This epidemiologic assessment of population-based cohorts investigates the change in treatment for chronic kidney disease associated with population-based screening compared with measuring blood pressure and assessing glycemia. How frequently is population-based screening for chronic kidney disease (CKD) associated with a change in recommended treatment compared with a strategy of measuring blood pressure and assessing glycemia?This epidemiologic assessment of 126 242 adults screened for CKD in population-based cohorts from China, India, Mexico, Senegal, and the United States found that most treatment gaps identified by population-based screening for CKD were apparent by measuring blood pressure or glycemic control. Case finding, defined by testing for CKD only in adults with hypertension or diabetes, was associated with a lower frequency of testing and a greater proportion of individuals with identified treatment gaps compared with screening.These findings suggest that case finding was more efficient than population-based screening and detected most patients with CKD requiring treatment changes. Population-based screening for chronic kidney disease (CKD) is sometimes recommended based on the assumption that detecting CKD is associated with beneficial changes in treatment. However, the treatment of CKD is often similar to the treatment of hypertension or diabetes, which commonly coexist with CKD.To determine the frequency with which population-based screening for CKD is associated with a change in recommended treatment compared with a strategy of measuring blood pressure and assessing glycemia.This cohort study was conducted using data obtained from studies that evaluated CKD in population-based samples from China (2007-2010), India (2010-2014), Mexico (2007-2008), Senegal (2012), and the United States (2009-2014), including a total of 126 242 adults screened for CKD. Data were analyzed from January 2020 to March 2021.2. For individuals with CKD, the need for a treatment change was defined as not taking an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker or having blood pressure levels of 140/90 mm Hg or greater. For individuals with CKD who also had diabetes, the need for a treatment change was also defined as having hemoglobin A1c levels of 8% or greater or fasting glucose levels of 178.4 mg/dL (9.9 mmol/L) or greater. Case finding was defined as testing for CKD only in adults with hypertension or diabetes.The primary definition of CKD was estimated glomerular filtration rate less than 60 mL/min/1.73 mAmong 126 242 adults screened for CKD, there were 47 204 patients in the China cohort, 9817 patients in the India cohort, 51 137 patients in the Mexico cohort, 2441 patients in the Senegal cohort, and 15 643 patients in the US cohort. The mean age of participants was 49.6 years  in the China cohort, 42.9 years  in the India cohort, 51.6 years  in the Mexico cohort, 48.2 years  in the Senegal cohort, and 47.3 years  in the US cohort. The proportion of women was 57.3%  in the China cohort, 53.4%  in the India cohort, 68.8%  in the Mexico cohort, 56.0%  in the Senegal cohort, and 51.9% (51.0%-52.7%) in the US cohort. The prevalence of CKD was 2.5%  in the China cohort, 2.3%  in the India cohort, 10.6%  in the Mexico cohort, 13.1%  in the Senegal cohort, and 6.8%  in the US cohort. Screening for CKD was associated with the identification of additional adults whose treatment would change (beyond those identified by measuring blood pressure and glycemia) per 1000 adults: China: 8 adults ; India: 5 adults ; Mexico: 26 adults ; Senegal: 59 adults ; and the US: 19 adults . Case finding was associated with the identification of 46.2%  to 86.4%  of individuals with CKD depending on the country, an increase in the proportion of individuals requiring a treatment change by as much 89.6%  in the US, and a decrease in the proportion of individuals needing GFR measurements by as much as 57.8%  in the US.This study found that most additional individuals with CKD identified by population-based screening programs did not need a change in treatment compared with a strategy of measuring blood pressure and assessing glycemia and that case finding was more efficient than screening for early detection of CKD. Most individuals in LMICs cannot afford kidney replacement,4 and CKD that progresses to kidney failure kills millions of people each year.5 Because widely available and inexpensive treatments can slow or prevent loss of kidney function and CKD is asymptomatic until its later stages, some have advocated for population-based screening to enable early intervention in LMICs and high-income countries.6Chronic kidney disease (CKD) is a common condition that is associated with substantial morbidity and mortality.13 Sodium-glucose cotransporter-2 (SGLT2) inhibitors also improve outcomes in individuals with CKD,15 although these medications are not widely used at present, especially in LMICs. For a small proportion (<10%) of individuals with CKD, early detection is associated with the identification of an underlying condition, such as glomerulonephritis, and additional treatment.17 Any incremental benefit associated with screening occurs during the period between the detection of CKD by screening and when it would otherwise be detected. However, this assumes that earlier detection is associated with beneficial changes in treatment. This assumption is uncertain, given the overlap in the recommended treatment between CKD and other noncommunicable diseases (NCDs).19In theory, screening for CKD would allow for earlier initiation of treatment, delaying or avoiding progression to kidney failure. Treatments that are known to prevent progressive loss of kidney function in CKD include control of blood pressure, use of an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB), and control of blood glucose among individuals with diabetes.We designed the current study to estimate the yield associated with population-based screening for CKD in low-income, middle-income, and high-income settings, including China, India, Mexico, Senegal, and the United States. We hypothesized that most instances in which CKD is detected by population-based screening would not necessarily be associated with a change in treatment. We also hypothesized that testing for CKD among individuals with a self-reported history of hypertension, diabetes, or CKD and those with current evidence of hypertension or diabetes  would be associated with an increase in the proportion of individuals with detected CKD who would be recommended a treatment change and a significant decrease in the number of individuals who required testing for CKD.This epidemiologic assessment of population-based cohorts was approved by the Health Research Ethics Board at the University of Calgary. Informed consent was obtained from participants in the original cohort studies.20 India,21 Mexico,22 Senegal,23 or the United States.24 All studies measured kidney function with estimated glomerular filtration rate (eGFR) or albuminuria on a single occasion. The Mexico and Senegal studies excluded participants receiving kidney replacement, whereas the others did not. The Mexico study also excluded individuals who reported that they had CKD, whereas the other studies did not. Details of each cohort are presented in the eMethods in the Data were obtained from 5 previously completed studies, each of which evaluated the prevalence of CKD in a population-based sample from 1 of the countries of interest: China,2 at the time of the study visit; a second measure more than 3 months from the initial measure was not required. In sensitivity analyses, we considered 2 alternative definitions of CKD: (1) eGFR less than 60 mL/min/1.73 m2 or severe albuminuria1 and (2) eGFR less than 45 mL/min/1.73 m2 with or without severe albuminuria.2 Severe albuminuria was defined as the presence of any 1 of the following: albumin-to-creatinine ratio greater than 300 mg/g or greater than 30 mg/mmol; protein-to-creatinine ratio greater than 500 mg/g or greater than 50 mg/mmol; dipstick urinalysis of 2 or greater for albumin. We focused on severe rather than moderate albuminuria because it is associated with worse prognosis, may be less likely to be a false positive finding, and is more readily detected using dipstick urine testing, which is especially relevant for LMICs.The primary definition of CKD was based on eGFR less than 60 mL/min/1.73 mA history of diabetes, CKD, or hypertension was based on self-report and definitions used by each study  levels of less than 8% 27 in the India and US cohorts and by fasting blood glucose levels of less than 178.4 mg/dL (9.9 mmol/L) based on a published conversion factor19 for the Mexico, Senegal, and China cohorts given that HbA1c data were not available. Participants with appropriate glycemic control were considered not to require any change to their glycemic treatment. We chose a threshold of less than 8% because it will tend to overestimate the benefits of early detection compared with an individualized threshold of less than 6.5%  to 8%.27Appropriate glycemic control was defined by hemoglobin A1c levels of 8%  or more in the India and United States cohorts, or having fasting glucose levels of 178.4 mg/dL (9.9 mmol/L) or more in the Mexico, Senegal, and China cohorts. Given that taking an ACEI or ARB may not be associated with a benefit among individuals with CKD and well-controlled albuminuria but without diabetes, this definition may be associated with overestimated benefits of early detection.For participants with CKD but not diabetes, the need for a treatment change was defined as not taking an ACEI or ARB or having blood pressure levels of 140/90 mm Hg or more. For participants with CKD and diabetes, the need for a treatment change was defined as not taking an ACEI or ARB, having blood pressure levels of 140/90 mm Hg or more, having HbA18 We also assumed that detecting uncontrolled glycemia required a treatment change. Therefore, the situation in which a measurement of kidney function would influence treatment decisions was defined by the identification of CKD in a participant without hypertension or diabetes who was not receiving an ACEI or ARB.We assumed that detecting hypertension suggested the need to control blood pressure and that first-line treatment for individuals with CKD and hypertension would be an ACEI or ARB.2) and the definition of CKD used in the second sensitivity analysis , screening was defined as measuring eGFR in all participants. In the definition of CKD used in the first sensitivity analysis , screening included measuring eGFR and albuminuria. Case finding was defined by measuring eGFR in the subset of participants with a self-reported history of hypertension, diabetes, or CKD or with blood pressure levels of 140/90 mm Hg or more or with laboratory evidence of diabetes, HbA1c levels of 6.5% ) or more, or fasting blood glucose levels of 126.1 mg/dL (7.0 mmol/L) or more depending on cohort.For the primary definition of CKD  to identify 1 individual for whom a treatment change was required was calculated as 1 divided by the percentage of individuals for whom a treatment change was required. The data were expressed in tabular form and as Senn plots and stacked bar graphs.For each study, information on participant characteristics; prevalence of diabetes, hypertension, and CKD; blood pressure and glycemia control status; and ACEI