Background and objectives: New-onset diabetes after transplantation (NODAT) represents a primary cause of morbidity and allograft loss. We assessed prevalence and risk factors for NODAT in a population of Italian kidney transplant (KT) recipients. Methods: Data from 522 KT performed between January 2004 and December 2014 were analyzed. Participants underwent clinical examination; blood and urine laboratory tests were obtained at baseline, one, six, and 12-month of follow-up to detect glucose homeostasis abnormalities and associated metabolic disorders. An oral glucose tolerance test (OGTT) was performed at six months in 303 subjects. Results: Most patients were Caucasian (82.4%) with a mean age of 48 ± 12 years. The prevalence of abnormal glucose metabolism (AGM) and NODAT was 12.6% and 10.7%, respectively. Comparing characteristics of patients with normal glucose metabolism (NGM) to those with NODAT, we found a significant difference in living donation  and age at transplant . Also, we observed that patients developing NODAT had received higher cumulative steroid doses . The NODAT group showed inferior allograft function compared to patients with NGM . NODAT patients were more likely to exhibit elevated systolic blood pressure and higher total cholesterol and triglyceride levels than controls. Conclusions: The prevalence of NODAT in our cohort was relatively high. Patient age and early post-transplant events such as steroid abuse are associated with NODAT development.  Kidney transplantation (KT) provides a survival advantage and superior quality of life over dialysis ,2. HowevEven though the International Congress Guidelines  and the The prevalence of glucose regulation abnormalities in KT recipients is extremely variable and mostly depends on the diagnostic criteria employed . Data onTo date, several modifiable and non-modifiable risk factors for NODAT have been identified . PutativManaging KT patients with NODAT is often challenging as they frequently show fluctuating renal function and increased susceptibility to drug-related adverse events . PossiblWe aimed to evaluate the prevalence of glucose metabolism abnormalities in a cohort of Italian contemporary KT recipients, focusing on the early post-transplant course and investigating post-transplant modifiable risk factors.In this single-center retrospective observational cohort study with a prespecified follow-up of 12 months, we analyzed data from patients who had undergone KT at the Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico  between January 2004 and December 2014. Patients with pre-transplant diabetes, multiple organ transplantation, and re-transplantation were considered in the cohort studied. Exclusion criteria were recipient age <18 years and allograft loss within six months of surgery. Treatments and procedures herein reported were in accordance with the ethical standards of the institutional committee at which it was conducted , as well as with the 1964 Helsinki declaration and its later amendments, or comparable ethical standards. All participants consented for research purposes at the time of activation on the transplant waiting list and their willingness to participate in future non-interventional research projects was confirmed before the transplant procedure. Donor data, organ details, recipient characteristics, and study-related outcomes were recorded in a central database by dedicated staff  and reviewed by the authors in December 2021. Enrolled subjects were thoroughly assessed at the time of transplant, and serial clinical and laboratory evaluations were performed at one (T1), six (T6), and 12 (T12) months of follow-up. Analyzed data included: donor type, cold ischemia time (CIT), recipient familiarity for diabetes mellitus, past medical history, age, gender, body mass index (BMI), primary renal disease (PRD), renal replacement therapy (RRT), dialysis vintage, hepatitis B virus (HBV), hepatitis C virus (HCV) and CMV serostatus, immunosuppressive therapy, renal function, systolic (SBP) and diastolic (DBP) blood pressure, glucose-homeostasis-related parameters, hemoglobin, serum uric acid, intact parathyroid hormone (iPTH), 25-hydroxivitamin D, calcium, phosphorus, and albumin levels, lipid profile, and alkaline phosphatase (AP) concentration. All samples were collected and processed centrally, after 12 h of fasting. Glucose-homeostasis-related parameters included fasting plasma glucose (FPG), basal insulinemia, glycated hemoglobin (HbA1c) levels, and homeostasis model assessment (HOMA) index  at T1, TRenal function was evaluated by serum creatinine concentration (SCr), estimated glomerular filtration rate (eGFR) according to the Modification of Diet in Renal Disease (MDRD) formula , and 24 For iPTH detection and quantification, we used the electro-chemiluminescence immune-assay (ECLIA) and the E170 module for the Modular Analytics . The measurement range was 1.20–5000 pg/mL whereas the conversion was pg/mL × 0.106 = pmol/L .Serum vitamin D levels were assessed using an enzyme immune-assay  with highly specific 25-hydroxivitamin D sheep antibody and enzyme-labeled avidin (horseradish peroxidase). The sensitivity threshold was 5 nmol/mL (2 ng/mL). The specificity of the antiserum was tested with the following analytes calibrated at the level of 50% binding of the zero standard: 25-hydroxivitamin D3 , 25-hydroxivitamin D2 , 24,25-dihydroxyvitamin D3 , cholecalciferol , and ergocalciferol . The intra-assay precision was calculated from 10 duplicate determinations of two samples each, performed in a single assay (CV between 5.3% and 6.7%). Inter-assay precision was calculated from duplicate two-sample determinations performed in 11 assays (CV between 4.6% and 8.7%). p value <0.05. Analyses were performed using Statistica 10  and SPSS 20 .Categorical variables were described using proportions and percentages. Continuous variables were reported as mean (± standard deviation) or median (25°–75° percentiles) in case of abnormal distributions. Data were compared using Fisher’s exact test, chi-square test, Student’s t-test, Wilcoxon–Mann–Whitney U test, or ANOVA as appropriate. We assessed the predictive ability of a pool of variables for the risk of NODAT building linear and logistic regression models for univariate and multivariate analysis. Significance was defined as Between January 2004 and December 2014, 531 adult patients received a KT at our institution. Nine  of them experienced allograft loss within six months of transplant and were excluded from the study. The final analysis was carried out on 522 participants. The study population mostly included Caucasian recipients  on RRT , with a small disproportion between males (n = 295) and females (n = 227). The mean age at transplant was 48 ± 12 years and the vast majority of patients  received a deceased donor kidney . At six months of follow-up, 303  participants underwent OGTT. As specified above, non-compliant patients  as well as those with pre-transplant history of diabetes mellitus  or NODAT diagnosis before T6  were exempt from the test. p = 0.0008), previous exposure to HBV infection , living donation , and age at transplant . Patients who eventually developed AGM were also more likely to have autosomal dominant polycystic kidney disease  or vascular nephropathy  as the primary cause of ESRD. On the contrary, ethnicity, gender, RRT modality, dialysis vintage, and previous exposure to HCV or CMV infections were substantially similar  and six  months of follow-up. Regarding other immunosuppressants, our data did not show any significant difference. However, the preferential use of tacrolimus  over cyclosporine, and the limited number of recipients on sirolimus or everolimus  did not allow a proper comparison between groups. Analyzing the exposure to immunosuppressive medications, we found that patients with NODAT had received higher cumulative steroid doses than those with NGM, particularly at one . Furthermore, the NODAT group was characterized by higher SBP , BMI , and uric acid levels  than the NGM one. In addition to worse glucose-homeostasis-related parameters such as FPG, HbA1c, and HOMA index , NODAT patients exhibited higher total cholesterol  and triglyceride levels  with reduced HDL cholesterol concentrations  compared to recipients with NGM. Mineral metabolism biomarkers including iPTH, 25-hydroxivitamin D, calcium, phosphorus, and AP levels, as well as serum albumin and 24 h proteinuria were not significantly different.Notably, recipients with NODAT showed higher SCr concentration and lower eGFR than patients with NGM, at every time point of the study  or NODAT 12.6%) among our KT recipients was lower than that reported in the literature (> 20%) .6% among,37. SuchThe importance of pre- and post-transplant OGTT for early detection of glucose metabolism abnormalities cannot be emphasized enough . The facIn line with other studies, the present analysis demonstrates the association between specific demographic and clinical characteristics at the time of transplant and future NODAT development. In particular, familial predisposition to diabetes , older aDonor and transplant characteristics were also evaluated. Basically, our findings suggest that deceased donor recipients are more likely to develop NODAT than their living donor counterpart and confirm the association between high-dose steroid use and post-transplant glucose metabolism abnormalities. The beneficial effect of living donation on NODAT susceptibility recognizes several reasons. First of all, living donor kidneys ensure better long-term allograft survival and function than deceased donor ones ,55. SecoFinally, comparing several clinical and laboratory parameters recorded during the first post-transplant year, we found that patients with NODAT exhibited worse renal function, higher systolic and diastolic blood pressure, increased total cholesterol and triglycerides levels, and higher uric acid concentrations than recipients with normal glucose metabolism. The association between diabetes (both pre- and post-transplant) with hypertension and lipid disorders is well-documented ,55. The We recognize that our study has several limitations including retrospective nature, relatively small sample size, short-term follow-up, and lack of protocol allograft biopsies. Also, we could not assess the impact of different immunosuppressive regiments on NODAT susceptibility. However, it describes a homogeneous population of Italian KT recipients on a triple-agent CNI-based immunosuppressive scheme, consistently and rigorously managed by a dedicated multidisciplinary team. The prevalence of NODAT in our cohort of KT recipients was relatively high. Age at transplant, BMI, and total steroid dose within the first post-transplant month were associated with NODAT development. The systematic application of pre- and post-transplant screening protocols with OGTT, as well as tailored immunosuppression and prompt dietician referral could reduce NODAT-related complications. In the near future, studies addressing causal relationships, long-term patient- and allograft-related outcomes, and pre-emptive strategies are warranted.


