Diabetic retinopathy and kidney disease share underlying mechanisms of microvascular damage and are often comorbid in people with diabetes. We evaluated whether there is a relationship between retinal capillary perfusion as measured by swept-source optical coherence tomography angiography and estimated glomerular filtration rate (eGFR) and albuminuria in patients with diabetes and chronic kidney disease (CKD).  A cross-sectional pilot study was conducted at the University of Washington among a subset of participants with diabetes and CKD participating in a larger cohort study. Participants were excluded if they were known to have kidney disease from conditions other than diabetes. Ten participants (11 eyes) were included. Retinal nonperfusion (RNP) and vessel density (VD) were measured by swept-source optical coherence tomography angiography in 30° and 60° field of view (FOV) regions centered at the fovea. Correlations of RNP and VD with eGFR and albuminuria were analyzed. 2, and urine albumin-to-creatinine ratio of 162 mg/g. Mean (SD) RNP was 6.6% (4.2%) and 16.9% (7.7%) in 30° and 60° FOV regions, respectively. eGFR was negatively correlated to RNP in both the 30° and 60° FOV regions , and correlations were stronger among a subset of 7 participants with evidence of diabetic retinopathy on exam and fundus photos. The estimated GFR was not significantly correlated with vessel density. Urine albumin-to-creatinine ratio was not significantly correlated with RNP or VD.  Participants had a mean age of 72 years, hemoglobin A1c of 8.1%, eGFR of 45 mL/min/1.73 m Our proof-of-concept study showed that lower eGFR was significantly correlated with retinal nonperfusion in participants with diabetes and CKD. Advanced retinal imaging may enhance the noninvasive evaluation of kidney function in diabetes. Diabetes mellitus is a worldwide epidemic expected to affect 700 million people by the year 2045 . DiabetiDiabetes is thought to damage the microvasculature of the retina and kidney in similar ways. While the exact molecular mechanisms of how hyperglycemia causes vascular damage are not completely understood, experimental evidence has supported a contribution from the polyol pathway, increased inflammatory oxidative stress, increased advanced glycation end products, and activation of protein kinase C in diabetic kidney disease and diabetic retinopathy . In the Chronic kidney disease (CKD) is usually diagnosed by abnormalities in functional markers while diabetic retinopathy is typically diagnosed by direct observation with ophthalmoscopy with or without fundus photographs. Until recently, there was no way to quantitatively measure the degree of ischemia or nonperfusion of the retina, so direct correlations with kidney function could be made. We now have the ability to quantitatively collect data about the retinal microvasculature using swept-source optical coherence tomography angiography (SS-OCTA), a noninvasive retinal imaging method which allows for three-dimensional examination of blood flow and vascular abnormalities at multiple layers of the retina, resolving capillary structure with a lateral resolution of 10–20 microns . Unlike If strong relationships exist between the degree of microvascular complications in the eyes and kidney, OCTA may prove to be a useful tool in identifying features of CKD among people with diabetes.We conducted a cross-sectional study examining the associations of retinal capillary nonperfusion (RNP) and vessel density (VD) with estimated glomerular filtration rate (eGFR) and albuminuria from 10 participants with type 2 diabetes (T2D) and CKD. Participants were recruited from the Continuous Glucose Monitoring to Assess Glycemia in Chronic Kidney Disease (CANDY) study, a prospective cohort study comparing patterns of hypoglycemia in individuals with T2D with and without CKD . ParticiThe CANDY study included adults with a clinical diagnosis of T2D who were being treated with insulin or a sulfonylurea . IndividN = 5) or kidney pathology other than diabetic kidney disease (N = 2). Specifically, one patient was excluded due to CKD related to heart transplantation and calcineurin inhibitor toxicity, and one patient was excluded due to CKD resulting from familial focal segmental glomerulosclerosis. Ten participants were included in the study. Of the 10 people included in the study, one participant had both eyes analyzed and nine participants had 1 eye analyzed due to poor quality scans of the fellow eye or limited patient tolerance to complete scanning of the fellow eye. Thus, eleven total eyes were included in the study.Of the patients enrolled in the CANDY study, twenty-five patients with CKD were contacted and seventeen patients presented to the clinic for imaging with SS-OCTA. Seven patients were excluded due to poor quality scans  blood flow images. In the 12 mm x 12 mm scan, 500 A-lines produced one B-scan, and B-scans were acquired at 500 different spatial locations and repeated two times at each location. This scanning protocol resulted in a uniform spacing of 24 μm between pixels in the final en face projected OCTA images. The output datasets were processed using the complex optical microangiography (OMAG) algorithm [SS-OCTA was performed using a 100 kHz Plex Elite 9000 device , which uses a central wavelength of 1060 nm, a bandwidth of 100 nm, a 100 kHz A-line rate, and an A-scan depth of 3 mm in tissue. The axial resolution was approximately 5 lgorithm .en face images. The en face images were montaged through an automated process to an approximately 20 mm × 20 mm image as shown in Base scans of 12 mm x 12 mm were obtained in this study. To achieve a wide FOV image, four base scans were performed in each retinal quadrant as labeled in 2 where capillaries were not detected. The value of 0.03 mm2 was chosen based on similar analyses of 10 normal eyes from 10 volunteers and is similar to the value found in physiologic studies investigating retinal intercapillary distance [Image processing was carried out to prepare the scan for RNP and VD analyses. A Hessian filter was applied to the montaged blood flow image to distinguish the vessel patterns. Binarization and a reversion process were performed on the output image to obtain the nonvessel map as shown in distance .RNP and VD values were obtained for each eye within retinal sectors encompassing 30° and 60° centered at the fovea . RNP wasSerum creatinine, urine albumin, and urine creatinine measurements were obtained from two study visits, which occurred approximately 3 weeks apart . EstimatDemographic  and medical history data were obtained through self-reporting (13). Hemoglobin A1c was measured from whole blood samples collected over two study visits using high-performance liquid chromatography, and the mean of these values was calculated. Diabetic retinopathy status was determined by retina specialists based on the Early Treatment Diabetic Retinopathy Study definition, which uses features seen on the exam including microaneurysms and retinal hemorrhages, venous beading, intraretinal microvascular abnormalities, and neovascular vessel growth . The diat-test was used for continuous variables, and Pearson's chi-squared test or Fisher's exact test was used for categorical variables. When both eyes were included, the generalized linear mixed model approach was adapted to adjust the correlated observations. The comparison of vessel density and nonperfusion density between the participants with DR and DWR was analyzed using the generalized linear mixed model method. Each individual eye was considered a separate data point. For correlation analyses, linear regression and linear fitting were performed. Analyses were conducted with IBM SPSS Statistics for Windows, version 26.0 . p values of less than 0.05 were considered statistically significant.To compare the demographic data of the DR group and diabetes without retinopathy (DWR) group, the independent Eleven eyes from 10 participants were included in the study. The mean age of the ten included participants was 72 (6.9) years, the mean urine ACR was 162.1, the mean eGFR was 45.4 (SD 11.0), and the mean HgBA1c was 8.1 (SD 1.3) . Sixty pOut of the 11 eyes, 4 eyes were left eyes and 7 eyes were right eyes. Eight eyes were pseudophakic and 3 eyes were phakic. Six eyes were characterized as mild DR, 1 eye as severe DR, and 4 eyes as DWR (40%). There were no cases of macular edema, and no eyes underwent photocoagulation. For all participants regardless of DR status, mean 30° RNP was 6.58% (SD 4.2%), mean 60° RNP was 16.9% (SD 7.71%), mean 30° VD was 45.12% (SD 1.81%), and mean 60° VD was 41.54% (SD 3.7%) . When seR = −0.686, p=0.004) was statistically significant, and the association between eGFR and 60° RNP approached statistical significance . There was no significant association between eGFR and VD. When separated by the DR status, eGFR in DR participants showed a statistically significant correlation with 30° VD , with 30° RNP , and with 60° RNP . There was no significant association between urine ACR and either VD or RNP.As seen in In this study, we evaluated whether there is a relationship between retinal capillary perfusion as measured by OCTA and kidney function parameters including eGFR and urine ACR in people with diabetes and CKD. When all eyes meeting study criteria were analyzed collectively, a strong correlation was found between eGFR and RNP in the 30° FOV, with the same analysis in the 60° FOV approaching statistical significance. The correlation between RNP and eGFR was found to be stronger and statistically significant in both the 30° and 60° analyses when excluding eyes that did not show clinical signs of DR. Our study suggests that decreased perfusion of the retinal microvasculature in patients with T2DM is associated with CKD as measured by eGFR, and this association was stronger in eyes with DR.Our study is a pilot for further large-scale study, which may provide better insights on the utility of OCTA to evaluate parameters of diabetic kidney disease. Nonetheless, our small-scale study found strong correlations between retinopathy and kidney disease and raised important issues for consideration in the future application of these methods. First, the correlation of RNP and eGFR was much stronger when the subset of eyes without clinical DR was excluded. There are multiple possible explanations for this finding. The number of included eyes without DR in the study was 4, which is likely too small to identify a meaningful correlation. Perhaps with larger sample size, a meaningful correlation could be found even in eyes without DR. Another possible explanation is that RNP needs to reach a certain severity threshold in order to correlate with eGFR, which may not be achieved until clinical signs of DR are apparent. Finally, diabetic kidney disease likely represents a heterogeneous group of disorders, with perhaps only some mechanisms correlating with eye disease. Since DR participants had low urine ACR, they may have had different contributing mechanisms to their kidney disease, therefore weakening the relationship. Examining eyes with DR using OCTA in conjunction with patients undergoing kidney biopsy may be one avenue of future research to investigate this possibility.A second insight provided by our study is that OCTA parameters could potentially be used to identify patients whose kidney disease may be from multiple causes. One participant in our study who met the study criteria was a clear outlier who had no signs of clinical DR, had minimal RNP, but had the second-lowest eGFR of all included participants (see asterisks in The third insight provided by our study was the lack of correlation between urine ACR and either retinal capillary parameter. Since higher urine ACR is related to greater kidney damage, we expected higher associated retinal capillary loss. The reason for the absence of correlation is unclear but may be due to a small sample size. A larger-scale study may ultimately reveal a correlation or provide additional insights.In contrast to our study, Cao et al. reported that average vessel density in the superficial capillary plexus and deep capillary plexus measured with OCT-A is not associated with creatinine in DM2 patients . PerhapsOur study reaffirms prior reports of a correlation existing between the clinical assessment of diabetic retinopathy and renal dysfunction , 27. PriOCTA has already proven to be a useful modality in the evaluation of DR in the field of ophthalmology, and our study suggests that it may also find utility in evaluating for diabetic kidney dysfunction and assessing underlying CKD mechanisms. Due to the invasive nature and associated risks of renal biopsy, alternative modalities for assessing renal function that can predict the degree of diabetic kidney damage or detect alternative contributions to kidney dysfunction should be explored. It is possible that data obtained from OCTA could be paired with traditional kidney parameters to better understand the pathophysiology of a particular patient's renal dysfunction or better inform the decision to proceed with renal biopsy, such as in the outlier participant highlighted in This pilot study has several limitations. The main limitation is that the study was a single-center study with small sample size. Our center's proficiency in obtaining high-quality OCTA images has improved since the time of this study. Another limitation is that our study was cross-sectional, and we were unable to look at disease progression over time. The cross-sectional design makes it impossible to determine the characteristics that account for the observed correlations, whether they are risk factors for both retina and kidney disease or confounders for the observed correlations. Lastly, we did not have any kidney tissue available to confirm whether the low eGFRs were from diabetes versus other kidney pathologies. Large-scale, prospective study including patients undergoing renal biopsy as part of their routine care would account for these limitations.in vivo, which may serve as an important avenue to noninvasively collect data on the burden of systemic microvascular disease from diabetes. Our pilot study suggests that retinal vascular loss as detected on OCTA correlates with eGFR and could inform our understanding of diabetic kidney disease and its heterogeneous mechanisms. A further large-scale study is warranted to elucidate the clinical utility of these methods in the field of nephrology.In conclusion, OCTA is an imaging modality with the ability to resolve retinal capillary alterations in diabetic eyes with a lateral resolution of 24 microns when using our methodology. The collected images approach the scale where they begin to resemble histology


