Poisoning from BAAs can lead to severe morbidity and mortality. We aimed to determine the utility of extracorporeal treatments (ECTRs) in BAAs poisoning.We conducted systematic reviews of the literature, screened studies, extracted data, and summarized findings following published EXTRIP methods.A total of 76 studies  met inclusion criteria. Toxicokinetic or pharmacokinetic data were available on 334 patients . For intermittent hemodialysis, atenolol, nadolol, practolol, and sotalol were assessed as dialyzable; acebutolol, bisoprolol, and metipranolol were assessed as moderately dialyzable; metoprolol and talinolol were considered slightly dialyzable; and betaxolol, carvedilol, labetalol, mepindolol, propranolol, and timolol were considered not dialyzable. Data were available for clinical analysis on 37 BAA poisoned patients , and no reliable comparison between the ECTR cohort and historical controls treated with standard care alone could be performed. The EXTRIP workgroup recommends against using ECTR for patients severely poisoned with propranolol . The workgroup offered no recommendation for ECTR in patients severely poisoned with atenolol or sotalol because of apparent balance of risks and benefits, except for impaired kidney function in which ECTR is suggested . Indications for ECTR in patients with impaired kidney function include refractory bradycardia and hypotension for atenolol or sotalol poisoning, and recurrent torsade de pointes for sotalol. Although other BAAs were considered dialyzable, clinical data were too limited to develop recommendations.BAAs have different properties affecting their removal by ECTR. The EXTRIP workgroup assessed propranolol as non-dialyzable. Atenolol and sotalol were assessed as dialyzable in patients with kidney impairment, and the workgroup suggests ECTR in patients severely poisoned with these drugs when aforementioned indications are present.The online version contains supplementary material available at 10.1186/s13054-021-03585-7. Half-lives and clearances of BAAs obtained during ECTR are summarized in Table When measured from dialysate collection, the amount of BAA removed divided by the reported ingested dose during hemodialysis (when adjusted for a 6-h treatment and bioavailability) was 24% for atenolol , 18% forData for continuous kidney replacement therapy (CKRT) are sparse: in 3 cases of atenolol overdose, CKRT removed between 8 and 25% of total body burden adjusted for a 6-h period , 128, wiAn increase in serum/blood concentrations was often observed following ECTR, often referred as “rebound,” in both pharmacokinetic studies , 83, 92 Dialyzable for atenolol, nadolol, practolol, and sotalol; Moderately dialyzable for acebutolol, bisoprolol, and metipranolol; Slightly dialyzable for metoprolol and talinolol; Not dialyzable for betaxolol, carvedilol, labetalol, mepindolol, propranolol, and timolol. Some publications report that metoprolol may be dialyzable based on achievable clearance of 80–120 mL/min [Table 0 mL/min . HoweverAlthough extracorporeal clearance of BAAs is independent of kidney function, its relative impact compared to total body clearance will increase for some BAAs as kidney function declines. This can be illustrated graphically Fig. : for exaDialyzable” for one case of hemodialysis and “Moderately dialyzable” for one case of hemoperfusion-hemodialysis in series.Only 7 patients that could be assessed for dialyzability grading had normal kidney function, and only two reports were identified for a BAA  whose grading may differ depending on kidney function , 15. ForAmong case reports and case series, the panel acknowledged variability in methodological quality and lack of reporting of critical information . The eviAs reflected by changing trends in the management of BAA poisoning over almost 40 years, treatments were very heterogeneous. In particular, only eight patients received high-dose insulin euglycemic therapy and four patients received ECLS, treatments now considered likely to improve outcome . For theFor sotalol, resolution of dysrhythmias/torsade de pointes was rapid with intermittent hemodialysis, often occurring during or just after treatment , 121, whIn summary, clinical improvement from ECTR was generally noted with BAAs considered dialyzable such as atenolol and sotalol when high-efficiency ECTRs were used, whereas this was questionable with other BAAs or when techniques with lower efficiency were used.To further measure the effect of ECTR, outcomes of the ECTR cohort were compared to historical controls not receiving ECTRs Table . UnfortuAs per EXTRIP methods, the workgroup only voted on BAAs for which the number of patient clinical reports were sufficient. Although there were 4 reports for acebutolol and talinolol, they were not considered to be of sufficient quality to permit elaborations of recommendations.Propranololrecommend against performing ECTR in addition to standard care rather than standard care alone .In patients severely poisoned with propranolol, we Atenolol, we suggest performing ECTR in addition to standard care rather than standard care alone when refractory bradycardia and hypotension is present In patients severely poisoned with atenolol and kidney impairment*, we make no recommendation for or against performing ECTR in addition to standard care rather than standard care alone In patients severely poisoned with atenolol and normal kidney functionSotalol, we suggest performing ECTR in addition to standard care rather than standard care alone when refractory bradycardia and hypotension and/or recurrent torsade de pointes is present In patients severely poisoned with sotalol and kidney impairment*, we make no recommendation for or against performing ECTR in addition to standard care rather than standard care alone .In patients severely poisoned with sotalol with normal kidney functionwe suggest against performing ECTR solely based on the QT interval .In patients severely poisoned with sotalol, Kidney impairment” was defined as stage 3B, 4, or 5 CKD  or AKI as KDIGO stage 2 or 3 AKI. In the absence of a baseline serum creatinine concentration, kidney impairment was defined as an eGFR < 45 mL/min/1.73m2 in adults; and in children with no baseline creatinine, the use of KDIGO criteria of AKI stage 2 and 3 after imputing a baseline serum creatinine using the Schwartz 2009 formula assuming 120 mL/min/1.73m2 of "normal" eGFR. The presence of oligo/anuria unresponsive to fluid resuscitation should be considered as impaired kidney function, regardless of serum creatinine concentration *“Severe BAA poisoning can lead to bradycardia and hypotension refractory to vasopressors and inotropes, occasionally causing death . AssuminPropranolol has a short half-life and a high endogenous clearance independent of kidney function. These attributes added to extensive protein binding make this drug non-dialyzable regardless of the ECTR used. Although the data were limited, ECTR did not appear to accelerate clinical recovery and the mortality from ECTR cases was higher than historical controls. For these reasons, the workgroup recommended against ECTR for propranolol poisoning (Median: 1.0/Upper quartile: 1.0/Disagreement index: 0.0).Dialyzable” in patients with kidney impairment. Although the number of cases is small, clinical improvement from sotalol and atenolol poisoning appears to coincide with initiation of ECTR, especially when high efficiency techniques are used. It is conceivable that relevant patient-important outcomes (PIOs), such as length of vasopressor requirement, long-term sequelae, and mortality would be reduced with ECTR in this population. In patients who already have vascular access in place, the risk associated with insertion is already taken into account, so the risk-benefit ratio is even lower. The workgroup suggested ECTR in patients with impaired kidney function for both atenolol (Median: 7.0 / Lower quartile: 4.0 / Disagreement index: 0.59) and sotalol (Median: 7.0 / Lower quartile: 4.0 / Disagreement index: 0.59); the workgroup nevertheless acknowledged that the initiation of ECTR, even without net ultrafiltration, might exacerbate hemodynamic instability and may not be possible to perform. The benefit of ECTR is theoretically less for patients poisoned with atenolol or sotalol and normal kidney function, even if the addition of ECTR can approximately double total clearance; the duration of toxicity is expected to be much shorter in this population. For these reasons, the workgroup considered that, at the time of writing, the benefits and harms were balanced with considerable knowledge gaps and made no recommendation for patients poisoned with atenolol or sotalol and normal kidney function.Atenolol and sotalol both have endogenous clearances  that are highly dependent on kidney function. The contribution of ECTR in patients with kidney impairment is considerable. The greater the impairment in kidney function, the greater the relative toxicokinetic effect of ECTR. Both are considered to be “A major consideration for sotalol is its ability to cause QT prolongation, which is uncommon with other BAAs and can lead to life-endangering torsade de pointes, a poor prognostic indicator in sotalol poisoning. Obviously, the workgroup is not advocating ECTR for the treatment of torsade de pointes, as ECTR would not be technically feasible. However, recurrent torsade de pointes is indicative of severity and of a role for ECTR initiation. For non-recurrent torsades, ECTR is not justified. In the literature, there is no clear QTc duration cut-off which predicts torsade de pointes . The risAlthough monitoring of poison concentrations is useful in some settings, there remain too many uncertainties in the concentration-effect relationship to provide a threshold concentration for ECTR initiation in BAA poisoning. Hypotension and bradycardia are poorly related to atenolol concentrations , QT inteAdditional pharmacokinetic data in ESKD patients are needed, especially during hemodialysis, for acebutolol (because of imprecision about sampling in studies), betaxolol, bopindolol, carteolol, cetamolol, nadolol, oxprenolol, pindolol, sotalol, and timolol. In addition, clinical cases of poisoning with toxicokinetic data of ECTR is required for acebutolol, atenolol, bisoprolol, metoprolol, nadolol and sotalol in patients with normal GFR or slightly impaired GFR.Toxicokinetic/toxicodynamic relationships should better evaluate if serum concentrations can determine the utility of ECTR in clinical decision-making. Better prognostic markers on admission would also be useful to determine which subset of patients are most likely to benefit from ECTR.The added value of ECTR to ECLS should be demonstrated. In patients with impaired kidney function, additional studies could help characterize if the transfer of an unstable patient for ECTR with or without ECLS could potentially be beneficial and within which timeframe this could be useful. If ECLS is unavailable in the initial center, studies could compare clinical outcomes associated with transfer for ECLS vs. hemodialysis alone at the initial center.we recommend using intermittent hemodialysis rather than any other type of ECTR .In patients severely poisoned with atenolol or sotalol requiring ECTR: when all modalities are available, If ECTR is used for poison removal, then the most efficient modality at removing atenolol or sotalol should be selected, i.e., intermittent hemodialysis. In the rare circumstance that intermittent hemodialysis is unavailable but other techniques are, then