Asthma is a heterogeneous disease, characterized by chronic inflammation and oxidative stress of the airways. Several inflammatory pathways including activation of the receptor for advanced glycation end products (RAGE) have been described in the course of the disease. DJ-1 is a redox-sensitive protein with multifaceted roles in mast cell homeostasis and an emerging role in the pathogenesis of asthma. Moreover, cardiac function abnormalities have been described via echocardiography in patients with asthma. The main aim of this study was to investigate the plasma levels of RAGE, its ligands and DJ-1 in asthmatic patients pre- and post-treatment along with echocardiographic indices of cardiovascular function. The study population was divided into two groups. Group A included 13 patients with newly diagnosed bronchial asthma who were free of treatment for at least two weeks and Group B included 12 patients without asthma. An echocardiography examination was performed on all patients. The plasma levels of RAGE, its ligands , the interleukins  and DJ-1 were measured. No differences were noted among the two groups for baseline characteristics and echocardiographic indices of cardiac function. In Group A, 31% suffered from mild asthma, 54% from moderate asthma and 15% from severe asthma. Plasma levels of IL-6, AGEs and AGE/RAGE ratio were increased and those of S100A12 and DJ-1 were decreased in asthmatics. Pharmacotherapy with corticosteroids/β2-agonists decreased IL-6, and AGEs, and increased DJ-1. In search of novel approaches in diagnosing and treating patients with asthma, S100A12, ratio AGE/sRAGE, and DJ-1 in addition to IL-6 may prove to be useful tools. There are, however, patients with asthma characterized by non-T2 inflammation pathways, driven by IL-6, IL-1β, and IL23 [Asthma is one of the major noncommunicable diseases, affecting 1–18% of the population globally . In mostThe receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface receptors acting as a pattern recognition receptor . RAGE liThere are few reports investigating the relationship between asthma and heart disease. Prospective epidemiological studies have reported higher cardiovascular event rates in asthma patients than those without asthma ,16. TherBiomarkers are increasingly recognized to have significant clinical value in the early identification and progression of various cardiovascular diseases. There are many heart conditions, such as congestive heart failure, ischemic heart diseases, diabetic cardiomyopathy, and cardiac remodeling, in which the severity of the cardiac pathology can be mirrored through these cardiac biomarkers ,18,19. DThe receptor for advanced glycation end products (RAGE) is expressed in the heart in cardiomyocytes, vascular cells, fibroblasts, and infiltrating inflammatory cells . ExperimAlthough various therapeutic agents have been developed for asthma and heart failure, respectively, therapeutic drugs for each disease may adversely affect another disease . We conducted a prospective observational study to clarify whether the coexistence of asthma is a poor prognostic factor for heart-related disease. The aim of this study is to investigate the plasma expression of novel  in comparison to more common  inflammatory markers in asthmatic patients with different inflammatory phenotypes, and the cardiac impact through heart ultrasound findings. A total of 25 subjects, 13 with newly diagnosed asthma and 12 non-asthmatic subjects , were included in this study . Asthmat® recording). Exhaled nitric oxide was measured with the NO CLD88 SP-ECOMEDICS device. Skin prick testing was performed to the most relevant aeroallergens according to the GA2 LEN study [Medical history, in particular respiratory symptoms and asthma control test, and use of smoking and alcohol were ascertained by a questionnaire. Smoking and alcohol use were classified as current habitual use or not. Height and weight were measured, and BMI (BMI: kilograms per meter squared) was calculated as an index of the presence or absence of obesity. Blood pressure (BP) was measured in the sitting position using an upright standard sphygmomanometer. Spirometry was performed with a Viasys JAEGER type APS-Pro spirometer and post-bronchodilation values were measured after inhalation of 400 mg salbutamol , plasma glucose, HbA1c, creatinine, urea, aspartate aminotransferase (AST), and alanine aminotransferase (ALT), total serum IgE and specific IgE for the positive skin prick test. The above-mentioned parameters were evaluated at a commercial laboratory. Blood samples were drawn in tubes without additives, containing heparin or citrate (for routine biochemistry).For AGE, S100B, S100A12, S100A8/A9, sRAGE, DJ-1, IL-6, and IL-1β determination, blood samples were collected in tubes containing EDTA, centrifuged at 4 °C and immediately divided into aliquots. Plasma samples were stored at −70 °C until analysis. The plasma concentrations of S100A8/S100A9, sRAGE, DJ-1, S100B, IL-6, IL-1β and S100A12 were quantified using the human S100A8/S100A9 heterodimer (sensitivity—21.5 pg/mL), sRAGE (sensitivity—16.14 pg/mL), DJ-1/Park7 (sensitivity—62.5 pg/mL), S100B (sensitivity—50 pg/mL), IL-6 (sensitivity—6.4 pg/mL), IL-1β (sensitivity—1 pg/mL), S100A12 (sensitivity—7.8 pg/mL) DuoSet ELISA kits, respectively, together with the DuoSet ELISA Ancillary Reagent Kit 2 according to the manufacturer’s instructions . The plasma concentration of AGE (Advanced Glycation End) was quantified with the Assay Kit (sensitivity—0.5 mg/mL) . All samples were processed blindly.t-test or the Mann–Whitney U-test as appropriate. Differences in categorical data were evaluated via χ2 or Fisher’s exact test. Limitations regarding the small number of participants were the main reason we performed correlations, rather than regression analysis. Correlations were estimated using Spearman’s correlation method for nonparametric variables and Pearson correlation for numerical variables. Values of p < 0.05 were considered statistically significant.Normally distributed variables are expressed as mean and standard deviation. Non-normally distributed data are presented as median and inter-quartile range (IQR). Differences in continuous variables were estimated using A total of 13 asthmatic patients were included in this study, with a mean age of 36 years. Of the cohort, nine (69%) were allergic, with at least one positive skin prick test to aeroallergens. Demographic characteristics of the population included in our study are shown in All study groups were comparable with respect to age, BMI, and levels of common biochemistry measures and CRP. All the asthmatic patients had a positive bronchodilator response after 400 mg salbutamol with a mean increase in FEV1′ of 370 mL (12.4%) vs. 180 mL (0.5%) in control group.p = 0.043).Furthermore, patients with asthma had increased mean levels of fractional exhaled nitric oxide (FeNO) in comparison to controls . FeNO was used as a surrogate biomarker for type 2 inflammation, and the data suggest that patients with higher FeNO levels respond better to inhaled corticosteroid (ICS) treatment . AllergyAll subjects (control and asthmatic) were in sinus rhythm with normal left ventricular ejection fraction (LVEF > 50%) calculated according to the modified Simpson’s method . Asthmatn = 8) of the asthmatic patients with severe asthma for 12 weeks decreased IL-6 and AGE, and increased DJ-1  and DJ-1 together with the biomarker for disease ratio AGEs/sRAGE  were detsed DJ-1 .p < 0.05) correlations between S100B, S100A8A9, DJ-1, IL-6, and post-treatment levels of FEV1″, FEV1″/FVC, and MEF75–25. Negative correlations were obtained between S100B and post-treatment (post-Rx) FEV1″/FVC , S100B and post-Rx MEF75–25 , S100A8A9 and post-Rx FEV1″/FVC, and S100A8/A9 and post-Rx MEF75–25  and controls were screened via echocardiography and plasma inflammatory markers were assessed and compared to controls. Apart from a modest increase in pulmonary artery systolic pressure in asthmatics, there were no differences between the two groups regarding cardiac findings.To better understand the inflammatory/oxidative response in asthmatics, we quantified the plasma levels of a novel set of markers the RAGE ligands and the antioxidant DJ-1. The diverse markers assessed provide us with novel opportunities in understanding the inflammatory/oxidative response(s) in patients with asthma. RAGE ligands that prolong the inflammatory response through internal pathways and DJ-1 may play a key role in the pathophysiology of asthma.A wide range of clinical and experimental studies have found that RAGE plays a significant inflammatory role in the pathogenesis of allergic airway disease ,25. RAGEAsthma has been reported to be associated with oxidative stress ; yet, noThe pro-inflammatory cytokine IL-6 was increased in patients versus control and 3 months post-pharmacotherapy, the levels were decreased. The pleiotropic role of IL-6 , which pThe plasma levels of AGE and ratio of AGE/sRAGE were higher in asthmatic patients irrespective of unchanged plasma sRAGE as compared to control subjects. Ratio AGE/sRAGE depicts a surrogate biomarker which can be used for asthma diagnosis, and subsequent management and treatment which affect the ratio could demonstrate benefits for asthmatics.2-agonists, we observed a decrease in IL-6 and AGEs and an increase in DJ-1 levels. Moreover, DJ-1 positively correlated with small airway disease as depicted by post-Rx MEF75–25. Furthermore, S100B and S100A8/A9 inversely correlated with post-Rx Tiffenaeu (FEV1″/FVC) and post-Rx MEF75–25, suggesting that asthma is under control inflammation wanes. An unexpected finding was the positive correlation of IL-6 with post-FEV1″; however, it may reflect the better response to treatment in patients with higher burden of inflammation.Following treatment of asthma with inhaled corticosteroids and long-acting βThis study has certain strengths and limitations. The diversity of the measured inflammatory markers  together with the measurement of echo-derived parameters of cardiac function can be marked as strengths of the present study. Several limitations should also be acknowledged. The relatively small number of participants as a first diagnosis of asthma was a prerequisite and there are limitations inherent to the cross-sectional, observational design, as we evaluated association, not prospective prediction or causation. The ELISA detection system used in the present study could measure only total sRAGE levels and cannot discriminate between specific soluble RAGE variants (cRAGE and esRAGE); therefore, decreased sRAGE levels as determined by this assay may be caused by a decrease in distinct circulating sRAGE isoforms. We had to exclude inflammatory markers with very low to undetectable plasma concentrations. Nonetheless, the selected biomarkers have completeness of measurements, indicating acceptable quality of quantification. Our population is <40 years. Therefore, generalization of the results to an older age category should be carried out with caution. Our study only indicates an association; we believe that further studies are needed to establish the causal role of DJ-1, RAGE, and its ligands in the pathogenesis of asthma.Despite these limitations, the findings discussed here indicate that the AGEs-RAGE system and DJ-1 are closely related with the pathophysiology of asthma, and AGEs/sRAGE ratio, S100A12 and DJ-1 could serve as novel biomarkers to predict asthma treatment. It is tempting to speculate that, in the upcoming years, targeting S100A12 and DJ-1 may be an effective viable therapy in patients with severe, persistent asthma.In conclusion, we suggest that the plasma measurement of IL-6, AGE/sRAGE ratio, S100A12 and DJ-1 provides a promising and non-invasive technique that facilitates the detection of inflammation and measurement of therapeutic efficacy in asthmatics. However, long-term prospective studies are warranted to elucidate their role in asthma and to investigate whether modulation of the circulating levels of pro-inflammatory/antioxidant proteins can modify disease severity.