CYP2C9*2 and/or *3 alleles were associated with higher TTR,while amiodarone, acetaminophen and verapamil co-medication were associated withlower TTR. Our data suggest that TTR is influenced by co-medication and geneticfactors. Thus, individuals in use of glibenclamide may need a more carefulmonitoring and genetic testing  mayimprove the anticoagulation management. In addition, in order to reach andmaintain the INR in the target for a longer period, it is better to discuss doseadjustment in office instead of by telephone assessment. Other studies areneeded to confirm these results and to find more variables that could contributeto this important parameter.Warfarin is an oral anticoagulant prescribed to prevent and treat thromboembolicdisorders. It has a narrow therapeutic window and must have its effectcontrolled. Prothrombin test, expressed in INR value, is used for dosemanagement. Time in therapeutic range (TTR) is an important outcome of qualitycontrol of anticoagulation therapy and is influenced by several factors. The aimof this study was to identify genetic, demographic, and clinical factors thatcan potentially influence TTR. In total,422 patients using warfarin wereinvestigated. Glibenclamide co-medication and presence of Oral anticoagulants are extensively used in clinical practice to prevent and treatthromboembolic disorders .CoumariPoor coagulation control is associated with greater risk of bleeding andthromboembolic events and environmental factors associated with TTR.In order to guarantee a safe and effective treatment with warfarin, the knowledge offactors related to TTR are important in addition to algorithms for drug adjustment.Therefore, the aim of this study was to investigate the association between genetic according to the manufacturer’srecommended protocols.Genetic material was extracted from whole blood using the PureLink Genomic DNAPurification Kit according to the manufacturer’sinstructions. Prothrombin time was measured at the hospitals CentralLaboratories. p>0.05 wereremoved one at a time, always choosing the variable with higherp-value. ANOVA or Student’s t-tests wereused to select variables for inclusion in the regression model. Variables withp<0.10 were included in the linear regression, but onlyvariables with p<0.05 in the regression were kept in themodel. All analyses were performed with the SPSS 18.0 software.Hardy-Weinberg Equilibrium was estimated by the chi-square test. Linearregression was used to estimate the influence of genetic and non-genetic factorson TTR through the enter method. Variables with The patients’ average age was 62.3 ± 13.9 years. Most patients were males (53.7%) ofEuropean ancestry (93.6%). Mean TTR was 59.5% of treatment days. The averagewarfarin dose was 33.0 mg/week . Theindp<0.001). Therefore, “type ofmanagement” was included in the regression model as a confounder , which means that there are other important factors that were not addressedin this study. It is possible that factors that change during treatment might have agreater impact on TTR, like the number of times that patients have theirprescription changed, changes in vitamin K consumption during treatment,comorbidities, and other medications. This could also explain the great discrepancyin results observed among the studies.CYP2C9*2 and/or *3 allele carriers may need amore careful monitoring. Moreover, the present results about patient assessment mayencourage hospitals to approach patients by in office appointments. Other studiesare needed to confirm these results and to find more variables that could contributeto this important parameter.Besides the genetic factor, this study showed that variables of easy access, likeco-medications, can influence INR control quality outcomes. Special attention andbetter management of these factors can improve warfarin therapy and, consequently,offer a therapy with higher efficacy and safety for the patients. Glibenclamideamiodarone, acetaminophen, and verapamil users that are also


Vascular calcification is a prominent feature in chronic kidney disease (CKD) and diabetes mellitus. A recent report suggests that angiotensin II is protective to vascular calcification. Therefore, we investigated the relationship between vascular calcification and use of angiotensin-converting-enzyme inhibitor (ACEI) and/or angiotensin II receptor blocker (ARB) from a cross-sectional view.2) who underwent thoracoabdominal plain computed tomography scan were included in this study. The total vascular calcification volume  was calculated with a three-dimensional imaging software and standardized by body surface area (BSA). The relevance between log [Calc/BSA] and ACEI/ARB use was investigated by multivariate linear regression analyses with or without a time-duration factor of ACEI/ARB use.A total of 121 predialysis CKD patients  20.2 (11.8 - 40.3) mL/min/1.73 m2 in 121 patients. In multivariate analyses adjusted with age, sex, ACEI/ARB and log [eGFR], ACEI/ARB use is significantly and positively associated with log [Calc/BSA] . Even after the adjustment by age, sex, log [eGFR], phosphate, diabetes mellitus, systolic blood pressure, warfarin, hypertension, dyslipidemia, low-density lipoprotein cholesterol, diuretics and ACEI/ARB, ACEI/ARB use is significantly and positively associated with log [Calc/BSA] . When 90 patients whose time-duration of ACEI/ARB use was clear in medical records were studied, a multivariate analysis adjusted with age, sex, log [eGFR], and ACEI/ARB duration factors showed that the longer use of ACEI/ARB more than 2 years was significantly, independently and positively associated with log [Calc/BSA] .The Calc/BSA was 5.62 (2.01 - 12.7) mL/mACEI/ARB user was associated with vascular calcification in predialysis patients with low eGFR. Prospective studies with larger numbers of patients or more in vitro studies are needed to confirm whether this phenomenon is due to the use of ACEI/ARB itself, the underlying disease condition or the prescription bias.The online version contains supplementary material available at 10.1186/s12882-020-02198-6. Vascular calcification is often found in patients with chronic kidney disease (CKD) or diabetes mellitus (DM), and is closely associated with cardiovascular events and mortality , 2. VascAnatomically, vascular calcification is classified into two types: intimal and medial calcification. The intimal layer of the vascular walls is mainly composed of endothelium and is commonly associated with atherosclerotic plaques in pathologic conditions. Therefore, intimal calcification often leads to stenosis or occlusion of the vessels, as in coronary artery disease. In contrast, the medial layer of the vascular walls is composed of smooth muscle cells and elastin-rich extracellular matrix. Medial calcification, also known as Mönckeberg’s calcification, is often associated with CKD. As medial calcification affects elastin-rich matrixes, a reduction or loss of vascular elasticity or vascular tone is the major problem, rather than stenosis of the vascular lumen. Many clinical studies suggest that hypertension, DM, dyslipidemia, aging, smoking, and genetic factors, which are known as “traditional” Framingham risk factors, promote vascular calcification. Non-traditional risk factors, including inflammation, oxidative stress, advanced glycation end products, and abnormal mineral metabolism (e.g. high serum phosphate) are also associated with vascular calcification , 5.The renin-angiotensin system is known to be a major pathogenic factor in vascular smooth muscle cell apoptosis, growth, and differentiation. Suggestively, it is likely to play a role in calcification . CalcifiBut, a recent report indicated that angiotensin II prevents phosphate-induced calcification in human aortic smooth muscle cells in vitro by increasing magnesium influx, activating ERK1/2, and inhibiting canonical Wnt/beta-catenin signaling pathways . This stWe retrospectively investigated 152 patients who underwent thoracoabdominal plain computed tomography (CT) scan between May 2014 and April 2018 in the department of nephrology, National Hospital Organization Osaka National Hospital. We excluded 31 individuals because of maintenance dialysis (14 cases), continuous hemodiafiltration (2 cases), fulminant hepatitis (1 case), a history of aortic aneurysm treatment or surgical operation to major large arteries (8 cases), extremely low value of creatinine due to the decreased muscle volume (1 case), lacking data of blood pressure on the day of CT scan (1 case), and/or lacking lipid data profile within 15 days from the day of CT scan (5 cases). One individual had two conditions of the above-mentioned exclusion criteria. In the remaining 121 patients, clinical data, including laboratory tests, past history, comorbidities, and medications, were collected. DM was defined as a casual blood glucose level ≧200 mg/dL, hemoglobin A1c≧6.5%, or the use of antidiabetic medications. Hypertension was defined as systolic blood pressure ≧140 mmHg, diastolic blood pressure ≧90 mmHg, or use of antihypertensives. Dyslipidemia was defined as a low-density lipoprotein cholesterol (LDL-C) level ≧140 mg/dL, high-density lipoprotein cholesterol level <40 mg/dL, triglyceride level ≧150 mg/dL, or the use of lipid-lowering medications. Systolic blood pressure (SBP) on the day of CT scan was collected. Current prescription of warfarin, ACEI and/or ARB on the day of CT scan was collected from medical records. ACEI and/or ARB were basically prescribed to patients with CKD such as those accompanying decreased eGFR or proteinuria, patients with cardiovascular diseases or patients with DM especially with proteinuria/albuminuria.