A better understanding of how cardiorespiratory fitness (CRF) and adiposity interact to associate with arterial blood pressure over time remains inconclusive. Thus, the aim of the present study was to examine whether changes in CRF moderates the association between body fat percentage (BF%) and arterial blood pressure in children and adolescents.Projeto Esporte Brazil protocols and peak oxygen uptake (VO2peak) was estimated. BF% was determined by the measures of tricipital and subscapular skinfolds using equations according to sex. Systolic and diastolic blood pressure  were measured with a sphygmomanometer according to standard procedures. Moderation analyses included multiple linear regression models adjusted for sex, age, pubertal status, height, socioeconomic level, skin color, and the arterial blood pressure variable itself at baseline.This is an observational longitudinal study with 407 children and adolescents aged 8–17 years followed-up for three years from a city in Southern Brazil. Participants were evaluated in 2011 and 2014. CRF was measured by validated field-based tests following the 2peak at baseline with SBP (β = − 0.646 CI95% = − 0.976  − 0.316) and DBP (β = − 0.649 CI95% = − 0.923  − 0.375) at follow-up and a positive association between BF% at baseline with SBP  and DBP  at follow-up. In addition, results indicated a significant interaction term between changes in VO2peak and BF% at baseline with both SBP (p = 0.034) and DBP at follow-up (p = 0.011), indicating that an increase of at least 0.35 mL/kg/min and 1.78 mL/kg/min in VO2peak attenuated the positive relationship between BF% with SBP and DBP.It was observed a significant inverse association between VOCRF moderates the relationship between BF% and SBP and DBP in children and adolescents. The prevalence of hypertension has increased worldwide in the last years, affecting not only the adult population anymore. Evidence of a systematic review and meta-analysis show a global estimation prevalence of 4% and 10% of children and adolescents presenting hypertension and prehypertension, respectively  and prevDespite multifactorial origins , hyperteThis is an observational longitudinal study with participants from the Schoolchildren’s Health Study, which began in 2011. All children and adolescents enrolled in 25 randomly selected public  and private schools from Santa Cruz do Sul, Brazil, were invited to participate in the baseline assessment to be part of a cross-sectional study  , 10. AllThis study was approved by the University of Santa Cruz do Sul research ethics committee (nº 1.836.983) and it was conducted following Resolution 466/2012 of the National Council of Health in Brazil. The schoolchildren’s parents or legal guardians signed free and informed consent forms.All measurements were taken at University of Santa Cruz do Sul at baseline 2011) and follow-up (2014) periods. Arterial blood pressure was measured with a sphygmomanometer with appropriate brachial perimeter and a stethoscope were placed on their arm. Then, SBP and DBP were determined by manual auscultation, with the student sitting, resting for five minutes prior to measurement, which was made early in the morning. Each device had three different sized cuffs so that researchers could select the most suitable for each arm circumference. Two measurements on the right arm were made, and the lowest blood pressure recorded. All procedures were adopted following the VI Brazilian Guidelines for Hypertension [ and follThe BF% was determined through the measures of tricipital and subscapular skinfolds, evaluated using a Lange® caliper  by the same evaluator at both the 2011 and 2014 time points. Each skinfold was evaluated twice, and if the difference between measurements was higher than 2 mm, a third evaluation was performed. The lowest value was used for analyses. The BF% was calculated using equations of Slaughter et al.  accordinProjeto Esporte Brasil [Projeto Esporte Brasil [2peak) by the following equations: 9-min test → VO2peak = 47.547 + 0.008 * (Test) – 0.805 * (BMI) + 4.236 * (Sex) [6-min test → VO2peak = 41.946 + 0.022 * (Test) – 0.875 * (BMI) + 2.107 * (Sex) [test is the value of meters performed by the student; and sex equals to 1 and 0 for boys and girls, respectively.The CRF was assessed by the 9-min running and walking cardiorespiratory fitness test in 2011, described by e Brasil , and by e Brasil . The ind * (Sex) ; and 6-m * (Sex) ; where tInformation about age, sex, and skin color were obtained through a self-reported questionnaire. Height was measured on the anthropometric scale with a coupled stadiometer. The pubertal status was evaluated at follow-up using Tanner´s criteria . The part-test was used to verify differences between sexes, whereas the t-test for paired samples was used to verify differences between baseline and follow-up scores. Effect size (Cohen’s d) was calculated. Values of d < 0.39 indicated a small difference; 0.40 < d < 0.79 indicated a medium difference; and d > 0.80 indicated a large difference [2peak) and adiposity with blood pressure at follow-up. Moderation analyses were tested using multiple linear regression models through PROCESS macro, which is a program extension for the Statistical Package for Social Sciences (SPSS) version 24.0 . The following models were tested: a) associations between changes in CRF (VO2peak) with SBP and DBP at follow-up; b) associations between BF% at baseline with SBP and DBP at follow-up; c) Interactions between changes in CRF (VO2peak) and BF% at baseline with SBP and DBP at follow-up.Descriptive data are presented as means and standard deviations for continuous variables and absolute and relative frequencies for categorical variables. Initially, we adopted an exploratory analysis according to box-plot visual inspection, scatter-dot graphs to verify the behavior of variables concerning linearity and agreement; also all variables were checked for normality through the Shapiro–Wilk test. The independent student fference . Effect 2peak) moderated the relationship between BF% at baseline with SBP and DBP at follow-up. This technique verifies the association between the independent and dependent variable across different levels of the moderator variable . In the context of the current study, the technique highlights specific changes in CRF (VO2peak) cut point in which the significant relationship between BF% at baseline with SBP and DBP at follow-up appears or disappears. All analyses were adjusted for sex, age, pubertal status, height, socioeconomic level, skin color/ethnicity, and the dependent variable itself at baseline. The probability value p < 0.05 was considered as significant for all analysis.The Johnson-Neyman technique was used to probe interactions by assessing whether changes in CRF , considering the following parameters: test power (1-β) = 0.95, a significance level of α = 0.05, and effect size of 0.05. The number of predictors considered was 10, and the minimum number of participants was established as 348. However, to avoid probably difficulties with sample loss, an increase of 15% was assumed, totaling 400 children and adolescents.2peak , SBP and DBP , as well as lower BF%  at follow-up, while girls showed higher VO2peak , SBP  and DBP  at follow-up. In addition, boys had lower BF%  and higher VO2peak at both baseline and follow-up  than girls. Lastly, boys exhibited a higher decrease of BF% and a higher increase of VO2peak compared to girls, whereas girls exhibited a higher increase of SBP (d < 0.39).The general sample characteristics of the whole sample and stratified by sex are presented in Table 2peak at baseline with SBP and DBP at follow-up and a positive association between BF% at baseline with SBP and DBP at follow-up, after adjustments for sex, age, pubertal status, height, socioeconomic level, skin color, and the arterial blood pressure variable itself at baseline. Also, change in VO2peak was negatively associated with SBP and DBP following the same adjustments, whereas changes in BF% showed no relationship with both arterial blood pressure variables . A second major strength was the use of a relatively large randomly selected sample of Southern Brazilian school-aged children and adolescents obtained at two time-points across a 3-year time span. In addition, there are few longitudinal studies that demonstrate the association between CRF, BF%, and arterial blood pressure in the pediatric population. However, some limitations also should be pointed out, the use of both 6- and 9-min running and walking tests to evaluate CRF, to minimize this limitation the estimation of VO studies , 27. TheChanges in CRF moderated the association between baseline BF% with arterial blood pressure at follow-up. Therefore, our findings highlight the need of enhancing CRF levels over time, once it may exert a protective role on arterial blood pressure levels, even when considering the deleterious influence of adiposity.