hemoperfusion, CKRT, sustained low-efficiency dialysis (SLED), or prolonged intermittent renal replacement therapy (PIRRT) can be used, preferably the modality providing the best solute clearance and quickest to deliver. Although CKRT and other “slower” techniques such as SLED/PIRRT are often preferred for patients with hemodynamic compromise, this applies specifically to those requiring net ultrafiltration. It is therefore uncertain if CKRT or SLED/PIRRT would be better tolerated than intermittent hemodialysis in patients not requiring net ultrafiltration. It is acknowledged that all techniques may exacerbate hypotension to some extent for various causes including fluid and solute shifts, and electrolyte fluxes.Regardless of technique, ECTR parameters should be optimized to enhance clearance   and to rImportantly, if dialysis is performed for sotalol poisoning, the input of a nephrologist is recommended to ensure that the serum magnesium concentration remains above 1 mmol/L and serum potassium concentration within 4.5-5 mmol/L to minimize the risk of dysrhythmias, including torsade de pointes. Magnesium may be added to the dialysate or administered intravenously to offset its elimination during ECTR.Data with hemoperfusion and high-cut off dialysis should be assessed in poisoning from highly protein-bound BAAs with reasonably low volume of distribution and plasma clearance such as penbutolol, oxprenolol, and carvedilol.we recommend stopping ECTR based on clinical improvement In patients severely poisoned with atenolol or sotalol requiring ECTR, The indication to stop ECTR, once initiated, should be reliant on clinical indicators of improvement. These include appropriate heart rate and blood pressure for adequate end organ perfusion, weaning of ECLS, decreasing inotropic and vasopressor requirements, and sustained cessation of torsade de pointes if applicable. It is recognized that QT interval prolongation may persist even at therapeutic sotalol concentrations so the use of this target for cessation is not recommended. In addition, there is no predefined duration of ECTR to treat BAA poisoning as this will depend on the type and amount of BAA ingested, as well as the underlying kidney function in some cases. The workgroup suggested not to cease ECTR solely based on a target serum concentration, as safe thresholds are not well known, and assays are infrequently available to guide judgement.Our work has several strengths. This is the first systematic review of the use of extracorporeal therapy in BAA poisoning. This systematic review summarizes the best evidence on the use of extracorporeal therapy in BAA poisoning using the most stringent guideline methodology (GRADE). No articles were rejected based on language or year of publication. It also provides clinical recommendations following a voting process using a two-round modified Delphi procedure from an international collaborative comprising recognized experts from various clinical specialties and resource settings. Limitations of the study are inherently associated with the quality of articles used for the drafting of recommendations. In many cases, details regarding these articles were of poor quality. There were insufficient data to draft recommendations on BAAs other than propranolol, atenolol, and sotalol due to the limited published evidence available; however, the workgroup acknowledged there was little clinical plausibility of a clinical benefit from ECTR for non-dialyzable BAAs such as betaxolol, carvedilol, esmolol, labetalol, mepindolol, and timolol.In conclusion, poisoning from BAAs can cause serious toxicity and death. β-adrenergic antagonists have different physicochemical properties and pharmacokinetics which will affect their removal by ECTR. The EXTRIP workgroup assessed propranolol as non-dialyzable. Atenolol as well as sotalol were assessed as dialyzable in patients with kidney impairment and the workgroup suggests ECTR in patients severely poisoned with these drugs when aforementioned indications are present.Additional file 1. Detailed methods and glossary.


Atherosclerotic renal artery stenosis (ARAS) is frequently related to ischemic nephropathy, secondary hypertension, and end-stage renal failure. Thus, this study aimed to explore whether certain circulating long noncoding RNAs (lncRNAs) may be used as potential specific ARAS biomarkers.p value cutoff was set at .05. According to these criteria, six lncRNAs were identified from 1150 lncRNAs. After validation by quantitative PCR (qPCR), these lncRNAs were independently validated in blood from groups of 18 ARAS patients, 18 non-ARAS individuals, and 18 healthy volunteers, furthermore, the predictive value of lncRNA PR11-387H17.6 was further assessed using blood from groups of 99 ARAS patients, 49 non-ARAS individuals, and 50 healthy volunteers. A receiver operating characteristic (ROC) curve analysis was performed to assess the performance of these lncRNAs as biomarkers.In the present study, a microarray analysis was performed to screen for lncRNAs in renal artery tissue from four ARAS patients and four non-ARAS individuals. To identify specific lncRNAs as candidate potential biomarkers of ARAS, we used the following criteria: the fold change was set to >3.0 (compared with non-ARAS tissues), and p= .006).In the ROC analysis, the area under the curve (AUC) of PR11-387H17.6 was 0.733, with 52.5% sensitivity and 84.8% specificity in predicting the occurrence of ARAS. After considering the risk factors, the AUC of PR11-387H17.6 was 0.844, and the optimal sensitivity increased from 52.5% to 74.5%, although the specificity decreased from 84.8% to 81.9%. In the multivariable logistic analysis, PR11-387H17.6 was an independent predictor of major adverse events (OR: 3.039; 95% CI: 1.388–6.654; PR11-387H17.6 is a potential diagnostic biomarker of ARAS. The lncRNA levels in blood cells are regulated in ARAS. Thus, further investigations of the role of lncRNAs in ARAS are warranted. Renal artery stenosis (RAS) is generally defined as a reduction in the luminal diameter in one or both renal arteries . StenosiLong noncoding RNAs (lncRNAs) constitute a novel class of molecules that range from 200 to over 10,000 nucleotides and lack the ability to code proteins . The recThus, the aim of our study was to identify specific circulating lncRNAs that may serve as potential ARAS biomarkers. LncRNAs were screened by a microarray analysis and validated in CAD patients and healthy volunteers in different cohorts with or without ARAS.This study used a single-center study designed to advance the diagnosis of ARAS at the General Hospital of Northern Theater Command. In total, 121 patients with ARAS, which was defined by the following:(1) aged 18–80 years; (2) one of RAS ≥50% and coronary artery lesions graded as ≥50% narrowing of luminal diameter, 71 patients without ARAS  undergoing percutaneous coronary angiography and renal arteriography were enrolled in this study between 1 May 2015 and 31 September 2016. Simultaneously, arterial blood samples were collected from 68 apparently healthy volunteers . The initial ‘microarray cohort’ comprised renal artery tissue from a discovery group of four ARAS patients and four non-ARAS individuals. The association between the lncRNA expression and the risk of ARAS was analyzed in two separate cohorts. The training group comprised 18 ARAS patients, 18 non-ARAS individuals, and 18 healthy volunteers. To investigate the specificity of the association between PR11-387H17.6 and ARAS, a validation group comprising 99 ARAS patients, 49 non-ARAS individuals, and 50 healthy volunteers was also analyzed. The exclusion criteria for this study were as follows: (1) renal size <7.5 cm on the stenotic side; (2) age less than 18 or greater than 80 years; (3) eGFR <15 mL/min; (4) malignant tumors or other severe systemic diseases ; (5) serious acute infection within 6 weeks before admission; (6) active chronic inflammatory disease; and (7) suspected drug or alcohol abuse. The diagnosis was based on the final diagnosis based on coronary and renal artery angiography at discharge according to the ACC/AHA classification [After angiography, peripheral blood samples (5 mL) were collected from the radial arteries of each patient in test tubes containing EDTA. The hematocytes were carefully collected, divided into aliquots and stored at −80 °C before use. The total RNA was extracted using TRIzol Reagent  according to the manufacturer’s instructions. All steps were performed at 4 °C.2O, and 2.0 µL of the synthesized cDNA. The reaction conditions were as follows: 95 °C for 10 min, followed by 35 cycles of 95 °C for 15 s and 60 °C for 60 s. The Ct value was defined as the cycle number at which the fluorescence exceeded the threshold. The levels of the lncRNAs in the peripheral blood were calculated using the CT (ΔCt) method because currently, no consensus exists regarding stable and suitable internal controls for lncRNAs in blood samples. The changes in gene expression were calculated using the equation 2–ΔCT [The total RNA was extracted from the white blood cells and dissolved in 10 µL of DNase/RNase-free deionized water . The quantity and quality of the total RNA from the peripheral blood were determined using a NanoDrop instrument , and the samples were used only if the ratio of the absorbance at 260 and 280 nm (A260/280) was between 1.5 and 1.9. RNA samples at concentrations of 1 μg were used for each reverse transcription reaction. Then, the RNA was used for the cDNA synthesis using a PrimeScript 1st Strand cDNA Synthesis Kit  according to the manufacturer’s instructions. Then, quantitative real-time PCR was conducted using EvaGreen 2X qPCR MasterMix  according to the manufacturer’s instructions. The 20 µL final reaction mixture contained 10 µL of EvaGreen 2X qPCR MasterMix, 0.6 µL of forward primer, 0.6 µL of reverse primer, 6.8 µL of nuclease-free Hon 2–ΔCT .Supplementary Table S1.The relative expression levels of the lncRNAs in the peripheral blood leukocytes were normalized to the expression of the endogenous control gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH)  using the comparative CT (ΔCt) method. The lncRNA levels were log-transformed by considering the base 10 logarithm of the skewness of their distribution. A melt curve analysis was performed to confirm the specificity of the amplification and lack of primer dimers. The quantitative PCR (qPCR) primers for the lncRNAs are listed in supplementary data analysis. The quantile normalization and subsequent data processing were performed using the open-source R software package. Agilent Feature Extraction software (version 11.0.1.1) was utilized to analyze the acquired array images. Differentially expressed lncRNAs that statistical significantly differed between two groups were defined by Volcano Plot filtering. The differentially expressed lncRNAs between two samples were identified by fold change filtering. Hierarchical clustering was performed to show the distinguishable lncRNA expression patterns among the samples. To identify a potential biomarker candidate lncRNA, all lncRNAs were screened according to the following criteria: the fold change was set to >3.0 (compared with non-ARAS tissues), and p value cutoff was set at .05.For the initial lncRNA screening, RNA was isolated from samples of renal artery tissue collected during a nephrectomy surgery from eight individuals . Written informed consent for the surgery was obtained from the eight patients or their families. The total RNA from each sample was quantified using a