However, in the last decade, particular attention has been paid to neonatal extracorporeal therapies for acute kidney care, an area in which technology has made giant strides in recent years. Peritoneal dialysis (PD) is the kidney replacement therapy (KRT) of choice in the youngest age group because of its simplicity and effectiveness. However, extracorporeal blood purification provides more rapid clearance of solutes and faster fluid removal. Hemodialysis (HD) and continuous KRT (CKRT) are thus the most used dialysis modalities for pediatric acute kidney injury (AKI) in developed countries. The utilization of extracorporeal dialysis for small children is associated with a series of clinical and technical challenges which have discouraged the use of CKRT in this population. The revolution in the management of AKI in newborns has started recently with the development of new CKRT machines for small infants. These new devices have a small extracorporeal volume that potentially prevents the use of blood to prime lines and dialyzer, allow a better volume control and the use of small-sized catheter without compromising the blood flow amount. Thanks to the development of new dedicated devices, we are currently dealing with a true “ The Structure of Scientific Revolutions” published in 1962, Thomas Kuhn, an American philosopher of science, introduced the concept of “paradigm shift” [In his book “Kidney replacement therapies (KRT) in children are currently well-established procedures, both in the acute and chronic settings. In the late 1960s, PD started to be used for acute kidney injury (AKI) in pediatric patients, whereas the first chronic PD programs began in the early 1970s. The period from 1960 to 1970, the so-called first development decade, also saw preliminary experiences in the clinical use of chronic HD in children through pumpless systems. Since then, advances of KRT in children have occurred, although not at the same pace with adults. Data from European Society of Pediatric Nephrology (ESPN)/European Renal Association (ERA) Registry indicate that, from 2007 to 2016, incidence of children aged < 15 years commencing chronic KRT remained stable, ranging from 5.5 per million age-related population (pmarp) to 6.6 pmarp, whereas prevalence increased from 26.4 pmarp in 2007 to 32.1 pmarp in 2016 [However, in the last decade, particular attention has been focused on neonatal dialysis, especially in acute extracorporeal therapies, where most of the innovations have been concentrated and a scientific revolution is likely occurring. In this review, we aim to analyze the four sequential steps that, in our opinion, have led to a paradigm shift in the dialysis treatment of neonates and infants with AKI or who require an acute kidney support because of fluid overload, electrolyte imbalances, or metabolic syndromes.KRT in neonates and infants is one of the most challenging and demanding treatments in nephrology. PD is the method of choice for initiating KRT in the youngest age group in the context of both stage 5 chronic kidney disease (CKD 5) and AKI –8. The pHowever, extracorporeal blood purification therapies (HD and continuous kidney replacement therapy (CKRT)) provide faster fluid removal and, using both diffusion and convection, a more rapid clearance of small, middle, and larger molecular weight substances. These techniques are, therefore, more efficient for acute conditions, such as in the case of significant fluid overload, in hypercatabolic circumstances, inborn errors of metabolism, or when a toxin removal is required. Given the advantages on clearance and UF, the treatment of pediatric AKI in high-income countries is mainly based on the use of HD or CKRT instead of PD.AKI is a common complication in intensive care units (ICUs), occurring in 20–30% of patients in pediatric ICU , 15 and Though the incidence of AKI is high among patients admitted in neonatal ICUs, the use of kidney support in neonates is still uncommon. According to data emerging from the AWAKEN study (Assessment of Worldwide Acute Kidney Injury Epidemiology in Neonates), 4% of infants with AKI (25 out of 605) received KRT, and only 0.7% were treated with CKRT or HD . It shouThe employment of extracorporeal dialysis in small children is associated with a series of clinical challenges, including difficulties of vascular access, hypotension on connection, hypothermia due to an immature temperature body control and thrombocytopenia . These cThe vascular access: in very small children, well-functioning vascular access can be difficult to place; moreover, the rates of infectious and mechanical complications are very high [ery high . Access ery high . Howeverery high . A higheery high .The blood pump: blood pumps integrated in conventional HD machines are characterized by two moving rollers normally placed at 180° interval that squeeze a flexible plastic tube, moving the fluid inside along in a specific direction. The resulting pressure necessitates adequate catheter blood flow that directly depends on catheter size dimensions. Thus, when conventional HD or CKRT machines are used with small-sized central venous catheters, dialysis kinetics might be inadequate, and a suboptimal rate of blood flow significantly increases the risk of clotting. Given the Poiseuille law, keeping constant the blood flow with a smaller size catheter requires a proportional increase in venous circuit pressures; when exceeding the safe threshold of + 200 mmHg, this might, in turn, result in several machine alarms that prevent treatment continuation.The extracorporeal volume: the priming volume of the extracorporeal circuit should ideally not exceed 10% of a patient’s circulating blood volume, which is usually assumed to be 80–90 mL/kg in neonates and infants. The higher this ratio, the more the patient’s blood is decreased at the start of extracorporeal treatment, leading to an increased risk of cardiovascular instability. The initiation phase of extracorporeal treatment is widely recognized as a hemodynamically critical procedure. In a study of 174 children undergoing CKRT, low blood pressure at dialysis initiation was found in 53 patients (30.4%) [ (30.4%) . When thFluid removal accuracy: the relatively low body weight of patients and neonatal hemodynamics require a high precision in fluid balance assessment and monitoring during extracorporeal therapies. The better systemic fluid balance control in conventional HD and CKRT is set at ± 30 ml/h. Consequently, there are no adult monitors for continuous or intermittent kidney support currently approved for treating patients of low body weight (< 8 kg).From a technical point of view, the following are probably the most important barriers to a safe CKRT in neonates and infants:2 filter, setting a dialysate flow rate in the range of 0–400 ml per hour and an UF rate in the range of 0–60 ml per hour. A recent study by Crosier et al. has shown that, when used in small infants, two modern CKRT devices with conventional circuits, the Prismaflex and Aquarius, do not have the capacity to deliver precise or reliable UF, or to record its volume correctly even when they are set to produce zero UF, but the NIDUS volumetrically controlled circuit does [The revolution in the management of neonatal AKI has recently started with the development of new CKRT machines adapted or specifically designed for young children. The new monitors have smaller circuits that reduce extracorporeal volume and limit the need for blood priming, have more precise control systems that minimize machine errors, provide smoother flow rate adjustment, and allow the use of smaller-sized catheters. In 1995, Everdell et al. reported the results of a manual syringe-driven HD technique to treat 3 babies weighing 630, 808, and 1140 g, using a single-lumen access line, and without the need for blood-priming . This ciuit does . A clini2), with a priming volume of 26, 32, and 41 ml, respectively. The CARPEDIEM monitor provides slow continuous ultrafiltration (SCUF), pre- or post-dilution continuous veno-venous hemofiltration (CVVH), continuous veno-venous hemodialysis (CVVHD), and plasma exchange, with an ultrafiltration error of 1 g/h [In the first decade of the twenty-first century, Ronco and colleagues were working on wearable and miniaturized kidney replacement devices with the purpose of making them portable, thus prolonging the HD treatments as long as possible to improve the patient outcome. On the way to the wearable artificial kidney, new discoveries have been made, such as a complete system for HD in newborns . The Carof 1 g/h . The bloof 1 g/h , 30. A sAquadex™  is a device developed for adult patients with congestive heart failure to control the fluid overload in a condition of diuretic resistance. This machine has been developed to perform only SCUF, without clearance, allowing simplification of the circuit, which, therefore, has a minimal priming volume (33 mL). In 2013, there were no devices specifically developed for small pediatric patients in the USA, and Askenazi and colleagues chose Aquadex™ as the smallest adult-based extracorporeal device to adapt it for neonates and infants. Therefore, a modified version was developed by adding a pre-filter replacement fluid, administered with an infusion pump through the access line, entirely removed as ultrafiltrate. The resulting dialysis mode was, therefore, a real CVVH, implementing the monitor with a convective clearance component . DespiteIn recent years, there has been, for the first time in history, the conception, testing, and approval of dialysis devices specifically dedicated to small children. These new machines have been approved with varying time lines in most Western countries, bursting into the pediatric world, rapidly changing clinical practice. The new dialysis devices were initially used in patients in whom PD was contraindicated or proved ineffective, with adequate results on clearance, fluid removal, and safety. Clinicians quickly realized the versatility and precision of these extracorporeal treatments, which provided greater dialysis efficiency than PD and allowed for fluid management planning , 26, 33.Despite differences in definition and staging, acute kidney dysfunction in critically ill patients is a risk factor for mortality, and AKI is a recognized “deadly syndrome.” In the AWAKEN study, infants with AKI had a mortality rate of 9.7%, significantly higher than those without AKI (1.4%) . When AKThe development and clinical application of these new tools would result in significant advancements in the care of the vulnerable and highly demanding patient population of neonates and infants with severe AKI or other conditions that could benefit from extracorporeal kidney support . As suggested by Tal et al., survival of more neonates with AKI could lead to a change in topography of the pediatric CKD 5 population, with more children having long-term comorbidities and changing demands on resources .However, the use of this innovative technology is still precluded in resource-poor countries and, given the high complexity of the target patient population, should involve a multidisciplinary decision-making process. The possibility to integrate more KRT options for small children increases the demand for resources and will require adequate training and established protocols and procedures. A recent educational review provides detailed recommendations on how to build a comprehensive and integrated neonatal kidney support therapy program in those countries where technologies and resources are available .There is also hope that the scientific revolution occurring in the field of neonatal and infant CKRT will open new perspectives in pediatric dialysis technology and raise awareness of companies about the importance of bridging the gap in chronic HD treatment of small children with CKD 5, currently still an “orphan disease.”3%5%10%20%What is the safe threshold of priming volume for an extracorporeal dialysis treatment (as a percentage of the patient’s blood volume)?the three-roller pump, which allows for controlled flows even in small-sized cathetersthe ability to perform CVVHDthe possibility of using the device with catheters of different sizesthe possibility to use three different filtersWhat is one of the greatest technical innovations of the CARPEDIEM dialysis machine?the small size of the hardwarethe accuracy of the scales and alarmsthe ability to perform multiple types of extracorporeal treatmentsthe possibility of performing blood primingWhat makes a device, specifically designed for neonatal dialysis, safe and reliable?the patient’s lack of compliancethe requested size of the vascular access and the need for circuit primingthe inadequate warming system for dialysis fluidsthe absence of a dedicated fluid management monitoring toolWhat is one of the biggest challenges of neonatal CKRT when performed with adult dialysis machines?Answers are given following the reference list.


