added the sensitivity analysis in further subdivided blood pressure categories .We added the following sentence to the text .In addition, S4 Fig have been added.Minor points- Do you have any data of compliance to the therapy for the three different groups of admission SBP?You have raised an important point; however, we could not assessed compliance to the medication therapy.We added the following sentence to Study limitaions .“Finally, we could not assess the prescription status and patient adherence during the follow-up period. After the index hospitalization, patients taking β-blocker, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, and CCB at discharge might have discontinued them, whereas patients not taking these medications at discharge might have started them anew.”- Some syntax errors are present in the paper, please revise the global English formThank you for pointing out. We modified it to an appropriate English form.AttachmentResponse Reviewers.docxSubmitted filename: Click here for additional data file. 18 Jun 2021Admission systolic blood pressure as a prognostic predictor of acute decompensated heart failure: a report from the KCHF registryPONE-D-21-09482R1Dear Dr. Kato,We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.Within one week, you’ll receive an e-mail detailing the required amendments. 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The conclusions must be drawn appropriately based on the data presented. Reviewer #1: PartlyReviewer #2: Yes**********3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: YesReviewer #2: Yes**********4. 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: YesReviewer #2: Yes**********5. 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: YesReviewer #2: Yes**********6. 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 authors answered to the comments raised. The paper has been improved, although its contents substantially replicate data already published.Reviewer #2: Authors responded satisfactorily to all comments and now the paper is improved and worth of pubblication. In particular, statistical analyses and "results" section have been re-organized and better elucidated. In "Discussion" section authors added further comments on the clinical implications that this paper coud have on daily practice. English form has been revised properly.**********what does this mean?). If published, this will include your full peer review and any attached files.7. PLOS authors have the option to publish the peer review history of their article (If you choose “no”, your identity will remain anonymous but your review may still be made public.Do you want your identity to be public for this peer review? 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Chronic kidney disease (CKD) patients are characterized by a high residual risk for cardiovascular (CV) events and CKD progression. This has prompted the implementation of new prognostic and predictive biomarkers with the aim of mitigating this risk. The ‘omics’ techniques, namely genomics, proteomics, metabolomics, and transcriptomics, are excellent candidates to provide a better understanding of pathophysiologic mechanisms of disease in CKD, to improve risk stratification of patients with respect to future cardiovascular events, and to identify CKD patients who are likely to respond to a treatment. Following such a strategy, a reliable risk of future events for a particular patient may be calculated and consequently the patient would also benefit from the best available treatment based on their risk profile. Moreover, a further step forward can be represented by the aggregation of multiple omics information by combining different techniques and/or different biological samples. This has already been shown to yield additional information by revealing with more accuracy the exact individual pathway of disease. Chronic kidney disease (CKD) is a common chronic disease which has been recognized as an independent predictor for cardiovascular (CV) fatal and non-fatal events, mortality from any cause, and kidney failure  ,2. The p2) levels were associated with a two to threefold increased risk for all-cause and CV mortality independently of age, gender, proteinuria levels and other potential confounders. Similarly, the risk for ESKD increased exponentially moving from optimal eGFR to cut-offs of 45 mL/min or 15 mL/min [It has been well demonstrated that the presence of CKD exposes patients to an increased risk for all-cause mortality; CV events ; and CKD progression, namely the onset of the more advanced stage of CKD, known as ESKD, that often, due to the severe metabolic and hemodynamic complications involved, requires referral to renal replacement therapies . A series of four meta-analyses carried out by the CKD Prognosis Consortium, which synthetized data derived from the U.S general population, high-risk populations and patients with CKD, provided important evidence regarding this point ,17,18. I5 mL/min ,17,18. T5 mL/min  compared5 mL/min ,22,23,245 mL/min . It has 5 mL/min  on avera5 mL/min . A large5 mL/min . In the 5 mL/min ,10. Afte5 mL/min ,14. Alth5 mL/min . RAASis 5 mL/min . Despite5 mL/min . Hence, 5 mL/min . In addi5 mL/min . This di5 mL/min . The ‘ne5 mL/min . The devBiomarker discovery has been greatly implemented with the introduction of ‘omics’ techniques. Samples derived from kidney biopsies, urine and blood can be used to generate proteomic, genomic, metabolomic and transcriptomics biomarkers that may be more strongly and accurately linked to the pathophysiologic mechanisms of disease than traditional markers such as eGFR ,35,36,37http://www.fda.gov/cber/guidelines.htm, last accessed: 14 October 2021) defined genomic markers as the quantifiable expression of gene function or gene regulation, which may consist of the expression of a single gene or a combined gene panel. For each case, an ideal genomic marker for CKD should correlate with the functional and structural changes in the kidney cells. Genomic profiling has unprecedented success in identifying the monogenic causes of CKD, with approximately 500 genes identified so far with the majority of these in the pediatric population [Proteomics has garnered a great interest since it may be well assessed using urine as the study sample. This approach has multiple advantages. In fact, urine samples are easy to collect and are almost routinely requested by clinicians for monitoring the response to treatment and for stratifying risk of future outcomes in patients with CKD ,39. Morepulation . In the pulation ,48. Furtpulation . Metabolpulation ,52. It hpulation . Moreovepulation ,55. Withpulation . Howeverpulation ,58,59. Tpulation . The trapulation . Microarpulation . Omics apulation . In the pulation  or the dpulation . PCA is pulation . This en2 [Several studies based on omics analysis have been carried out with etiologic or prognostic aims namely for improving risk stratification of CKD patients on future cardiovascular and renal events as well as to reach a better knowledge of pathophysiological mechanisms of disease. The general purpose of prognostic research in CKD is to find a biomarker that should be able to improve the prediction of an event beside and beyond the clinical intuition of clinicians and the already available laboratory and clinical parameters. In CKD patients, it has already been demonstrated that variables such as age, gender, eGFR and albuminuria (or proteinuria) levels allow a good prediction of renal and cardiovascular endpoints ,68. From2 ,102. Nev2 . Several2 ,105. The2 . The pat2 ,107. GC-2 . Moreove2 . With re2 . A recen2 . In part2 . In diab2 . In gene2 ,114. Mor2 . In the 2 . In CKD 2 . It has 2 .p < 0.001). In fact, other studies revealed a significant change in CKD273, toward the values observed in healthy subjects, after treatment with RAASis or MRA [An ambitious role of omics in CKD is the detection of subjects who will likely respond to a specific treatment. This function can be similar to that of predictive biomarkers and confers on them the diction of predictive omics . The evas or MRA ,122. Hens or MRA . This trs or MRA ,124. Gens or MRA ,126. In s or MRA ,128. Mans or MRA ,130,131.s or MRA .Furthermore, metabolomics biomarkers have been proposed to be candidates as good predictors for response to treatment. In experimental models, niacinamide gained particular interest since its mediator, the PPARγ-coactivator-1α (PGC1α), is quantifiable in renal tissue and urine as an omics biomarker. The intraperitoneal infusion of niacinamide increased NAD levels in the kidney, a coenzyme critical for activating energetic metabolism and which may offer protection against kidney failure and CV risk . The invPrediction of cardiovascular outcomes in CKD patients needs to be improved. A number of initiatives have been implemented in the general population with the aim of improving individual awareness of CV damage and reinforcing prevention strategies. The Joint British Societies launched a self-assessed risk score where patients are allowed to personally select those risk factors that deserve to be improved . In the As we mentioned in the previous sections, a lot of evidence has been provided thus far but, in most cases, they have been assessed in settings different from CKD patients. This is a key point since CKD patients differ from the general population and other high-risk patients (type 2 diabetes or hypertensive patients) for baseline characteristics, risk factors, and long-term prognosis ,144,145.Another important aspect of omics research is related to the clinical trials design for personalized medicine. There are several clinical trial designs which are currently used in evaluating the efficacy and safety of nephroprotective treatments at an individual level, i.e., by focusing on selecting the ‘right drug for the right patient’ . Three mIn conclusion, omics research in CKD patients has been started and has provided much important information. Significant steps forward have indeed been made with respect to both prognosis and prediction of future CV and renal events in CKD. However, future studies may be oriented toward the correct definition of the role of omics specifically in CKD patients, the implementation of multi-omics integrated approaches and, hopefully, the integration of omics in the novel designs of randomized clinical trials.