In summary, the risk of kidney disease progression was relatively higher in patients with PKD compared to other causes of CKD. However, the composite of CVD and death was relatively higher in patients with DN-related CKD than in those with GN- and HTN-related CKD.The causes of chronic kidney disease (CKD) affects its outcomes. However, the relative risks for adverse outcomes according to specific causes of CKD is not well established. In a prospective cohort study from KNOW-CKD, a cohort was analyzed using overlap propensity score weighting methods. Patients were grouped into four categories according to the cause of CKD: glomerulonephritis (GN), diabetic nephropathy (DN), hypertensive nephropathy (HTN), or polycystic kidney disease (PKD). From a total of 2070 patients, the hazard ratio of kidney failure, the composite of cardiovascular disease (CVD) and mortality, and the slope of the estimated glomerular filtration rate (eGFR) decline according to the cause of CKD were compared between causative groups in a pairwise manner. There were 565 cases of kidney failure and 259 cases of composite CVD and death over 6.0 years of follow-up. Patients with PKD had a significantly increased risk for kidney failure compared to those with GN [Hazard ratio (HR) 1.82], HTN (HR 2.23), and DN (HR 1.73). For the composite outcome of CVD and death, the DN group had increased risks compared to the GN (HR 2.07), and HTN (HR 1.73) groups but not to the PKD group. The adjusted annual eGFR change for the DN and PKD groups were − 3.07 and − 3.37 mL/min/1.73 m Although CKD patients share similar pathophysiologies involved with the kidney disease progression, the course and speed of CKD progression and associated complications differ according to the underlying causes. Therefore in the KDIGO guidelines, the cause of CKD is considered one of the important predictors of the outcome, together with other variables such as the glomerular filtration rate category, the albuminuria category, and other comorbid conditions5. However, the relative risk for adverse outcomes according to the specific cause of CKD has not been well studied6. Direct comparisons of outcomes according to the specific cause of CKD are important to understand the natural progression of CKD and to characterize possible complications according to the cause of CKD. This is critical for CKD management during the predialysis period, both to slow progression and to improve long-term outcomes. In addition, this knowledge can help determine high-risk groups among the CKD population so that resources can be prioritized and therapies can be more targeted.Chronic kidney disease (CKD), which is rapidly increasing in prevalence and incidence, is a heterogeneous set of diseases caused by various risk factors and comorbid conditions10. However, previous studies did not cover all of the major CKD etiologies or stages or address all major outcomes. Due to the limitations, the results cannot be extrapolated to the entire adult CKD population.A few studies have investigated relative risks for adverse outcomes in the CKD population according to specific causesIn this study, we analyzed the hazard ratio for kidney progression and the composite outcome of cardiovascular disease (CVD) and all-cause mortality according to the cause of CKD in a prospective cohort. To investigate the effects of the causes of CKD on the outcomes, overlap weighted methods were used to adjust for the possible confounding factors. Additionally, we analyzed the annual rates of estimated glomerular filtration (eGFR) decline according to the cause of CKD to determine kidney progression patterns according to CKD etiology.11. Patients were classified into four groups according to the specific cause of CKD at enrollment: glomerulonephritis (GN), diabetic nephropathy (DN), hypertensive nephropathy (HTN), and Polycystic kidney disease (PKD). Each group classification was determined based on pathologic diagnosis if a biopsy result was available . Otherwise, group classifications were based on clinical diagnoses. The biopsy-proven GN consisted as following – 40% IgA nephropathy, 7% focal segment glomerular sclerosis, 6% membranous nephropathy, 5% crescentic GN, 2.4% minimal change disease, and 1.5% lupus nephritis. Non-biopsy-proven GN was defined as the clinical history manifesting chronic GN and the presence of albuminuria or glomerular hematuria with or without an underlying systemic disease causing GN. The active GN population taking immunosuppressant at enrollment was excluded to minimize the heterogeneity by treatment. Diagnosis of DN was strictly based on albuminuria in a patient with type 2 diabetes and the presence of diabetic retinopathy. To exclude DN patients who may have combined GN, diabetic patients with glomerular hematuria were not included in the DN group. HTN was diagnosed by a history of hypertension and the absence of a systemic illness associated with kidney damage. Only the patients with proteinuria < 1.5 g/day and a proportion of urine albumin < 50% of urine protein were included in HTN to exclude the GN population. To diagnose PKD, unified ultrasound criteria were used12. Other causative diseases was categorized as ‘unclassified’ and excluded from our analysis.This was a longitudinal study of a prospective cohort of CKD patients in Korea, called KNOW-CKD (KoreaN cohort study for Outcome in patients With Chronic Kidney Disease). KNOW-CKD is a multicenter prospective cohort study that enrolled adult predialysis patients with CKD stages G1 to G5A total of 2238 patients enrolled in the study from April 2011 to February 2016. After excluding patients with unclassified etiology or without follow-up data, 2070 patients were finally analyzed in this study for survival analysis with follow up until March 31, 2020. To determine the annual eGFR change and trajectory, we included only those patients (n = 1952) with more than two creatinine measurements  using an isotope dilution mass spectrometry-traceable method. For eGFR, the CKD -EPI equation based on serum creatinine was usedBoth kidney failure and the composite of kidney failure and/or creatinine doubling were used as kidney outcomes. Kidney failure was defined as starting maintenance dialysis (required for longer than 3 months) or receiving kidney transplantation. Another outcome was the composite outcome of CVD and all-cause death. CVD was defined as any first event of the following that needed hospitalization, intervention, or therapy during the follow-up period : acute myocardial infarction, unstable angina which needed admission due to aggravated coronary ischemic symptoms, percutaneous coronary artery intervention or coronary bypass graft surgery, ischemic or hemorrhagic cerebral stroke, cerebral artery aneurysm, congestive heart failure, symptomatic arrhythmia, aggravated valvular heart meant by requiring hospital admission, any pericardial disease that required hospital admissions such as pericarditis, pericardial effusion, or cardiac tamponade, abdominal aortic aneurysm, or severe peripheral arterial disease Table .14. Overlap weighting is a PS method that tries to mimic important attributes of randomized clinical trials. This method can overcome the potential limitation of adjusting the difference in measured characteristics using classic PS methods of inverse probability of treatment weighting (IPTW). Overlap weighting overcomes these limitations by assigning weights to each patient that are proportional to the probability of that patient belonging to the opposite group15. PSs were calculated using a logistic model with the following variables since they showed significant differences among the four groups: age, sex, body mass index, CKD stage, mean blood pressure, CVD, hemoglobin, serum uric acid, calcium, phosphorous, albumin, total cholesterol, high-density lipoprotein, low-density lipoprotein, fasting blood sugar, intact parathyroid hormone, urine protein-to-creatinine ratio, high-sensitivity C-reactive protein, diuretics use, statin use, and angiotensin converting enzyme inhibitor or angiotensin receptor blocker use in this study. The log10 transformed values were used for PS calculation with the non-normally distributed variables such as parathyroid hormone, urine protein-to-creatinine ratio, and high sensitivity C-reactive protein. The patients in the compared group were weighted by the probability of the reference group (1-PS), and the patients in the reference group were weighted by the probability of the compared group (PS). For two groups of CKD causes, we applied the overlap weighting method to each set, resulting in a total of 6 sets. To visually compare distributions of balance, the density plots were created  and 95% confidence intervals (95% CI). To estimate annual eGFR change, generalized linear mixed models were constructed with random intercepts and slopes with an unstructured model for the correlation structure. The results were expressed as estimates (standard errors). In the adjusted models, the variables used in PS score calculation were further adjusted. Spaghetti plots showing the individual trajectories of eGFR during follow-up were drawn to determine patterns of eGFR decline according to cause of CKD. P for the quadratic term was tested using polynomial mixed models with random intercepts and slopes. A P value less than 0.05 was considered statistically significant. SAS 9.4  and R version 3.5.3  were used.The chi-square test or Anova was used to compare the baseline characteristics. Non-normally distributed variables such as parathyroid hormone, urine protein/creatinine, and high sensitivity C-reactive protein were compared by Kruskal–Wallis test. The four groups had significant differences in baseline characteristics including age and baseline eGFR; we therefore used the overlap propensity score (PS) weighting method to minimize the effects of confounding factors on outcomesd Figure . Additio2. By CKD classification, 38.6% of patients were diagnosed with GN, 24.5% with DN, 19.5% with HTN, and 17.4% with PKD.The mean age of the population was 53.5 ± 12.2 years and 38.7% of subjects were female from a total of 2070 patients. At study entry, the mean eGFR of all total patients was 53.2 ± 30.8 mL/min/1.73 mP < 0.001). The proportion of males and the prevalence of pre-existing CVD was higher in the DN  and HTN  groups than in the GN  and PKD  groups (P < 0.001 for both). Mean eGFR was lower in DN (36.4 ± 21.8 mL/min/1.73 m2) and HTN (42.3 ± 21.9 mL/min/1.73 m2) groups than GN (60.1 ± 31.4 mL/min/1.73 m2) and PKD (72.7 ± 32.8 mL/min/1.73 m2) groups (P < 0.001). After overlap weighting for each 6 sets, the statistical differences between groups disappeared in all variables  kidney failure events and 723 (34.9%) composite kidney events. There were 259 (12.5%) events of the composite of CVD and death. The specific cause of CVD and death were summarized in Table P = 0.169). Similar results were obtained for DN in multivariate Cox regression analyses. PKD showed increased risk of the composite of CVD and death compared to GN  and HTN  in the Cox regression analysis. In the cause-specific regression analysis, PKD showed a significantly higher risk of the composite outcome of CVD and death compared to GN  however, the significance disappeared in the set with HTN (P = 0.334) , HTN , and DN  in Cox regression analysis. However, the DN, HTN, and GN groups did not show a significant difference in the risk of kidney failure or composite kidney outcome compared to each other . The overall rate of annual eGFR decline was also fast in the DN group, ranging from − 3.87 to − 2.68 mL/min/1.73 m2 per year for stages G1 to G4. In the HTN group, rates of annual eGFR decline were slow for stages G2 to G3b but eGFR declined slightly faster in stages G4 and G5. In the GN group, rates of annual eGFR decline were faster in the more advanced CKD stages. When we visualize the trajectory patterns of eGFR decline, CKD etiologies were classified into two groups: the DN group (P for quadratic term = 0.608) group showed a linear decline pattern in eGFR, while the GN, HTN, and PKD groups  showed a convex decline pattern with the acceleration of the annual eGFR decline as the eGFR lowered  cohort data reported the relative risks of a few adverse outcomes according to the CKD etiologies9. The CKD in Children (CKiD) study compared the rate of progression of kidney disease according to the cause of CKD in children10. However, the results from these studies are difficult to