Diabetes is the leading cause of kidney disease. Up to 40% of the population with diabetes experience diabetic kidney disease (DKD). The correlation of DKD with insulin resistance (IR) indices has been shown in previous studies. In this study, the objective was to evaluate surrogate IR indices, including the Triglyceride-Glucose (TyG) index, Visceral Adiposity Index (VAI), Lipid Accumulation Product (LAP), and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) to find the most valuable index for the correlation between albuminuria and IR in the type 2 diabetes (T2D) population. Albuminuria is defined as urine albumin excretion of > 30 mg/day.In this cross-sectional study, 2934 participants were enrolled and evaluated for urinary albumin excretion, and albuminuria was detected in 526 of the entries. The logistic regression models and Receiver Operating Characteristic (ROC) curve analysis were performed to assess the relationship of TyG index, VAI, LAP, and HOMA-IR's with albuminuria in patients with T2D.The TyG index had the highest association (OR 1.67) with the presence of albuminuria in patients with T2D, followed by HOMA-IR (OR 1.127), VAI (OR 1.028), and LAP (OR 1.004). These four indices remained independent after adjustment for multiple confounders. Based on the ROC curve, TyG revealed the best area under the curve (AUC) for revealing albuminuria with sufficient accuracy (AUC: 0.62) in comparison with other measured indices. The calculated TyG index cut-off point for the presence of albuminuria was 9.39.Among the indices, TyG index had the most significant correlation with albuminuria in patients with T2D. Diabetes is the most common metabolic disorder with numerous micro- and macrovascular complications, including, diabetic nephropathy , 2. AlbuStudies have indicated that IR and related mechanisms are pathogenic factors for renal failure . IR is aAlthough the gold standard method for evaluation of IR is hyperinsulinemic-euglycemic clamp (insulin clamp), this technique is costly and rather sophisticated to perform in clinic , 13. AnoTherefore, several attempts have been made to discover other indices that could be more accessible for assessing IR . FurtherTo the best of our knowledge, there has been no relevant literature that compares the relationship between these four indices and albuminuria in patients with T2D. Thus, the present study was aimed to evaluate this relationship and to identify the cut-off point for the most valuable index to reveal albuminuria in patients with T2D.This is a cross-sectional study of an ongoing cohort which was carried out in the outpatients Diabetes Clinic of Vali-Asr Hospital , a large tertiary referral center. All eligible patients with T2D who attended the outpatient clinic between 2011 and 2021 were enrolled consecutively in the study.The ethical committee of the Tehran University of Medical Sciences (TUMS) approved the study with the registered number of IR.TUMS.IKHC.REC.1400.085.T2D was diagnosed according to the 2022 American Diabetes Association guidelines , and albApplied exclusion criteria were non-diabetic renal diseases, feverish infection or history of infectious disease in the last six months, any chronic disease , and recent excessive exercise.Demographic factors and clinical data of participants, including age, sex, height, weight, waist circumference, blood pressure (systolic and diastolic), duration of diabetes, and medications for diabetes and dyslipidemia were recorded.The body weight and height of enrolled patients were measured to the nearest 0.1 kg and 0.001 m, respectively. Waist circumference was calculated at the central point between the lower level of the lowest palpable rib and the highest of the iliac crest to the nearest 0.001 m. Blood pressure was evaluated after a ten-minute rest. The measurement was repeated after 15 min, and the average was recorded as the blood pressure value.Blood samples were taken after ten or more hours of fasting at 8:00 am. Fasting blood sugar (using hexokinase enzyme method) and fasting insulin ) were measured.Participants' serum creatinine level was evaluated by the Jaffe technique . Accuracy of random samples were evaluated by the central reference laboratory , which the results and kits approval was met. Hemoglobin A1c (HbA1c) was measured by high performance liquid chromatography . Fasting plasma glucose (FPG) and 2-h postprandial (2hPP) glucose measurements were conducted using enzymatic colorimetric methods by the glucose oxidase test. The estimated glomerular filtration rate (eGFR) was calculated by the Chronic Kidney Disease Epidemiology Collaboration Equation . HOMA-IROtherwise, the enzymatic method was used. Also, two hours later (10:00 am), 2-h postprandial glucose (2 h-PPG) was measured through the hexokinase enzyme method.The Estimated glomerular filtration rate (eGFR) was calculated in participants by the Cockcroft-Gault formula  as descrCreatinine clearance (ml/min): [(140 − age) × body weight] /[plasma creatinine × 72] .The definition of TyG, VAI, LAP, and HOMA-IR indices are:The TyG index was defined as the Ln [fasting TG (mg/dL) * fasting glucose (mg/dL)/2] for both genders.The VAI index was calculated through sex-specific formulas; males (waist circumference (cm)/(39.68 + (1.88*BMI)) *(TG/1.03) *(1.31/HDL-C); females: (waist circumference (cm)/(36.58 + (1.89*BMI)) * (TG/0.81) *(1.52/HDL-C), where both TG and HDL-C levels are reported in mmol/L.The LAP index was determined as (waist circumference(cm) – 65) * (TG (mmol/L)) in males and (waist circumference(cm) − 58) * (TG (mmol/L)) in females.The HOMA-IR index was calculated by: fasting glucose in mmol/l*fasting insulin in μU/ml/22.5SPSS version 24 was used for statistical analysis. The normality of the data was evaluated using Kolmogorov–Smirnov tests. Continuous variables with normal distribution are provided as mean ± standard deviation and categorical variables are presented as frequency and percentage (%).The TyG, HOMA-IR, LAP, and VAI indices, were compared among patients with and without albuminuria by univariate analyses, using t-tests to compare continuous variables and chi-square for categorical ones between the groups.ROC curve analysis was performed and the Youden index was used to calculate the optimized cut-offs value of TyG, HOMA-IR, LAP, and VAI indices.The Logistic regression models were used to measure the relationship between the indices and albuminuria among T2D patients in univariate and multivariate logistic regression analyses. A univariate logistic regression analysis was conducted on each index. Two multivariable models were constructed for each index. Model 1 was adjusted for sex, age, blood pressure; other models (model 2) were adjusted for the duration of diabetes, blood LDL-C level, retinopathy, lipid-lowering agents use (divided into three categories), and waist circumference (was not adjusted in models which are included the LAP and VAI indices due to their formulas) in addition to model 1's confounders. Finally, model 2 was adjusted for HOMA-IR to demonstrate whether these indices remained independent (model 3). P-value less than 0.05 was considered statistically significant during analysis.A total of 2934 participants with T2D were included in this study. Patients were divided into two groups depending on the presence of albuminuria. In 526 participants albuminuria was detected, and 2408 T2D patients did not meet the albuminuria criteria.The mean age of participants was 56.46 years, of whom 52.9% were women. Albuminuria was more common in men (52.9%). In addition, 54.2% of patients without albuminuria were women.Those with albuminuria had higher diastolic blood pressure and longer duration of diabetes .Also, more proportion of patients with albuminuria (140 patients: 26.7%) had cardiovascular diseases compared to another group (530 patients: 22.0%). Similarly, the proportion of patients with retinopathy in the group with albuminuria (128 patients: 24.4%) was higher than the other (222 patients: 9.2%). In addition, patients with albuminuria had higher FBS (182.39 mg/dL), HbA1c (8.32%), and Triglyceride (207.34 mg/dL) levels.The total cholesterol and LDL-C were higher in patients with T2D and albuminuria compared to those without albuminuria ).Moreover, TyG, HOMA-IR, LAP, and VAI indices were higher in patients with albuminuria .However, age, non-HDL-C, HDL-C, eGFR, and the HbA1c did not show a significant difference  between the two groups , followed by HOMA-IR , VAI  and LAP . The regression analysis demonstrated that with each unit increase of the TyG index, the risk of developing albuminuria increased by 1.67 times, and this relation was independent of HOMA-IR ). On the other hand, the results showed that VAI had the smallest AUC 0.55 , and the calculated AUC for HOMA-IR and LAP were 0.59  and 0.57 , respectively Fig. .Fig. 1ROThe best-calculated TyG cut-off for albuminuria evaluation was 9.39 with 0.64 and 0.55 sensitivity and specificity, respectively  . In paraAfter examining LAP, VAI, and TyG indices, Fiorentino et al. concluded that the LAP index had the most correlation with IR and subclinical vascular damages. In Fiorentino’s study, subjects had been chosen from a population with different degrees of insulin sensitivity, including normal glucose tolerance, impaired glucose tolerance, impaired fasting glucose, and patients with T2D . HoweverFurthermore, Ying Pan et al. showed that there was a significant association between TyG index and albuminuria in hospitalized patients . HoweverOf the calculated indices of insulin resistance in this study, we concluded that the TyG index had the most significant correlation with albuminuria in patients with T2D. Due to the simplicity and practicality of calculating the TyG index, its utilization would be a favorable method for evaluating albuminuria. Nevertheless, extensive and longitudinal research is needed to confirm these relationships.This study compared the association of TyG, LAP, VAI, and HOMA-IR indices and albuminuria in the T2D population for the first time and indicated that all mentioned indices have a significant relationship with the presence of albuminuria. In addition, our study was conducted on a large cohort of individuals with T2D who were enrolled over a decade.However, some shortcomings need to be interpreted in this study. First, this was a cross-sectional study that could not determine causality. Another drawback of this study was the inability to compare these indices with the hyperinsulinemic-euglycemic clamp test which is the gold standard method for detecting insulin sensitivity and glucose utilization.