In total, 8 out of 34 patients (23.5%) with low copeptin concentrations <10 pmol/L were hypotensive. Copeptin was highest in the adjusted mixed-effect regression analysis within the first day (+20% at 14 h) and decreased significantly at 108 h (−27%) compared to baseline (p = 0.002). Moreover, we found a significant association with vasopressor-inotrope treatment intensity, infancy (1–12 months) and cardiopulmonary bypass . In conclusion, high copeptin values were associated with arterial hypotension and severity of disease in critically ill children. This study does not support the hypothesis that low copeptin values might be indicative of arginine-vasopressin deficiency.Low copeptin levels may indicate inadequate arginine-vasopressin release promoting arterial hypotension, whereas high copeptin concentrations may reflect disease severity. This single-center prospective non-randomized clinical trial analyzed the course of blood copeptin in critically ill normo- and hypotensive children and its association with disease severity. In 164 patients ), the mean copeptin concentration at baseline was 43.5 pmol/L. Though not significantly different after 61 h (primary outcome, mean individual change: −12%,  Critically ill children frequently suffer severe arterial hypotension in various conditions, including respiratory and cardiac failure, septic shock, postsurgery, asphyxia and brain injury. Treatment for arterial hypotension comprises intravenous fluid, vasopressor and inotrope administration to maintain adequate perfusion pressure ,2,3. HowRecently, intravenous vasopressin was introduced to the medical armament of pediatric intensive care medicine. It is used in addition to or instead of standard inotrope-vasopressor treatment ,10,11,12Since endogenous plasma AVP is difficult to measure in vivo ,21,22, tFurther, there is a growing body of literature for the association of plasma copeptin with severity of disease and adverse outcome in both adults and children. It has been shown that non-favorable outcomes could be predicted in a variety of pediatric pathologies, such as community-acquired pneumonia ,26, congThe aim of this prospective observational study was to characterize the course of blood copeptin in critically ill children admitted to the intensive care unit (ICU). The primary objective was to describe the average change of blood copeptin concentrations in normotensive and hypotensive patients after admission to ICU. The secondary objective was to describe the change of blood copeptin over a period of up to 168 h and to explore the association of blood copeptin concentrations with the following clinical covariates: (a) age; (b) sex; (c) length of ICU stay; (d) length of respiratory support; (e) intensity of catecholamine therapy; (f) severity of disease score; and (g) rate of death at day 28. We first hypothesized an association between copeptin values and arterial hypotension, and second, a correlation between elevated copeptin concentrations and both severity of disease and adverse outcome.This study was designed as a single-center prospective non-randomized clinical trial. It was conducted in critically ill children admitted to the mixed medical and surgical tertiary care intensive care unit of the University Children’s Hospital of Zurich . The study was approved by the local Swiss ethics committee and registered in national  and international  registries.All patients, irrespective of their medical condition, between their first day of life and 18th birthday admitted to the intensive care unit of the University Children’s Hospital of Zurich were eligible if the following conditions were met: ability of the caretaker or the adolescent (if ≥14 years of age) to understand verbal and written instructions and informed consent in the local language (German). Exclusion criteria were: impossibility to obtain written informed consent from the caretaker or adolescent (if ≥14 years of age) within 24 h for any reason. Children with syndromes were not excluded.t-test for mean difference between baseline and 48 h of d = 0.3 ng/mL, approximate sd = 0.8 ng/mL [For the sample size estimation, we took into account the average length of stay in our unit: (median (10–90th percentile)): 1.3 (0.4–9.2) days. Therefore, we defined the study period relevant for the primary outcome  as 48 h, and the sample size was calculated to compensate for patients discharged early. A sample size of 62 × 2.5 × 1.1 = 170 patients was recommended, assuming 80% power, and two-sided 5% significance level with an effect size of 0.36  were planned to be taken from all study patients at specific time points , processed and stored at −80 °C for later analyses. All methods of blood withdrawal  were used. The exact time points for each patient were determined by otherwise medically indicated blood withdrawals to avoid unnecessary pain or catheter manipulation, and therefore, variation in exact blood withdrawal timing was expected. Study blood samples were centrifuged and aliquoted in the internal laboratory of the University Children’s Hospital of Zurich. All plasma tubes were labeled with anonymous barcodes to be analyzed at B∙R∙A∙H∙M∙S GmbH  in Hennigsdorf, Germany, via the B∙R∙A∙H∙M∙S Copeptin proAVP KRYPTOR Assay. The lower limit of quantification was 1.23 pmol/L; the upper limit of quantification was 2000 pmol/L. The manufacturer reported for the values between 2 and 4 pmol/L and between 4 and 50 pmol/L intra-assay precision of <15% and <4–8% and inter-assay precision of <18% and <5–10%, respectively.The following clinical variables were collected. For baseline assessment: age; sex; weight; Pediatric Index Of Mortality II score ; main diagnosis ; surgery ; cardiopulmonary bypass and its duration (minutes); aortic cross clamp and its duration (minutes); length of respiratory support ; length of stay in pediatric intensive care unit , death within 28 days after study inclusion. For the primary endpoint at the time of copeptin blood sampling: systolic and mean blood pressure (mmHg). For secondary endpoints, in addition to the above-mentioned baseline variables: vasopressor-inotrope doses expressed as modified Wernovsky score : dopamine dose (µg/kg/min) + dobutamine dose (µg/kg/min) + 100 × epinephrine dose (µg/kg/min) + 100 × norepinephrine dose (µg/kg/min) + 10,000 × vasopressin dose (U/kg/min) + 10 × milrinone dose (µg/kg/min) ,33; totat-test. Supplementary analyses also considered the changes in levels between T0 and T1 (≈12 h), T1 and T2 (≈24 h), and T2 and T3 (≈48 h).The primary analysis was the mean difference in (log-transformed) blood copeptin levels between T0 and T3 (≈48 h), analyzed using a two-sided paired The difference in blood copeptin levels between patients with arterial normo- and hypotension between baseline and 48 h after intensive care unit (ICU) admission was analyzed using mixed-effects ANOVA, taking into consideration the repeated measures from each patient with a random intercept effect. Age-specific systolic arterial hypotension was defined according to t-tests. The association of the longitudinal trajectory of all obtained blood copeptin levels with clinical covariates was analyzed using mixed-effects linear regression of the log-transformed copeptin values with study time included as both categorical and continuous variable. Residual diagnostics were used to verify the appropriateness of the associated linear modeling assumptions. Univariable models were fitted, followed by adjusted analyses using forward and backward deletion for variable selection with p < 0.05 according to the likelihood ratio test, considering all variables from univariate models with p < 0.1 as inclusion criteria. The following covariates were investigated: (a) as patient baseline characteristics: age, gender, main diagnosis, PIM II, surgery, type and duration of respiratory support, length of ICU stay and (b) as time-varying variables (time-matched with copeptin sampling): systolic blood pressure (continuous and categorized as hypo-/normotension), mean arterial blood pressure, vasopressor-inotrope use (yes/no) and treatment (VIS: continuous and categorized as 0/>0–10/>10), volume of fluid administration (continuous and categorized as >/≤100 mL/kg/d), steroid use and dose. The interaction of blood-pressure–copeptin association with vasoactive drugs, total fluids and steroid administration were additionally assessed. Continuous covariates were also clinically categorized as follows: age: 0–1 months, 1–12 months, 1–5 years, 5–12 years, ≥12 years; length of ICU stay: >/≤4 days; respiratory support : ≤24 h, 24–48 h, 48–168 h, >168 h; total fluids >/≤100 mL/kg/day; cardiopulmonary bypass (if performed): <60 min, 60–120 min, 120–180 min, >180 min; aortic cross clamping (if performed): <60 min, 60–120 min, >120 min.Secondary endpoints: The general change in copeptin levels between all consecutive time points  was assessed using two-sided paired p < 0.05, unless stated otherwise.Mechanistic modeling of the time course was initially planned but was not performed, as no typical kinetic pattern was observed. Statistical significance was set to n = 583 samples: n = 164 at T0 = ICU admission/study start, and n = 150/106/80/51/32 at median actual time (interquartile range) into the study of T1 = 14 h ; T2 = 37 h ; T3 = 61 h ; T4 = 108 h ; T5 = 179 h . Overall , the median copeptin was 46 pmol/L (20.4–114) (range: 2.4–1552.6 pmol/L). In total, 83 (50.6%) patients experienced at least one period of hypotension, corresponding to 211 out of 583 (35.2%) matched measurements with systolic blood pressure values and copeptin values obtained simultaneously. The changes in copeptin over time overall and stratified by hypotension are shown in Between December 2017 and June 2019, 170 patients were included in this study. One patient was discharged from the ICU before the first blood sample could be taken. For one patient, the caretakers signed the consent before a planned surgery, but the patient did not need postoperative intensive care unit admission. Out of the remaining 168 patients, 164 patients (characteristics: p = 0.36). Mean copeptin levels were higher in patients with hypotension ; mean copeptin levels at T0 were 43.5 pmol/L (geometric mean) in normotensive patients (=reference). We found eight patients with low copeptin values during arterial hypotension . For the primary analysis, the description of copeptin change between baseline and T3, there was no difference , and between T2 and T3 , a difference was found. Individual copeptin levels significantly decreased between T1 and T2: −0.52, corresponding to a mean individual change by −41%, p < 0.001.Furthermore, between T0 and T1 . Between the other time points, no significant change was observed .When considering the change in copeptin levels between all consecutive time points, individual copeptin levels significantly decreased between T3 and T4  were also found for surgery/type of surgery , study time , main diagnosis , age , systolic blood pressure ; association with mean arterial pressure: p = 0.034), steroid use (positive linear association with dose), total fluid volume (lower copeptin in patients with high fluid administration > 100 mL/kg/d compared to those receiving ≤100 mL/kg/d), length of stay (lower levels in patients staying ≤4 days compared to >4 days), invasive mechanical ventilation  and PIM II (log-transformed: positive linear association). No significant associations were found for the other covariates, including the interaction terms.The results of the mixed-effects linear regression of log-transformed copeptin values are shown in In the adjusted analysis, only the vasopressor-inotrope treatment  postoperatively. He died on the 15th postoperative day on ECMO due to acute bleeding complications following a surgical revision. His copeptin values were 33.3/12.6/16.6/10.7/28.7/17.7 pmol/L at T0–T5. These were well within the range of the other patients and did not point toward a non-favorable outcome. Third, we used PIM II score as a surrogate for severity of disease. The inclusion of PIM II score was based on availability in the study hospital. We extracted the actual PIM II score from patients’ medical records and did not calculate it because of the preference for real-world data. There might be newer scores  with higMedian copeptin concentrations were significantly elevated in critically ill children when compared to published copeptin values of healthy children. In addition, this study did not evidence a correlation between arterial hypotension and inadequate low copeptin concentrations. Therefore, copeptin’s potential role in guiding exogenous vasopressin administration seems to be limited in neonatal and pediatric intensive care patients. Importantly, copeptin was positively associated with clinical conditions reflecting disease severity and might be useful as a marker to predict short-term outcomes.