-1.094 × age (years) -0.287  (mL/min/1.73m2). Body surface area (BSA) for our Japanese patients was calculated with Fujimoto’s formula as follows: BSA = body weight (kg) 0.444 x height (cm) 0.663 × 0.008883  was compared among group 1, group 2 and group 3 by Tukey-Kramer HSD test. The relevance between log [Calc/BSA] and the duration of ACEI/ARB was investigated by tendency analysis (Jonckheere-Terpstra trend test) and multivariate linear regression analysis.p < 0.05 was considered statistically significant.Data are reported as percentages or means ± standard deviation (SD) for normally distributed variables, and as medians (interquartile range) for non-normally distributed variables. To minimize skewness, the eGFR and Calc/BSA were transformed using the natural logarithm. Calc/BSA was confirmed not to include 0 value in our 121 patients. The relevance between log [Calc/BSA] and ACEI/ARB use was investigated by several multivariate linear regression analyses. Statistical analyses were performed using JMP  and Excel add-in software . In the multivariate analysis, Our study subjects underwent CT scan in order to investigate the presence or absence of malignancy 91 cases), locate the source of infection (18 cases), evaluate aortic aneurysm or aortic dissection (4 cases), investigate the cause of anemia (4 cases), evaluate renal artery calcification (2 cases), and for other miscellaneous reasons (9 cases). A single CT examination often detected more than one such condition in a total of 121 patients. A representative vascular calcification image is shown in Fig.  cases, l2. The mean log [Calc/BSA] was 1.67 ± 1.20. The mean log [eGFR] was 3.1 ± 0.8, which corresponds to an eGFR of 20.2 (11.8 - 40.3) mL/min/1.73m2. The relationships between log [Calc/BSA] and either of age, log [eGFR], SBP, warfarin, diuretics, malignancy or ACEI/ARB were investigated. Log [Calc/BSA] was significantly associated with age (p < 0.0001), log [eGFR] (p = 0.0226) or systolic blood pressure (p = 0.0306) as shown in Fig. p = 0.0287). The association of ACEI/ARB with log [Calc/BSA] was marginally significant (p = 0.0586) . The association of malignancy with log [Calc/BSA] was not significant (p = 0.8414). In univariate analyses, the difference of the median values of log [Calc/BSA] was 1.10 with or without warfarin  included in the analysis are provided in Table Next, we performed multivariate linear regression analyses for the outcome of log [Calc/BSA] Table . In modeP = 0.0060) with Tukey-Kramer HSD test. There was a significant trend that the longer the duration of ACEI/ARB, the higher log [Calc/BSA] (P = 0.0022) with Jonckheere-Terpstra trend test. In multivariate linear regression analysis where log [Calc/BSA] was adjusted by age, sex, log [eGFR], and the duration category of ACEI/ARB, the longer duration of ACEI/ARB more than 2 years showed an independent and positive association with log [Calc/BSA] . Although the differences were statistically significant, the value was quite small. In other words, whether ACEI/ARB has a clinically significant impact on the vascular calcification or not remains unknown.Our results suggest that ACEI/ARB user might be independently and significantly associated with vascular calcification in predialysis patients with low eGFR. However, the difference of log [Calc/BSA] with or without ACEI/ARB was about from 0.1671 to 0.2781 in multivariate analyses (Table In the present study, use of warfarin was not associated with log [Calc/BSA] in multivariate analysis, but was significantly associated in the univariate analysis. Considering that warfarin inhibits matrix Gla protein, a vitamin K-dependent protein produced by vascular smooth muscle, and also a key inhibitor of vascular calcification , our resThe present study mainly targeted the aorta in humans with reduced eGFR which is evident from representative image in Fig. Vascular biology and bone biology have many regulatory mechanisms in common , 18. In The present study has several limitations. First, the study population comprised patients with CKD in the nephrology unit of Osaka National Hospital. Additionally, patients who undergo thoracoabdominal CT tend to have severe disorders. Therefore, a selection bias is unavoidable. Second, as this was a retrospective cross-sectional observational study, it cannot show causal relationships. The present study results do not completely rule out the possibility that patients on ACEI/ARB were formerly at high risk for vascular calcification. In other words, our present results might be the results of unobvious confounding factors. Thirdly, a prescription bias may be unavoidable. But we have already confirmed that there were no statistical differences among Group 1, Group 2 and Group 3 in terms of age, sex, albumin, corrected calcium, phosphate, product of corrected calcium and phosphate, log [eGFR], phosphate binder with calcium, phosphate binder without calcium, and SBP except for DM . MagnesiACEI/ARB user might be associated with vascular calcification in predialysis patients with low eGFR. This result is consistent with in vitro study showing that angiotensin II modulation influences calcification. Prospective studies with larger numbers of patients or more in vitro studies are needed to confirm whether the observed phenomenon is due to the use of ACEI/ARB itself, the underlying disease condition or the prescription bias.Additional file 1.


Conclusions: Despite possible FD recurrence after transplantation of 11.1%, allograft and patient survival are comparable among kidney transplant recipients with vs. without FD.Background: Fabry disease (FD) is a rare X-linked lysosomal storage disorder with progressive systemic deposition of globotriaosylceramide, leading to life-threatening cardiac, central nervous system, and kidney disease. Current therapy involves symptomatic medical management, enzyme replacement therapy (ERT), dialysis, kidney transplantation, and, more recently, gene therapy. The aim of this systematic review was to assess outcomes of kidney transplantation among patients with FD. Methods: A comprehensive literature review was conducted utilizing MEDLINE, EMBASE, and Cochrane Database, from inception through to 28 February 2020, to identify studies that evaluate outcomes of kidney transplantation including patient and allograft survival among kidney transplant patients with FD. Effect estimates from each study were extracted and combined using the random-effects generic inverse variance method of DerSimonian and Laird. Results: In total, 11 studies, including 424 kidney transplant recipients with FD, were enrolled. The post-transplant median follow-up time ranged from 3 to 11.5 years. Overall, the pooled estimated rates of all-cause graft failure, graft failure before death, and allograft rejection were 32.5% (95%CI: 23.9%–42.5%), 14.5% (95%CI: 8.4%–23.7%), and 20.2% (95%CI: 15.4%–25.9%), respectively. In the sensitivity analysis, limited only to the recent studies (year 2001 or newer when ERT became available), the pooled estimated rates of all-cause graft failure, graft failure before death, and allograft rejection were 28.1% (95%CI: 20.5%–37.3%), 11.7% (95%CI: 8.4%–16.0%), and 20.2% (95%CI: 15.5%–26.0%), respectively. The pooled estimated rate of biopsy proven FD recurrence was 11.1% (95%CI: 3.6%–29.4%), respectively. There are no significant differences in the risks of all-cause graft failure ( Fabry disease (FD) is a rare, progressive, multisystemic, and X-linked inherited lysosomal disorder, caused by genetic variations in GLA , which encodes α-galactosidase  ,19. The Fabry nephropathy is one of the causes of chronic kidney disease, similar to diabetic kidney disease, which could progress to end-stage kidney disease in the fifth decade of life . It has The role of kidney transplantation in FD has been subjected to certain controversies. Some evidence suggests that kidney transplant increases serum α-gal A ,37,38 anA comprehensive search of several databases, from each database’s inception to February 28, 2020, was conducted. The databases included OVID MEDLINE (1946 to February 2020), EMBASE (1988 to February 2020), and the Cochrane Database of Systematic Reviews (database inception to February 2020). The systematic literature review was conducted independently by two investigators (M.L.G.S. and C.T.) using the search strategy that consolidated the terms of ) AND . The actual strategy listing all search terms used is available in the online Eligible studies must be clinical trials, observational studies  that reported incidence and/or outcomes of kidney transplantation among patients with FD. Retrieved articles were individually reviewed for eligibility by two investigators (M.L.G.S. and C.T.). Discrepancies were addressed and resolved by a third investigator (W.C.). Inclusion was not limited by language, age, sample size, or study duration. The following data were extracted: first author name, year of publication, number of patients, duration of follow-up, diagnosis of FD, mean age, sex, incidence of FD recurrence, patient survival, graft survival, and allograft rejection. The primary outcome was allograft survival.2 statistic and the chi-square test. A value of I2 of 0% to 25% represents insignificant heterogeneity, 26% to 50% low heterogeneity, 51% to 75% moderate heterogeneity, and 76 to 100% high heterogeneity [We calculated pooled estimated rates of FD recurrence, patient survival, graft survival, and allograft rejection among kidney transplant patients with FD. A random-effects model was used due to the expected clinical heterogeneity in the included populations . All pooogeneity .p-value of less than 0.05 indicates the presence of publication bias. The meta-analysis was performed by the Comprehensive Meta-Analysis 3.3 software . The data for this meta-analysis are publicly available through the Open Science Framework (URL: osf.io/amrxq/).Publication bias was evaluated using the Egger test . A p-valIn total, 11 studies, including 424 kidney transplant recipients with FD, were enrolled  46,47,4,54,55,562 = 50%), 14.5% (95%CI: 8.4%–23.7%), and 20.2% (95%CI: 15.4%–25.9%), respectively .The pooled estimated rate of biopsy proven FD recurrence was 11.1% (95%CI: 3.6%–29.4%), respectively. There are no significant differences in the risks of all-cause graft failure (P = 0.10)  or mortaHere, we reported that the pooled estimated rates of all-cause graft failure, graft failure before death, and allograft rejection were 32.5%, 14.5%, and 20.2%, respectively, with a median follow-up time ranging from 3 to 11.5 years. We also found no significant difference in the risk of all-cause graft failure or the mortality among recipients with and without FD. However, the incidence of graft failure in FD patients is overtly higher than those with diabetes. One retrospective cohort study showed that the incidence of graft failure in diabetic patients was 6.7% compared to 2.8% in nondiabetic patients . OverallIn 1975, the American College of Surgeons and the National Institute of Health Renal Transplant Registry reviewed the outcomes of kidney transplantation in several congenital metabolic diseases. The good outcomes following kidney transplantation were highlighted in patients with Alport syndrome, amyloidosis, cystinosis, and others with the exception of FD and oxalosis. The graft survival after one year was only 33% without reported evidence of relapses . The 5-yWe also demonstrated that the incidence of all-cause graft failure (28.1%) and death-censored graft failure (11.7%) have declined over time, especially in studies published after 2001 or when enzyme replacement therapy (ERT) became available, whereas the incidence of allograft rejection remained unchanged (20.2%). Earlier studies among Fabry patients after kidney transplantation reported a rise in galactosidase enzyme levels secondary to lysosomal enzyme release from transplanted organ ,60,61. HOne of the challenges with ERT is the development of ERT antibodies, as this complicates treatment among Fabry disease patients ,66. In pThe long-term outcome of kidney transplantation in FD patients was reintroduced after several newer studies reported promising data on graft survival and patient survival. The European Renal Association Registry reported 72% graft survival and 84% patient survival after 3-year follow-up . SimilarHere, we reported the incidence of FD recurrence in kidney transplant patients for the first time (11.1%) with a median follow-up duration ranging from 3 to 11.5 years. Since 1972, the data on recurrent FD post-kidney transplant have been scarcely reported due to small sample sizes. Most studies were retrospective and had quite different biopsy and transplant timings. However, recurrent FD was determined by histological features from the kidney biopsy . Some poOur study is the first systematic review to report the allograft outcomes of Fabry nephropathy. However, some limitations may be imposed. First, given the observational design in nature, the reported findings may be subjected to selection bias. Some included studies were published before ERT was established, and it is well known that this treatment had a profound impact on the outcome of the disease. Thus, we performed additionally analysis including only the recent studies (year 2001 or newer when ERT became available) and demonstrated the pooled estimated rates of all-cause graft failure, graft failure before death, and allograft rejection of 28.1%, 11.7%, and 20.2%, respectively. Second, the transplant outcomes of Fabry nephropathy were not directly compared to other diagnoses. Thus, the clinical applicability of our findings should be adopted with caution. Third, although sample sizes were pooled, the total number of subjects remained small. Fourth, the majority of FD patients included in our systematic review were males and data on patients’ comorbidities were limited. Thus, future studies are needed to assess outcomes of kidney transplantation among female patients with FD.In summary, the allograft and patient outcomes in patients with FD are comparable to other kidney diseases with a recurrence rate of 11% during a follow-duration of up to 11.5 years.