CKD is a progressive condition that may affect individuals of all ages, althoughit is particularly prevalent among the elderly. Aging is a risk factor for severalcomorbidities, and in the kidney it has been associated with decreased glomerularfiltration and renal parenchymal changes resulting from cellular senescence and thecumulative effect of nephrotoxic drugs prescribed to patients. Thus, screening and identifying CKD in elderly individuals is particularlyimportant to optimize health care in this important segment of the population.The definition of chronic kidney disease (CKD) based on functional impairment (glomerularfiltration rate < 60 mL/min/1.73 m observed the role of proteinuria as a marker of kidney damage in elderly personswithout a history of hypertension or cardiovascular disease. Few studies in medicalliterature have looked into this subject. However, since elderly are at risk of CKD, screening this population for thecondition is warranted. This fact does not make the study less important but diminishes its originality.However, the relevance of the study by Nunes et al. has been reinforced by a recent publication highlighting that not assessingalbuminuria is a missed chance to provide better kidney care to American adults9.In the study “A chronic kidney disease prevention campaign: proteinuria and the elderly”,Nunes et al.2, inthe study by Nunes et al. the diagnosis of CKD was based on only one renalmorphofunctional assessment. This procedure presents a methodological issue frequentlyfound in screening studies, with consequences seldom discussed in the literature. Mostof the results published in the study were within expectations, with proteinuriaassociated with higher blood pressure and blood glucose levels. Interestingly, age wasassociated with proteinuria, regardless of comorbidity, although the authors mentionedin the discussion section that when the model was adjusted for diabetes mellitus, agewas no longer a risk factor for proteinuria. The discussion of proteinuria in kidneydisease progression and as a marker of endothelial injury is present in the study andagrees with pertinent literature. In conclusion, the study by Nunes et al. confirmed the need to look at proteinuria in elderly patients to identify kidneydisease, improve patient survival and quality of life, and decrease the cost of care inan important portion of the population.Another noteworthy fact is that unlike what is recommended by KDIGO 2022


Pregnancy in females with kidney disease is not uncommon and is associated with adverse maternal and fetal outcomes. The use of contraception in females with chronic kidney disease remains low. We sought to describe the perspectives of female patients with advanced chronic kidney disease on the use of contraception.Qualitative study.We conducted 5 focus group interviews involving 16 adult female patients with advanced chronic kidney disease  in the United States, following which thematic saturation was reached.Interview transcripts were analyzed thematically.We identified the following 5 themes: 1) variable knowledge regarding reproductive health with kidney disease, 2) inadequate counseling about contraceptive use, 3) lack of interdisciplinary coordination regarding contraceptive use, 4) insufficient educational resources available to guide the contraceptive discussion, and 5) need for research to better understand reproductive needs in females with kidney disease.Patients were from a single center in the United States, and the study is limited by the transferability of findings to other settings.Patients with chronic kidney disease report emotional challenges with reproductive health, lack of counseling and care coordination, and insufficient resources for contraceptive use. Strategies to strengthen these factors may improve the quality of reproductive care and increase contraceptive use for females with chronic kidney disease.Pregnancy in females with kidney disease is common and associated with a higher risk of adverse maternal and fetal outcomes, but the use of contraception remains low. Little is known about female patients’ experiences in contraceptive use that may contribute to low contraceptive use in this high-risk population. In the present study using focus group interviews, patients with chronic kidney disease reported emotional challenges with reproductive health, lack of counseling and care coordination, and insufficient resources for contraceptive use. Interventions are needed to strengthen these factors to improve the quality of reproductive care and increase contraceptive use for females with chronic kidney disease. XXXEditorial, Chronic kidney disease (CKD) affects up to 3% of females during their childbearing years, presenting unique and challenging needs to reproductive health care for this population.,,,Unplanned pregnancies are common worldwide in females with kidney disease and have been reported to range from 30%-50%.Currently, the approach to contraceptive counseling in patients with CKD is widely variable. With an increasing focus on shared decision making, the clinical practice should involve explicit consideration of female patients’ values.Potential participants were recruited by clinicians practicing at the University of Cincinnati from outpatient nephrology, kidney transplant, and gynecology clinics. Clinicians identified patients as eligible if they identified as a woman of childbearing age with a history of kidney disease. Participants provided informed consent for participation in the qualitative study, which included a physician chart review and the digital recording of the focus group sessions. All participants were given an honorarium of $50 (clin card) for their participation.We conducted 5 focus groups with 16 participants virtually via Zoom. Each focus group comprised 2-4 participants. Focus groups were conducted until thematic saturation was reached. Each focus group lasted approximately 60 minutes in length. Each focus group was led by the principal investigator (SS) or trained moderator (PG). The question guide was developed based on a literature review and team discussions . QuestioAll identifying personal information was removed before content analysis. Two research team members independently developed a coding scheme representing the relevant concepts addressed during the discussions. Using thematic analysis, the qualitative consultant assisted the principal investigator in reading the transcripts line by line, identifying key concepts, themes, and representative quotes, and developed a preliminary coding scheme to determine participants’ reasons for choices. Similar concepts were grouped into themes and subthemes, which emerged during the focus group discussions. Reaching thematic saturation allowed us to reduce overlap and redundancy among the categories. The revised themes and transcripts were entered into HyperRESEARCH software . The preliminary findings were discussed among the research team members, who were given 2 weeks to provide additional perspectives (member checking). Feedback was integrated into the analytical framework. The University of Cincinnati institutional review board approved the study  and followed the Consolidated Criteria for Reporting Qualitative Health Research.2 for kidney transplant recipients and 23-80 mL/min/1.73 m2 for nondialysis nontransplant patients with CKD. Demographic and clinical characteristics are shown in Sixteen female patients participated in the study. The median age at the time of the study was 36 years . Of the 16 patients, 10 (62.5%) were White, and 6 (37.5%) were Black. Diabetes was the cause of CKD in 6 (37.5%) of the participants, with 5 (31.25%) having documented glomerulonephritis, 2 (12.5%) with hypertension, and 3 (18.75%) having ‘other’ as the cause of their CKD. Nine (56.25%) patients in our cohort were kidney transplant recipients, 3 (18.75%) had nondialysis nontransplant CKD, and 4 (25%) were receiving maintenance dialysis, of which 2 were receiving home dialysis . Regarding kidney function, eGFR ranged from 31-97 mL/min/1.73 mWe identified the following 5 major themes: 1) variable knowledge regarding reproductive health, 2) inadequate counseling about contraceptive use, 3) lack of interdisciplinary coordination regarding contraceptive use, 4) insufficient educational resources available to guide the contraceptive discussion, and 5) need for research to better understand reproductive needs in females with kidney disease. The themes and respective subthemes are described in the following sections, with illustrative quotations provided in Participants shared that their knowledge regarding reproductive health with kidney disease teams based on their experience or research, not from counseling by health care providers. Patients express frustration and “heartache” caused by a lack of knowledge regarding fertility and reproductive health.Respondents state that they wish their physician had brought up the conversation of contraception and fertility earlier during their interactions. They also feel that physicians do not discuss contraception and pregnancy unless they bring it forward. The timing of education is critical to patients, so that they can address their family planning goals.Respondents report needing more counseling regarding their reproductive health from their nephrologists. They state that “endocrinologists and gynecologists” try to counsel them; however, patients are still hesitant to follow their guidance due to the complexity of their kidney disease. They report not knowing which one works with their immunosuppressants and are reluctant to add new medications.Participants also stated that they were never offered contraceptives and were unaware they should be using contraception. Others expressed being denied contraception, even when the patient attempted to obtain contraception herself. One participant shared how she tried to get contraception after having a miscarriage to prevent that from occurring again but was denied.Quality of counseling is a recurring subtheme; participants express wanting more “detail” and “pros and cons” related to contraception. Participants emphasize knowing the dangers of getting pregnant while getting dialysis or during kidney failure. Still, they lack thorough counseling to understand why they need contraception and the best contraceptive methods given their kidney disease.The lack of interdisciplinary coordination is a clear theme that emerges. Participants repeatedly report that “everything is sectioned off” and that there is “no communication” between their gynecologist and nephrologist. Due to this lack of coordination, participants report feeling “confused.” They also discuss how they receive different answers and responses from providers, increasing confusion.When discussing interdisciplinary care, patients describe their care as “sectioned off” without coordination. Patients feel like an “intermediary” and need to coordinate discussions themselves because physicians do not “cross-communicate” with each other. They report that physicians only address concerns about their specialty and do not move beyond their specialty.Patients also question whether all physicians have the appropriate training to educate patients about contraception and kidney disease. They express that physicians' lack of training in women’s health could contribute to the poor interdisciplinary approaches and patient education.Participants reiterated that a lack of educational resources forces them to turn to search Google and the internet, which can lead to the spread of misinformation. This can also cause further frustration and anxiety.Many participants express going to kidney disease Facebook groups to learn about contraception and pregnancy. This is a place where females with kidney disease can share their stories and hardships and learn about fertility related to kidney disease.Participants report inadequate information about contraceptive use, which affected their decision making and choice regarding the most appropriate contraception in the context of kidney disease. Participants express that when discussing pregnancy and kidney-health, physicians highlight the importance of preventing pregnancy because of immunosuppressants and their effects, but not how to prevent pregnancy. We also see a reoccurrence of a lack of trust in physicians and health care providers to educate patients about contraception, fertility, and reproductive health in patients with kidney disease.Participants were asked, “What steps do you think will guide to increase the awareness of contraception with kidney disease?” They expressed that more research in reproductive health and kidney disease would help. They have stated, “What about us” and described feeling isolated and forgotten by the research community.Participants believed that the research needs to be better distributed to females with kidney disease, so