The 3-year cumulative incidence of 50% eGFR decline and KRT endpoint was significantly higher in DKD patients . The Cox regression analyses showed that the increased systolic blood pressure (SBP), DKD, decreased serum albumin (Alb), and higher CKD stages were risk factors for the 50% eGFR decline endpoint; the increased SBP, DKD, decreased serum Alb, serum creatinine (Scr), higher CKD stages, presence of proteinuria and CVD were risk factors for KRT endpoint; the increased age, decreased hemoglobin (Hb), decreased serum Alb were risk factors for all-cause death endpoint; the increased age, decreased serum Alb were risk factors for CVD events endpoint. Appropriate preventive or therapeutic interventions should be taken to control these predictive factors to delay the development of CKD complications, thereby improving the prognosis and reducing the disease burden of the high-risk populations.Diabetic kidney disease (DKD) is emerging rapidly as the leading cause of chronic kidney disease (CKD) worldwide. In this 3-year prospective, multicenter cohort study, a total of 1138 pre-dialysis CKD patients were recruited. Patients were categorized into two groups according to the etiologies of DKD and non-diabetic kidney disease (NDKD). Propensity score matching was performed to adjust for confounding factors, resulting in 197 patients being assigned to DKD and NDKD groups, respectively. The primary endpoints were 50% estimated glomerular filtration rate (eGFR) decline and initiation of kidney replacement therapy (KRT). The secondary endpoints were all-cause death and the development of cardiovascular disease (CVD) events. We found that DKD patients have a higher risk to develop 50% eGFR decline endpoint (HR:2.30, 95%CI [1.48–3.58],  A systeTherefore, the present prospective cohort study aimed to further evaluate the differences in prognosis between DKD and NDKD patients. The primary objective of the present study was to assess the long‐term outcome of 50% estimated glomerular filtration rate (eGFR) decline and kidney replacement therapy (KRT) events between DKD and NDKD patients. And the secondary objective was to compare the outcome of all-cause death and cardiovascular disease (CVD) events in DKD and NDKD patients. In this way, it can be elucidated whether patients with DKD carry a worse prognosis than NDKD patients, and prognostic risk factors can also be explored. It is anticipated that our study may provide some preventive or therapeutic interventions for CKD patients by controlling these associated risk factors. At the same time, the disease burden of CKD patients can be reduced and the quality of life and prognosis of CKD patients can be improved through effective prevention.2.2.1.et al. from the Dryad repository (DOI: 10.5061/dryad.kq23s). In conclusion, a total of 1138 CKD patients with stages 2–5 according to the Kidney Disease Improving Global Outcomes (KDIGO) classification who were not on dialysis from the Tokyo Medical and Dental University Hospital and its 15 affiliated hospitals in the Tokyo metropolitan area were recruited. Etiology of kidney disease in each patient was determined by the physician who was treating the patient at the time of enrollment, based on patients’ past histories, clinical characteristics and findings, and histological findings in biopsied kidney specimens [A 3-year prospective, observational, multicenter cohort study from the Chronic Kidney Disease Research of Outcomes in Treatment and Epidemiology (CKD-ROUTE) study was used for data analysis . The despecimens . This stpecimens ,10. And pecimens ,10.2.2.In our present study, the participants were divided into two groups according to the etiologies of CKD. DKD patients were defined as the DKD group and other types of CKD were defined as the NDKD group. Propensity score matching (PSM) (1:1) was performed using a logistic regression model to reduce potential confounding factors including gender, age, systolic blood pressure (SBP), body mass index (BMI), hemoglobin (Hb), serum albumin (Alb), serum creatinine (Scr), eGFR, the prevalence of CVD, the prevalence of hypertension, CKD stage, proteinuria, urinary occult blood, use of renin-angiotensin system inhibitors (RASI), use of calcium channel blocker (CCB), and use of diuretics. Individual propensity scores were calculated and patients between DKD and NDKD groups were matched using the nearest-neighbor matching algorithm with a caliper value = 0.02. After PSM, 197 patients were assigned to each group respectively. Therefore, a total of 394 CKD patients were analyzed in our present study.2.3.The primary endpoints in our study were composite kidney endpoints  includin2.4.t-test was used to compare normally distributed continuous variables between DKD and NDKD groups and presented as mean ± standard deviation , 95% confidence interval (CI), and P-value. Cox regression analyses were performed for the primary and secondary outcomes to further determine prognostic factors for 50% eGFR decline, KRT, all-cause death, and CVD events endpoints. The proportional hazard (PH) assumption was tested graphically through the Schoenfeld residual test for all variables using the cox.zph function in the survival R package. The variables that met the PH assumption were directly entered into the Cox proportional hazard models. The variables that didn’t meet the PH assumption were included in the model as time-dependent covariates (T_COV_variables: variables*ln(time)). Univariate Cox regression analyses were performed for all variables to calculate the p-values. Variables with a p-value <0.05 in the univariate Cox regression analyses were entered into multivariate Cox regression models to identify the independent risk factors for primary and secondary endpoints. All P values presented are based on two-tailed tests, and p < 0.05 was considered statistically significant.Cumulative hazard curves of the primary and secondary endpoints were analyzed 3.3.1.p > 0.05). Characteristics of the cohorts before and after PSM are presented in A total of 1138 CKD patients were recruited in the CKD-ROUTE study, including 851 NDKD patients and 287 DKD patients. Before PSM, the baseline characteristics were significantly different between DKD and NDKD groups. After PSM, a total of 394 patients (197 pairs) remained for further analyses and the matched groups were well‐balanced. There were no statistically significant differences between the two groups after PSM (3.2.p < 0.05). There were no significant differences in the incidence of secondary outcomes between the two groups (p > 0.05) (The primary outcomes (50% eGFR decline and initiation of KRT) and secondary outcomes  were defined as research endpoints in the present study. We calculated the 3-year cumulative incidence of endpoints and compared the differences in incidence between the DKD and NDKD groups. The results showed that the overall incidence of 50% eGFR decline, KRT, all-cause death, and CVD events were 20.30%, 28.68%, 10.15%, and 15.74%. The cumulative incidence of 50% eGFR decline, KRT, all-cause death, and CVD events for NDKD patients were 13.71%, 22.34%, 9.64%, and 13.71%. The cumulative incidence of 50% eGFR decline, KRT, all-cause death, and CVD events for DKD patients were 26.90%, 35.03%, 10.66%, and 17.77%. The incidence for primary endpoints was significantly higher in the DKD group than that in the NDKD group ( > 0.05) .3.3.p < 0.001) (p < 0.05) (p > 0.05)  and secondary outcomes  between two groups. The results revealed that patients with DKD have a significantly higher risk to develop 50% eGFR decline endpoint than those NDKD patients  . The ris < 0.05) . And NDK < 0.05) . No sign > 0.05) .Figure 1.Cumulative hazard curves of endpoints. Primary endpoints: (A). 50% eGFR decline endpoint, (B). KRT endpoint. Secondary endpoints: (C). All-cause death endpoint, (D). CVD events endpoint.3.4.p > 0.05). However, variables Scr and the prevalence of CVD violated the PH assumption in the KRT endpoint (p < 0.05). So, time-dependent covariates  were constructed in the analysis of the KRT endpoint. The detailed Schoenfeld residual plots can be seen in the Supplementary Materials .The PH assumption tests were performed for variables in each endpoint and the results showed that all the variables associated with 50% eGFR decline endpoint, all-cause death endpoint, and CVD events endpoint met the PH assumption (p < 0.05), DKD , decreased serum Alb , higher CKD stages  were independent risk factors for the progression of 50% eGFR decline endpoint , DKD , decreased serum Alb , Scr (HR: EXP(2.076–0.892*In(t)), p < 0.001), higher CKD stages , presence of proteinuria , prevalence of CVD (HR: EXP(2.813–0.894*In(t)), p < 0.001) were independent risk factors for KRT endpoint , decreased Hb level , decreased serum Alb level  were independent risk factors for all-cause death endpoint , decreased serum Alb level  were independent risk factors for CVD events endpoint .The Cox regression models for 50% eGFR decline, KRT, all-cause death, and CVD events endpoints were all statistically significant  and KRT endpoints . On the contrary, NDKD patients yielded a lower cumulative incidence of primary endpoints and a longer progression-free survival time compared with DKD patients. Therefore, compared with other etiologies of CKD, patients with DKD have a higher risk to progress to ESRD and require an earlier KRT which imposes substantial health and economic burden on patients and society.However, there was no significant difference between the two groups in the occurrence of secondary endpoint events including all-cause death and CVD events after PSM. The multivariate Cox regression analyses also showed that DKD is one of the risk factors for 50% eGFR decline and KRT endpoints but not for all-cause death and CVD events after adjusting for other potential confounding factors. It has been established that there is an enhanced inflammation and oxidative stress , activatTo further investigate the potential predictive factors for CKD endpoints, we performed the multivariate Cox regression analyses and we found that the increased SBP, DKD, decreased serum Alb, higher CKD stages were independent risk factors for 50% eGFR decline endpoint. Additionally, we also found that the increased SBP, DKD, decreased serum Alb, Scr, higher CKD stages, presence of proteinuria, prevalence of CVD were independent risk factors for the KRT endpoint; the increased age, decreased Hb level, decreased serum Alb level were independent risk factors for all-cause death endpoint; the increased age, decreased serum Alb level were independent risk factors for CVD events endpoint. Previous studies have proved that lower serum Alb level is associated with CKD progression  and is aWe also found that the increased SBP, DKD, higher CKD stage were risk factors for not only 50% eGFR decline endpoint but also KRT endpoint. In summary, these indicators were closely associated with the deterioration of kidney function. A previous study revealed that approximately 60% to 90% of CKD patients may be combined with hypertension , we alsoIn conclusion, this prospective multicenter cohort study based on the East Asian population suggests that DKD patients remain at a higher risk to develop 50% eGFR decline and KRT endpoints even after matching for the baseline characteristics. The increased SBP, DKD, decreased serum Alb, higher CKD stages were independent risk factors for 50% eGFR decline endpoint. The increased SBP, DKD, decreased serum Alb, Scr, higher CKD stages, presence of proteinuria, prevalence of CVD were independent risk factors for the KRT endpoint; the increased age, decreased Hb level, decreased serum Alb level were independent risk factors for all-cause death endpoint; the increased age, decreased serum Alb level were independent risk factors for CVD events endpoint. Attention should be paid to the high-risk population and early preventive or therapeutic interventions should be taken to delay the development of CKD complications, thereby improving the prognosis and reducing the disease burden of CKD patients.The present study exhibits some limitations. Despite a PSM design has been used to assemble a balanced cohort, potential biases may exist in unmeasured or unknown factors. Next, the CKD-ROUTE study is restricted to Japanese patients in East Asia, hence its generalizability to other races may be limited. In recent years, the application of sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors have largely improved the prognosis of DKD patients, therefore further studies are needed to investigate the outcomes between the two groups after treatment.Click here for additional data file.Click here for additional data file.Click here for additional data file.Click here for additional data file.