The association between arterial stiffness and cardiovascular risk in CKD and ESRD patients is well established. However, the relationship between renal function estimation and properties of large arteries is unclear due to the four different methods used to quantify glomerular filtration. This study investigated the relationship between carotid-femoral pulse wave velocity (c-fPWV), as a measure of arterial stiffness, and accepted metrics of renal function. SCr formula based on SCr, (ii) CKD-EPICysC formula based on CysC, (iii) CKD-EPISCr/CysC formula based on Cr and CysC, and (iv) MDRD.  This cross-sectional study was conducted in 431 health examination individuals in China, enrolled from January 2017 to June 2019. c-fPWV and blood pressure were measured, and blood samples were obtained for all participants. Four different methods were used to determine the estimated glomerular filtration rate (eGFR) as described by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) equations: (i) CKD-EPISCr, CKD-EPICysC, CKD-EPISCr/CysC, and MDRD equations were 91.9 ± 15.6, 86.8 ± 21.4, 89.6 ± 18.3, and 90.7 ± 16.6 ml/min/1.73m2, respectively. c-fPWV was significantly and negatively correlated with eGFR determined by CKD-EPISCr , CKD-EPICysC , CKD-EPISCr/CysC , and MDRD  equations. After adjusting for confounding factors, c-fPWV remained significantly and negatively correlated with eGFR determined by the CKD-EPICysC equation  and significantly and positively correlated with age , systolic pressure , and hypoglycemic drugs .  Of all of the study participants , 23.7% had diabetes mellitus and 66.6% had hypertension. The average eGFR values determined by the CKD-EPICysC showed an independent relation with c-fPWV. In a health examination population in China, c-fPWV is negatively correlated with eGFR determined by four different equations; however, only the metric of eGFR determined by the equation for CKD-EPI The prevalence of chronic kidney disease (CKD) is increasing every year and has become a global public health problem. The prevalence in the general population worldwide has reached 14.3% . Based oThe association between arterial stiffness and cardiovascular risk in CKD patients is well established , 6. The There are many formulas for calculating renal function in CKD patients, and the correlation between different formulas and arterial stiffness is still controversial. A study has suggested that the relationship between estimated glomerular filtration rate (eGFR) and arterial stiffness is nonlinear . ModeratCarotid-femoral pulse wave velocity (c-fPWV) is an effective noninvasive measure of arterial stiffness and can predict adverse cardiovascular outcomes and all-cause mortality in unselected populations –15. Our This is a cross-sectional study conducted in a health examination population at Ruijin Hospital from January 2017 to June 2019. c-fPWV was measured, and blood samples were taken in all participants. Inclusion criteria are as follows: (1) age ≥18 years old; (2) agree to participate in this study and sign an informed consent form. Exclusion criteria are as follows: (1) patients with valvular disease and cardiomyopathy; (2) patients with atrial fibrillation, atrioventricular, and intraventricular block; (3) cardiovascular or cerebrovascular disease in the past 3 months; and (4) myocardial infarction, chronic heart failure in the past 3 months; and (5) tumor patients.c-fPWV was measured using applanation tonometry with a Millar transducer and SphygmoCor software . The c-fPWV measurement was performed by placing the transducer at the femoral and then the carotid artery. Distance was measured on the body surface from the suprasternal notch to femoral and carotid artery sites, and the subtraction distance method was used to determine cfPWV from the foot-to-foot pulse transit time between the carotid and femoral pulses in reference to the R wave of the electrocardiogram.Cystatin C was measured by colloidal gold colorimetric method. Creatinine was measured using the picric acid method. Both were determined by Beckman Coulter AU5800 automatic biochemistry analyzer.SCr formula based on Cr, CKD-EPICysC formula based on CysC, and CKD-EPISCrCysC formula based on Cr and CysC [2]; SCr(umol/L); CysC: (mg/L)):MDRDIn 2012, the Kidney Diseases Improving Global Outcomes (KDIGO) guidelines recommend the use of Chronic Kidney Diseases Epidemiology Collaboration (CKD-EPI) formula for eGFR to assess renal function. This series of formula is based on creatinine (Cr) and cystatin C (CysC), mainly including CKD-EPIand CysC . Each eqand CysC , 18 (b)SCrageGFR = 144 × (SCr/62) − 0.329 × 0.993ageGFR = 144 × (SCr/62) − 1.209 × 0.993ageGFR = 141 × (SCr/80) − 0.411 × 0.993ageGFR = 141 × (SCr/80) − 1.209 × 0.993CKD-EPI(c)CysCage × 0.932GFR = 133 × (CysC/0.8) − 0.499 × 0.996age × 0.932GFR = 133 × (CysC/0.8) − 1.328 × 0.996ageGFR = 133 × (CysC/0.8) − 0.499 × 0.996ageGFR = 133 × (CysC/0.8) − 1.328 × 0.996CKD-EPI(d)SCr-cysCageGFR = 130 × (SCr/62) − 0.248 × (CysC/0.8) − 0.375 × 0.995ageGFR = 130 × (SCr/62) − 0.248 × (CysC/0.8) − 0.711 × 0.995ageGFR = 130 × (SCr/62) − 0.601 × (CysC/0.8) − 0.375 × 0.995ageGFR = 130 × (SCr/62) − 0.601 × (CysC/0.8) − 0.711 × 0.995ageGFR = 135 × (SCr/80) − 2.07 × (CysC/0.8) − 0.375 × 0.995ageGFR = 135 × (SCr/80) − 2.07 × (CysC/0.8) − 0.711 × 0.995ageGFR = 135 × (SCr/80) − 0.601 × (CysC/0.8) − 0.375 × 0.995ageGFR = 135 × (SCr/80) − 0.601 × (CysC/0.8) − 0.711 × 0.995CKD-EPIGFR = 186 × (SCr)P values at least 140 mmHg and/or diastolic BP (DBP) values at least 90 mmHg [Hypertension is defined as office SB  90 mmHg , or curr 90 mmHg , or curr 90 mmHg , or currP < 0.05 was considered statistically significant throughout the analyses. The association of eGFR with c-fPWV was assessed by means of linear regression. Linear regression statistics were used to compare the slope of the lines by using standardized coefficients of eGFR in four formulas and c-fPWV. The analyses were performed using SPSS, version 17.0 . The nonlinear regression correlation analysis between eGFR and c-fPWV was also performed by using univariate curve fitting analyses and the performance of the simple linear regression model, and the quadratic regression model for CKD-EPICysC was compared by ANOVA test using R software (4.1.2).Continuous variables are presented as mean ± SD. Pearson test was used to evaluate the correlation between normally distributed univariate variables and c-fPWV. A two-sided All studies were in compliance with the Declaration of Helsinki, Good Clinical Practice guidelines, and applicable regulatory requirements. All participants provided written informed consent to participate for the respective study, which was approved by the Human Research Ethics Committee at Ruijin Hospital, Shanghai Jiao Tong University School of Medicine.2. A total of 23.7% of the study participants had diabetes mellitus. 287 (66.6%) participants had hypertension. 32.3% (139) participants were smokers. The average values of eGFR for CKD-EPISCr, CKD-EPICysC, CKD-EPISCr/CysC, and MDRD equations were 91.9 ± 15.6, 86.8 ± 21.4, 89.6 ± 18.3, and 90.7 ± 16.6 (ml/min/1.73m2), respectively.We enrolled 431 participants in our study. The characteristics of participants are shown in 2) than the mildly reduced group for the different equations , CKD-EPICysC , CDK-EPISCr/CysC , and MDRD  equations. In addition, study groups based on age showed that c-fPWV was significantly and negatively correlated with eGFR of CKD-EPISCr , CKD-EPICysC , CDK-EPISCr/CysC , and MDRD  equations in age ≥60 years . We further performed the univariate curve fitting analyses to evaluate the correlations between CKD-EPICysC, CKD-EPISCr/CysC, CKD-EPISCr, MDRD, and c-fPWV in health examination individuals. We noticed that the adjusted R2 values for the regression models were significantly reduced in the nonlinear models  except for the quadratic regression models. Furthermore, we found the coefficients for the quadratic terms were not significant except MDRD   evaluated by CKD-EPICysC equation. Otherwise, c-fPWV was significantly and positively correlated with age , SBP , HR , and FPG . Further model , LDL, FPG, and smoking) c-fPWV was also significantly and negatively correlated with eGFR  evaluated by CKD-EPICysC equation. c-fPWV was also significantly and negatively correlated with eGFR  evaluated by CKD-EPICysC equation in model 3  , LDL, and FPG) showed the predictors of c-fPWV, with c-fPWV considered as the dependent variable. c-fPWV was significantly and negatively correlated with eGFR ( agents) .Glomerular filtration rate (GFR) is an independent predictor of kidney injury, all-cause death, cardiovascular death, and renal failure . Given tIn this study, we investigated the relationship between arterial stiffness as measured by c-fPWV and renal function in a population undergoing health assessment. Irrespective of the eGFR formula used, c-fPWV is significantly and negatively correlated with eGFR. This result is consistent with previous studies , 24.A large sample study also found that arterial stiffness is related with the