that they can make informed decisions regarding their reproductive and sexual health. They also express a need for research specific to females with kidney disease instead of treating them like “the standard.” They also hope the counseling is geared to each individual need rather than “lumping” patients into groups.Among reproductive-aged females with advanced CKD, our qualitative study using focus group interviews revealed the following themes on contraceptive use: 1) variable knowledge regarding reproductive health, 2) inadequate counseling about contraceptive use, 3) lack of interdisciplinary approach, 4) insufficient educational resources, and 5) need for further research. Interviews with participants revealed a desire for a more thorough discussion of contraception with kidney-health care providers, and patients further advocated for multidisciplinary kidney care.,Females with kidney disease are not completely informed of changes in fertility and reproductive health that are associated with kidney disease. Prior reports note females with CKD felt the information regarding their reproductive health was often unhelpful and incomplete,Participants reported that kidney doctors did not provide counseling regarding contraceptive use during routine clinic visits. Although nephrologists play a major role in caring for patients with kidney disease, only 46% counsel their female dialysis patients about contraception.Study participants highlighted the lack of communication between nephrologists and gynecologists as one of the barriers to contraceptive use. Segmented care of female reproductive health between disciplines results in patient frustration and a lack of trust in the health care system. Hendren et al,,,There are inadequate educational resources to guide contraception discussions. While evidence-based data regarding contraceptive use in CKD exist,Research regarding kidney disease and reproductive health tends to focus on the physiologic outcomes of pregnancy and the safety of contraceptive methods.There are potential limitations to our study. The study population was recruited from a single-site urban academic medical center; therefore, the opinions and themes do not likely represent those of all patients with CKD. In addition, we did not collect information on prior pregnancies and contraceptive use from the participants.Based on the themes and subthemes that emerged from the interviews, we identified the following 5 domains that should be addressed to improve care regarding contraceptive use in females with kidney disease: 1) contraceptive counseling, 2) multidisciplinary care, 3) physician-patient communication, 4) patient support groups, and 5) physician training. We have outlined suggested strategies and actions for each domain based on our participant’s experiences in In conclusion, patients with CKD report emotional challenges with reproductive health, lack of counseling and care coordination, and insufficient resources for contraceptive use. Unplanned pregnancies among patients with kidney disease are associated with increased risks of obstetric and fetal complications,


Kim-1 and Ngal were significantly higher in MWF-D rats, as were the amounts of PRAT and MAT. A diabetes-induced upregulation in IL-1, IL-6, Tnf-α, and Tgf-β was observed in both the PRAT and the MAT. Col1A1 was increased in the PRAT but not in the MAT of MWF-D, whereas IL-10 was lower and higher in the PRAT and the MAT, respectively. Urinary albumin excretion and blood pressure were not further increased by diabetes induction, while heart weight was higher in the MWF-D. In conclusion, our results show a proinflammatory and profibrotic in vivo environment in PRAT induced by diabetes which might be associated with kidney damage progression in the MWF strain.Perirenal adipose tissue (PRAT) surrounding the kidney is emerging as a player and novel independent risk factor in diabetic kidney disease (DKD); DKD is a complication of diabetes and is a major cause of increased cardiovascular (CV) risk and CV mortality in affected patients. We determined the effect of diabetes induction on (i) kidney and CV damage and (ii) on the expression of proinflammatory and profibrotic factors in both the PRAT and the mesenteric adipose tissue (MAT) of Munich Wistar Frömter (MWF) rats. The 16-week-old male MWF rats (n = 10 rats/group) were fed standard chow (MWF-C) or a high-fat/high-sucrose diet for 6 weeks together with low-dose streptozotocin (15 mg/kg i.p.) at the start of dietary exposure (MWF-D). Phenotyping was performed at the end of treatment through determining water intake, urine excretion, and oral glucose tolerance; use of the homeostatic model assessment–insulin resistance index (HOMA-IR) evidenced the development of overt diabetes manifestation in MWF-D rats. The kidney damage markers  Chronic kidney disease (CKD) is a common progressive, incurable condition which will soon become the fifth leading cause of death worldwide . The risMajor long-term macro- and microvascular complications of DM and CKD include endothelial dysfunction, blood pressure increase, and the development of arterial stiffness, leading to reduced coronary artery perfusion, increased cardiac workload, and chronic cardiac dysfunction ,6. DiabeDKD is a heterogeneous disease regarding its pathophysiology, histopathology, clinical manifestations, and rate of progression. The etiology of DKD is complex and multifactorial, involving both metabolic and hemodynamic factors; comorbidities, such as hypertension or obesity, affect its clinical course. In many cases, kidney dysfunction may not be primarily caused by DM, but it can develop or be promoted in the context of preexisting kidney damage .Perirenal adipose tissue (PRAT), a visceral fat depot surrounding the kidney , is emerThe Munich Wistar Frömter (MWF) rat is a genetic model of spontaneous and progressive non-diabetic albuminuria development  that mirIn this context, we aim to determine the effect of diabetes induction on the expression of proinflammatory and profibrotic factors in PRAT in comparison with another visceral adipose tissue depot—the mesenteric adipose tissue (MAT). Moreover, we aim to analyze the impact of diabetes on the preexisting kidney and cardiovascular damage in the MWF strain. For this purpose, we have treated 16-week-old MWF rats, which already exhibited CKD and its CV complications, with low-dose streptozotocin (STZ) together with short-term exposure to a high-fat high-sucrose (HF/HS) diet; we analyzed the metabolic, kidney, and CV damage.As shown in MWF-D rats showed a significant increase in both fasting and postprandial blood glucose as compared to the MWF-C group. Fasting insulin levels were similar to the control strain, whereas postprandial insulin was significantly lower in MWF-D .To determine whether MWF-D had a worse glycemic control, a GTT was performed. As shown in The MWF-D group exhibited the classical features of diabetes, i.e., higher water intake D, higherp < 0.05; normalized by tibia length). No differences were observed between MWF-C and Wistar (35.33 ± 4.4 mg/mm). UAE . UAE A was higmm). UAE B was sigKim-1  and significantly lower in the MWF-D-ins group . In contrast, no effect of diabetes was observed in either LV wall thickness determined using MRI  is associated with a decrease in the estimated glomerular filtration rate (eGFR) in patients with obesity  and diabtor AT1R , balanceposition ; therefoe system . To notee system ; howeverIL-10. Moreover, Col1A1 expression is not enhanced in MAT despite the increase in Tgf-β, suggesting that there is not an overt fibrotic response in this adipose depot yet. The differential expression of inflammatory and profibrotic factors between PRAT and MAT highlights the phenotypic differences between two adjacent adipose tissue depots, as previously reported for other adipose pads /22.5. Urine glucose was determined using the glucose Trinder method .Urine was collected placing the animals in metabolic cages for 24 h after a 1-day adaptation period and urinary albumin excretion (UAE) and creatinine clearance were determined as previously described ,57.−1 ketamine hydrochloride and 12 mg·kg−1 xylazine hydrochloride, i.p.) and blood pressure waves were recorded in a PowerLab system  to calculate both systolic (SBP) and diastolic blood pressure (DBP) [On the last day, both carotid and femoral arteries were catheterized under anesthesia (80 mg·kgre (DBP) ,24. Pulsre (DBP) ,24: D . For each slice of the CINE sequence, the left ventricle (LV) was segmented in the images corresponding to diastole and systole. The LV volume for each slice was summed to obtain the total left ventricular volume at the end of diastole and systole . The heart rate for each rat was calculated as the mean value of the heart rate during the entire CINE experiment. The ejection fraction (EF), cardiac output (SV), and cardiac output (CO) were obtained from these data.Magnetic resonance imaging (MRI) was performed with a Biospec BMT 47/40 spectrometer  operating at 4.7-Teslas and equipped with a 12 cm gradient system. Animals were anesthetized with a mixture of 3% isoflurane in oxygen (1.5 L/min for induction and 1.0–1.5% at 1.0 L/min for maintenance). Body temperature was maintained at 36 °C. Heart rate and respiration were monitored and used to trigger image acquisition with 1025 SAM monitoring and gating system . Several gradient echo images with different orientations were acquired to localize the short axis planes. Images were cardiac and respiratory triggered and up to seven slices were acquired in a cardiac cycle. Repetition time (TR) was variable depending on the animal’s heart and respiration rate. Other imaging parameters were as follows: echo time (TE) = 2.7 ms; flip angle (θ) = 80°; field of view (FOV) = 6 × 6 cmGapdh, Tbp, and Atpaf-1 as housekeeping genes and SYBR Green Master Mix . All primer sequences are detailed in Total RNA was isolated from the kidney, heart, PRAT, and MAT using Qiazol Reagent . The samples were processed using RNA Spin illustraTM . The concentration and purity of RNA were assessed with NanoDropTM 2000/c . Reverse transcription was performed on 500 ng of RNA with iScript cDNA synthesis kit  using random hexamer primers. Optimal annealing temperature and amplicon sizes were checked for each pair of primers. RT-qPCR analyzes were performed in a CFX96 Instrument . A measure of 10.00 ng of cDNA from ten samples of each group were run in duplicate and the mRNA levels were determined using intron-skipping primers with p < 0.05), with a required power of 80%, a difference of 1.6 typical deviation to be detected, and 10% sample loss. Continuous variables were compared by Student’s t test or one-way ANOVA followed by a Dunnett test comparing MWF-D with the (non-diabetic) MWF group as control. Categorical variables were compared using Fisher’s exact test. Data analysis was performed with GraphPad Prism 8 for animal data. Data are presented as mean ± standard error of the mean and statistical significance was considered for p < 0.05.The number of animals per group was calculated to reach a significance level of 5% (


