Cardiovascular disease is highly prevalent and the leading cause of mortality in patients with chronic kidney disease, end-stage kidney disease, and kidney transplantation. However, kidney transplantation offers improved survival and quality of life, with an overall reduction in cardiovascular disease events; therefore, it remains the optimal treatment choice for those with advanced kidney disease. Pretransplantation cardiovascular assessment is performed prior to wait-listing and at routine intervals with the principal goal of screening for asymptomatic cardiac disease, intervening when necessary to improve long-term patient and allograft survival. Current clinical practice guidelines are based on expert opinion, with a lack of high-quality evidence to guide standardized screening practices. Recent studies support de-escalation in screening with avoidance of preemptive revascularization in asymptomatic patients, but they fail to provide clear guidance on how best to assess the cardiovascular fitness of this high-risk group. Herein we summarize current practice guidelines, discuss key study findings, highlight the role of optimal medical therapy, and evaluate future directions for cardiovascular disease assessment in this population. Cardiovascular disease (CVD) is the leading cause of death for patients with advanced chronic kidney disease (CKD) and end-stage kidney disease (ESKD). When compared to maintenance dialysis, kidney transplantation offers improved survival and quality of life. However, the burden of CVD persists and is the leading cause of death with a functioning allograft.1 All major types of CVD are represented in kidney transplant recipients, including coronary artery disease, heart failure, valvular heart disease, cerebrovascular disease, arrhythmias, and pulmonary hypertension. Decreased renal metabolic clearance leads to a uremic milieu with enhanced oxidative stress and proinflammatory cytokines. Hemodynamic changes lead to increased arterial wall stress and accelerated vascular calcifications. Hypervolemia leads to increased myocardial wall stress and can precipitate left ventricular hypertrophy, dysfunctional myocardial conduction, and pulmonary hypertension. Additionally, disorders of bone mineral metabolism and anemia of chronic kidney disease have been associated with a higher risk of CVD.Given the desire to maximize utility of scarce donor organs, the goals of pretransplantation cardiovascular risk stratification are (1) screening for asymptomatic coronary artery disease (CAD) or silent ischemic heart disease, (2) screening to determine optimal candidates for transplantation, and (3) screening to enhance long-term patient and allograft survival. Testing should appropriately identify those recipients who can withstand the perioperative surgical and anesthetic risk while excluding those with significant CAD burden that may lead to premature death.3 Similarly, physical function status can provide key information on candidate fitness or frailty and is predictive of posttransplant outcomes.5 Broad use of these additional tests is limited by availability, and implementation varies from center to center.The method of screening to provide risk prediction involves a combination of history and physical examination, blood tests, electrocardiograms, functional status evaluation, and a combination of noninvasive and invasive strategies. Modality for functional assessment of coronary heart disease varies by center expertise and local availability, while coronary angiography is limited by a candidate’s residual renal function. Recent studies of high-sensitivity troponin show that it may be a useful biomarker in patients with CKD and reflect not only myocardial injury but also other cardiovascular events, including stroke and peripheral arterial disease.8 Although these guidelines exist, the approach to CVD assessment in the kidney transplant candidate varies greatly by provider and center. Cheng et al. surveyed transplant providers in the United States (US) in 2020 and found a heavy reliance on noninvasive testing with myocardial perfusion scintigraphy or dobutamine stress echocardiography and a predilection towards aggressive evaluation and revascularization of asymptomatic patients with abnormal stress test results.9 Similarly, Nimmo et al. surveyed transplant nephrologists in the United Kingdom in 2021 and discovered a wide variation in screening practices among the 23 kidney transplant centers, with all expressing concern about the lack of evidence upon which their practice is based.10 Randomized controlled trial evidence is not available to guide screening for asymptomatic CAD before transplantation. Moreover, a growing body of evidence consistently shows a lack of efficacy in demonstrating survival benefit in preemptive screening and intervention in asymptomatic patients and may deprive patients the opportunity to receive a transplant. The following highlights our current understanding of CAD in patients with advanced kidney disease and discusses the available evidence in kidney transplant candidates.Current screening guidelines are outlined in 17Historically, studies of ischemic heart disease largely excluded patients with advanced CKD or ESKD, and management of this population was based on extrapolation and low-quality evidence from observational studies; however, recent trials have allowed a more objective assessment .11,12,132 or dialysis dependence) and moderate or severe ischemia on stress testing were randomized to either treatment with an invasive strategy of coronary angiography and revascularization (if indicated) with medical therapy, or a conservative strategy with medical therapy and subsequent angiography in those whom medical therapy failed. Contrary to the original expectation, the invasive strategy did not confer cardioprotective benefit, with no difference observed between the primary outcomes of 3-year event rate of death or nonfatal myocardial infarction (MI) . Furthermore, the invasive strategy was associated with a 3.76-fold higher hazard ratio of stroke and 48% higher hazard ratio of death or initiation of dialysis, likely related to atheroembolic complications of coronary angiography and revascularization .18Optimal management of CAD in the CKD population was assessed by Bangalore et al. in the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches - Chronic Kidney Disease (ISCHEMIA-CKD) trial. A total of 777 patients with advanced kidney disease  and the other half to revascularization (angioplasty or coronary artery bypass surgery). Of the 13 who were medically managed, 10 had a cardiovascular event within a median of 8.4 months compared to only 2 of the 13 revascularized patients. Unfortunately, despite its small size and conduct in a different treatment era, this became the basis for routine angiography for diabetic renal transplant candidates with revascularization for symptomless stenosis.19 This questioned the practice of routine revascularization, particularly in patients undergoing high-risk vascular surgeries, for which kidney transplant could be considered equivalent.In 2004, McFalls and colleagues in the Coronary-Artery Revascularization before Elective Major Vascular Surgery (CARP) trial assessed long-term outcomes of 510 patients with clinically significant CAD (> 70% stenosis) scheduled for elective vascular surgery , randomized to pre-op revascularization, or none. Median time between randomization and elective surgery was 36 days longer in the revascularization group. There was no difference between 30-day post-elective procedure MI or mortality at 2.7 years between the two groups. Medical therapy was optimized in both groups, with utilization rates of beta-blockers exceeding 80%, statin use of 50%, and aspirin use of 70%.P = .68) for those listed and not listed, respectively. The 3-year cumulative incidence of major adverse cardiovascular events (MACE) did not differ based on intervention, with rates of 29% in the invasive strategy and 30% in the conservative strategy. An invasive strategy with preemptive revascularization compared with conservative optimal medical therapy (OMT) did not improve all-cause mortality or nonfatal MI in these patients. Surprisingly, nonprotocol-specified angiography was performed in one-third of listed patients in the conservative strategy, with 20% of them receiving revascularization . This may have impacted the potential difference in outcome but more importantly points to the persistent lingering concern of clinicians regarding nonintervention on waitlisted patients with evidence of inducible moderate or severe myocardial ischemia.20Most recently, an important post hoc analysis of the ISCHEMIA-CKD trial argues against routine revascularization for stable kidney transplant candidates. Herzog and colleagues evaluated 194 of 777 transplant candidates with chronic coronary syndrome and at least moderate ischemia on myocardial perfusion scan. Compared to nonlisted patients, listed patients were younger (60 years vs 65 years) and more likely to be on dialysis (85% vs 44%), had less anginal symptoms, and were more likely to receive angiography regardless of treatment assignment. Among patients assigned to an invasive approach, the adjusted hazard ratio for the primary outcome was 0.91 and 1.03 , and no statistically significant association was observed between screening for asymptomatic CAD by angiography or stress test and MACE. These findings suggest that most of these transplant candidates were deemed acceptable cardiac risk, but it raises a question of whether others who may benefit from the superior treatment option of a transplant were unnecessarily excluded. It also highlights the possibility of a different etiology for cardiovascular disease in those with advanced CKD and posttransplant MACE.22 Current screening practices that focus only on atherosclerotic burden fail to fully assess cardiac risk and may be harmful or wasteful, leading to delays in listing, unnecessary exposure to ionizing radiation, loss of residual kidney function, and ultimately exclude patients inappropriately labeled as “high risk” from proceeding with a life-saving transplant.Over 50% of cardiovascular deaths in transplant recipients are related to dysrhythmias rather than atherosclerotic events and are likely due to the high prevalence of systolic and diastolic dysfunction, left ventricular hypertrophy, myocardial stunning and fibrosis, electrical instability, and extraosseous vascular calcifications observed in these patients. More should be done to address the electrolyte and volume derangements that directly correlate with cardiac events, in particular sudden cardiac death.28The medical management of stable ischemic heart