NanoDrop ND-1000. The RNA was pre-amplified and was subjected to a LncPath™ Human Cardiovascular Disease Pathway LncRNA Array , which allowed for the simultaneous detection of 1150 lncRNAs and 1673 coding transcripts. After filtering the low-intensity lncRNAs, the lncRNAs in the eight samples were subjected to quantile normalization and t-tests or non-parametric paired tests for abnormal distributions. The discrete variables were compared using chi-square or Fisher’s exact tests. A logistic regression analysis was performed to determine the demographic and clinical factors that predicted the endpoints. Multivariate logistic regression was utilized to calculate the odds ratios (ORs) and corresponding 95% confidence intervals. Univariate and multivariate logistic regression analyses were performed to analyze the independent risk factors among the ARAS patients. We generated receiver operating characteristic (ROC) curves to assess the diagnostic values of the six biomarkers. The area under the curve (AUC) was used as a measure of the diagnostic accuracy of the biomarkers. A p value<.05 was considered statistically significant. The statistical analyses were performed using SPSS Statistics 17.0 .The data are presented as the means ± SD or number (percentage) of patients. The continuous variables were compared using paired Student’s >1.5 and p< .05. To ensure that the potential lncRNA markers could be easily measured in the clinic, we selected biomarkers from the 43 upregulated lncRNAs using the following strategy: a fold change >3.0 and p< .05. Only the following six lncRNAs met these criteria: RP11-387H17.6, BC080653, RP1-32B1.4, RP5-1068H6.3, GHRLOS, and XLOC_009769.To determine whether specific lncRNAs were expressed in the ARAS patients, we profiled the tissue lncRNA expression in four ARAS patients and four non-ARAS individuals using the LncPath™ Human Cardiovascular Disease Pathway microarray. The lncRNA levels in the renal artery tissue significantly differed between the two groups as illustrated by the hierarchical clustering analysis . Of the Supplementary Table S1.To validate the increased expression of RP11-387H17.6, BC080653, RP1-32B1.4, RP5-1068H6.3, GHRLOS, and XLOC_009769 in the peripheral blood cells from the ARAS patients, these lncRNAs were quantified in blood cell samples obtained from a training group comprising 18 ARAS patients, 18 non-ARAS patients, and 18 healthy volunteers. The clinical and demographic characteristics of the patients are shown in To determine the relationship between these lncRNA levels and ARAS, an ROC analysis was performed. The AUCs were 0.826 for RP11-387H17.6, 0.756 for BC080653, 0.770 for RP1-32B1.4, 0.725 for RP5-1068H6.3, 0.755 for GHRLOS, and 0.534 for XLOC_009769  and 3. Tn = 99; non-ARAS individuals, n = 49; and healthy volunteers, n = 50). The model and criteria used were the same as those used in the training group. The clinical and demographic characteristics of this population are summarized in As the above analyses involved two different groups, we further assessed RP11-387H17.6 as a biomarker of ARAS in a large validation group . To determine whether these factors had an additive effect on the predictive value of the lncRP11-387H17.6 levels, we performed another ROC curve analysis of lncRP11-387H17.6 and these combined risk factors in the validation group. The diagnostic prediction was increased. The optimal sensitivity of lncRP11-387H17.6 for ARAS increased from 52.5% to 78.9%, although the specificity decreased from 84.8% to 81.9%. The optimal AUC was 0.844 (95% CI = 0.789–0.898) .The results of this study show that the expression levels of lncRP11-387H17.6 in peripheral blood cells are regulated in ARAS. Older age, systolic blood pressure and lncRP11-387H17.6 were shown to be a significant risk factors for ARAS. A model based on clinical variables may be useful for the clinical identification of high ARAS risk patients who may be proper for renal arteriography at the time of cardiac catheterization.ARAS results in a progressive loss of renal function and accounts for 90% of cases of renal occlusive vascular disease . SeriousRecently, an increasing number of lncRNAs have been associated with cardiovascular diseases. For example, the altered expression of lncRNA-P21 has been declared in CAD , and hypp<.05. The expression of these six lncRNAs was verified by qPCR and ROC curve analysis; the AUC of RP11-387H17.6 was 0.826; thus, we further validated this lncRNA. RP11-387H17.6 was selected as the best candidate biomarker for diagnosing ARAS. Among the six lncRNAs with significant expression changes in the renal artery samples, only RP11-387H17.6 could be used as a peripheral blood marker, indicating that the examination of the peripheral blood markers was less sensitive than the examination of the tissue markers. This study shows that expression levels of lncRNAs in blood cells from ARAS patients are extremely variable, and this result is consistent with the fact that only a portion of lncRNAs in tissues can be released to the peripheral blood. As circulating lncRNAs may be correlated with the local lncRNA expression signature in a specific pathology, lncRNAs may be useful potential additional biomarkers.We used several strategies to decrease the problems associated with statistical analysis of high-throughput biological data . First, 43 lncRNAs that were differentially expressed in the peripheral blood cells of individuals with or without ARAS were filtered. To facilitate the confirmation of the target biomarkers, we chose 43 lncRNAs that were upregulated in peripheral blood cells. Only six of these upregulated lncRNAs had average normalized expression intensities >3 with The stenotic kidney shows significant microvascular rarefaction accompanied by increased fibrosis and a marked deterioration of renal function. The damage and early loss of the renal micro-vessels and the deterioration of the renal angiogenic response ) are important determinants of the progression of renal injury and likely demarcate the point of often irreversible damage in the stenotic kidney . Our stuA growing body of evidence from both experimental  and humaThe primary limitation of this study was that the patients were recruited from one hospital in Shenyang, Liaoning; thus, whether our findings also apply to patients in different areas and races is unknown. Therefore, the validity of our findings should be further verified in additional prospective cohorts. Second, kidney tissue was unavailable, and the renal expression of lncRNAs might differ from their expression in peripheral blood cells. Third, due to the lack of data regarding the duration and systemic effects of hypertension, evaluating the possible effects of hypertension on nephroangiosclerosis in ARAS and hypertension patients is challenging. However, based on the clinical profiles of the groups in this study, the ARAS group was likely to have a higher cardiovascular risk than the other groups. Nevertheless, the application of our results to other cohorts should be performed with caution, and further studies are needed. Finally, although this study has shown that lncRNAs had altered in patients with ARAS a potential association with cardiovascular risk factors, LncRNAs have not been studied on the pathological basis of ARAS, only made a hypothesis of some pathological relationship, which needs further experimental verification.In conclusion, the lncRNA RP11-387H17.6 in peripheral blood cells is differentially expressed between the ARAS patients and the controls. Our findings indicate, for the first time, that the lncRNA RP11-387H17.6 is a potential specificity biomarker of ARAS and may offer an additional component for the study of the disease. Prospective clinical trials should be conducted to determine the usefulness of the lncRNA RP11-387H17.6 as a stable biomarker of ARAS. Furthermore, a better understanding of the role of lncRNA in the post-stenotic kidney may provide novel biomarkers of the outcomes of restorative renal repair in ARAS.Click here for additional data file.


IntroductionDiabetes mellitus (DM) is a significant and common risk factor for the development of peripheral vascular disease (PVD). Peripheral vascular disease is the atherosclerotic narrowing of peripheral arteries and has a high prevalence among patients with diabetes.Material and methodsA cross-sectional study was conducted in the Department of Medicine of Ayub Teaching Hospital, Abbottabad. A total of 271 diagnosed diabetic patients aged 40 years or above were included in the study. Ankle-brachial pressure index (ABPI) was measured using a hand-held Doppler device and sphygmomanometer. An ABPI < 0.9 was taken to be abnormal. The risk factors were noted through history taking, physical examination, and appropriate investigations. ResultsOur study sample included 271 patients. A hundred and forty-five (53.5%) of them were males, and 126 (46.5%) were females. Fifty-three (19.9%) out of 271 patients had peripheral vascular disease. The prevalence of peripheral vascular disease was stratified among smoking (p=0.00), hypertension (p=0.00), obesity (p=0.004), and hypercholesterolemia (p=0.005) to determine if there was any association between these and peripheral vascular disease. A p-value less than 0.05 was taken to be significant.ConclusionThis study showed a significant association between PVD and smoking, hypertension, hypercholesterolemia, and obesity. Diabetes mellitus (DM), or simply diabetes, is one of the significant health hazards worldwide . DiabeteAccording to the International Diabetic Federation (IDF), in the year 2019; more than 463 million people were suffering from DM around the world, and this figure is expected to rise to 700 million by 2045 [Among the long-standing complications, peripheral vascular disease (PVD) is one of them and is associated with more deaths and amputation . PVD, whPVD has become a global health problem affecting more than 200 million people around the world . One reaVarious risk factors have been described for the increased predisposition to the development of PVD in DM. The common factors observed are hypertension 80.9%), hypercholesterolemia (74.0%), smoking (22.8%), obesity (49.6%), and dyslipidemia (50%) %, hyperc. Other fThis study aimed to report the relationship of different risk factors with silent PVD and assess its magnitude since no local data is available. In addition, the use of ankle-brachial pressure index (ABPI) was evaluated in the early diagnosis of asymptomatic PVD in people with diabetes.This cross-sectional descriptive study was conducted from September 1, 2016 to August 31, 2017, at the Department of Medicine, Ayub Teaching Hospital, Abbottabad. Our sample included 271 patients enrolled through convenient sampling (non-probability sampling). Only patients suffering from DM for the last five years or more who did not exhibit symptoms of peripheral vascular disease and were aged 40 and above were included in the study. Similarly, those patients who were on vasodilators, lipid-lowering agents, or antiplatelet therapy or patients presenting with hypovolemia or renal failure requiring dialysis were excluded from the study to control confounding. Those diabetic patients with impaired ankle-brachial index (ABI), i.e., < 0.9, as measured by the radiologist, were considered to have peripheral vascular disease. The radiologist was kept blind and used a pulse wave Doppler . The following common risk factors were considered as smoking (at least one pack/day for three or more years) , hyperteOur