Hypertension is one of the primary predictor of mortality among end-stage renal disease (ESRD) patients on dialysis. However, there is no consensus on an ideal blood pressure range for this population.To identify an ideal systolic blood pressure range based on optimal survival among ESRD patients on dialysis.A systematic search for clinical trials assessing the impact of different systolic blood pressure range on mortality among ESRD patients on hemodialysis was conducted through PubMed, EBSCOhost, Science Direct, Google Scholar, and Scopus. All randomized control trials (RCTs) involving ESRD patients on hemodialysis with primary or secondary outcome of assessing the impact different systolic blood pressure range (< 140 and >140 mm Hg) on all-cause mortality were included. The quality of reporting of the included studies was evaluated using the Jadad scale. Two researchers independently conducted eligibility assessment. Discrepancies were resolved by discussion and consultation with a third researcher when needed. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated.P = 0.08). Four RCTs were able to achieve a systolic blood pressure of >140 mm Hg at the end of trial, with the RR for reduction of mortality of 0.72 . Overall, pooled estimates of the six RCTs suggested the reduction in systolic blood pressure statistically reduce all cause of mortality  among ESRD patients on hemodialysis.A total of 1,787 research articles were identified during the initial search, after which six RCTs met our inclusion criteria. According to the Jadad scale, all six RCTs scored 3 points each for quality of reporting. Four RCTs employed pharmacological intervention while two RCTs assessed non-pharmacological intervention. Of the six RCTs, two studies were able to achieve a systolic blood pressure of <140 mm Hg at the end of trial with a RR for reduction in mortality of 0.56 . Hypertension among end-stage renal disease (ESRD) patients on hemodialysis is common and is one of the main contributors towards high mortality and morbidity among these patients. Several studies have shown a “U-shape” relationship between high blood pressure and mortality, implying that blood pressure levels below certain range is more harmful than higher levels . HyperteBenefits of lowering blood pressure in hypertensive patients have long been established through randomized controlled trials (RCTs). The SPRINT trial reported the beneficial effects of reducing blood pressure to 120 mm Hg, which include reduction in fatal and non-fatal cardiovascular events and overall mortality rates . HoweverGiven the methods and timing of blood pressure measurements are variable, the relationship between hypertension and mortality among hemodialysis patients is complex. Clinical practice guidelines suggest a pre-dialysis blood pressure of <140/90 mm Hg and post dialysis blood pressure of <130/80 mm Hg . HoweverThis ambiguity and uncertainty revolving around ideal blood pressure ranges among hemodialysis patients prompted the authors to perform a systematic review and meta-analysis to identify ideal systolic blood pressure that corresponds to optimal survival among hemodialysis patients.The preferred reporting framework for systematic review and meta-analysis, the PRISMA statement was strictly adhered to while performing the literature search and reporting of results.A systematic search for clinical trials assessing the impact of different systolic blood pressure ranges (<140 and >140 mm Hg) on mortality among ESRD patients on hemodialysis was conducted. PubMed, EBSCO host, Science Direct, Google Scholar, and Scopus search engines were searched for original research articles published to date (March 2019).hypertension, blood pressure, dialysis, end-stage renal disease, end stage renal failure, mortality, survival, and death. We limited the search results to clinical trials and articles published in English.The keywords and MESH terms used were The inclusion criteria applied were RCTs with primary or secondary outcome of assessing the impact different systolic blood pressure range (<140 and >140 mm Hg) on all-cause mortality among ESRD, hypertensive adults (>18 years old) on regular hemodialysis for at least 1 year. Both pharmacological and non-pharmacological intervention that was administered for at least 6 months to reduce blood pressure were included. Only studies with a minimum follow-up period of 1 year and published in English language were included.Two researchers independently reviewed the titles and abstracts of all potential research articles that met the inclusion and exclusion criteria. Any differences were resolved through discussion or by consulting a third reviewer. Full texts of the eligible research articles were retrieved and screened for eligibility by two researchers independently. Any differences were resolved through discussion or by a third reviewer.The Jadad scale was used to assess the quality of reporting of RCT in this study. The Jadad scale is a three-item scale assessing the randomization, blinding, and drop-out methods. For each item, a study was awarded one point if it described randomization, double blind or dropout, respectively. If randomization or blinding method is judged appropriate, an additional one point was awarded for each item. Conversely, if the randomization or blinding method is judged inappropriate, one point was deducted from that item. Since randomization procedure is fundamental to the quality of RCT, one point was deducted if randomization procedure was not described. Blinding was considered appropriate if the article specifies whom the blinding involved. The original Jadad scale only considers double blinding as an appropriate method. Keeping in view of our objectives, we scored single blinding as an appropriate method as well. Next, articles were assessed with regards to information on patient withdrawal or exclusion after enrollment for any reason. These included decision by patient or investigator, loss to follow-up, change in treatment or any reason that may introduce bias. Articles were also assessed if they have mentioned or were clear from data shown that all patients were included in final outcome analysis or provided details of patient dropout. The final quality score for each article may range from 0  to 5  .Following review and selection of the full texts, one researcher independently extracted data from each included study and recorded them on a standardized data extraction sheet.2 statistic. A fixed effect model was used when I2 < 50%, which indicated heterogeneity. If I2 > 50%, a random effects model was used after consideration of the potential sources of heterogeneity. Publication bias was assessed using a funnel plot.Quantitative synthesis or meta-analysis was performed using REVMAN 5 software. The number of all-cause mortality in each group and the relative risk (RR) with 95% confidence interval (CI) were calculated. Authors performed subgroup analysis based on systolic blood pressure >140 and <140 mm Hg and all-cause mortality reported in the included studies. Heterogeneity between studies were assessed using both the Chi-square test and the IA total of 1,787 articles were identified during the initial search. Following the elimination of 280 duplicate articles, 1,507 titles and abstracts were screened against the inclusion and exclusion criteria, and a total of 25 articles met the inclusion criteria  studies were not given any points for blinding domain as they did not include information on blinding  compared to 12 (7.6%) in the intervention arm.P = 0.08). The results suggested that there was 44% of risk reduction in mortality rates among patients that were able to achieve systolic blood pressure <140 mm Hg. Overall, heterogenicity  was negligible among the studies  compared to 65 (12.9%) in the intervention arm.P = 0.003). The results suggested interventions applied to achieve systolic BP >140 mm Hg was able to significantly reduce the risk mortality by 28%. heterogenicity  was moderate  among ESRD patients on hemodialysis. Thereby suggesting that the patients receiving any form of intervention to reduce blood pressure had 31% decreased risk of mortality compared to standard arm patients. Overall, heterogenicity  was low, thereby suggesting there was not much variation among the selected studies  suggested that the reduction in systolic blood pressure significantly reduce all-cause mortality  as their pharmacological interventions. ARBs and Angiotensin-converting Enzyme Inhibitors (ACEIs) are both commonly used in clinical practice for ESRD patients as they are the first line antihypertensive agents recommended by the National Kidney Foundation KDOQI guidelines . It is sThe use of antihypertensive agents is one the prime strategies to manage blood pressure among hemodialysis patients. With reports also suggesting that antihypertensive agents may also be associated with low blood pressure and intradialytic complications, an unexpected point of use of these antihypertensive agents may well be paradoxically associated with higher blood pressure . ExcessiThe ultimate aim of renal replacement therapy is to improve patient survival and clinical outcomes. Surprisingly, there is no consensus on ideal blood pressure among ESRD patients on hemodialysis. Basis for this lack of consensus appears to be multifactorial that includes lack of agreement on best blood pressure measurement time related to the hemodynamic instability observed in this population. The current meta-analysis assessed survival as an outcome to establish the ideal blood pressure range among ESRD patients, thereby providing a rationale to use <140 mm Hg systolic blood pressure as an ideal target.RA and RS have drafted the first version of the manuscript. All authors have been involved in all stages of the study design and have participated in writing the protocol whereas submission to PROSPERO was done by RS and RA. CM was involved in data extraction whereas RS and RA overlooked the process. Meta-analysis was performed by RA. IS was involved in qualitative analysis, manuscript write up, and critical review All authors approved the final manuscript. Data can be accessed by all the authors throughout and after the study.This study was funded by Taylor's University, Malaysia (TRGS/ERFS/2/2018/SOP/018). The source of funding had no role in the design, conduct or any influence in the study.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.