decline in renal function, and vascular stiffness could be a target for delaying decline in eGFR. Each SD of higher c-fPWV was associated with 7% greater risk of incident CKD . AdequatThe relationship between renal function and arterial stiffness may be bidirectional. Phosphate retention in CKD patients and calcification of human aortic smooth muscle cells leads to increase in large artery stiffness . Several216. The MDRD formula has the highest accuracy in patients with moderate to severe renal impairment, but it decreases with improved renal function [In our study, all renal function formulas showed a significant correlation. It should be noted that some studies have not found a link between mild renal impairment and arterial stiffness , 11. Thefunction , as in ofunction . Serum cfunction .Cystatin C is considered to be an ideal endogenous GFR marker that is more sensitive than serum creatinine and can reflect the filtration function of the kidney . CystatiCysC is more sensitive to detect kidney injury and predict kidney outcome [CysC is the formula of choice to predict death in community-dwelling older men [CysC formula is more accurate to estimate GFR in a population with normal to mildly reduced renal function; the correlation between arterial stiffness and true GFR still requires further investigation. It should be noted that the CKD-EPICysC method is more suitable for the detection of renal function in nondialysis patients, but not for dialysis patients [A study in a Chinese population suggested that the eGFR equation combined with cystatin C is superior to eGFR based on creatinine in early detection of kidney injury, and CKD-EPI outcome . Anotherlder men . Based opatients .Our study also found that c-fPWV was significantly higher in people with moderately reduced GFR than those with mildly decline ones. Briet et al.  study alThis study has some limitations. Firstly, it was a small cross-study study, and so, it is difficult to explicitly distinguish associations and causality. The results need to be further confirmed in large prospective studies. Secondly, the study examines an Asian population, and so, findings may not necessarily be extrapolated to other ethnic groups. Third, the results of serum of creatine in all equations, even the CKD-EPI equations, was measured with the picric acid method that would be higher than the enzymatic method; therefore, it would overestimate the eGFR. Fourth, diabetic patients are not excluded; otherwise, the sample size would be reduced in this study, but it will be considered in future studies. Finally, as subjects were undergoing health assessment, findings will need to be further explored in future studies using different formulas for renal function and measuring arterial stiffness in patients with CKD.CysC had higher correlation than others and also showed an independent relation with c-fPWV.In a health examination population in China, c-fPWV is negatively correlated with eGFR evaluated in different four equations. The equation of CKD-EPI


N = 200 chronic heart failure (CHF) patients was recruited at cardiology centers in Germany (n = 100) and Pakistan (n = 100). Results indicated that trait-EI predicted better mental component of HRQoL in Pakistani and German CHF patients. Friends as social support appeared relevant for German patients only. Qualitative data indicate an internal locus of control in German as compared to Pakistani patients. Strengthening the beneficial role of social support in Pakistani patients is one example of how the current findings may inspire culture-specific treatment to empower patients dealing with the detrimental effects of CHF.Religion and social support along with trait emotional intelligence (EI) help individuals to reduce stress caused by difficult situations. Their implications may vary across cultures in reference to predicting health-related quality of life (HRQoL). A convenience sample of  Germany and Pakistan are two countries with distinct cultural differences. German society reinforces an autonomous and independent self as compared to Pakistani culture where an individual grows with a relational and interdependent self. Among other important aspects of culture, the two countries predominantly differ in terms of both religion and social support system.Azaan  or arranging religious sermons. In addition, Piri-mureedi is the most prevalent aspect that influences Pakistani Muslim society even before its creation. Pir is the title given to the hereditary descendants of the Islamic saint whereas mureed are their followers. Those who have a belief on Piri-mureedi follow them in every aspect of life even for the treatment of illnesses particularly in Multan, Pakistan. Multan, where this study recruited Pakistani patients, is famous as city of saints because there are more than 20 shrines of Sufis, which have been taken care by the Gaddinashine/Pirs. A large population residing in Multan and further followers from across the country visit the city to celebrate annual ceremonies of these saints as well as to consult the native healers.In Pakistan, religion has influenced every dimension of living from birth until death such as In Germany, religion differs considerably between regions. The Politbarometer survey 2016  have vital influence on health and well-being across the life span  CHF patients aged 18 years and above, and/or no current or prior diagnosis of psychosis and substance abuse were recruited from the cardiology centers in Pakistan and Germany. Participants were referred to the experimenter by the consultant cardiologist on duty. All participants provided signed-informed consent prior to study participation. The study protocol was approved by local ethics commission, complied with the regulations of the Declaration of Helsinki, and adhered to guidelines for good clinical practice.The study was a cross-sectional survey conducted in Germany and Pakistan. Trait Emotional Intelligence Questionnaire-Short Form  to 100 (no impairment) and were summarized into a mental and physical summary score. Cronbach’s alpha in the current sample was excellent .The In addition to a self-report questionnaire for assessing socio-demographic data, the following set of measures was applied:how religious would you rate yourself’), a discrepancy score (DS) was calculated by subtracting the self-rating of how important religion is for one’s life minus the self-rating of oneself as a religious practitioner. Higher scores indicate that a person falls short of their ideal when it comes to actual religious practice. Similarly, from two questions on the importance of family and friends in coping , an index of quality of social support (QSS) was obtained by adding them. Higher scores indicate better social support.Additionally, general information on religion and social support was gathered using four single-item questions in the national languages of Germany and Pakistan, i.e., German and Urdu, respectively, to be answered on 10-point Likert scales. Higher values indicate higher levels of general religiosity and social support. From two questions on religion , qualitative information was obtained via four open questions concerning illness knowledge, culture-specific methods of treating illness, frequent worries and culture-specific preferred methods of dealing with worries.2 tests were carried out for categorical variables. Correlation analysis was carried out to examine the relationship of all variables with trait-EI. Later, hierarchical regression analysis was conducted to check the predictive value of trait-EI, DS, QSS, interaction of trait EI and DS as well as trait EI and QSS for predicting mental and physical component summaries of HRQoL.The analyses were conducted with IBM SPSS Statistics 23 IBM Corp . Means, 2 tests were used to identify differences between Germany and Pakistan. Next, to identify differences between individual categories in the two countries, post hoc analysis was carried out. For this purpose, adjusted residuals for each category were transformed into p-values and the p value was adjusted by dividing .05 by the number of rows x columns for each theme  and 100 German  CHF outpatients. The two samples differ significantly in terms of age:  and living arrangements: Chi2(12.85), df = 1, ϕ = − .27, p < .001. Most of the patients in Pakistan reported living in extended family households  as opposed to the nuclear family system, which is prevalent in Germany . Both samples differ partially significantly (Chi2 (131.09), df = 38, ϕ = .82, p < .001) regarding the member providing financial support to the family when controlling for marital status. The results were significant for married (Chi2 (109.42), df = 27, ϕ = .87, p < .001) and widowed (Chi2 (25.73), df = 11, ϕ = .91, p < .01) category and remained non-significant for single, separated, and divorced individuals. It shows that in the Pakistani sample among married patients, mostly the patient themselves  compared to both spousal partners in the German sample , whereas among widowers mostly the children  in the