To observe the clinical effectiveness of noninvasive positive pressure ventilation in patients with respiratory failure complicated by diabetes.  From May 2021 to May 2022, 90 patients with respiratory failure complicated by diabetes treated in our hospital were recruited and randomly assigned to receive either medication (control group) or noninvasive positive pressure ventilation (study group), with 45 patients in each group. The clinical endpoint was therapeutic outcomes. P < 0.05). Patients with noninvasive positive pressure ventilation showed better pulmonary function indices versus those with medications (P > 0.05). There was no significant difference in arterial oxygen (PaO2), carbon dioxide partial pressure (PaCO2), and arterial oxygen pressure/inspired fraction of O2 (PaO2/FiO2) between the two groups prior to the intervention (P > 0.05). However, patients in the study group had significantly elevated PaO2 and PaO2/FiO2 and lower PaCO2 levels than those in the control group (P < 0.05). Following the intervention, noninvasive positive pressure ventilation resulted in significantly lower inflammatory factor levels versus medications (P > 0.05). After the intervention, markedly better glucose control was observed in the study group versus the control group (P < 0.05). The incidence of complications in the control group was 2.38%, which was significantly lower than that of the control group (16.67) (P < 0.05).  Noninvasive positive pressure ventilation resulted in significantly lower Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS) scores versus medications ( Noninvasive positive pressure ventilation effectively suppresses the inflammatory response, improves the blood gas analysis index, and eliminates the negative emotions of patients, thereby maintaining hemodynamic stability and improving clinical efficacy with a better safety profile. Further studies are recommended prior to clinical promotion. Chronic obstructive pulmonary disease (COPD) results in a high risk of respiratory failure, and given the decreased immunity of the body with age and physiologic changes related to breathing, COPD features a high prevalence among the elder population and compromises their respiratory function. Moreover, long-term respiratory insufficiency may result in chronic illnesses such as diabetes, and untimely or improper management of the disease is associated with a high risk of disease progression , 2. DiabMultiple therapeutic approaches such as low-flow oxygen inhalation and atomization therapy have been previously adopted for the management of respiratory insufficiency aggravated by diabetes. However, their efficacy remains much to be desired , 4. In tWith the advancement of medical technology, mechanical ventilation has made substantial progress in the treatment of severe respiratory failure and has shown significant therapeutic outcomes , 6. Noni2. In the study group, there were 29 males and 16 females, aged 66-85 (69.62 ± 6.85) years, disease duration of 3-10 (6.35 ± 1.48) years, and a BMI of 20-28 (23.82 ± 1.34) kg/m2. The patient characteristics between the two groups were comparable (P > 0.05).From May 2021 to May 2022, 90 patients with respiratory failure complicated by diabetes treated in our hospital were recruited and randomly assigned to receive either medication (control group) or noninvasive positive pressure ventilation (study group), with 45 patients in each group. The control group contained 23 males and 22 females, aged 65-84 (69.53 ± 6.78) years, disease duration of 2-9 (6.29 ± 1.43) years, and a body mass index (BMI) of 19-29 (23.73 ± 1.38) kg/mhttp://www.randomizer.org/). For concealment of allocation, the randomization procedure and assignment were managed by an independent research assistant who was not involved in the screening or evaluation of the participants.The randomization was carried out using an online web-based randomization tool .Patients who had confirmed respiratory failure by clinical examinationWith complete medical historyWith high complianceInclusion criteria  are the following:With neurological disordersWith insufficiency of important organsWith abnormal coagulation functionWith immune system disorders, systemic infections, or organic brain diseasesExclusion criteria are the following:2O (1 cm H2O is 0.098 kPa), and the inspiratory pressure was set to 4 cm H2O, gradually adjusting to 6 cm H2O according to the patient's state of health; the respiratory rate was maintained at 25 times per minute, and the oxygen flow was set to 8-12 mL/kg. The patient's physical signs were continuously monitored during treatment, including heart rate, blood pressure, and respiratory rate. The breathing rate was maintained at 20 times per minute, and the inspired oxygen concentration was maintained within 30%. A support pressure of 10 cm H2O may be applied externally.After admission, the control group received targeted drug treatment, including anti-infection, correction of electrolyte imbalance, nutritional support, blood gas analysis, and ECG monitoring. The study group adopted noninvasive positive pressure ventilation assistance. (a) The oxygen tube was connected to the side port of the mask, and a noninvasive ventilator was connected; (b) the breathing rate was reduced to S/T (lower than the respiratory rate selected by the researcher). In the early stage of the treatment, the initial pressure was set to 1.5 cm HAll patients received TCM decoction. The ingredients of the decoction include 30 g of gypsum and yam each, 15 g of Trichosandra, 15 g of astragalus, 10 g of dodder, 10 g of Poria cocos, 10 g of Anemarrhena, 5 g of dried radix rehmanniae, 5 g of Ophiopogon japonicus, and 5 g of Scrophulariaceae, which were decocted with water and administered once daily, with a half dose administered in the morning and a half in the evening.The Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS) were used to assess the patient's psychological status before and after the intervention. According to the scale, there are 20 items and a 4-level scoring method. A total score of SAS > 50 and SDS > 50 indicate anxiety and depression.Before and after the intervention, the forced vital capacity (FVC), forced expiratory volume in one second (FEV1), FEV1/FVC, maximum voluntary ventilation (MVV), and maximum carboxylation capacity (VCmax) of the patients were assessed.2), carbon dioxide partial pressure (PaCO2), arterial oxygen pressure/inspired fraction of O2 (PaO2/FiO2), and the oxygenation index.Arterial blood gases were measured before and after the intervention to determine the arterial oxygen  and C-reactive protein (CRP) were measured using the enzyme-linked immunosorbent assay.Fasting blood glucose and glycosylated hemoglobin levels were measured before and after the intervention. Between the two groups, complications such as respiratory muscle weakness, ventilator-associated pneumonia, and acute pulmonary edema were recorded.t-test for normally distributed variables and the Mann–Whitney U test for nonnormal variables. The data were analyzed with the software SPSS 20.0. The count data were expressed as “n (%)” and analyzed using the chi-square test. The measurement data were expressed as mean ± standard deviation . Noninvasive positive pressure ventilation resulted in significantly lower SAS and SDS scores versus medications (P < 0.05) (SAS and SDS scores did not differ significantly between the two groups prior to the intervention ( < 0.05) .P > 0.05) (Patients with noninvasive positive pressure ventilation showed better pulmonary function indices versus those with medications ( > 0.05) .2, PaCO2, and PaO2/FiO2 between the two groups prior to the intervention (P > 0.05). However, patients in the study group had significantly elevated PaO2 and PaO2/FiO2 and lower PaCO2 levels than those in the control group (P < 0.05) (There was no significant difference in PaO < 0.05) .P > 0.05). Following the intervention, noninvasive positive pressure ventilation resulted in significantly lower inflammatory factor levels versus medications (P > 0.05) (There was no significant difference in the levels of inflammatory factors between the two groups prior to the intervention ( > 0.05) .P < 0.05)  .P < 0.05) The incidence of complications in the control group was 2.38, which was significantly lower than that of the control group (16.67) . Noninvasive positive pressure ventilation resulted in better outcomes in terms of the above indices versus medications (P < 0.05), suggesting that this method can be used to effectively improve the arterial blood gas index and effectively mitigate the inflammatory response of the body. The reason may be that timely ventilation clears secretions of the respiratory tract and bronchi, enhances partial pressure of oxygen in the body while dredging the trachea, corrects hypoxemia, improves breathing conditions, and promotes the recovery of arterial blood gas indices. Moreover, ventilation drains sputum, improves respiratory dysfunction, and reduces respiratory muscle fatigue, thereby enhancing tissue oxygen supply, acid-base balance disorders, and compensation for water and electrolyte imbalances. Several studies have shown that noninvasive ventilation could improve gas exchange, correct hypoxemia, control hypercapnia, and improve cardiac function. At this stage, anaerobic glycolysis is converted to aerobic oxidation, which increases glucose metabolism, decreases liver glycogen disintegration and release, and raises blood sugar levels. The vagus nerve and cardiopulmonary receptors are activated to promote insulin sensitivity [Noninvasive ventilation can effectively correct hypoxia, reduce COsitivity –17.Furthermore, the present study revealed a lower incidence of complications in the study group (2.38%) versus the control group (16.67%), indicating a high safety profile. It has been stated that noninvasive positive pressure ventilation should be used as early as possible to dilate the pulmonary blood vessels of patients, thereby maintaining pulmonary functional residual capacity, reducing intrapulmonary shunts, improving pulmonary ventilation, decreasing respiratory failure symptoms, reducing inflammation caused by hypoxia, and accelerating recovery . The reaNoninvasive positive pressure ventilation effectively suppresses the inflammatory response, improves the blood gas analysis index, and eliminates the negative emotions of patients, thereby maintaining hemodynamic stability and improving clinical efficacy with a better safety profile. Further studies are recommended prior to clinical promotion. However, it is worth noting that the operation of noninvasive positive pressure ventilation differs from invasive ventilation in that more emphasis is placed on the standardization of the operation and adequate communication with the patient. The standard of operation is directly related to the effectiveness of noninvasive positive pressure ventilation –24.The present study has the following limitations: (1) the small sample size in this trial failed to objectively evaluate the significant differences between the two groups. (2) This study used more subjective efficacy assessment criteria, and the subjective perceptions of individuals differed greatly, resulting in difficulties in providing an absolutely objective and accurate description of the ratings on the scale. (3) The follow-up period after treatment in this trial was short, which failed to observe the long-term treatment effect.In conclusion, noninvasive positive pressure ventilation effectively suppresses the inflammatory response, improves the blood gas analysis index, and eliminates the negative emotions of patients, thereby maintaining hemodynamic stability and improving clinical efficacy with a better safety profile. Further studies are recommended prior to clinical promotion.