generalize to the entire CKD population because they include only a subset of the major CKD etiology or analyzed for only some of the major outcomes. This might be due to the difficulty of the study design and analysis technique since many risk factors of kidney disease progression are related to the cause of CKD and can act as potential confounders.The KDIGO Guideline states that the cause of CKD should be considered as one of the important predictors of the outcome16. Several studies adopted this method to analyze the effect of sex, cancer type, monitoring or treatment on the outcome between groups with significant differences in baseline characteristics20. By employing this method, we could analyze the hazard ratio for the outcomes between two groups of CKD causes after adjusting for potential confounders. The result showed that patients with PKD had significantly increased risks for kidney outcomes compared to other CKD causes. Surprisingly, the DN group did not show an increased risk of kidney failure compared to other CKD causes. However, the patients in the DN group showed worse outcomes regarding the composite outcome of CVD and mortality compared to the HTN and GN groups. The high risk of CVD and death in the DN group shown in this study was consistent with other well-known studies22.In this prospective cohort study, we compared the relative risks of both kidney outcomes and the composite outcome of CVD and death according to the cause of CKD. Patients were classified into GN, HTN, DN, or PKD groups based either on pathologic diagnoses or clinical judgement criteria at study entry. The baseline characteristics differed according to the cause of CKD in our study population. To overcome this limitation, we used the overlap weighting method. This is particularly advantageous when the comparator groups are initially very different from each other and can achieve good balance and minimize the variances as shown in previous studies24. This could be due to differences in baseline clinical characteristics, including CKD stages, PKD genotypes and/or effects of ethnicity. In this study, there are both early and advanced stage PKD patients in our cohort (about 60% were stage G1 or G2) whereas PKD patients in CRISP and HALT studies only included early stage CKD patients and MDRD study enrolled only advanced stage CKD patients24.We further analyzed the rates of annual eGFR decline to better understand kidney disease progression patterns according to the specific causes of CKD. The rate of GFR decline was faster in the DN and PKD groups compared to the GN and HTN groups. The DN and HTN population had a similar rate of annual eGFR decline to that shown in previous reports; however, the annual rates of decline of eGFR in the PKD group was relatively slower in our study than those reported in previous studies24. Therefore, more efforts on early detection, assessment, and proper management of PKD-related risk factors such as genotype, kidney volumes, hypertension, and kidney-related complications may improve individual PKD patients’ kidney outcomes in the future.Although the annual eGFR declining rate in the PKD group was slightly slower than in previous reports, patients in the PKD group showed the poorest kidney outcomes compared to those with other causes of CKD. The annual rate of eGFR decline was the fastest in the PKD population. The PKD group showed an increased risk of kidney failure with HRs of 1.73, 1.8 and 2.2 compared to the DN, GN, and HTN groups, respectively. This is a similar result to previous reports22. These differences between CVD and kidney outcomes in DN population shown in the previous studies and in our study suggest that different pathophysiology would exist between CVD or mortality and kidney progression.In our study results, the risk of poor kidney outcome was not increased in the DN group, compared to other CKD causes when the confounding factors were adjusted using the overlap weighting methods. This implies the importance of managing the common risk factors and comorbidities in the DN population. However, the risk of CVD and mortality was significantly increased in the DN group compared to the GN and HTN groups. The high risk of CVD and death in the DN population is well known and there have been efforts to find out effective treatments to improve the outcome. However, the strict control of blood glucose levels showed improvement in kidney outcomes but did not in the CVD or death25. However, in the PKD group events due to cerebral aneurysm and infection were the most frequent cause of CVD and death, respectively which correspondence with previous studies26.The CVD and mortality risk was also higher in the PKD population than the GN and HTN population. The PKD group had a similar risk of CVD and mortality to the DN group, but the specific causes of CVD and mortality were different between PKD and DN groups. In the DN group, about 43% of the composite of CVD and mortality were major adverse cardiovascular events such as acute coronary syndrome, coronary revascularization, ischemic stroke, or heart failure which were known major CVD events from the previous studies27. In DN population, there was a linear association between eGFR and age over time in overall27. In PKD population, a non-linear curved eGFR trajectory was seen regardless of the kidney growth rate23. In this study, we observed the kidney deterioration pattern and acceleration time differed according to the cause of CKD using a prospective longitudinal cohort. Therefore, patient follow-up and monitoring strategies should be individualized according to the CKD stages, and cause of CKD.In this study, we further analyzed eGFR decline patterns according to the cause of CKD. A linear eGFR trajectory was observed in DN group, and the rate of annual eGFR decline was faster in the earlier CKD stages. GN, HTN, and PKD groups showed faster annual eGFR declining in advanced CKD stages. This result is similar to the previous studies that reported trajectory eGFR decline of DN and PKDThis study has several advantages over existing studies in providing important information about the natural course of CKD progression and extrarenal complications according to CKD etiology. Here, we provided basic information about the hazard ratio of major outcomes from four major causes of CKD within a prospective cohort followed over a long-term period. Robust and up-to-date statistical methods were used to compare the relative risk of major outcomes by the causes of CKD after adjusting for possible confounders. The group size of PKD and GN were big enough for the comparison and statistics. CKD patients older than 18 years with any CKD stage were enrolled to reflect the overall CKD population.28. The overall CVD incidence is similar to that of the Japanese CKD cohort (CKD-JAC) and this might be the characteristic of the Asian CKD population29. Since this is a result from a cohort of Asian CKD patients, the present study warrants further investigation for patients of non-Caucasian ethnicity. Finally, a group with a different composition of GN subtypes may have shown different hazard ratio compared to the other CKD groups evaluated in this study.Although, there are several limitations to this study. Baseline characteristics differed among groups. Therefore we used the overlap weighting method to adjust for possible confounding factors. However, there may still have been residual confounders that affected our findings. Furthermore, the etiologic diagnoses of CKD were based on clinical criteria rather than pathologic diagnoses for many patients. Thus, some clinically diagnosed patients might have been misclassified. The issue due to cross-group events, such as the occurrence of new GNs during follow-up in patients in the HTN group, was not considered in the analysis of this study. We could not analyze the risk of each individual type of cardiovascular event or focused on major adverse cardiovascular events since the overall incidence of CV events was relatively lower in our cohort, compared to the Western CKD cohortsWe found that patients with PKD had higher risk of kidney progression than patients with DN, GN, or HTN. After adjustment, the DN group did not show an increased risk of kidney failure but had a higher risk of CVD and mortality than patients with GN and HTN. Our findings support the importance of individualized monitoring and management of CKD patients based on the etiology and stage of CKD.Supplementary Information.


Diabetic kidney disease (DKD) has been well recognized as a microvascular complication of diabetes mellitus. Perfusion of intrarenal arteries is closely related with development of DKD. The aim of the present study was to investigate relation of ultrasonography performance of intrarenal arteries and grade of DKD.  From May to December at 2021, a total of 54 DKD patients and 36 non-DKD cases were recruited. Ultrasonography performance of intrarenal and arteries at lower extremity was examined by high-resolution ultrasound diagnostic equipment; maximum (Vsmax) as well as minimum (Vdmin) blood velocity of arteries were recorded, and resistance index (RI) of arteries were calculated. Blood routine and biochemical parameters were determined from clinical laboratory of our hospital.  According to eGFR grading, 42.50% of the 54 DKD cases are at Grade 1, and 18.52%, 11.11%, 9.26%, and 18.52% cases were at Grade 2, 3a, 3b, and 4-5, respectively. Blood urea and creatinine were significantly positively related with progress of DKD, while level of Hb was negatively related with DKD. By ultrasonography; we found that Vsmax and Vdmin of main renal artery (MRA), segmental renal artery (SRA), and interlobular renal artery (IRA) were significantly reduced compared with healthy cases; IR of the above arteries was dramatically elevated, and changes of the above data were more obvious than that of lower extremity. Vdmin of MRA, SRA, and IRA was negatively related with grading of DKD, while RI was positively related with the grading. Converging from RI and level of Hb, we found that the level of Hb is positively related with healthy status of the kidney, while RI of the arteries is negatively with that.  Resistance index (RI) of intrarenal arteries, obtained from ultrasonography combining with level of hemoglobin (Hb), is the predictor of progress of DKD. With the world population aging progress, diabetic kidney disease (DKD) has become a leading contributor to end stage of renal failure (ESRF) . It is eClinically, DKD is arbitrarily diagnosed with appearance and content of proteinuria. For instance, once the urine protein exceeds 300 mg/L or microalbuminuria above 30-300 mg/day, the patients will be clinically diagnosed . HoweverDKD has been well recognized as a microvascular complication of diabetes mellitus. Lesion of the vascular wall and decrease of tissue perfusion is the central event during development of vascular disease as well as DKD, and they are positively related with development of DKD. Therefore, seeking a technique that reflects their early changes in cases with diabetes might help early diagnosis of DKD. In the present study, we compiled vascular perfusion of kidney and function of peripheral arteries using ultrasonic diagnosis, and further investigated relationship between grade of DKD and ultrasonic performances. Our current study may supply an noninvasive method and strategy for early diagnosis of DKD in diabetes cases.All study population were recruited from Department of Nephrology of our hospital from May to December 2021. In general, all newly in-hospitalized DKD cases during the above period that met with the following criteria were included, and all recruited volunteers with non-DKD during this period were included. Finally, a total of 54 DKD patients  aging from 28 to 84 years old (age = 57.72 ± 12.29) and 36 non-DKD cases  aging from 21 to 72 years old (age = 46.78 ± 11.69) were included. All included cases have signed informed consent before study. All study plan, data collection, and ultrasonic operation were approved by Ethics Committee of Guangdong Provincial Hospital of Traditional Chinese Medicine .The inclusion criteria for DKD were as follows: (1) age ≥ 18 years old; (2) DKD was diagnosed according to clinical practice guideline of Kidney Disease Outcome Quality Initiatives (K/DOQI) . Staging of DKD is as follows: (1) Grade 1: eGFR ≥ 90; (2) Grade 2: 89 ≥ eGFR ≥ 60; (3) Grade 3a: 59 ≥ eGFR ≥ 45; (4) Grade 3b: 44 ≥ eGFR ≥ 30; (5) Grade 4: 