Acupuncture is effective in symptom and quality of life improvement of chronic asthma, but the efficacy differences between different acupoints are uncertain. In terms of the theory of Meridian-viscera Association, the study aims to investigate the different effectiveness between acupoints in Lung meridian and the acupoints in Heart meridian, so as to provide the evidence to develop a better prescription of the acupuncture treatment of chronic persistent asthma.This study is a multicentral randomized controlled trial. A total of 68 chronic persistent asthma patients will be randomly allocated into two groups: the Lung meridian group and the Heart meridian group. This trial will include a 2-week baseline period, a 4-week treatment period with 12 sessions’ acupuncture, and an 8-week follow-up period. The primary outcome is the Asthma Quality of Life Questionnaire (AQLQ). Secondary outcomes are the Asthma Control Test (ACT), Peak Expiratory Flow (PEF), and Forced Expiratory Volume in 1 s (FEV1). The AQLQ and ACT will be collected at baseline, week 4, week 8, and week 12 after randomization. PEF, FEV1, the Self-rating Anxiety Scale (SAS), and the Self-rating Depression Scale (SDS) will be assessed at baseline and week 4.The results will provide evidence for acupuncture prescription selection and the clinical efficacy improvement. The results of this trial will also be used to determine whether or not a full definitive trial will go ahead, which will further confirm the theory of Meridian-viscera Association.http://www.chictr.org.cn/showproj.aspx?proj=43803) ChiCTR1900027284. Registered on 7 November 2019Chinese Clinical Trial Registry (Supplementary information accompanies this paper at 10.1186/s13063-020-04844-8. Asthma is characterized by bronchial hyper-responsiveness and chronic airway inflammation and accompanied by episodic wheezing, chest tightness, breathlessness, and cough , 2. AsthAccording to the 2019 Global Initiative for Asthma (GINA) guidelines on the management of asthma , decreasAcupuncture, as a main complementary and alternative therapy, has traditionally been used to control asthma in China for thousands of years. Recently, accumulating evidence has supported the benefit of acupuncture for asthma , 18. It According to the theory of traditional Chinese acupuncture, the Lung meridian connects with the lung directly, while the Heart meridian associates with the lung indirectly. Both the acupoints on Lung meridian and on the Heart meridian are commonly used for preventing and controlling asthma in clinical practice . Hence, A two-arm, multi-center, randomized controlled trial will be conducted at the First Affiliated Hospital of Chengdu University of Traditional Chinese Medicine (CDUTCM) and the First Affiliated Hospital of Anhui University of Traditional Chinese Medicine. Sixty-eight eligible asthma patients diagnosed with the guide for asthma management and prevention of updated GINA 2019 [This trial is reported in accordance with the Standard Protocol Items: Recommendations for Intervention Trials (SPIRIT) guidelines  Table 11 and folWe will use an online or messaging system performed by a clinical information management system  to complete the randomization. When participant-recruiting staffs in sub-center accept an eligible asthma patient, they will enter the patient’s name, gender, age, and medical history in the central randomization system. Then, a random number and an identification code, which are unique for each participant, will be assigned and delivered to the acupuncturists. The allocation number will be concealed from all the participants.The allocation will be concealed from all the participants. Patients will be told that they will receive one of the two effective interventions randomized after enrolment. As patients in the two groups will adopt different acupoints, interventions of each patient will be performed in separated cubicles to refrain the communication among patients in the two groups and will be asked to wear an eye-patch when they receive treatment. Outcome assessors, data collectors, and statisticians will also be blind to the procedure and result of randomization, group allocation, and intervention. We do not anticipate any requirement for unblinding as the acupuncturist is not blinded, but if required, the Trial Manager, Data Coordinator will have access to group allocations and any unblinding will be reported.Participants will be mainly recruited from inpatients and outpatients in the respiratory department of the First Affiliated Hospital of CDUTCM, the Fifth People’s Hospital of Chengdu and the First Affiliated Hospital of Anhui University of Traditional Chinese Medicine. The recruitment strategies also include delivering leaflets at outpatients, posting advertisements in communities, and distributing news on the website of the Chengdu University of TCM and our WeChat public account. All potential asthma patients diagnosed with the GINA criteria will take a physical examination, which includes an x-ray plate, lung function test, electrocardiograph, routine blood test, liver function test, kidney function test, blood immune test (IgE), and urine and feces routine tests. The respiratory physician will make the final diagnosis of potential patients.According to a previous study that investigates the therapeutic effect of acupuncture for asthma , the meaPatients fulfilling the following 7 items will be included: (1) aging from 18 to 65 years, (2) diagnosed as chronic persistent asthma by respiratory physicians according to the guide of GINA 2019 and medical history, (3) having mild or moderate asthma according to the GINA 2019, (4) having increased in the FEV1 of > 12% and > 200 mL from the pre-bronchodilator value, (5) the FEV1/forced vital capacity (FVC) < 70%, (6) without participating in any other clinical trials or receiving acupuncture due to asthma within 1 month, and (7) having signed informed consent.Patients who match any of the following 8 items will be excluded: (1) be hospitalized in intensive care unit due to acute exacerbation of asthma in the previous 3 months (representing patients at highest risk of adverse asthma outcomes); (2) be diagnosed as other pulmonary diseases such as bronchiectasis, tuberculosis, abscess, cystic fibrosis, alpha 1 antitrypsin deficiency, or restrictive lung disease; (3) having serious cardiovascular diseases such as uncontrolled heart failure, coronary disease, myocardial infarction, severe hypertension, or uncontrolled arrhythmia; (4) having other uncontrolled diseases including liver or kidney or hematopoietic diseases, endocrine and immune diseases, mental disorders, and malignancy; (5) asthma occurs only when accidentally exposed to allergens or chemical sensitizers; (6) having lower respiratory tract infection  or taking systemic glucocorticoids more than 10 days for severe acute asthma attacks within 1 month before enrollment; (7) currently be pregnant or breast feeding at the time of enrolment or planned pregnancy within the study period; or (8) having any acupuncture contraindications, such as serious atopic, infectious dermatopathy, thrombocytopenic purpura, or hemophilia.The acupuncture treatment of each group will consist of 12 sessions of 30 min duration, each administered over a period of 4 weeks (three sessions per week). All the acupuncture manipulation will be performed by licensed acupuncturists with at least 5 year’s clinical experience.The manual acupuncture stimulation will be performed at bilateral Taiyuan (LU9), Lieque (LU7), and Chize (LU5) for patients in group A, and manual acupuncture stimulation will be performed at bilateral Shenmen (HT7), Yinxi (HT6), and Shaohai (HT3) for patients in group B Fig. .Fig. 2Ldeqi sensation. Then needles will be retained at the acupoints for 30 min. In order to maintain the deqi sensation, the above procedures will be manipulated intermittently during the 30 min.The acupuncture manipulation of these two groups is as follows: the disposable sterile filiform needles  will be inserted into acupoints with the depth of 10–30 mm after skin disinfection by alcohol. Manipulations of twirling, lifting, and thrusting will be performed in order to induce Patients can use the inhaled doctor-directed Seretide  or Symbicort (formoterol and budesonide) as conventional therapy following the respiratory physicians’ instruction. Participants will be not allowed using other interventions during this trial but will be permitted to use inhaled salbutamol or other medication advised by doctors in an emergency. The name of medications, specifications, dose, duration of use, time of symptom relief, etc. will be recorded in details.There should be at least 6 h between the use of salbutamol and lung function measurements. A stable dose of inhaled glucocorticoids and antihistamines should be maintained for at least 2 months prior to enrollment and during this study. If patients’ desensitization therapy is in the “maintenance” phase, the medication used should be maintained at a stable dose of at least 1 month prior to the enrollment and during this study. Short courses of antihistamine therapy or inhaled glucocorticoid therapy are allowed to treat hay fever. Short-term (< 10 days) use of systemic corticosteroids, aerosol therapy , and antibiotic therapy will be permitted during this study.In this study, the standard version of AQLQ will be used . This quAsthma control will be evaluated using the Asthma Control Test (ACT) , 27. ThePEF and FEV1 are determined using spirometry and body plethysmography before and after bronchodilation with a short-acting bronchodilator in accordance with recommendations of the national guidelines , 30.The Self-rating Anxiety Scale (SAS)  and the AQLQ and ACT will be evaluated at baseline (week 0), after the intervention (week 4), and at the follow-up . The PEF, FEV1, SAS, and SDS will be assessed at baseline (week 0), after the intervention (week 4). The asthma diary will be assessed during the whole trial (week 0– week 12). The expectation for efficacy in patients will be evaluated at baseline . The firAll data will be managed with printed and electronic Case Report Forms (CRFs). Primary entries are not allowed to be changed and any correction should be explained with a signature in the appended notes. Only outcome assessors have access to CRFs, and double-data entry will be performed. The research team in Chengdu is responsible for all aspects of the organization. The Ethics Committee of the First Affiliated Hospital of Chengdu University of TCM will be supervising this trial and data every 3 months and will make the final decision to terminate the trial. The process will be independent from investigators and the sponsor. Interventionists will monitor adverse events and respond appropriately with encouragement and suggestions. All researchers, physicians, and related personal are required to understand and adhere to protocol details.All data will be analyzed by an independent statistician using SAS 9.4 software . All efficacy and safety analyses will be strictly conducted according to the intention-to-treat (ITT) principle. Multiple imputation will be used to deal with missing data. Continuous variables will be described with means and standard deviation (SD) or median, maximum, minimum, P25, and P75, as appropriate. And categorical variables will be described with percentage and frequencies.t test or Wilcoxon rank-sum test, as appropriate. Separate ANCOVA analyses will be performed for each secondary outcome, the AQLQ and ACT at week 8 and week 12 follow-up. Categorical variables will be analyzed using the chi-squared test or Fisher’s exact test, as appropriate.The comparison between groups will be analyzed by the analysis of covariance (ANCOVA) if the change of outcomes from baseline to 4 weeks is normally distributed. The outcome variable will be the change of AQLQ from baseline to week 4, and covariates will be age, gender, duration of disease, and the expectation of acupuncture in the ANCOVA analysis. The non-parametric ANCOVA will be conducted if the change is not normally distributed. The comparisons between time points within groups will be analyzed using the paired sample The center effects will be included in the analysis model. A subgroup analysis between inpatient and outpatient participants in each group will be performed exploratively. Statistical results will be presented as point estimates of effect sizes accompanied by confidence intervals.Participants with fainting, infection, or other severe adverse events should be discontinued from treatment and processed immediately. Any adverse events will be recorded by patients, acupuncturists, and outcome assessors. Acupuncture related adverse events include bleeding, dizziness, pain, infection, and so on. Besides, any other severe events also will be recorded in the CRFs in detail and be monitored by the Ethics Committees.The trial protocol is reviewed and revised by the experts in acupuncture, methodology, pneumology, and statistics. The related staff will be trained using a prespecified standard operating procedure. The compliance of patients will be improved through health education and timely follow-up. The outcomes will also be evaluated by outcome assessors if the participants discontinue acupuncture or deviate from protocol.This is the first RCT focused on the efficacy differences of the acupoints on the Lung meridian compared to the acupoints on the Heart meridian for treating chronic persistent asthma. The results will provide evidence for acupuncture prescription selection and the clinical efficacy improvement. The results of this trial will also be used to determine whether or not a full definitive trial will go ahead, which will further confirm the theory of Meridian-viscera Association.The theory of Meridian-viscera Association emphasizes the diagnostic and therapeutic values based on the mutual relation in physiology and pathology between meridians and viscera. That is, visceral physiological functions and pathological changes will manifest in the corresponding meridians or the acupoints , and theThe efficacy evaluation will be performed from the following three aspects: the quality of life, symptoms, and emotion of asthma patients. Asthma affects patients’ daily life seriously ; the impwww.chictr.org.cn) on 7 November 2019 . The patient recruitment of this trial has not been started and will begin on November 25, 2019, and will be completed on October 31, 2021.This trial is registered on the Chinese Clinical Trial Registry (http://Additional file 1. SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents.