and ARB use were estimated and recorded in a standardized form. Results were checked (S.T.) and expressed as No. (%) with 95% CI. When evaluating population-based screening, we calculated the proportion of individuals in the overall population who required a treatment change, then stratified these results by whether detecting the need for a treatment change required knowledge of CKD status. We calculated the proportion of individuals with CKD detected by population-based screening and categorized this population into 3 groupsWe then calculated the number of individuals for whom the assessment of CKD status would be required using the case-finding approach. Additionally, we calculated the number and proportion of individuals with CKD identified and the proportion of those identified for whom a treatment change would be required through case finding using the same methods as those used to evaluate population-based screening described previously. We calculated the percentage reduction in number of individuals who would have eGFR measurements and the increase in the proportion of individuals with CKD identified who required a treatment change for the case-finding vs population-wide screening approaches. Additionally, we calculated the proportion of individuals with CKD in each cohort identified by case finding. Data were reported as means or percentages with 95% CIs calculated using Excel 2019 (Microsoft Corporation). Data were analyzed from January 2020 to March 2021.Among 126 242 adults screened for CKD, there were 47 204 patients in the China cohort, 9817 patients in the India cohort, 51 137 patients in the Mexico cohort, 2441 patients in the Senegal cohort, and 15 643 patients in the US cohort. The mean age of participants was 49.6 years  in the China cohort, 42.9 years  in the India cohort, 51.6 years  in the Mexico cohort, 48.2 years  in the Senegal cohort, and 47.3 years  in the US cohort. The proportion of women was 57.3%  in the China cohort, 53.4%  in the India cohort, 68.8%  in the Mexico cohort, 56.0%  in the Senegal cohort, and 51.9%  in the US cohort .2), the prevalence of CKD was 2.5%  in the China cohort, 2.3%  in the India cohort, 10.6%  in the Mexico cohort, 13.1%  in the Senegal cohort, and 6.8%  in the US cohort. Among individuals in these cohorts with CKD, the proportion identified with CKD prior to screening  was 14.2%  in the China cohort, 6.2%  in the India cohort, 0% in the Mexico cohort, 6.3%  in the Senegal cohort, and 13.2%  in the US cohort. Among individuals with CKD, the proportion who required a treatment change ranged from 68.7%  in the US cohort to 97.8%  in the India cohort. However, with the exception of individuals in Senegal, most individuals with CKD who required a treatment change could be identified without checking kidney function by measuring blood pressure or testing for diabetes ; India: 5 adults ; and the US: 19 adults  . In the 2 or severe albuminuria) was 3.0%  in the China cohort, 2.9%  in the India cohort, 11.3%  in the Mexico cohort, 14.8%  in the Senegal cohort, and 8.1%  in the US cohort. Using the second sensitivity definition , the prevalence of CKD was 0.5%  for China, 0.8%  for India, 2.0%  for Mexico, 5.2%  for Senegal, and 2.2%  for the United States.The prevalence of CKD using the first sensitivity definition  per 1000 individuals for India to 69 individuals  per 1000 individuals for Senegal  per 1000 individuals for China to 12 individuals  per 1000 individuals for Senegal  for China, 351 individuals  for India, 324 individuals  for Mexico, 81 individuals  for Senegal, and 323 individuals  for the United States. Findings were not sensitive to varying the proportion of ACEI or ARB use in China or Mexico  or more, or fasting blood glucose levels of 126.1 mg/dL or more. When CKD was assessed in this subroup (case finding), the number of participants who required assessment of CKD status was decreased while the proportion of participants with CKD who required a treatment change was similar or was increased compared with screening the entire population , whereas India had a less favorable NNS (189) and the United States and China had intermediate NNS values . These results suggest that although the wealth of a country may be associated with the yield of screening for CKD, other factors, such as the prevalence of CKD and other NCDs, access to health care, and the availability of low-cost NCD treatment, may also be associated with this outcome. In addition, some regions may have an increased prevalence of CKD without accompanying diabetes or uncontrolled blood pressure; this nontraditional CKDBecause it is more economically efficient to treat individuals with known conditions rather than searching for new diagnoses, it may appear more rational to allocate resources to increasing drug coverage for individuals with previously identified NCDs rather than to population-based screening. However, the decision to screen may appropriately consider other factors, such as raising awareness, mapping local causes of CKD, and responding to perceived population burden.32 Case finding was associated with the identification of most individuals with CKD for 4 of 5 countries studied but would miss 53.8% of individuals with CKD in the Senegal cohort, perhaps associated with decreased access to specialist care in this rural population. These results suggest that further work is needed to assess the optimal strategy for case finding and determine how best to integrate case finding for CKD with treatment of other NCDs. As for all early detection programs, jurisdictions that pursue case finding should attempt to minimize overtesting and harms associated with testing.If early detection of CKD is desired, our findings suggest that case finding is more efficient and cost-effective than population-based screening. Case finding was associated with a significant decrease in the number of individuals who required eGFR testing and increase in the proportion of individuals with CKD for whom a treatment change was indicated. This builds on previous work suggesting that case finding is associated with favorable cost utility.33 Our results suggest that although population-based screening for CKD may be associated with identification of a large number of individuals whose treatment should change, the need for these changes would be similarly apparent after simply assessing blood pressure, assessing glycemic control, and using an ACEI or ARB as first-line therapy for individuals with hypertension. There may be other benefits associated with early detection of CKD, such as increased use of living donor transplantation, more time to discuss an appropriate modality choice for those who require kidney replacement, more cautious use of intravenous contrast, up-titration of existing ACEI or ARB regimens, discontinuation of nephrotoxic medications, or the opportunity to adjust drug dosing for eGFR.33 In addition, multiple measurements of eGFR even when the initial value is more than 60 ml/min/1.73 m2 may help to trigger early intervention for individuals with rapid loss of kidney function. However, these speculative benefits seem unlikely to be associated with large differences in health outcomes on a population level,16 and a strategy based on multiple measurements among individuals would be very resource intensive.Prior work has focused on the proportion of individuals who are identified as having CKD, assuming that treatment would change for most or all such individuals.26 If blood pressure control were defined as in this guideline, a smaller number of individuals would have controlled BP and the potential benefit associated with screening for CKD would be smaller than we estimated in this study. Conversely, the 2021 Kidney Disease Improving Global Outcomes guideline recommends control of systolic blood pressure to less than 120 for most adults with CKD.34 Using a target of less than 130/80 mm Hg for individuals without CKD and a target of less than 120 for individuals with CKD may be associated with increased numbers of patients for whom screening or case finding with eGFR and albuminuria would be associated with a treatment change. This is because as many as 20% of US adults with CKD may have systolic blood pressure from 120 to 130.35We defined adequate blood pressure control as levels less than 140/90 mm Hg. The 2017 American College of Cardiology/American Heart Association guideline recommends a blood pressure target of less than 130/80 mm Hg for almost all adults, including those with CKD.There were some differences in the design of the cohorts  and in the demographic characteristics of participants across cohorts, likely associated with differences in the source populations. The consistency of our conclusions across these different settings may increase confidence in the findings. However, our analysis also has several limitations that should be considered. First, 3 of 5 cohorts were subnational samples rather than nationally representative samples. However, the consistency of the results across all 5 settings suggests that it is unlikely that exclusive use of national data would have influenced our conclusions. Second, we did not have data on family history of CKD or occupation, which could also be used to inform case finding. Third, we defined CKD based on a single measurement of kidney function. Although this may have been associated with an overestimation of CKD prevalence, it should not have affected our conclusions because obtaining a confirmatory measurement would be associated with decreased prevalence of screen-detected CKD. Fourth, we estimated the proportion of participants in China and Mexico who were using ACEI or ARB using data from the United States. However, a sensitivity analysis suggests that this assumption was associated with little change in the study results. Fifth, we could have considered the use of statins and SGLT2 inhibitors, which are associated with improved outcomes among individuals with CKD. However, the high cost of SGLT2 inhibitors suggests that they will be infrequently used in LMICs at present and reinforces the opportunity cost associated with detecting additional cases of CKD as opposed to treating known cases. Sixth, our findings may not apply in settings where ACEI and ARB are infrequently used as first-line treatment for hypertension among individuals without CKD. Seventh, other system-level characteristics, such as health insurance coverage, accessibility of health services, and national priorities, may make early detection more or less appealing.These findings suggest that measuring eGFR or albuminuria in population-based screening programs may not be associated with more frequent identification of an indication for a change in treatment in comparison with simply measuring blood pressure, inquiring about antihypertensive medication use, assessing glycemic control, and first-line use of ACEI or ARB therapy among individuals with diabetes or hypertension. These data add to evidence suggesting that population-based CKD screening is not a wise use of resources but may warrant re-evaluation if SGLT2 inhibitors become less expensive and more widely available, especially in LMICs. If the early detection of CKD is desired, case finding may be appropriate, given that it was associated with an increase in the yield of individuals who required a treatment change and a decrease in the need for diagnostic testing.