Pakistani sample compared to patient themselves in the German sample  were the members who provide financial support to the family.The sample comprised of 100 Pakistani (Chi2 (87.98), df = 39, ϕ = .67, p < .001). The results were significant for married (Chi2 (60.76), df = 28, ϕ = .65, p < .001) and widowed (Chi2 (21.45), df = 10, ϕ = .83, p < .05) category and remained non-significant for single, separated, and divorced individuals. It shows that in the Pakistani sample among married patients, mostly the patient themselves  compared to both spousal partners in the German sample ; whereas among widowers mostly the patient themselves  were the members who made important family decisions.Similarly, significant differences were observed regarding the individual who made important family decisions (2 (248) = 274.38, p = 1.20) and accounted for only 1.85% of the data. Missing values were imputed with the 'series means methods’  along with interaction terms (Trait EI x DS & Trait EI x QSS) were added.R2 = .00) for PCS. However, when statistically controlled for age, the other predictor variables contributed 8.9% change in R2 (R2 = .89). The model for Pakistani sample was, however, not significant  = 1.51, p = .18). For German sample, the variable age contributed 1.2% (R2 = .012). When statistically controlled for age, the change in R2 was 10.2% (R2 = .114). The model narrowly missed significance  = 1.95, p = .08). The individual contribution of each predictor is given in Table The analysis revealed that for Pakistani sample, the variable age contributed 0% (R2 = .003) while after controlling for age, the R2 changed 23% and the model was also significant  = 4.65, p ≤ .001). Among the potential predictors trait, EI appeared to be the predictor of MCS among Pakistani CHF sample . For German sample, after statistically controlling for the individual variable age (R2 = .004), the change in R2 was 23.8% and the model was significant  = 4.82, p ≤ .001). In the German sample, trait EI was also the predictor of MCS among German CHF sample .In case of MCS, the analysis showed that for Pakistani sample, age contributed .3% , df = 12, ϕ = .58, p < .001). However, post hoc analyses showed that there were no significant differences among individual categories between the two cultures .The qualitative analyses revealed 13 prominent categories that the patients considered as a reason for their CHF , df = 9, ϕ = .85, p < .001). Figure n = 77, 77% vs. Germany n = 17, 17%, p < .0025).The two cultures differed with regards to the type of treatment obtained (Chi2(57.16), df = 11, ϕ = .53, p < .001). Family-related worries were the most common in both cultures. However, fear of deteriorating health was more prevalent in the German CHF patients as opposed to fear of God in the Pakistani sample. However, Post hoc analysis did not show any significant differences among individual categories between two cultures (p > .002).Participant’s responses were coded into 12 categories as evident from Fig. Chi2 (93.28), df = 9, ϕ = .68, p < .001). Post hoc analysis showed that Germany and Pakistan differed significantly in terms of religious coping  and exercise .Figure The present study was a cross-cultural comparison between German and Pakistani cardiology patients on the roles of religion, social support and trait-EI as coping mechanisms in maintaining health-related quality of life (HRQoL). Additionally, the roles of trait-EI, discrepancy score in religious beliefs and practices (DS) as well as quality of social support (QSS) along with the interactions of trait EI with DS and QSS in predicting HRQoL were explored.The results revealed that despite similar levels of trait-EI, religion was more prevalent in the Pakistani sample. Yet, in the Pakistani CHF patients, the higher their trait-EI, the greater was the importance given to religion. This confirms earlier findings supporting the relationship between EI and religiosity Butt . HoweverAnother important difference between cultures was that most of the Pakistani CHF patients lived in an extended family household as the main breadwinner and decision-maker. Part of the sample from Pakistani community also reported to be dependent on their children who were the primary financial supporter in a considerable number of families when controlled for marital status. Although not measured directly but it could be speculated from the given information that, first, this underlines the major impairment created by CHF. Second, these socioeconomical and family factors might have resulted in a failure to maintain a balance between the obligations owed to God and the responsibilities toward humanity and consequently in high DS for the patients themselves.In the German sample, the patient alone or mutually with the spousal partner was the decision-maker. In addition, the majority of the German CHF patients lived in a nuclear family system. Interestingly, the German CHF patients comparatively reported better physical and mental component summaries of HRQoL. Perhaps living in a large family with limited financial resources in combination with physical and psychological health problems has fostered dysfunctional family coping after the onset of illness, financial burden, and less knowledge regarding illness in the Pakistani CHF patients. This may have affected the emotional processing of the Pakistani CHF patients and contributed to poor HRQoL. In contrast, the shared responsibility in German spousal relationships may have contributed to more healthy social roles and interactions that focus on finding an adequate level of support. In large family systems, overprotective social support may be more common. According to the self-determination theory  than their own health. This attitude fits a collectivistic ideology that is obviously more prominent in Pakistan than Germany. Unfortunately, this may contribute to a more interdependent self-image, or in other words stronger external locus of control, which may undermine experiences of autonomy and self-efficacy.Although these may be important and theoretically well-supported aspects that could explain the cultural differences found in the current study, other characteristics may also contribute. For example, considering Germany one of the leading industrialized nations, while Pakistan is counted under the developing countries, future research should focus on factors such as feasible access of professional support . In addition, age was found to be significantly different between the two samples making the German CHF sample approximately eleven years older yet with better HRQoL than the Pakistani CHF sample. Future research should focus on the socio-economic factors and their effect on age in different societies such as Pakistan and Germany. Moreover, provision and implementation of modern web-based intervention can help improve psychosocial well-being of CHF individuals. Recently a multi-centered six-week web-based randomized controlled trial was found significantly effective in alleviating anxiety and depression and improving psychosocial well-being of heart failure patients. The patients showed significant improvement (compared to the control group) at six weeks and one-year post-assessment (Schulz et al. Albeit we aimed for parsimonious, yet plausible and ecologically valid explanations, all causal interpretations need to be made with caution. Future research with prospective and experimental designs will show whether the hypotheses generated from these approaches can be confirmed. In these studies also the situation-specific importance of religion, in particular concerning how religion and the importance associated with it contributes to each person’s life individually, may be an important issue. In this respect, it is suggested to replicate the study, however with not only a dimensional but temporal focus on religion and its associated adaptive outcomes in CHF individuals. Finally, it should be noted that the current findings cannot be generalized to all socioeconomic classes as well as all Muslims and Christian communities across the globe, since religious believe and practice greatly varies along with nationalities and associated cultures.The current findings highlight the role of higher trait-EI for better mental component of HRQoL in the Germany and Pakistani CHF patients. The effect was stronger in German CHF patients. In the Pakistani CHF patients, external locus of control may explain the lack of the positive effect of high trait-EI on HRQoL. These findings show options for culture-specific tailoring of therapeutic and social support that may aim for strengthening self-efficacy and lowering the distress created by high levels of DS in the Pakistani sample. In the German CHF patients, resource-oriented approaches may further strengthen the positive effects of problem-solving-oriented strategies such as implementing a healthy life style and may further optimize the utility of social support. Future studies may confirm the effectiveness of such approaches in experimental and prospective designs.