This study aims to develop and evaluate a non-imaging clinical data-based nomogram for predicting the risk of vision-threatening diabetic retinopathy (VTDR) in diabetes mellitus type 2 (T2DM) patients.Based on the baseline data of the Guangdong Shaoguan Diabetes Cohort Study conducted by the Zhongshan Ophthalmic Center (ZOC) in 2019, 2294 complete data of T2DM patients were randomly divided into a training set (n=1605) and a testing set (n=689). Independent risk factors were selected through univariate and multivariate logistic regression analysis on the training dataset, and a nomogram was constructed for predicting the risk of VTDR in T2DM patients. The model was evaluated using receiver operating characteristic (ROC) curves and area under the curve (AUC) in the training and testing datasets to assess discrimination, and Hosmer-Lemeshow test and calibration curves to assess calibration.p = 0.000), BMI , systolic blood pressure (SBP) , diabetes duration , and glycated hemoglobin (HbA1C)  were independent risk factors for T2DM patients with VTDR. A nomogram was constructed using these variables. The model discrimination results showed an AUC of 0.7193 for the training set and 0.6897 for the testing set. The Hosmer-Lemeshow test results showed a high consistency between the predicted and observed probabilities for both the training set  and the testing set .The results of the multivariate logistic regression analysis showed that Age (OR = 0.954, 95% CI: 0.940-0.969, The introduction of Age, BMI, SBP, Duration, and HbA1C as variables helps to stratify the risk of T2DM patients with VTDR. Diabetic macular edema (DME) is classified as either present or absent . Vision-The main treatments for VTDR include panretinal photocoagulation, intravitreal injection of anti-vascular endothelial growth factor, and vitreoretinal surgery . PrimaryLogistic regression, as a commonly used statistical method, can be applied in various clinical medical scenarios, including but not limited to the following aspects: 1)Disease Prediction: Logistic regression can predict whether patients have a certain disease based on their clinical data. 2)Risk Assessment: Logistic regression can be utilized to assess the risk of patients developing a specific disease. 3)Diagnostic Assistance: Logistic regression can assist physicians in disease diagnosis. 4)Drug Development: In the drug development process, logistic regression can predict the efficacy and safety of new drugs. By establishing models, researchers can evaluate the therapeutic effects of different drugs on diseases and identify the most promising candidates. 4)Survival Analysis: In clinical observations and epidemiological studies, logistic regression can be used to analyze patients’ survival data, predict their survival rates, and identify factors that affect survival. Overall, logistic regression plays a crucial role in clinical medicine, providing an effective predictive and decision-making tool for physicians and researchers to improve patient health outcomes and the quality of medical services.In clinical prediction models, logistic regression analysis is commonly used for predicting the onset and diagnosis of diseases by analyzing the probability of an individual developing a certain outcome event at different values of the predictive indicator. Through logistic regression analysis of multiple factors, independent influencing factors for the outcome event are identified as predictive indicators in the prediction model. Then, multiple predictive indicators are integrated and analyzed using regression analysis to generate a risk nomogram based on a certain proportion .Currently, there are few clinical prediction model studies on DR and VTDR based on non-imaging data. Ke et al. constructed a risk nomogram for predicting the development of VTDR in mild NPDR patients by introducing three variables, including 2-hour C-peptide, UACR, and sural nerve conduction impairment (SNCI). The model achieved a sensitivity, specificity, and AUC of 66.7%, 89.5%, and 0.75, respectively, in the testing set .In most areas of China, there are standard management and regular physical examination protocols for diabetic patients. However, the screening and management system for diabetic retinopathy (DR) remains incomplete. Therefore, the purpose of this study is to develop and validate a VTDR risk prediction scoring model based on systemic parameters and non-ophthalmic imaging data, using the T2DM cohort study data. The goal is to provide a simple scoring system for regions with limited medical resources and primary healthcare institutions. This system can be used to identify high-risk individuals for VTDR, addressing the gaps in existing medical facilities and enhancing healthcare accessibility for at-risk populations.22.1The main workflow of this study summarized in 2.2a) The baseline data of 2677 patients were collected from the Guangdong Shaoguan Diabetes Cohort Study conducted by Zhongshan Ophthalmic Center (ZOC), Sun Yat-sen University in Guangzhou, China in 2019.b) All patients were diagnosed with T2DM.c) All patients underwent fundus photography and OCT examinations, and experienced ophthalmologists diagnosed and verified DR and DME. Patients with severe NPDR, PDR, and/or DME were defined as having VTDR.2.3PubMed, EMBASE, and other websites were searched using keywords such as “T2DM” and “VTDR” to identify relevant literature and determine the variables to be included in the study. The following patient data were extracted: ID number, Age, Gender, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), duration of diabetes(Duration), smoking status(Smoking), alcohol consumption(Alcohol), alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), serum creatinine (SCr), uric acid (UA), total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein cholesterol (LDL-C), blood glucose (GLU), glycated hemoglobin (HbA1C), and whether VTDR occurred. The extracted data were organized and merged into one file based on the patient ID number.2.4All categorical variables, including gender, duration of diabetes, smoking, alcohol consumption, residence, and whether VTDR occurred, were assigned values. The assigned values are shown in 2.5Logistic regression analysis is a statistical technique used to analyze the relationships between multiple variables, where the outcome variable is a categorical variable, including binary, unordered categorical, and ordered categorical variables. The number and types of independent variables are not limited. In this study, the well-organized data was randomly divided into training and testing sets in a 7:3 ratio. Single-factor analysis was conducted on all variables in the training set, and variables with a p-value< 0.05 were included in the multivariable logistic regression to identify independent influencing factors. The multivariable logistic regression is based on the logistic regression model, which establishes a linear equation to describe the relationship between independent variables and log odds. The log odds are then converted to probabilities for predicting and interpreting the outcome categories. The logistic regression model can be represented by the following equation:logit(p) represents the log odds, p is the probability of the event occurring, X1, X2,…, Xn are the independent variables, and β0, β1, β2,…, βn are the model parameters (coefficients). By estimating the parameter values, the best-fitting model can be obtained to predict the probability of the outcome variable.We establish a predictive model to identify independent influencing factors of VTDR in patients with T2DM and present it in the form of a Nomogram.2.6The ROC curve and AUC was used to evaluate the discrimination of the predictive model, with an AUC range of 0-1, where 1 indicates complete consistency and 0.5 indicates poor consistency. The Hosmer-Lemeshow test and calibration plot were used to calibrate the predictive model and judge the consistency between the predicted probability and the observed probability. When P>0.05 for the Hosmer-Lemeshow test, it can be considered that the predictive model has good calibration.The calibration plot is a commonly used visual tool for assessing the consistency between model-predicted probabilities and actual observed outcomes. In the calibration plot, the x-axis represents the predicted probabilities from the model, while the y-axis represents the frequency or probabilities of the observed outcomes. The predicted results refer to the model’s outputs obtained by predicting new, unseen samples based on input features and learned parameters. On the other hand, the observed outcomes represent the known class labels of the actual observed samples, which are used to compare the accuracy and effectiveness of the model’s predictions.3P<0.05 was considered statistically significant.Continuous variables that conform to normal distribution are expressed as mean and SD values, while other continuous variables are expressed as median (25-75 percentile). Categorical variables are expressed as percentages. Single-factor analysis and multivariate logistic regression were used to eliminate variables with limited predictive ability. Logistic regression was used to establish a predictive model, and a Nomogram was used to predict the incidence rate. All data were analyzed using SPSS version 27.0 and R version 4.2.2 software, and 44.1A total of 2677 patients with T2DM were collected and summarized. Individuals with missing variables were excluded, resulting in a final sample of 2294 patients with T2DM. Among them, 370 patients were diagnosed with VTDR, with a prevalence of 16.13%.4.2The original dataset consists of 2294 cases, which were randomly divided into a training set and a testing set. The training set includes 1605 cases (70%), and the testing set includes 689 cases (30%). The distribution differences of the 21 variables between the two groups were not statistically significant (P>0.05), as shown in 4.34.3.1SPSS was used to perform statistical description on the relevant variables in the training set (1605 cases). The results showed that there were statistically significant differences (P<0.05) in 11 variables, including Age, BMI, SBP, DBP, Duration, ALT, AST, BUN, SCr, GLU, and HbA1C, between the two groups, as shown in 4.3.2The 11 variables identified through univariate analysis, including Age, BMI, SBP, DBP, Duration, ALT, AST, BUN, SCr, GLU, and HbA1C, were included in the binary logistic regression analysis using SPSS. The results showed that Age, BMI, SBP, Duration, and HbA1C (5 variables) were independent risk factors for VTDR in patients with T2DM (P<0.05), as shown in 4.4This study used the multi-factor binary logistic regression method to select the predictive factors and built a nomogram model to predict the incidence of VTDR in T2DM patients using the “rms” package in Rstudio, based on the predictive factors selected from the multiple factor analysis Figure 2An example application is as follows: assuming that a 55-year-old (55 points) patient who has been diagnosed with type 2 diabetes mellitus for 10 years (32 points) has a BMI of 20 (40 points), a systolic blood pressure of 160 mmHg (34 points), and an HbA1C of 10% (45 points), his total score would be approximately 206, and the corresponding score would predict that the patient would have a probability of developing VTDR of about 65%.4.54.5.1The discrimination results show that the training set AUC is 0.7139 (4.5.24.5.2.1P=0.9742) and the testing set .The results of the Hosmer-Lemeshow test show a high level of consistency between the predicted probabilities and the observed probabilities in both the training set , i.e., for every 1-year increase in the age of an individual with T2DM, there was a 4.6% decrease in the risk of concurrent VTDR. This finding indicates that younger patients are at a higher risk of developing the disease compared to older patients. Contrasting with some earlier statistical studies which did not suggest age as a risk factor for DR, our results align with recent epidemiological studies , i.e., for every 1-unit increase in BMI in individuals with T2DM, there was a 5.8% decrease in the risk of concurrent VTDR. Previous studies have found a possible neutral association between BMI and DR, indicating the existence of both protective and adverse effects , suggesting that for every 1-unit increase in SBP in individuals with T2DM, there was a 1.4% increase in the risk of concurrent VTDR. We found a positive correlation between the increase in SBP and the occurrence of VTDR, which is consistent with previous research , i.e., for every 1 percentage point increase in HbA1C in individuals with T2DM, there was a 32.5% increase in the risk of concurrent VTDR. Research has found that the optimal cutoff point for distinguishing HbA1C variables between patients with and without DR is 8.15% (The study found an OR for HbA1C of 1.325 (95% CI: 1.221-1.438, is 8.15% , 36, 37.is 8.15% . Studiesis 8.15% . TherefoAfter integrating all independent factors, this study included five variables, Age, BMI, SBP, Duration, and HbA1C, in the construction of a column chart model. Discrimination analysis showed that the training set AUC was 0.7193 and the testing set AUC was 0.6897, which was lower than Ke, J.’s prediction model . HoweverHowever, this study still has limitations. Although this study developed a new nomogram for T2DM complicated with VTDR, the modeling and validation data were both from epidemiological data in the same region and did not conduct application experiments in the real world. Therefore, this model still needs further improvement and validation.6Age, BMI, SBP, Duration, and HbA1C are independent factors that influence the development of VTDR in T2DM patients. Among them, the increase in SBP, Duration, and HbA1C is positively correlated with the incidence of VTDR, while the increase in age and BMI is negatively correlated with the incidence of VTDR. By introducing these 5 variables, the nomogram can help stratify the risk of VTDR in T2DM patients. However, further validation and improvement are still needed to enhance the reliability and generalizability of this model in real-world settings.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving humans were approved by Zhongshan Ophthalmic Centre Ethics Review Committee. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin.DG, LF, and YC: methodology, formal analysis, and writing – original draft. IC, JG, ZY, and XS: methodology and writing – review & editing. WY and JW: conceptualization, resources, writing – review & editing, and funding acquisition. All authors contributed to the article and approved the submitted version.