disease patients with advanced kidney disease should follow that of the general population. Emphasis on physical activity, dietary restriction of saturated fat, and tobacco cessation are particularly challenging but feasible interventions. In patients with ESKD, anemia management and optimization of bone mineral metabolism abnormalities are also necessary. Existing standards of medical management are summarized in 29 Despite its exclusion of advanced CKD (eGFR < 20 mL/min) and all ESKD patients, it remains the largest randomized controlled trial for this population. An intensive blood pressure goal of systolic < 120 mm Hg significantly reduced the rates of adverse cardiovascular events and all-cause mortality. When considering the optimal guideline-based antihypertensive regimen, renin-angiotensin-aldosterone system (RAAS) blockade via angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) along with beta-blockers in heart failure remains a cornerstone for patients with advanced kidney disease. However, both the achievement of these blood pressure targets and the use of these medications remains suboptimal.The vast majority of pre-kidney transplant candidates are hypertensive. Recommendations on hypertension management in nondialysis-dependent CKD patients are summarized in the Kidney Disease Improving Global Outcomes (KDIGO) guidelines and are largely informed by data from the Systolic Blood Pressure Intervention Trial (SPRINT).16 While diminished renal function and hyperkalemia may be observed with RAAS blockade, aggressive use of these agents needs to be pursed. A recent review by Qiao et al. found that discontinuation of ACEIs or ARBs in patients once eGFR < 30 mL/min was associated with a higher risk of MACE and mortality within 5 years of discontinuation compared with those who remained on them; however, they saw no statistically significant difference in the risk of ESKD. Therefore, continuation of RAAS inhibition therapy in patients with declining kidney function may be associated with cardiovascular benefit without excessive harm of ESKD.30 Management of blood pressure in ESKD patients must focus on maintenance of euvolemia in addition to antihypertensive agents.32Observations from the ISCHEMIA-CKD trial showed that at the time of enrollment, less than 50% of patients had systolic blood pressure < 140 mm Hg, and over 54% were not on RAAS blockade.33 Lipid management in patients with ESKD remains controversial due to conflicting evidence.High-intensity statin use has proven to be a safe and effective way to reduce CVD risk, but they are underused in the CKD population. Mefford et al. assessed statin use among US adults with CKD between 1999 and 2014 and found that over 65% of adults with CKD met the indication for statins based on the 2013 American College of Cardiology/American Heart Association (ACC/AHA) cholesterol guidelines, yet only 35.7% were taking a statin between 2011 and 2014.36 In both the 4D Study and AURORA trial, statin use compared to placebo resulted in a significant reduction in low-density lipoprotein (LDL) cholesterol but no reduction in the primary outcomes of cardiovascular death, nonfatal MI, or stroke. The SHARP trial, however, showed a possible benefit in lowering the incidence of atherosclerotic cardiovascular events with the combination of simvastatin and ezetimibe. Several meta-analyses and post-hoc analyses have continued to demonstrate discordant results, but the overall perception is that statins may be associated with decreased all-cause and cardiovascular mortality in this population. In the posttransplant setting, KDIGO guidelines recommend that all kidney transplant recipients be treated with a cholesterol-lowering agent regardless of LDL level, based on evidence from the Assessment of Lescol in Renal Transplantation (ALERT) trial.38The impact of statin therapy for reduction of MACE in ESKD patients was assessed in the 4D Study , AURORA , and SHARP  trials.24 These medications remain underutilized—as low as 32% in eligible patients with CKD and type 2 diabetics—largely due to cost and patient or physician preference.39 A collaborative approach among primary care providers, nephrologists, endocrinologists, and cardiologists should be pursued to enhance use.Strict glycemic control is an important factor in medical management of CKD patients with diabetes. Recent guidelines strongly support the use of SGLT2-inhibitors after multiple studies have shown benefit in glycemic control along with reduction in CVD risk and CKD progression.40 Wait-list maintenance and transplant candidate readiness remain challenging tasks for transplant centers, accounting for the rising trend in kidney transplantation costs.41 Despite recommendations by ACC/AHA that periodic screening of asymptomatic patients is uncertain, the current standard of care remains screening at regular intervals, either annually for diabetic patients or every 2 to 3 years for all other wait-listed patients. It is unclear whether eliminating this annual testing in asymptomatic candidates is noninferior to continued CVD screening for the primary prevention of MACE. The Canadian-Australian Randomized Trial of Screening Kidney Transplant Candidates for Coronary Artery Disease  study will test the hypothesis that eliminating screening for asymptomatic candidates is noninferior to annual testing.42 Additionally, a modeled cost-utility analysis of Australian and New Zealand kidney transplant candidates on the wait list by Ying et al. demonstrated an incremental cost-effectiveness ratio of $11,122 per quality-adjusted life year gained, with no screening compared to regular screening and a survival advantage of 0.49 life-year with no further screening.43 These trials will provide critical information to guide transplant centers on the optimal assessment and management of transplant candidates.While living kidney donation allows a predictable timeline to transplantation, wait times on the deceased donor kidney transplantation list are prolonged, with less than half transplanted within 5 years of listing and variable transplant rates based on donation service area and geographic location.Patients with advanced chronic kidney disease carry a high burden of cardiovascular risk factors, which lead to increased mortality both before and after transplantation. The optimal modality for screening and management of ischemic heart disease is unclear, and testing should not be overlooked for other cardiac pathology, such as valvular disease, diastolic dysfunction, and dysrhythmias. Current screening guidelines are based on moderate-quality evidence. Given the lack of survival benefit with preemptive screening and intervention in asymptomatic patients and the elevated risk of harm, de-escalation of cardiac screening appears warranted. The focus of current practice guidelines suggests that asymptomatic kidney transplant candidates should receive optimal medical therapy, with revascularization reserved for high-risk subsets. Additional studies are needed to guide a standardized evidence-based approach to screening that balances precision and resource utilization.There is no convincing evidence that preemptive revascularization in pretransplant candidates with stable coronary artery disease improves posttransplantation outcomes.Optimal medical therapy and meeting dialysis metrics remain the foundation for management of asymptomatic cardiovascular disease in patients with advanced kidney failure.Additional tools, such as physical performance testing and biomarkers, require more careful study and may aide in the assessment of cardiac fitness in kidney transplant candidates.


To explore the biological variation (BV) of kidney injury markers in serum and urine of healthy subjects within 24 hours to assist with interpretation of future studies using these biomarkers in the context of known BV.A), within-subject (CVI), and between-subject (CVG) biological variation were calculated.Serum and urine samples were collected every 4 hours  from 31 healthy subjects within 24 hours and serum creatinine (s-Crea), serum β2-microglobin (s-β2MG), serum cystatin C (s-CYSC), serum neutrophil gelatinase-associated lipoprotein (s-NGAL), urine creatinine (u-Crea), urine β2-microglobin (u-β2MG), urine cystatin C (u-CYSC), urine neutrophil gelatinase-associated lipoprotein (u-NGAL) were measured. Outlier and variance homogeneity analyses were performed, followed by CV-ANOVA analysis on trend-corrected data (if relevant), and analytical  of serum kidney injury markers was less than 0.6, while the II of urinary kidney injury markers was more than 1.0.The concentration of kidney injury markers in male was higher than that in female, except for u-CYSC and u-NGAL. There were no significant difference in serum and urine kidney injury markers concentration at different time points. Serum CVThis study provides new short-term BV data for kidney injury markers in healthy subjects within 24 hours, which are of great significance in explaining other AKI / CKD studies. Although the diagnostic window is advanced to 48 hours, changes in s-Crea levels are affected by body weight, age, sex, drugs, muscle content, and protein intake; furthermore, when the glomerular filtration rate (GFR) is significantly reduced to below 50%, the s-Crea level begins to increase. In addition, urine output is easily affected by physiological reactions, pathological factors, and drugs, such as diuretics; therefore, the sensitivity and specificity of the KDIGO standard in diagnosing AKI are not high, and it is particularly important to find biomarkers for the early diagnosis of AKI.The causes of kidney injury are diverse, and the underlying mechanisms are complex. According to the cause of the disease, kidney injury can be divided into acute kidney injury (AKI) and chronic kidney disease (CKD). The global incidence of AKI in hospitalized patients ranges from 3.0% to 18.3 % , 3. Curr2-microglobulin (β2MG), can be used as a potential serum marker for a GFR. An increase in urinary β2MG (u-β2MG) excretion can be used as an indicator of kidney tubular injury, and this might have new value in evaluating glomerular filtration function and kidney tubular diseases. Cystatin C (CYSC) is a good marker that reflects glomerular dysfunction faster and is more sensitive than Crea [A new marker, βhan Crea . CYSC cahan Crea . Furtherhan Crea , 8. Howe2MG, CYSC, and NGAL in the serum and urine of healthy individuals within 24 hours, and to study the biological variation in the biomarkers from the collected samples.The European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) conducts a meta-analysis of the biological variation estimates of biomarkers, and establishes various biomarker biological