study was approved by the chairperson of the Institutional Review Board (IRB) and hospital ethical committee at Ayub Teaching Hospital, Abbottabad under the IRB number ATH/EC- 9/16(1). Informed consent was taken from the patients, and the purpose and details of the research work were explained to them. All patients were then subjected to detailed history and examination followed by relevant investigations.ABI was measured using a hand-held Doppler device and sphygmomanometer. Systolic blood pressure in both arms  was checked after instructing the patients to lie in the supine position for 10 minutes. A higher value of the two forces was considered the denominator. Next, the blood pressure in the posterior tibial artery and dorsalis pedis artery was measured in both legs. The higher of the two blood pressures were taken as the numerator for each foot. ABI was calculated separately for each leg as the ratio of the systolic pressure in the dorsalis pedis or posterior tibial artery (whichever was higher) to the pressure in the brachial artery.ABPI = PLeg/ParmPLeg is the systolic pressure in each leg measured either in the posterior tibial artery or dorsalis pedis artery - whichever was higher & Parm is the higher of the systolic pressure in both arms .An ABPI < 0.9 was considered abnormal. The patients were divided into two groups . The associated risk factors, i.e., smoking, hypertension, obesity, and dyslipidemia, were noted through history, examination, and investigation, respectively, in both groups. All the information was recorded on the pre-designed pro forma.Data were analyzed statistically using the software SPSS Inc. Released 2007. SPSS for Windows, Version 16.0. Chicago, SPSS Inc. Mean was the measure for quantitative variables like age, duration of diabetes, BMI, blood pressure, and ABPI. Categorical variables like PVD were described as frequencies and percentages. PVD was stratified among diabetic patients to see the effect modifications. The chi-square test at a 5% significance level was used to show an association of risk factors.A total of 271 patients were studied in this study. The oldest patient was 80 years old, while the youngest patient was 40 years, with a mean of 56.15. A hundred and forty-five (53.5%) patients were men and 126 (46.5%) were women. Some other characteristics are shown in Table PVD was diagnosed in 53 (19.6%) patients out of 271. Among the 53 patients, eight (15.09%) had type 1 DM, and 45 (84.91%) had type 2 DM. The total number of patients with type 1 DM was 54 (19.9%), and the total number of patients with type 2 DM was 217 (80.1%). A significant association was noted between PVD and smoking , hypertension , hypercholesterolemia , and obesity . No significant association between type of diabetes and PVD was found .Literature shows that PVD is much more prevalent in diabetic patients compared to the general population. Its prevalence in the type 2 diabetic population of Pakistan is reported to be 16.97% in 2018 .Likewise, there are contradicting reports about the association of PVD with diabetes mellitus. On the one hand, reports suggest no relationship between the type of DM and peripheral vascular disease. However, some research work has suggested that PVD is more prevalent in type 2 DM . This maSimilarly, in our study, no significant association was found between the type of diabetes and PVD. However, we found that the association was statistically significant between PVD and smoking, hypertension, hypercholesterolemia, and obesity . Our study is following Wilcox et al. However, Wilcox et al. reported that smoking had the strongest association while obesity had the slightest association with PAD among the said factors .There are variable reports of the prevalence of PVD in Pakistan. The prevalence of PVD in this study was 19.9%. A report from Bahawal Victoria Hospital, Bahawalpur, shows a prevalence of 1.2% for PVD . There iSimilarly, Zia et al. 2007 reported that the frequency of PVD was 35% . They saAnother research published in 2012 by Ali et al. reported that the prevalence of PVD was more (39.28%) in patients with DM than in the general population. Among the diabetic population, it was more prevalent in females and those with concurrent hypertension . This stOur study had certain limitations. Firstly, there were no control groups to compare the effect modification. Secondly, our study population mainly comprised elderly diabetics, and therefore we could not study the development of PVD in the younger population. Thirdly, no emphasis was made to determine the association of PVD with the duration of DM. And finally, since it was the first-ever study of its kind in our region, no comparative data could guide the association between risk factors and the PVD in diabetic patients.Since this study was simply a descriptive cross-sectional study, it is recommended that a large-scale, randomized non-controlled trial be conducted in our region that should at least address the limitations in my research. This would help the investigators and clinicians determine the exact magnitude of PVD in this region and its associations with the common risk factors. Since PVD is more common in diabetic patients, this segment of the general population needs more attention as far as PVD is concerned. Therefore, a large-scale study will be valuable in addressing potential complications associated with the disease in this segment of the population.PVD is atherosclerotic blockage of vessels in lower limbs and is present in up to 14% of the general population. DM, however, is one of the most substantial risk factors for PVD and its associated complications. Our study showed a strong association of PVD with cigarette smoking, hypertension, hypercholesterolemia, and obesity. To decrease the risk of developing PVD, vigorous measures are needed to control these risk factors. Diabetic patients should be encouraged to quit cigarette smoking. They should be advised to maintain their high blood pressure if they are also diagnosed with hypertension through either salt restriction or antihypertensive medication. Problems of overweight, obesity, and hypercholesterolemia should be addressed accordingly to reduce the risk of the development of PVD.


Acute respiratory distress syndrome (ARDS) is a life-threatening condition involving acute hypoxemic respiratory failure. Mechanical ventilation remains the cornerstone of management for ARDS; however, potentially injurious mechanical forces introduce the risk of ventilator-induced lung injury, multiple organ failure, and death. Extracorporeal membrane oxygenation (ECMO) is a salvage therapy aimed at ensuring adequate gas exchange for patients suffering from severe ARDS with profound hypoxemia where conventional mechanical ventilation has failed. ECMO allows for lower tidal volumes and airway pressures, which can reduce the risk of further lung injury, and allow the lungs to rest. However, the collateral effect of ECMO should be considered. Recent studies have reported correlations between mechanical ventilator settings during ECMO and mortality. In many cases, mechanical ventilation settings should be tailored to the individual; however, researchers have yet to establish optimal ventilator settings or determine the degree to which ventilation load can be decreased. This paper presents an overview of previous studies and clinical trials pertaining to the management of mechanical ventilation during ECMO for patients with severe ARDS, with a focus on clinical findings, suggestions, protocols, guidelines, and expert opinions. We also identified a number of issues that have yet to be adequately addressed. Acute respiratory distress syndrome (ARDS) is characterized by acute respiratory failure with severe hypoxemia. Lung-protective mechanical ventilation strategies with lower tidal volumes and lower airway pressures remain the mainstay of ARDS management aimed at improving survival ,2. HowevExtracorporeal membrane oxygenation (ECMO) is a rescue therapy aimed at improving gas exchange for severe ARDS patients with life-threatening hypoxemia refractory to conventional mechanical ventilation ,8,9,10. ECMO allows an ultra-protective ventilation to lower tidal volumes and airway pressures aimed at mitigating VILI ,8,15,16.This review article examined previous studies, clinical trials, and organization protocols pertaining to mechanical ventilator settings in patients with severe ARDS undergoing venovenous (VV) ECMO, focusing on clinical findings, recommendations, guidelines, and expert opinions.VILI results from interaction between mechanical ventilation and lung parenchyma, and is caused by excessive mechanical stress or strain to the lung parenchyma a. Both mThe adverse effects of mechanical ventilation in cases of ARDS can be categorized as follows: (1) a non-physiological increase in transpulmonary pressure; (2) a non-physiological increase or decrease in pleural pressure during positive or negative pressure ventilation. The primary adverse effects associated with excessive transpulmonary pressure and pleural pressure are VILI and hemodynamic alterations, respectively . MechaniThe individual pathophysiological conditions associated with the occurrence of VILI include functional lung size, the extent of lung inhomogeneity, and lung recruitability ,6. Thus,The most common cause of death among ARDS patients is multiple organ failure ,2. DamagECMO is meant to limit mechanical forces and thereby may prevent VILI, biotrauma, and the risk of mortality. One randomized controlled trial reported that significant reductions in plateau pressure, tidal volume, and driving pressure by VV ECMO significantly reduce the risk of pulmonary biotrauma in patients with severe ARDS, compared with standard protective-lung ventilation (as indicated by cytokine concentrations) .Recent studies reported that extrapulmonary organ failure during ECMO was significantly correlated with mortality among patients with severe ARDS ,26,27,28ECMO allows for a reduction of tidal volumes and airway pressures  to mitigate the risk of further VILI ,8. NonetNo previous studies have compared the modes of ventilation during ECMO in terms of clinical outcomes. Many patients are deeply sedated and paralyzed during the initial phase of ECMO involving pressure- or volume-controlled ventilation. Pressure-controlled modes allow the daily monitoring of tidal volume increase as a function of lung compliance or clinical condition improving. As a result, pressure-controlled modes are widely preferred in the initial phase of ARDS, as indicated by their inclusion in Extracorporeal Life Support Organization (ELSO) guidelines ,15,30.One international multicenter prospective cohort study reported that 50% of ARDS patients received volume-targeted ventilation, whereas 40% received pressure-targeted ventilation prior to ECMO. Note, however, that the usage of pressure-targeted modes increased with the duration of ECMO, as follows: day 1 (69%), day 7 (71%), and day 14 (82%) . The EOLMP refers to the amount of energy per unit of time transmitted to the lung parenchyma during mechanical ventilation, and probably contributes to the development of VILI and clinical outcomes. MP is derived from the volume, pressure, flow, and respiratory rate. Thus, it is reasonable to assume that MP is superior to individual ventilator parameters in predicting the risk of VILI .Researchers have yet to define a safe MP threshold for patients with critical illnesses with or without ARDS. One experimental model reported the occurrence of lung