P = .027) and increased the odds for infection by 11% . TTV was quantified at a median of 14 days before rejection was diagnosed and 27 days before onset of infection, respectively. We defined a TTV load between 1 × 106 and 1 × 108 copies/mL as optimal range to minimize the risk for rejection and infection. These data support the initiation of an interventional trial assessing the efficacy of TTV‐guided immunosuppression to reduce infection and graft rejection in kidney transplant recipients.The nonpathogenic and ubiquitous torque teno virus (TTV) is associated with immunosuppression in solid organ transplant recipients. Studies in kidney transplant patients proposed TTV quantification for risk stratification of graft rejection and infection. In this prospective trial (DRKS00012335) 386 consecutive kidney transplant recipients were subjected to longitudinal per‐protocol monitoring of plasma TTV load by polymerase chain reaction for 12 months posttransplant. TTV load peaked at the end of month 3 posttransplant and reached steady state thereafter. TTV load after the end of month 3 was analyzed in the context of subsequent rejection diagnosed by indication biopsy and infection within the first year posttransplant, respectively. Each log increase in TTV load decreased the odds for rejection by 22% (odds ratio [OR] 0.78, 95% confidence interval [CI] 0.62‐0.97;  page 1963.This trial defines an optimal plasma level range of the nonpathogenic and ubiquitous torque teno virus, which reflects the immunosuppression of its host, to minimize the risk for rejection and infection in kidney allograft recipients in the first year after transplantation. Fernández‐Ruiz comments on  ABMRantibody‐mediated rejectionBLborderlinec/mLcopies/milliliterCIconfidence intervalDSAdonor‐specific antibodiesIQRinterquartile rangeNPVnegative predictive valueORodds ratioPPVpositive predictive valuepPVNpresumptive polyomavirus nephropathyPVNpolyomavirus nephropathyTCMRT cell–mediated rejectionTTVtorque teno virus1Kidney transplantation represents the only curative treatment for patients with end‐stage renal disease. After transplantation, immunosuppressive drugs are crucial to reducing the risk of organ rejection. Apart from this desired effect, immunosuppression increases the risk for infectious disease, being one of the leading causes of death after kidney transplantation.+ lymphocyte function, using ImmuKnow® , resulted in less infectious events.Two assays to characterize the immune function of solid organ recipients were proposed,In kidney transplant recipients, recent data suggest a potential of TTV quantification for risk prediction of infectious events22.1The prospective observational “TTV Quantification for the Prediction of Organ Rejection in Kidney Transplantation; TTV‐POET” trial included all 386 consecutive adult (≥18 years of age) recipients of a kidney allograft transplanted at the Medical University Vienna, Austria, between January 1, 2016 and June 30, 2018. Patients were followed at the outpatient clinic of the Medical University Vienna for 12 months after transplantation or until dropout due to change of outpatient care center, graft loss, or death. The present study was approved by the local institutional review board  and registered at the German Clinical Trials Registry (register number: DRKS00012335). An interim analysis of the present study including patients transplanted in 2016, restricted to infectious events, has been published elsewhere.2.24 copies/milliliter (c/mL) was defined as presumptive polyomavirus nephropathy (pPVN) and polyomavirus nephropathy (PVN) was defined by biopsy. Cytomegalovirus (CMV) syndrome was defined by CMV replication and the presence of attributable symptoms according to current consensus definitions.Aspergillus, and Pneumocystis jirovecii.The primary outcome of the TTV‐POET trial was predefined as biopsy proven graft rejection according to Banff classification. Protocol biopsies were not included in this analysis. Immunohistochemical assessment of C4d staining was evaluated on paraffin‐embedded sections. Multilayering of basement membranes of peritubular capillaries and glomerular basement membranes were assessed by electron microscopy. Histopathological lesions were categorized following the 2015 and 2017 updates of the Banff classification.2.3All patients received triple immunosuppression with tacrolimus, mycophenolic acid, and corticosteroids. All HLA compatible patients received induction therapy with interleukin‐2 receptor blockade . Recipient of an HLA‐incompatible kidney, defined by preformed donor‐specific anti‐HLA antibodies (DSA), underwent IgG immunoapheresis and depleting antibodies  according to a local protocol.2.4All patients received prophylaxis with trimethoprim‐sulfamethoxazole for 6 months after transplantation with 50% of the therapeutic dose adapted to kidney function and valganciclovir both for 3 months in CMV IgG‐negative recipients of a CMV IgG‐positive organ, in case of Epstein Barr virus IgG‐negativity and after treatment with depleting antibodies and IgG immunoapheresis with 50% of the therapeutic dose adapted to kidney function. Screening for CMV and BK polyomavirus after transplantation was performed by polymerase chain reaction (PCR) from peripheral blood once per week until discharge from the ward, on the first visit at the outpatient clinic, on month 3 after transplantation, and every 3 months thereafter. Epstein‐Barr virus PCR from peripheral blood was performed in Epstein‐Barr virus IgG‐negative recipients on the first visit at the outpatient clinic, 1 month after transplantation, monthly until month 6 after transplantation, and every 3 months thereafter. We did not perform specific screening for other viral infections or bacterial and fungal infections.2.53 to 1 × 1011 c/mL and limit of detection was 7 × 102 c/mL.TTV was quantified prospectively per protocol in the peripheral blood at the following predefined time points: before transplantation and after transplantation once per week until discharge from the ward, on the first visit at the outpatient clinic, on month 3 after transplantation, and every 3 months thereafter. Treating physicians were unaware of the TTV results. TTV DNA was extracted from 200 μL of plasma using the NucliSENS easyMAG platform , as recommended by the manufacturer. TTV DNA was quantitated by TaqMan real‐time PCR, as described previously with laboratory developed primers.2.6U test was used to compare TTV between groups. Generalized linear models were used to estimate the effect size of the association between allograft rejection and infection, respectively and TTV. Effect size was displayed as odds ratio (OR) and 95% confidence interval (95% CI). For sensitivity analysis restricted to a single event per person, the first event after transplantation was selected. Potential confounders of the effect size of the association between TTV and rejection and infection, respectively, were assessed using bivariate analysis. Potential effect modifiers were tested using Mantel‐Haenszel strata. A change in the effect size of > 10% was defined as significant. For multivariate analysis, co‐variables were selected on the basis of clinical relevance. For multivariable modeling, backward elimination was used and the “rule of 10” was applied to define the maximum of variables. A P < .05 was the predefined limit of significance. Log normally distributed variables were log transformed. MS EXCEL 2010 (Microsoft), IBM SPSS Statistics 24.0 (SPSS Inc), and STATA 15  were applied for data analysis.The Mann‐Whitney 33.1A total of 386 patients received a kidney transplant at the Medical University Vienna between January 1, 2016 and June 30, 2018. Median recipient age at transplantation was 55 years, 35% were female, 19% had a history of prior kidney transplantation, 82% received a kidney from a deceased donor, and 9% had preformed DSA . All pretransplant TTV‐negative patients except two turned TTV positive after transplantation.Plasma for TTV analysis was sampled before transplantation and longitudinally per‐protocol after transplantation in all 386 patients. In total 3265 TTV quantifications were performed. Prior to transplantation, 88% of the patients had detectable TTV in the peripheral blood  and preceded subsequent biopsies by a median of 14 days (IQR 1‐15). Baseline characteristics of the 37 patients are detailed in Table 6 c/mL, IQR 1.7 × 105‐1.3 × 108 c/mL vs median 2.5 × 108 c/mL, IQR 5.8 × 106‐9.3 × 108 c/mL; P = .028) in subsequent biopsies. The odds for rejection decreased by 22% with every log level increase of TTV . Sensitivity analysis restricted to one biopsy per patient (n = 37) and biopsies without BL lesions (n = 37), respectively, showed similar effect size of the association between TTV level and rejection, respectively . Applying receiver operating curve, an area under the curve of 0.73  was calculated to classify rejection by TTV level  of 77%, and a positive predictive value (PPV) of 50%. Diagnostic accuracy for each log level of TTV is displayed in Table 7 c/mL, high NPVs (range 84%‐87%) were calculated and PPV was high below TTV level of 105 c/mL (range 57%‐85%).Patients with allograft rejection had lower levels of TTV compared to patients without rejection . The odds for an infection increased by 11% with every log level increase of TTV . Sensitivity analysis including only one event per patient (n = 274) showed similar effect size for the association between TTV level and infection . Further subgroup analysis showed a comparable effect size for the association between TTV level and infections which did not require hospitalization . The largest effect size was calculated for BK infections  followed by CMV disease  and infections restricted to opportunistic pathogens . A smaller effect size was found for infections with extracellular bacteria . Applying receiver operating curve, an area under the curve of 0.62  was calculated to classify infection by TTV level  and the highest PPV was calculated for TTV loads above 1010 c/mL (range 44%‐67%).Quantification of TTV in the 785 events included in this analysis revealed higher level of TTV in the plasma drawn from individuals experiencing an infectious event in the subsequent observation period, compared to patients without infection . In general, TTV loads quantified by the TTV R‐gene® kit are lower compared to the in‐house assay applied in our study. Moreover, plasma samples collected during the present study were processed at the day of blood draw, whereas Fernández‐Ruiz and colleagues analyzed samples stored at −80°C. In line with our data, they described a similar delta in TTV level between patients experiencing infection and patients without infection. This aspect underscores the importance of standardized TTV quantification to enable comparability between laboratories.A main goal of the present trial was to define