variation databases for interpreting clinical experimental results and defining analytical performance specifications –11. CurrP > 0.05). The inclusion criteria were: healthy individuals without chronic diabetes, hypertension, goiter, cardiovascular and cerebrovascular diseases, no history of medication, and a stable lifestyle. All participants participated in the completion of the questionnaire survey to verify their health status, collect information about lifestyle, and conduct related physical examinations to ensure that all inclusion criteria were met [Samples were collected from 31 healthy volunteers from September to November 2019 in the Chengdu Pidu Traditional Chinese Medicine Hospital, including 17 males  and 14 females . There were no significant differences in their age, blood pressure, or heart rate , six serum samples were collected within 24 hours. The serum had naturally precipitated from the whole blood samples after being placed at room temperature for 30-90 min. The blood was centrifuged at 3,000 2MG and CYSC was 68912, and the batch number of NGAL was 0619021, which were provided by Sichuan Maccura Industrial Company.The specimens were thawed at room temperature, and the concentrations of the bio- markers were determined by the same operator using a Hitachi 7180 automatic biochemical analyzer system. Before testing, the analyzer was calibrated in accordance with the manufacturer's instructions, and all samples of the participants were tested twice. β2MG, CYSC, and NGAL were determined by the latex immunoturbidimetry. Crea was determined by the highly specific sarcosine oxidase method. The measured value of the method can be traced to the highest standard ID-MS method for the determination of Crea, and the measurement performance can meet clinical requirements. Internal quality control uses two levels of quality control products. The batch number of Crea was 48811/45813, which was provided by the Bio-rad Company of the United States. The batch number of βP <0.05 was considered to indicate statistical significance. The Shapiro-Wilk test was used to verify whether the test data were normally distributed [A) was obtained from repeated measurement data in the same analysis batch. The Bartlett and Cochran tests [I) and between-subject variation (CVG). The 95% confidence interval (CI) was calculated according to Roraas [T is the total number within subject’s variation, and Z is the probability of statistical significance , and calculations were performed as follows:Student’s t-test was used to test the difference in average values between male and female groups, and tributed . Logarittributed . The anaan tests , 20 wereo Roraas . The refo Roraas . CVT is 2MG, s-CYSC, s-NGAL, u-Crea, u-β2MG, u-CYSC, and u-NGAL were skewed. As described in the methods section, outlier detection was performed for each analyte, with No. 29 s-β2MG and 22 u-β2MG excluded. The changes in the concentrations of biomarkers are shown in Fig. We collected six samples from 31 people within 24 hours, including 186 serum samples and 186 urine samples. After repeated measurement, 744 results could be analyzed. Within 24 hours, the concentrations of s-Crea, s-βP<0.05). The serum and urinary kidney injury markers were higher in male than in female, except u-CYSC and u-NGAL. These data are shown in Table The characteristics of subjects were presented in Table 2MG, s-CYSC, s-NGAL, u-Crea, u-β2MG, u-CYSC, and u-NGAL at different collection time points  within 24 hours were not statistically significant (P > 0.05). These data are shown in Table The levels of s-Crea, s-βA, CVI, CVG, RCV, and II at a 95 % CI for the serum and urine biomarkers of kidney injury showed different individual differences between males and females. These data are shown in Table The CV2MG was higher in male than in female [I of serum samples of 31 healthy subjects was around 5–10%, the CVI of urine specimens was above 40%, and the CVI of kidney injury serum markers was lower than urine CVI, consistent with the report of related studies [G was all higher than CVI, and urine CVG was lower than CVI. CVI is important for personalized reference intervals, and CVG is important for population-based reference intervals. RCV and II calculated using biological variation data influence the application of reference intervals in the clinic.Biological variation research requires strict time and resource management, and is a challenging study. Our study is the first time to evaluate the serum and urine specimens of kidney injury markers simultaneously within 24 hours. Baseline characteristics of 31 healthy subjects were not significant, except for BMI. There were significant differences in serum and urine kidney injury markers between females and males. Consistent with previous studies, Crea was higher in male than in female , while Nn female . The con studies –31. SeruI and CVG of s-Crea within 24 hours were 7.41%  and 24.82 % , respectively, which were higher than the short-term biological variation reported by Carobene and Judith [I and CVG of u-Crea at 24 hours were 47.40%  and 37.58% , which were higher than the values published in the biological variation database data in 2014 [S-Crea –34 is std Judith , 37. The in 2014 . The cau2MG is produced, synthesized, and released constantly in individuals with a normal kidney function, and it is then reabsorbed and decomposed through glomerular filtration and in proximal kidney tubules (99%). Although the β2MG content in the urine of normal people is very small, β2MG is related to many disease processes. s-β2MG and u-β2MG concentrations are increased in many disease conditions; thus, this might limit the usefulness of β2MG as a biomarker for diagnosis. The levels of s-β2MG and u-β2MG in vivo are reliable and easy to detect. Several studies have analyzed the ability of β2MG to be used for the evaluation of kidney function and have reported that β2MG is superior to s-Crea in detecting changes in kidney function [2MG has been used not only to evaluate kidney tubular function, but also to monitor glomerular function. In this study, the CVI and CVG of s-β2MG and u-β2MG were 10.27% , 17.41 , 53.00%  and 32.17% , respectively. The CVI of s-β2MG was higher than the online number reported in 2014 [G. The BV of u-β2MG has not been reported.The biomarker βfunction . β2MG ha in 2014 , and theI and CVG of s-CYSC were 4.70%  and 14.07% , respectively, and the results were similar to those published on the website [I and CVG of u-CYSC were 59.85%  and 57.80% , respectively. CYSC can be freely filtered by the glomerulus and is completely reabsorbed and decomposed in the proximal kidney tubules; however, it cannot be secreted into the lumen by the kidney tubules. Therefore, a large amount of CYSC does not appear in urine. The urine CYSC content in our study was very small or not, and we estimated BV by very low urinary CYSC levels.CYSC is a cysteine protease inhibitor protein produced by nucleated cells, it was superior to other kidney injury markers for not being affected by age, sex, body weight, and inflammation. It is reported that CYSC used to detect AKI earlier than Crea . In rece 95% CI, .25–18.81 website . The CVII and CVG of s-NGAL and u-NGAL were 11.64%  and 22.20%  and 61.82%  and 24.46% , respectively. The EFLM has not published a report on the BV of NGAL and this study fills this gap.NGAL has been recently used as a biomarker for the early diagnosis of AKI. It has the advantages of early, rapid, highly specific, and sensitive detection, which are less affected by other factors, and has attracted some attention in the field , 41. NGARCV is a statistical concept introduced in clinical judgment of two consecutive test results. When evaluating the change of test results, the numerical change of the results should be the sum of the inherent changes of the two test results. When assessing the changes in the test results, when the difference between the consecutive test results exceeded the RCV, the change in the results remained clinically significant even though the results were still within the reference interval. If the two test results are less than the RCV value of the laboratory, even if beyond the reference value range, it is not necessary to determine the abnormal results immediately, it is recommended to review in a few days. In this study, the RCV of kidney injury markers s-Crea, s-β2MG, s-CYSC, s-NGAL, u-Crea, u-β2MG, s-CYSC and u-NGAL were 21.88%, 29.31%, 15.32%, 33.09%, 131.73%, 168.01%, 206.59%, 172.90%.I / CVG. When II> 1.4, it means that the individual specificity of the test item is low, the variation between individuals is less than the variation of individuals themselves, and any small change in the patient's physiological state immediately exceeds the reference value range, indicating that the reference value range can be used to evaluate the continuous change in individual results, which is suitable for population screening. When II<0.6, it means that the individual specificity of the test item is high, the variation between individuals is greater than the variation of individuals themselves, and the reference value of the reference interval is limited. As a result, the test results of patients with abnormal results often fall within the reference interval representing the variation between individuals. The results of this study showed that the serum marker II value of kidney injury were less than 0.6, and the urine marker II value was greater than 1.0.II =CVThis study had some limitations. First, the evaluation of the short-term biological variation in markers was performed using in young healthy individuals within 24 hours. The differences in biological variation with respect to markers between children and the elderly or between individuals of different nationalities, specific disease statuses, detection methodologies and regions were not considered. Second, this study did not stratified for age and was biased towards young adults. Third, this study did not adjusted for urinary Crea. Further studies are needed.I than urine CVI, serum CVG higher than CVI, and urine CVG lower than CVI. Urine marker II for kidney injury is higher than serum marker and is suitable for evaluating clinical decision-making with a population-based reference interval, while serum is more reasonable to evaluate them clinically using an individual-based reference interval or RCV.This study followed a rigorous protocol from 31 healthy subjects with narrow BV, providing the basis for biological variants in kidney injury markers s-Crea, s-β2MG, s-CYSC, s-NGAL, u-Crea, u-β2MG, u-CYSC and u-NGAL within 24 hours in healthy populations. The data of our study showed lower serum CV