edema and lung damage when MP exceeded a threshold of 12 J/min . High MPp = 0.004) [ECMO provides ultra-protective ventilation by reducing airway pressure and energy load  transmitted to the lungs, which can potentially promote lung healing and mitigate further lung injury. There is currently no clearly defined threshold for MP during ECMO by which to predict outcomes for patients with severe ARDS. One recent study reported that the 90-day hospital mortality was significantly higher among patients with high mean MP (>14.4 J/min) during the first 3 days of ECMO, compared to patients with low mean MP (≤14.4 J/min)  .A given energy load  could have a diversity of effects on the respiratory system depending on the pressure, volume, and respiratory rate as well as the individual pathophysiology of the lungs, such as the functional lung size, the extent of inhomogeneity, and recruitability ,6. Theorp = 0.010 versus adjusted HR 1.060, p = 0.005, respectively) [Specific power is defined as power per ventilated lung unit or power referenced to the dimensions of the ventilated lung. It is assumed that specific power enables more accurate predictions of VILI ,37. In actively) .2O [Lung-protective ventilation strategies that lower tidal volume  to reduce stress and strain on the lungs have survival benefits for ARDS patients. Typically, the tidal volume is reduced to as low as 4 mL/kg PBW in cases where the plateau pressure exceeds 30 cmH2O ,31,38.2O, and typically maintain below 4 mL/kg PBW as ultra-protective ventilation during ECMO to minimize the risk of VILI [p < 0.001) [For severe ARDS patients supported with ECMO, tidal volumes are often adjusted with the aim of achieving plateau pressure ≤ 24 cmH of VILI ,13,27. O< 0.001) . It is uPositive end-expiratory pressure (PEEP) is the pressure used to maintain the alveolar opening during end expiration. Higher PEEP levels are meant to increase mean airway pressure to improve oxygenation, reduce tidal lung stress and strain, maintain alveolar recruitment, and prevent alveolar collapse at end expiration to decrease the risk of lung inhomogeneity, VILI, and intrapulmonary shunt ,39.The potential harmful effects of PEEP include increased pleural pressure, elevated right atrial pressure, and a reduced pressure gradient for venous return, which can contribute to decreased cardiac output. PEEP has also been shown to increase pulmonary vascular resistance, which elevates right ventricular afterload and could further reduce cardiac output ,39.2 tables, dead space), respiratory mechanics , and/or imaging studies  [2 strategy in terms of mortality or days free from mechanical ventilation [The optimal PEEP is generally estimated using gas exchange (PEEP/FiOimaging) . Howevertilation . A recentilation .ECMO allows for lower tidal volume ventilation , which may contribute to atelectasis and severe ventilation/perfusion mismatch unless PEEP is appropriately increased to keep part of the lung open . Unfortu2O [p = 0.0006) [Researchers have yet to determine the optimal PEEP target during ECMO; however, one study suggested a value of ≥10 cmH2O . ELSO gu2O . One ret 0.0006) .2O) has been strongly recommended for patients with ARDS [Plateau pressure is defined as the pressure obtained at end-inspiration after a 0.5 s inspiratory pause when patients are sedated and paralyzed. Mechanical ventilation using lower inspiratory pressures  and mortality was lower among patients who had lower intensity of applied ventilation following ECMO initiation [2O at the time of ECMO initiation to 24 ± 7 cmH2O during the first 2 days of ECMO (p < 0.001) [One systematic review summarized ventilation practices for ARDS patients with ECMO. The results reported that after ECMO support, plateau pressure was decreased by a median of 4.3 cmHitiation . Another< 0.001) . One coh< 0.001) .Driving pressure refers to the difference between the plateau pressure and PEEP, which is inversely proportional to respiratory system compliance. Respiratory system compliance is correlated with the amount of aerated lung tissue available for tidal ventilation  in patients with ARDS ,43. It iOne post hoc observational study of 3562 patients with ARDS in nine randomized controlled trials reported that for patients with ARDS, driving pressure is the ventilation variable with the greatest predictive value for mortality . However2O are defined as ultra-protective ventilation [2O at the time of ECMO initiation to 14 ± 4 cmH2O within the first 2 days of ECMO (p < 0.001) [Researchers have yet to establish a clearly defined safe upper limit for driving pressure during ECMO, and values below 15 cmHtilation . One int< 0.001) . Other s< 0.001) ,22. One < 0.001) . HoweverTranspulmonary pressure refers to the difference between pressure inside the alveoli and pleural pressure, largely involved with distending the lung parenchyma. Esophageal manometry is the method used clinically to measure pleural pressure in assessing the pathophysiology and mechanics of the respiratory system, which consider the effect of chest wall ,45. At tUnlike plateau pressure and driving pressure, transpulmonary pressure reflects directly the individual physiology of the patient, and may therefore have a better impact on clinical outcomes and mortality in ARDS patients ,46,47, p2O) rather than the upper limit of plateau pressure (30 cmH2O). They reported that this approach improved oxygenation and offset the need for ECMO implementation [One case series of patients with influenza A (H1N1)-associated ARDS supported with ECMO adjusted PEEP according to the upper physiologic limit of transpulmonary pressure  over time . It appe2) within an acceptable range. A few studies have examined the effect of respiratory rate on VILI and clinical outcomes. The LUNG SAFE study reported a link between increased respiratory rate and increased hospital mortality in patients with ARDS [Lung-protective ventilation aimed at reducing tidal volumes has been shown to provide survival benefits for ARDS patients; however, it often brings with it the risk of respiratory acidosis, even in cases where the respiratory rate is increased. Note also that a higher respiratory rate has been shown to cause lung damage, even under lower tidal volumes. Respiratory rate is usually adjusted to maintain the partial pressure of carbon dioxide in arterial blood  should be maintained at a low level to reduce the risk of oxygen toxicity and reabsorption atelectasis [2 at 0.3–0.5 [VV ECMO is widely used to promote gas exchange in order to improve arterial oxygenation in patients with severe ARDS. Systemic arterial saturation of roughly 80% is typical during VV ECMO support. High initial blood flow in the extracorporeal circuit can be lowered to maintain arterial saturation of 80–85% . The fralectasis . Some st 0.3–0.5 ,27. None 0.3–0.5 .ECMO gives the lungs a chance to rest; however, researchers have yet to establish evidence-based guidelines pertaining to optimal mechanical ventilation strategies during ECMO. Spontaneous breathing can have protective or deleterious effects, depending on the severity of lung injury, the strength of spontaneous activity, respiratory patterns, patient-ventilator dyssynchrony, and the phase and duration of ARDS . In caseFew ARDS patients are able to tolerate ECMO strategies based on spontaneous breathing, due largely to the fact that patients requiring ECMO support are most severe with high respiratory drive. During the initial phase of ECMO support, researchers advise neuromuscular blockade to eliminate patient–ventilator dyssynchrony and thereby mitigate the risk of P-SILI ,56. Seda2 levels decreased [However, titrating the amount of extracorporeal carbon dioxide removal could influence and control respiratory drive during ECMO and may allow spontaneous breathing in select patients with ARDS . In patiecreased . This inResearchers have yet to determine whether near-apneic or apneic ventilation during ECMO  could be used to decrease the intensity of mechanical ventilation and thereby minimize the risk of VILI and biotrauma.2O, tidal volume 10 mL/kg, respiratory rate 16–20 breaths per minute) exhibited severe histologic lung injury with early fibroproliferative response. Note that near-apneic ventilation  was more effective than conventional protective ventilation  in reducing this response [In one experimental model, patients with severe ARDS supported with ECMO who underwent nonprotective ventilation for 24 h  under ECMO may be the optimal ventilation strategy to minimize the risk of VILI (reflected by plasma cytokine concentrations) .Near-apneic or apneic ventilation strategies require that patients be sedated and paralyzed without spontaneous breathing to prevent patient–ventilator dyssynchrony and P-SILI; however, this can lead to atelectasis. Maintaining apneic or near-apneic ventilation may require total ECMO dependent with a high blood flow rate to ensure adequate oxygenation. Note that researchers have yet to establish how long this approach (extreme lung protection) can feasibly be administered in clinical practice .n = 10). Large randomized controlled trials will be required to confirm the efficacy of this approach in terms of clinical outcomes.A very low respiratory rate can be used to reduce the ventilation load transmitted to lung parenchyma and thereby prevent lung injury; however, it is important to weigh the benefits against the risks. One of the studies mentioned above employed an animal model of ARDS and the other study enrolled a small sample of ARDS patients (2R) is used to reduce respiratory acidosis by clearing carbon dioxide; however, the low blood flow associated with this procedure (approximately 200–1500 mL/min) is insufficient to improve oxygenation. Nonetheless, ECCO2R makes it possible to reduce tidal volumes, airway pressure, and the respiratory rate [Patients with ARDS receiving low tidal volume are prone to hypercapnia and corresponding respiratory acidosis. Extracorporeal carbon dioxide removal , or ventilator-associated pneumonia .Although there have been advances in supportive care and innovations in extracorporeal support techniques, there are many potential collateral effects or complications associated with ECMO and these can be lethal. Close daily monitoring to minimize the risk of ECMO-related complications is necessary, and requires intensive education and training . Therefo2), and renal failure [The common complications directly related to the ECMO circuit are oxygenator failure, blood clots in oxygenator and other circuit, and other cannula or mechanical-related problems . Bleeding is the most common complication during ECMO because of systemic anticoagulation and thrombocytopenia, and is one of the leading causes of mortality. Other complications not directly related to the ECMO circuit include thromboembolism, hemolysis, disseminated intravascular coagulation, culture-confirmed infection at any site, neurologic injury (e.g., rapid decrease in PaCO failure ,10.ECMO provides ultra-protective ventilation in patients with severe ARDS, thereby allowing the lungs to rest, and may reduce the risk of progressive VILI and subsequent multiple organ failure. The collateral effects of ECMO may be devastating and should be investigated. Mechanical ventilation settings should be tailored to the individual; however, researchers have yet to establish optimal ventilator settings or determine the degree to which ventilation load can be decreased. Large-scale, prospective, randomized controlled trials are still required to answer these questions.