BackgroundHypertension (HTN) is endemic in India and it is considered a public health challenge in both economically developed and developing nations. Unfortunately, despite its high prevalence, its awareness, treatment, and control status are low in urban as well as rural Indian populations.ObjectivesTo determine the burden of hypertension and prehypertension in a Community Health Center (CHC) and to find the association of hypertension with the age group and sex of study subjects.MethodologyA cross-sectional study was carried out among 713 patients of age 20 years and above attending the Out Patient Department (OPD) of the Community Health Centre (CHC), Barwala in the Hisar district of Haryana. JNC 7 classification of blood pressure was used to diagnose hypertension. The collected data was analysed using the Statistical Package for Social Sciences (SPSS) version 20.0. Appropriate statistical tests were used.ResultOut of the total patients enrolled, 200 (28.1%) were found to be hypertensives. The burden of prehypertension was further observed to be 28.1%. About (61.6%) of OPD patients were female. Among hypertensive patients, nearly half (48.8%) were in the age group of 60-80 years whereas the majority of the hypertensives (56%) were females.ConclusionIn our study, more than 50 percent of OPD patients were found to have hypertension and pre-hypertension. Health-seeking behavior was more among females. Hypertension (HTN), among other non-communicable diseases, is endemic in India . It is c<0.05 was considered statistically significant. Ethical clearance was obtained from the Institutional Review Board (IRB) of Maharaja Agrasen Medical College, Agroha vide reference no. MAMC/Pharma/IEC/19/14 of Institutional Ethics Committee for Human Research before starting the study. Informed and written consent was obtained before enrolling the patients.A cross-sectional study was carried out among 713 patients aged 20 years and above attending the out-patient department (OPD) of the Community Health Center (CHC), Barwala in the Hisar district of Haryana, in North India. CHC Barwala caters to 8 Primary Health Centers namely Barwala, Dhansu, Agroha, Landhri, Uklana, Pabra, Daulatpur, and Hasangarh, and covers a population of approximately 157,981. The total OPD census was 8640 during the period of data collection. The study was conducted from March 2019 to August 2019. A formula for cross-sectional study for calculation of sample size was used before proceeding with the study. Assumptions made for the calculation of sample size were based on NFHS 4 data with an expected prevalence of hypertension to be 22.4%, an alpha error of 5%, and an acceptable error in the measurement to be 3%. Study subjects were initially chosen by selecting the first patient randomly from one to five by lottery method then every 5th study subject was chosen by systematic random sampling. All patients aged 20 years & above including pregnant females who attended OPD of CHC, Barwala, and willing to participate were included in the study. However, patients with any acute severe illness and any women with pregnancy-induced hypertension were excluded from the study. Variables such as name, age, sex, and BP readings were recorded in a register. JNC 7 classification of blood pressure for adults was used to classify the BP readings into normal, prehypertension, and hypertension. Cut-off values for BP were taken as patients with either systolic BP ≥ 140 or diastolic BP ≥ 90 or both were considered hypertensive. Patients with either systolic BP between 120-139 mmHg or diastolic BP between 80-89mmHg or both were considered as prehypertensive. Blood pressure was measured by using an aneroid sphygmomanometer. Participants were made to sit quietly for at least 5 minutes with the back supported by the chair backrest, with feet on the floor and arms supported at heart level. The BP measurements were performed on the left arm after resting the arm on the table at the level of the heart. Systolic blood pressure (SBP) was noted at the point when the first of two or more Korotkoff sounds heard (onset of phase 1) and the disappearance of Korotkoff sound (onset of phase 5) was used to define diastolic blood pressure (DBP). Patients with either systolic BP ≥ 140 or diastolic BP ≥ 90 or both were considered as hypertensive. BP was measured by a primary care physician. The average of the 2 blood pressure readings, as recommended by JNC 7, was taken. The collected data were analyzed using the Statistical Package for Social Sciences (SPSS) version 20.0. Appropriate statistics  were applied to draw relevant inferences. A p-value of Among 713 patients attending the OPD, 200 (28.1%) patients were found to be hypertensive and 513 (71.9%) patients as non-hypertensive (180 as prehypertensive and 333 as normotensive). The overall burden of hypertension and prehypertension was observed to be 28.1% and 25.2% respectively . The burden of hypertension was maximum (48.8%) in the age group of 60-80 years. The observed difference between increasing age and the burden of hypertension was found to be statistically significant (p<0.001). Among males and females, the burden of hypertension was found to be 32.1% and 25.5% respectively. The observed difference between sex and the burden of hypertension was not found to be significant (p = 0.056). The mean systolic BP of hypertensive patients and non-hypertensive patients were 152.35 ±13.85 mmHg and 110.75±13.49 mmHg respectively, and this difference between mean systolic BP of the two groups was found to be statistically significant (p = 0.001). The mean diastolic BP of hypertensive patients and non-hypertensive patients were 97.09 ± 10.13 mmHg and 70.64 ± 9.08 mmHg respectively, and this difference between the mean diastolic BP of the two groups was found to be statistically significant (p = 0.001)  of them were in the age group of 40-59 years. The majority of OPD patients (61.6%) were females. The observed difference between age group and sex was found to be statistically significant (p=0.01) Table . This siA meta-analysis conducted in 2014 by Anchala et al.  found a Other studies which reported a higher prevalence of hypertension were those carried by Awino et al.  (36.9%) A much lower prevalence was also found in some studies carried out by Gudina et al.  (13.2%) Age group-wise comparison of hypertensionAge is known to be an important risk factor for hypertension. As age advances, so did the prevalence of hypertension among both sexes. Similar findings were reported in our study where hypertensive were older (51.62 ±12.82) as compared to non-hypertensive (42.36 ±12.61) which was found to be statistically significant at p<0.001. This finding was consistent with a study done by Siddiqui et al.  in whichIn our study, the number of hypertensive patients increases with increasing age groups. In lower age groups (20-39 years), 11% of patients reported having hypertension, followed by 32.6% and 48.8% in 40-59 years and 60-80 years, respectively, which was statistically significant with a p-value <0.001. Kafle et al. , DhunganSex-wise comparison of hypertension. This study reported a prevalence of hypertension among males to be 38.4%, and a 28.4% prevalence of HTN was reported among females. [In the current study, among 713 OPD patients, 32.1% of males and 25.5% of females are reported to have HTN. Almost similar prevalence was reported by a study carried out by Dhungana et alfemales.  (male: 4females.  (male 38females. . In thisfemales. ,25,26.Despite our efforts, this study had some limitations which have been accounted for while analyzing and reporting the findings of the study. One of the limitations of the study was that the patients were enrolled in a government-operated healthcare facility. This may not reflect the actual burden in the population. This was primarily due to operational feasibility.The present study confirmed a high burden of hypertension in the study area. It was also found that the burden of hypertension increased significantly with advancing age. Therefore, it is necessary that effective preventive and control measures are implemented with a special focus on the geriatric age group. Further, one-fourth of people were categorized as pre-hypertensives and hence, control strategies for the prevention of hypertension should be implemented with a special focus on preventing the progression of prehypertensives to hypertensives. Health camps should be routinely organized.