29 ≥ eGFR ≥ 15; (6) Grade 5: eGFR < 15.All laboratory data were obtained from clinical laboratory of Guangdong Provincial Hospital of Chinese Medicine-Zhuhai Hospital. Estimated glomerular filtration rate (eGFR) was determined according to the following equation: eGFR = 186 × ScrReal-time ultrasonography at B-mode was carried out in each participant using a high-resolution ultrasound diagnostic equipment (Phillips) by well-trained and validated examiners. Maximum (Vsmax) as well as minimum (Vdmin) blood velocity of arteries of lower extremity including common femoral artery (CFA), superficial femoral artery (SFA), popliteal artery (POA), anterior tibial artery (ATA), posterior tibial artery (PTA), peroneal artery (PEA), dorsalis pedis artery (DPA), arteries within the kidney including main renal artery (MRA), segmental renal artery (SRA), and interlobular renal artery (IRA), at both sides were recorded. Resistance index (RI) of the arteries was obtained according to the following equation: RI = (Vsmax − Vdmin)/Vsmax. Mean value of the right and left side of the above values were obtained for further analysis.t-test or one-way ANOVA. Multiple linear regression of the data was obtained by GraphPad Prism 9. P values <0.05 is considered to be statistically significant.Data are expressed as mean ± SD or otherwise indicated. Data are analyzed by GraphPad Prism 9 using A total of 36 healthy as well as 54 DKD cases were included in this study. Within the DKD cases, 42.59% were female, and 62.96% were between 41 and 65 years old . AccordiP < 0.001 vs. ctl). These data suggested that renal perfusion was reduced in DKD.To firstly evaluate haemorheological changes of renal arteries for DKD cases, maximum (Vsmax) as well as minimum (Vdmin) blood velocity of main renal artery (MRA), segmental renal artery (SRA), and interlobular renal artery (IRA) were recorded. As shown in P < 0.05 vs. ctl), but no statistical significance was found for Vsmax in other arteries at lower extremity.To further determine changes of arteries in lower extremity, Vsmax in common femoral artery (CFA), superficial femoral artery (SFA), popliteal artery (POA), anterior tibial artery (ATA), posterior tibial artery (PTA), peroneal artery (PEA), and dorsalis pedis artery (DPA) was analyzed. As shown in Converging with the above data, ultrasonic changes of CFA as well as arteries within the kidney were related with DKD to some extent.″3″. No statistical significance was found in Vsmax or ultrasonographic changes of CFA concerning their relation with DKD grading.To explore relation of ultrasonographic changes of CFA and arteries within the kidney of with grading of DKD, Vsmax, Vadmin as well as RI of the arteries were analyzed. As shown in Converging from the above data, we can conclude that Hb and RI are two pivotal parameters that closely related with grading of DKD. To further define correlation among the data above, multiple linear regression analysis was conducted. As shown in With the aging progression around the world, diabetic kidney disease (DKD) has becoming one of the major reason that contributes to end stage renal disease (ESRD). Although it has been well recognized that early-diagnosis is pivotal to inhibit progression of DKD, a noninvasive, real-time, and dynamic method that reflect status of the kidney is still rare. In the present study, we supplied an equation that reflect correlation among eGFR, resistance index of arteries within the kidney, and level of Hb. Our present finding may help clinicians for early diagnosis and treatment of DKD.It was reported that about 30-40% of cases with type 2 diabetes mellitus are likely to have kidney lesion ; more imIt has been well recognized that decreased perfusion of the kidney plays a key role in the development of DKD . A findiIt has been well understood that hemoglobin (Hb) production is closely related with secretion of erythropoietin (EPO). Recent findings have found reduced EPO, and anemia are independent risk factors for microvascular diseases including DKD –17. In tIt should be noted that as there is still no well recognized ultrasonography that predict progress of the damage of kidney; the current finding is just an alternative for clinicians, and it cannot replace the gold standard of biopsy on diagnosis of renal damage. On the other hand, recent advances in finding biomarkers of early DKD in diabetic population by omics and molecular-biology also supplied an alternative method. For instance, long noncoding RNAs (lncRNAs) have been suggested to play a role in early development of DKD , and glyIn summary, we show in the present that resistance index (IR) of intrarenal arteries obtained from ultrasonography combining with level of hemoglobin (Hb) are predictor of grading DKD. Our present finding supplied an alternative and noninvasive method for early diagnosis of DKD.


Implant-supported removable partial dentures (ISRPDs) provide effective prosthodontic treatment for partially edentulous patients. ISRPDs offer greater patient satisfaction and better oral function compared with removable partial dentures (RPDs) by enhancing denture stability and support. However, few clinical studies have focused on RPD design in patients with mandibular Kennedy Class II edentulism. The aim of this case reports was to investigate the oral function, oral health-related quality of life, and satisfaction of four patients with unilateral distal-extension mandibular RPDs with the same design which were replaced with ISRPDs. In addition, we investigated how each patient’s evaluation varied with the change from RPD to ISRPD.Four patients had unilateral distal-extension mandibular edentulism and were missing the first and second molars and the first and second premolars. They received one implant  at the position equivalent to the first molar in the edentulous residual ridge perpendicular to the occlusal plane. Implant position was determined by surgical guide plate. RPDs were fabricated after the residual mucosal membrane had healed. The basic design of the RPD was as follows: a cobalt–chromium alloy cast metal framework denture with a lingual bar as the major connector, a double Akers clasp on the molars and an auxiliary retainer on the premolar as indirect retainers, and a wrought wire clasp and a cast cingulum rest (combination clasp) as direct retainers. Masticatory performance, occlusal force, oral health-related quality of life, and satisfaction were estimated at baseline, and at time points after insertion of the RPD and after insertion of the adapted ISRPD. Each evaluation item showed a tendency for improvement on insertion of the new RPD. Masticatory performance and satisfaction tended to be better after insertion of the ISRPD than after insertion of the RPD.Our findings suggest that ISRPDs provided better patient satisfaction and masticatory performance than RPDs in patients with mandibular Kennedy Class II edentulism.Trial registration UMIN Clinical Trials Registry and Japan Registry of Clinical Trials, UMIN000025283 and jRCTs012180003. Registered 19 February 2016 and 17 December 2018, https://www.umin.ac.jp/ and https://jrct.niph.go.jp/ Many previous studies have reported on the effectiveness of implant-supported removable partial dentures (ISRPDs) for partially edentulous patients. According to a review and meta-analysis by Park et al. , ISRPDs Therefore, the aim of this pilot case report was to investigate masticatory performance, occlusal force, OHRQOL, and satisfaction in patients with unilateral distal-extension mandibular edentulism who have been fitted with ISRPDs with the same RPD design concept in a small sample. In addition, we investigated how each patient’s evaluation varied when changing from an RPD to an ISRPD.Four patients  with a mean age of 70 ± 7.5 years who had unilateral distal-extension mandibular edentulism and were missing the first and second molars and the first and second premolars received dental implants and ISRPDs at the department of Removable Prosthodontics, Hokkaido University Hospital, from December 2016 to March 2021. None of the patients had complete maxillary dentures, temporomandibular disorders, xerostomia, poor oral hygiene, or any serious systemic diseases. All patients had previous mandibular denture before registration in this study.The following information was collected for each patient: age, sex, number of remaining teeth and occlusal support, and Eichner classification. We obtained the patients’ information, masticatory performance, occlusal force, OHRQOL, and satisfaction at baseline (BL) . The patients’ BL information is shown in Table Each patient received an implant  at the position equivalent to the first molar in the edentulous residual ridge perpendicular to the occlusal plane. Implant position was determined by surgical guide plate. The RPDs were fabricated after the residual mucosal membrane had healed. The basic design of the RPD is shown in Fig. At 3 months after insertion of the RPD (R1), masticatory performance, occlusal force, OHRQOL and satisfaction were measured. A second surgery was then carried out and a 5.0-mm-high healing abutment was connected to the implant body. The denture base of the ISRPD was relined to contact with the top of the healing abutment with acrylic resin , and relieve around abutment. The healing abutment served a role in supporting the denture. At 3 months (IS1), 6 months (IS2) and 12 months (IS3) after fitting the ISRPD, masticatory performance, occlusal force, OHRQOL and satisfaction were again measured.Additionally, the information on adverse events from implant placement to the end of the observation period, 30th September 2022, was collected.® 16.2.0  with a significance level of 0.05.All time points were compared using the Wilcoxon signed rank test about every evaluation. All statistical analyses were performed using JMPThe patients’ reported outcomes were recorded for OHRQOL and the degree of satisfaction with the treatment.OHRQOL was measured using the Oral Health Impact Profile (OHIP) , 6. ThisSatisfaction with esthetics, pain, comfort, stability, speaking, and mastication as well as general satisfaction was measured using a 100-mm linear visual analog scale (VAS) .Oral function (masticatory performance) was assessed by using a gummy jelly and measuring occlusal force with a pressure-sensitive sheet.The patients were asked to chew a gummy jelly  for 20 s . They weOcclusal force was measured with a pressure-sensitive sheet . The patients sat in a dental chair with their occlusal plane parallel to the floor. The sheet was placed along the maxillary dentition. They were instructed to clench on the sheet with maximum force in the intercuspal position for 3 s. Then, the occlusal force was measured with a computerized imaging scanner . The occlusal force test was performed three times, and the mean of the results was used for the analysis .Written informed consent was obtained from the patients for publication of this study. The study protocol was approved by Hokkaido University Certified Review Board .The results for each evaluation item indicated an improvement with the insertion of the new RPD. Masticatory performance was better after the ISRPD was fitted than after the initial insertion of the RPD. The improvement in masticatory performance was greater on the prosthesis side than on the natural dentition side. Masticatory performance remained stable between R1 and IS3.Occlusal force varied greatly due to individual differences, and the effect of fitting the ISRPD could not be clearly shown. However, when Case 3 was excluded, the ISRPD improved occlusal balance on both sides.In Case 4, the OHIP-49 summary score improved from 111 to 23 points on insertion of the RPD. In the other cases, there was little change in the scores; the mean values revealed a tendency for improvement, but the influence was less than that in Case 4.All satisfaction evaluation scores improved with the insertion of the RPD. Scores for esthetics, speaking, and pain remained much the same with the change from RPD to ISRPD, while the other scores improved. Satisfaction levels at IS3 were maintained from R1 to IS3, except in Case 3.There was no significant difference among the time points for masticatory performance, occlusal force, OHIP scores, and VAS scores due to the extensive individual differences. In addition, masticatory performance, occlusal force, OHRQOL and satisfaction tended to improve with the insertion of the new RPD, but no significant