In the orthostatic position, the normalized gain was significantly higher for the symptomatic OH group than for the asymptomatic OH group and HC group . A symptomatic OH in the PD population indicates an impaired cerebral autoregulation ability in the orthostatic position. Cerebral autoregulation tends to be impaired in the supine position in the OH population.Orthostatic hypotension (OH) is an early non-motor manifestation of Parkinson's disease (PD). However, the underlying mechanism of hemodynamic changes in patients with PD and OH remains unclear. This study aimed to investigate the dynamic cerebral autoregulation changes in patients with PD with OH. Ninety patients with PD and 20 age- and sex-matched healthy controls (HCs) were recruited. The patients' non-invasive blood pressure (BP) and cerebral blood flow velocity were simultaneously recorded at supine and orthostatic positions during the active standing test (AST). Transfer function analysis was used to determine autoregulatory parameters including gain  and phase difference . Sixteen patients (17.8%) in the PD population were diagnosed with OH (PD-OH). The AST results were normal for 74 patients (82.2%) (PD-NOR). In the supine position, the PD-OH group had a lower phase degree than the PD-NOR group (50.3 ± 23.4 vs. 72.6 ± 32.2 vs. 68.9 ± 12.1,  Parkinson's disease (PD) is a neurodegenerative disorder characterized by α-synuclein aggregation in the central and peripheral nervous systems, which could result in various non-motor manifestations , includiOrthostatic hypotension (OH) is an early non-motor manifestation of PD. It is defined as a decrease of 20 mmHg in systolic blood pressure (SBP) or 10 mmHg in diastolic blood pressure (DBP) 3 min after standing . The OH Dynamic cerebral autoregulation (dCA) refers to the capacity of adapting cerebral vasoconstriction and vasodilation to blood pressure (BP) fluctuations within a certain range to regulate and stabilize cerebral blood flow . A previThe patients with PD were recruited from the neurology ward of the Capital Medical University Xuanwu Hospital in China from January 2021 to September 2021. The PD was diagnosed according to the United Kingdom (UK) Brain Bank criteria . All diaAll examinations were performed in a silent room free of distraction, with a maintained room temperature of 20–24°C. The participants were asked to avoid alcohol, caffeine, and nicotine and discontinue dopamine and vasoactive medications 24 h before the examination. After 10 min of relaxation in the supine position, they were asked to perform the AST, which involved lying in the supine position on the bed for 10 min and standing for 10 min . The symTo assess the presence of OH symptoms, we administered the Orthostatic Hypotension Questionnaire (OHQ). The OHQ consists of two parts: Orthostatic Hypotension Symptom Assessment (OHSA) and Orthostatic Hypotension Daily Activities Scale (OHDAS). The OHSA includes six domains of subjective feelings: (1) dizziness, lightheadedness, faintness, or impending “blackout”; (2) visual disturbance ; (3) weakness; (4) fatigue; (5) trouble concentrating; and (6) head/neck discomfort. The OHDAS evaluates the impact of OH symptoms on daily activities that require standing and/or walking for a brief or extended period of time within the past seven days. Each item is scored from 0 to 10, with 0 representing no symptoms and 10 representing the worst possible symptoms. The OHQ score is calculated as the average of the OHSA and OHDAS scores . We cateBaseline BP was measured at the brachial artery  in the supine position. During a 10-min supine period, three BP readings were recorded. We used EMS-9D PRO  to simultaneously record non-invasive continuous BP (NIBP) and cerebral blood flow velocity (CBFV) in both the supine and standing positions during the entire procedure. The recorded NIBP  and CBFV  were used to calculate the cerebral autoregulation parameter based on the transfer function analysis (TFA) , which w2 was monitored using a nasal cannula connected to the EMS-9D. All procedures were performed by a professional ultrasound doctor.Meanwhile, a low phase and a high gain represented impaired dCA. An NIBP was measured using a servo-controlled plethysmograph at the middle finger. Two 2-MHz transcranial Doppler probes were placed over the temporal window and fixed with an adjustable head frame. Continuous CBFV was measured in the left and right middle cerebral arteries (MCAs) at a depth of 50–60 mm using the EMS-9D PRO . The exhaled COt-test was used to compare the two groups. Bonferroni corrections were used to compare multiple groups. Receiver operating characteristic (ROC) analysis was performed to identify the cutoff value. The areas under the curve (AUCs), optimal threshold values, sensitivity, and specificity were calculated. Statistical significance was defined as a two-sided p-value of <0.05, and the confidence intervals (CIs) were set at 95%. The statistical analyses were performed using IBM SPSS (version 22.0) and GraphPad Prism (version 6.01).This research was designed as a single-center cross-sectional case-control study. Normally distributed continuous variables were expressed as mean ± standard deviation, continuous variables with skewed distribution were expressed as medians (interquartile ranges), and categorical variables were expressed as numbers (percentages). For equivalent variables with a normal distribution, the independent Student's This study was approved by the board of the ethics committee of the Capital Medical University Xuanwu Hospital. All participants voluntarily took part in the research with informed consent.In total, 90 patients with PD  were recruited in this study . Further details have been provided in p = 0.050; 92 ± 14 vs. 85 ± 11 mmHg, p = 0.029), whereas HR was lower in the PD-OH group than in the PD-NOR group . p = 0.006). However, MV remained stable throughout the procedure (p = 0.10). Further details are provided in In total, 16 patients (17.8%) had OH, of whom eight were symptomatic. General characteristics, such as sex, BMI, hypertension, disease duration, and motor symptoms, were equally distributed between the PD-NOR and PD-OH groups. The use of medications, such as antihypertensives and levodopa , did not differ in the groups. The MMSE and MOCA scores were also not significantly different. The patients in the PD-OH group were older than those in the PD-NOR group . However, no significant difference was found between the phase degrees of the PD-OH and HC groups. The gain was equally distributed across the groups in the supine and orthostatic positions.As shown in p = 0.046). In the orthostatic position, the normalized gain was significantly higher for the symptomatic OH group than the asymptomatic OH and HC groups . The MAP and MV were not different for the groups in the supine position. However, the symptomatic OH group had a lower MAP than the asymptomatic OH group and the HCs in the orthostatic position . The MV was significantly decreased in the symptomatic OH group (40 ± 4 vs. 50 ± 20 vs. 55 ± 8). The cerebral autoregulation parameters for each group are presented in Our research showed dCA function preservation in all participants with PD. However, compared with the healthy population, dCA was associated with a risk of impairment in the PD-OH group in the supine position and was compromised in the symptomatic PD-OH subgroup in the orthostatic position.Blood volume redistributes to the lower limbs and splanchnic organs when changing to a standing posture, resulting in reduced cardiac output which contributes to low cerebral perfusion . When auIn patients with dysfunctional cerebral autoregulation, unstable flow through the distal capillary may injure the cerebral microcirculation. This, in turn, will damage the microvascular system and induce several downstream sequelae including the disruption of the blood-brain barrier, neuroinflammation, cerebral microbleeds, and white matter lesions. Previous studies have reported a strong correlation between small vessel disease with a decline in cognitive performance and executive function in older adults , 24. GroOrthostatic hypotension (OH) presents in up to 41% of patients with dementia. Anang et al. followed 80 patients who are cognitively intact with PD for 4.4 years and found that the risk of developing dementia increased by 84% for each 10 mmHg drop in SBP during postural changes . Centi eSeveral limitations of this study should be clarified. First, this was a single-center case-control study. A larger cohort study should be conducted to confirm our findings. Second, the comprehensive assessment of cognitive impairment in patients with OH requires redesign. Although MMSE and MOCA are the most commonly used clinical cognitive function assessment methods, they could still not reflect the real status of some patients. Third, the active standing and head-up tilt (HUT) tests are used to detect OH, and previous studies have reported that they are better at predicting clinical outcomes even though the AST can simulate daily patient postures well . Our tesIn conclusion, our research showed that in patients with PD with OH, there is an impaired tendency of autoregulation in the supine position. The symptomatic OH group demonstrated damaged cerebral autoregulation in the orthostatic position.