A relevant percentage of IgAN patients experience a progressive decline in kidney function. According to the KDIGO guidelines, proteinuria and eGFR are the only validated prognostic markers. The role of interstitial macrophages in kidney biopsies of IgAN patients and the outcome of patients treated with renin–angiotensin system inhibitors (RASBs) alone or combined with glucocorticoids were evaluated. Clinical and laboratory records , MEST-C parameters of the Oxford classification, C4d deposition, peritubular capillaries, and glomerular and interstitial macrophages in 47 IgAN patients undergoing kidney biopsy consecutively between 2003 and 2016 were examined. A high number of interstitial macrophages significantly correlated with peritubular capillary rarefaction and impairment of kidney function. Cox’s multivariable regression analysis revealed that a value > 19.5 macrophages/HPF behaved as an independent marker of an unfavorable outcome. Patients exhibiting > 19.5 macrophages/HPF treated at the time of diagnosis with RASBs combined with methylprednisolone had an estimated probability of a favorable outcome higher than patients treated with RASBs alone. Thus, a value > 19.5 macrophages/HPF in IgAN biopsies can predict an unfavorable outcome and endorse a well-timed administration of glucocorticoids. Studies evaluating urine biomarkers associated with peritubular capillary rarefaction in patients with marked macrophage infiltration may help personalized treatment decisions.  IgA nephropathy (IgAN), the most frequent primary glomerulonephritis ,2, is anIn a previous study, we showed for the first time that the interstitial macrophage number positively correlated with hypertension and S1 and T1 scores . In this2) were recorded at the time of biopsy. Hypertension was defined as systolic blood pressure > 135 mm Hg and/or diastolic blood pressure > 85 mm Hg or the use of anti-hypertensive agents. In the kidney biopsies of patients with hypertension, typical vascular lesions were observed. Clinical and laboratory records of 47 IgAN patients  undergoing kidney biopsy consecutively between January 2003 and December 2016 were reviewed. Patients included in the study were more than 15 years of age and underwent biopsy before any immune-suppressive treatment. Patients with diabetes mellitus, autoimmune diseases, abnormal hypergammaglobulinemia, and liver diseases were excluded from the study. After biopsy, 16 patients were treated with RASBs, 10 with corticosteroids, and 18 with RASBs and corticosteroids. Three patients with normal kidney function, proteinuria < 1 g/24 h, and only mild mesangial hypercellularity received no treatment. Hematuria, proteinuria (g/24 h), serum creatinine level (mg/dL), blood pressure, and estimated glomerular filtration rate (eGFR) (mL/min per 1.73 mn = 11), methylprednisolone (1.5–1 mg/kg/die) in combination with RASBs (n = 11), or methylprednisolone (0.5–1 mg/kg/die) (n = 5); methylprednisolone was administered for 6 months. Three patients with normal kidney function, proteinuria < 1 g/24 h, and kidney biopsies with only mild mesangial hypercellularity received no treatment.Follow-up time was considered as the interval time between kidney biopsy and the last outpatient visit. Hematuria, proteinuria, serum creatinine levels, and eGFR data at the end of follow-up were available for 30 patients. The evaluation of the impairment of the kidney function, based on the eGFR at the time of biopsy and at the end of follow-up  was performed using the Kidney Disease Outcome Quality Initiative (KDOQI) guidelines, which defines five stages: I: eGFR ≥ 90 mL/min; II: eGFR = 60–89 mL/min; III: eGFR = 30–59 mL/min; IV: eGFR = 15–29 mL/min; V: eGFR ≤ 15 mL/min [Formalin-fixed paraffin-embedded sections were stained with hematoxylin–eosin, PAS, and Masson’s trichrome. Direct immunofluorescence was performed on fresh frozen tissue with FITC-conjugated polyclonal antibodies to detect IgG, IgM, IgA, C3, and fibrinogen . IgAN biopsies were evaluated according to the revised Oxford Classification ,8,9. EacStaining of endothelial cells with anti-CD31 murine MoAb (Dako) was performed using the Ultravision LP polymer detection method  after antigen retrieval by heating the sections in Tris-EDTA buffer (pH 8.0). To control for non-specific staining, the primary antibodies were replaced by irrelevant matched MoAb or immune serum, as appropriate. The mean number of peritubular capillaries (PTC) in the cortical area was evaluated using a Nikon Eclipse Te 2000-U microscope equipped with the Nikon Nis Vers. D ver 5.21 image analysis software. The mean number of PTC was calculated by dividing the total number of PTC by the number of HPF (magnification ×40). The mean number of HPF counted per biopsy was 36.53 ± 22.10. In 45 cases, tissue sections were available to perform C4d immunostaining. Paraffin sections were stained using a polyclonal anti-C4d antibody  as previously described . Biopsiet, Shapiro–Wilk, Breush–Pagan, and Durbin–Watson tests, respectively. The follow-up median time was 50 months (C.I. 95%: 39–75) and the primary end point went from the time of kidney biopsy to the date of the impairment of the kidney function or to the date of the last available information on the patient’s status. All medians and life tables were computed using the product-limit estimate by Kaplan and Meier and the curves were examined by means of the log-rank test. For the univariable and multivariable analyses, continuous variables were converted to binomial variables based on the initial analysis of the distribution of the variable values, and according to the results of ROC analyses. Univariable and multivariable analyses were performed by Cox’s proportional hazards model and the prognostic accuracy was assessed by Harrell’s concordance index (C-index). The proportional hazards assumption was assessed by visual inspection of log-log survival curves and by linear regressions of scaled Schoenfeld residuals versus time. Collinearity was verified by computing variance inflation factors (VIF) from the covariance matrix of parameter estimates. The backwards stepwise procedure, based on the lowest AIC value, was utilized to reduce the variable numbers in the Cox’s regression model. Event-free survival probabilities, given the covariates and follow-up time, were calculated for the model fitted by the reduced multivariable Cox’s regression. A p value < 0.05 was considered statistically significant, evaluating the yield of two-tailed statistical tests. Statistical analyses were performed using the JMP version 13.0  and R Studio software version 3.3.3 .Results are expressed as means ± SE or medians, as appropriate. Wilcoxon/Kruskal–Wallis and Spearman’s rho correlation tests were used for the statistical analysis of the distributions of interstitial macrophage and peritubular capillary values according to clinical and pathological variables. The standard multiple linear regression model, fitted using the ordinary least squares estimation technique, was utilized to explain variations in the number of interstitial macrophages that can be attributed to variations in the explanatory variables. The backwards stepwise procedure, based on corrected Akaike’s information criterion (AIC), was used to include only the necessary explanatory variables in the prognostic model. Assumptions of the ordinary least squares regression model were verified through residual diagnostics. In particular, exogeneity, normality, homoscedasticity, and independence assumptions were assessed by Student’s Kidney biopsies from 47 patients showed predominant IgA immunoreactivity in the mesangial area of glomeruli, as required for the diagnosis of IgAN. Immune-reactivities for IgG, IgM, C3, and fibrinogen were observed in 11, 28, 46, and 22 kidney biopsies, respectively. In 45 cases, C4d immunostaining was performed. Glomeruli, mesangial areas, and peritubular capillaries (PTC) were C4d negative. p = 0.0087) (p = 0.0003) and a negative correlation with eGFR (p = 0.0002) were observed  . A positobserved .p = 0.0102, 0.001, 0.0108, respectively) (p = 0.0108) between interstitial macrophages and PTC  . Fibrosi and PTC . The PTCp = 0.054) (p = 0.0390)  . As in p 0.0390) . 2 = 0.49; F-statistic: 7.871 on 5 and 41 DF, p-value: 0.000029), , .p < 0.0001, p < 0.0001)  (p < 0.006) or scored S0/T0 (p < 0.0001) (p = 0.0002)  C, wherea 0.0001) E. Then,  0.0001) F. The nu 0.0002) G.p = 0.032). At the 5-year follow-up, the estimated proportions of event-free patients were 14.5% ± 12.9 SE and 63.7% ± 15.5 SE for patients with high (>19.5/HPF) and low (≤ 19.5/HPF) mean macrophage number, respectively. Patients with a value > 19.5 macrophages/HPF showed a risk of unfavorable outcomes 3.12 times higher (C.I. 95%: 1.043–1.77) than patients with a value of ≤19.5 macrophages/HPF. Follow-up data were available for 30 IgAN patients. Thirteen patients (43.3%) experienced an unfavorable outcome (stage 2 or lower at the time of the diagnosis and no improvement or a worse stage at the end of follow-up). The Kaplan–Meier analysis showed that the estimated probability of an unfavorable clinical course was higher for patients with a mean number of interstitial macrophages > 19.5/HPF as compared to patients with a mean number ≤ 19.5/HPF  . In addition to serum creatinine value > 1.2 mg/dL, and the type of therapy, the mean number of interstitial macrophages/HPF > 19.5/HPF behaved as an independent prognostic marker of an unfavorable outcome   with a significant global = 0.034) .Glucocorticoids are well known inhibitors of macrophage pro-inflammatory functions , and treInflammation contributes to the development of hypertension . RASBs aAs anti-inflammatory pathways underlying a combined therapy could converge C, we comEvent-free survival curves based on the Cox regression estimates adjusted at the basal levels of the confounding covariates were calculated as a function of the number of interstitial macrophages corresponding to quartiles Q2 (19/HPF), Q3 (23/HPF), and Q4 (27/HPF), and the type of therapy . The estimated event-free survival probabilities were inversely associated with the