To investigate body fluid status in diabetic macular edema (DME) patients and the extent to which it is affected by renal function.One hundred and thirty-two eyes from 132 patients with diabetes mellitus (DM) were prospectively collected in this cross-sectional, observational study. Thirty-five were DM patients without diabetic retinopathy (DR), 31 were DR patients without DME, and 66 were DME patients. The fluid status of each participant was quantified with extracellular water-to-total body water ratio (ECW/TBW) using a body composition monitor. Central subfield thickness (CST) and macular volume (MV) were obtained using optical coherence tomography (OCT). Urine albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate (eGFR), and albumin was obtained using serum and urine laboratory data.P = 0.003) and DR patients without DME . In multilinear regression, fluid overload was positively related to DME and UACR . In the binary logistic regression for DME risk, the area under the receiver operating characteristic curve (AUROC) increased significantly by adding ECW/TBW along with UACR and age (AUC: 0.826 vs. 0.768).ECW/TBW was significantly increased in DME patients  compared to DM (38.1 ± 0.7, %, DME patients had elevated body fluid volume independent of kidney functions. The assessment of extracellular fluid status may help in the management of DME. The burden of diabetes mellitus (DM) is growing globally, with a worldwide estimated prevalence of 4.1% in 2010 expected to increase to 7.7% by 2030 . Our groInterestingly, while DKD has been proven associated with the elevation in extracellular fluid volume , a recenIn this paper, the fluid statuses among different DM patients, including DR patients with or without DME and diabetic patients with or without DR, were investigated. By further exploiting associated changes of fluid status and renal function parameters in DME, this study proposed a novel hypothesis for the role of body fluid status in DME mechanisms. It provided significant clinical evidence to guide future DME management and treatments.This was a cross-sectional observational study. Diabetic patients diagnosed with or without DR and DME by a multi-disciplinary team at Guangdong Provincial People's Hospital were prospectively included from May 2020 to February 2021. Medical records were reviewed by a chief-resident doctor from the department of ophthalmology and a chief-resident doctor from the department of endocrine of Guangdong Provincial People's Hospital. All patients included were informed of the study contents and signed written consent. This study was conducted following the Declaration of Helsinki and under the supervision of the Research Ethics Committee of Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences (registration number: GDREC2018380H).Patients aged 18 years or older, diagnosed with DM, with or without DR and DME, and capable of going through funduscopic examination, optical coherence tomography (OCT) scans, and BCM were included in the study. Exclusion criteria were receiving pan-retinal photocoagulation, intravitreal injection or pars-planar vitrectomy within 3 months, other retinal diseases including age-related macular disease, retinal vascular occlusion, retinal vasculitis, macular hole, and epiretinal membrane, significant cataract affecting fundus examination, and severe systemic diseases including myocardial infarction, stroke, CKD at end-stage, and under hemodialysis or peritoneal dialysis.All patients were examined for the following characteristics and parameters: age, sex, height, body weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), history of hypertension, DM duration. Hypertension was defined as SBP ≥140 mmHg or DBP ≥ 90 mmHg . Diagnos2) and impaired (<60 mL/min/1.73 m2) according to the definition of CKD , intraocular pressure (IOP), dilated fundus examination, fundus photography, and OCT. BCVA was examined with the Snellen chart and converted into the logarithm of minimal angle of resolution (logMAR) . IOP wasAll patients underwent BCM examination , which measured different body compositions via direct segmental multi-frequency bioelectrical impedance analysis (DSM-BIA). An eight-electrode system connecting to the ankles and two fingertips of each patient's hand segments the human body into five parts, including the right arm, left arm, right leg, left leg, and trunk, and measures different body parts compartments. The instrument uses a current of 6 frequencies, including 1 kHz, 5 kHz, 50 kHz, 250 kHz, 500 kHz, and 1 MHz, the varied cell membrane conductivities from high-frequency to low-frequency current are therefore translated into extracellular water (ECW) and intracellular water (ICW) with different impedance . In the 2 tests were carried out to compare non-parametric variables among the three groups. Tests for homogeneity of variance were conducted on the general characteristics, BCM parameters, and renal function parameters, and no variate was found significant. For each participant, the one eye with higher CST, MV, and more severe DR stage was included in the data analysis. Analysis of variance (ANOVA) was applied to compare the quantitative characteristics, including age, SBP, DBP, BMI, BCVA, IOP, blood test parameters, and BCM results among three groups. Two multivariate linear models were carried out to estimate the effect of renal functions on body fluid status among three diabetic groups after adjusting for significant covariates identified in the univariate linear model. Step-by-step multivariate binary logistic regressions with a backward method were conducted to predict DME risk. The models' receiver operating characteristic (ROC) curves were then drawn to demonstrate their predictive power quantified by the area under the curves (AUC). All statistical analysis was performed using SPSS software . A P < 0.05 indicates statistical significance.Participants were divided into three groups, including DM group (without DR), DR group (diagnosed with DR but no DME), and DME group (diagnosed with DR and DME) according to their diagnosis. Normally distributed continuous variables were shown as mean ± standard deviation in n = 35), DR group (n = 31), and DME group (n = 66). As for general characteristics, there was no statistically significant difference in sex, age, hypertension, blood pressure, weight among the three groups , and there were significant differences in DM duration (P < 0.001) and BMI (P = 0.013). BCVA, CST and MV were significantly different among three groups  while IOP was not (P = 0.942).One hundred thirty-two patients  with 132 eyes were enrolled in the study. post-hoc analysis, systemic parameters including urea and PLR in both the DME group and DR group were significantly higher than the DM groups , while hemoglobin, 25-hydroxyvitamin D, eGFR were significantly lower than the DM group . UACR  and MLR  was found elevated in the DME group compared to DM group. As for BCM parameters, the DME group had significantly higher ECW/TBW than both the DM group and DR group (P < 0.001). No significant differences of PBF, VFA, BMR, and SMI were detected among three groups .All parameters of blood test and BCM parameters were found normally distributed. In the test of homogeneity, PhA and ECW/TBW showed a high level of collinearity. Hence PhA was excluded in further analysis. In the P < 0.05). No significant association was found between MAP and ECW/TBW (P = 0.188). In the multivariate linear model, DME, DR, age, MAP, and albumin showed significant impact on ECW/TBW , while eGFR was not significantly associated with ECW/TBW . In the multivariate model focusing on UACR, only DME, age, and UACR were positively associated with ECW/TBW , while MAP showed a negative association with ECW/TBW (P = 0.005).P = 0.009), UACR stage , and ECW/TBW  entered the model under the probability for removal at 0.05. Details were shown in In the binary logistic regression analysis with backward method of the risk of DME, age . The patients/participants provided their written informed consent to participate in this study.JY, QP, and YL contributed to the study conception and design. Material preparation and data collection were performed by AL, JX, XZ, RC, YC, and ZW. Data analysis was conducted and the first draft of the manuscript was written by JY and QP. DC and LZ contributed to the manuscript reviewing and editing and funding acquisition. All authors read and approved the final manuscript.This work was funded by Guangzhou Municipal Science and Technology Bureau (grant 202102080008) and Bethune-Merck Diabetes Research Fund (G2018030).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.


Kidney allografts with multiple renal arteries (MRA) are not infrequent and have been historically associated with a higher risk of developing vascular and urologic complications. Reports of kidney transplantation using MRA allografts in the pediatric population remain scarce. The aim of this study was to evaluate if transplantation of allografts with MRA with a surgical intent of creating a single arterial inflow using vascular reconstruction techniques when required, and without the routine use of surgical drains or ureteral stents, is associated with an increased risk of complications when compared to single renal artery (SRA) grafts.t-tests. Time-to-event distributions were compared using the log-rank test.We retrospectively analyzed all pediatric renal transplant recipients performed by a single surgeon at our center between January 2015 and June 2022. Donor and recipient demographics, intraoperative data, and recipient outcomes were included. Recipients were divided into two groups based on SRA vs. MRA. Baseline variables were described using frequency distributions for categorical variables and means and standard errors for continuous variables. Comparisons of those distributions between the two groups were performed using standard chi-squared and p = 0.39). There were no cases of delayed graft function or graft primary nonfunction. No surgical drainage or ureteral stents were used in any of the cases. One patient in Group 2 developed a distal ureter stricture. The geometric mean serum creatinine at 6- and 12-months posttransplant was 0.7 */ 1.2 and 0.9 */ 1.2 mg/dl in Group 1 and 0.7 */ 1.1 and 0.7 */ 1.1 mg/dl in Group 2. Two death-censored graft failures were observed in Group 2, with no significant difference observed between the two groups (p = 0.48).Forty-nine pediatric transplant recipients were analyzed. Of these, 9 had donors with MRA (Group 1) and 40 had donors with SRA (Group 2). Native kidney and liver mobilization was performed in 44.4% (4/9) of Group 1 vs. 60.0% (24/40) of Group 2 cases (Our study demonstrates that pediatric renal transplantation with MRA grafts, using a surgical