change was observed after fitting of the ISRPD. However, the masticatory performance on the prosthetic side tended to improve with the insertion of the ISRPD.Swelling after surgery of located implant occurred in all cases, but all healed. In addition, there was a case in which medication was required due to swelling of the surrounding gingiva after insertion of the healing abutment in Case 1. Loosening of healing abutments were occurred in Case 1 and 4.All patients were cured by adjusting the dentures, while they complained of discomfort and pain at insertion of new dentures. Adverse events after ISRPD insertion are shown in Table This study was a pilot case study in patients with mandibular unilateral distal-extension edentulism (Kennedy Class II) to investigate the effect of the treatment with RPDs and ISRPDs on patients’ reported outcomes and oral function in a small sample.Because many previous ISRPD studies , 11 haveThere was no statistically significant difference in the treatment effect between the RPD and the ISRPD. However, OHRQOL at the 3 months after the insertion of the RPD or ISRPD tended to be higher than at the baseline. This improvement in OHRQOL could be accomplished by wearing a properly designed RPD with sufficient support, retention, and stability using a metal framework. It is reported that the minimal clinically important difference is 14 points in the OHIP-49 . The varHowever, one study  reportedIn terms of patient satisfaction, all outcomes after treatment with an RPD tended to be better than those before treatment. RPDs and ISRPDs tended to achieve similar results for speaking, esthetics, and pain. For these outcomes, the effect of strengthening the denture support with dental implants might be small. Additionally, patient satisfaction in terms of mastication, comfort, and stability tended to be better in ISRPDs than in RPDs. These factors would be directly influenced by suppressed denture movement by a dental implant in the edentulous space.Masticatory performance tended to improve after RPD insertion in comparison with the that at baseline, and improved even further after ISRPD insertion. The improvement of masticatory performance was greater on the edentulous side. It is highly probable that denture movement was suppressed by the dental implant in the edentulous space, which contributed to the improved function , 3.Occlusal force tended to be a higher after insertion of a new RPD than at baseline. The occlusal force on the natural dentition side also tended to decrease from R1 to IS3, but there was no significant difference among the time points. Additionally, taking the mean values into account, the amount of change in the occlusal force was not large, and the balance of occlusal force between the natural dentition side and the prosthesis side would be practically equal. Murakami et al.  reportedIn this case report, dental implant was inserted at the part corresponding to the first molar position. It is not clear how the implant position affects clinical effects in Kennedy Class II. There is the experimental study that the distally implant position suppresses the movement of the denture, and the medially implant position suppresses the movement of the abutment tooth , 14. In The weighted mean cumulative survival rate of the implants with ISRPDs in mandibular Kennedy Class I was reported at 96.60% (95% CI = 92.97–98.79) . There wThis study was a pilot case report with a small sample size for a large-scale interventional clinical trial. Because clinical evidence for ISRPDs is still lacking, a pilot study was necessary before proceeding with future clinical trials and experimental studies.There was no statistically significant difference in patient-reported outcomes and oral function between RPDs and ISRPDs in this study. Although it is difficult to generalize the results of this study, our findings indicate a tendency towards improvement in patient-reported outcomes and oral function with ISRPDs in patients with mandibular Kennedy Class II edentulism. These findings may be useful as a reference for clinical studies of ISRPDs in patients with unilateral partial edentulism.The results of this case report suggest that patients with mandibular Kennedy Class II edentulism experienced greater satisfaction and improvement in masticatory performance with ISRPDs than with RPDs.


Hyperuricemia and dyslipidemia are associated with left ventricular hypertrophy (LVH), while the effect of ApoE gene polymorphism on the correlation between serum uric acid (UA) level and severity of LVH in patients with coronary heart disease (CHD) has not been clarified.This was a retrospective observational study of patients with CHD. Patients were divided into groups of ε4 carriers and non-ε4 carriers based on sanger sequencing. The association of ApoE ε4 gene polymorphism, serum UA level, and LVH, determined by cardiac color Doppler ultrasound, was evaluated by multivariate analysis.P = 0.025) and increased in non-ε4 carriers . The risk of LVEDD enlargement tended to decrease in ε4 carriers  and increased in non-ε4 carriers . The risk of LVEF reduction was reduced in ε4 carriers  and increased in non-ε4 carriers . The risk of LVEDD enlargement decreased in ε4 carriers  and increased in non-ε4 carriers .A total of 989 CHD patients who underwent ApoE genotyping were enrolled and analyzed. Among them, the frequency of the ApoE ε4 genotype was 17.9% . There were 159 patients with LVH, 262 with end-diastolic LV internal diameter (LVEDD) enlargement, 160 with left ventricular ejection fraction (LVEF) reduction, and 154 with heart failure. Multivariate analysis showed that for every increase of 10 μmol/L in serum UA level, the risk of LVH decreased in ε4 carriers (odds ratio (OR) = 0.94, 95% confidence interval (CI): 0.890–0.992, High serum UA levels decreased the risk of LVH in ApoE ε4 carriers with CHD, while increased the risk of LVH in non-ε4 carriers. Heart failure (HF) is one of the leading causes of hospitalization and death worldwide, and progressive left ventricular remodeling plays an important role in the pathophysiology of HF. Left ventricular remodeling is characterized by left ventricular hypertrophy (LVH), atrioventricular dilation, interstitial fibrosis, and worsening of cardiac dysfunction , 2. LVH,LVH is not only mediated by the mechanical stress of pressure overload, but also by various neurohormonal factors , includiThis retrospective observational study included patients with CHD who were admitted to the Beijing Chaoyang Hospital  between January 2015 and December 2016. The inclusion criteria were as follows: (1) patients who aged >18 years old; (2) patients who were angiographically diagnosed with CHD; (3) patients who underwent echocardiography; (4) patients with available ApoE polymorphism status. The exclusion criteria were as follows: (1) severe organ failure and malignant diseases; (2) patients with the ε4/2 genotype ; or (3)Genomic DNA extracted from whole-blood specimens was analyzed for ApoE polymorphisms using polymerase chain reaction-reverse hybridization . Plasma 2  or LVMI ≥110 g/m2  using the 2007 Guidelines for the Management of Arterial Hypertension presented by the European Society of Hypertension (ESH) and of the European Society of Cardiology ; abnormally distributed, continuous variables were expressed as median (interquartile range) or tertile, and were analyzed using a non-parametric test . Categorical variables were expressed as percentage and number, and were analyzed using the Chi-square test. Logistic regression analysis of associations of serum UA level with LVH, LVEDD enlargement, LVEF reduction, and HF was performed using univariable and multivariable models. The interaction terms between serum UA level and ApoE genotype groups for all outcomes were evaluated. The statistical analysis was performed using SPSS 21.0 software . A two-sided P < 0.05 was considered statistically significant.Normally distributed continuous variables were expressed as the mean ± standard deviation (SD), and were analyzed using the Student's A total of 1,493 patients with CHD were included in the study, of whom 17 patients with the E4/2 genotype were excluded, and 487 patients with missing covariates were ruled out. The data of 989 participants were analyzed . Among aP = 0.043) and had a higher LDL-C level , a lower HbA1c level , a higher maximum diastolic blood pressure (DBP) , and a lower current systolic blood pressure (SBP) .Participants' demographic and biochemical characteristics are summarized in The comparison of outcomes grouped by gender and ApoE genotype is shown in There were 159 patients with LVH and 262 patients with LVEDD enlargement among the 989 patients. In both univariable and multivariable models, a high serum UA level increased the risk of LVH and LVEDD enlargement . After aP = 0.025] and increased in the non-ε4 carriers  as serum UA level increased (for every increase of 10 μmol/L). The interaction effect for LVH between serum UA level and ApoE genotype groups was significant (P (for interaction) = 0.013). The risk of LVEDD enlargement tended to decrease in the ε4 carriers  and significantly increased in the non-ε4 carriers   = 0.94, 95% confidence interval (CI): 0.890–0.992, = 0.003) .There were 160 patients with LVEF reduction and 154 patients with HF among the 989 patients. In both univariable and multivariable models, a higher serum UA level increased the risk of LVEF reduction and HF. After adjusting for gender, age, heart rate, hypertension, diabetes, dyslipidemia, eGFR, history of receiving ACEIs/ARBs/β-blockers/statins, and smoking status, the risk of LVEF reduction and HF was escalated by 2 and 2%, respectively, for every increase of 10 μmol/L in serum UA level .Hyperuricemia, hypercholesterolemia, and ApoE gene polymorphism are all important risk factors, affecting left ventricular remodeling. Data analysis in our study showed that hyperuricemia increased the risk of LVH, LVEDD enlargement, LVEF reduction, and HF in patients with CHD, which is consistent with results of a previous research . Serum UIn vitro and in vivo studies have shown that UA is an important antioxidant in plasma, accounting for about 60% of the total antioxidant capacity of human plasma, and it can neutralize several harmful pro-oxidants, such as peroxynitrite, hydroxyl, and iron-containing free radicals, eliminating the activated erythrocyte-mediated organ damage by generating free radicals , which helps remove excess cholesterol from the blood, and transports it to the liver for metabolism. ApoE also helps remove chylomicrons and VLDL from the blood and binds to liver receptors, including LDL receptors, LDL receptor-associated proteins, and VLDL receptors as a ligand. The affinity of ApoE2 and hepatic lipoprotein receptor is poor, resulting in a reduction in the metabolism of lipoprotein decomposition of the triglycerides. Partial removal of TG from chylomicrons or VLDL creates remnants, and the ApoE4 is associated with the increased removal of these lipoproteins, leading to the high levels of cholesterol and LDL . It incrradicals . Superoxradicals , 33. Datradicals , 35. Patradicals . CD11c, radicals –39. It hradicals , suggestradicals . In concradicals , 43. Actradicals . Thereforadicals . Dose-reradicals . The expradicals  conducteThe main limitation of this study is the cross-sectional design, which may affect the confirmation of causality, and further prospective study needs to be conducted to determine the relationship between serum UA level, ApoE polymorphism, and LVH. UA can increase the phagocytotic activity of macrophages by increasing the production of TNF-α, TLR4, and CD11c, and reduce the expression levels of CD206, CX3CR1, and CCR2. As a metabolic ligand, its pro-inflammatory effect on human macrophages partly depends on URAT1, which needs to be further studied.In conclusion, a high serum UA level reduces the risk of LVH in ApoEε4 genotype, while increases the risk of LVH in non-ε4 genotype in CHD patients.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by the Clinical Research Ethic Committee of Beijing Chaoyang Hospital . The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.YG designed the study. XZ and JL performed the research and wrote the manuscript. M-LZ and KL analyzed the data. MC participated in data collection. All the authors contributed to editorial changes in the manuscript and read and approved the final manuscript. YG also participated in the writing of the article.