Excessive plantar pressure leads to increased risk of diabetic foot ulcers. Diabetic peripheral neuropathy (DPN) and peripheral arterial disease (PAD) have been considered to be associated with alterations in gait and plantar pressure in diabetic patients. However, few studies have differentiated the effects with each of them.  To investigate the plantar pressure distribution in diabetic patients, with DPN and PAD as independent or combined factors.  112 subjects were recruited: 24 diabetic patients with both DPN and PAD (DPN-PAD group), 12 diabetic patients with DPN without PAD (DPN group), 10 diabetic patients with PAD without DPN (PAD group), 23 diabetic patients without DPN or PAD, and 43 nondiabetic healthy controls (HC group). The in-shoe plantar pressure during natural walking was measured. Differences in peak pressure, contact area, proportion of high pressure area (%HP), and anterior/posterior position of centre of pressure (COP) were analysed.  Compared with HC group, in DPN-PAD group and DPN group, the peak pressures in all three forefoot regions increased significantly; in PAD group, the peak pressure in lateral forefoot increased significantly. The contact area of midfoot in the DPN-PAD group decreased significantly. PAD group had larger HP% of lateral forefoot, DPN group had larger HP% of inner forefoot, and DPN-PAD group had larger HP% of total plantar area. There was a significant tendency of the anterior displacement of COP in the DPN-PAD group and DPN group. No significant differences were observed between the D group and HC group.  DPN or PAD could affect the plantar pressure distribution in diabetic patients independently or synergistically, resulting in increased forefoot pressure and the area at risk of ulcers. DPN has a more pronounced effect on peak pressure than PAD. The synergistic effect of them could significantly reduce the plantar contact area of midfoot. Diabetic patients are prone to many complications during the course of disease. Diabetic foot syndrome is one of the most serious chronic complications of diabetes mellitus, leading to foot ulcers or even lower extremity amputation. Diabetic foot ulcer (DFU) is the most common cause of nontraumatic limb amputation . It is eDFU is associated with multiple factors. The main pathophysiological factors include peripheral neuropathy, macroangiopathy, and the repetitive trauma caused by increased plantar pressure . Other cDiabetic peripheral neuropathy (DPN) is a common complication in diabetic patients. DPN could lead to reduced peripheral sensation and compromised proprioceptive feedback control of human locomotion . Motor nPeripheral arterial disease (PAD) is a progressive disease caused by the atherosclerosis that leads to ischemia of lower limb tissue and promotes the development of ulcers . There wPrevious studies have mainly focused on the plantar pressure in diabetic patients with neuropathy rather than vasculopathy. Moreover, few studies have removed the influences of PAD in patients with DPN or removed the influence of DPN in patients with PAD. Thus, there was a gap in knowledge about how DPN and PAD affect plantar pressure in diabetic patients independently or synergistically. The aim of this study was to investigate the characteristics of in-shoe plantar pressure during natural walking in diabetic patients with DPN or PAD, more specifically, to assess the plantar pressure parameters in diabetic patients “with DPN and PAD,” “with DPN without PAD,” “with PAD without DPN,” and “without DPN or PAD.” Identifying the changes in plantar pressure could contribute to awareness of the risks of diabetic complications and help improve therapy interventions such as exercise programs or therapy footwear.112 subjects were recruited in this study: 24 diabetics with DPN and PAD (DPN-PAD group), 12 diabetics with DPN and no PAD (DPN group), 10 diabetics with PAD and no DPN (PAD group), 23 diabetics without either DPN or PAD (D group), and 43 nondiabetic healthy controls (HC group). Patients were recruited from Tianjin Medical University Chu Hsien-I Memorial Hospital. The study was approved by the Institutional Review Board of Tianjin University of Science and Technology. All experiments were performed in accordance with the World Medical Association's Declaration of Helsinki. Subjects involved were informed of the research procedure and signed the informed consent. Demographic and anthropometric data of subjects are shown in Data of age, height, weight, and BMI were obtained from medical records or by interview. The diagnosis of DPN and PAD and HbA1c levels were obtained from medical records of diabetes patients. Subjects were excluded if they had any of the followings: current or a history of foot ulcers, foot deformity, lower limb amputations in either limb, and unable to walk repeatedly unaided over a distance of 10 m. The presence of intermittent claudication was not considered in PAD patients. In this study, the plantar pressure data of subjects were collected for walking 10 meters, which was much shorter than the distance of the onset of intermittent claudication . In addition, several studies have revealed altered gait parameters in PAD patients both with and without intermittent claudication , 24.The plantar pressure experiment was carried out with T&T Medilogic 5.8.1 measurement system . The dynamic sampling frequency was 300 Hz. Uniform flat shoes and thin cotton socks with suitable sizes were assigned to subjects. All subjects walked 10 meters on a straight walkway with self-selected speed and stride length.The plantar pressure in steady gait cycle was included for analysis, and data of initial and terminal stage were excluded to eliminate the effects of acceleration and deceleration. The plantar area was segmented into 7 regions, namely, toes, lateral forefoot, inner forefoot, medial forefoot, midfoot, lateral heel, and medial heel, respectively. The schematic image of plantar regions is shown in The trajectory of centre of pressure (COP) formed butterfly diagram. The anterior/posterior position of COP was the distance between the intersection point of butterfly diagram and the zero position , as shown in Statistical analysis was performed using SPSS software 21.0 . Mean and standard deviation of each group were calculated. Kolmogorov–Smirnov test was performed to assess normal distribution. One-way ANOVA was performed to analyse the differences of plantar pressures between the four diabetic groups and control group, and the significant level of the differences was 0.05.The absolute peak pressures are shown in The normalized peak pressures and the results of difference analysis between groups are shown in The normalized plantar contact area is shown in The HP% of segmented plantar regions is shown in The normalized anterior/posterior position of COP is shown in As shown in Although the difference of peak pressure in inner forefoot in PAD group was not significant compared with HC group, it also showed increasing tendency and the pressure level was close to that of DPN-PAD group. This suggested that the alteration of plantar pressure in diabetic patients with PAD began in lateral forefoot, followed by inner forefoot. Atherosclerosis resulted in insufficient oxygen and nutrients. Long-term vasculopathy causes altered muscle morphology and mitochondrial function, resulting in decreased muscle strength . Myers eTo the author's knowledge, the plantar contact area during walking in these specific populations has not been reported. Pataky et al.  reportedIn DPN group, no significant differences of segmented contact area were observed, but significant increase of peak pressures were observed in all three forefoot regions. This suggested that the increased peak pressure may not be due to the altered contact area, but to the tendency of the anterior displacement of weight-bearing, which was confirmed by the results in Another important parameter analysed in this study was the proportion of the high pressure area. Owings et al.  investigA noteworthy result in our study is that compared with the HC group, no significant differences of plantar pressure parameters were observed in the D group. The consistent results have been found in other study . HoweverHowever, the lack of significant differences between the D group and HC group differs from Pataky's . They foA potential limitation of this study is that the microvascular complications such as nephropathy and retinopathy was not considered. Future research on potential factors associated with macroangiopathy and microangiopathy could be helpful to further understand the mechanism of the plantar pressure alteration in diabetic patients. The current results could be considered as a preliminary demonstration of the independent and synergistic effects of DPN and PAD on plantar pressure in diabetic patients.The current study provides the evidence for learning the independent or synergistic effects of peripheral neuropathy and peripheral arterial disease on plantar pressure in diabetic patients. Identifying the changes in plantar pressure distribution helps to carry out physical therapy interventions, such as exercise program, offloading footwear, and therapeutic orthosis. The alteration of plantar pressure in diabetic patients was a gradual process, and significant changes occurred after the combination of DPN or PAD. DPN and PAD could independently affect plantar pressure in diabetic patients, leading to higher pressure in forefoot and larger area at risk of ulcers. The prevention and/or control of DPN and PAD and the redistribution of plantar pressure from forefoot onto the whole foot should be highlighted in clinical practice.


Stroke volume (SV)/LA volume (LAV), another index for LAV overload, was not a significant prognostic factor of re-admission for HF during this time. Conclusion: LA overload was an important prognostic factor for HF re-readmission during the first year after enrolment in patients with HFpEF, but the indices relating to LA overload differed by sex.Objective: We aim to clarify the differences in the association between re-admission for heart failure (HF) and left atrial (LA) overload indices by sex in heart failure and a preserved ejection fraction (HFpEF). Methods: We analyzed 898 HFpEF patients hospitalized for acute decompensated HF. Blood tests and transthoracic echocardiography were performed before discharge. The primary endpoint was re-admission for HF during the first year. Results: The ratio of diastolic elastance to arterial elastance ( There is considerable variation in the relationships between the relative indices of left atrial (LA) volume and pressure , which cWe enrolled 898 patients with prognostic data recruited (June 2016–February 2020) from the Prospective Multicenter Observational Study of Patients with Heart Failure with Preserved Ejection Fraction (PURSUIT HFpEF) registry   at dischWe previously reported the method for data collection and follow-up/clinical outcome . SurvivaLaboratory data, such as levels of creatinine and NT-proBNP, and TTE parameters were examined when patients were stabilized before discharge. Estimated glomerular filtration rate (eGFR) was calculated using the standard method. Blood pressure and heart rate measurements were performed along with the echocardiographic examination and were recorded according to the American Society of Echocardiography or European Society of Echocardiography guidelines ,13. VoluThis research was conducted without patient involvement. The PURSUIT HFpEF registry was managed in accordance with the principles of the Declaration of Helsinki. The study protocol was approved by the ethics committee of each participating hospital. The protocol  was approved by the ethics committee of Yao Municipal Hospital (2016-No.0006). All participants provided written informed consent regarding the design and conduct of the study during the indexed hospitalization. We performed only essential examinations in routine clinical practice.Continuous variables are expressed as mean ± standard deviation, whereas categorical variables are presented as frequencies and percentages. Intergroup differences in categorical variables were assessed using the chi-square test, while those for continuous variables were assessed using Student’s t-test. Each cutoff point of the prognostic factors for re-admission for HF was evaluated using receiver operating characteristic (ROC) curve analysis . To havep < 0.05 in general analyses and was set at p < 0.1 for an interaction analysis. All statistical analyses were performed using EZR , a graphical user interface for R .Statistical significance was set at A comparison of the clinical and laboratory characteristics and medications between men and women is shown in In a comparison of the clinical data between the patients with low and high LAVI before discharge, age, systolic blood pressure, NT-proBNP and eGFR levels, and the incidence of male sex and atrial fibrillation were significantly different between the two groups . In thosp = 0.006) and E/e’  were also significant prognostic factors during the first year.For re-admission for HF, age, LAVI, Ed/Ea, and eGFR and NT-proBNP levels were all significant factors during the first year in the univariable Fine–Gray analysis . SV/LAV p = 0.130) or E/e’ in place of Ed/Ea  was not significant for re-admission for HF in the multivariable Fine–Gray analysis. In the multivariable Fine–Gray analysis by adjusting for comorbidities in all patients, NT-proBNP level and LAVI, but not age, eGFR level, or Ed/Ea, were significant prognostic factors during the first year in all patients . SV/LAV p = 0.280). When SV/LAV ratio was used in place of LAVI in the multivariable model, SV/LAV ratio was not significant during the first year in women . In the Fine–Gray model, the interaction for sex was significant only in Ed/Ea (p = 0.078, When the analysis was performed in each sex, a marked difference was observed between the sexes. In men, Ed/Ea and NT-proBNP level were significant for this endpoint, and LAVI was only a significant prognostic factor in women during the first year . When E/In men, Ed/Ea in association with NT-proBNP level was significant for re-admission for HF during the first year in patients with HFpEF. However, LAVI, but not SV/LAV ratio, was significant for re-admission for HF in women.In older patients, a reduction in the number of HF admissions may be essential in real-world clinical practice. We previously reported that SV/LAV ratio, but not LAVI, is a significant prognostic factor for HF re-admission during the three years after discharge in patients with HFpEF . LA voluOnce the left atrium is enlarged, it does not shrink even after a substantial volume reduction. Any disease except for certain valvular diseases does not induce only LA volume or pressure overload. LAV is an indicator of a long-term LV filling pressure elevation, and a morphologically enlarged LAV may be a secondary phenomenon. The cardiothoracic ratio and LAVI in patients with HFpEF are larger in women than in men , althougIn contrast, it may be difficult to enlarge the left atrium during the short-term period in men, leading to higher LA pressure, resulting in the finding that Ed/Ea, a relative index for LA pressure overload, was a determining factor for HF re-admission during that time in men. A positive interaction of Ed/Ea between sexes for HF re-admission strongly suggests this issue. In other words, apparent LA enlargement may not be a useful marker for HF re-admission in men.We included laboratory data in the multivariable Fine–Gray model by adjusting for comorbidities and revealed a significant association with NT-proBNP level in men, but not in women, during the first year in the case of re-admission for HF. The reason for this between-sex difference is as yet unclear. NT-proBNP level may reflect the extent of LA pressure overload more than that of LA volume overload if LV performance is the same. Since LV enlargement might be a long-term change in HFpEF, the time from first diagnosis of HF or structural heart disease to index hospitalization may be taken into account in the analysis.Current treatment strategies in HFpEF are limited, but there are now promising results using SGLT2 inhibitors that show significantly reduced cardiac death or hospitalization for HF ,18. HoweLA overload was an important factor for HF re-readmission in older patients with HFpEF, although the indices for LA overload differed by sex during the first year.