approach to achieve a single renal artery ostium, can be safely performed while achieving similar outcomes as SRA grafts and with a low complication rate. Renal transplantation remains the best therapy for the pediatric population that suffers from end-stage kidney disease (ESKD), offering improved development and growth . Based opostoperative complications up to 3 months, estimated glomerular filtration rate (eGFR) and renal function up to 1 year, and graft survival up to 4 years posttransplant, irrespective of allograft type or reconstruction technique. Despite finding a significantly higher postoperative lymphocele rate in the multiple vessel cohort (p = 0.024), the authors concluded that MRA allografts can be safely used in pediatric renal transplantation with equivalent perioperative complication rates and graft survival outcomes to single artery allografts. De Coppi et al (p < 0.01). Specifically, the SRA group had lower serum creatinine levels when compared to the groups with MRA at 1 year, but these differences disappeared by 5 years posttransplant. The authors attributed their results to an increased warm ischemic time (WIT) in the group with MRA, an important factor that highlights the importance of creating a single orifice when faced with MRA with efforts to minimize WIT by anastomosing a single lumen to the recipient artery  results, data remain scarce, and few publications have demonstrated the safety of using renal grafts with MRA . In theipi et al  reportedt artery .via vascular reconstruction when necessary) in as many MRA cases as possible, evaluating the occurrences of vascular, urologic, and surgical complications and overall clinical outcomes. Given that there have been relatively few reports of pediatric kidney transplants in which donor kidneys with MRA were utilized, we were interested in comparing our overall results with those reported by others.The objective of this study was to perform a comparative retrospective analysis of pediatric kidney transplant recipients who received MRA vs. SRA allografts, with a surgical intent to create a single orifice  who underwent KT by a single surgeon at this center between January 2015 and June 2022 were included. Again, the surgical approach for both MRA and SRA allografts was to create a single arterial inflow using vascular reconstruction techniques when required, thereby minimizing WIT in the MRA cases, and without the routine use of surgical drains or ureteral stents. This study was approved by the Institutional Review Board at the University of Miami and follows the Helsinki Declaration (as revised in 2013). Written informed consent for transplantation was required and obtained from all subjects’ parents or a legal surrogate. Last follow-up date for the study was September 15, 2022.All pediatric patients were evaluated by a pediatric transplant nephrologist and transplant surgeon prior to transplantation. They underwent a complete workup including laboratory studies , radiographic imaging with echocardiogram, ultrasound of the abdomen, chest x-ray, and electrocardiogram (ECG). Currently, at our institution, we do not have cut-offs for recipient weight and height. Each patient is evaluated individually, and decisions were made in a multidisciplinary approach. All recipients began aspirin 81 mg daily on postoperative day 3 and remained on this regimen indefinitely. To monitor development of vascular and/or urological complications, baseline Doppler Ultrasound (DU) was performed immediately after surgery, and then repeated at 1, 3, and 12 months postoperatively. If there were any vascular or urological concerns, further imaging with magnetic resonance angiography and/or Tc99m MAG-3 renal scintigraphy was performed.Patients were categorized into two groups according to presence of MRA or SRA of the donor kidney allograft. Group 1 was defined as the pediatric recipients that underwent a kidney transplant of an allograft with MRA—in each of these cases, back table reconstruction was required. Group 2 was defined as recipients that underwent a kidney transplant with an allograft having a SRA; none of these cases required any back table reconstruction prior to implantation.A modified Gibson incision was made on the right lower quadrant and carried through the abdominal layers. The peritoneum was reflected medially, and the iliac vessels were exposed. Minimal possible dissection was performed, just enough to allow for vascular clamping of the vessels, avoiding unnecessary injury to the lymphatic system and subsequent lymphocele development. Based on the recipient's size, a liver and native right kidney mobilization was performed in an effort to accommodate an adult renal allograft . DependiThe renal allografts were prepared on the back table. Single or multiple renal arteries were identified and cleaned from surrounding tissue. The renal vein was isolated. If a right kidney from a deceased donor was used, the cava was reconstructed to increase the length of the right renal vein using 6-0 polypropolene sutures. Nontraumatic vascular clamps were placed. The allograft was brought to the field; we routinely perform the arterial anastomosis first using 7-0 polypropylene sutures, followed by the venous anastomosis with 6-0 prolene. Restoration of blood flow to the graft was performed followed by positioning of the kidney in the retroperitoneum, sitting on top of the right psoas muscle. Finally, the ureter was anastomosed to the bladder using a Miami Transplant Institute (MTI) ureteral technique , and theEx vivo reconstructions were performed during bench surgery according to the case-specific anatomy utilizing surgical loupes at 2.5× magnification. All of the vascular reconstructions were performed with 8-0 prolene. Five of the grafts with MRA were from living donors and underwent reconstruction by creating a single orifice in order to decrease warm ischemia time , and estimated blood loss (EBL). Serum creatinine was obtained at 6- and 12-months posttransplant. eGFR was calculated using Schwartz's original formula, where the constant of proportionality (k) is adjusted for the child's age and sex . Acute rt-tests for continuous variables, and log-rank tests for time-to-event variables. For skewed distributions, t-tests comparing geometric means were performed using natural logarithmic transformed values. P-values < 0.05 were considered to be statistically significant.Baseline variables were described using frequency distributions for categorical variables, and means and standard errors for continuous variables (geometric means and corresponding standard errors were used for skewed distributions). Medians and ranges of continuous variables were also provided. Tests of association with the likelihood of having MRA (yes/no) vs. SRA were performed using Pearson chi-squared tests for categorical variables, standard two-sample N = 7 vs. 10.9 ± 0.2, N = 30; p = 0.04). There were no significant differences regarding distributions of living donor status, donor age, laterality, or percentage of glomerulosclerosis on biopsy, as demonstrated in A total of 49 pediatric transplant recipients were included in the analysis. Of these, 9 had donors with MRA and were characterized as Group 1, and 40 recipients receiving a donor kidney with SRA were characterized as Group 2. We did not identify any significant differences when comparing both groups regarding the distributions of recipient age, sex, years on dialysis, height, weight, or diagnosis of end-stage renal disease . Mean dop = 0.39) (p = 0.85). The mean cold ischemia time was 10.0 ± 3.5 h for Group 1 and 15.6 ± 2.0 h for Group 2 (p = 0.22). Estimated blood loss was also not significantly different between the two groups  of the cases in Group 1 and 60.0% (24/40) in Group 2 ( = 0.39) . Of noteo groups .The clinical outcomes of both groups are described in N = 9 vs. 0.7 */ 1.1, N = 36, p = 0.68), with similar results at 12 months posttransplant . Mean eGFR at 12 months posttransplant between the two groups was also similar (p = 0.91) .The geometric mean serum creatinine at 6 months posttransplant for Groups 1 and 2 were similar  . In addip = 0.48 and 0.71, respectively).Among the 46 patients who were alive with a functioning graft at last follow-up, median follow-up was 24.2 (range: 2.4–72.7) months posttransplant. There were two cases of (death-censored) graft failure observed in the donor SRA group related to acute rejection (triggered by overt nonadherence in taking the prescribed immunosuppressive medications in one case). One case of death with a functioning graft was observed in the same group (Group 2) due to a cardiovascular event at home causing severe anoxic brain injury. The rates of (death-censored) graft failure and death with a functioning graft were not significantly different between the two groups , likely due to the relatively low sample size in the MRA group. Similar results were reported in other publications , a randomized trial with a larger sample size would clearly be the gold standard for making more reliable statistical comparisons. In our study, good statistical power only existed for detecting large differences between Groups 1 and 2, as well as between LDKT recipients of MRA grafts who required vascular reconstruction to achieve a single orifice vs. deceased donor recipients of MRA grafts who did not require such vascular reconstruction. Despite this study limitation, we observed no vascular or urological complications among any of the MRA recipients. Second, this was an evaluation of pediatric transplant recipients performed at a single center by a single, highly experienced transplant surgeon. While one might expect that the results achieved by a single transplant surgeon using the same surgical approach, i.e., to perform careful vascular reconstructions among LDKT grafts with MRA with the goal of achieving a single orifice in each case , would be more homogenous in comparison with those achieved by multiple surgeons using “more conventional” approaches, the observed favorable results reported here (by a single transplant surgeon) does need to be verified by others.The present study aims to strengthen the pediatric kidney transplant data pool regarding the use of grafts with MRA. The continuing disparity between organ pool availability and an increasing waiting list of pediatric patients with end-stage renal disease requests greater use of extended criteria donors while also decreasing the discard rate of renal allografts . As demoIn summary, our study demonstrates that pediatric renal transplants with MRA can be safely performed and without the routine use of surgical drains or ureteral stents, achieving similar outcomes as SRA grafts and with a low complication rate.