the optimal TTV range for reduced risk of graft rejection and infection in the first year after kidney transplantation providing a basis for an interventional randomized controlled trial to evaluate the efficacy of TTV‐guided immunosuppression. For this purpose, we included TTV levels after month 3 posttransplant, because steady state does not occur before this time point. Patients with subsequent allograft rejection had a median TTV load of 3.5 × 10The major strengths of the present trial are the prospective design, the large sample size, and the unselected cohort of consecutive kidney transplant recipients. Detailed and prospective documentation of clinical characteristics allowed for the analysis of possible confounders and effect modifiers. The major limitation of the study is the single center design. Second, follow‐up was limited to 12 months after transplantation, and third, the number of biopsy proven rejections was small. Finally, the present data suggest independent association of TTV and rejection and infection due to level of immunosuppression, respectively, but did not prove causality. Similar to reports by SpanishTaken together the results of our study provide evidence for the value of TTV quantification for risk stratification of clinically relevant graft rejection and infection after kidney transplantation. Moreover, we defined an optimal TTV range as a basis for an interventional trial to test the efficacy of TTV‐guided immunosuppression reducing infection and rejection after kidney transplantation.American Journal of Transplantation.The authors of this manuscript have no conflicts of interest to disclose as described by the  Click here for additional data file. Click here for additional data file.


Recent studies suggest that circulating microRNA (miRNA) plays a potential role in the physiopathology of both conditions. To date, circulating miRNA expression has been studied separately in both conditions, but never jointly. The primary treatment of OSA is continuous positive airway pressure (CPAP), whereas bariatric surgery (BS) is the treatment of choice for MO. We have thus initiated the Epigenetics modification in Morbid Obesity and Obstructive Sleep Apnoea (EPIMOOSA) study .Obstructive sleep apnoea (OSA) and morbid obesity (MO), defined by a body mass index ≥35 kg/mEPIMOOSA is a prospective non-interventional cohort study aiming to recruit 45 MO patients who are candidates for BS. Three groups will be formed: MO without OSA, MO with OSA without CPAP and MO with OSA and CPAP. All of them will be followed up in 4 visits: baseline, 6 months prior to BS and 3, 6 and 12 months post-BS. At baseline, OSA status will be assessed by home sleep polygraphy (HSP), and CPAP will be adopted according to national guidelines. A specific standardized questionnaire  and anthropometrical examination will be performed at each visit. Blood samples will be obtained at each visit for immediate standard biochemistry, haematology and inflammatory cytokines. For bio-banking, serum, plasma, and circulating exosomes will also be obtained. Twenty-four hours of blood pressure and electrocardiogram (ECG) Holter monitoring will be performed at all visits. A new HSP will be performed at the last visit. Finally, the three groups will be sex- and age- matched with participants in the EPIOSA study, an ongoing study aimed at understanding epigenetic changes in non-obese OSA patients.EPIMOOSA will evaluate changes in circulating miRNA in MO with or without OSA for the first time. In addition, EPIMOOSA will be able to elucidate the influence of OSA in MO patients and how specific and combined treatments alter miRNA expression. Obesityc levels , 5.Obesity is closely related to the development of obstructive sleep apnoea (OSA)  and obesAdipose tissue from obese patients, regardless of the coexistence of OSA, suffers chronic hypoxia due to its poor vascularization, which increases the level of hypoxia-inducible factor (HIF) , 10. RecCirculating exosomes are extra-vesicular vesicles that contain lipids, proteins and miRNAs that contribute to remote cell signalling and communication mechanisms in both physiological  and pathThe hypothesis of the EPIMOOSA study is that patients with a morbid obesity (MO) and OSA have a specific inflammatory phenotype and that, hypoxia-induced epigenetic changes act in synergy with the subclinical state of inflammation inherent to morbid obesity to develop this phenotype. If this hypothesis holds to be true, these changes should be reversed with CPAP and bariatric surgery (BS). In addition, we further aimed to identify epigenetic changes among exosomal miRNAs in MO patients with and without OSA and to determine whether CPAP and BS modify their levels.This is a 2-year prospective, longitudinal, non-interventional cohort study. It will be conducted in the Sleep and Bariatric Surgery Units at the Royo Villanova and Miguel Servet University hospitals in Zaragoza, Spain. The researchers of the EPIMOOSA study have a variety of expertise related to the management of sleep and respiratory disorders, obesity, endocrinology, biostatistics, biomedical informatics, molecular biology and epigenetics. Two scientific centres will provide core services for the analysis of inflammatory biomarkers and genetics  and epigenetic data analysis .Patients will be selected from the bariatric surgery waiting list from both hospitals according to the selection criteria set out in Table 2.The control group will comprise subjects without comorbidities from the EPIOSA study that is currently underway . PatientThree groups of patients will be studied in the EPIMOOSA cohort: a) subjects with MO and without OSA; b) patients with MO and OSA who do not need CPAP therapy; and c) patients with MO and OSA who require CPAP therapy. Each group will include at least 12 subjects who complete the 2-year follow-up after their inclusion at the baseline visit. The sample size was calculated to reveal significant differences in the epigenetic changes between the groups with OSA and the control group (main objective). In a previous study, Kim et al.  demonstrTable 2), and neck, waist, and hip circumferences (cm); e) blood pressure, measured according to the European Society of Hypertension/European Society of Cardiology clinical practice guidelines [The following clinical data and complementary tests will be recorded at each visit: a) sociodemographic data, clinical, surgical and family history, and regular medications; b) level of daytime sleepiness based on the Epworth scale ; c) leveidelines ; and f) idelines .We will use a validated home polygraphy system . The device continuously records airflow, chest movement, oxygen saturation, snoring, and body position. We define apnoea as a lack of airflow for more than 10 s and hypopnea as the reduction of airflow (> 50%) for over 10 s accompanied by a decrease in oxygen levels of more than 4%. The apnoea–hypopnoea index  is calcuEC-3H/ABP  that combines a 3-channel EKG Holter and an ambulatory blood pressure monitor. These studies will be conducted the day after the home sleep study and over the 24-h period before the blood sample collection. They will be interpreted according to the guidelines published by the Spanish Society of Cardiology [All patients will complete a 24-h blood pressure and electrocardiogram study. This measure will be performed using a Labtech®rdiology .Fasting blood samples will be collected at each visit. Venous blood samples will be obtained with 21G Abbocaths, and arterial samples will be obtained with 23G ProVent® kits for blood gas analysis. Glucose, triglycerides, total cholesterol, HDL, LDL, and apolipoprotein A and B blood levels will be analysed by spectrophotometry . High-sensitivity C-reactive protein (hsCRP) will be determined within 2 h of collecting the blood samples using flow nephelometry. In total, 15 mL of blood will be used to obtain serum and plasma, and 5 mL of EDTA will be used to conduct genetic and epigenetic studies; these samples will be stored in a freezer at − 80 °C until analysis. Arterial blood gas analysis will be performed at baseline and at the last visit.Circulating exosomes and the encapsulated miRNA will be studied at the Translational Unit of the Miguel Servet Hospital in Zaragoza. Exosomes will be isolated with the miRCURY™Exosome Isolation Kit , and miRNA will be obtained using the miRNeasy Serum/Plasma Advanced Kit  as previously described . After eThe study has already been initiated thanks to support from SEPAR and will overlap with the Bariatric Surgery Unit’s care strategy. The recruitment period will last for 2 years, while the follow-up will run for 6 months after the home sleep study and 1 year after surgery. As seen in Fig. n > 2) will be performed using a nonparametric Kruskal-Wallis test followed by a Mann-Whitney U test when appropriate. Pairwise comparisons were performed using a nonparametric Mann-Whitney test unless otherwise indicated. Chi-square tests will be performed for categorical variables. c) Pearson’s or Spearman’s correlation, depending on the variables’ normality, will be used to evaluate the relationship between systemic inflammation and clinical variables. d) The interindividual variability of miRNA will be determined through the coefficient of variation. GraphPad Prism 8 (GraphPad Software) and SPSS version 23.0 (IBM) statistical packages will be used for all analyses.We have predefined the following statistical procedures: a) Description of populations. They will be expressed as mean values ± standard deviation for quantitative variables or as numbers and frequencies for qualitative variables. b) Difference between groups: Groupwise comparisons  adults with OSA and did not find any changes in methylation or FOXP3 expression. However, we found the dysregulation of certain miRNAs in circulating exosomes (miRNA320-5p and miRNA132-3p) associated with cardiovascular diseases that produced a non-uniform response to CPAP therapy [In the context of OSA, different epigenetic markers have been evaluated, specifically DNA methylation and, more recently, the role of miRNAs. Our group has previously studied non-obese (BMI < 30 kg/m therapy . Those f therapy .The role of miRNA in OSA is currently a popular area of research. A sub-analysis of the HIPARCO clinical trial  revealedThe relationship between OSA and MO has been well documented , showingOur study aims to evaluate, for the first time, whether patients with MO with/without OSA develop epigenetic dysfunction in circulating exosomes involved in accelerated incidents of cardiovascular diseases. Our study will provide a better understanding of the role of CPAP therapy in patients with MO/OSA overlap and the effect of BS-induced weight loss. The results could also give rise to new biomarkers to improve phenotyping in patients with either or both of the conditions and, possibly, novel therapeutic targets.