Large trials have shown that sodium glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of adverse kidney and cardiovascular outcomes in patients with heart failure or chronic kidney disease, or with type 2 diabetes and high risk of atherosclerotic cardiovascular disease. None of the trials recruiting patients with and without diabetes were designed to assess outcomes separately in patients without diabetes.We did a systematic review and meta-analysis of SGLT2 inhibitor trials. We searched the MEDLINE and Embase databases for trials published from database inception to Sept 5, 2022. SGLT2 inhibitor trials that were double-blind, placebo-controlled, performed in adults (age ≥18 years), large (≥500 participants per group), and at least 6 months in duration were included. Summary-level data used for analysis were extracted from published reports or provided by trial investigators, and inverse-variance-weighted meta-analyses were conducted to estimate treatment effects. The main efficacy outcomes were kidney disease progression , acute kidney injury, and a composite of cardiovascular death or hospitalisation for heart failure. Other outcomes were death from cardiovascular and non-cardiovascular disease considered separately, and the main safety outcomes were ketoacidosis and lower limb amputation. This study is registered with PROSPERO, CRD42022351618.2). Compared with placebo, allocation to an SGLT2 inhibitor reduced the risk of kidney disease progression by 37%  with similar RRs in patients with and without diabetes. In the four chronic kidney disease trials, RRs were similar irrespective of primary kidney diagnosis. SGLT2 inhibitors reduced the risk of acute kidney injury by 23%  and the risk of cardiovascular death or hospitalisation for heart failure by 23% , again with similar effects in those with and without diabetes. SGLT2 inhibitors also reduced the risk of cardiovascular death  but did not significantly reduce the risk of non-cardiovascular death . For these mortality outcomes, RRs were similar in patients with and without diabetes. For all outcomes, results were broadly similar irrespective of trial mean baseline eGFR. Based on estimates of absolute effects, the absolute benefits of SGLT2 inhibition outweighed any serious hazards of ketoacidosis or amputation.We identified 13 trials involving 90 413 participants. After exclusion of four participants with uncertain diabetes status, we analysed 90 409 participants (74 804 [82·7%] participants with diabetes [>99% with type 2 diabetes] and 15 605 [17·3%] without diabetes; trial-level mean baseline eGFR range 37–85 mL/min per 1·73 mIn addition to the established cardiovascular benefits of SGLT2 inhibitors, the randomised data support their use for modifying risk of kidney disease progression and acute kidney injury, not only in patients with type 2 diabetes at high cardiovascular risk, but also in patients with chronic kidney disease or heart failure irrespective of diabetes status, primary kidney disease, or kidney function.UK Medical Research Council and Kidney Research UK. Large placebo-controlled trials have shown that sodium glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of cardiovascular disease, and particularly hospitalisation for heart failure, in patients with type 2 diabetes at high risk of atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease. There is good evidence to support the use of SGLT2 inhibitors as a foundational therapy to prevent cardiovascular death or hospitalisation for heart failure in patients with heart failure, irrespective of ejection fraction or history of previous diabetes.11Evidence before this studyIn our previous systematic review and meta-analysis reported in 2021, we systematically searched MEDLINE and Embase from inception to Aug 28, 2021, for large double-blind placebo-controlled sodium glucose co-transporter-2 (SGLT2) inhibitor trials. We identified 11 large trials with low risk of bias conducted in three at-risk populations . Overall, SGLT2 inhibitors reduced the risk of kidney disease progression and the composite of cardiovascular death or hospitalisation for heart failure, both by about a quarter. Relative risks were markedly consistent across the different patient groups. However, data were limited in patients without diabetes who were eligible for inclusion . Estimates of the effects of SGLT2 inhibitors on kidney disease progression in patients without diabetes were based on around 100 events from the chronic kidney disease trial and around 100 events from the heart failure trials. This limits the quality of evidence for making clinical practice recommendations. The influence of diabetes on the effects of SGLT2 inhibitors on acute kidney injury, cardiovascular and non-cardiovascular mortality, and safety outcomes was also not explored in the previous meta-analysis.Added value of this studyThe majority of people with chronic kidney disease do not have diabetes, and thus more information about SGLT2 inhibitors in this patient group has particular public health importance. Since 2021, two placebo-controlled SGLT2 inhibitor trials (EMPA-KIDNEY and DELIVER) have studied a large number of people without diabetes. EMPA-KIDNEY recruited 6609 patients with chronic kidney disease including 3569 patients without diabetes, and DELIVER recruited 6263 patients with heart failure with mildly reduced or preserved (>40%) ejection fraction including 3109 patients without diabetes. By incorporating data from these trials and standardising outcome definitions, the current updated meta-analysis shows that in the studied patients with chronic kidney disease or heart failure (in whom chronic kidney disease was common), SGLT2 inhibitors safely reduced the risk of kidney disease progression by 37%  and of acute kidney injury by 23% , compared with placebo, with similar reductions in patients with and without diabetes. Apparent benefits on kidney disease progression were also similar across the range of studied kidney function, and appeared unmodified by primary kidney diagnosis.Implications of all the available evidenceThis meta-analysis provides high-quality evidence to support guideline recommendations for the use of SGLT2 inhibitors as a foundational therapy to reduce the risk of kidney disease progression and acute kidney injury not only in patients with type 2 diabetes at high cardiovascular risk, but also in patients who have chronic kidney disease or heart failure, irrespective of diabetes status, primary kidney diagnosis, or level of kidney function.2),2), including 3569 (54·0%) without diabetes.Two recent placebo-controlled SGLT2 inhibitor trials have provided important new information on the effects of SGLT2 inhibitors on kidney disease progression and other outcomes in patients without diabetes. DELIVER randomly assigned 6263 patients with stable heart failure and an ejection fraction of greater than 40%, including 3109 (49·6%) patients without diabetes  with discrepancies resolved by consensus discussion . For tri2 or <10 mL/min per 1·73 m2) or death from kidney failure  from randomisation, end-stage kidney disease , a sustained low eGFR ; and other kidney disease or diagnosis or unknown combined.Analyses were done separately in patients with and without diabetes at baseline . When possible, diabetes-specific (or primary kidney diagnosis-specific) effects of treatment were obtained from Cox models reported in trial publications. When these effects were unavailable , log rel2 tests for heterogeneity were used to assess whether treatment effects differed between those with and without diabetes at recruitment, by trial population  and by primary kidney diagnosis. Heterogeneity was also assessed post hoc for the lower limb amputation outcome, comparing CANVAS with the other 12 trials combined. In forest plots, trials were ordered by their mean baseline eGFR values and effect modification by kidney function was assessed by a standard χ2 test for trend across the set of ordered results. Heterogeneity and trend p values were interpreted in the context of the multiple exploratory hypotheses being tested and the absence of individual participant-level data. For trials reporting median eGFR and its IQR, mean and SD values were estimated.Tests of between-study heterogeneity were conducted in our previous meta-analysis published in 2021, which established that effects were generally similar across its included trials (excluding DELIVER and EMPA-KIDNEY).Rates of outcome events were presented per 1000 patient-years. For the outcomes of kidney disease progression, acute kidney injury, cardiovascular death or hospitalisation for heart failure, ketoacidosis, and lower limb amputation, absolute benefits and harms of SGLT2 inhibitors versus placebo per 1000 patient-years were estimated by diabetes status and patient group. Absolute effects were estimated by applying the diabetes status-specific RRs, or their 95% CIs, to the corresponding mean event rates in the placebo arms (first event only). As in our previous report,All analyses were performed in SAS (version 9.4) and R (version 3.6.2). Our outline protocol was registered in PROSPERO on Aug 5, 2022 (CRD42022351618).The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.Our literature searches identified 15 large trials . Two lar2 in the type 2 diabetes and high atherosclerotic cardiovascular disease risk trials, 51–66 mL/min per 1·73 m2 in the heart failure trials, and 37–56 mL/min per 1·73 m2 in the chronic kidney disease trials. Median follow-up was longest for the type 2 diabetes and high atherosclerotic cardiovascular disease risk trials (2·4–4·2 years), intermediate for the chronic kidney disease trials (1·3–2·6 years), and shortest for the heart failure trials (0·8–2·2 years).Four trials included 42 568 patients with type 2 diabetes and high risk of atherosclerotic cardiovascular disease; five trials included 21 947 patients with heart failure ; and four trials included 25 898 patients with chronic kidney disease . Thus across all trials, allocation to an SGLT2 inhibitor was associated with a 15% increase in the risk of lower limb amputation . Compared with patients with diabetes, the baseline absolute risk of lower limb amputation was markedly lower among patients without diabetes. The RRs for amputations did not appear to vary depending on mean baseline eGFR . In all the trial populations studied to date, the absolute benefits of SGLT2 inhibition considerably outweighed any serious hazards.Large placebo-controlled trials of SGLT2 inhibitors have assessed patients with type 2 diabetes, chronic kidney disease, and heart failure, but no previous trial has been specifically powered to assess kidney or cardiovascular effects in patients without diabetes. Our key objective was to perform a collaborative meta-analysis incorporating all of the available evidence from all large SGLT2 inhibitor trials in populations with chronic kidney disease, heart failure, and type 2 diabetes at high cardiovascular risk, to compare the effects of SGLT2 inhibitors on the risk of kidney disease progression, acute kidney injury, and other key outcomes in patients with and without diabetes. Our analyses included information from around 90 000 trial participants, including about 16 000 people without diabetes. We defined kidney disease progression on the basis of a sustained decrease in eGFR (≥50%) from randomisation, a need to start maintenance dialysis or receive a kidney transplant, sustained low eGFR, or death from kidney failure. Our results showed that SGLT2 inhibitors reduce the risk of kidney disease progression by 37% and acute kidney injury by 23%, with similar effects in patients with and without diabetes. Patients with a wide range of kidney function have been studied in the reported trials, and despite attenuation of the effects of SGLT2 inhibitors on glycosuria with lower kidney function,The outcome of a sustained decrease in eGFR ≥50%) from randomisation has been widely used to explore effects on kidney disease progression in subanalyses of the DAPA-CKD trial.