Hemodynamic monitoring is the centerpiece of patient monitoring in acute care settings. Its effectiveness in terms of improved patient outcomes is difficult to quantify. This review focused on effectiveness of monitoring-linked resuscitation strategies from: (1) process-specific monitoring that allows for non-specific prevention of new onset cardiovascular insufficiency (CVI) in perioperative care. Such goal-directed therapy is associated with decreased perioperative complications and length of stay in high-risk surgery patients. (2) Patient-specific personalized resuscitation approaches for CVI. These approaches including dynamic measures to define volume responsiveness and vasomotor tone, limiting less fluid administration and vasopressor duration, reduced length of care. (3) Hemodynamic monitoring to predict future CVI using machine learning approaches. These approaches presently focus on predicting hypotension. Future clinical trials assessing hemodynamic monitoring need to focus on process-specific monitoring based on modifying therapeutic interventions known to improve patient-centered outcomes. Hemodynamic monitoring techniques can identify cardiovascular insufficiency (CVI) and guide personalized hemodynamic therapies when linked to clinical examination to assess perfusion adequacy. Effective hemodynamic monitoring to achieve these goals should be associated with improved outcomes. Still, no hemodynamic monitoring device will improve outcomes unless coupled to an appropriate and effective treatment . ClinicaIt is difficult to define monitoring effectiveness. To monitor or not and to treat or not both have outcomes which can be good or bad. Improved outcomes are directly related to a more effective use of therapies while minimizing iatrogenic effects by limiting those therapies in patients less likely to benefit from their use. Such analyses will probably be patient, process and condition specific. We will focus on effectiveness of monitoring-linked resuscitation strategies by three lenses Table . First, 2) is universally used in emergency transport, high dependency units and intra-operatively. Although useful in identifying supplemental oxygen resistant hypoxemia, a large scale randomized clinical trial demonstrated no measurable benefit in perioperative patients [Electrocardiographic (ECG) monitoring in patients with acute coronary syndrome often identifies clinically relevant arrhythmias that indicate worsening ischemia and/or progression to malignant arrhythmias before death . Since tpatients . Accordi2 is mandatory during surgery without validation [causal [Since the effects of intra-operative CVI are devastating and because both anesthesia and surgical manipulations alter cardiovascular function close monitoring of blood pressure (BP), heart rate, and SpOlidation . Advancelidation   by targeting hemodynamic endpoints using fluids, inotropes, vasopressors and red blood cells [P = 0.07) [Hemodynamic monitoring-based preoptimization goal-directed therapy (GDT) algorithms (preoptimization) aim to improve global oxygen delivery  , adding  = 0.07) , includi = 0.07) . While O = 0.07) . However = 0.07) , nor did = 0.07) . Thus, c = 0.07) . A subseAlthough every patient is different, the practical translation of that into patient-specific treatment algorithms has been slow. Furthermore, when hemodynamic monitoring is used to assess therapeutic challenges in an unstructured fashion, the FENICE study revealed profound practice variability . The ref2) and arterio-venous O2 and CO2 (v-aCO2) gradients help to identify tissue hypoperfusion. Central venous oxygen saturation (ScvO2) and v-aCO2 gap can be used as a surrogate for SvO2 [2 < 70% documents circulatory stress while v-aPCO2 > 6 mmHg is consistent with tissue hypoperfusion [2 saturation (StO2) by near infrared spectroscopy in response to a transient vascular occlusion test identifies occult circulatory shock, is non-invasive and easy to perform [2 is minimally informative [Although it is relatively easy to identify variables to trigger resuscitation, it is less clear on when to stop it. Effective resuscitation is usually measured by return of normal end-organ function. However, such clinically relevant end-points usually occur long after sufficiency is achieved. Therefore, clinicians often resuscitative beyond levels needed to attain sufficiency, leading to volume overload and excess vasoactive drug exposure. Mixed venous oxygen saturation , a costless universally available technique with unique characteristics that may be pivotal for assessing circulatory effectiveness and is more sensitive than skin mottling to identify CVI . MeasuriFluid administration is the first treatment undertaken in most patients with CVI. However, volume expansion poses two problems . CO incrP < 0.001), related to decreased cardiovascular, infectious and abdominal complications. The ICU length of stay was reduced  [A meta-analysis of 14 randomized control post-surgical trials before 2014 (961 participants) showed that a dynamic assessment of volume responsiveness GDT reduced post-operative morbidity  . Two sub = 0.02) . One sur = 0.02) .Four randomized trials in patients with early septic shock were done assessing volume responsiveness as a positive response to passive leg raising –56. The −1 min−1) within 1 h of hypotension resulted in less fluid administration, less cardiogenic pulmonary edema, fewer arrhythmias and a lower mortality [At the early phases of resuscitation, fluid and vasopressor administration is often required . While tortality . The CLOortality  was stoportality .dyn), estimates the dynamic changes in pressure as flow is varied in hypotensive patients [dyn will vary inversely with flow to maintain a constant blood pressure through baroreceptor feedback. Thus, Eadyn is less useful in normotensive patients [dyn is not arterial elastance, though it does reflect ventriculo-arterial coupling [dyn < 1.0 in a hypotensive volume responsive patient predicts whose blood pressure will not increase with increasing CO [dyn to initiate vasopressor therapy and assess its impact of organ perfusion and outcomes.Pathological decreased vasomotor tone (vasoplegia) is a common cause of hypotension. Vasoplegia will limit the BP increase to fluids even if volume responsive. Low diastolic pressure may indicate vasodilation and need of vasopressors. The diastolic shock index (heart rate/diastolic blood pressure) > 2.5 was associated with increased risk of death . As proppatients . Howeverpatients . Also, Ecoupling . Severalasing CO , 73–75. dyn can be used to wean vasopressors in normotensive vasopressor-dependent patients. Guinot et al. [dyn identified those norepinephrine-dependent patients whose with a Eadyn > 1 could have their vasopressor decreased without hypotension, whereas if Eadyn was < 1 vasopressor weaning as associated with hypotension. Using Eadyn thresholds to start norepinephrine weaning in post-cardiac surgery vasoplegia patients Guinot et al. showed a 50% reduction in both norepinephrine time and dose, less arrhythmias and a one-day decrease in ICU length of stay [Eat et al.  in septit et al.  in the p of stay .Less aggressive treatment is sometimes associated with better outcomes in critically ill patients. Less red blood cell transfusions, conservative fluid management and lower tidal volume mechanical ventilation in ARDS patients improve outcomes. Similarly, the non-specific use pulmonary artery catheterization may have led to greater resuscitation and worse survival . SimilarNo clinical trials have compared hemodynamic monitoring-guided resuscitation from shock to no hemodynamic monitoring conditions, thus most studies compare threshold values of monitor-specific hemodynamic values on specific outcomes when specific treatments or drugs are used to reach those hemodynamic values. The monitoring and management of CVI can be separated into “phases” of care, defined by changing monitoring and management priorities, defined as salvage, optimization, stabilization and de-escalation . During 2 to cellular oxygen demand. At the macro-circulatory level, inadequate DO2 can be due to hypoxemia, low hemoglobin concentration, and/or inadequate CO. All cause a low SvO2 [2 