This study was aimed to assess the patient's knowledge and awareness about hypertension and adherence to antihypertensive medication among hypertensive patients.  The descriptive cross-sectional study was conducted in three medical clinics of Colombo South Teaching hospital, Kalubowila, Sri Lanka, from April 2019 to September 2019. Total of 384 hypertensive patients were recruited by systematic randomized controlled sampling and interviewed with validated questionnaires to assess their knowledge about hypertension and adherence to antihypertensive medication. Data were analyzed using SPSS (version 21) analytical package, and the chi-squared test was performed.  The total sample consisted of 384 hypertensive patients with a mean age of 59.32 (±12.34SD). This included 180 (46.9%) males and 204 (53.1%) females. The male : female ratio was approximately 9 : 10. Most of patients were with primary and ordinary educational status (65.9%), normal body mass index (54.9%), mild elevation of LDL cholesterol (76.3%), and coexistent ischemic heart disease (39.6%). The knowledge about hypertension among majority of patients was reasonable. However, they were unaware about normal values of blood pressure  and diagnostic values of hypertension . Moreover, they were unaware of their blood pressure values at time of diagnosis , at recent clinic visit , and target level . Most patients had adequate knowledge about the risk factors and complications of hypertension and were aware of their target organ damage (70.3%). Most patients believed that medication alone is not sufficient to control blood pressure  and adequate control of their blood pressure reduces complications . Most of the patients (71.8%) had reasonable good drug compliance. The forgetfulness was commonly attributed for nonadherence .  The knowledge about hypertension among majority of patients was reasonable. But, they were unaware about their disease status and their diagnosis, target, and recent blood pressure values. Most of patients had adequate knowledge about the risk factors and complications of hypertension. However, they were unaware about their target organ damage due to hypertension. The drug compliance was reasonable among them. The forgetfulness was common reason for nonadherence. Therefore, healthcare professionals should implement individualized educational programmes to increase the awareness of disease status, appropriate blood pressure levels, and adherence of treatment to improve the outcome of patients. Hypertension is a common noncommunicable disease and one of the major risk factors for stroke, coronary artery diseases, and chronic kidney disease . HypertePrompt recognition of the importance of systolic blood pressure is mandatory for medical professionals as one of the major public health and medical challenges in the prevention and treatment of hypertension . Screenist April, 2019, to 30th September, 2019.A cross-sectional study was conducted among hypertensive patients attending medical clinics, Colombo South Teaching Hospital, Kalubowila, from 1There were no previous studies carried out to evaluate the knowledge, awareness of hypertension, and adherence to medication among hypertensive patients attending medical clinics, Colombo South Teaching hospital, Kalubowila, Colombo. Therefore, sample size was calculated by a single population proportion formula considering 5% of absolute precision required on either side of the proportion, 0.5 of anticipated population proportion, and critical value (1.96) with specified confidence interval of 95%. With the addition of 5% nonresponse rate, the yield sample size was 384. The number of potentially eligible participants and who refused were 9649 and 24, respectively. The participants were selected by simple random sampling technique.N is the minimal sample size, Z is the critical value (1.96) of specified confidence interval which is 95%, p is the anticipated population proportion (0.5), d is the absolute precision required on either side of the proportion (5%), and N = 384.Sample size calculation is as follows:Therefore, the calculated minimum sample size according to the above equation is as follows.A nonresponse rate of 5% is assumed. Thus, the final sample = 384.The patients above 18 years who are mentally competent, previously diagnosed as hypertensive by consultant physicians, and attending to medical clinics for 3 months or more at Colombo South Teaching Hospital, Kalubowila, were included and those who were pregnant and those who were unable to give consent was excluded in this study.The pretested validated questionnaire was used to collect the data of knowledge, awareness of hypertension, and adherence to medication among the hypertensive patients. The variables which were studied in this research were sociodemographic variables, knowledge and awareness of hypertension, adherence to medications, and reasons for nonadherence.2)). The cholesterol values were recorded from their clinic records.The blood pressure measurements were measured by medical officers on day of interview, using a mercury sphygmomanometer, in a comfortable resting position, sitting with forearm supported and the palm upward. The target blood pressure of <130/80 mm Hg for patients with diabetes and chronic kidney disease and <140/90 mm Hg for patients with nondiabetic and nonchronic kidney disease (7) was considered as target levels. The weight and height were measured using a standard electronic weight scale and standard height scale, and BMI was calculated based on weight and height using standard equation (BMI = weight (kg)/height (m(1). Interviewer-Administrated Pretested Questionnaires. The Hypertension Fact Questionnaire was designed as a tool, using the existing literature, practicing physicians, and cardiologists to assess the knowledge and awareness among the hypertensive patients. It was a pretested validated questionnaire. It was a self-prepared pretested questionnaire based on preexisting facts related to hypertension without copying originality and was obtained content expert validation of facts from two medical professors, two consultant physicians, one cardiologists, two senior registrars, and one highly qualified English, Sinhala, and Tamil teachers. It was pretested during the pilot study with patients. The questionnaire was initially designed in English and then translated to Sinhala and Tamil languages. The questionnaire consists of twenty-one and twelve questions with different appropriate responses to assess the patients' knowledge and awareness on hypertension, respectively. The knowledge and awareness of hypertension among participants were calculated depending on the number of questions with the correct responses of each participant. Their medication adherence and the reasons for nonadherence were studied using the modified version based on the Morisky Medication Adherence Scale.P value less than 0.05 and presented using narrative texts and tables.The collected data were entered in Microsoft Excel sheet and were analyzed using SPSS (version 18) analytical package. The results were presented as counts, percentages, table of frequencies, and mean ± SD for continuous variables. The significance was declared at Ethical clearance was obtained from the ethical review committees, Colombo South Teaching Hospital, Kalubowila, and Faculty of Medical Sciences, University of Sri Jayewardenepura, Sri Lanka, and was approved by the Board of Study, Postgraduate Institute of Medicine, University of Colombo. Informed written consent was obtained from all participants.The total sample consisted of 384 hypertensive patients with a mean age of 59.32 (±12.34SD). This included 180 (46.9%) males and 204 (53.1%) females. The male : female ratio was approximately 9 : 10. The majority of patients were Sinhalese in ethnicity (84.1%). Most of patients were with primary or ordinary level educational status (65.9%), normal body mass index (54.9%), mild elevation of LDL cholesterol (76.3%), and coexistent ischemic heart disease (39.6%) .The mean response values of overall questions related to knowledge about hypertension among majority of patients was reasonable (72.3%). However, 31% (95% CI 1.92-2.09) patients were aware about the normal values of blood pressure, and only 9.9% (95% CI 2.26-2.40) patients were aware about the cutoff values of hypertension. 69% (95% CI 1.64-1.88) patients had thought that the blood pressure increased with age. 41.7% (95% CI 1.67-1.81) patients believed that medication alone is not sufficient to control blood pressure. Most patients were aware that uncontrolled blood pressure could lead to heart failure , heart attack , and stroke , whilst fewer patients were aware of renal  and ophthalmological  complications. Most of patients had adequate knowledge about the risk factors for developing of hypertension .The patients were interviewed about awareness of hypertension with pretested validated questionnaires and results were shown in All participants were interviewed about adherence to their medications and reasons for nonadherence. The questionnaire contains six questions, which had yes, no, and cannot remember type responses and one multiple choice question. The results are shown in P > 0.05). However, their awareness of diagnosis, diagnostic values, cutoff values, and target values of hypertension differed significantly with the educational status (P < 0.05).The patient's knowledge of risk factors and complications related to hypertension did not differ significantly with age, sex, and educational status  control, and systolic blood pressure is a strong independent risk factor for cardiovascular mortality and morbidity . HoweverPrescriptions of the multiple drugs and poor compliance of the patients are major challenges in clinical practices that results in failure of treatment of hypertension. Hypertension is mostly a chronic asymptomatic condition. Therefore, patients may not feel any physical symptoms and may forget to take their medicine or feel that there is no need to take them until they know the need to take drugs regularly for a long time. Our study showed that most patients have known that hypertension is a serious medical issue and were aware of taking their medication important to control their blood pressure with reasonable drug compliance. Furthermore, our research showed various reasons for patients not taking antihypertensive drugs. Among them, forgetfulness was common reason for nonadherence of their medication. Some people thought taking drugs was unnecessary as they were not experiencing symptoms of hypertension. Some of them preferred traditional medicines and have not taken due to religious misbeliefs. An article which reviewed adherence to cardiovascular medications from among 76 studies showed same findings. The poor knowledge, negative perception about medication, side effects, and high medication cost were the most common predictors of poor drug adherence . SocioecLifestyle interventions have the potential to reduce the need or number of medications in treatment of hypertension which includes reduced alcohol intake, reduced sodium chloride intake, increased physical activity, and control of overweight. In addition, several studies have showed globally that demographic factors increase the risk of uncontrolled hypertension among hypertensive patients , 18. OurAccording to Farquhar's model of behavior change, our study results showed most patients had sufficient knowledge about hypertension, but only a few showed real motivations to change . MoreoveOur study revealed that the patients of a tertiary care hospital had sufficient general knowledge of hypertension but were unaware about their disease status and their diagnosis, target and recent blood pressure values, and about their target organ damage. Most of patients had adequate knowledge about the risk factors and complications of hypertension. Most of the patients had reasonable good drug compliance. The forgetfulness was commonly attributed for nonadherence. It is important to assess the extent of awareness of control of blood pressure levels among patients. That will be helpful to be part of educational programs and interventions designed to improve the control of hypertension. Therefore, healthcare professionals should implement individualized educational programmes to increase the awareness of disease status, appropriate blood pressure levels and adherence of treatment to improve outcome of patients. This study specifies potential areas where appropriate education of not only hypertension but also BP control could be an apt tool for the improvement of hypertension knowledge of patients.We have not carried out a study to assess the knowledge, awareness, and medication adherence following the educational interventions. Therefore, further large-scale studies should be carried out to assess the participants' perceptional level following interventions.