Obstructive Sleep Apnea (OSA) is associated with the presence and severity of Non-Alcoholic Fatty Liver Disease (NAFLD). We aimed to investigate the relationship between the severity of OSA and NAFLD and to recognize a polysomnographic parameter correlated with progression of fibrosis, determined by a non-invasive score of liver fibrosis, FIBrosis-4 index (FIB-4), in patients affected by severe obesity and OSA.2), divided into classes according to severity of OSA evaluated with Apnea Hypopnea Index (AHI): OSAS 0 or absent (17%), mild OSA (26%), moderate OSA (20%), severe OSAS (37%). We studied anthropometric, polysomnographic, biochemical data and FIB-4. A multiple regression model was computed to identify a polysomnographic independent predictor of FIB-4 among those parameters previously simple correlated with FIB-4.We enrolled 334 patients .The severity of OSA was associated with a decrease in High-Density Lipoprotein–cholesterol (HDL) and an increase in BMI, triglycerides, Homeostasis model assessment insulin-resistance index (HOMA), transaminases and FIB-4. FIB-4 correlated with sex, age, BMI, AHI, mean percentage oxyhaemoglobin (meanSaO2%), number of desaturations, platelets, transaminases, HDL, triglycerides and HOMA. The only variables independently related to FIB-4 were sex, BMI, triglycerides and meanSpO2 (MeanSpO2% represented an independent determinant for the worsening of FIB-4 in patients with severe obesity and OSA. Hence, it could hypothesize a clinical role of meanSaO2% in recognizing patients with obesity and OSA and higher risk of developing advanced fibrosis and, thus, to undergo further investigation.Evidence obtained from well-designed cohort analytic studies. In the last decades we observed a pandemic increase in the prevalence of metabolic diseases such as obesity, Type 2 Diabetes Mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) –3 and, oOSA is characterized by repetitive episodes of partial or total loss of respiratory airflow during sleep with the collapse of the upper airway during inspiration and is accompanied by strenuous breathing . In geneIn the same way, NAFLD positively correlates with visceral fat depot and obesity comorbidities (such as T2DM and OSA) worsen the histopathological features of NAFLD , 19. As Identifying patients with the greatest risk of evolution of NAFLD to NASH represents a challenge for clinicians. It is worth to note that fibrosis is the predictive criterion for a poor prognosis , 25, 26 A growing amount of evidence has correlated OSA with the presence of NAFLD and it has been demonstrated a direct association between the severity of the former and the progression of the latter . Thus, O2) were enrolled at the Centre for the Study and Integrated Treatment of Obesity, Padua University Hospital, in the period 2013–2019. Patients underwent a multi-disciplinary evaluation according to a standard clinical protocol and a complete medical history was taken regarding eating, physical activity, smoking and drinking habits, drugs, past and current medical conditions. Indeed, these patients underwent to polysomnography according to the suspect of OSA on the basis of clinical evaluation and a validated questionnaire . These subjects were also eligible for bariatric surgery and, thus, provided the result of a simple abdominal ultrasound scan (US), as pre-surgery exam according to a standard clinical protocol. All US confirmed the presence of fatty liver. Specific exclusion criteria for this study were previous bariatric surgery, continuous positive airway pressure therapy (CPAP), unavailability of all clinical anamnestic, anthropometric, biochemical and polysomnographic parameters, excessive alcohol consumption .For each patient, all blood tests were performed in the morning, after 8 h of fasting. All biochemical blood analyses have been performed with standard diagnostic kit according to WHO First International Reference Standard: fasting plasma glucose (FPG) , basal insulin, IL-6, TNFα , high-sensitivity C-Reactive Protein (hs-CRP) , Leptin , vitamin D3 . Platelets were measured by flow cytometry , lipid profile  by spectrophotometer . Low Density Lipoprotein–cholesterol (LDL–cholesterol) was calculated according to Friedewald . ALT, ASThe insulin-resistance index was indirectly estimated using the homeostasis model assessment (HOMA) as follow: [fasting serum insulin (μU/ml) x fasting plasma glucose (mmol/l)]/22.5 .9/l) x ALT1/2] [FIB-4 was calculated using the following formula: [age (years) x AST]/[platelet counts  and a complete cardiorespiratory night monitoring was carried out for at least 8 h. During polysomnography peripheral, blood oxygen saturation, respiratory flow in the upper airway, respiratory movements of the chest and abdomen, snoring phases, the position of the patient, blood pressure and electrocardiogram with acquisition of peripheral signals were recorded. The recorded layout and thus the criterion for assigning hypopneas scoring was automatically analyzed by the DOMINO software®, validated by SOMNOmedics, and subsequently it was manually validated by an expert operator according to the most recent American Academy of Sleep Medicine (AASM) criteria . The antr) and the relative p values were calculated to analyze simple linear correlations between two variables. A multiple regression model with adjustment for presence of diabetes, hypertension and dyslipidemia was computed with FIB-4 as the dependent variable and the variables found to be simple correlated with FIB-4 as independent variables. Variant Inflation Factor (VIF) was considered as measure of multicollinearity and a value greater than 4 was considered as cut off for excluding variables from the analysis. In all analyses, the p values were two-sided and a p value lower than 0.05 was considered statistically significant.Statistical analyses were performed using the SigmaPlot v.14 . All variables were tested by normal Test (Shapiro–Wilk test) and Equal Variance Test (Brown-Forsythe). One Way Analysis of Variance was used when Normality Test and Equal Variance Test have been passed  or, if not, with the Kruskal–Wallis One Way Analysis of Variance on Ranks ). Chi-square test was carried out for categorical variables. Pearson’s correlation coefficient (2 (IQR 38.5–49.9). Patients with hypertension were 204 (61.1%); dyslipidemia, defined according to recent guidelines [p < 0.001). Particularly, patients with more severe OSA displayed a greater number of nocturnal desaturations, a lower average and minimum oxyhaemoglobin saturation values and they spent more time with saturation values less than 90%.Three hundred and thirty-four patients with severe obesity had a mean age of 48 ± 12 years (range 18–79), 158 were male (47%) and the mean BMI was 44.78 ± 8.99 kg/m2 IQR .5–49.9. idelines , 101 patp < 0.001), age (p < 0.001), weight (p < 0.001), presence of hypertension (p < 0.001) and dyslipidemia (p = 0.015); even though not statistically significant, the percentage of patients with diabetes was gradually higher going through OSA classes. Consensually, the more severe OSA the higher were FPG (p < 0.001), insulin (p < 0.001), and HOMA (p < 0.001) levels. Moreover, HDL and TG levels significantly decreased (p < 0.001) and increased (p = 0.008), respectively, with OSA severity. We found that only IL-6 (p = 0.024) and not hs-CRP and TNF-a, was associated with OSA severity. Interestingly, also Vitamin D3 levels were statistically different between OSA classes.The progression versus higher levels of OSA severity was associated with male  and a decrease of platelets (p = 0.042), with OSA severity. The relationship existing among the two diseases has been demonstrated by the association between AHI and the score of liver fibrosis, FIB-4 (p < 0.001) , age , diabetes , dyslipidemia , hypertension , AHI ; meanSaO2% ; nSaO2 < 90% , BMI , platelets , AST , ALT , GGT , HDL , TG , HOMA , leptin  (Table r)).FIB-4 values were significantly correlated with sex  , and transaminases, platelets and age because already included in the FIB-4 score. In this model, TG, sex, meanSaO2%, BMI and HOMA were the only variables independently correlated with REE in 334 patients with obesity (We have investigated the relationship between the presence and severity of OSA and liver fibrosis in a large sample of patients with severe obesity undergoing polysomnography for diagnostic reasons. Consensually with literature, OSA was associated with a greater severity of obesity both in terms of BMI and metabolic complications. We demonstrated an independent correlation between the mean SaO2% values, an OSA severity index, and FIB-4 values, suggesting an independent role of this parameter in recognizing patients with greater risk of NAFLD progression towards stages characterized by growing fibrosis.In our population the prevalence of hypertension, dyslipidemia and diabetes increased consensually with the severity of the OSA, with statistical significance for the two first, in agreement with previous studies , 11, 40.Focusing on transaminases levels, we noticed that they were similar in the group without OSA and with mild OSA; on the other hand, in the groups with more severe degrees of OSA, a pathological increase in transaminases has been reported. These data seemed to confirm an association between worsening AHI and NAFLD, although recent guidelines have underlined that transaminases have a poor predictive value for the evolution from NAFLD to NASH , 3. In pConsequently, non-invasive biomarkers and scores could become a screening tool to identify patients living with obesity and OSA to be referred to liver biopsy and therefore to prevent NAFLD progression. Indeed, could be useful to recognize those patients with OSA and higher risk to develop severe fibrosis. With this aim we focused on polysomnographic parameters which describe OSA severity. To investigate the role of different polysomnographic parameters as independent predictors of liver fibrosis, we computed a multiple regression model with FIB-4 as the dependent variable. In this model, TG, sex, meanSaO2%, BMI and HOMA were the only variables independently correlated with FIB-4 in 334 patients with obesity. It is well known how TG and insulin resistance contribute to pathogenesis to NAFLD , that NAOur study has some limitations. Firstly, we enrolled patients affected by severe obesity in a center where bariatric surgery is the main suggested treatment. This may explain the high prevalence of obesity-related comorbidities. Furthermore, the distribution of patients in the OSA classes is not balanced. The great sample size of subjects with severe OSA is explained by the fact that polysomnography is a survey that requires a not negligible commitment of time and health resources and is therefore prescribed only for symptomatic patients or with high scores on predictive tests for OSA. Indeed, electroencephalogram is lacking, nevertheless the polysomnographic analysis was performed according to the most recent AASM criteria  and, thuIn conclusion, our study shows that the presence and severity of the OSA, defined by international guidelines based on the AHI, is associated with an increased in TG values and insulin resistance, suggesting an underling common pathogenetic mechanism between OSA and NAFLD. Furthermore, we demonstrated the association of fibrosis, and OSA severity in adult patients with severe obesity, confirming previous studies , 33, 44.OSA correlates with NAFLD and OSA patients should be screened for the presence and severity of NAFLD.It is unclear the association between polysomnographic parameters and markers/scores of fibrosis.meanSaO2 is independently related to FIB-4, suggesting a clinical implication for recognizing patients with obesity and OSA and a higher risk of developing advanced fibrosis.