Electroconvulsive therapy (ECT) is an effective therapy for psychiatric disorders, but is associated with acute hyperdynamic responses including transient hypertension and tachycardia. This study aimed to assess the effectiveness of premedication with dexmedetomidine for hemodynamic attenuation after ECT and to evaluate its effects on seizure duration, postictal asystole duration, post ECT agitation and recovery time.Twenty-four psychiatric patients who underwent a total of 72 ECT sessions (three sessions per patient) were randomly allocated to receive either dexmedetomidine 0.5 mcg/kg intravenous, dexmedetomidine 1 mcg/kg intravenous, or saline (control group) 15 min before the first ECT session. The patients subsequently received the other two premedication options for their next two ECT sessions. Blood pressure and heart rate were recorded at 5, 10, and 15 min after drug infusion and at 2.5, 5, 7.5, 10, 15, 20, 25, and 30 min after ECT. Asystole duration, seizure duration, post ECT agitation and recovery times were also recorded.p = 0.002). Diastolic blood pressure and heart rate were significantly lower in the dexmedetomidine 1 mcg/kg group  compared with the control group. Asystole duration, seizure durations, post ECT agitation and recovery times were similar between the groups.The baseline characteristics were similar between the groups. Systolic blood pressure in both dexmedetomidine groups was significantly lower than that in the control group after ECT , principal investigator: Pattika Subsoontorn, date of registration: 15/07/2017. Electroconvulsive therapy (ECT) is an effective therapy for psychiatric disorders in patients who have not responded to pharmacotherapy. In ECT, a generalized seizure is induced by a brief unilateral or bilateral electrical stimulus. ECT causes generalized autonomic nervous system stimulation, initially producing bradycardia induced by parasympathetic nerve stimulation, followed immediately by more prominent sympathetic stimulation that results in transient tachycardia and hypertension . The acuMany drugs, such as α-2 adrenergic agonists, β-blockers and opioids, have been used to attenuate the acute hemodynamic responses typically induced by the ECT stimulus –7. AlphaThis study was a crossover, double-blind randomized controlled trial conducted during May 2017 to April 2018 in Ramathibodi Hospital, Mahidol University, Thailand. The study participants were selected from patients recommended for ECT by a psychiatrist, and who were between 18 to 70 years old with an American Society of Anesthesiologist (ASA) physical status of I–III. The exclusion criteria were patients with liver disease, severe ventricular dysfunction, advanced heart block, or an allergy to the study drugs, or who were currently pregnant or using any β-blockers or narcotics. Informed consent was obtained from all eligible patients, or from relatives of patients who were unable to make an informed decision, before enrollment in the study., the study was registered before participant recruitment with Thai Clinical Trials Registry . The registration number is TCTR20170715003, date of registration: 15/07/2017. The sample size was calculated from a previous study [After obtaining approval from Ramathibodi Ethics Committee (ID 02–60-15)The primary outcomes were post-ECT blood pressure and heart rate (HR). The secondary outcomes were incidence of post-ECT agitation, seizure duration (motor and EEG), asystole duration  and recovery time. The asystole duration was determined by the absence of ventricular contraction detected on an electrocardiogram. Patients enrolled in the study were randomly assigned by computer-generated random numbers to receive one of three premedications that were given 15 min before their first ECT session. The patients subsequently received the other two premedication options for their next two ECT sessions. After randomization, sequence pattern for each patient would be enclosed in envelope. Patients were blinded from the study drugs. The drug solutions were prepared by an anesthesiologist who was involved in the study, but administration was performed by an anesthetic nurse who was blinded to the study drugs.Each patient was evaluated by an anesthesiology resident before the procedure. Baseline characteristics of the patients, including name, height, weight, comorbidities, current medication and ASA physical status, were recorded. If the patient was on antihypertensive medication, it was continued as usual before the ECT. After standard monitoring, patients in group A received dexmedetomidine 0.5 mcg/kg, patients in group B received dexmedetomidine 1 mcg/kg and patients in the control group received saline. All solutions were prepared in a total volume of 25 mL and given by intravenous (IV) infusion over 15 min. Arterial blood pressure and HR were recorded immediately before, and at 5, 10 and 15 min after starting the drug infusion.Immediately after the drug infusion was completed, anesthesia was induced with thiopental 2–3 mg/kg or propofol 1–2 mg/kg. The total dose of propofol or thiopental that each patient received was recorded. After loss of consciousness, a pneumatic tourniquet was applied to one leg and inflated to isolate the leg circulation and allow for an accurate assessment of the motor seizure. Succinylcholine  was then administered and ventilation was assisted with 100% oxygen in all patients. When paralysis was achieved, the electrical stimulus was applied. After cessation of the EEG and clinical motor seizure, manual ventilation was initiated until the patient’s spontaneous breathing was sufficient and the airway was patent. Patients were then transferred to the postanesthesia care unit and monitoring was continued.Arterial blood pressure and HR were recorded immediately after ECT and then in 2.5-min intervals up to 10 min, then 5-min intervals up to 30 min. Through treatment session, acceptable blood pressure and heart rate were defined as within 20% lower or higher than each patient baseline (immediately before start premedication). If unacceptable blood pressure or heart rate persist longer than 5 min, in-charged anesthesiologist would give treatment as appropriate. The duration of EEG seizure, motor seizure and asystole were recorded. The recovery time was recorded as the time from the end of succinylcholine administration until the patient was obeying commands. The agitation degree was evaluated by a postanesthetic care nurse using a postictal agitation 4-point numeric rating scale . The CONSORT diagram is shown in Fig. p-values were Bonferroni-adjusted  with time as a within-group variable. SPSS 20.0  was used for statistical analysis. A p-value less than 0.05 was considered statistically significant.Nominal data, such presence of underlying diseases, were summarized as number and percentage of patients. Continuous data, such as age and blood pressure, were summarized as mean ± standard deviation (SD), or median and interquartile range (IQR) based on normality of the distribution. Group comparisons were performed using a chi-square test (Fisher’s or Monte Carlo) for categorical variables and one-way ANOVA or the Kruskal–Wallis test for continuous variables. For repeated measurements and subsequent post hoc tests for systolic blood pressure, diastolic blood pressure and HR, the repeated measures ANOVA was used. The The study included 10 male and 14 female participants. The recruitment and data collection were between July 2017 to February 2018. In total, 72 ECT sessions were evaluated from three separate treatment sessions per patient. No participants were excluded from the study due to exclusion criteria. Baseline characteristics were shown in Table p = 0.002). Post hoc analysis indicated a significant difference for both the dexmedetomidine 0.5 mcg/kg group  and dexmedetomidine 1 mcg/kg group . The peak systolic blood pressure occurred at 5 min after ECT, and the dexmedetomidine 1 mcg/kg group had the lowest measurement at this time point .After administration of dexmedetomidine, systolic blood pressure of all groups was decreased from baseline within 15 min. However, the values were still within the acceptable range. Systolic blood pressure measurements in both dexmedetomidine groups were significantly lower than those in the control group at all time points after ECT (p = 0.016). Post hoc analysis indicated that diastolic blood pressure was significantly lower in only the dexmedetomidine 1 mcg/kg group compared with control group at all time points after ECT .Diastolic blood pressure was significantly lower in the dexmedetomidine groups compared with the control group (p = 0.012). However, when comparing between the groups, the only significant differences were between the dexmedetomidine 1 mcg/kg group and control group at all time points after ECT . The carry-over effect was minimized by adequate washout period at least 24 h interval between each premedication drug before each ECT session. The carry-over covariates (period of measurement 1–3) were drop and re-run the repeated measures ANOVA for systolic, diastolic blood pressure and heart rate to check if there was significant carry-over effect. The results yielded no significant (p > 0.05).HR measurements after drug administration and ECT were shown in Fig. p = 0.048), with the lowest duration measured in the dexmedetomidine 1 mcg/kg group. However, post hoc analysis indicated no significant differences with p > 0.0167 with Bonferroni correction; 0.05/3 pairs = 0.0167 .Secondary outcomes were shown in Table This study demonstrates that dexmedetomidine can attenuate the hemodynamic response after ECT. Either dexmedetomidine 0.5 mcg/kg or 1 mcg/kg attenuated hypertension immediately after ECT for at least 30 min, the maximum length of time measured in this study. The two dexmedetomidine doses produced similar degrees of blood pressure attenuation. However, only dexmedetomidine 1 mcg/kg decreased the tachycardia response compared to the control group, as indicated in the post hoc analysis. Dexmedetomidine administration had no statistically significant effect on recovery time, quality of ECT or motor and EEG seizure durations. Asystole duration, a complication after ECT, was also not affected by the drug administration.Dexmedetomidine has been used in previous studies to attenuate the hemodynamic response in stress situations , 14. In Postictal asystole after ECT has been previously reported –18. The Motor seizure duration was decreased in the dexmedetomidine 0.5 mcg/kg and 1 mcg/kg groups compared with the control group. Motor seizure duration greater than 20–25 s is usually considered as adequate treatment .Asystole is an uncommon but potentially fatal complication after ECT. Post-stimulus asystole occurs just after electrical stimulation, whereas postictal asystole occurs just after seizure-induced tachycardia stops . Sharp, Recovery time was slightly longer in the dexmedetomidine groups compared with the saline group, but this was not statistically or clinically significant. The recovery time difference was between 5 to 10 min. Although post ECT agitation scores were similar between the groups, patients who received dexmedetomidine 1 mcg/kg seemed to be calmer and less agitated; most of the patients had an agitation score of 1 and none had agitation scores of 3–4. This favorable result is similar to many previous studies , 23, 24.This study had a few strengths and limitations that were worth noting. The study’s strengths were that it was a crossover, double-blind randomized controlled trial with no other medications interfering with the results of the study, such as beta-blockers or atropine. However, it is necessary to note that this study was a single-center clinical trial with a limited sample size. Multicenter or psychiatric disease-specific studies with larger sample sizes should be considered. Additionally, all of the patients in this study had previously received an ECT treatment course. We did not limit the induction agents depending on individualized effective regimens use before the study began, so patients received thiopental, propofol, or a combination. This may affect seizure duration measurements, as propofol produces shorter seizure times compared with thiopental .Dexmedetomidine 1 mcg/kg administered 15 min before ECT attenuated the hemodynamic response, including suppressing the systolic, diastolic and HR increases, during ECT without affecting recovery time. It also did not prolong the post-stimulus asystole duration. However, motor seizure duration was slightly shorter with this dexmedetomidine dose than with the 0.5 mcg/kg dose or saline, which may affect the quality of ECT. Decreasing the dexmedetomidine dose to 0.5 mcg/kg improved motor seizure duration compared with dexmedetomidine 1 mcg/kg, but also decreased the degree of hemodynamic attenuation.