can be > 70% despite ongoing CVI due to impairment of oxygen extraction [2 > 6 mmHg (or > 0.8 kPa) identifies patients for whom an increase in CO may be beneficial in sustaining organ perfusion despite a SvO2 > 70%. If the v-aPCO2 is < 6 mmHg (or < 0.8 kPa), it is unlikely that increasing CO would reverse organ hypoperfusion. In those situations where despite initial resuscitation, persistent organ dysfunction and evidence of tissue hypoperfusion persists  despite a normal (or high) ScvO2 and normal v-aPCO2, marked microcirculatory disorders and/or mitochondrial dysfunction, poorly responsive to macrohemodynamic therapeutic manipulations, probably exist. This situation can occur during septic shock and is termed refractory shock. Response to resuscitative measures can be assessed by noting the trends in blood lactate [During the optimization phase, the main goal is to adapt DOlow SvO2 . The spelow SvO2  and echotraction , 86. A v lactate  or CRT [ lactate , 87. Exp lactate . No clinWith successful treatment, stabilization should follow the optimization. This phase is characterized by both the absence of shock, and lack of imminent threat of shock. Echocardiography may help to wean inotropes when cardiac dysfunction is resolving. Fluid removal is often needed as vascular unstressed volume reverts to baseline levels and third space fluids are resorbed . At thisARDS patients can suffer CVI due to associated sepsis. ARDS is often associated with right ventricular dysfunction and increase pulmonary capillary permeability. Thus, potential major detrimental consequences of fluid administration on hemodynamics may occur. The causes of ARDS can be complex and causes of death are multiple, making it difficult to demonstrate any benefit on survival from hemodynamic therapeutic protocols. Since no monitoring device has been demonstrated to cause harm per se, it seems unreasonable to manage such complex patients without appropriate invasive hemodynamic tools since clinical and biochemical signs are often misleading , 84. BedTPTD reports extravascular lung water (EVLW), a measure of the amount of pulmonary edema, and pulmonary vascular permeability index (PVPI), a measure of the lung capillary leak. Both variables can be viewed as markers of lung tolerance to fluid administration. Since TPTD is coupled with the pulse contour analysis technique in the same device, such systems enable assessment of volume responsiveness. These systems provide assessment of the benefit/risk balance of fluid infusion: volume responsiveness to assess the benefits and EVLW and PVPI to assess the risks of pulmonary edema. Two randomized studies compared outcomes of critically ill patients monitored with pulmonary artery catheter to TPTD , 90. OvePerhaps the newest frontier available to optimize care through precise and personalized monitoring is the use of machine learning approaches –96 to feDifferent hypotension prediction models in various settings  using different monitoring methods  to report a continuous hypotension prediction index (HPI) have been created. The best predictions of impending hypotension occur within 5–15 min of its occurrence, making them best suited for emergency and intra-operative care environments. One commercial HPI algorithm (Acumen™) uses both invasive and non-invasive estimates of the arterial pressure waveform . Other mThe proven efficacy of treatments based on specific hemodynamic monitoring have improved patient outcomes are small but relevant. Most studies identify improved process of care as surrogates for effectiveness, such as less volume of fluid infused and shorter time in hypotension. Importantly, the need for disease and process-specific clinical trials to include focused patient-centered outcome appears both warranted and essential if we are to continue to use monitoring to efficiently and effectively direct patient care and identify instability in the future. We are at the cusp of finding the optimal path where hemodynamic monitoring, coupled to an optimized patient care algorithm, produces the best clinical outcomes. A one-size-fits-all approach may prevent patients from receiving life-saving fluid and vasoactive medication administration when needed and may encourage the use of these interventions when futile.


To the Editor,IL‐4 and IL‐13 are Type‐2 (T2) inflammatory cytokines and key drivers in T2 immune response, which is considered to play a central role in the pathogenesis of several atopic diseases such as atopic dermatitis (AD) and asthma. Dupilumab, a fully human monoclonal antibody, binds to the α‐subunit of the interleukin (IL)‐4 receptor and blocks the signaling pathway of IL‐4 and IL‐13.This study consecutively included adult AD patients with comorbid asthma and at least one measurement of the Asthma Control Questionnaire (ACQ)‐5 , and/or FEV1, who started dupilumab treatment for AD and participated in the BioDay registry from October 2017 to June 2022. The ACQ‐5 was used as patient‐reported outcome, consisting five questions on symptom control of asthma. Following The Global Initiative for Asthma (GINA)‐guidelines controlled asthma in a real‐life setting is defined as ACQ‐5 < 0.5.n = 236) at baseline, and significantly improved over time (p < 0.00), with −0.24  at week 16 and −0.26  at week 52. Mean FEV1 at start of treatment was 2.96 L  and significantly improved over time (p < 0.00) with 0.10 L (95% CI 0.03–0.16) and 0.12 L (95% CI 0.05–0.19) at week 16 (n = 81) and 52 (n = 64), respectively. No significant change for ACQ‐5 and FEV1 was found between week 16 and 52. Secondary effectiveness endpoints are presented in Figure n = 22) was 23.43 ppb (95% CI 16.37–33.53) and significantly decreased over time (p < 0.00), to 13.13 ppb  at 16‐weeks and to 15.24 ppb  at 52‐weeks of treatment  investigating the efficacy and safety of dupilumab in patients with uncontrolled asthma showed a more impressive effect on the primary endpoints.As shown in the Appendix, no profound effect of T2‐indicator, blood eosinophilia, at the start of treatment was found regarding the effectiveness of dupilumab on FEV1. On the contrary, in the asthma studies,A limitation of the study is the missing data due to the daily practice setting and COVID‐pandemic. Additionally, spirometry measurements were only conducted in patients using inhaled corticosteroids thereby excluding patients with mild asthma.In conclusion, 1 year of dupilumab treatment primarily indicated for AD resulted in a significant improvement of comorbid asthma with the largest effect in the first 16 weeks. Dupilumab treatment in AD patients provides an additional advantage for patients with comorbid asthma.All authors have made substantial contributions to conception and design of this study and have been involved in drafting or revising the manuscript. All authors have given final approval of the version to be published an agreed to be accountable for all aspects of the work. Lotte S. Spekhorst had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.Lotte S. Spekhorst is a speaker for Abbvie. Marlies de Graaf is an advisor, consultant, speaker or investigator for Sanofi‐Genzyme, Regeneron Pharmaceuticals, LEO Pharma and Eli Lilly. Lisa P. van der Rijst has nothing to disclose. Nicolaas P. A. Zuithoff has nothing to disclose. René C. Schweizer has nothing to disclose. Marijke Kamsteeg has nothing to disclose. Inge Haeck is an advisor, consultant, speaker or investigator for Sanofi‐Genzyme, LEO pharma, AbbVie and Eli Lilly. Anneke M. T. van Lynden‐van Nes has nothing to disclose. Paula van Lumig has nothing to disclose. Geertruida L. E. Romeijn has nothing to disclose. Marie‐Louise Schuttelaar is an advisor, consultant, speaker and/or investigator for AbbVie, Pfizer, LEO Pharma, Regeneron, Sanofi Genzyme, Eli Lilly and Galderma. She has received grants from Regeneron, Sanofi Genzyme, Novartis and Pfizer. Marjolein S. de Bruin‐Weller has been a consultant, advisory board member, and/or speaker for AbbVie, Almirall, Arena, Aslan, Eli Lilly, Galderma, Janssen, Leo Pharma, Pfizer, Regeneron, and Sanofi‐Genzyme.Regeneron Pharmaceuticals; AbbVie; Sanofi; LEO Pharma; Eli Lilly and Company; Pfizer.Supplementary Material S1Click here for additional data file.