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the board of the Ethics Committee of Capital Medical University Xuanwu Hospital. The patients/participants provided their written informed consent to participate in this study.YX, QinL, EX, JZ, QiuL, and SM collected the data. QinL conducted data analysis and wrote the manuscript. YX and QinL put forward the study concepts and interpreted the results. YX and YH revised the manuscript and commented on the data. YX, QinL, and YH participated in the study design and manuscript revision. All authors have read and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Objective: to identify new single-nucleotide polymorphisms (SNPs) in genes encoding proteins involved in methotrexate (MTX) metabolism and to evaluate the associations of these SNPs with MTX toxicity or intolerance in a southern Spanish cohort of patients with rheumatoid arthritis (RA). Methods: An observational, retrospective, and multicenter study was conducted at three participating hospitals in southern Spain. The main variable was intolerance to MTX , defined as an interruption of treatment due to adverse events or toxicity. Patients being treated with MTX and bDMARDs (combined treatment) at the time of the study visit were considered “tolerant” of MTX. Ten polymorphisms were selected for sequencing in our patients according to a literature review. Each polymorphism was classified according to three possible genotypes  and one heterozygous (AG)), and the association of these combinations with MTX intolerance was evaluated. Results: A total of 227 patients were included in the final analysis (107 intolerant of MTX and 120 tolerant). A significant association was observed between MTX intolerance and the GGH-T401C AA/AG genotype  in comparison with the GG genotype. On the other hand, an inverse association was observed between the ABCC2-C24T TT/TC genotype and intolerance to MTX  in comparison with the CC genotype. Conclusion: This study provides new data on the association between genetic polymorphisms and MTX intolerance, which may contribute to the development of new biomarkers and personalized medicine in patients with RA. Rheumatoid arthritis (RA) is an autoimmune rheumatic disease characterized by synovial inflammation and cartilage damage, which leads to joint destruction and mobility limitations in patients receiving inadequate treatment .Although RA is a chronic disease, knowledge of its pathogenesis has facilitated the development of new drugs that are increasingly effective. Both the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) recommend the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and conventional synthetic antirheumatic drugs (csDMARDs) as first-line treatment in patients with active disease as soon as possible, and both organizations agree on the use of methotrexate (MTX) as the first drug of choice ,3. MTX cPolymorphisms in genes encoding transporters and enzymes mediating the biotransformation and elimination of MTX have been suggested as one cause of adverse events . In factDespite the extensive study of these gene polymorphisms, no reliable biomarker has been identified to predict MTX intolerance or toxicity in patients with RA. Personalized medicine focuses on the identification of SNPs present in transporters and enzymes mediating the elimination of MTX and might provide valuable information to predict MTX intolerance and toxicity in these patients.Therefore, we decided to conduct this study with the aim of identifying new SNPs in genes encoding proteins involved in MTX metabolism and to evaluate the associations of these SNPs with MTX toxicity or intolerance in a southern Spanish cohort of patients with RA.This observational, retrospective and multicentre study was conducted at 3 participating hospitals in southern Spain . Consecutive patients with RA fulfilling the following inclusion criteria were selected for this study: (a) diagnosis of RA according to the ACR/EULAR criteria , (b) curPatients receiving MTX and bDMARD treatment (combined treatment) at the time of the study were considered “tolerant” to MTX. Patients receiving bDMARD monotherapy at the study visit were asked about the reason for MTX discontinuation. In cases of discontinuation due to adverse events or toxicity , these patients were considered “intolerant” to MTX. Investigators were asked if the intolerance was caused by the MTX and confirmed the resolution of the adverse event after MTX withdrawal to ensure that the intolerance was due to MTX. In the case of MTX discontinuation for reasons other than toxicity , the patient was not included in the analysis.All patients provided written informed consent, and the study was approved by the ethics committees of the three hospitals.Active transport of MTX: RFC-1-G80A (SMP rs1051266);MTX polyglutamate formation: GGH-T401C (SNP rs11545078);Folate cycle and purine synthesis: MTHFR-C677T (SNP rs1801133), MTHFR-A1298C (SNP rs1801131), DHFR (SNP 1105525), SHMT1-c1303C > T (SNP rs1979277) and ITPase-C94A (SNP rs34743033), and the latter is located in the noncoding sequence;MTX extraction pumps: ABCC2-C24T (SNP rs717620), ABCB1-c3435C > T (SNP rs1045642) and SLCO1B1 (SNP rs11045879), the last of which is located in the noncoding sequence.Eight polymorphisms in seven genes encoding proteins involved in MTX metabolism (pharmacokinetics and pharmacodynamics) and MTX toxicity, as well as two polymorphisms located in noncoding sequences, were selected for sequencing in our patients according to a literature review. The analyzed polymorphisms were involved in:Genomic DNA was obtained from blood samples collected during the previous 5 years before the initiation of the study and stored at each hospital. However, DNA was extracted from saliva samples obtained from patients at the University Hospital Virgen de las Nieves using a buccal swab and the QlAamp DNA Mini kit  according to the purification protocol provided by the manufacturer and stored at −40 °C.® probes . The analysis was performed according to the manufacturer’s instructions. Allelic variants , cytosine (C), guanine (G), and thymine (T)) were determined using StepOne v2.3 software .The 10 polymorphisms were sequenced using a real-time polymerase chain reaction system for the discrimination of alleles using TaqManThis study involved two different variables: one is intolerance to MTX , defined as an interruption of treatment due to adverse events or toxicity, and the other is tolerance to MTX  at the time of the study visit.Sociodemographic characteristics: age and sex;Disease-related variables: disease duration (months), age at diagnosis, time since bDMARD initiation (months), and duration of MTX treatment (months);Disease activity at the time of the study visit: c-reactive protein (CRP) in mg/dL, erythrocyte sedimentation rate (ESR) in mm/h, number of tender joints (NTJ), number of swollen joints (NSJ), physician assessment , patient assessment , Disease Activity Score 28 (DAS28), Simple Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI).In addition to the polymorphisms, the following variables were collected:Among patients belonging to the “intolerant” group, the reasons for MTX withdrawal and adverse events were recorded.The study was approved centrally by the Ethics Committee at the Reina Sofia University Hospital (protocol code RCC-MTX-2016-01), and each participant signed an informed consent form before inclusion in the study.The sample size was estimated considering an alpha risk of 5% and a power of 80% to detect a minimum odds ratio of 2.2 for the presence of polymorphisms associated with toxicity or intolerance to MTX. According to the hypothesis that the polymorphism rate would be 50% in the group of “intolerant” patients  and a 3:1 inclusion ratio, the minimum estimated sample size was 251 controls (tolerant patients) and 93 cases (intolerant patients).t-test or Mann–Whitney test.Qualitative variables were compared between the two groups  using the chi-square or Fisher test, and continuous variables were compared using the All genetic variants were tested for deviation from Hardy–Weinberg equilibrium. Each polymorphism was classified according to the three possible genotypes  and one heterozygous (AG)), and the association of these genotypes with MTX intolerance was evaluated using the chi-square test.p-value < 0.05 was considered significant.Finally, alleles of each polymorphism were classified into two groups according to the presence of one base and using the homozygosity