Atherosclerotic lesions of the coronary arteries are still in charge of significant annual morbidity and mortality despite intense therapeutic advancements. Genome-born elements contribute substantially to the atherosclerosis process. ANRIL is one of the long non-coding RNAs with outstanding functions particularly regulation of genes involved in atherosclerosis development. In this study, we measured ANRIL expression  in hypertensive patients with coronary artery disease (CAD) compared with peers without CAD. Among hypertensive patients who were candidates of angiography, 25 subjects with CAD and the equal number without CAD were considered as the case and control groups, respectively. Different categories of data were recorded through a predefined questionnaire. Before angiography, blood samples were obtained. After RNA extraction and cDNA synthesis, quantitative PCR was performed using specific primers for circular and linear ANRIL. Age and gender were not different between the groups. Most of the parameters of the lipid profile besides creatinine and blood urea nitrogen were remarkably worse in the case group. Circular ANRIL was significantly lower in the case group while linear counterparts were significantly higher in this group. Circular/linear ratio was also significantly lower in the case group. To overcome growing devastating trend of CAD, scrutinizing different factors involved in the initiation and development of atherosclerosis is a must. Atheroprotective role of circular ANRIL and atheroprogressive role of linear ANRIL were shown in our patients with hypertension. Genetic traits contribute substantially to the development of atherosclerosis in the coronary arteries2. About 98% of the transcribed RNAs in the cell have no open reading frames, i.e. no capacity to produce protein3. Earlier, they were considered as transcriptional noise. However, harboring a wealth of information revealed their potential for regulation of different mechanisms. One type of these untranslated elements is long non-coding RNAs (lncRNAs) with more than 200 nucleotides long4. They modulate genes' expression in order to fine-tune biological processes like cell growth and development, angiogenesis, and inflammation8. Accordingly, footprints of lncRNAs are evident in many disorders such as cancers, Alzheimer disease, and cardiovascular impairments10.The greatest share in cardiovascular toll has been allocated to coronary artery disease (CAD)15. This type of association is independent of traditional risk factors like hypertension, obesity, smoking, or lipid profile disorders. The INK4/ARF locus at chromosome 9p21 contains the codes for three tumor suppressor genes. Transcription of this gene cluster in the antisense direction produces a 3.8 kb lncRNA named Antisense Non-coding RNA in the INK4 Locus 17. ANRIL is implicated in different components of the atherosclerosis process like vascular endothelial cells, vascular smooth muscle cells, mononuclear phagocytes, and atherosclerotic plaques20. Regulation of gene expression is the prime function of ANRIL21. Other than locally, ANRIL also works remotely via chromatin modulation, binding to transcription factors, and regulation of miRNAs22. Furthermore, ANRIL is underwent complex tissue-specific pattern of splicing which leads to the production of multiple isoforms24. Also, Circular ANRIL, discovered in 2012, is a derivative of linear ANRIL that is subjected to back-splicing26. Based on its linearity or circularity abundance, it may have promoting or protecting role for atherosclerosis. Moreover, ANRIL could be a potent diagnostic and prognostic indicator for coronary heart disease (CHD)21. Elucidation of differential gene expression is useful for understanding the pathogenesis of atherosclerosis, which in turn smooths the road for more efficient preventive, and therapeutic interventions21.Genome wide association studies demonstrated that atherosclerotic vascular disease, CAD, stroke, myocardial infarction, and aortic aneurysm are all associated with chromosome 9p2127, but it also augments the adverse effects of other cardiovascular risk factors in CAD patients28. Lack of association between Chr9p21 locus and hypertension indicates that ANRIL possibly exert its function through a novel mechanism29. On the other hand, an association between ANRIL levels and hypertension was reported30. In one study, both ANRIL and hypertension were shown to be independent risk factors for restenosis in CAD patients, and interaction between ANRIL and hypertension was statistically significant31. As it seems, there is a complicated relation between hypertension and ANRIL expression. In order to investigate the role of ANRIL in atherosclerosis exclusively, the study was conducted on hypertensive patients (diastolic blood pressure of ≥ 90 mmHg and/or systolic blood pressure of ≥ 140 mmHg32).The importance of hypertension is not only related to the fact that it is among the most strong driving factors for atherosclerotic plaque formation30. Our hypothesis is that there might be a difference in the expression level of circular and linear ANRIL as well as circular/linear ratio in hypertensive patients with CAD compared with non-CAD peers.The expression of ANRIL in diabetic CAD patients was previously investigated33. In catheterization laboratory, only patients with hypertension were included. Hypertension was defined as systolic and diastolic blood pressure of equal or more than 140/90 mmHg32. Those with previous experiences of heart diseases (except for coronary atherosclerosis), chronic kidney disease, obstructive pulmonary disorders, and any other inflammation were excluded. Case group (n = 25) were hypertensive patients with CAD and control group (n = 25) were hypertensive patients without CAD, according to the angiography findings.This study was in accordance with the Declaration of Helsinki, and approved by the regional ethics committee  by ID "IR.SUMS.REC.1397.990". Patients who were suspicious to CAD, and referred for angiography were considered during DEC-2019 to FEB-2021. Decision for doing angiography was made by an interventional cardiologist according to the American College of Cardiology guidelineA predefined questionnaire was used by a nurse to obtain participant's data. Some of these data like age, gender, fasting blood sugar (FBS), total cholesterol, high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol LDL-C, triglycerides (TG), TG/HDL-C ratio, LDL/HDL ratio, creatinine, and blood urea nitrogen (BUN) were extracted from blood analysis report. Some of the others like smoking status, education stage, and existence of dyslipidemia, diabetes, and history of coronary atherosclerosis besides family history for hypertension, diabetes, atherosclerosis, and sudden death were asked from the patients themselves. Other ones like systolic and diastolic blood pressure, overweight, and body mass index (BMI) were measured by the nurse.Before angiography, blood samples were collected in anticoagulant tubes, and stored at – 80 °C until use. The expression analysis of circular and linear ANRIL was carried out through reverse transcriptase polymerase chain reaction (RT-PCR) assay. After full thawing at room temperature, samples were subjected to RNA extraction by RNX-plus kit  in accordance to the manufacturer instructions. Afterwards, cDNA was synthesized with SMO-BIO cDNA synthesis Kit (Taiwan). cDNA was then used as a template for downstream quantitative PCR with specific primers. GAPDH was used for internal control. Primer sequences were as follows:−ΔΔCt method was applied to determine fold changes expression of genes. Normality was checked by kurtosis and skewness indices as well as Q–Q plot. We used independent sample t test for analyzing Ct data.According to the sample size, normality of variables was checked by Shapiro–Wilk test. Continuous variables were expressed as mean ± SD, and categorical variables were presented as number (percent). Independent sample t test, Mann–Whitney test, and chi-square-test were used to compare continuous and categorical variables, as appropriate. The SPSS 26 for Windows was used for statistical analysis . For gene expression analysis, 2This study was in accordance to the Declaration of Helsinki, and approved by the regional ethics committee, IR.SUMS.REC.1397.990.Written informed consent was obtained from each patient to take part in the study.The authors declare that the personal information of each patient would be confidential. The patients had taken their consent for publication of data before enrolling in the study.The mean age of the patients was 57.3 ± 11.6 years with dominance of female gender. Both groups were hypertensive with no significant difference neither in systolic, nor in diastolic blood pressure. FBS and BMI were not different between the two groups. Unlike triglycerides, lipid profile including total cholesterol, HDL-C, and LDL-C were significantly undesirable in the case group. Moreover, TG/HDL-C ratio and LDL/HDL ratio as well as creatinine and BUN were significantly higher in the case group  in the 9p21 locus are also in charge of differential expression of ANRIL isoforms between subjects. Indeed, the expression level of circular ANRIL is suspected to a mosaicism in primary smooth muscle cells and macrophages of the vascular tissues44. So, there is a need to scrutinize the role of circular ANRIL in decreasing the risk of atherogenesis at single-cell scale.Atheroprotection that is originated from 9p21 locus is associated with low linear and high circular ANRIL expression. It seems that the level of expression of the two isoform types in relation with each other is a critical factor for determination of atherosclerosis development. In other interesting words, circularization could be considered as a genius strategy that deployed by the cell to prevent adverse effects of linear ANRIL (onset and progression of atherosclerosis)45. The pathogenesis of CAD is explained with the involvement of a plethora of chemokines, cytokines, and growth factors, which act combinatorial in different stages46. Inflammatory diseases including CAD change the expression of lncRNAs. This unique feature render lncRNAs as diagnostic biomarkers and therapeutic targets48. To substantiate, ANRIL level was found to be associated with IL6/IL8 levels in blood which indicates a relationship between ANRIL and CAD30.CAD is considered as an inflammatory and proliferative disorder30. However, a study concluded that ANRIL expression is not correlated with the lipid profile49. In our study, there were no differences in some cardiovascular risk factors like age, gender, FBS, hypertension, TG, BMI, and diabetes between CAD positive and negative participants. In consistent with other study, higher level of linear ANRIL translates into increased atherosclerosis50. Similar to our finding, the expression of circular and linear ANRIL was reported to be inversely correlated51. Those patients with overexpressed circular ANRIL and highest circular/liner ANRIL ratio develop less CAD. Expression of linear ANRIL was not changed by circular ANRIL overexpression44. In another investigation, five lncRNAs were measured in the peripheral blood of patients with myocardial infarction (MI) who underwent percutaneous coronary intervention. ANRIL was reported to be upregulated in this population30.Age, diabetes status, and hypertension are among the factors that change the levels of ANRIL52. ANRIL expression was significantly increased in a population of diabetic patients with CAD possibly due to imposed dysregulation in neighboring or inflammatory genes. After adjusting for confounding variables, only linear ANRIL was significantly different between CAD and non-CAD patients. This shows superior value of linear ANRIL in atherosclerosis studies compared with circular- and circular/linear ratio.ANRIL was upregulated in diabetic patients with CHD (2.34 folds) compared with peers without CHD50. This discrepancy may be originated from differences in the genetic or environmental factors of the studied population which affect the development and severity of atherosclerosis. In one study on patients with acute MI, four lncRNAs including ANRIL were differentially expressed. Also, all the lncRNAs were associated with hypertension and left ventricular dysfunction, one of the lncRNA was found to be in relation with diabetes, and the association of the other one with smoking was confirmed30.However, we did not find any association between ANRIL expression, even linear isoform, and atherosclerosis severity (single vessel- versus multivessel disease) in contrast to other study22. The underlying reasons for such disparities among the studies may be due to the splicing complexity of ANRIL and differences in the sample-originated factors like ethnicity, age, and health status35. Splicing variants and binding sites in the cells and tissues are among the sophisticated features of ANRIL that remain to be elusive21.Inconsistent findings about ANRIL are entirely possible. For instance, one SNP increases ANRIL expression followed by pro-proliferative function in the endothelial, macrophage, or vascular smooth muscle cells resulting in atherosclerosis while another polymorphism at the same position decreases proliferative isoforms in the beta cells promoting diabetes44. Although therapeutic activation of circular ANRIL seems to be beneficial for inhibiting atherosclerosis progression, it will be accompanied by certain side effects since ANRIL have multiple targets other than cardiovascular system. These challenges limit the studies on ANRIL21.In therapeutic view, circular ANRIL could be a potent tool for treatment of atherosclerosis and other proliferative disorders based on its stability against degradation and antiatherogenic-antiproliferative characteristicsIt would be better if we had ANRIL expression levels in normotensive subjects with and without CAD. A more comprehensive assessment of ANRIL expression in relation to high blood pressure and CAD pathogenesis was feasible in this way. Some data, as previously mentioned in the methods section, were asked from the patients themselves that may be in contrast to the documented findings from blood analysis report. In this case, the parameters of blood analysis is more reliable. Also, defining certain cutoff values of ANRIL expression corresponding to different CAD severity merits future investigation.Circular-, linear-, and circular/linear ANRIL were differentially expressed in hypertensive CAD patients compared with those without CAD.