Chronic kidney disease (CKD) is known to be associated with several co-occurring conditions. We aimed at exploring multimorbidity patterns associated with CKD, as well as the impact of physical performance and CKD severity on them in a population of older outpatients.2), cognitive impairment, depression, hearing impairment and vision impairment were included in the analyses. Physical performance was assessed by the Short Physical Performance Battery (SPPB) and used as stratification variable. Pairs of co-occurring diseases were analyzed by logistic regression. Patterns of multimorbidity were investigated by hierarchical cluster analysis.Our series consisted of 2252 patients enrolled in the Screening of CKD among Older People across Europe multicenter observational study. Hypertension, stroke, transient ischemic attack, cancer, hip fracture, osteoporosis, Parkinson’s disease, asthma, chronic obstructive pulmonary disease, congestive heart failure, angina, myocardial infarction, atrial fibrillation, anemia, CKD  contributed to a wide cluster including cardiovascular, respiratory and neurologic diseases, as well as osteoporosis, hip fracture and cancer.CKD was among the most frequently observed conditions and it was rarely observed without any other co-occurring disease. CKD was significantly associated with hypertension, anemia, heart failure, atrial fibrillation, myocardial infarction and hip fracture. When stratifying by SPPB, CKD was also significantly associated with vision impairment in SPPB = 5–8 group, and hearing impairment in SPPB = 0–4 group. Cluster analysis individuated two main clusters, one including CKD, hypertension and sensory impairments, and the second including all other conditions. Stratifying by SPPB, CKD contribute to a cluster including diabetes, anemia, osteoporosis, hypertension and sensory impairments in the SPPB = 0–4 group. When defining CKD as eGFR< 45 or 30 ml/min/1.73 mCKD and its severity may contribute significantly to specific multimorbidity patterns, at least based on the cluster analysis. Physical performance as assessed by SPPB may be associated with not negligible changes in both co-occurring pairs and multimorbidity clusters.NCT02691546).The SCOPE study is registered at clinicaltrials.gov ( The progressive aging of the population in industrialized countries is accompanied by a dramatic increase in the prevalence of multiple chronic diseases . TraditiChronic kidney disease (CKD) is among the most frequent chronic conditions observed among older patients, and it dramatically impacts health status and survival in the general population, as well as in older populations –14. AlthAdditionally, data about the impact of potentially relevant stratification variables on patterns of multimorbidity are very limited. Current evidence suggests that age, sex, and race/ethnicity may be associated with small but not negligible changes in multimorbidity patterns . HoweverFinally, CKD severity may also affect multimorbidity patterns. Indeed, many of CKD-related concordant comorbidities, such as anemia, osteoporosis and heart failure, are known to be associated with the severity of CKD .By including a detailed collection of data about diagnoses and comprehensive geriatric assessment including short physical performance battery (SPPB) , the ScrThe SCOPE study (European Grant Agreement no. 436849), is a multicenter 2-year prospective cohort study involving patients older than 75 years attending geriatric and nephrology outpatient services in participating institutions in Austria, Germany, Israel, Italy, the Netherlands, Poland and Spain. Methods of the SCOPE study have been extensively described elsewhere . BrieflyOverall, 2461 patients were initially enrolled in the study. Of them, 209 patients were excluded from this study because of incomplete baseline data, thus leaving a final sample of 2252 patients to be included in the analysis.2. eGFR was calculated by creatinine-based Berlin Initiative Study (BIS) equation [Diagnoses were ascertained by the study physician by clinical history and physical examination. Physicians asked the participants to show all clinical records and prescription forms or drug containers of the drugs used. The following diagnoses were included in the analysis: hypertension, stroke, transient ischemic attack (TIA), cancer, hip fracture, osteoporosis, Parkinson’s disease, asthma, chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), angina, myocardial infarction, atrial fibrillation. Chronic kidney disease was defined on the basis of estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 mequation . Such eqequation , 21. Cogequation . Depressequation . Vision equation , and patFurther variables included in the analysis were age, sex, and physical performance. Physical performance was measured by SPPB . The SPP2, to define CKD.First, descriptive analysis of the study population grouped according to SPPB score was provided. Data were reported as mean ± SD for continuous variables and number (percentage) for categorical ones. Chi-square test was used to analyze categorical variables, while ANOVA one way was used for continuous ones. For each chronic disease included in the analysis, its prevalence with and without co-occurring disease(s) was estimated. The expected prevalence of disease pairs involving CKD was computed and compared with the observed co-prevalence. To confirm the results of the pairs analysis and to control for possible confounders, logistic regression models were conducted to analyze the association between each pair of co-occurring diseases. This analysis was adjusted for age, sex, and all of the other diseases. To analyze different patterns of associative multimorbidity, without any a priori hypothesis, we used a hierarchical agglomerative clustering approach to create dendrograms. A binary distance measure (squared euclidean distance) was used to produce the distance matrix resulting in more distinctive clusters compared with other proximity measures. For dendrograms analysis we used the Ward method as previously reported  to find Statistical analysis was carried out by using SPSS for Win V23.0 statistical software package .General characteristics of the study population are reported in Table n = 24) not able to do any SPPB tasks and scoring 0 at physical performance assessment. Patients with lower SPPB scores were older and more frequently women  patients, while 614 patients (27.3%) had SPPB = 5–8, and 247 patients (11.0%) had SPPB = 0–4. This latter group included only a minority of patients , CHF , atrial fibrillation  and hip fracture  among patients with SPPB score = 9–12. At variance, the significant co-occurring pairs involving CKD were those with hypertension , CHF , anemia  and vision impairment  among patients with SPPB = 5–8. Finally, significant co-occurring pairs among patients with SPPB = 0–4 were those involving hypertension , anemia  and hearing impairment .Finally, patterns of multimorbidity from cluster analysis are reported in Fig. 2, the strength of the association of CKD with hypertension, sensory impairments, osteoporosis, anemia and CHF increased together with CKD severity  and SPPB = 0–4 (hearing impairment). Thus, it seems that a simple physical performance test, already known to predict mobility disability, ADL dependency, rehospitalization and death –31, may While the association between CKD and cardiovascular diseases, anemia, diabetes and mineral bone disease (including fractures) is well recognized and extensively addressed in clinical guidelines where specific recommendations are provided for these conditions , the comp <  0.001) [Given the mean age of enrolled patients, the association between CKD and sensory impairment may be simply related to older age independent of kidney function. However, several potential mechanisms may underly such association. Hearing loss was found to be highly prevalent among CKD patients , 37, and  0.001) . Diabeti  0.001) . It is w  0.001) . DespiteCluster analysis provided quietly consistent results showing that CKD may contribute to a cluster of multimorbidity including hypertension and sensory impairments in the whole study population. These findings are somewhat different from those reported in former studies and characteristics of population, as well as the list of diagnoses included in the analysis likely account for these differences. Marengoni et al. identified five major clusters  in a population of 1099 community-dwelling people aged 77 or more. However, CKD was not included in the list of diagnoses . In the Interestingly, when stratifying analysis according to physical performance, the cluster including CKD was “enriched” by a sub-cluster including anemia and osteoporosis ) and diabetes (i.e. a leading cause of CKD) among patients with lowest SPPB scores. Thus, both co-occurring pairs and clustering of diseases may change as a function of SPPB among older people in the present study, and SPPB is among the most useful frailty tools for the identification of patients that may benefit from interventions aimed at improving functional capacity in primary care settings . Our finFinally, this is the first study including CKD severity in the analysis of multimorbidity patterns. Indeed, CKD severity was not considered in former multimorbidity studies , 10. BesLimitations of our study deserve to be mentioned. The cross-sectional design did not allow to investigate pathways leading to multimorbidity and the prognostic impact of specific multimorbidity patterns. Additionally, the list of diagnoses included in the analysis could not be considered exhaustive. However, we used a list of diagnoses very similar to that already used in studies investigating multimorbidity patterns. Nevertheless, the prevalence of individual diseases and that of individual diagnoses with multimorbidity was somewhat higher in the SCOPE study population compared to former studies , 6, 10, CKD contributes significantly to multimorbidity in a population of older outpatients and it was rarely observed without any co-occurring disease. The most significant co-occurring pairs involving CKD included hypertension, anemia, CHF, atrial fibrillation, myocardial infarction, hip fracture, and to a lesser extent hearing impairment, diabetes and cancer. Cluster analysis showed that CKD may cluster with hypertension and sensory impairments. Physical performance as assessed by SPPB may be associated with not negligible changes in both co-occurring pairs and multimorbidity clusters. These findings strengthen the need of assessing physical performance and investigating interventions targeting physical function among complex multimorbid patients in an attempt to improve outcomes and reduce costs associated with multimorbidity. Finally, CKD severity may significantly affect patterns of multimorbidity, which suggests that disease severity should be further investigated in multimorbidity studies.