Hypertension is a universal public health challenge and a leading modifiable risk factor for cardiovascular disease and death. It is also called high blood pressure, described by two measured quantities systolic blood pressure (SBP) 140 mmHg or greater and diastolic blood pressure (DBP) 90 mmHg or greater. As the result, this study aims to use the joint model application to identify the factors that affect longitudinal changes in fasting blood sugar, SBP, and survival time to death of hypertension patients and their associations admitted to the Arba Minch General Hospital. We considered a total of 354 random samples of hypertension patients who had under follow-up at Arba Minch general hospital from January 2012 to February 2020. Among 2330 hypertension patients under follow-up, 354 were selected with a simple random sampling technique, and data was collected from the patient’s medical cards. After evaluating the longitudinal data with a linear mixed model and the baseline data with Cox proportional models, the joint models of both sub-models were assessed in R software version 4.2. According to the findings, the association between longitudinal changes (FBS, SBP, and time to death in hypertension patients was statistically significant. Ages, place of residence, lifestyle change, stages of hypertension, blood cholesterol level, related diseases, adherence to treatment, family history of hypertension patients, and DBP at baseline were associated factors that affect survival time and longitudinal measurement of FBS and SBP of the patients. The computed association parameters revealed subject-specific values. The subject-specific linear time slope of FBS and SBP was negatively related to the hazard rate of time to death of hypertension patients in Arba Minch general hospital. To reduce the risk of hypertension in patients, health professionals, governmental organizations, and non-governmental organizations must promote the implementation of community-based screening programs for early detection of hypertension. Hypertension is the biggest risk factor liable for 9.4 million deaths and illnesses worldwide and this makes it the only most vital explanation for morbidity and mortality worldwide4.According to a systematic review conducted on awareness of hypertension in Africa, the levels of awareness, treatment, and control varied widely from country to country. Also, A study in Afghanistan and in sub-Saharan African countries such as Uganda, South African, Tanzania, and Nigeria) showed that hypertension the leading cause of morbidity and mortality6.In Ethiopia different study showed that hypertension is growing health problem and it is one of risk factor for non-communicable diseases. Also meta-analysis on the prevalence of hypertension in Ethiopia found that it is increasing with an estimated prevalence of 19.6%. In the last few years, due to the lifestyle change from urbanization and demographic transition the burden of hypertension could be rise7. This study aimed to use the joint model application to identify the factors that affect longitudinal changes in fasting blood sugar (FBP), SBP, and survival time to death of hypertension patients and their associations admitted to the Arba Minch General Hospital.Patients' health can be evaluated using both longitudinal and time-to-event data, and they frequently co-occur. The longitudinal trajectories might also be connected to the duration of the event. The results of separate analysis of longitudinal data and survival data may be inaccurate or biased. On the other hand, joint models of longitudinal and survival data take into account all available data at once and offer accurate and effective predictionsThis study has been conducted on data taken from Arba Minch General Hospital (AMGH) which is located in South nation nationality people regional state Gamo zone, Arba Minch town, 750 km from Addis Ababa, Ethiopia. This hospital serves as a General hospital for the people in the surrounding area.To achieve the study’s objective, a retrospective study was done to collectimportant information from the medical files of patients with hypertension.To achieve the study’s objective, a retrospective study was done to collect important information from the medical files of patients with hypertension. The data for this study were collected from patients' medical cards, which contained epidemiological, laboratory, and clinical information regarding the patients who had been followed up at Arba Minch General Hospital from January 2012 to February 2020. The timing of the death of hypertension patients was the survival endpoint of interest.The research proposal of this study was checked and approved by Arba Minch University department of statistics and ethical clearance committee of the University. So, Informed consent has been waived by the ethical committee of the University. All study procedures were performed following relevant guidelines and regulations laid down by the Committee.The letter of ethical clearance was obtained from the institutional review board of Arba Minch University, and Arba Minch General Hospital gave permission to collect data of hypertension patients from recorded cards. For the purpose of confidentiality, there were no links with individual patients and all data had no personal identifier and were kept confidential and therefore Informed consent has been waived by Arba Minch University ethical committee.The longitudinal changes in systolic blood pressure, fasting blood sugar and the survival time of hypertension patients after initiating medication were the study’s response variables. The longitudinal measurements were measured repeatedly over time for each hypertension patient under follow up. The survival time was measured time in months of a patient to the associated death event. Moreover, it is time to death event of the patient under the follow-up.The Explanatory variables considered in this study were: observed time, square of observed time gender, base line age, place of residence, alcohol use, Khat intake, tobacco use, status of stress, stages of hypertension disease, life style change, blood cholesterol level, adherence to treatment, related diseases, family history of hypertension patients, DBP, diabetes of mellitus status were all factors considered.Different statistical models such as the joint model, the longitudinal linear mixed-effect (LME) model; and the event time model were investigated. The analysis was carried out using R software version 4.2.A linear mixed-effect model for longitudinal data and a Cox proportional hazard (PH) model for survival data, with an association parameter, show the effect of longitudinal measurement on hypertension patients survival time to death.8.The SBP and FBS measurements were collected longitudinally from the same individuals throughout several observation times. The LME model is a parametric linear model for longitudinal or repeated measurement data that quantifies the associations between a continuous dependent variable and a large number of predictor factors. It builds on the traditional linear regression model by accounting for both fixed and random factors. Subject-specific effects are included in the random effectLet kresponse variable from the T represents the observations across all response variables and subjects shown in  died, while 319 (90%) were censored , and Bayesian information criteria (BIC) values than those in other covariate structure, indicating that heterogeneous first order autoregressive variance–covariance is the best fit for our data when compare to the other covariance structures for the longitudinal change in SBPand FBSof hypertension data Table .Table 3CThe model with random intercept and slope was chosen as the most parsimonious model for the LME model for the longitudinal change of SBPandFBSdue to lower values of AIC and BIC for both FBS and SBP Table .Table 4Sp-value < 0.009 and p-value < 0.001 respectively. The significance of the association parameter suggests that there is a strong dependence (association) between longitudinal changes (SBP and FBS) with survival time of hypertension patients.The association parameters The joint model analysis in Table p < 0.002), 0.297, HR = 1.346 (p < 0.007), 0.17, HR = 1.18 (p < 0.002), 0.0183HR = 1.018 (p < 0.0015), and 0.221, HR = 1.247 (p < 0.001) were significant effect respectively at 5%level of significance  the survival time of hypertension patients’ decrease. And an increase in raised blood cholesterol level, poor adherence to treatment, related diseases, positive family history of hypertension patients, base line FBS level measurement, base line diastolic blood pressure measurement respectively increases hazard to death although the survival time of patient declines.11. Also, the current study reveals that the stage of hypertension, family history of adherence to treatment, related disease, and smoking tobacco are identified as risk factors that affect the longitudinal change (SBP and FBS) and survival time of the patients. This finding is similar to the finding of a study in Uganda12. But, this result was contradictory to research conducted in eastern Ethiopia13.In this study, smoking tobacco, Khat use, and alcohol use were significantly associated with survival time of hypertension. The study reveals that patients who did not use alcohol did not use Khat and did not smoke tobacco had a better survival probability than those who used alcohol, Khat and smoking tobacco. Similarly, Ayalew et al. indicated that alcohol use is a potential risk factor for hypertension, and they also found hypertension was significantly higher in individuals who use alcohol than in those who did not use it14. This study finds that there is a strong dependence between SBP, FBS, and survival time of hypertension patients at AMGH, and suggests that joint model analysis rather than separate model analysis for such kind of dependence outcomes, clinical and medical studies. These findings are agreed with previous researchers’ findings17. In this study, the finding regarding the relationship between place of residence of patients and survival time until hypertension associated death was similar with finding in Addis Ababa Ethiopia reported that place of residence has a significant effect on hypertension patients' survival time14. Moreover, we found that a family history of hypertension disease was a statistically significant risk factor for death in hypertension patients; this finding is consistent with the findings of other researchers18. The current study found that age was related to the survival time of hypertension patients. This result is consistent with findings from a study in Ethiopia and Uganda14. Our study found that Khat intake was associated with the survival time of hypertension patients. These results are consistent with findings from a study19 that identified that Khat chewing is one of the risk factors for hypertension mortality.The purpose of this study was to use the joint model application to identify the factors that affect longitudinal changes in SBP, FBS, and survival time to death of hypertension patients and their associations admitted to the Arba Minch General Hospital. In this study, the founding from the analysis of the survival sub-model shows that variables like age, alcohol use, Khat use, lifestyle change tobacco use, blood cholesterol level, family history, diabetic status, and stage of hypertension were significantly associated with survival time of the patients. The study revealed that the variables place of residence and observation time had significant associations with changes in SBP. This finding was similar to the finding in Jimma University specialized hospital, south-west Ethiopia reported that place of residence, and observation time have significant effects on change in SBP measurementThe linear mixed-effect model with subjective values of SBP and FBS was a good fit for the longitudinal changes in SBP and FBS evaluations in this investigation. At a 5% level of significance, the variables including observed time, square of observed time, age, place of residence, alcohol use, lifestyle change, tobacco use, blood cholesterol level, adherence to treatment, family history, and diastolic blood pressure were significantly associated with longitudinal measurement of (SBP and FBS) Joint models were used with the assumptions of a linear mixed effect model for the longitudinal change of (SBP and FBs) with survival time of hypertension patients data collected from AMGH. Model comparison was employed to select fitted model, Weibull parametric model was fitted model for survival analysis. In survival sub-model covariates: baseline age, place of residence, lifestyle change, Khat intake, stages of hypertension disease, blood cholesterol level, related diseases, adherence to treatment, family history, and baseline diastolic blood pressure measurement were significantly affect the survival time of hypertension patients at 5% level of significance. In joint model analysis, association parameters were significant at a 5% level of significance. Thisindicates that there is a strong dependence between longitudinal changes (SBP and FBS) and with survival time of patients. The negative sign of the estimated association parameter indicates longitudinal changes (SBP and FBS) measurementwere negatively associated with the survival time of the patients in the study area, implying lower values of the SBP and FBS measurements associated with better survival time of the patients. Based on the findings, we recommended that patients in societies who have positive family history should take action on early detection and prevention mechanisms as well as should be aware of the risk factors. Also for further improvements, the Policymakers, concerned bodies, and Arba Minch General Hospital should give more attention and intervention to identified risk factors in society, and Programs should design to improve the surveillance systems and implementations of community-based screening programs for early detection of hypertension are recommended.