of the other base as a reference. For example, SNPs with homozygous AA and GG and heterozygous AG genotypes were grouped as AA vs. GG/AG to determine the association between MTX intolerance and the G base. These associations were tested through univariate and multivariate logistic regression analyses using the variable “tolerant/intolerant” as the dependent outcome and the polymorphisms as explicative variables. Goodness of fit was evaluated with the Hosmer–Lemeshow test. All the contrasts were bilateral, and a www.project-redcap.org, accessed on 6 September 2021), and the reporting of this study conforms to the STROBE statement [Statistical analyses were conducted by RAIER  using SPSS v25 software Clinical data were collected using the Research Electronic Data Capture (RedCap) system  and 120 were tolerant of MTX . The mean age was 60.0 (12.1) years, and 78.4% were female. The mean age at RA diagnosis was 44.2 (12.2) years, and the mean disease duration was 1.48 (7.8) years.p < 0.05). On the other hand, the homozygous CC genotype of SNP rs717620 (ABCC2-C24T gene) was more frequent among the intolerant patients than among the tolerant patients , while the heterozygous TC genotype of the rs717620 polymorphism was less prevalent among the intolerant group .p = 0.035) compared with the GG genotype. On the other hand, an inverse association was observed between the ABCC2-C24T TT or TC genotypes and intolerance to MTX  compared with the CC genotype.In p = 0.037 and OR 0.54, 95% CI 0.32–0.93, p = 0.026, respectively)  .MTX represents the first-line treatment for patients with RA, either in monotherapy or in combination with other drugs . MTX is In our study, we identified one polymorphism associated with MTX intolerance (SNP rs11545078 AA or AG in the gene GGH-T401C) and one polymorphism associated with MTX tolerance (SNP rs717620 TT or TC in the gene ABCC2-C24T). GGH (gamma-glutamyl hydrolase), which is encoded by the GGH gene, is an enzyme that participates in MTX polyglutamate formation, facilitating the elimination of MTX from the cell. Thus, our results suggest that the genetic variant in GGH-T401C  may be associated with MTX intolerance or toxicity in patients with RA. Similarly, previous studies conducted in other RA cohorts indicated that patients with the TT 401C > T genotype showed increased GGH activity compared with patients with the CC or CT genotype, suggesting an association between the TT genotype and an inadequate response to MTX. In addition, a study published by García-Bournissen et al. . Both stAccording to several studies, the MTHFR variants A1298C and C677T are two of the most important polymorphisms associated with MTX toxicity ,19,20,21Interestingly, we found that the SNP rs717620 TT or TC genotype from the gene ABCC2-C24T was associated with MTX tolerance. This gene encodes ATP-binding cassette subfamily C member 2, a multispecific organic anion efflux transporter that affects biliary excretion of endogenous and xenobiotic compounds, such as MTX . Based oRFC1-G80A is one of the most analyzed polymorphisms in studies of MTX in patients with RA, but inconsistent results have been published regarding its role in the prediction of the therapeutic response and toxicity. We did not find an association between this polymorphism and MTX intolerance in our patients, suggesting that its effect on MTX outcomes is mild and may be influenced by a combination with some other genetic factors, as described in previous studies .This study has some limitations and some strengths. One limitation is the retrospective nature of the study, as we retrospectively collected information on MTX discontinuation. However, the genetic burden and polymorphisms do not change over time, ensuring the reliability of the genotyping of these patients. The sample size represents another limitation, since our estimation revealed the need for 251 controls (or tolerant patients) and we recruited 120 controls. The sample size may explain why we did not obtain significant differences in some polymorphisms that have been described as associated with MTX intolerance in the literature, such as MTHFR A1298C. One strength of this study is the exclusion of patients who interrupted MTX treatment for reasons other than toxicity or intolerance, such as clinical improvement, inefficacy, or voluntary interruption. In addition, all patients included resided in southern Spain, reducing genetic variability.In conclusion, our results show that MTX intolerance is significantly associated with the presence of the AA or AG genotype of the GGH-T401C polymorphism compared with the presence of the GG genotype in a cohort of patients with RA. In addition, we confirmed greater MTX tolerance in carriers of the TT or TC genotype of the ABCC2-C24T polymorphism compared with CC carriers. This study provides new data on the association between polymorphisms and MTX intolerance, which might contribute to the development of new biomarkers and personalized medicine for patients with RA. Future studies conducted in other populations and with greater sample sizes should be conducted to confirm these relationships.


The Neutrophil-to-Lymphocyte Ratio (NLR) and the Platelet-to-Lymphocyte Ratio (PLR) are inflammatory biomarkers for several diseases, such as cancer and cardiovascular morbidities; however, there are currently few studies on kidney diseases. We aimed to evaluate nondialysis patients and determine the association of NLR and PLR with inflammation in these patients.  A prospective cross-sectional study was conducted with 85 patients at different stages of chronic kidney disease (CKD), treated at the Kidney Disease Prevention Center of the University Hospital of the Federal University of Maranhão. This study included adult nondialysis patients diagnosed with CKD. The participants' blood samples were collected for a high-sensitivity C-reactive protein (hs-CRP) test and blood count. They were divided into two groups according to the presence or absence of inflammation based on the hs-CRP value (<0.5 mg/dL). NLR and PLR were calculated based on the absolute number of neutrophils, lymphocytes, and platelets and were compared between them and with hs-CRP. Statistical analysis was performed using the Stata software, with the Shapiro–Wilk, Mann–Whitney, Spearman's Correlation, and receiver operating characteristic curve tests. This study was approved by the local ethics committee. n = 64) and without inflammation (n = 21). The mean age was 61.43 ± 14.63 y. The NLR and PLR values were significantly different between the groups with and without inflammation . However, only PLR showed a significant positive correlation with hs-CRP (p=0.015). The best cutoff point for NLR to detect inflammation was 1.98, with 76.19% sensitivity and 48.44% specificity. For PLR, it was 116.07, with 85.71% sensitivity and 51.56% specificity. There was no significant difference between the area under the NLR and PLR curve  for this population.  The participants were categorized into two groups: with inflammation ( This study showed that PLR was positively correlated with hs-CRP in nondialysis CKD patients and can be used to identify inflammation in this population. Chronic kidney disease (CKD) is characterized by progressive and irreversible loss of renal function. It is a major health issue worldwide, which leads to end-stage renal failure (ESRD) . A systeCKD has high morbidity and is associated with increased cardiovascular mortality, with 5 to 10 million annual deaths worldwide, followed by infections , 4. InflThe chronic systemic inflammation in the CKD, sometimes referred to as low-grade chronic inflammation, is characterized by 2-3-fold increase of acute-phase protein and inflammatory mediators, slow developing, persistent, and of multifactorial origin , 8.While the source(s) of chronic inflammation in CKD can vary, the negative implications of elevated inflammatory markers are clear, such as reduced renal function and high chances of mortality. Within the predialysis CKD population, the prevalence of inflammation is great and is an important indicator of patient health and outcome , 6.