% from ra2. A total of 489 kidney disease progression outcomes accrued in those with an eGFR less than 30 mL/min per 1·73 m2 in those two trials.2 (based on grade B levels of evidence),2 or 30 mL/min per 1·73 m2.2 with continued use below this level. Several hundred participants in the chronic kidney disease trials had an eGFR below 20 mL/min per 1·73 m2 at randomisation or during follow-up , providing indirect evidence to support initiation of SGLT2 inhibitors in selected patients with an eGFR less than 20 mL/min per 1·73 m2.Based on the average risk in different trial populations, we estimated that for every 1000 patients with chronic kidney disease treated for one year with an SGLT2 inhibitor, 11 first kidney disease progression events would be prevented in patients with diabetes, and 15 would be prevented in patients without diabetes. In these patients, such treatment also appeared to result in an estimated four to five fewer acute kidney injury events in patients with and without diabetes. Individual trials have shown that kidney benefits translate into important reductions in the need for dialysis or kidney transplantation,NCT05374291), and data are insufficient to assess the effects on kidney and cardiovascular clinical outcomes for patients with other kidney diagnoses excluded from the chronic kidney disease trials  and for patients with type 1 diabetes  from around 90 000 people recruited into 13 relevant SGLT2 inhibitor clinical trials. The inclusion of new EMPA-KIDNEY and DELIVER data has more than doubled the number of outcomes previously available for kidney disease progression in patients without diabetes.diabetes .44, 60 FIn conclusion, our meta-analysis of the available large placebo-controlled SGLT2 inhibitor trials has shown that in the studied populations, SGLT2 inhibitors safely reduce the risk of kidney disease progression, acute kidney injury, cardiovascular death, and hospitalisation for heart failure in patients with chronic kidney disease or heart failure, irrespective of diabetes status. The proportional benefits were similar in patients with and without diabetes and appeared to be evident across the wide range of kidney function studied. In the trials of patients with chronic kidney disease, we also found that the proportional benefits on kidney disease progression were similar across the range of primary kidney diagnoses studied. The data from these large trials therefore support a central role for SGLT2 inhibitors as a disease-modifying therapy for chronic kidney disease, irrespective of diabetes status, primary kidney diagnosis, or level of kidney function.will.herrington@ndph.ox.ac.ukCorrespondence to: Assoc Prof William Herrington, Medical Research Council Population Health Research Unit at the University of Oxford, Nuffield Department of Population Health, Oxford OX3 7LF, UK All analysed summary data were extracted from published sources that are publicly available or were requested from individual trials (and are provided in the presented tables and figures). For the purpose of open access, the authors have applied a Creative Commons Attribution (CC BY) licence to any Author-Accepted Manuscript version arising.NS, RH, KJM, AJR, SYAN, DZ, PJ, DP, MJL, CB, JRE, and WGH report institutional grant funding from Boehringer Ingelheim and Eli Lilly for the EMPA-KIDNEY trial. NS additionally reports institutional grant funding from Novo Nordisk. RH additionally reports institutional grant funding from Novartis; and trial drug supply from Roche and Regeneron. CB additionally reports grant funding from the UK Medical Research Council, the UK National Institute for Health and Care Research Health Technology Assessment, and Health Data Research UK; and advisory roles for Merck, the National Institute for Health and Care Research Health Technology Assessment, the British Heart Foundation, and the European Society of Cardiology. WGH additionally reports funding from the UK Medical Research Council–Kidney Research UK Professor David Kerr Clinician Scientist Award. BLN reports consultancy fees and honorarium paid to his institution by AstraZeneca, Bayer, Boehringer Ingelheim, Cambridge Healthcare Research, American Diabetes Association, Renal Society of Australasia and Janssen; and advisory board membership (fees paid to institution) with AstraZeneca, Bayer, and Boehringer Ingelheim. SJH and MB are full-time employees of Boehringer Ingelheim International. SDA reports institutional grant funding from Vifor Int and Abbott Vascular; consultancy or advisory board fees from CVRx, Amgen, Respicardia, Novo Nordisk, Brahms, Novartis, Sanofi, and Cordio; and additional leadership or advisory board roles with Vifor Int, Bayer, Boehringer Ingelheim, Servier, Abbott Vascular, Impulse Dynamics, AstraZeneca, Bioventrix, Janssen, Cardior, V-Wave, Cardiac Dimensions, and Occlutech. JB reports consultancy fees and honorarium from Abbott, Adrenomed, Amgen, Applied Therapeutics, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharma, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sequana Medical, and Vifor. DZIC reports institutional grant funding from Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL-Behring, and Novo Nordisk; and consultancy fees and honorarium from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, AbbVie, Janssen, Bayer, Prometic, Bristol Myers Squibb, Maze, Gilead, CSL-Behring, Otsuka, Novartis, Youngene, Lexicon, and Novo Nordisk. JBG reports institutional grant funding from Boehringer Ingelheim-Lilly, Merck, Roche, and Sanofi and Lexicon; and consultancy fees from Boehringer Ingelheim-Lilly, Bayer, AstraZeneca, Sanofi and Lexicon, Hawthorne Effect and Omada, Pfizer, Valo, Anji, Vertex, and Novo Nordisk. C-CL is an employee of Merck Sharp & Dohme (a subsidiary of Merck & Co) and owns stock and/or stock options in Merck & Co. FRMcC reports grant funding from NIDDK, Satellite Healthcare, Advanced Medical, and Fifth Eye; and consultancy fees from GlaxoSmithKline, Advanced Medical, and Zydus Therapeutics. DKMcG reports consultancy fees from Merck & Co, Applied Therapeutics, Metavant, Sanofi, Afimmune, Lilly USA, Boehringer Ingelheim, Novo Nordisk, Bayer, GlaxoSmithKline, Lexicon, Altimmune, and Esperion; and other honorarium from Kirkland & Ellis, Pfizer, GlaxoSmithKline, Janssen, Afimmune, Sanofi, Boehringer Ingelheim, Merck & Co, AstraZeneca, Novo Nordisk, Esperion, and Lilly USA. JJVMcM reports institutional grant funding from AstraZeneca; consultancy fees from Abbott, Alkem Metabolics, Eris Lifesciences, Hikma, Lupin, Sun Pharmaceuticals, Heart.Org (Medscape Cardiology), ProAdWise Communications, Radcliffe Cardiology, Servier, and The Corpus; and fees paid to his institution for other advisory roles by Cytokinetics, Amgen, AstraZeneca, Theracos, Ionis Pharmaceuticals, DalCor, Cardurion, Novartis, GlaxoSmithKline, Bayer, KBP Biosciences, Boehringer Ingelheim, and Bristol Myers Squibb. MP reports personal fees from AbbVie, Actavis, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Moderna, Novartis, Reata, Relypsa, and Salamandra. VP reports consultancy fees, honorarium, or advisory roles supported by AbbVie, Bayer, Boehringer Ingelheim, Chinook, GlaxoSmithKline, Janssen, Pfizer, AstraZeneca, Baxter, Eli Lilly, Gilead, Merck, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Otsuka, Retrophin, Roche, Sanofi, Servier, and Vitae. MSS reports institutional grant funding from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Daiichi-Sankyo, Eisai, Intarcia, Ionis, Medicines Company, MedImmune, Merck, Novartis, Pfizer, and Quark Pharmaceuticals; and consultancy fees from Althera, Amgen, Anthos Therapeutics, AstraZeneca, Beren Therapeutics, Bristol Myers Squibb, and DalCor. SDS reports institutional grant funding from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, the National Heart, Lung, and Blood Institute , Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and consultancy fees from Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Puretech Health. MV reports grant funding or advisory board fees from Amgen, AstraZeneca, American Regent, Baxter HealthCare, Bayer, Boehringer Ingelheim, Cytokinetics, Pharmacosmos, Relypsa, Novartis, Roche Diagnostics, Lexicon Pharmaceuticals, Galmed, Occlutech, Impulse Dynamics, Sanofi, and Tricog Health; speaker fees from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics; and actively participates on clinical trial committees for studies sponsored by Galmed, Novartis, Bayer, Occlutech, and Impulse Dynamics. CW reports institutional grant funding from Boehringer Ingelheim; and consultancy fees and honorarium from Boehringer Ingelheim, AstraZeneca, Merck Sharp & Dohme, and Bayer. SDW reports institutional grant funding from Abbott, Amgen, Anthos Therapeutics, ARCA Biopharma, AstraZeneca, Bayer HealthCare Pharmaceuticals, Daiichi-Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals, Janssen Research and Development, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Roche, Siemens Healthcare Diagnostics, Softcell Medical, The Medicines Company, and Zora Biosciences; and consultancy fees from AstraZeneca, Boston Clinical Research Institute, Icon Clinical, and Novo Nordisk. FZ reports consultancy fees from Amgen, Applied therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cardior, Cereno Scientific, CEVA, Cellprothera, CVRx, Novartis, Novo Nordisk, Servier, Merck, Bristol Myers Squibb; and honorarium or other personal fees from Boehringer Ingelheim, Merck, Bayer, Vifor, Fresenius, Roche Diagnostics, Hogan and Lovells, and Acceleron. HJLH reports grant funding from AstraZeneca, Boehringer Ingelheim, Janssen, and Novo Nordisk; consultancy fees from AstraZeneca, AbbVie, Bayer, Boehringer Ingelheim, CSL Behring, Chinook, Dimerix, Eli Lilly, Gilead, Goldfinch Bio, Merck, Novartis, Novo Nordisk, Janssen, and Travere Therapeutics; and other payment or honorarium from AstraZeneca, Novo Nordisk, and Eli Lilly. MJL additionally reports institutional grant funding from Novartis and Janssen; and trial drug supply from Roche and Regeneron.