This article aims to provide a comprehensive overview and better understanding of the SGLT2 inhibitor and its benefits as it pertains to renal pathophysiology. It summarizes our recent understanding on the mechanisms of action of SGLT2 inhibitors, discusses the effects of SGLT2 inhibitors on diabetes and DKD, and presents future research directions and therapeutic potential.As the prevalence of diabetic kidney disease (DKD) continues to rise, so does the need for a novel therapeutic modality that can control and slow its progression to end-stage renal disease. The advent of sodium-glucose cotransporter-2 (SGLT2) inhibitors has provided a major advancement for the treatment of DKD. However, there still remains insufficient understanding of the mechanism of action and effectiveness of this drug, and as a result, its use has been very limited. Burgeoning evidence suggests that the SGLT2 inhibitors possess renal protective activities that are able to lower glycemic levels, improve blood pressure/hemodynamics, cause bodyweight loss, mitigate oxidative stress, exert anti-inflammatory and anti-fibrotic effects, reduce urinary albumin excretion, lower uric acid levels, diminish the activity of intrarenal renin-angiotensin-aldosterone system, and reduce natriuretic peptide levels. SGLT2 inhibitors have been shown to be safe and beneficial for use in patients with a GFR ≥30mL/min/1.73m It is the major source of fuel in the human body and comes in various forms such as monosaccharides, disaccharides and polysaccharides, such as starch. The body maintains fasting glucose levels at around 80mg/dL in order to provide a continuous supply of glucose to tissues that are unable to synthesize glucose on their own, such as brain and red blood cells. In order to provide the body with a continuous source of glucose during the fasting state, it is stored in the form of glycogen with the most abundant stores located in the liver and skeletal muscle. It is also synthesized endogenously in the liver and kidney from non-carbohydrate sources by gluconeogenesis. These precursors include lactate, glycerol, alanine, and glutamine. The kidney primarily uses lactate, glutamine, and glycerol with lactate being the largest source of substrate for gluconeogenesis in the kidney (Glucose C6H2O6 is a (SLC2A) gene family and utilize facilitated diffusion to transport glucose across the cell membrane. There are currently 14 GLUT genes identified in the human body and are located in fetal tissues, erythrocytes, blood-brain barrier, neurons, adipose tissue, striated muscle, testes, small intestine epithelium, liver cells, pancreatic beta cells, and renal tubular cells  where it reabsorbs 10-20% of the glucose that escapes uptake by SGLT2. SGLT3 is expressed in the enteric neurons and is believed to be a glucose sensor  and sodium-dependent glucose transporters (SGLTs). GLUTs are members of the solute carrier family 2A ar cells . In partSLC5A gene family, part of the Sodium Solute Symporter (SSS) superfamily of proteins and capable of transporting glucose. The SGLT2 transport protein (SLC5A2) is the transporter responsible for 80-90% of glucose reabsorption located and abundantly expressed on the brush border membrane of the S1-S2 segments of the early proximal convoluted tubule of the kidney (-/-) (The SGLT2 is a member of the e kidney . Additioe kidney . Using iey (-/-) . This diey (-/-) .+-to-sugar transport stoichiometry which more resembles SGLT2 (1:1 rather than the 2:1 for SGLT1). Relative to human SGLT1, there is between 50-70% identity and 67-84% similarity in the sequences for SGLT2 (Although the atomic structure of human SGLT (hSGLT) has not yet been established, the structure of a bacterial homolog Vibrio parahaemolyticis (vSGLT) with 32% amino acid identity to hSGLT1 has been solved and refined to 2.7 A , 12. The+/K+ ATPase pump which creates the intracellular Na+ electrochemical gradient needed for the operation of the SGLT2 to drive the transport of Na+ and glucose into the cells. Glucose moves against its electrochemical gradient following sodium transportation along its gradient in 1:1 stoichiometry. The intracellular glucose is then diffused to the interstitium through GLUTs located on the basolateral membrane of the PCT cells.The SGLT2 is a high-capacity and low-affinity co-transporter located at the apical brush border of the PCT extending from the S1 to S2 segments. Located at the basolateral membrane of the PCT is the Navia both glycogenolysis and gluconeogenesis (In the fasting (postabsorptive) state in healthy individuals, the kidney contributes around 20-25% of the glucose released into the circulation by gluconeogenesis (15–55 g/day), with the liver responsible for the remainder ogenesis . Renal gogenesis –16. In tIn the postprandial state, gluconeogenesis increases renal glucose release more than twofold accounting for ~60% of the endogenous glucose release during the 4-6 hours period following meals. The mechanism is unknown but thought to allow for repletion of hepatic glycogen stores by permitting suppression of hepatic glucose release . In T2DM.The first SGLT2 inhibitor, phlorizin, was isolated from the root bark of the apple tree in 1835 and was originally used as an antipyretic. It was 50 years later that its glycosuric effects were observed and research began to discover its mechanism of action. Phlorizin was subsequently found to be a potent but non-selective inhibitor of many isoforms of SGLT. However, due to its poor bioavailability (15%), low SGLT2 selectivity, and gastrointestinal side effects from SGLT1 blockade, phlorizin failed to progress to use in humans . NeverthIn addition to diabetes management, SGLT2 inhibitors have shown promise in the areas of chronic kidney disease (CKD), and are able to reduce uric acid levels, attenuate oxidative stress, exert anti-inflammatory actions, improve fibrosis, decrease blood pressure, decrease body weight, and mitigate hyperlipidemia, cardiovascular disease, and even some cancers, such as early-stage lung adenocarcinoma  and pancThe glycosuric effect of SGLT2 inhibitors induces a sustained diuretic and natriuretic effect that activates compensatory mechanisms to increase fluid and food intake to stabilize body fluid volume. A study performed by Masuda et al.  revealedAlbuminuria is one of the commonly used clinical indicators of diabetic nephropathy (DN) and is an independent and modifiable risk factor for cardiovascular events, kidney injury and mortality. In addition to blood pressure and glycemic control, the current clinical management of DKD is largely confined to the use of blockades of the renin-angiotensin-aldosterone system (RAAS), which is of limited utility with unsatisfying therapeutic efficacy . The advIn another study, a group reviewed the data from the EMPA-REG OUTCOME trial to assess the differential outcomes in kidney function by examining the slopes of eGFR changes. The study had originally shown that empagliflozin reduced the rate of cardiovascular events and slowed the progression of kidney disease among patients with T2DM and high cardiovascular risk. A review of this data showed that empagliflozin is able to significantly retard eGFR decline over about 3 years of treatment, including in patients at an increased risk for progressive renal impairment. Furthermore, the slope patterns of empagliflozin therapy revealed an action on intrarenal hemodynamics with an initial transient decline in eGFR ensued by sustained long-term preservation of renal function, reminiscent of the effects achieved with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. After discontinuation of empagliflozin treatment, the slopes of eGFR changes demonstrated a quick upward shift toward the baseline, inferring a swift loss of the renal hemodynamic effect . The renThe CREDENCE randomized trial had shown that among patients with T2DM and DN characterized by albuminuria and no more than a mild reduction in GFR, canagliflozin at the dose of 100 mg/d reduced the risk of end-stage kidney disease, doubling of serum creatinine from baseline, and death from renal or cardiovascular disease when compared to placebo. The renoprotective effects observed with this study are likely due to improved blood pressure control secondary to decreased sodium reabsorption in the PCT, thereby causing increased sodium delivery to the macula densa in the distal renal tubule and inducing afferent vasoconstriction by tubuloglomerular feedback, leading to lowered glomerular hyperfiltration .2. These benefits were attained on the background of universal use of renin-angiotensin system (RAS) blockades. Canagliflozin therapy also led to an acute drop in eGFR followed by a decrease in albuminuria at week 3 that was significant in every eGFR subgroup, although the drop was least in those with screening eGFR of 30 to <45 ml/min per 1.73 m2. Furthermore, canagliflozin led to a slower eGFR decline in every eGFR category compared with placebo, with no evidence that the benefit differed among eGFR subgroups. The findings raise important questions on whether these agents would benefit kidney disease outcomes in nondiabetic settings  and increased glycosuria resulting in increased lipid utilization and decreased triglyceride levels from gluconeogenesis induced by increased glucagon release from the pancreatic alpha-cells. Furthermore, SGLT2 inhibitors induced an osmotic diuretic effect due to increased glucosuria and natriuresis, but they did not observe an ongoing fluid loss. As a consequence of the diuretic effects, there was a reduction in arterial blood pressure after 3-6 months of treatment. SGLT2 inhibitors have also been observed to improve vascular stiffness, resulting in increased elasticity and more efficient blood pressure regulation . Furthervia suppression of the AGE-RAGE axis  and the receptor for advanced glycation end product (RAGE) production, upregulation of protein kinase C (PKC), and by direct modification of intracellular molecules . DapagliAGE axis .In vitro, in cultured human proximal tubular cells exposed to high ambient glucose, empagliflozin was able to mitigate the expression of inflammatory/fibrotic markers including IL-6 and collagen IV, consistent with an anti-inflammatory and anti-fibrotic activity (per se a damage-associated molecular pattern (DAMP), that is able to activate the NLRP3 inflammasome and cause inflammation. An elevated plasma uric acid level can independently predict the development of CKD and has been associated with the progression towards renal failure  levels . The met2 with or without RAS blockade. There is strong evidence from the clinical trials that SGLT2 inhibitors should be prioritized in patients with T2DM and CKD with a presenting GFR of 30-40mL/min/1.73m2. The CEDENCE trial suggested that the combined use of SGLT2 inhibitors and RAS blockade should be well tolerated from a hemodynamic perspective as no participants were at increased risk of developing AKI, volume depletion, or hyperkalemia. Most importantly, in the CREDENCE trial, participants whose eGFR fell to <30mL/min/1.73m2 were continued on randomized treatment until dialysis or transplantation. As a result, the FDA now permits the continued use of canagliflozin with an eGFR <30mL/min/1.73m2 until dialysis or transplantation in patients already initiated on therapy (Up to this moment, SGLT2 inhibitors have been shown to be safe and beneficial for use in patients with a GFR ≥30mL/min/1.73m therapy . Another therapy . or Fournier’s gangrene, has been reported (2, regardless of the magnitude of albuminuria (Currently, the use of SGLT2 inhibitors is limited due to the high cost. Along with their increasing use, there is also the concern for serious, if not fatal, infections that have deterred most physicians from initiating therapy. Indeed, SGLT2 inhibitors-induced glycosuria makes the genital area more conducive to bacterial infections, and life-threatening infection of the genitals and areas around the genitals, such as necrotizing fasciitis of the perineumreported . In addireported . Howeverreported , the EMPreported , the SCOreported , the VERreported , and thereported . Some ofuminuria , 31. Of uminuria .Diabetes-associated kidney disease is a major precipitating factor resulting in renal replacement therapy. The advent of SGLT2 inhibitors has provided a major advance for the prevention and treatment of T2DM, CKD, and cardiovascular events. Beyond the glycosuric effects, SGLT2 inhibitors have exhibited renal protective properties, which are associated with improved glycemic control, improved blood pressure/hemodynamics, weight loss, prevention of oxidative stress, anti-inflammatory properties, anti-fibrotic processes, reduction in albuminuria, reduction in intrarenal RAS activation, antioxidant and anti-inflammatory effects, reduction in plasma uric acid levels, metabolic reprogramming and reduction in natriuretic peptide levels. Despite concerns over the safety issues related to serious but rare infective complications, clinical use of SGLT2 inhibitors in patients with DKD seems to be effective, safe, and well-tolerated, resulting in a unique renoprotective action and cardiovascular benefits. Future research efforts are merited to understand the exact molecular mechanism responsible for the beneficial activity of SGLT2 inhibitors in diabetic patients, to reveal the most suitable diabetic patients to receive SGLT2 inhibitor treatment, and to test the potential of SGLT2 inhibitors in improving non-diabetic CKD in men.RG devised the conceptual ideas. JS performed the literature search and drafted the original manuscript. BC drew the figures. LD, DM, and RG contributed to revision. All authors agreed that the entire concept and ownership of this work belong to RG. All authors contributed to the article and approved the submitted version.The research work was supported in part by the Research Incentive Fund from the University of Toledo. R. Gong was supported by the U.S. National Institutes of Health grant DK114006. The funders had no role in the design and conduct of this study, collection and interpretation of the data, or preparation and approval of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


P = 0.003), SBP at night , and diastolic blood pressure (DBP) at night  decreased significantly. Also, there was no statistically significant change in morning  and night diastolic  BPV and morning systolic BPV  over time during the intervention period, except for that night systolic BPV had a downward trend  and had decreased 2.04 mmHg  after intervention. The use of 18% of the substitute salt did not increase BPV during the intervention and even may decrease it, which indicates its control effects on blood pressure. This study is the first one to observe the effect of 18% sodium substitute salt on the home blood pressure variability, providing a basis for further experiments.At present, the effect of substitute salt in reducing sodium intake and blood pressure is relatively clear. The present study is a phase I clinical trial involving 43 hypertensives in which the effect of 18% sodium substitute salt on the home blood pressure variability (BPV) was observed for 8 weeks with weekly follow-up. Finally, 4 patients were lost, and 39 patients completed the intervention and were included in the analysis. Daily home blood pressure and weekly adverse events were collected. The systolic blood pressure (SBP) in the morning (−10.0 mmHg, 95% CI: −16.5 to −3.5,  It is well known that excessive salt intake is closely related to an increase in blood pressure and the risk of cardiovascular-related events . The Worhttp://www.clinicaltrials.gov (NCT03226327).This study was completed in the Public Health Department of the People's Hospital of Nan'an District, Chongqing, China. A total of 43 patients diagnosed with primary hypertension were included from May to July 2018. Inclusion criteria: (1) age in the range of ≥50 and ≤ 75 years; (2) not having plans to move out of the community in the next three months; (3) not cooking at home less than 3 times or one day during the study; and (4) written informed consent provided before enrollment in the trial. Exclusion criteria: (1) history of acute myocardial infarction or stroke in the past 3 months and history of malignancy or expected lifetime less than 1 year; (2) hypercortisolism or aldosteronism; (3) acute disease, such as upper respiratory infection, fever, and diarrhea; (4) disease or disabilities that could exert potential influence on their adherence to the intervention, including deafness and dementia, as well as severe depression and other mental disorders; (5) salt substitute use in the family; (6) family members not willing to use the salt substitute; (7) chronic renal failure at stage 4 or above or with renal replacement therapy; (8) abnormal liver function, with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level greater than 2 times the upper limit of normal, or total bilirubin level greater than the upper limit of normal; and (9) abnormal blood potassium level, <3.5 mmol/L or >5.5 mmol/L, or current use of potassium-preserving diuretics. The study has been approved by the Institutional Review Board of Peking University (IRB00001052−17110). The trial was registered at This study is a phase I clinical trial of single arm. After the subjects and their family signed the informed consent, subjects completed baseline questionnaires and medical examination . 18% substitute salt instead of traditional salt was used for 8 weeks, and patients were measured home blood pressure every day, while follow-up staff visited the patients once a week to collect information of antihypertensive drug use and safety.In this study, the 18% sodium substitute salt of “Man Li Kang” was developed by Chongqing Institute of Biotechnology Co., Ltd.: name: solid compound condiment, standard of execution:Q/SWS0025S, food production license number: SC10650012000709, and food circulation permit: SP5009051610016538, and the main ingredients include potassium chloride (35%), sodium chloride(18%), and calcium chloride(10%). The blood pressure measuring instrument adopts a pulse-wave electronic sphygmomanometer (RBP-9801).Before the start of the study, follow-up staff was trained in relevant knowledge of blood pressure measurement. Then, each subject was trained in blood pressure measurement by the follow-up staff, and a home blood pressure measurement handbook was distributed to all subjects. Patients were required to complete 3 blood pressure measurements at time in the morning and evening (from 6 to 9 o'clock am/pm) every day. Besides, during the weekly follow-up, the follow-up staff would confirm with the subjects whether the blood pressure measurement method is correct or not. Also, the blood pressure measurement results were automatically uploaded to the terminal management system in real time through the device. The researchers collected the blood pressure data for 8 weeks for sorting and analysis.Follow-up staff used a uniform electronic scale to weigh the weekly salt used by each patient and calculate the weekly salt usage of the patient.The 24-hour urine of patients was collected at baseline and after the intervention, sent to a local grade-A tertiary hospital for testing. The items include 24-hour urinary sodium, potassium, calcium, magnesium, urinary creatinine (Cr), and urinary microalbumin (U-ALB).Three blood pressure measurements were required per time, and the last 2 averages were included in the analysis. BPV is represented by standard deviation (SD) of blood pressure per week. The baseline blood pressure was taken as an average measured three times, respectively, in the morning and evening on the first day of intervention.P values less than 0.05 were considered statistically significant.Statistical analysis was carried out using SPSS 22.0 . A total of 1953 pieces of complete blood pressure measurement data were collected in the morning, with a missing rate of 9.45% and 1871 in the evening, with a missing rate of 14.33%. The missing data of home blood pressure were filled by multiple imputations . QuantitIn this study, we enrolled 43 patients, with 4 lost because of the intolerability of the taste of the substitute salt. 39 patients were finally analyzed by per protocol (PP), including 20 males and 19 females, aged 67.1 ± 7.9 years, with a body mass index (BMI) of 26.6 ± 3.6. Among them, 14 subjects reduced the doses of antihypertensive drugs and 25 subjects had the doses unchanged. Blood pressure at baseline is shown in P = 0.021), urinary sodium/potassium decreased significantly compared with baseline (P = 0.001), and urine sodium decreased by 13.82 mmol/24 h on average, but there was no statistically significant difference (P = 0.220). U-ALB/Cr increased compared with baseline (P = 0.002), but urine calcium and magnesium had no significant changes compared with baseline (P > 0.05)  . The per > 0.05) .P = 0.003), SBP at night , and DBP at night  all decreased significantly compared with the baseline. Also, the SBP in the morning  decreased significantly at 3 weeks, and the SBP at night  dropped at 2 weeks  and night diastolic  BPV and morning systolic BPV  over time during the intervention period, except for that night systolic BPV had a downward trend  and had decreased by 2.04 mmHg  after intervention. Furthermore, the night diastolic BPV  and morning systolic BPV  also decreased, but the difference was not statistically significant (The analysis of the mixed linear model showed that the SBP in the morning (−10.0 mmHg, 95% CI: −16.5 to −3.5,  2 weeks . There wnificant . The datNo serious adverse events occurred during the intervention. Other adverse events included the following: one patient had constipation at the first week, two patients developed fatigue, two patients developed dizziness and headache, and one patient had itching in the neck, back, and abdomen at the 3rd week.The Guidelines for Rational Use of Medicine in China suggest that it should be necessary to follow the principle of long-term efficacy and stability in regard to controlling blood pressure , which cThe sodium content of traditional substitute salt is high, usually around 70% , and somBefore intervention, we collected the clinical blood pressure of the patient at baseline, and the family self-measured blood pressure during 8 weeks of intervention. Compared to the baseline, we observed a decrease in blood pressure in the first week of the intervention and then a greater decrease in the second and three weeks. We have conducted a more detailed analysis of visit and home blood pressure in a separate article . The SBPPrevious studies have shown that the results of BPV are closely related to the number of blood pressure measurements , 31 and A study by Ozkayar et al.  showed tThere are still some limitations in this study. Firstly, the study was based on a phase I clinical trial that resulted in a limited sample size, and there are possibly sampling errors that make the results unstable. Furthermore, we used the BPV in the first week of intervention as the reference to observe the changes in BPV of patients during the intervention. If BPV decreased and stabilized in the first week of intervention due to the 18% substitute salt with gold sodium potassium ratio of 1 : 2, the effect of intervention may be underestimated. On the other hand, if BPV was significantly increased in the first week due to the influence of comprehensive factors compared with before the intervention, but as the intervention continued, the BPV gradually decreased after the body adapted to the intervention, the effect of this salt in reducing BPV would be overestimated.Although 18% substitute salt has lower sodium content, its application in hypertensive patients did not cause an increase in blood pressure variability and even reduced the evening systolic blood pressure variability of the patients, which indicates that the 18% substitute salt has a good effect of controlling blood pressure. However, further long-term randomized controlled trials are still needed to verify this finding.