α [It is predicted that early and specific detection of inflammation might improve the quality of life of those and decrease the rate of mortality and morbidity . Nowadayα , 10.However, in the present socioeconomic status, it is important that we seek cost-effective biological markers. Previous studies have demonstrated that the neutrophil-to-lymphocyte (NLR) ratio and platelet-to-lymphocyte ratio (PLR) have begun to be used with an indicator of systemic inflammation and have been widely studied in malignancies –15, hypeNLR and PLR are inexpensive, convenient, and measured easily and have demonstrated utility in stratifying mortality from cardiac events  and progTherefore, the present study was designed to evaluate nondialysis patients and sought to determine the relationship of NLR and PLR with inflammation in these patients.This was a cross-sectional study conducted with nondialysis chronic kidney disease (CKD) patients treated at the Kidney Disease Prevention Center (CPDR) at the University Hospital of the Federal University of Maranhão (HUUFMA).A nonprobabilistic sample was formed by male and female adult and elderly patients with a diagnosis of CKD who were not on dialysis and were treated at the CPDR outpatient clinic during a 12-month period (September 2016 to August 2017). The exclusion criteria were pregnant women, patients with amputations, with only one kidney, with a history of hospitalization and surgeries  in the 3 months prior to the beginning of data collection, and history of dialysis, liver failure, chronic consuming diseases , and/or infectious diseases.Participants, regardless of skin color or financial status, were selected by a doctor during outpatient care and referred to pharmaceutical assistance. During the pharmaceutical appointment, patients were informed about the study and invited to participate. A total of 101 patients of both sexes with a diagnosis of nondialysis CKD agreed to participate in this study . HoweverThis study was conducted in two stages. The first stage was an interview to collect demographic, socioeconomic, lifestyle, and comorbidities data. In the second stage, data were collected from electronic medical records and blood samples to perform the hs-CRP and complete blood count test.The hs-CRP test was performed using serum with the immunoturbidimetry methodology with a Roche Cobas 6000 analyzer . The complete blood count was performed using the Advia 2120 Hematology System .The levels of urea and creatinine were obtained from the HUUFMA electronic records. The glomerular filtration rate value was calculated using the Chronic Kidney Disease Epidemiology Collaboration Creatinine Equation (2009) through the mobile application eGFR , based on data from the National Kidney Foundation. NLR and PLR were obtained by dividing the absolute neutrophil count by lymphocytes and between platelets and lymphocytes, respectively.Participants were categorized according to the presence of low-grade inflammation based on the hs-CRP value, a gold-standard method for the detection of inflammation. As the cutoff point for hs-CRP, participants with no inflammation were those who obtained a result <0.5 mg/dL .The comorbidities found were arterial hypertension, diabetes mellitus, and cardiovascular disease and were determined by previous self-reported diagnosis.U test for the evaluation of NLR and PLR as inflammatory markers in people with CKD, and the coefficient of Spearman's correlation to compare the numerical distributions of each marker with the hs-CRP. The Youden test was used in the receiver operating characteristic (ROC) curve to identify the cutoff points of the markers with the best sensitivity and specificity. The area under the curve (AUC) was used to assess the markers' performance and comparison. The level of significance used for the statistical tests was 5%. The data are presented in tables and graphs.Data were tabulated in Microsoft Excel , and the statistical analysis was performed using Stata software . Initially, descriptive analyses were performed using absolute and relative frequencies for categorical and mean variables, standard deviation for numerical variables with normal and median distribution, and interquartile range for those without normal distribution. Normality was assessed using the Shapiro–Wilk test. For inferential analysis, the chi-square and Fisher's exact tests were used to compare categorical variables between groups with and without inflammation, the Mann–Whitney This study was approved by the local ethics committee under number 2.015.866, with all participants signing an informed consent form.The final sample consisted of 85 participants categorized into two groups according to the presence of inflammation (24.7%) and absence of inflammation (75.3%). The mean age was 61.43 ± 14.63 y, with a predominance of female patients (55.29%). The most prevalent comorbidity found was arterial hypertension (92.94%) .p < 0.001). The levels of urea and creatinine and the glomerular filtration rate did not show significant differences between the groups. NLR and PLR showed median levels of 2.11 (1.41–3.36) and 121.95 (94.72–157.45), respectively, with a statistically significant difference between groups for NLR (p=0.045) and PLR (p=0.004)  was used as a cutoff point to separate the group with and without inflammation, as described in the methodology. The median values of the group without inflammation were 0.09 mg/dL and 0.88 mg/dL for the group with inflammation (p=0.004) .  Table p=0.045 and p=0.004, respectively), confirming that both are markers that alter or stand out in inflammatory processes for nondialysis patients with CKD, as shown in The results showed a statistically significant difference between the groups with and without inflammation based on NLR and PLR values . However, this correlation did not occur for NLR and hs-CRP , as shown in A statistically significant positive correlation was found between PLR and hs-CRP (p=0.186)  .NLR is a parameter that provides information on both inflammation and the stress response. As for PLR, a high platelet count and a low level of lymphocytes are associated with different cardiovascular outcomes . In thisThe objective of this study was to evaluate nondialysis CKD patients and determine the association of NLR and PLR with inflammation in these patients, and the results showed that both biomarker values significantly increased in patients with inflammation.The study by Chávez Valencia  pointed Some studies that focused only on NLR outlined its advantages compared to other inflammatory markers. Malhotra et al.  concludeIn some studies, NRL stood out as an inflammatory marker, reaching higher levels than other markers such as hs-CPR and interleukins and in some outcomes as an indicator of acute kidney injury in patients with sepsis and as an indicator of cardiovascular events in patients with end-stage renal disease , 37. YosThe data presented here corroborate the findings of these authors, showing that NLR changes in the group with nondialysis CKD, but in the studied population, it was not positively correlated with hs-CPR.On the other hand, few studies have shown evidence of the use of PLR as an inflammatory marker in this population. It is considered a recently defined hematological parameter, which is associated with both aggregation and inflammation pathways and may be more valuable than the isolated platelet or lymphocyte count .There was a positive correlation between PLR and hs-CPR, a gold-standard method for the detection of inflammation in this population. Similar findings were presented in a study conducted in Turkey, where patients on hemodialysis and peritoneal dialysis had higher PLR than NLR, in addition to being positively correlated with other inflammatory markers, such as cytokines and tumor necrosis factor-alpha , highligChávez Valencia et al.  concludeIn this context, NLR and PLR show a great advantage compared to other markers in the evaluation of inflammation since it is a simple, relatively inexpensive, and universally available method  that couAs for the determination of the markers' cutoff points, the best sensitivity and specificity values were 1.98 for NLR and 116.07 for PLR. The literature presents great variability as for cutoff values for these markers. Tonyali et al.  found a As for PLR, a cutoff value of 136.85 was found in patients who underwent cardiovascular surgery . The stuThe difference of performance and comparison between the markers was not significant in this study. Li , who alsThese findings indicate that studies with larger, randomized, and multicenter samples are still needed to better assess the performance of these markers in nondialysis renal disease patients.The present study has as limitations the fact that it is cross sectional with local sampling that was nonprobabilistic and relatively small for some statistical analyses, and a cause-and-effect relationship cannot be defined in the findings of this study. On the other hand, this study was conducted in a reference center for the prevention and treatment of CKD in a capital city that concentrates a representative sample of the population of the state. In summary, the data from the present study were able to confirm the association between the values of NLR and PLR and the presence of inflammation in this population. Nevertheless, the literature has few studies on this theme, showing the need for larger, controlled studies to analyze the use of these markers in patients with CKD and their implementation in clinical practice.The study showed that PLR was positively correlated with hs-CPR in nondialysis CKD patients and, thus, can be used to identify inflammation in this population.