number of interstitial macrophages in patients treated both with RASBs alone A and in We report, for the first time, that a marked interstitial macrophage infiltration correlated with microvascular rarefaction in kidney biopsies of IgAN patients. Moreover, interstitial macrophage infiltration was an independent risk factor for a progressive decline in kidney functions. The combination of corticosteroids and RASBs therapy administered after kidney biopsy improved the outcome, particularly when numerous interstitial macrophages were present. Our patients did not exhibit active  or chronic severe histopathological lesions, and only two patients underwent ESKD at the end of follow-up. Thus, they formed a suitable group to analyze predictive factors of disease progression. Early studies concerning various types of glomerulonephritis have shown that tubulointerstitial damage correlates with progression to ESKD more than glomerular damage ,36,37. IThe reduction in microvascular density or “capillary rarefaction” causes a defective delivery of oxygen/nutrients to the tubules and induces HIF-1-dependent pro-fibrotic mechanisms, including tubular cell–myofibroblast transdifferentiation ,43,44, tIn different pathological conditions, distinct mechanisms underlie the microvascular damage . In IgANBy a multivariable analysis, we have shown, confirming our previous results, that a low eGFR predicted a high macrophage number . In thisA high number of glomerular macrophages does not correlate with clinical or pathological parameters ,17. HoweTo date, there are no univocal indications for treating IgAN patients with glucocorticoids.It has been proposed that distinct MEST-C scores could be exploited to suggest a personalized immunosuppression ,62,63,64According to the KDIGO guidelines, however, the evidence to support an immunosuppressive treatment decision based on the MEST-C criteria is insufficient, and only patients showing proteinuria > 1 g/die following a six-month treatment with RASBs are at high risk of progression and should be considered for the immunosuppressive therapy . HoweverAt the time of diagnosis, we administered a six-month treatment with glucocorticoids alone when a marked interstitial inflammatory infiltrate was observed in the absence of hypertension. RASBs alone were administered in the presence of proteinuria > 1 g/die and/or hypertension without a marked interstitial inflammation. RASBs in combination with a six-month treatment with methylprednisolone were administered when proteinuria was >1 g/die and/or hypertension were associated with active lesions and/or marked interstitial inflammation. The combined therapy clearly reduced the deleterious effect of increasing amounts of interstitial macrophages, suggesting that a timely addition of glucocorticoids in selected patients was advantageous. A limitation of this study is the relatively small number of patients with follow-up data. In addition, being a retrospective analysis, it was not possible to investigate the mechanisms underlying PTC rarefaction. Nonetheless, we have shown that a high number of interstitial macrophages in IgAN is an independent prognostic indicator for the risk of an unfavorable outcome and could endorse the choice of a well-timed administration of glucocorticoids.Thus, the number of CD68-positive cells should be routinely evaluated, and prospective studies concerning urinary biomarkers connected with this lesion are desirable to support personalized treatment decisions at the time of biopsy, and throughout the follow-up.


The renin–angiotensin–aldosterone system (RAAS) is a major target for treating hypertension and preventing various complications. Mineralocorticoid receptor (MR) antagonists are recommended as specific drugs to ameliorate hyperactive MR signaling, especially for patients with idiopathic hyperaldosteronism. However, the clinical implications of an increased RAAS activity and angiotensin II level induced by MR antagonist administration remain unclear. A 72-year-old Japanese man was referred to our university hospital for refractory hypertension management. He has also had type 2 diabetes mellitus and nephropathy for 8 years. MR antagonists, initiated based on the diagnosis of primary aldosteronism, effectively improved his hypertension. However, proteinuria of 2.5 g/g creatinine, concomitant with an increase in both active renin concentration and plasma aldosterone concentration, occurred. Additional administration of an angiotensin II receptor blocker successfully reduced the plasma aldosterone concentration and proteinuria (<0.3 g/g creatinine). Preserved renal function was confirmed for 1 year thereafter. In conclusion, this case suggests that the angiotensin II receptor is a potential target to treat proteinuria concomitant with primary aldosteronism. RAAS reactivation should be considered when an MR antagonist is initiated for patients with primary aldosteronism, especially idiopathic hyperaldosteronism. Regulation of the renin–angiotensin–aldosterone system (RAAS) is the mainstream treatment of hypertension and prevention of hypertension-related complications. Hyperactivity of mineralocorticoid receptor (MR) signals leads to disorders of the cardiovascular system and kidneys via chronic inflammation and fibrosis in the related organs . AdminisPrimary aldosteronism (PA) frequently occurs with hypertension, accounting for approximately 5% to 13% of all hypertension cases [The blockade of MR signaling using MRAs is a specific and effective medical treatment and is recommended especially for idiopathic hyperaldosteronism . AdditioHerein, we present a patient with idiopathic hyperaldosteronism concomitant with diabetes mellitus and CKD with macroproteinuria. Diagnosis of PA was considered a key factor in preventing CKD progression in this case. This case provides evidence that angiotensin II receptor blockade is a potential therapeutic strategy for patients with PA to prevent the progression of systemic complications.A 72-year-old Japanese man with hypertension was admitted to our university hospital for examination and treatment of PA. He had undergone a subtotal thyroidectomy due to Graves' disease at 26 years of age and continued levothyroxine to manage hypothyroidism. He had a history of hemorrhage in the brainstem at 54 years of age, when he was diagnosed with hypertension, and had been taking antihypertensive drugs since then. Sustained hypertension despite various drug regimens and a relatively high ratio of plasma aldosterone concentration (PAC)  to PRA  in July 2018 led to further evaluation for PA at 69 years of age in November 2018. Notably, his urinalysis did not reveal proteinuria following administration of 100 mg/day irbesartan, 50 mg/day eplerenone, and 10 mg/day amlodipine. At the same time, his blood pressure was 135/73 mmHg.The patient's laboratory examinations, performed in the absence of antihypertensive drugs except for calcium antagonists (40 mg/day of nifedipine CR) administered for over 2 months, revealed hypokalemia . Urinalysis demonstrated proteinuria; however, no occult blood was observed . The cap2 (Diabetic kidney disease (DKD) stage III was diagnosed based on proteinuria of 2.9 g/day and an estimated glomerular filtration rate (eGFR) of 56.9 mL/min/1.73 m2 ; bilater2 . The pat2 . Based o2 . His ser2 . The cha2 for over 1 year after a transient decrease). His potassium level has been regularly monitored and maintained within the normal range throughout the clinical course (The blood pressure of the patient decreased gradually and has been maintained around the target range by administering multiple antihypertensive medications. Additionally, there has been no further progression of renal dysfunction (eGFR approximately 40 mL/min/1.73 ml course .RAAS reactivation associated with MRA administration is a potential risk factor for proteinuria progression, which may cause renal dysfunction and cardiovascular disease. MRA administration overrides PRA suppression via MR blockade, even in patients with PA, and has been suggested to elevate angiotensin and aldosterone sequentially , 5. We cRegulation of reactivated RAAS using an ARB can reduce proteinuria and halt the progression of renal dysfunction in patients with PA. We first demonstrated a reduction in proteinuria following ARB co-administration in patients with PA treated with an MRA. This case also revealed that ARB administration reduced PAC, which had earlier increased, and MRA administration released PRA suppression. Both angiotensin II and aldosterone can exacerbate proteinuria and renal dysfunction independently , althougThe RAAS activity, which includes aldosterone, should be regulated as a critical target for improving the prognosis of patients with MR-associated hypertension. RAAS regulation using ARB/ACE inhibitors is the gold standard treatment for hypertension, whereas hyperactivated MR signaling is a proposed critical target for post-RAAS regulation therapy . HyperacThis case report has 4 limitations. First, further large-scale prospective studies are required to confirm our results. Second, we could not rule out the effect of reduced blood pressure and/or β-blocker administration on proteinuria or renal function, although the effectiveness of ARB administration in a patient with PA itself is a notable finding. Third, owing to the lack of data on proteinuria during single administration of MRAs, we could not investigate the effectiveness of high-dose MRAs completely. Fourth, we could not conclude whether we can apply this result to patients with aldosterone-producing adenomas.We present the first case that demonstrated angiotensin II receptor as a potential target for treating proteinuria in a patient with PA.The blockade of RAAS reactivation associated with MRA administration was required to prevent proteinuria progression. Furthermore, prevention of renal dysfunction was observed for over 1 year.RAAS activity, including the activity of both aldosterone and angiotensin II, should be emphasized as a critical target for improving the prognosis of patients with MR-associated hypertension, including PA.