Hypothermic oxygenated machine perfusion (HOPE) was recently tested in preclinical trials in kidney transplantation (KT). Here we investigate the effects of HOPE on extended-criteria-donation (ECD) kidney allografts (KA). Fifteen ECD-KA were submitted to 152 ± 92 min of end-ischemic HOPE and were compared to a matched group undergoing conventional-cold-storage (CCS) KT (n = 30). Primary (delayed graft function-DGF) and secondary  endpoints were analyzed within 6-months follow-up. There was no difference in the development of DGF between the HOPE and CCS groups . Serum urea was lower following HOPE compared to CCS (p = 0.003), whereas the CCS group displayed lower serum creatinine and higher eGFR rates on postoperative days (POD) 7 and 14. The relative decrease of renal vascular resistance (RR) following HOPE showed a significant inverse association with serum creatinine on POD1  as well as with serum urea and eGFR. Besides, the relative RR decrease was more prominent in KA with primary function when compared to KA with DGF (p = 0.013). Here we provide clinical evidence on HOPE in ECD-KT after brain death donation. Relative RR may be a useful predictive marker for KA function. Further validation in randomized controlled trials is warranted.Trial registration: clinicaltrials.gov . Ischemia–reperfusion injury (IRI) constitutes a significant source of morbidity and mortality after KT and is frequently associated with delayed graft function (DGF) and primary non-function (PNF)3.Kidney transplantation (KT) has evolved as the mainstay of treatment for end-stage renal disease (ESRD)4. Over the last decades several strategies have been employed, aiming at reconditioning poor quality ECD-KA6. These include hypothermic- and normothermic machine perfusion (HMP and NMP), hypothermic oxygenated machine perfusion (HOPE), controlled oxygenated rewarming as well as regional perfusion protocols8. Although, numerous studies demonstrated the potential benefits of HMP in DCD and DBD (donation after brain death) kidney transplantation, the translation of this technology into routine clinical practice is still limited11.In the context of a global organ shortage, extended criteria donor (ECD) kidney allografts (KA) are more and more considered for transplantation. These ECD-allografts, however, are also associated with an increased susceptibility to ischemia–reperfusion injury and a higher probability to develop PNF and/or DGF13. Real-time detection of perfusion parameters, such as flow- and renal vascular resistance (RR), for viability- and allograft quality assessment during machine perfusion are becoming increasingly important14. Although, tissue oxygen consumption is markedly decreased at 4–10 °C, there is still a significant cellular metabolism15. The technique of HOPE evolved in parallel to HMP and, in addition to HMP, provides active perfusate oxygenation at a partial pressure of 60–100 kPa16. In preclinical trials, end-ischemic reconditioning of KA with HOPE effectively mitigated downstream macrophage-, endothelial activation and increased cellular energy household via various mitochondrial pathways17 .With the increase of ECD-KT, a proper matching of donors and recipients poses a great challenge. The kidney donor profile index (KDPI) was implemented in an attempt to objectively assess KA quality and is based on a subjective macroscopic evaluation during retrieval and before KA implantation22. The present prospective case-matched pilot study aims to provide novel clinical evidence and compares the effects of HOPE versus CCS in human ECD-DBD kidney transplantation.The beneficial effects of HOPE over non-oxygenated HMP and conventional cold storage (CCS) have been suggested in preclinical and retrospective clinical studies23.The present investigator-initiated prospective clinical study was conducted to evaluate the effects of HOPE on ECD kidney allografts in DBD kidney transplantation. Fifteen patients, who received ECD kidney allografts at the Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany (UH-RWTH) between February 2018 and September 2019 were included in this study. These 15 patients were case-matched in a ratio of 1:2 to historical cohort of patients, transplanted following CCS between 2007 and 2017  cerebrovascular cause of death; (2) history of arterial hypertension; or (3) serum creatinine greater than 1.5 mg/dL (132.6 µmol/L) at the time of collection25. The classification of the ECD allografts was based exclusively on the above-mentioned clinical criteria and no preallocation biopsy was performed to determine allograft quality.Extended criteria donor (ECD) kidney allografts were retrieved by local procurement teams within the Euro Transplant network. Following cross-clamping, allografts were removed and transported in a standardized fashion on crushed ice. Required data regarding the donor and the allograft were collected in a standardized manner and were transferred to designated case report files (CRFs). As per previous studies, ECD was defined as deceased donors ≥ 60 years oldGerman or English-speaking patients older than 18 years, suffering from end-stage-renal-disease, listed for KT, and receiving ECD-KA at the University hospital RWTH Aachen were included. Patients undergoing re-KT, pregnant patients, patients undergoing combined- or living donor transplantation procedures, receiving any investigational drug within 30 days before inclusion or unable to provide an informed consent were excluded . Written informed consent from the participants was collected in our out-patient clinic. Data were obtained using study-specific CRFs completed by the members of the study team.27. Oxygenation of the perfusate was carried out with medical-grade O2 with a pO2 of 60–80 kPa by an oxygenator included as a disposable part of the setup. Perfusion parameters were automatically registered by the device. Grafts were flushed with Belzer machine perfusion solution to wash out the residual histidine-tryptophan-ketoglutarate (HTK) solution, immediately before HOPE. Storage, management, and use of the aforementioned medical products were carried out according to the manufacturer’s guidelines.End-ischemic HOPE  was applied in the operating theater of the UH-RWTH after regular organ procurement, transport and back-table preparation via the renal artery for at least 60 min with a perfusion pressure of 25 mmHg using 1 L of recirculated perfusate  at 0–4 °C,  at 3- and 6 months post-transplantation. Perfusion parameters including flow and renal vascular resistance (RR) were analyzed as absolute values of RR (and flow) as well as relative alterations during HOPE compared to baseline.The primary endpoint of the study was delayed graft function (DGF), defined as the need for dialysis within the first 7-days post-KT. Secondary endpoints included creatinine reduction ratio day 2 (CRR2 = creatinine day 1 − creatinine day 2/creatinine day 1) and CRR5 (CRR5 = pre-transplant creatinine − creatinine day 5/pre-transplant creatinine), alterations of renal resistance- and flow during HOPE, the incidence of postoperative complications within the first 90 postoperative-days as assessed by the Clavien-Dindo classification (CD) and the comprehensive complication index (CCI)32. Matching criteria included urinary output over the last 24 h before retrieval, cold ischemic time (CIT), and the recipients' Charlson comorbidity index (CCi) before KT33. Continuous variables were compared using the Mann Whitney U test or one-way analysis of variance (ANOVA). Two-way analysis of variance (ANOVA) was used for the time-course analysis of laboratory parameters. Spearman's rank-order was used to further analyze the association of various clinical and perfusion parameters. Data were expressed as mean and standard deviation. Statistical significance was defined as p < 0.05 and the statistical analysis has been performed using SPSS Statistics v24 .Propensity score matching was used for patients with HOPE-treated KA and for those undergoing CCSNo participant who received a HOPE-treated kidney allograft, was lost to follow-up. One recipient was readmitted and died 5 months following KT due to a fulminant influenza virus infection with a well-functioning KA.Fifteen patients  transplanted