Background: Galectin-3  is a multifunctional glycan-binding protein shown to be linked to chronic inflammation and fibrogenesis. Plasma Gal-3 is associated with proteinuria and renal dysfunction, but its role has never been confirmed with kidney biopsy results. In our study, we aimed to explore the expression of Gal-3 in biopsy-proven patients, and we tested the hypothesis that chronic kidney disease (CKD) leads to upregulation of plasma Gal-3 expression in corresponding biopsy findings and RNA sequencing analysis.Method: In 249 patients  who underwent kidney biopsy, plasma levels of Gal-3 were measured to estimate the association of renal fibrosis. Relationships between plasma Gal-3 levels, estimated glomerular filtration rate (eGFR) and renal histology findings were also assessed. We further examined the gene expression of Gal-3 in RNA-sequencing analysis in biopsy-proven patients.Results: Compared to patients without CKD, CKD patients had higher levels of plasma Gal-3 . Plasma Gal-3 was inversely correlated with eGFR (P = 0.005) but not with proteinuria. Higher Gal-3 levels were associated with interstitial fibrosis, tubular atrophy and vascular intimal fibrosis. RNA-sequencing analysis showed the upregulation of Gal-3 in fibrotic kidney biopsy samples, and the differentially expressed genes were mainly enhanced in immune cell activation and the regulation of cell-cell adhesion.Conclusions: Plasma Gal-3 levels are inverse correlated with eGFR but positively correlated with renal fibrosis, which may be involved in the immune response and associated pathways. These findings support the role of Gal-3 as a predictive marker of renal fibrosis. Chronic kidney disease (CKD) remains a major public health problem and is one of the leading causes of mortality and morbidity worldwide –3. CKD pin vitro model, Gal-3−/− fibroblasts showed reduced collagen production in response to transforming growth factor-beta 1 (TGF-β1). Moreover, in an in vivo model, Gal-3 knockout mice exhibited a decrease in collagen accumulation and resistance to the development of fibrosis  is a β-galactoside-binding lectin protein encoded by a single gene (LGALS3) located on chromosome 14 . Gal-3 pfibrosis , 20. Becfibrosis , Gal-3 mIn the general population, data from the Framingham Offspring Study, which involved 2,450 subjects, showed that higher plasma levels of Gal-3 were associated with a higher risk of CKD but not with the risk of albuminuria . Other sTo address this problem, we performed a prospective study on patients who underwent kidney biopsy to examine the association between their plasma Gal-3 levels and renal histopathology findings. In addition, we examined the gene expression of Gal-3 using RNA-sequencing analysis in kidney specimens. The present study aimed to (1) characterize the associations between plasma Gal-3 and clinical variables and laboratory results, (2) investigate whether plasma Gal-3 was associated with the pathological findings of CKD, such as renal fibrosis and/or tubular atrophy, and (3) identify the gene expression of Gal-3 using RNA-sequencing analysis in kidney biopsy specimens. We also attempted to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses to explore the possible pathogenesis and potential pathways of Gal-3 in the development of renal fibrosis.All patients who underwent renal biopsies at the Taipei Veteran General Hospitals between 2018 and 2021 were included in this cohort study. Patients who were younger than 20 years of age, who were unable or unwilling to provide signed informed consent or who were missing plasma Gal-3 measurements were excluded from our study. Finally, 249 patients who underwent renal biopsies and signed the informed consent form were enrolled. The study protocol was approved by the Institutional Review Board of the Taipei Veteran General Hospitals (2018-06-008B).2 (m2)], systolic blood pressure, and diastolic blood pressure. The underlying comorbidities included diabetes mellitus, coronary artery disease, congestive heart failure, hypertension, dyslipidemia and malignancy. The laboratory parameters assessed were low-density lipoprotein cholesterol, uric acid, albumin, and eGFR. Urinary samples were collected from the patients, and the urine albumin-to-creatinine ratio (UACR) and urine protein-to-creatinine ratio (UPCR) were calculated.Information for all enrolled patients, including demographic data, underlying comorbidities and laboratory results, was collected. The demographic data included age, sex, body mass index [BMI, calculated using the following formula: weight (kg)/heightBlood samples were collected at the time of renal biopsy, immediately centrifuged and stored frozen at −80°C until assayed. The plasma Gal-3 concentration was measured as picograms per milliliter (pg/mL) using an inhouse multiplex bead-based immunoassay , 26. TheKidney biopsies were reviewed by one pathologist using light microscopy (LM), immunohistochemistry and electron microscopy. Formalin-fixed and paraffin-embedded kidney biopsy specimens were used for LM. The kidney specimens sent for LM were stained with hematoxylin and eosin (H&E), periodic acid–Schiff (PAS) and Masson's trichrome stains. Immunofluorescence staining was performed on frozen kidney specimen sections, which were then examined for immunoglobulin or complement deposits inside the tissues. Electron microscopy examinations of the kidney specimens were performed to observe the ultrastructure of the glomerulus and tubulointerstitium. Pathological findings, including glomerular descriptions , tubulointerstitial descriptions  and vasculature descriptions  were examined.> 2 and P-value < 0.05 were considered the cutoff values for identifying DEGs.After kidney biopsy specimens were obtained, kidney biopsy specimens were storage in RNAlater and then frozen in −80°C until microdissection. During microdissection, the morphology of glomeruli was identified and carefully picked up by fine forceps in microscopy. After then, the renal tubulointerstitial segments were sent for RNA-sequencing analysis. RNA was extracted using the RNeasy mini kit, and RNA sequencing was performed on the Illumina NovaSeq 6000 platform at 150 bp paired end . The annGO is a structured, controlled vocabulary to unify the representation of genes and classify gene functions. The enriched GO terms included three non-overlapping ontologies, including biological process (BP), cellular component (CC) and molecular function (MF) , 33. KEGP < 0.05. Data were analyzed using SAS software  and R software (version 3.5.2 for Windows).In our study, plasma Gal-3 was considered to be a continuous variable and a categorical variable according to the tertile of plasma Gal-3 levels. Correlations between Gal-3, eGFR, serum creatinine, UPCR and UACR were assessed using Pearson's correlation. We also analyzed non-linear associations between plasma Gal-3 levels and eGFR change by restricted cubic spline plots with three knots using tertile of plasma Gal-3 levels. The statistical significance was >1039.9 pg/mL, respectively). The mean (SD) age of the patients was 57.2 (16.3) years and 62.3% were male. Among them, 64 (25.7%) patients had diabetes mellitus and 105 (42.2%) patients had hypertension. The UACR and UPCR did not differ between the groups.The demographic and clinical characteristics of our patients are shown in P = 0.005; 2), and 69 (27.7%) were in the non-CKD group. Patients in the CKD group had significantly higher levels of plasma Gal-3 than those in the non-CKD group  and a positive correlation between Gal-3 levels and serum creatinine (P = 0.005) were found , GBM rigid (P = 0.029), glomerular necrosis (P = 0.017), and extracapillary hypertrophy (P = 0.039). Higher Gal-3 levels were associated with interstitial fibrosis (P = 0.028) and tubular atrophy (P = 0.032). For vascular structure, higher Gal-3 levels were also associated with increased vascular intimal fibrosis (P < 0.001) and vascular necrosis (P = 0.017).As shown in n = 5; the degree of interstitial fibrosis > 50%) and non-fibrotic controls (n = 5). Heatmaps of the up- and downregulated genes among the DEGs are presented in We compared the transcriptome profile of renal tubulointerstitial compartments between fibrotic kidney biopsy samples :PRJNA770300.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: The studies involving human participants were reviewed and approved by Taipei Veteran General Hospitals (2018-06-008B). The patients/participants provided their written informed consent to participate in this study.S-MO, M-TT, H-YC, F-AL, W-CT, K-HL, F-PC, Y-PL, R-BY, and D-CT: conception and study design. S-MO, M-TT, H-YC, F-AL, W-CT, K-HL, F-PC, and D-CT: data acquisition. S-MO, M-TT, R-BY, and D-CT: data analysis/interpretation and statistical analysis. S-MO, M-TT, H-YC, F-AL, W-CT, K-HL, F-PC, Y-PL, R-BY, and D-CT: drafting of the manuscript. All authors contributed to the article and approved the submitted version.This work was supported in part by the Ministry of Science and Technology, Taiwan ; Taipei Veterans General Hospital ; Taipei, Taichung, Kaohsiung Veterans General Hospital, Tri-Service General Hospital, Academia Sinica Joint Research Program (VTA110-V1-3-1); Taipei Veterans General Hospital-National Yang-Ming University Excellent Physician Scientists Cultivation Program (No. 104-V-B-044); Institute of Biomedical Sciences, Academia Sinica (IBMS-CRC110-P04 and AS-VTA-110-03) and Foundation for Poison Control (FPC-109-002).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.