ABO blood group antibodies have not been generated or are at low titer during early infancy. Therefore, in theory, ABO-incompatible kidney transplantation (ABOi KT) may be successfully achieved in small infants without any pre-transplant treatment. We report here the first ABO-incompatible deceased donor kidney transplantation (ABOi DDKT) in an infant. The recipient infant was ABO blood group O, and the donor group A. The recipient was diagnosed with a Wilms tumor gene 1 (WT1) mutation and had received peritoneal dialysis for 4 months prior to transplant. At 7 months and 27 days of age, the infant underwent bilateral native nephrectomy and single-kidney transplantation from a 3-year-old brain-dead donor. No pre- or post-transplantation antibody removal treatment was performed, since the recipient's anti-iso-hemagglutinin-A Ig-M/G antibody titers were both low (1:2) before transplantation and have remained at low levels or undetectable to date. At 11 months post-transplant, the recipient is at home, thriving, with normal development and graft function. This outcome suggests that ABOi DDKT without antibody removal preparatory treatment is feasible in small infants, providing a new option for kidney transplantation in this age range. Blood group ABO-incompatible kidney transplantation (ABOi KT) has been an effective strategy to relieve donor kidney shortage and reduce waitlist mortality of patients with end-stage renal disease . ApproprBlood group ABO antibodies in the serum are formed naturally. Their production is stimulated when the immune system encounters the “missing” ABO blood group antigens in foods or micro-organisms . Iso-hemWe reasoned that ABOi DDKT would be safe during early infancy because of the recipients' relative immunologic immaturity. We therefore performed ABOi DDKT in an infant without any preparatory blood group antibody-removal procedures either pre- or post-transplantation. To our knowledge, this is the first report of ABOi DDKT in an infant.The kidney transplant recipient, a male infant, was born at 38 weeks gestational age with a birth weight of 3,370 g. He presented with disturbed sleep and had recurrent diarrhea and abdominal distension since birth. Various oral probiotic supplements were administered, and he was treated by doctors of traditional Chinese medicine but did not improve. The patient developed nausea and vomiting at about 2 months after birth, concomitant with fever and eclampsia. After symptomatic treatment, the fever and eclampsia improved, but symptoms of vomiting, diarrhea, and abdominal distension worsened. At the age of 3 months, he developed apparent oliguria. Subsequent clinical laboratory tests indicated a significant increase in serum creatinine (>500 μmol/L). The infant was then admitted to the pediatric intensive care unit (PICU) for therapy and was diagnosed with kidney dysfunction with end-stage renal disease, chronic diarrhea, severe anemia, decompensated metabolic acidosis, dilutional hyponatremia, pleural effusion, and hypertension. Further genetic testing confirmed the diagnosis of a Wilms tumor gene 1 (WT1) exon 9 heterozygous mutation.9/L. Infusions of red blood cells and thrombocytes were performed as symptomatic therapy. After 16 days of PICU hospitalization and CRRT, the patient was transferred to a general ward for follow-up treatment. During his time in the PICU, he developed catheter-related sepsis and bilateral bronchiolitis. Optimized anti-biotics were used, and catheter replacement and a ventilator-assisted breathing were performed to treat these complications. Ten days after the infant was moved out of the PICU, he received peritoneal dialysis catheterization and laparoscopic orchiopexy. The infant recovered uneventfully from these surgical procedures and then was gradually switched from CRRT to regular peritoneal dialysis. At the age of 3 months, he was referred to our institution for kidney transplantation.The recipient then received regular continuous renal replacement treatment (CRRT) through vascular access via catheterization of the right femoral vein. His hemoglobin level dropped to 35 g/L and his platelet was count 10 × 10In the ensuing months of dialysis and waitlisting for a blood group O-matched pediatric donor kidney, the infant developed recurrent pneumonia and peritonitis. He was admitted to the PICU 3 times because of life-threatening illness. After 4 months of waitlisting, a kidney from a 3-year-old donor donated after brain death from cerebral trauma became available in our hospital. However, the donor was ABO-incompatible. The recipient infant was ABO blood group O, and the donor group A. Pre-transplant measurements using reported microcolumn gel card method  showed tThrough a midline abdominal incision, the bilateral native kidneys with WT1-related renal disease were removed, and the new renal allograft was placed in the right flank inside the abdomen. With the aid of surgical loupes (2.5× magnification), a large donor aortic patch  was anastomosed end-to-side to the recipient's abdominal aorta using a running 7-0 Prolene suture. Before the arterial anastomosis was closed, the artery was flushed with a sodium chloride/papaverine solution (3 mg/ml) to prevent renal vasospasm after blood reperfusion. The donor's renal vein with a Carrel vein cuff was anastomosed end-to-side to the recipient's inferior vena cava, using a running 7-0 Prolene suture. During the transplant surgery, the catheter placed through right femoral vein had to be retracted, since the cranial catheter tip end reached the vena cava and caused mural thrombosis inside the vena cava. We had to clear the thrombo-embolus to make an idea site for venous anastomosis . The ureThe infant did not receive any procedures for blood group antibody removal either before or after transplantation. Post-operative immunosuppression included basiliximab (induction), cyclosporine (first), tacrolimus (later), mycophenolate mofetil, methylprednisolone and prednisone . The immIn the early period after the transplantation, the infant received CRRT twice to treat severe acidosis, possibly caused by the cumulative side effects of consecutively administering sodium nitroprusside to lower his blood pressure. He recovered smoothly otherwise. Graft function was uneventfully recovered, with serum creatinine and blood urea nitrogen rapidly declining to normal levels within 10 days after transplantation . MeasureAt 11 months post-transplantation, the infant is thriving  at home, is developmentally appropriate, and has normal graft function (last serum creatinine level: 33 μmol/L).The WT1 gene mutations observed in patients with Denys-Drash and Frasier syndrome are associated with genitourinary development and tumorigenesis. Kidney transplantation is recommended for children who progress to real failure . Our infThe developmental patterns of ABO iso-hemagglutinins is correlated with age . The relDespite of the successful implementation of such ABO-incompatible deceased organ transplantation in infants, until now, ABOi DDKT had not been reported in infants. Kidney allografts seem to be more tolerogenic than are heart allografts . ABOi LDIn summary, we report the first successful ABOi DDKT performed in an infant without any immunological pre-treatment. This outcome suggests that ABOi DDKT is feasible in small infants whose ABO blood group antibodies have not yet appeared or are at low titer, providing another option to offer life-supporting kidney transplantation to this age group, especially, the cases with severe disease and rare opportunities to receive a blood type matched donor kidney.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Medical Ethics Committee, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. Written informed consent was obtained from the individual(s), and minor(s)' legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.GC, LZ, DZ, and ZG performed the surgery. DZ wrote the manuscript. LZ and GC revised and edited the manuscript. LW performed the flow. All authors participated in patient management and data collection. All authors contributed to the article and approved the submitted version.This study was supported by Tongji Hospital Clinical Research Flagship Program (2019CR108) and National Natural Science Foundation of China (82170774).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Background: Widespread neural and microvascular injuries are common in chronic kidney disease (CKD), increasing risks of neurovascular complications and mortality. Early detection of such changes helps assess the risks of neurovascular complications for CKD patients. As an extension of central nervous system, the retina provides a characteristic window to observe neurovascular alterations in CKD. This study aimed to determine the presence of retinal neurovascular impairment in different stages of CKD.Methods: One hundred fifteen non-diabetic and non-dialytic CKD patients of all stages and a control group of 35 healthy subjects were included. Retinal neural and microvascular parameters were obtained by optical coherence tomography angiography (OCTA) examination.Results: CKD 1–2 group (versus control group) had greater odds of having decreased retinal ganglion cell-inner plexiform layer thickness (GC-IPLt) , increased ganglion cell complex-focal loss volume (GCC-FLV) , and GCC-global loss volume (GCC-GLV) . The presence of advanced stages of CKD (CKD 3–5 group versus CKD 1–2 group) had greater odds of having decreased retinal vessel density in superficial vascular plexus (SVP)-WholeImage , SVP-ParaFovea , SVP-ParaFovea , deep vascular plexus (DVP)-WholeImage , DVP-ParaFovea , and DVP-PeriFovea . Besides, stepwise multivariate linear regression among CKD patients showed that β2-microglobulin was negatively associated with GC-IPLt , and parathyroid hormone was positively associated with increased GCC-FLV  and GCC-GLV . Urine protein to creatinine ratio was positively associated with increased GCC-FLV  and GCC-GLV .Conclusion: Retinal neuronal impairment is present in early stages of CKD (stages 1–2), and it is associated with accumulation of uremic toxins and higher UACR, while retinal microvascular hypoperfusion, which is associated with worse eGFR, was only observed in relatively advanced stages of CKD (stages 3–5). The results highlight the importance of monitoring retinal neurovascular impairment in different stages of CKD. As an emerging public health issue, chronic kidney disease (CKD) is predicted to be the fifth most common cause of death worldwide by 2040 . Uremia As an extension of the brain and sharing the same embryological origin with the CNS. Previous investigations have shown that both retinal neural impairment and microvascular hypoperfusion can be detected in CKD patients (stages 3–5) using OCTA . HoweverTherefore, we conducted this cross-sectional study in CKD patients of all stages without a history of DM or dialysis, aiming to investigate the changes of retinal neurovascular parameters detected by OCTA in patients of different CKD stages and further analyze the association between neurovascular alterations and CKD-related risk factors.This cross-sectional study included a total of 150 eyes from 115 CKD patients and 35 healthy subjects. The study was conducted in the Department of Ophthalmology and the Department of Nephrology, Guangdong Provincial People’s Hospital from August 2019 to December 2020. The procedures followed the ethical standards of the Research Ethics Committee of Guangdong Provincial People’s Hospital [registration number: GDREC2020069(R1)] and the Helsinki Declaration. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. Informed consent was obtained from all participants.2 for 3 months or more] (2 (stage 1), 60∼89 ml/min/1.73 m2 (stage 2), 30∼59 ml/min/1.73 m2 (stage 3), 15∼29 ml/min/1.73 m2 (stage 4), and less than 15 ml/min/1.73 m2 (stage 5)  or decreased kidney function  . The eGFor more] . Severitstage 5) . The CKDThe exclusion criteria were patients with (1) any type of DM; (2) HblAc>6.5%; (3) history of dialysis ; (4) any ocular issue that may impair ocular circulation ; (5) inadequate quality of OCTA image ; (6) any severe systemic diseases ; (7) women who were pregnant.All participants underwent comprehensive ophthalmic examinations including best-corrected visual acuity (BCVA) , autorefraction, intraocular pressure, slit-lamp examination, and color fundus photography. Retinal microvasculature and neural parameters were measured with Optical Coherence Tomography Angiography (OCTA).Optical Coherence Tomography Angiography with RTVue-XR Avanti  is a device combining structural and functional imaging by analyzing the changing variance in light speckle created by erythrocyte flow over multiple scans . The OCTThe detailed procedures of the OCTA examination were shown in Retinal vascular retinal layers were visualized as follows: a set of high definition (HD) Angio Retina Scan (6*6mm) was captured to evaluate the VD of the macular, which contained superficial retinal plexus and deep retinal plexus. The boundaries of each layer were segmented as follows: a slab extending from 3 to 15 μm from the internal limiting membrane (ILM) was generated to detect the superficial vascular plexus (SVP), and a slab extending from 15 to 70 μm below ILM to detect the deep vascular plexus (DVP) . BesidesAs for the retinal neural parameters, a ganglion cell complex (GCC) scan was used to measure retinal ganglion cell-inner plexiform layer thickness (GC-IPLt), which was defined as the layer between the retinal nerve fiber layer (RNFL) and IPL within a 6-mm circle. An optic nerve head (ONH) scan was obtained for the measurement of RNFL thickness (RNFLt). The average RNFLt was measured over a 3.45-mm-diameter circle centered on the ONH.All the retinal VD and layer thickness retinal VD and layer thickness were calculated automatically and quantitatively using the AngioVue SSADA software . Both ey1C), Scr, blood urea nitrogen (BUN), hemoglobin (HGB), cholesterol (CHOL), low-density lipoprotein (LDL), urine albumin to creatinine ratio (UACR), urine protein to creatinine ratio (UPCR), parathyroid hormone (PTH), albumin (ALB), and β2-microglobulin (β2-M).Medical history and laboratory data in the last 3 months were collected. Demographic and blood test data were extracted from the electronic medical record system by a trained researcher (YF) and double-checked by an ophthalmologist (XZ). The basic information included age, sex, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), duration of CKD, and the history of smoking, hypertension, and cardiovascular disease (CVD). Laboratory tests included glycated hemoglobin  were used for presenting quantitative variables for normal distribution, medians and interquartile range (IQR) for abnormal distribution, and numbers (percentages) were used for categorical variables. In the comparison of basic characteristics among three groups, one-way ANOVA was used for normally distributed continuous data and the Kruskal–Wallis H test was used for non-normally distributed continuous data, and Bonferroni’s correction was used for post hoc analysis. χ2 tests were utilized to compare categorical variables. Mann–Whitney test was applied to compare the duration of CKD between the CKD 1–2 group and the CKD 3–5 group. Crude logistic regression models were used to compare the OCTA parameters (dependent variables) between different groups  without adjusting confounders. We also used adjusted logistic regression models  to adjust the confounders, including age, sex, BMI, SBP, DBP, history of smoking, history of CVD, Hb1Ac, CHOL, and LDL. Partial correlation analysis was used to determine risk factors associated with the OCTA parameters in the CKD patients after controlling for age, sex, BMI, history of smoking, history of CVD, RE, and IOP. Besides, stepwise multivariate regression was performed to figure out the independent risk factors for the retinal neurovascular alterations in the CKD patients. Age, sex, BMI, history of hypertension, history of smoking, history of CVD, eGFR, BUN, PTH, UACR, HGB, CKD duration, Hb1Ac, β2-M, and LDL were independent variables entered into the model. Finally, Spearman correlation analysis was used to determine the relationship between BCVA and OCTA parameters in all subjects.SPSS version 25.0  was used to perform statistical analyses. A two-sided p < 0.05). The CKD 3–5 group showed significantly higher results of SBP, DBP, Hb1Ac, Scr, BUN, BCVA (logMAR), as well as decreased eGFR and HGB compared to the CKD 1–2 group and the control group . Besides, the CKD 3–5 group also showed significantly higher results of age, BMI, PTH, β2-M, history of hypertension, and CVD compared to the CKD 1–2 group . No significant difference was found in sex, history of smoking, CHOL, SER, and IOP among the three groups. Duration of CKD, UACR, UPCR, and ALB and the etiology of CKD were comparable between the CKD 1–2 group and the CKD 3–5 group. Besides, the signal strength index of the macular, disk, GGG, and ONH areas and the overall quality index of the macular and disk areas are comparable among the three groups (The basic characteristics of the participants were summarized in e groups .p < 0.05). Also, significantly reduced GCCt and increased GCC-GLV were found in the CKD 3–5 group compared to the CKD 1–2 group. A representative picture showing the changes in GC-IPLt, GCC-FLV, and GCC-GLV in CKD groups and control group was shown in p < 0.001). No significant difference was found in all microvascular parameters between the CKD 1–2 group and the control group. No significant difference was found in VD in all RPC regions among the three groups.Comparisons of OCTA parameters among the three groups were shown in b showed that the presence of early stages of CKD (CKD1–2 group versus control group) was significantly associated with decreased GC-IPLt , meaning one-micrometer increase of GC-IPLt is associated with 0.92-fold risk of CKD after adjusting for the confounding factors. Meanwhile, the presence of early stages of CKD (CKD1–2 group versus control group) was significantly associated with increased GCC-FLV  and GCC-GLV . Further investigation in the crude model 2b showed that the presence of advanced stages of CKD (CKD 3–5 group versus CKD 1–2 group) had greater odds of having decreased VD in SVP-WholeImage , SVP-ParaFovea , SVP-PeriFovea , DVP-WholeImage , DVP-ParaFovea , DVP-PeriFovea , and increased GCC-GLV .r = 0.199∼0.355, all p < 0.05) and negatively with β2-M, BUN, and PTH . Furthermore, GCC-FLV and GCC-GLV were positively correlated with β2-M, BUN, UPCR, UACR, and PTH  and negatively with eGFR . Partial correlation of GCC variables and eGFR were shown in The results of partial correlation analyses of OCTA parameters and CKD-related parameters among all 115 CKD patients were shown in The result of stepwise multivariate linear regression between OCTA parameters and clinical data among all 115 CKD patients was presented in r = –0.399 ∼ –0.514, all p < 0.05), while positively with GCC-GLV .The results of correlation analyses of BCVA and OCTA parameters among all subjects were shown in Two crucial findings were observed in this cross-sectional study. Firstly, our study revealed that retinal ganglion cell complex impairment occurs in the early stages (CKD stages 1–2) without detectable retinal microvascular rarefaction and RNFL damage in non-diabetic and non-dialytic CKD patients. Secondly, among CKD patients, the accumulation of uremic toxins of β2-M and PTH, and higher UACR was independently associated with retinal ganglion cell complex impairment, while reduced eGFR was associated with deceased retinal microvascular perfusion.2 (CKD stages 3–5) and failed to include earlier stages CKD patients with an eGFR of > 60 ml/min/1.73 m2  using parameters such as proteinuria or UACR to detect early renal damage and declining renal function. Our study evaluated retinal neural parameters in non-diabetic CKD patients of stages 1–2  and revealed that retinal neuronal impairment, which might even precede microvascular rarefaction and retinal axon damage, could be detected in earlier CKD stages than those reported in prior studies , while no significant difference was found in all retinal microvascular parameters and RNFLt in the CKD 1–2 group compared to the control group, suggesting that retinal neuronal impairment has already existed in early CKD stages even in the absence of histologically assessed microvascular rarefaction and retinal axon damage. In fact, neurological complications, such as cognitive deterioration, cerebrovascular stroke, and cranial neuropathy, are common in CKD patients . Recent  studies .On the other hand, significantly decreased RNFLt was observed in CKD patients according to previous studies . HoweverStepwise multivariate linear regression was used to figure out independent risk factors associated with neurovascular alterations in the CKD patients of our study. It was shown that higher β2-M was associated with thinner GG-IPLt, and excessive PTH was associated with increased GCC-FLV and GCC-GLV, indicating the underlying pathophysiology of retinal neurodegeneration in CKD patients was related to the neurotoxic effects exerted by uremic toxins. In fact, as CKD progresses, there is the accumulation of organic toxic products which is considered highly associated with the incidence and progression of neurological complications . Our resAnother interesting finding is that higher UACR was independently associated with increased GCC-FLV and GCC-GLV. Previous studies have documented that albuminuria was independently associated with POAG , an oculIn addition, we also found that retinal VD decrease was detected in more advanced CKD stages (stages 3–5) and was associated with declined eGFR. This is consistent with the fact that microangiopathy and cardiovascular complications of CKD are also more prevalent in these patients . Thus, t2), and parameters of the retinal ganglion cell complex layer can be used as indicators of early neuronal damage in these patients. Secondly, once retinal neuronal damage (such as GCC loss) is detected, the eGFR should be closely monitored to reduce CKD-related microangiopathy and other adverse cardiovascular complications.There are two major implications of our findings. Firstly, strict control of uremia and close monitoring of neuronal impairment should be started in CKD patients at early stages  and it is associated with accumulation of uremic toxins and higher UACR, while retinal microvascular hypoperfusion, which is associated with worse eGFR, was only observed in relatively advanced stages of CKD (stages 3–5). The results highlight the importance of monitoring retinal neurovascular impairment in different stages of CKD.yuhonghua@gadph.org.cn.The raw data supporting the conclusions of this article will be made available by the authors, upon request to HY, The studies involving human participants were reviewed and approved by the Research Ethics Committee of Guangdong Provincial People’s Hospital [registration number: GDREC2020069(R1)]. The patients/participants provided their written informed consent to participate in this study.HY, XY, ZY, XZ, YH, and YC: conception and design. XZ, YL, BL, PZ, YX, CL, GW, HK, ZL, ZD, YR, and YF: analysis and interpretation of data. XZ, YH, YC, and ZL: drafting the manuscript and revising it. HY, XY, ZY, XZ, YH, and YC: providing intellectual content of critical importance to the work described. All authors approved the final version to be published.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.