after HOPE-treatment of the KA were compared to a historical cohort of 30 patients  transplanted after CCS between 2007 and 2017 (1:2 matching). Age and body mass index of both donor and recipient, as well as CIT, warm ischemia time (WIT) and recipient comorbidities assessed by the Charlson comorbidity index (CCi), were equally distributed in both groups without statistical differences. Recipient- and donor characteristics are summarized in Table Delayed graft function did not differ significantly between the groups. Eight patients in the HOPE group and 10 patients in CCS suffered from DGF (53% vs. 33% p = 0.197). While there was no PNF in the CCS group, one patient receiving a HOPE-treated KA  developed PNF.Laboratory parameters over the first postoperative days, including serum creatinine, serum urea and eGFR were comparable in both groups Table . While sConsidering the potential effects of hemodialysis on these laboratory parameters, patients with DGF were excluded from further analysis and the aforementioned differences disappeared Fig. C.The mean time on HOPE was 152 ± 92 min (range: 70–331 min). The predefined minimum of 60 min of perfusion was extended while awaiting crossmatch results when preoperative dialysis of the recipient was necessary or for other logistic reasons. The total cold preservation time was kept as short as possible (646 ± 227 min) and organ preservation was not prolonged due to HOPE logistics. Mean renal artery flow was 63 ± 18 ml/min at start of HOPE and increased to 87 ± 46 ml/min after 60 min. The maximal flow was measured immediately before disconnecting the kidney from the machine with a mean of 90 ± 47 ml/min  during the later phase of KA perfusion Fig. A.A significant inverse association was found between the relative decrease of RR during HOPE with serum creatinine on POD1 and 2  Fig. B, serum More importantly, the relative RR values following 60 min of HOPE were significantly higher in KA with primary function compared to those developing DGF  and the CCI (32 ± 22 vs. 36 ± 24 p = 0.647) were lower in the HOPE group but did not reach statistical significance . No significant difference was observed in death censored graft survival . Retention parameter 6-months after the transplantation were similar in both groups. Detailed clinical data are presented in Table The present study demonstrates the safety and feasibility of end-ischemic HOPE in human ECD kidney transplantation. While our primary endpoint—i.e. the difference in the number of transplanted patients with delayed graft function—was not reached, we show unique clinical data on the effects of HOPE in KT using ECD-DBD allografts. In this setting, a relative decrease of renal resistance during HOPE was identified as a potential parameter to better predict post-transplant kidney allograft function.34. As the susceptibility to ischemia–reperfusion injury and the risk of DGF and PNF are considerably higher in ECD allografts, pretransplant viability assessment and reconditioning of these KA is of utmost clinical importance35. The present prospective clinical trial is one of the first controlled clinical studies reporting the use of HOPE as an innovative end-ischemic machine perfusion approach in human KT using ECD-DBD kidney allografts.Kidney transplantation evolved as the mainstay of treatment for ESRD. Donor allografts that would have previously been deemed unsuitable for transplantation due to their compromised quality, have nowadays become an essential part of the organ pool and are being routinely transplanted in ECD programs36, only very limited data is available on the value of these parameters in the setting of end-ischemic HOPE and ECD-DBD kidney transplantation37. In non-oxygenated HMP lower absolute renal vascular resistance values were generally associated with better post-transplant outcome and overall KA function14. In the present study, however, we could not confirm these findings as the initial RR in KA with good primary function was significantly higher compared to the RR in those who developed DGF38. To further explore these findings, we investigated the relative changes of RR and flow parameters during HOPE. One of the most important observations was a significant association between laboratory parameters of kidney function and the relative decrease of RR during the first 60 min of HOPE followed by a consequential increase in flow. These results are in line with Bissolati et. al. describing the assessment of dynamic RR patterns in a non-oxygenated HMP setting as being more predictive of post-KT outcome compared to the traditional Karpinski’s histological analysis of pre-transplant biopsies13.Although, pre-clinical and small clinical case-series suggested the potential role of perfusion parameters  in the quality assessment of KA before transplantation14. Despite that, the authors do not recommend the use of the absolute RR as a stand-alone quality assessment tool. This recommendation is supported by a study by Sonnenday et. al. where 11 out of 14 ECD-KA were successfully transplanted after they were discarded by multiple centers due to poor perfusion parameters39. In the present HOPE-study, no KA was rejected solely based on perfusion parameters.Jochmans et. al. validated the association between RR and kidney allograft quality. In their study, the authors analyzed RR of 302 KA treated by non-oxygenated HMP after DCD or DBD and identified the absolute RR value at the end of the perfusion to be an independent risk factor for DGF and 1-year graft failureWith regards to our findings, we assume that relative alterations of RR during HOPE are more important than the absolute baseline value and that a relative RR decrease may serve as a quality indicator for post-transplantation KA function in ECD-DBD kidney transplantation. Interestingly, after 1 h of HOPE perfusion, RR and flow parameters have reached their plateau and we could not detect any further significant alterations Fig. . Based o41, the present trial did not show significant differences in the development of DGF in KA undergoing HOPE treatment compared to KA treated with CCS (p = 0.197). Similarly, a recent report by Summers et. al. could not show a clinical benefit of non-oxygenated HMP in kidney transplantation. The authors used cold pulsatile machine perfusion in a British cohort of 51 KA after DCD and transplanted the kidney pair of the same donor after CCS. They could neither show significant differences in the incidence of DGF nor in the incidence of acute cellular rejection42.In contrast to the results of recent cohort studies on NMP and HMP44. This circumstance may have led to a higher rate of dialysis compared to our historical cohort. Clinical outcomes, such as complications, DGF, and death censored graft survival were not superior in the HOPE group compared to CCS. While serum urea showed significantly favorable alterations in the HOPE group on POD 1, it was superior in CCS during the subsequent days.The findings of the present study should be interpreted in light of potential limitations. First, the most important and obvious limitation of our study is the single-center, non-randomized pilot study design which resulted in a limited power of our statistical analysis when interpreting between-group differences in terms of clinical outcomes such as DGF and complications. Therefore, no significant differences have been found in terms of any of the clinically relevant primary and secondary outcome measures. These non-superior results limit the value of any definitive conclusion of our study about the use of HOPE as an alternative method to CCS. Second, we acknowledge that DGF may be an inadequate primary endpoint, especially in case-matched study design. Thresholds for dialysis initiation can differ between clinicans and may have changed over the yearsIn conclusion, the present study provides novel clinical data on the use of HOPE in ECD-DBD kidney transplantation. The relative decrease of renal vascular resistance as a novel marker to better predict post-transplant allograft function may be an important parameter for real-time viability assessment of HOPE-treated kidney allografts. Further validation in randomized controlled clinical trials is warranted.