Recovery of sufficient kidney function to liberate patients with severe acute kidney injury (AKI-D) from renal replacement therapy (RRT) is recognized as a vital patient-centred outcome. However, no clinical consensus guideline provides specific recommendations on when and how to stop RRT in anticipation of renal recovery from AKI-D. Currently, wide variations in clinical practice regarding liberation from RRT result in early re-start of RRT to treat uraemia after premature liberation or in the unnecessary prolonged exposure of unwell patients after late liberation. Observational studies, predominantly retrospective in nature, have attempted to assess numerous surrogate markers of kidney function or of biomarkers of kidney damage to predict successful liberation from RRT. However, a substantial heterogeneity in the timing of measurement and cut-off values of most biomarkers across studies allows no pooling of data, and impedes the comparison of outcomes from such studies. The accuracy of most traditional and novel biomarkers cannot be assessed reliably. Currently, the decision to discontinue RRT in AKI-D patients relies on daily clinical assessments of the patient’s status supplemented by measurement of creatinine clearance (> 15 ml/min) and 24-h urine output (> 2000 ml/min with diuretics). Clinical trials objectively comparing the success of validated biomarkers for guiding optimal timed liberation from RRT in AKI-D will be required to provide high-quality evidence for guidelines. Recovery of native kidney function after an episode of severe acute kidney injury (AKI-D) requiring acute renal replacement therapy (RTT) is recognized as a vital patient-centred outcome for survivors of AKI-D. The once-conventional wisdom that AKI is a predominantly entirely reversible condition has been challenged. Patient demographic factors , pre-existing renal diseases (reduced eGFR or pre-admission proteinuria) and other co-morbidities, severity of acute disease (multiorgan failure), or the frequency, severity, type and duration of AKI, and possibly RRT  are independent risk factors for maladaptive repair and de novo chronic kidney disease or end-stage renal disease (ESRD) –7. DepenRenal replacement techniques, particularly continuous haemodiafiltration and intermittent haemodialysis (IHD), are the cornerstone of supportive management of severe AKI-D. RRT is increasingly used in ICU patients to substitute excretory kidney functions while awaiting sufficient recovery of kidney function from AKI-D. The primary goals of RRT are: (a) to correct of metabolic, electrolyte and acid–base abnormalities, (b) to optimize volume status and allow parenteral nutrition and antibiotic administration, and (c) to allow recovery from renal injury and other organ damage. RRTs are life-saving procedures. However, these techniques do not come without their own problems. They may prolong the duration of severe AKI-D or impede complete recovery of native kidney function . The risThe objective of this narrative review is a critical appraisal of clinical, physiological and biochemical parameters for assessing recovery of native kidney function and testing the optimal timing for liberation from RRT.Readiness testing is the evaluation of objective clinical and kidney function criteria to determine whether a patient may be able to be successfully and safely liberated from RRT. Liberation describes the process of immediate discontinuation of full renal support that the patient receives from RRT. Weaning refers to the attempt to gradually decrease the amount of support that the patient receives from RRT (i.e. shift from continuous modes of RRT to IHD or decreasing the frequency of IHD).The success or failure of the approach for liberation impacts on the outcome of survivors. Patients who liberate successfully may have less morbidity, mortality and resource utilization than patients who require prolonged RRT or reinstitution of RRT –15.No clinical guidelines currently provide clear recommendations on the optimal timing of liberation from acute RRT in AKI-D patients recovering renal function , 17. TheThe wide variation in clinical practice regarding the optimal liberation strategy is illustrated by large randomized controlled trials (RCTs) that used varied urine output (UO) cut-off criteria for the decision on RRT discontinuation. The VA/ATN trial network defined recovery of kidney function on the basis of creatinine clearance, measured with the use of 6-hourly timed urine collection when urine flow increased to more than 30 ml/h or when there was a spontaneous fall in serum creatinine. RRT was discontinued if the creatinine clearance was greater than 20 ml/min . DecisioAt present, the criteria for defining “successful discontinuation” vary across published studies. Most authors defined successful liberation from RRT as a specified period during which the patient did not receive further RRT. However, these periods varied considerably and ranged from 3 to 60 days.There are several reasonable definitions . SuccessAnother definition of sustained recovery to dialysis independence is that AKI-D patients receive no RRT for 7 days (the most frequently used period).Furthermore, successful cessation of RRT may be defined by no need to have dialysis for 14 days or until either death or the end of the observation period.Numerous parameters, including traditional surrogate markers of renal function as well as novel kidney biomarkers , have beThe translation of the results from cohort studies to daily clinical practice is hampered by considerable limitations and deficiencies in the available studies.First, the retrospective/prospective single-centre cohort studies may suffer from of residual confounding and bias. Most studies utilized small sample sizes and heterogeneous study populations . There were wide variations in time-points of sampling even for the same variable. The authors used various definitions of successful discontinuation of RRT. All studies lacked prospective and external validation of the threshold of the surrogate marker or kidney biomarker. Only a minority of studies reported sensitivity and specificity. Few variables  were tested in at least two studies Tables , 3 and 4Second, RRT liberation was mostly not based on standardized assessment criteria. The decision was made by the attending physician based on empiricism.Third, both traditional markers of renal function, such as serum creatinine concentration  and UO , as well as novel kidney biomarkers are significantly affected by extrarenal factors. NGAL is one of the critical components of bacterial defence mechanisms in the circulation. NGAL concentration in the circulation markedly increases in response to bacterial infection. NGAL is mostly filtered by the glomerulus and then reabsorbed by proximal tubules. Markedly elevated serum NGAL concentrations may overload the absorption capacity of tubular epithelia, and excess NGAL proteins emerge in the urine. Thus, the utilization of NGAL in predicting onset of AKI or renal recovery from AKI in sepsis patients has been questioned. Other inflammatory disorders, like cancer or atherosclerosis, also limit the accuracy of NGAL as a marker of AKI . The risFourth, the assessment of renal recovery for AKI- D patients may differ between continuous and intermittent RRT. Small solutes such as serum creatinine and blood urea nitrogen concentrations of patients treated with intermittent RRT are cleared from the blood and are in a non-steady state, complicating the use of timed excretion rates or clearances. Therefore, 24-h excretion rates used to assess recovering native kidney function need to be done during the interdialytic period on non-dialysis days and by measurement of serum creatinine at two time-points. By contrast, steady-state concentrations of this surrogate marker during continuous renal replacement therapy (CRRT) allow calculations of creatinine clearance at 2, 6 or 24 h. Generally, creatinine clearance values obtained from patients with AKI overestimate the true glomerular filtration rate due to tubular creatinine secretion. To achieve a more accurate creatinine clearance the kinetic estimated GFR has been used in small study populations , 18.Katulka et al. conducted a systematic review and meta-analysis to identify predictors of successful liberation from acute RRT in critically ill patients with AKI D . Twenty-Moreover, the traditional criterion UO (400–500 ml/24 h without diuretics) does not seem to be sufficient on its own to guide the optimal timing of liberation from RRT in patients with AKI-D. Utilizing an standardized clinical assessment and management plan that functioned as a decision-making algorithm, Mendu et al. conducted a prospective cohort study to assess the adherence of front-line clinicians caring for ICU patients with AKI D . DiscontThe association between diuretic-induced UO and successful discontinuation of RRT has been evaluated rarely. The findings of these studies were variable. Certainly, diuretics may make liberation from RRT easier in volume-overloaded AKI patients. Uchino et al. reported that for patients on diuretics, a UO threshold of 2330 ml/ 24 h had the highest sensitivity and specificity. This threshold compared to a cut-off value of 400 ml/24 h in patients not receiving diuretics showed a higher positive predictive value (88% vs. 81%) .n = 557) compared to oliguric patients treated with diuretics (n = 619) [Jeon et al. found higher sensitivity (81% vs. 72%), specificity (72% vs. 69%) and AUC-ROC values (0.82 vs. 0.75) for non-oliguric patients receiving diuretics (n = 619) . Raurichn = 619) . Anothern = 619) .The collaborators of the ATN trial utilized the variable creatinine clearance for prediction of renal recovery. Patients with a 6-h creatinine clearance > 20 ml/min were trailed off RRT, whereas patients with a 6-h creatinine clearance < 12 ml/min had RRT continued . RetrospKinetic GFR has been used in small populations of selected patients to achieve a more accurate contemporaneous creatinine clearance for critically ill patients. However, kinetic GFR has not gained widespread use yet. In the study by Yoshida et al. the multivariate model used to predict successful liberation from RRT included UO at day 0 (the day of CRRT cessation) and kinetic GFR at day 1 . The areIndividual studies reported insufficient or conflicting data on 24-h urinary creatinine or urea excretion rate. Currently, no meaningful assessment of these variables is possible , 34.Novel biomarkers for kidney function  or kidney damage  have shown promise for prognostication of AKI and have been assessed in studies evaluating RRT discontinuation as well as kidney function recovery and kidney damage repair Tables .Serum cystatin C was the most studied novel biomarker, and this variable appeared promising for guiding discontinuation . The smaChen et al. conducted a prospective observational study to determine the optimal timing for discontinuation of CRRT by evaluating serum NGAL in critically ill patients with AKI-D . The totA small prospective study investigated whether urine NGAL and UO alone or in combination could be used as predictors of successful discontinuation of CRRT in 54 critically ill patients. Twenty-two of the 54 patients recovered renal function defined as dialysis independency at 72 h, while 32 did not. With a predictive value of 93% the combination of urine NGAL at 6 h after CRRT cessation and the 24-h UO prior to CRRT cessation proved to be the best diagnostic test for CRRT liberation .In a small retrospective cohort study, 69 patients were analyzed to determine the predictive ability of plasma NGAL and plasma B-type natriuretic peptide (pro BNP) for subsequent recovery of kidney function. Recovery was defined as alive and independent from dialysis at 60 days . Brain nThe prospective study with 102 ICU patients with AKI-D by Yang et al. aimed to explore the prognostic value of several biomarkers  measured upon discontinuation of RRT for their value in predicting 60-day survival and renal recovery . The autThe use of novel biomarkers remains largely experimental at present, and so far cannot be used as a primary predictor for liberation from RRT. While there are no validated novel biomarkers for prediction of the optimal timing of RRT liberation, preliminary evidence suggests that both functional and damaged biomarkers can aid the assessment of recovery of kidney function and help to guide the process of RRT liberation.Previous narrative reviews and a recent editorial emphasized the importance of daily clinical assessment while considering RRT liberation for AKI-D patients , 18, 41.To date, a wide range of different candidate markers have been evaluated predominantly in small, single-centre, retrospective studies encompassing mixed populations of critically ill patients with severe AKI requiring continuous RRT. There is a need for replication of the most promising surrogate markers  or novel kidney biomarkers (serum cystatin C and NGAL) in larger prospective randomized trials of selected ICU patients with a high pre-test probability of renal recovery . The diagnostic utility of a biomarker should be reported not only by specificity and sensitivity but also by its positive predictive value and negative predictive value. The candidate biomarker should predict renal recovery with high precision and should not be affected by confounding variables .Further work is needed to reduce the heterogeneity of reported cut-offs by ideal measurements of the intervals  and selection of patients. The overall feasibility of the candidate biomarkers should be validated in the real-word setting. At present, classical surrogate markers or novel biomarkers of kidney function seem to be more promising than biomarkers of kidney damage.Given the limitations of the sparse literature on this topic, it is evident that there are no consensus criteria regarding successful RRT discontinuation. The establishment of generally accepted liberation criteria is a necessary step for RRT discontinuation decision making. Evidence-based and successful liberation from RRT could potentially improve patient outcomes by limiting RRT duration.