We evaluated biomarkers related to kidney fibrosis for the outcome of patients with IgA nephropathy (IgAN). Clinical parameters  and histological findings were assessed in 134 patients with IgAN at the time of diagnosis and followed up prospectively . We measured biomarkers of collagen and laminin turnover in serum and urine collected at the time of kidney biopsy using a novel enzyme-linked immunosorbent assay. Linear discriminant analysis and logistic regression models were used to predict the patient’s kidney outcome. Five serum and urine biomarkers of laminin and collagen turnover  could significantly differentiae IgAN patients with a worse prognosis. Clinical parameters (glomerular filtration rate (GFR), proteinuria) distinguished patients at risk of IgAN progression with a specificity of 87.3% and a sensitivity of 45.2% (area under the curve-AUC 0.751). The addition of the biomarkers significantly increased the prognostic ability with a specificity of 85.1% and a sensitivity of 73.3% (AUC 0.905). We have identified three serum  and two urinary markers  that significantly improve the prognostic ability of markers of kidney function to identify an IgAN patient’s risk of progressing to ESKD. IgA nephropathy (IgAN) is the most common primary glomerulonephritis with severe prognosis, and will see 30–50 % of patients developing end stage kidney disease. The main hallmark of chronic kidney diseases (CKD) is kidney fibrosis, which is caused by an imbalance between extracellular matrix formation and degradation ,2. The eIn our study we evaluated serum and urine biomarkers of extracellular matrix turnover in patients with IgAN. The biomarkers we evaluated in our study, such as sPRO-C6 , sPRO-C3 , uPRO-C6/Cr , uPRO-C3/Cr , serum LG1M (fragment of MMP-laminin γ 1degragation) and urinary C3M/creatinine  are related to kidney fibrosis, which has been proven and described previously in other publications. We hypothesized that markers related to kidney fibrosis might help to predict kidney outcome in patients with IgAN and subsequently lead to targeted treatment with respect to active or chronic lesions.We evaluated 134 Czech patients with biopsy-proven IgAN and a mean follow-up of 56.5 months. A total of 91 men with an average age of 45.9 years and 40 women with an average age of 42.4 years were examined in our cohort. All subjects were Caucasians. We divided the patients into three groups according to the changes of kidney function. The non-progressor group (NONPROG) included patients with a stable kidney function (mean decrease in the level of serum creatinine of 4% at the end of follow-up), the progressor group (PROG) included patients with a mean increase of serum creatinine at least of 35% at the end of the follow-up, and the end-stage kidney disease group (ESKD) included patients with a mean increase of the level of serum creatinine of 125% with the necessity of kidney replacement therapy by the end of the follow-up. The mean age of patients was 43.8 years for NONPROG, 48.8 years for PROG and 42.2 years for ESKD . The repBasic statistical data of clinical and biochemical parameters at the time of biopsy are shown in NONPROG; PROG; ESKD: classification according to clusteringNONPROG: average concentration of S-creatinine decreased by 4%PROG: average concentration of S-creatinine increased by 35%ESKD: average concentration of S-creatinine increased by 125%sLG1M—levels of a fragment of MMP-laminin γ 1degragation measured in serum at the time of biopsy (ng/mL)sPRO-C3—levels of the N-terminal pro-peptide of collagen type III measured in serum at the time of biopsy (ng/mL)sPRO-C6—levels of the C-terminal pro-peptide of collagen type VI in serum measured at the time of biopsy (ng/mL)uC3M/Cr—levels of a fragment of MMP-mediated degradation of collagen type III measured in urine  at the time of biopsy (ng/mg)uPRO-C6/Cr—levels of the C-terminal pro-peptide of collagen type VI measured in urine  at the time of biopsy (ng/mg)uPRO-C3/Cr—levels of N-terminal pro-peptide of collagen type III measured in urine  at the time of biopsy (ng/mg)eGFR—estimated glomerular filtration rate at the time of biopsy (ml/min)PU—proteinuria (g/24 h)CRP—C-reactive protein (mg/L)Creatinine in serum (µmol/L)Classification according to progressive changes in creatinine (3 groups):p value was 0.001)  .We evaluated clinical parameters and biochemical markers and their ability to differentiate patients according to potential progression of kidney insufficiency. Using the Kruskal–Wallis test, we determined clinical parameters and biochemical markers that correlated with the probability of kidney failure in our cohort. Biomarkers and clinical parameters with a p-value less than 0.0001 were able to differentiate patients with a severe course of the disease with statistical significance. These markers allowed us to identify patients with a worse prognosis for kidney survival. Biochemical markers sLG1M, sPRO-C3, sPRO-C6, uC3M/Cr, uPRO-C6/Cr and clinical values of proteinuria, creatinine and eGFR were the biomarkers that could significantly separate patients into PROG+ESKD and NONPROG .Patients in our cohort who were in the ESKD group already had severe renal insufficiency at the time of biopsy, while some already met the parameters of kidney failure at the time of biopsy. These patients would not benefit from immunosuppressive treatment, therefore we excluded the ESKD group from the next measurements. We focused on identifying patients with a worsening kidney prognosis during the follow-up (PROG); these patients may benefit significantly from immunosuppressive treatment. We evaluated the prognostic potential of kidney function at the baseline for the risk of kidney outcome (differentiation of PROG and NONPROG). We tried to develop several prediction models, always using one variable , but sensitivity and specificity of individual clinical parameters and biomarkers for differentiating the PROG and NONPROG groups were not sufficient for any of those models. .Using a combination of all biomarkers, we achieved an improvement in the prediction of kidney outcome  compared to clinical parameters—eGFR and proteinuria . High sensitivity corresponds in our model to a good ranking of PROG patients and high specificity corresponds to a good ranking of NONPROG patients. .We built a model including the serum and urine biomarkers sLG1M, sPRO-C3, uPRO-C3/Cr, sPRO-C6, uPRO-C6/Cr, uC3M/Cr and eGFR and proteinuria. The addition of serum and urine biomarkers of extracellular matrix remodeling significantly improved the discriminatory ability of the markers of kidney function. The model had an accuracy of 82.9%, and the area under curve (AUC) was 0.905. .We then evaluated a model combining the markers of kidney function (eGFR), proteinuria and histological findings (MEST). The model had sensitivity of 35.9% and specificity of 100.0%, (AUC = 0.856) , showingAdding histological findings (MEST) to the model, including markers of kidney function and biomarkers of extracellular matrix remodeling, allowed us to obtain an almost perfect discrimination between PROG and NONPROG: sensitivity 56.3 %, specificity 100.0% (AUC = 0.986) .Formation and progression of interstitial kidney fibrosis is the most common pathway leading to loss of kidney function . PresencLaminins are glycoproteins containing an α, β, and γ chain, which are a major component of the basement membranes . LamininIn our study, we did not confirm a correlation between serum LGM1 levels and poor kidney prognosis. A statistically significant ability to predict worsened kidney outcome was demonstrated using only the whole block of biomarkers .Collagen type III is synthesized as procollagen containing a pro-peptide extension at both ends of the molecule. Increased concentration of N-terminal type III collagen pro-peptide (PRO-C3) occurs in many clinical conditions, where there is disintegration or accumulation of connective tissue, for example fibroproliferative, hematologic and malignant diseases . In a stIn the study with 500 patients with kidney impairment, PRO-C3 (a marker of collagen type III formation) and C3M  were measured in serum and urine using competitive enzyme-linked immunosorbent assays (ELISA). Urinary levels of C3M were inversely and independently associated with CDK progression and development ESKD and serum levels of PRO-C3 were associated with a risk of death . Using serum or urinary PRO-C3 alone, we were unable to identify patients with an increased risk of kidney failure with sufficient sensitivity. However, an association with impaired kidney prognosis was demonstrated using clinical parameters  and serum and urine biomarkers . In this case, the sensitivity of identifying high-risk patients was even higher than when using MEST.Alternative pathway complement activation can be demonstrated in patients with IgAN and Henoch–Schönlein purpura (HSP) ; in patiWe hypothesized an association between CRP and the development of kidney insufficiency, but this relation could not be demonstrated.p < 0.0001), with lower levels detected in the urine of patients with advanced CKD . We demonstrated that serum and urine biomarkers related to kidney fibrosis such sPRO-C6, sPRO-C3, uPRO-C6/Cr, serum LG1M and urinary C3M/creatinine predicted kidney outcome of patients with IgAN in the cohort of Czech IgAN patients. Serum and urinary markers of fibrosis in combination with clinical parameters  significantly increase the ability to identify patients at risk of progression of kidney insufficiency. Serum and urine fibrosis markers in our cohort reliably predict an unfavorable prognosis of the disease even without the use of histological parameters. The ability to predict a worsened prognosis of kidney disease using serum and urine biomarkers could help identify patients who should receive the immunosuppressive treatment even repeatedly during the course of the disease and thus avoid kidney re-biopsy. The results of our study are limited by the use a small file of patients of one ethnicity. In the future, it will be necessary to confirm our conclusions on larger files. In order to extend the clinical applicability of the findings it will also be necessary to expand the study to include research on patients of other ethnicities.