This study describes a PPP, a new pleural phenomenon related to the cyclic changes in the heart chambers volume. Although the importance of PPP remains largely unknown, we hypothesize that it could be related to lung atelectasis or lower lung and visceral pleura compliance.Pleural manometry enables the assessment of physiological abnormalities of lung mechanics associated with pleural effusion. Applying pleural manometry, we found small pleural pressure curve oscillations resembling the pulse tracing line. The aim of our study was to characterize the oscillations of pleural pressure curve  and to establish their origin and potential significance. This was an observational cross-sectional study in adult patients with pleural effusion who underwent thoracentesis with pleural manometry. The pleural pressure curves recorded prior to and during fluid withdrawal were analyzed. The presence of PPP was assessed in relation to the withdrawn pleural fluid volume, lung expandability, vital and echocardiographic parameters, and pulmonary function testing. A dedicated device was developed to compare the PPP to the pulse rate. Fifty-four patients (32 women) median age 66.5 (IQR 58.5–78.7) years were included. Well visible and poorly visible pressure waves were detected in 48% and 35% of the patients, respectively. The frequency of PPP was fully concordant with the pulse rate and the peaks of the oscillations reflected the period of heart diastole. PPP was more visible in patients with a slower respiratory rate ( The pulse is a fundamental parameter of physical examination. The first device for measuring the pulse rate was developed by a Venetian physician, Santorio Santori, in 1626 , and latpl) during thoracentesis. Thus, pleural manometry has been increasingly used to assess local abnormalities of lung mechanics in patients with pleural effusion (PE) [The ability of the lung to re-expand after pleural fluid withdrawal can be reliably assessed by measuring pleural pressure (Pion (PE) ,9,10. Whion (PE) ,13,14,15As these issues have not been evaluated previously, the general objective of the study was to evaluate a new physiological measurement in the pleural space, i.e., the PPP. The specific aims were as follows: (1) To assess how frequently and in which phase of the respiratory cycle the PPP can be observed in patients undergoing therapeutic thoracentesis; (2) to evaluate whether the PPP is strictly related to heart rhythm and changing volumes of heart chambers; and (3) to evaluate conditions associated with the presence of PPP, including cardiac and pulmonary function, pleural fluid volume, and lung expandability.pl measurements during pleural fluid withdrawal. The study conformed to the standards set by the Declaration of Helsinki. All patients signed an informed consent to participate in the study.This prospective, single center, observational, cross-sectional study was part of a larger research project supported by the National Science Centre, Poland (grant no. 2012/05/B/NZ5/01343). The study protocol was approved by the Institutional Review Board (KB 105/2012) and registered at ClinicalTrials.gov (NCT02192138). Consecutive patients with pleural effusion who had been referred to the Department of Internal Medicine, Pulmonary Diseases and Allergy for therapeutic thoracentesis (TT) were included. The patients underwent pre- and post-thoracentesis pulmonary function testing and echocardiography, as well as PAdult patients with PE occupying at least 1/3 of the ipsilateral hemithorax (in posteroanterior chest radiograph) were enrolled. Other inclusion criteria included no contraindications for TT and general health condition enabling the prolonged procedure of therapeutic thoracentesis. Consecutive patients were included to avoid selection bias.Echocardiography was performed by an experienced cardiologist at three time points: one hour prior to, and 3 and 24 h after thoracentesis. Patients were examined in the left lateral and supine position with a Vivid E9 cardiovascular ultrasound system  equipped with a M5S transducer (1.5–4.6 mHz). Two-dimensional images and Doppler recordings were acquired and stored on a dedicated workstation  and analyzed offline. Patients with poor image quality or arrhythmia, at the time of the echocardiography, were excluded from echocardiographic evaluation. Cardiac chamber dimensions and selected parameters of systolic and diastolic function of the left and right ventricles were assessed. The left ventricular end diastolic dimension (LVEDD) was measured in the parasternal long-axis view, whereas the right ventricular end-diastolic dimension (RVEDD) was measured in apical four-chamber view. Because of the suboptimal visualization of the endocardium, the left ventricular ejection fraction measured by using biplane Simpson method was not assessed performed. The left ventricular systolic function was assessed using LV fractional shortening (LVFS) , mitral annulus plane systolic excursion (MAPSE), and the mean of the lateral and medial mitral annulus systolic velocity (LV TDI S) using the tissue Doppler method . The left ventricular diastolic function was assessed using the ratio of the early to late pulse wave Doppler velocities of the mitral inflow (E/A) and tissue Doppler early diastolic velocities of the lateral (E’ lat), medial (E’med) part of the mitral annulus, and their mean value (E’ mean). The E/E’ ratio  was calculated as a measure of the left ventricular diastolic filling pressure. The right ventricular systolic function was measured using the tricuspid annulus plane systolic excursion (TAPSE). The right ventricular diastolic function was measured using the tricuspid annulus early diastolic velocity (RV E’). The results of Doppler recordings were averaged from 5 consecutive cardiac cycles.CO)  one day before, 3, and 24 h after pleural fluid withdrawal. The measurements were performed in accordance with American Thoracic Society and European Respiratory Society recommendations [All patients underwent lung function testing including spirometry, body plethysmography, and diffusion capacity for carbon monoxide  was inserted into the pleural cavity in the dependent region. The procedure of pleural fluid withdrawal and pleural manometry was performed as described elsewhere ,21. Briepl) curve oscillations were associated with pulse rate. After the placement of the pulsometer on the index finger, the rhythmical changes of blood volume in finger vessels were detected by illuminating the skin with the light from a light-emitting diode (LED) (A simple photoplethysmographic device (pulse recorder) was built to detect and register the pulse rate during the procedure and to assess whether pleural pressure (Pde (LED) . The amopl with regard to the presence of characteristic waves which were classified as visible (waves +), undetectable (waves −), and poorly visible (waves +/−)  independently evaluated the recorded traces of Pves +/−) A–D. Statpl recording, just before the termination of the procedure . The presence or the absence of waves in the first measurement point was assessed in relation to side and volume of PE, ability of lung to re-expand expressed as pleural elastance, vital signs , hemodynamic parameters measured in echocardiography, and pulmonary function. Variations of waves in subsequent measurement points were also evaluated.After TT completion, the records of pleural pressure curves were analyzed retrospectively at the following three measurement points that reflected the relative volume of withdrawn pleural fluid: (1) directly after pleural catheter insertion ; (2) after removal of 50% of total withdrawn pleural fluid volume; and (3) during the last Pp values were 2-tailed and p < 0.05 was considered statistically significant.Statistical analysis was performed using Statistica 13.1  and MedCalc Statistical Software version 13.2.2 . The Kolmogorov–Smirnov test was applied to determine data distribution. Since the majority of data showed non-normal distribution, data were presented as median and interquartile ranges . The differences among continuous variables in independent groups were tested using the nonparametric Kruskal–Wallis test and Dunn’s post hoc test. The respective differences in two independent groups were tested using the nonparametric Mann–Whitney U test. The Chi-square test was used to test the differences in terms of categorical variables. Correlations were assessed using Spearman’s rank correlation coefficient. All n = 44), nonspecific pleuritis (n = 4), tuberculous pleuritis (n = 1), heart failure (n = 1), and other causes (n = 4). The median volume of withdrawn pleural fluid in the entire group was 1800 mL, median baseline Ppl and closing Ppl were 3.4 (IQR −0.8 to 7.3) and −14.1 (IQR −18.8 to −7.1) cmH2O, respectively. Thus, the median pleural elastance calculated for the entire group was 8.5 (IQR 5.6 to 16.7) cmH2O/L.Sixty-two patients treated between September 2015 and November 2018 met the inclusion criteria and underwent TT with pleural manometry. Full records of pleural pressure curve were available for 54 patients. These patients were included in the final analysis. The study group included 32 women and 22 men, median age 66.5 years (IQR 58.5 to 78.7), right and left-sided PE in 28 and 26 patients, respectively. The pre-thoracentesis chest radiograph showed pleural effusion occupying more than one-third, but less than two-thirds, of the entire hemithorax in 19 patients; more than two-thirds, but not the entire hemithorax, in 22 patients; and the entire hemithorax in the remaining 13 subjects. The origins of pleural effusion were as follows: malignant pleural effusion . When the HR/RR ratio (ratio of HR to RR) was calculated and compared between the three subgroups, significant differences were found with the highest HR/RR ratio in the well visible PPP group . It could suggest that the higher the ratio (due to higher HR or lower RR), the PPP could be better visible. Although both median systolic and mean blood pressure, as well as heart rate (HR), were higher in groups with well visible and poorly visible waves as compared with the subgroup with undetectable PPP, the differences did not reach statistical significance . In contData on differences in echocardiography, spirometry, body plethysmography, and arterial blood gases between patients with well visible, poorly visible, and undetectable pulsation waves are shown in p = 0.037 and p = 0.079, respectively). With the exception of the lateral and medial mitral annulus systolic velocity assessed using tissue Doppler method (LV TDI S lat and LV TDI S med), there were no significant differences in echocardiographic parameters characterizing LV systolic function. Similarly, only one parameter reflecting LV diastolic function (LV TDI E’ med) was significantly higher in patients with visible waves (p = 0.008). When echocardiographic parameters were compared in redefined groups (well visible vs. poorly visible and undetectable waves), significant differences in parameters assessing left and RV systolic and LV diastolic function were even more pronounced  were found in the subgroup with well visible PPP  and partial pressure of oxygen (PaO2) between patients with well visible, poorly, and invisible oscillations were demonstrated , as compared with waves +/− and waves groups. There were no significant relationships between the presence of curve pulsation and pulmonary function and echocardiographic parameters evaluated after the procedure were noted.The presence of well visible waves in the last measurement point was related to significantly lower RR both prior and after procedure termination (pl waves are perfectly matched with the points on the ECG curve (directly after the T wave) which correspond to the smallest ventricular volumes during the cardiac cycle. Therefore, we believe these pleural pressure oscillations are caused by the cyclic changes in the volume of heart chambers during their systolic and diastolic phases. Because the small cyclic changes in Ppl are associated with heart hemodynamics, we proposed the term “pleural pressure pulse” to describe this phenomenon. In our opinion, this term is suitable because it suggests not only a causal relationship between the pleural pressure oscillations and the mechanic heart function but also indicates the same frequency of the pleural pressure oscillations and the pulse.Our study shows that pleural manometry performed in patients with PE can reveal low frequency pleural pressure oscillations associated with breathing and also high frequency and low amplitude oscillations which are related to heart hemodynamics. Furthermore, we demonstrated that the nadirs of PWe showed that the presence of the PPP can be registered in more than 80% of patients, including both patients with well visible and poorly visible waves . To the best of our knowledge, this is the first study which has demonstrated the presence of the PPP and analyzed its origin. It must be admitted, however, that PPP could have been seen on the pleural pressure curves presented in two earlier