Homocysteine (Hcy) is one of the main factors leading to arteriosclerosis, which is closely related to cardiovascular disease. Recent studies have found that serum Hcy levels are increased in patients with chronic heart failure (CHF), and it is speculated that Hcy may be a risk factor for CHF, but evidence-based medicine evidence is lacking. The aim of this study was to investigate the correlation between serum Hcy levels and CHF by means of systematic review.The databases of PubMed, Embase, The Cochrance Library, Web of Science, CNKI , VIP , Wanfang and China Biology Medicine disc were searched by computer. In addition, Baidu Scholar and Google Scholar were manually searched to collect all case–control studies related to serum Hcy and CHF. The search time limit was from database establishment to November 2020. Two reviewers independently screened the literatures, extracted the data and evaluated the risk of bias of the included literatures.In this study, we evaluated the correlation between serum Hcy levels and CHF by the levels of serum Hcy in CHF patients and non-CHF patients.This study will provide reliable evidence for the clinical value of serum Hcy in the field of CHF disease.DOI 10.17605/OSF.IO/QMPRC. The results of a survey of 20 cities in 10 provinces of China showed that the prevalence of CHF in people aged 35 to 74 years was 0.9% in 2000. Research data in developed countries showed that the prevalence of heart failure was about 2.0%, and the prevalence of heart failure increases with age, and the prevalence of heart failure can reach more than 10% in people over 70 years of age. Patients with CHF are often accompanied by symptoms such as dyspnea, fatigue or fluid retention, which affects the quality of life and also brings a heavy burden to the society.Chronic heart failure (CHF) is a clinical syndrome caused by impaired ventricular filling and ejection capacity which are caused by different etiologies, resulting in reduced ventricular ejection function and failure to meet systemic metabolic needs. and a risk factor for diseases such as breast cancer, Alzheimer's disease, and age-related macular degeneration.Some studies have also found a positive correlation between serum Hcy and BNP, HHcy can increase the 5-year risk of death in patients with heart failure. Tekin found that in patients with heart failure, serum Hcy gradually increased with the severity of cardiac function, and HHcy could reflect the severity of heart failure and may be an important predictor of mid-term death in patients with heart failure. At present, there are few studies on the relationship between serum homocysteine levels and CHF, and there is a lack of relevant evidence-based basis. Therefore, this study systematically evaluated the published studies on the relationship between serum homocysteine levels and patients with CHF at home and abroad in order to provide evidence-based medical evidence for the clinical value of Hcy in the field of CHF disease.Hcy is an important intermediate product in methionine and cysteine metabolism, and hyperhomocysteinemia (HHcy) is diagnosed when human serum Hcy level is greater than 15 μmol/L. HHcy is considered a marker of cardiovascular disease22.1This protocol of systematic review and meta-analysis will be drafted under the guidance of the preferred reporting items for systematic reviews and meta-analysis protocols (PRISMA-P). It will be registered in the open science framework (OSF) on December 5, 2020 (registration number: DOI 10.17605/OSF.IO/QMPRC).2.2Since this is a protocol with no patient recruitment and personal information collection, the approval of the ethics committee is not required.2.32.3.1We will collect all case–control studies on the relationship between serum Hcy levels and CHF, regardless of blind method, publication status, region, but language is limited to Chinese and English.2.3.2Patients with definite diagnosis of CHF, including nationality, race, age, gender, and course of disease. Healthy people were used as controls.2.3.3Serum Hcy levels.2.3.4Correlation between serum Hcy levels and CHF.2.41.Repeatedly published papers;2.Non-Chinese and English literatures;3.Literatures with incomplete data or unusable data;4.The patient was clinically diagnosed with a disease  that had a significant impact on the results of the study;5.Patients with CHF are taking immunosuppressive agents, antiepileptic drugs, etc.2.5CNKI, Wanfang Data, VIP, PubMed, Cochrane Library, Embase, Web of Science, and other databases were searched by computer, and the retrieval time was from the establishment of database to November 2020. Take “chronic heart failure,” “congestive heart failure,” “homocysteine” as the Chinese search terms and search in Chinese databases, including CNKI, Wanfang, VIP, China Biology Medicine disc; Take “Cardiac Failure,” “Heart Decompensation,” “L-Isomer Homocysteine” as the English terms and search terms and search in English databases, including PubMed, EMBASE, Web of Science, the Cochrane Library. In addition, manual retrieval was conducted on Baidu academic and Google academic, and all domestic and foreign literatures on the relationship between serum homocysteine and CHF were collected. Taking PubMed as an example, the retrieval strategy was shown in Table 2.6Referring to the Methods for inclusion in the Cochrane Handbook of Systematic Reviewers (Version 5.0), according to the PRISMA flow chart, two researchers independently screened the literature using EndNote X7 literature management software based on the above inclusion and exclusion criteria. The third researcher discussed and determined those studies that were difficult to include due to differences. At the same time, Excel 2013 was used to extract relevant information, including:1.Clinical research ;2.Exposure factors ;3.Key elements of bias risk assessment; Observation index.The literature selection process was shown in Figure 2.7The risk of bias of the included studies was independently evaluated by two investigators and the results were cross-checked, and the risk of bias of case–control studies was evaluated using the Newcastle-Ottawa-Scale (NOS) scale.2.82 test (the test level was α = 0.1), and the heterogeneity was quantitatively judged in combination with I2. If  indicated low heterogeneity, the fixed-effect model was used for Meta analysis. If  indicates heterogeneity among studies, the source of heterogeneity shall be analyzed. Clinical heterogeneity was treated by subgroup analysis. Statistical heterogeneity was considered if there was no significant clinical heterogeneity and methodological heterogeneity, so the random effects model was used for analysis. If the clinical heterogeneity is too obvious to be analyzed, the meta-analysis will not be performed, but descriptive analysis will be performed.RevMan5.3 software will be used for Meta analysis. For continuous weighted mean difference (WMD) is used if the measurement tool is consistent with the unit of measurement. If the measurement tool or unit of measurement is inconsistent, the standard mean difference (SMD) is used as the effect size. Each effect size is provided with its point estimate and 95% confidence interval (CI). The heterogeneity among the included study results was analyzed by χ2.8.1If the article had missing data, the authors were contacted by email to supplement the relevant information. If the authors could not be contacted, or the authors had lost relevant data, descriptive analysis was performed instead of meta-analysis.2.8.2Take subgroup analysis according to the geographical region; take subgroup analysis according to age; take subgroup analysis according to the included sample size.2.8.3To determine the stability of the outcome measures, sensitivity analysis was used to analyze each outcome indicator.2.8.4If the number of studies included in an outcome measure was not <10, a funnel plot was used for the assessment of publication bias. In addition, Egger's and Begg's test publication was used for the evaluation of potential bias.2.8.5The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) will be used to assess the quality of evidence. It contains 5 domains . And the quality of evidence will be rated as high, moderate, low, and very low.3,13 CHF is a progressive disease, and some studies suggested that the occurrence and development of CHF are associated with ventricular remodeling, changes in the sympathetic nervous system, endothelin, and Hcy, and its pathological and physiological mechanisms are more complex. In clinical practice, heart failure is diagnosed and evaluated mainly through medical history and relevant examinations. Comprehensive and accurate diagnosis is the premise and basis of effective treatment for patients with heart failure. Therefore, how to accurately diagnose and evaluate patients’ condition at an early stage has become the main research direction of many scholars.The occurrence of CHF is often accompanied by changes such as myocardial overload, myocardial cell injury, and apoptosis, which are mainly caused by injury factors such as coronary heart disease, hypertension, and inflammation, and finally lead to cardiac pumping dysfunction, which is a clinical manifestation of the development of cardiac disease to a serious and final stage.Raaf and others have found that HHcy can increase the level of transforming growth factor-β1 (TGFβ1), affect the balance between TIMP1 and MMP1, lead to dysregulation of extracellular matrix degradation, cause extracellular matrix remodeling, and affect cardiac function. In addition, homocysteine also increases the expression of type I collagen in cardiac fibroblasts and cause myocardial extracellular matrix remodeling.Therefore, HHcy will cause cardiomyocyte extracellular matrix remodeling, leading to myocardial tissue damage, with the changes in cardiac structure and infiltration of inflammatory cells, cardiac function gradually decreases, and finally heart failure develops.Okuyan also confirmed that serum Hcy levels are generally increased in patients with CHF, suggesting that serum Hcy may be involved in the process of CHF development. Other studies have found that serum Hcy levels are related to the severity of heart failure patients, and also affect the prognosis of patients. In a study of 108 CHF patients, it was found that the 3-year survival rate was 37% in patients with HHcy, while the 3-year survival rate was 73% in patients with normal Hcy, considering that HHcy can reflect the severity of CHF patients and is related to poor prognosis, whether the treatment of HHcy can improve the prognosis of CHF remains to be further studied. Therefore, it is necessary to analyze the existing studies on the relationship between serum Hcy level and CHF, and objectively evaluate the value of Hcy in the diagnosis, severity and prognosis of CHF, so as to provide reliable evidence for clinicians to apply Hcy to CHF patients. This study also has some limitations, with few included articles and small sample size. As only case–control studies were included, implementation and measurement bias could not be avoided due to the limitations of study design, and the time relationship between the increase of serum Hcy levels and the occurrence and development of CHF could not be determined. Due to the limitation of language ability, we only search the English and Chinese literatures, and may ignore the studies or reports in other languages.Hcy is a sulfur-containing amino acid, mainly derived from dietary intake of methionine. Some studies have reported that serum homocysteine can promote the production of oxygen free radicals in the body, damage vascular endothelial cells and vascular function, and further cause intimal thickening and stiffness of blood vessels, leading to atherosclerosis.Data curation: Xi Wang, Fu Wang.Funding acquisition: Jianbin Liu.Investigation: Fu Wang, Jun Cai.Software: Zhiquan Feng, Jun Cai.Supervision: Zhiquan Feng, Jun Cai.Writing – original draft: Xi Wang, Fu Wang.Writing – review & editing: Xi Wang, Jianbin Liu.