Chronic kidney disease (CKD) is one of the strongest risk factors for hypertension, and hypertension can exacerbate the progression of CKD. Thus, the management of CKD and antihypertensive therapy are inextricably linked. Research over the past decades has shown that the human kidney is more diverse than initially thought. Subjects with low nephron endowment are at increased risk of developing CKD and hypertension, which is consistent with the theory of the developmental origins of health and disease. Combined with other lifetime risks of CKD, hypertension may lead to a vicious cycle consisting of podocyte injury, glomerulosclerosis and further loss of nephrons. Of note, recent studies have shown that the number of nephrons correlates well with the number of podocytes, suggesting that these two components are intrinsically linked and may influence each other. Both nephrons and podocytes have no or very limited regenerative capacity and are destined to decrease throughout life. Therefore, one of the best strategies to slow the progression of CKD is to maintain the “numbers” of these essential components necessary to preserve renal function. To this end, both the achievement of an optimal blood pressure and a maximum reduction in urinary protein excretion are essential. Lifestyle modifications and antihypertensive drug therapy must be carefully individualized to address the potential diversity of the kidneys.  The human kidney is composed of functional units called nephrons . NumerouFrom a renal histopathologic perspective, chronic kidney disease (CKD) can be viewed as a comprehensive syndrome in which nephrons are gradually lost and the remaining nephrons show a transition to compensatory failure. Glomerular podocytes are largely responsible for the maintenance of glomerular structure and filtration function . DependiTo better understand the complex pathogenesis of CKD and hypertension, an understanding of the structural differences in the kidney that underlie the various clinical manifestations is essential. The primary objective of this review is to summarize the current knowledge concerning the number of nephrons and podocytes in relation to CKD and hypertension. Effective strategic approaches to CKD patients are then discussed, with a focus on antihypertensive therapy for renoprotection.Point of viewClinical relevanceRecent human and animal studies have shown that congenital and/or acquired reductions in nephrons and podocytes are important pathophysiological components in the common pathway of CKD progression. Combined lifestyle modifications and antihypertensive therapy are important to halt the progressive loss of these vital components for kidney health.Future directionFor effective population-level intervention for CKD, a noninvasive and simple method of evaluating the structural diversity in the kidneys, including the numbers of nephrons and podocytes, is needed.Considerations for the Asian populationThere is substantial concern that the number of nephrons and podocytes in the Asian population has been declining in recent years. A public health approach is needed to educate the population on the importance of proper dietary habits and a maternal-fetal environment suitable for kidney maturation.Most medical textbooks state that there are one million nephrons per kidney. However, even in healthy kidneys, there are individual differences in the weight, cortical volume, and number of nephrons, with large variations . In recePrevious studies have identified birth weight, sex, race, and genetic factors as determinants of the number of nephrons in an individual, with the maternal-fetal environment being considered to have a strong influence on the determination of nephron number . A repreFollowing these Aboriginal nephron number studies, 6 other races  have been evaluated thus far, and human nephron numbers have been reported to range from 210,000 to 2.7 million , 16–19. Various studies have identified birth weight, race, body size, and sex as factors that contribute to nephron numbers. The maternal-fetal environment has attracted attention as one of the most important factors . NephrogBlood pressure in childhood is inversely related to birth weight. Law et al. reported that the relationship between blood pressure and birth weight at 4 years old was characterized by systolic blood pressure being higher in cases with a lower birth weight and higher placental weight and that systolic blood pressure at 4 years old was on average 2.6 mmHg higher in cases with a birth weight of ≤ 3000 g than in those with a birth weight of > 3600 g . Severalin utero growth and adult blood pressure [As maternal and childhood height were also inversely correlated with the incidence of cardiovascular diseases, Barker et al. hypothesized that there would be an association between pressure . An invepressure . It is cReduced nephron numbers are associated with a variety of abnormalities during embryonic life. It is known that continuous low protein feeding of the mother results in a reduction in fetal birth weight, with a proportionally smaller kidney and reduced nephron number. Furthermore, glomerulosclerotic lesions develop in fetal rats as they mature after birth, and blood pressure increases in a salt-sensitive manner. Although evidence in humans is lacking, in epidemiological studies, historical events such as the Dutch Winter Famine, the Siege of Leningrad, and the Great Leap Forward in China have shown links between malnutrition during pregnancy and the subsequent development of impaired glucose tolerance, obesity, hypertension, and mental illness.Given the above information, Brenner et al. proposed the hypothesis that low-birth-weight infants are born with impaired renal development resulting in a reduced nephron number, which in turn leads to systemic and glomerular hypertension, forming a vicious cycle that gradually progresses to the eventual development of hypertension as an adult. They further hypothesized that a reduced nephron number and total glomerular filtration surface area were associated with the development of hypertension.The association between essential hypertension and a low nephron number was first reported in 2003 . The stuIt is well known that nephron number, salt intake, and blood pressure are closely related to each other. For example, in normal rats, blood pressure is hardly increased by excessive salt loading. In one-kidney nephrectomized rats, normal salt intake does not increase blood pressure, but hypertension develops under high salt loading. When more than 70% of the kidney is removed, the blood pressure increases even under normal salt intake and becomes increasingly elevated in response to salt loading . Salt seThe process of age-related glomerulosclerosis has long been a focus of attention. Aging causes a reduction and subsequent loss of glomerular capillaries, and the afferent and efferent arterioles form a direct connection at this time, which maintains the blood flow in the medulla . This, iSeveral studies have assessed age-related changes in nephron number in the human kidney. Brenner et al. postulated that a reduction in the number of nephrons to < 500,000 per kidney at birth may be essential for the development of hypertension in adulthood . RecentlA congenital or acquired reduction in the number of nephrons leads to glomerular hyperfiltration and glomerular hypertension as well as glomerular injury, resulting in glomerulosclerosis and a further reduction in the number of nephrons (hyperfiltration theory). This vicious cycle is considered an important pathogenesis of CKD progression, regardless of the underlying disease  Fig. 2)2). We alLow nephron numbers at birth and the subsequent effects of obesity, diabetes, and hypertension accelerate the decline in nephron number through glomerular hyperfiltration, making CKD more likely to develop. The hyperfiltration theory, which is the concept that a reduction in nephrons and subsequent glomerular hyperfiltration as well as glomerular injury result in glomerulosclerosis and further nephron loss, is widely accepted. In response to this concern, researchers have focused on the number of podocytes, since depletion of injured podocytes is a hallmark of progressive kidney diseases associated with glomerulosclerosis –38. In aUnlike nephron endowment, whether podocytogenesis and an increase in podocyte number are finished around the time of birth is unclear. Puelles et al. established a method for estimating podocyte number based on design-based stereology , which iAnother fundamental question is what factors regulate podocyte endowment. Some of the factors associated with nephron endowment were examined for podocyte endowment in experimental models. Maternal mild hypoxia in mice resulted in reduced podocyte numbers in male offspring but not in female offspring . We recePodocytes have a limited capacity to regenerate under normal conditions , 47. SinHypertension contributes to podocyte injury and affects podometrics. The podocyte number per glomerulus in 41 patients with biopsy-proven hypertensive nephrosclerosis was lower than that in living kidney donors . In addiNormal aging is the most powerful determinant of podocyte depletion during life. Puelles et al. showed that aging was associated with both a lower podocyte density and a lower podocyte number per tuft in autopsy kidneys from 19 Caucasian Americans without apparent kidney diseases using design-based stereology . A studyPodocyte depletion has been reported in most glomerular diseases, including diabetic nephropathy –61, IgA With regard to racial differences in podometrics, we found no apparent differences in podocyte numerical indices in previously reported data from Caucasians and our data from Japanese living-kidney donors . These sThe ultimate goal of blood pressure management in CKD patients with hypertension is to prevent progression to ESKD and the development of cardiovascular disease (CVD). The Japan Society of Hypertension Guidelines for the Management of Hypertension (JSH 2019) recommend an optimal target blood pressure of < 130/80 mmHg for hypertensive CKD patients with persistent proteinuria and < 140/90 mmHg for hypertensive CKD without proteinuria .There are some caveats regarding antihypertensive treatment for CKD patients. First, the disappearance of diurnal variation in blood pressure should be considered in CKD patients. Clinically, loss of nocturnal blood pressure decrease is frequently observed in CKD patients, presumably due to altered salt handling of the kidney . It is tA number of experimental studies have shown beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in various models of advanced kidney disease, including 5/6 nephrectomy models with extensive removal of nephron mass. The beneficial effects of ACE inhibitors have been attributed primarily to a reduction in single-nephron glomerular hypertension , 69, andSeveral prospective controlled trials have demonstrated that diuretics, including thiazide diuretics , 73 and In addition to their hypoglycemic effects, renoprotective effects of sodium glucose cotransporter-2 (SGLT-2) inhibitors have also been suggested , 80. TheA series of studies on the renoprotective effects of antihypertensive drugs revealed the multifaceted nature of CKD progression at the single-nephron level. Modifications in salt handling are commonly implicated in the effects of these drugs. This information suggests that salt sensitivity mechanisms are intrinsically involved in the progression of proteinuric CKD. It is noteworthy that all nephroprotective antihypertensive drugs show an initial GFR decline following their administration , 86. CarEarly studies have suggested that a reduced filtration surface is one of the mechanisms underlying impaired renal salt handling associated with congenital or acquired nephron mass reduction, leading to salt-sensitive hypertension , 88. TheRecent studies have shown the importance of an appropriate quantity of protein intake from different food sources for preventing incident hypertension . In patiObesity accelerates kidney injury by several mechanisms that may or may not be dependent on hypertension, including those induced by adipocytokines released from visceral fat . ObesityThe kidneys of elderly individuals are characterized by advanced atherosclerosis and decreased autoregulatory capacity of the intrarenal arteries. This situation may predispose elderly hypertensive patients to further pressure overload injury to the kidneys. Thus, it is intrinsically important to reduce pressure overload in elderly hypertensive patients. In support of this idea, a recent large-scale trial showed that strict blood pressure reduction was beneficial for reducing the risk of developing CVD in elderly hypertensive patients . HoweverThe Japanese population has long been known to be at high risk of hypertension and hypertensive disorders such as stroke . In receIn recent years, unfavorable social trends associated with kidney maturation, such as underweight in pregnant women and low birth weight in infants, have become more prominent worldwide, especially in Asian countries . In addiThe interrelationship between reduced nephron numbers, hypertension, and CKD is consistent with the concept of common pathways of renal disease progression established over previous decades in the field of nephrology. Recent studies have suggested that the number and function of podocytes constitute an important part of this relationship. A reduced nephron number with fewer filtration surfaces and an impaired salt handling capacity may induce single-nephron hyperfiltration, leading to maladaptive podocyte injury and persistent proteinuria. To interrupt this vicious cycle of CKD progression, the combination of lifestyle modification and appropriate antihypertensive drug therapy is essential, with full consideration of each individual’s clinical background. There is substantial concern that the number of nephrons and podocytes in the Asian population has been declining in recent years. Therefore, multifaceted measures, including sociological approaches, are urgently needed to prevent the incidence of hypertension and CKD in Asian countries.