publications. These include a graph presented in the paper by Boshuizen et al. , in whicpl trace registration during slow breathing and breath hold.We believe that one of the most important findings of our study is the observation on the significant differences in the RR and the heart to respiratory rate ratio between the above groups. On the basis of the significantly lower RR and the significantly higher HR/RR ratio in patients with well visible PPP, it could be hypothesized that the PPP would be visible in all patients with adequately low RR and high HR/RR ratio. Thus, the difference between HR and RR would by a prerequisite for the visibility of PPP. This hypothesis should be verified in future studies which would apply PThe PPP analysis requires a sensitive pleural manometer enabling measurement and registration of instantaneous pleural pressure. Therefore, it could have not been done with a simple water manometer or an overdamped water manometer used in earlier studies . This shPossible clinical applications of the PPP registration and analysis still needs to be established. We cannot exclude that the PPP could prove useful in clinical practice. This supposition is based on somewhat similar observations of the “lung pulse”. This phenomenon was first described by Lichtenstein et al.  as pulsapl and a higher elastance was found in patients with undetectable PPP, suggesting worse lung expandability. Hence, even in the absence of statistical significance, it could be hypothesized that the lack of PPP during breath holding in the baseline Ppl measurements suggest significant lung atelectasis and changes in the visceral pleura reflecting its lower compliance and worse expandability. The above hypothesis seems to be concordant with observations of Salamonsen [Searching for potential clinical applications of the PPP, we performed an extensive analysis of the relationships between the presence or absence of the PPP and numerous clinical parameters, including echocardiographic and pulmonary function data. Having no previous information on the PPP, we classified patients according to the visibility of PPP and analyzed the differences among patients with well visible, poorly visible, and undetectable PPP. Although no significant differences were demonstrated between patients with and without visible PPP in terms of the side of pleural effusion or the amount of pleural fluid, a trend towards a higher volume of withdrawn fluid in patients with well visible and poorly visible waves was observed. This could suggest that a more atelectatic lung is a better conducting medium. Moreover, a trend to a lower median initial Plamonsen  and Leemlamonsen , who repNevertheless, we found significant differences between the patients with well visible waves and the remaining patients in terms of parameters reflecting LV and RV systolic and LV diastolic function. It can be speculated that higher median LVEDD and RVEDD could be associated with a greater stretch of myocardium and consequently, with an increase in the stroke volume . Better We are aware of several limitations of this study. First, the total number of patients was relatively small. Due to dyspnea, fatigue, and poor performance status of some patients, high quality echocardiography and pulmonary function data were not available in 20% to almost 40% of patients initially enrolled in the study. Thus, a small number of patients in the studied groups could be responsible for the lack of statistical power in some analyses. Second, the results presented in this paper come from the retrospective analysis of data collected in the frame of a larger project designed to evaluate pathophysiology of large volume thoracentesis. Hence, we have no data on the appearance of the PPP in patients with small volume pleural effusion and only minor lung atelectasis. Third, our classification into the well visible, poorly visible, and undetectable PPP is subjective and observer dependent. However, in this very first study on the PPP, we had no other more explicit tools and methods to classify our findings. To make our classification more reliable, the PPP analysis was performed by two independent observers who further consulted their findings to reach an agreement. Fourth, as already mentioned, we have no data on the PPP visibility during the voluntary breath hold which could probably shed more light on this new phenomenon. This issue is certainly worth considering in the context of the new prospective studies.pl measurement during the large volume thoracentesis suggests significant lung atelectasis or lower lung/visceral pleura compliance and worse lung expandability.To conclude, our study demonstrates a new phenomenon termed pleural pressure pulse. The PPP represents low amplitude, cyclic pleural pressure alterations related to changes in the volume of the heart chambers. The relationships between the visibility of the PPP and a low respiratory rate, as well as the high heart to respiratory rate ratio, suggest that the detectability of the PPP largely depends on the above variables. Although the importance of the PPP monitoring remains largely unknown, we hypothesize that its appearance in the baseline P


Sclerostin is a hormone contributing to the bone-vascular wall cross talk and has been implicated in cardiovascular events and mortality in patients with chronic kidney disease (CKD). We analyzed the relationship between sclerostin and mortality in renal transplant recipients.600 stable renal transplant recipients  were followed for all-cause mortality for 3 years. Blood and urine samples for analysis and clinical data were collected at study entry. We performed Kaplan–Meier survival analysis and Cox regression models considering confounding factors such as age, eGFR, cold ischemia time, HbA1c, phosphate, calcium, and albumin. Optimal cut-off values for the Cox regression model were calculated based on ROC analysis.n = 65; sclerostin 57.31 ± 30.28 pmol/L) had higher plasma sclerostin levels than survivors  (p = 0.0036). Kaplan–Meier curve showed that baseline plasma sclerostin concentrations were associated with all-cause mortality in stable kidney transplant recipients . After multiple Cox regression analysis, plasma levels of sclerostin remained an independent predictor of all-cause mortality .Sixty-five patients died during the observation period. Nonsurvivors  contains supplementary material, which is available to authorized users. Kidney transplant recipients are a subset of patients with chronic kidney disease (CKD). And kidney transplantation is the treatment of choice for end-stage renal disease .Chronic kidney disease-mineral bone disease (CKD-MBD) is associated with increased morbidity and mortality among patients undergoing hemodialysis. Several markers of bone formation and turnover, including fibroblast growth factor 23 (FGF-23), bone-specific alkaline phosphatase and parathyroid hormone (PTH), have been shown to be associated with increased mortality . VasculaSclerostin (SOST) protein is a 213 amino acid protein transcribed from the SOST gene , 7. It iTherefore, we analyzed, whether sclerostin is a risk factor of all-cause mortality in kidney transplant recipients. To control for possible confounding, we performed multivariate Cox regression analyses considering known confounding factors –14.We analyzed a kidney transplant patient cohort as described recently, for details, see . Six hunDemographic data for recipients and donors  were extracted from hospital records and the Euro-transplant records of the patients. Albumin, creatinine, cholesterol, HbA1c, 1,25(OH)2D, calcium, phosphate, iPTH, fasting blood glucose and urinary protein were measured by standardized methods in the central clinical laboratories of Charité. All the used assays were subject to regular quality control. Sclerostin concentration was analyzed with the use of a commercial ELISA , according to the manufacturer’s instructions.We analyzed blood levels of calcium, phosphate, HbA1c, eGFR, albumin, patient age and cold ischemia time using the area under the receiver operating characteristic (ROC) curve to obtain optimal cut-off values for these parameters . When thT test. Survival rates were tested for significant differences with the log-rank test using the Kaplan–Meier method. Univariate Cox proportional hazards modeling was performed to investigate the relationship between clinical measurements and mortality based on previously identified researches [Plasma levels of sclerostin in survivors and nonsurvivors were compared using independent searches –14. To c2. Meantime since transplantation was 89.85 ± 75.32 months, and time on dialysis before renal transplantation was 49.51 ± 35.23 months. Mean plasma sclerostin concentration was 48.58 ± 25.67 pmol/L. The concentration of sclerostin was significantly (p = 0.0003) higher in male (51.58 ± 25.16 pmol/L) compared to female (43.85 ± 25.79 pmol/L) patients. Sclerostin concentrations were slightly higher in patients treated with Cyclosporin A versus Tacrolimus treated patients . Sixty-five patients died during the observation period.A total of 600 stable renal transplant recipients, 367 males and 233 females, aged 20–87 years, were included in this study. Patient demographics and relevant clinical and biochemical parameters are summarized in Table The underlying renal diseases are as follows: 474 of the 600 patients had primary renal diseases. Fifty-eight patients had secondary renal disease. In 68 patients, the underlying renal disease was unknown. More than 60 percent of patients had the primary glomerular disease, polycystic kidney disease and interstitial kidney disease. The underlying kidney diseases are described in Supplementary Table p = 0.0036). Sclerostin concentrations above 48.58 pmol/L were significantly associated with all-cause mortality in renal transplant patients .Nonsurvivors had higher plasma levels of sclerostin than survivors .We built three multivariate Cox regression models by gradually adding confounding factors, which were parameters that were statistically significant predictors in the univariate analysis Table . These tSince some studies –19 reporSubgroup analysis Fig.  revealedThis study demonstrated that elevated baseline plasma sclerostin is an independent risk factor of all-cause mortality in patients after kidney transplantation.Patient demographics and relevant clinical and biochemical parameters indicate that our study population was representative for a typical European post-transplantation cohort. The findings of our study are thus of general applicability , 21.In the non-transplanted CKD population, conflicting results concerning sclerostin-associated mortality risk were described –25. Our When analyzing male and female patients separately Fig. , we founSeveral other studies in dialysis cohorts analyzed the association of sclerostin with all-cause and cardiovascular mortality. These studies , 28–33, Fifty to 60 percent of deaths among kidney transplant recipients are directly attributable to cardiovascular disease, which has a reported incidence of approximately 1 per 100 person-years at risk , 35. TheIt was suggested that sclerostin—as an inhibitor of Wnt signaling pathways might play a role in the development of aortic valve and vascular calcifications. A study conducted by Hampson et al.  supportsOur study demonstrated that sclerostin is an independent risk factor of all-cause mortality in kidney transplant recipients. Preclinical studies—see above—suggest that an inhibition of the transmission of the Wnt signaling pathway by inhibiting LRP5/6 co-receptors, resulting in increased vascular calcification and cardiovascular events. Whether this pathway might explain our findings needs to be explored in more detail.A humanize monoclonal antibody targeting sclerostin is currently tested in clinical trials, Blosozumab . It has been studied with regards to the treatment of osteoporosis in postmenopausal women with low bone density . In addiSeveral limitations should be taken into consideration when the results of this study are interpreted. Although we analyzed 600 patients, the sample size may be a limitation in our study, which might affect the results of the Cox regression analysis of multiple risk factors. We only have valid data on all-cause mortality. Data on specific reasons of death, such as cardiovascular mortality and cardiovascular events, however, were not available. Moreover, our study was a single-center study, thus center-specific effects could not be excluded. Thus, confirmation in an independent cohort is important.Taken together, our study is the first to investigate the potential role of sclerostin in patients after kidney transplantation. Our data suggest that elevated baseline plasma sclerostin is an independent risk factor for all-cause mortality in patients after kidney transplantation. This is of particular clinical impact, since anti-sclerostin antibodies are currently under clinical investigation.Supplementary file1 (DOCX 72 kb)Below is the link to the electronic supplementary material.