The aim of this study was to evaluate the association between recurrence-free survival (RFS) and perirenal fat thickness (PFT) in a cohort of Chinese population with unilateral nephrolithiasis.We retrospectively reviewed the medical records of 81 patients with unilateral nephrolithiasis in our center from January 2019 to June 2019. PFT measured on computed tomography (CT) scans was evaluated. Kaplan-Meier curves and log-rank tests were used to assess significant differences in RSF between high-PFT and low-PFT groups within sexes. Univariable and multivariable Cox regression analyses were used to evaluate the potential risk factors for renal stone recurrence.p = .003 and.047, respectively). The PFT of stone-bearing kidney was significantly greater than PFT of non-stone-bearing kidney  . During the follow-up periods (median 31 months), 21 (25.9%) patients experienced ipsilateral renal stone recurrence. In addition, Kaplan–Meier survival curves showed that patients with low PFT had a significant better RFS than those with high PFT (p = .012). In the univariable Cox analyses, male sex and high PFT were significantly associated with a poor RFS . Moreover, both male sex and high PFT retained significance in the multivariable analyses .High PFT was significantly associated with high BMI and hyperlipidemia (Our findings suggested that PFT is a noninvasive and feasible parameter, which may help in the risk stratification of renal stone recurrence in the follow-up periods. Associations between nephrolithiasis and metabolic abnormalities has been previously reported . Given te marker . Howevere marker .n = 40) showed that stone-bearing kidney has a greater perirenal fat volume (PFV) than non-stone-bearing kidney [n = 81) from the southeast coast of China. We hope to describe the role of PFT in the risk stratification of renal stone recurrence.BMI is a self-reported parameter and only presents the overall obesity. It could not distinguish the muscle from fat content . Perireng kidney . Howeverg kidney . In our 2, less than 25 kg/m2 vs 25 kg/m2 or greater), history of diabetes mellitus (DM), hypertension and hyperlipidemia (HLD). Stone data were also collected, including stone diameter and chemical composition  vs. non-CO) and history of nephrolithiasis. Age at the first-time presentation has been reported as a risk factor of stone recurrence [N = 0), insufficient follow-up period  or residual stone burden (N = 3) were excluded. In addition, patients (N = 5) were excluded if they had a history of ipsilateral renal malignant tumor, hyperparathyroidism, impaired renal function (serum creatinine more than 1.5 mg/dl), infection stone, malformation of the urinary system, and other diseases that might affect the risk of renal stone recurrence along with patients less than 20 years old. According to the postoperative chemical composition of the stones, all the patients will receive recommendation on lifestyle changes, including increased fluid intake and diet alterations. Stone recurrence was defined as the radiographic findings of newly ipsilateral renal stone. Time to stone recurrence was defined as the interval between being stone free and stone recurrence [A total of 81 patients with unilateral renal stone disease (RSD), who were treated with percutaneous nephrolithotomy (PCNL) or retrograde intrarenal surgery (RIRS) in our center from January 2019 to June 2019 were retrospectively recruited. This study was conducted with the approval from the institutional ethics committee of the First Affiliated Hospital of Xiamen University. Patient data and metabolic risk factors were collected from the medical records, including gender, age at initial diagnosis (50 years old or younger vs. older than 50 years old), BMI . The evaluation of PFT was in accordance with previous studies for both stone-bearing and non-stone-bearing kidney [Routine abdominal CT scans  were performed prior to the surgical intervention. All the CT scans were reviewed by a senior urologist (HCH) who was blinded to the clinical and survival data before the evaluation and under the supervision of a senior radiologist (SC). The Bland-Altman analysis showed an almost null mean difference between PFT of the stone-bearing kidney measured by SC and HCH  and associated risk factors. All the statistical tests were performed using Statistic Package for the Social Science (SPSS) software (version 22.0), and statistical significance was defined as a p = .003 and .047, respectively). There was no significant difference regarding age, history of DM, hypertension and nephrolithiasis, stone data (size and number) and surgical methods (PCNL vs. RIRS) between high-PFT group and low-PFT group. The baseline clinicopathological parameters of the two groups (low PFT vs. high PFT) were described in Fifty-five male patients and twenty-six female patients with a median age of 50 years old were enrolled in this study. High PFT, defined as greater than sex-specific median value, was significantly associated with high BMI and HLD  had a BMI greater than 25 kg/m2 (p = .018). Moreover, male patients had a significant greater PFT of the stone-bearing kidney than female patients . Of interest, the PFT of stone-bearing kidney was significantly greater than PFT of non-stone-bearing kidney  .In total, 63 patients had postoperative stone analyses. There were 60 patients with CO-dominant calculi, whereas only 3 patients had Uric acid (UA) calculi. Male patients had a significantly greater BMI than female patients. There were only 4 female patients  had a BMI greater than 25 kg/mp = .012, The median follow-up period was 31 months, with 21  patients experiencing ipsilateral renal stone recurrence during the follow-up period. Patients with low PFT showed a significant better RFS than those with high PFT  [N = 10). In their study, Chinese renal stone patients had the lowest obesity rate (2%), and the obesity rate in Chinese renal stone formers was not higher than the obesity rate in general Chinese population [2) and non-obese patients in five-year stone-free rate  [2) was not significantly associated with RFS of renal stone after a median follow-up period of 31 months  . Howeverpulation . In a crctively) . In our 1 months , which iPrevious studies had reported a link between RSD and a number of health issues, including diabetes, hypertension, chronic kidney disease (CKD), and metabolic syndrome (MS) . MoreoveRecently, a study by Lama et al. , in 40 pp = .002), which showed the important role of PFT in the formation of renal stone. Moreover, high sex-specific PFT of the stone-bearing kidney was significantly associated with poor RFS in both unilateral and multilateral analyses, which added survival data presenting the role of PFT in risk stratification of the recurrence of renal stone. In our study, male sex was significantly associated with poor RFS of renal stone in both univariable and multivariable Cox analyses , which is consistent with the result of previous studies [p = .001), which may explain the difference in RFS between male patients and female patients in our study.These findings were further substantiated by the study of Tastemur et al., where more participants were included . However studies . Of inteLittle is known about the biochemical mechanisms that explain the association between perirenal fat accumulation and the formation and recurrence of RSD. BMI is related with changes in the biochemical components of urine, as well as urinary pH . In a reDyslipidemia has also been reported to be associated with calcium kidney stone disease. In a recent study, Huang et al. demonstrated a significant link between dyslipidemia and calcium kidney stone disease, where a higher serum total cholesterol (TC) and low-density lipoprotein (LDL) were all associated with lower urinary citrate in calcium oxalate stone formers. They also reported a significant higher level of oxidative stress markers in the higher serum TC and LDL calcium-containing stone disease subgroups . Tastemun = 3), while the majority of patients were CO-dominant stones in our study. Future studies with larger sample size of other stone types are needed to evaluate the association between PFT and stone types. In addition, the relatively small sample size and short follow-up period represent other limitations of our study.To the best of our knowledge, we are the first to evaluate the association between PFT and the formation and recurrence of RSD in a Chinese population, which were significantly different from American or European populations in the distribution of obesity. In our study, the PFT of the stone-bearing kidney was higher than non-stone-bearing kidney. Moreover, high PFT and male sex were all associated with a higher risk of stone recurrence. We suggested that PFT may be a readily available and significant predictor of renal stone formation and recurrence. Nonetheless, we did not evaluate the potential mechanisms underlying the association between PFT and the development of RSD in our study, which is a limitation of our study in addition to its retrospective nature. Furthermore, the number of patients with UA stones was markedly small (PFT is a significant predictor factor of the formation and recurrence of RSD in a Chinese population. We suggest that this noninvasive and feasible parameter may help in the risk stratification of renal stone recurrence during the follow-up periods.Click here for additional data file.