Diabetes mellitus is a major risk factor for heart failure. A recent consensus statement recommended annual cardiac biomarker testing (e.g. natriuretic peptide or high-sensitivity cardiac troponin) for all patients with diabetes. We aimed to identify patients at a higher risk of hospitalization for heart failure among patients with type 2 diabetes to prioritize those who would require screening.+DKD, and PU−DKD) were identified. A fatty liver index of ≥ 60 was defined as metabolic dysfunction–associated fatty liver disease (MAFLD). Patients were followed up until December 2018 or until outcomes developed. The Cox proportional hazard model was used to compare the risk of hospitalization for heart failure across groups.Overall, 1,189,113 patients who underwent two medical health checkup cycles (2009–2012 and 2011–2014) and had stable diabetic kidney disease (DKD) phenotype in the Korean National Health Insurance Service database were included in this study. After excluding those with concurrent proteinuria (PU) and reduced estimated glomerular filtration rate, three groups ], followed by the PU−DKD group  using the no-DKD group as the reference category. The risk of hospitalization for heart failure was comparable regardless of MAFLD status in patients who already had DKD. However, in the no-DKD group, the risk of hospitalization for heart failure was 1.4 times higher in patients with MAFLD than in those without .During an average of 6.6 years of follow-up, 5781 patients developed hospitalization for heart failure. After adjusting for covariates, the risk of hospitalization for heart failure was highest in the PUIn lines with the international consensus statement, we suggest that annual cardiac biomarker testing should be conducted at least in patients with DKD and/or MAFLD.The online version contains supplementary material available at 10.1186/s13098-023-01006-z. Heart failure (HF) is a global health problem with a rising prevalence rate , 2 mostlType 2 diabetes is a well-known risk factor for HF . Based oSeveral multivariable models have been used to predict the risk of HF in patients with diabetes , 14. AltThis study used data from the Korean National Health Insurance Service (NHIS), which is the sole insurance provider for all Korean residents. The NHIS-established databases (DBs) included the qualification, treatment, and medical checkup DBs . Briefly2 . Additionally, patients with proteinuric DKD with reduced eGFR (< 60 mL/min/1.73 m2) at the first examination were excluded since the very high-risk Kidney Disease: Improving Global Outcomes (KDIGO) categories are well known for poor cardiovascular outcomes [This study included 1,779,819 subjects with type 2 diabetes who underwent at least two general medical checkups in 2009–2012 and 2011–2014  or December 2018  code: E11–E14) and the prescription of relevant glucose-lowering drugs. When the participants did not meet the criteria above, they were defined as having type 2 diabetes if their fasting plasma glucose levels were ≥ 126 mg/dL during a medical checkup.2. Notably, positive proteinuria (PU) of ≥ 1 + was defined based on the urinary dipstick test. Additionally, the DKD phenotype was categorized into three distinct groups based on the eGFR levels  and PU (negative vs. positive) as follows: group 1 (no-DKD), normal eGFR and negative PU; group 2 (PU+DKD), normal eGFR and positive PU; and group 3 (PU−DKD), reduced eGFR and negative PU.The eGFR was determined using the equation from the Modification of Diet in Renal Disease study  and redux/(1 + ex) × 100, x = 0.953 × log (triglyceride) + 0.139 × body mass index + 0.718 × log (gamma-glutamyl transferase (GGT)) + 0.053 × waist circumference − 15.745). Particularly, an FLI of ≥ 60 was defined as MAFLD [The fatty liver index (FLI) was used to identify patients with MAFLD . Accordias MAFLD .Patients with HF were identified based on ICD-10 codes for heart failure (I50). Hypertension was indicated in patients according to the ICD-10 code for hypertension  and the prescribed antihypertensive medications. Participants were also considered hypertensive if their systolic blood pressure was ≥ 140 mmHg and/or diastolic blood pressure was ≥ 90 mmHg during a general medical checkup. Moreover, patients with dyslipidemia were identified by the ICD-10 code for dyslipidemia (E78) with treatment undergone using lipid-lowering agents or a total cholesterol level ≥ 240 mg/dL during a medical checkup. Proliferative diabetic retinopathy (PDR) was established if the participants had two or more diagnoses of diabetic retinopathy (H360) and a procedure code for pan-retinal photocoagulation .2). After overnight fasting, venous samples were used to evaluate fasting plasma glucose, total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), GGT, and hemoglobin levels.This study obtained laboratory results and clinical characteristics during the second examination. Body mass index was calculated as weight divided by height in meters squared  or non-heavy drinkers, and participants with or without regular exercise.The primary outcome of this study was the hospitalization of patients for HF. Cases were defined as patients who were admitted to a hospital with a discharge diagnostic code for HF (I50).Descriptive statistics were used to summarize baseline characteristics. Baseline characteristics across the groups were presented as numbers (percentages) for categorical variables and mean ± standard deviation for continuous variables. If the distribution of continuous variables was heavily skewed, the geometric mean was used. To analyze the differences in baseline characteristics between the groups, a one-way analysis of variance was used for continuous variables, and the chi-squared test was used for categorical variables.P < 0.05.The cumulative incidence of HHF was calculated using Kaplan–Meier estimates, and we performed a log-rank test to analyze the differences in HHF risk across groups. The incidence of HHF was expressed as the number of events per 1000 person-years. Cox proportional hazards regression analysis was performed to assess the hazard ratio (HR) for HHF across the groups. Model 1 was unadjusted; Model 2 was adjusted for age and sex; and Model 3 was adjusted for smoking, drinking, and physical activity. Additionally, Model 4 was adjusted for comorbidities, including hypertension, dyslipidemia, atrial fibrillation, and ischemic heart disease. Finally, Model 5 was further adjusted for fasting glucose, diabetes duration, hemoglobin levels, and insulin usage. Subgroup analyses with tests for interaction were performed according to age group (< 65 vs. ≥ 65 years), sex, and the presence or absence of prevalent HF. Statistical analyses were conducted using the SAS software . Statistical significance was set at +DKD group, and 3.4%  in the PU−DKD group. The prevalence of MAFLD was 25.1% , and patients with MAFLD were younger, more obese, and more likely to be male than those without MAFLD. Additionally, they tended to be current smokers and heavy drinkers and did not exercise regularly. The prevalence of hypertension and dyslipidemia was higher in patients with MAFLD than in those without MAFLD. Despite the shorter duration of diabetes, patients with MAFLD showed higher fasting plasma glucose levels than those without MAFLD. Predictably, the AST, ALT, and GGT levels were higher in patients with MAFLD than in those without MAFLD.Table −DKD group, followed by the PU+DKD and no-DKD groups  . This difference remained consistent after adjusting for social factors (model 3) and comorbidities (model 4). Notably, after adjusting for factors associated with the severity of diabetes (model 5), the effect of DKD phenotypes on HHF persisted .During a mean follow-up of 6.6 years, 5781 of 1,189,113 patients were hospitalized for HF. The incidence rate of HHF was highest in the PUP < 0.001)  Fig. . Contrarups Fig. .Fig. 1CuPreviously, a lower FLI cutoff for diagnosing MAFLD has been suggested in the Korean population . ConsequIn this study, we observed that proteinuria and renal dysfunction were risk enhancers for HHF in patients with type 2 diabetes, which is consistent with previous studies . In pati.Although the 2022 ADA consensus report on HF has mandated annual cardiac biomarker testing for all patients with diabetes , the pre+DKD (40%), followed by no-DKD (25%) and PU−DKD (20%). The highest MAFLD in PU+DKD is reminiscent of the severe insulin-resistant diabetes subtype, which is associated with an increased risk of fatty liver disease and macroalbuminuria [Notably, growing evidence suggests that individuals with MAFLD are at a higher risk of CKD  or cardiuminuria .or < 65 years; previous HF yes or no).Although the effects of NAFLD on CVD risk in patients with type 2 diabetes have been well established , 28, the+DKD than in PU−DKD group. Normoalbuminuric DKD has become a widely prevalent variant of renal impairment in diabetes. Women, older, and nonsmoking individuals with good glycemic control have a better chance of preserving normoalbuminuria, even in the case of declining renal function [CKD affects approximately 50% of patients with type 2 diabetes globally . In addifunction . Normoalfunction . This unfunction .−DKD group showed a higher HHF risk when combined with MAFLD, although the difference was not statistically significant. Surprisingly, the PU+DKD group without MAFLD showed a higher HHF risk than those with MAFLD. Albuminuria has been associated with HF risk independent of eGFR [. Otherwise, insulin resistance might be a shared mechanism related to HF in patients with underlying DKD or MAFLD. Previously, Parente et al. reported that the waist-height ratio (WHR), a marker of central obesity [As DKD is a risk factor for HF , we hypo of eGFR . Convers of eGFR . Althoug of eGFR , the dir of eGFR , and inc of eGFR , 40, pro of eGFR . Otherwi obesity , enhance obesity  which is obesity .Of note, the effect of glucose-lowering drugs that modify the risk of HHF (e.g. SGLT2 inhibitors) were not calculated in this study. Because SGLT2 inhibitors are recommended to patients with DKD or HF due to its cardiorenal protective effects , DKD pat, are promising for preventing HF in NAFLD or MAFLD [Interventional strategies for high-risk populations should also be considered. The Asia–Pacific Working Party on Nonalcoholic Fatty Liver Disease or the American Association for the Study of Liver Diseases recommends that pioglitazone be considered in patients with nonalcoholic steatohepatitis . Howeveror MAFLD .To the best of our knowledge, this is the first study to examine the effect of DKD and/or MAFLD on HHF in patients with diabetes with a relatively mild or moderate risk of CVD. To overcome the evaluation of eGFR and proteinuria status at a single point in time, we only included subjects with a stable DKD status over a two-year interval.However, this study has some limitations. First, this study used claims data previously gathered for reimbursement purposes; thus, the diagnostic codes for certain patients might be incorrect. Second, another drawback is using a urinary dipstick test rather than a direct measure of urinary albumin excretion. The accuracy of the dipstick test may be affected by urine-specific gravity or pH . In addiOur study’s results indicated that DKD and/or MAFLD increased the risk of HHF. In line with ADA’s HF guidelines, we suggest that annual cardiac biomarker testing should be conducted at least in patients with DKD or MAFLD. In addition, interventional strategies, including treatment with SGLT2 inhibitors and GLP-1 RA, should be considered to prevent HF and ultimately reduce HF-related morbidity and mortality.Additional file 1: Fig. S1. Study population (A) and study design (B). Table S1. Incidence rate and risk of hospitalization for heart failure according to the DKD phenotype. Table S2. Incidence rate and risk of hospitalization for heart failure according to the DKD phenotype and MAFLD. Table S3. Incidence rate and risk of hospitalization for heart failure in the no-DKD group stratified by FLI.