Then, we used the training set data to build a classification decision tree model that would choose the most accurate equation from the four equations of BIS-2, CKD-EPI(CysC), CKD-EPI(Cr-CysC) and Ruijin, and the equation was selected by the model to estimate GFR. Next, we utilized the test set data to verify our tree model, and compared the GFR estimated by the tree model with other 13 equations. Root Mean Square Error (RMSE), Mean Absolute Error (MAE) and Bland–Altman plot were used to evaluate the accuracy of the estimates by different methods. A classification decision tree model, including BSA, BMI, 24-hour Urine protein quantity, diabetic nephropathy, age and RASi, was eventually retrieved. In the test set, the RMSE and MAE of GFR estimated by the classification decision tree model were 12.2 and 8.5 respectively, which were lower than other GFR estimation equations. According to Bland–Altman plot of patients in the test set, the eGFR was calculated based on this model and had the smallest degree of variation. We applied the classification decision tree model to select an appropriate GFR estimation equation for CKD patients, and the final GFR estimation was based on the model selection results, which provided us with greater accuracy in GFR estimation.Chronic kidney disease (CKD) has become a worldwide public health problem and accurate assessment of renal function in CKD patients is important for the treatment. Although the glomerular filtration rate (GFR) can accurately evaluate the renal function, the procedure of measurement is complicated. Therefore, endogenous markers are often chosen to estimate GFR indirectly. However, the accuracy of the equations for estimating GFR is not optimistic. To estimate GFR more precisely, we constructed a classification decision tree model to select the most befitting GFR estimation equation for CKD patients. By searching the HIS system of the First Affiliated Hospital of Zhejiang Chinese Medicine University for all CKD patients who visited the hospital from December 1, 2018 to December 1, 2021 and underwent Gate’s method of  With the increasing prevalence of diabetes, hypertension, hyperuricemia and other diseases, the incidence of CKD is also rising with the passing years7. Some investigations have shown that nearly 120 million people suffer from CKD, which accounts for about 10.8% of the total population in China8, whereas the data in Europe and the United States is more severe9. However, when CKD progresses to End Stage Renal Disease (ESRD), the medical and social problems associated with it become more prominent, and CKD may become one of the leading causes of death ranking second to ischemic heart disease, stroke, infection and COPD by 204011. Therefore, preventing the progression of CKD effectively has become a pressing medical problem.Chronic kidney disease (CKD) mainly refers to the irreversible damage of renal structure and (or) function caused by various etiological factors125I-iothalamate or Technetium-99m-diethylenetriaminepentaacetic acid (99mTc-DTPA) and other exogenous markers dynamic clearance in the body to determine the GFR. Although inulin is considered as ‘the gold standard’ for determining GFR, this method is too complex and expensive to implement12. Gate’s method of 99mTc-DTPA renal dynamic imaging, recommended by the Nephrology Committee of Society of Nuclear Medicine as well and served as a reliable method for determining GFR, was only used in some medical centers and could not cover all patients13. Therefore, various endogenous markers such as creatinine, cystatin C, and β2-microglobulin have been widely applied to assess renal function in patients, and various equations have been utilized to estimate Glomerular Filtration Rate (eGFR).Correct assessment of renal function in CKD patients is important to clinical treatment and the estimation of patients’ outcomes. As an indicator of glomerular filtration function, Glomerular Filtration Rate (GFR) is currently considered to be the most valuable parameter for assessing renal function in patients. However, measuring GFR in CKD patients is not a simple clinical procedure. At present the main method is to detect inulin, iohexol, 14. Marco van Londen et al. in a study of living kidney donors found that none of the current eGFR estimation equation can accurately estimate the donor's GFR, which is likely to underestimate the true rate of decline in GFR in 3 months–5 years after donation15. In addition, some equations customized for specific ethnic groups also showed huge deviations in the validation population in subsequent studies16.Although estimating eGFR via endogenous markers such as creatinine and cystatin C is a relatively conventional method, it is limited by the accuracy of the estimation equation. If eGFR deviates too much from the actual GFR, it will affect the clinician's judgment of the patient's condition and therapeutic regimen. For example, Yeli Wang et al. found that the CKD-EPI equation was not a reliable estimate of GFR in the South Asian populationTherefore, we believe that developing new equations for specific crowds or based on new endogenous markers may not be an optimal solution. In this study, we attempted to construct a classification decision tree model to select a more appropriate eGFR equations for CKD patients, and obtaining a more accurate estimate of glomerular filtration rate.We eventually collected 518 eligible subjects, 70% (362) of whom were assigned to training set to construct the discriminant model and 30% (156) to test set to verify whether the model is accurate or reliable. In this study, most CKD patients were over 50 years old, with an average age of 60.63. The number of males was slightly larger than females, accounting for 61.88% in the training set and 66.67% in the test set. However, kidney transplant patients were excluded in this study. Only about one-third of patients had a renal biopsy with a definite renal pathology diagnosis, and half of them were diagnosed with diabetic nephropathy. Among primary glomerular diseases, IgA nephropathy accounts for the highest proportion, which is about 20% of all pathologically confirmed patients. Our study also included a small subset (8.11%) of CKD patients, who were taking calcium dobesilate. They were always excluded from the development of GFR estimation equations because calcium dobesilate interferes with creatinine measurement and causes overestimation of glomerular filtration rate. Details of patients’ clinical and demographic data are shown in Table A total of 28 variables, including patient demographic data, past medical history, medication status, renal pathology results and laboratory measurement, were used to construct a classification decision tree model. Then we filtrated 15 relatively important variables and further selected the relative key variables to build the final classification decision tree model  equation. CKD-EPI (CysC) equation may be more suitable for CKD patients with higher BMI and BSA, which may be related to the fact that cystatin C is less affected by metabolic factors than creatinine.BSA, BMI, 24-hour urine protein quantity, diabetic nephropathy, age and RASi were selected to constitute the final classification decision tree model. As shown in Fig. 2 standard body surface area. Finally, we found that the estimated GFR of Ruijing, BIS-2, CKD-EPI, abbreviated MDRD and classification decision tree model approximated to the levels measured by 99mTc-DTPA  were far less than the other 10 equations, indicating a more accurate estimation , CKD-EPI (Cr-CysC) and Ruijin equations for specific population, showing a more precise estimation of GFR for CKD patients. MAE can better represent the accuracy of estimating GFR by the model, and the MAE of the classification decision tree model in the test set was only 8.5, which was much lower than other estimation equations  clinically diagnosed with CKD; (2) 99mTc-DTPA GFR was measured at the time of visit, and creatinine, cystatin C were available. Exclusion criteria included the following: (1) aged < 18 years; (2) underwent hemodialysis or peritoneal dialysis treatment within three months prior to the creatinine and cystatin C detection; (3) critical information, such as age and gender, was missing.This is a retrospective study. We searched the HIS system of the First Affiliated Hospital of Zhejiang Chinese Medicine University for all CKD patients who visited the hospital from December 1, 2018 to December 1, 2021 and underwent Gate’s method of In this study, we collected the patients’ demographic data , conditions related to renal disease , previous history , medication  and so on.Du Bois equation is used to calculate the body surface area (BSA).Serum creatinine level was detected by sarcosine oxidase method with reagents purchasing from Zhongsheng Beikong Biotechnology Co., LTD. . Cystatin C was detected by latex enhanced immunoturbidimetry with reagents purchasing from Zhejiang Content Biotech Co., Ltd. . 24-hour Urinary Protein Quantity was detected by pyrogali-molybdic method with reagents purchasing from Beijing Leadman Biochemistry Co., Ltd. . The detection instrument is Abbott's ARCHITECT C16000 automatic biochemical analysis system (c16000659), and the specific detection is completed by the Clinical laboratory of Zhejiang Hospital of Chinese Medicine.99mTc-DTPA renal dynamic imaging35, which used Single photon emission computed tomography scanner . 99mTc-DTPA was used as renal dynamic imaging agent with a dose of 185 MBq. 99mTC-DTPA renal dynamic imaging was performed in supine position and collected in posterior position. 99mTc-DTPA 185 MBq was injected intravenously, and the collection procedure was started at the same time. Both kidneys were collected continuously. Low energy collimator, window width 20%, matrix 64 × 64, energy peak 140 keV, magnification 1–1.5. Dynamic collection was carried out for 31 min. Blood perfusion phase was collected for 1 min at 2 s/frame, and functional phase was collected for 30 min at 15 s/frame. The radioactivity count of the syringe was measured before and after injection. After the imaging was completed, the left and right kidneys and the background were manually delineated using ROI technology to generate time-radioactivity curves and calculate glomerular filtration rate of both kidneys.GFR was measured by Gate’s method of 25–P75) and categorical variables were described as N (n %). All the patients were randomly divided into two groups: 70% subjects (362) into the training set and 30% (156) into the test set.All continuous variables were presented as the mean :In maleIn femaleCKD-EPI(CysC):In maleIn femaleCKD-EPI(Cr-CysC):In maleIn femaleAsian modified CKD-EPI(Cr):In maleIn femaleBIS-2:MacIsaac:Ruijin:Xiangya:BIS-2, CKD-EPI(CysC), CKD-EPI(Cr-CysC) and Ruijin) with GFR measured by 99mTc-DTPA to obtain eGFR estimation equation with the smallest deviation for each patient as the best matched estimation equation. Then, we constructed a classification decision tree model of the optimal estimation formula according to the age, sex, body surface area, BMI, whether having the unilateral nephrectomy, history of hypertension, diabetes, cardiovascular disease, cerebral infarction, cerebral hemorrhage, cancer, hyperuricemia, gout, edema, whether taking calcium dobesilate, SGLT2i, RASi, beprostaglandin sodium, glucocorticoids, immunosuppressants, diuretics, smoking history, drinking history, pathological results of kidney biopsy, creatinine, cystatin, 24-hour urine volume, 24-hour urine protein of training set patients. In the construction process of classification decision tree model, CRT algorithm was selected as the basic algorithm for our model construction, where entropy was used to represent the information purity of each leaf and nodes were disassembled according to the highest information increment  and Mean Absolute Error (MAE) to evaluate the estimation effect of the model in the training set and the test set respectively, and take the estimation effect of test set as our result.https://www.R-project.org/.) for data analysis. We used rpart (Terry Therneau and Beth Atkinson (2019). rpart: Recursive Partitioning and Regression Trees. R package version 4.1–15.) and ggplot2  packages to construct classification decision tree model and plot Bland–Altman diagram.We sued R, version 3.5.3 . We also confirm that all research processes are carried out in accordance with relevant guidelines and regulations and under the supervision of the ethics committee and other regulators. Because our study was a retrospective analysis using data from the hospital information system, intervention of the subjects was not involved. We hid all patient information at the beginning of the study, fully protect the rights and interests of patients. So, the ethics committee has approved that we can exempt informed consent.Supplementary Information 1.Supplementary Information 2.