Childhood obesity speeds up the development of arterial stiffness and progressively increases the values of arterial pressure. The purpose of this study is to investigate the value of using pulse wave analysis (PWA) to measure arterial stiffness as a sign of vascular wall impairment in obese children. The research was focused on 60 subjects: 33 obese and 27 normal-weight. Ages ranged from 6 to 18 years old. PWA includes parameters such as pulse wave velocity (PWV), augmentation index (AIx), peripheral and central blood pressure , heart rate, and central pulse pressure (cPP). The device used was a Mobil-O-Graph. Blood parameters were taken from the subject’s medical history, not older than 6 months. A high BMI and a large waist circumference are linked to a high PWV. The levels of LDL-c, triglycerides (TG), non-HDL-c, TG/HDL-c ratio, and total cholesterol-HDL-c ratio significantly correlate to PWV, SBP, and cSBP. Alanine aminotransferase is a reliable predictor of PWV, AIx, SBP, DBP, and cDBP, while aspartate aminotransferase is a significant predictor of AIx, mean arterial pressure (MAP), cSBP, and cPP. 25-OH-Vitamin D negatively correlates with PWV, SBP, and MAP and significantly predicts the MAP. Cortisol and TSH levels are not significant to arterial stiffness in obese children without specific comorbidities and neither is fasting glucose in obese children without impaired glucose tolerance. We conclude that PWA contributes valuable data regarding patients’ vascular health and should be considered a reliable tool in the management of obese children. Obesity is a silent disease in children. Unhealthy eating and lifestyle behavior are symptoms of various causes that have to do with individual mental health, parental guidance, socio-economic and cultural diversity, access to nutrition, and education ,2,3. GloThe longer the evolution of obesity, the earlier and more likely the debut of complications. One of the most serious complications is the vascular damage associated with chronic inflammation, insulin resistance, and high blood pressure . CardiovObese children present a major risk of becoming obese adults with the above-mentioned disorders. Therefore, one of the main objectives of modern medicine is to decrease the prevalence of pediatric obesity. Prompt detection of vascular disruptions can be one of the means to improve the efforts for achieving this goal. Vascular dysfunction is fueled by processes such as atherosclerosis, arterial stiffness, and high blood pressure. All these processes begin in early childhood, but obesity is an aggravating factor, accelerating all probable complications . The patThe principal premise of the current research is that, although obese children are not expected to show pathological values for the markers assessing arterial stiffness and blood pressure, they do show increased values in contrast with their normal-weight peers. These values, which are correlated with clinical and blood parameters, may reveal a more comprehensive picture of the cardiovascular and metabolic status of the obese patient and, hence, broach the difficult subject of cardiovascular risk at younger and more malleable ages, when prophylaxis should be more efficient.The stiffness of the vascular walls can be evaluated by measuring the velocity of the pulse wave (PWV) , which rThe PWA includes another marker which measures the stiffness of the arterial wall, called the index of augmentation (AIx). The AIx is associated with peripheral arterial resistance and, thus, gives valuable information on the elasticity of small arteries . The AIxThe arterial stiffness in individuals with weight excess is linked to high blood pressure levels as well . In chilMultiple techniques, devices, and measurement sites can be used for performing a PWA. The devices are based either on tonometry or oscillometry. Conventionally, especially in adults, two-point estimation methods such as the carotid–femoral PWV or the brachial-ankle PWV are used ,42. SingThe current study investigates the utility of pulse wave analysis (PWA) in measuring the extent of the damage on the arterial wall in children with weight excess. The aim is to show that adding the PWA to our everyday evaluation of such patients is a reliable tool for creating a cardiovascular risk profile that can be useful in patient care. Providing additional scientific data with regard to childhood obesity’s effects on arterial stiffness is an important objective, as it also allows for the implementation of more effective preventive actions in such individuals.The research took place in the “Pius Brinzeu” Emergency County Hospital from Timisoara, Department of Pediatrics, from January 2022 until June 2022, on 60 children. Ages ranged from 6 to 18 years old.The recruitment was made from the chronically obese patients who showed up for a medical consult during the study period and who agreed to be part of the study. Only children with stagnating primary obesity were asked to participate (BMI higher than the 95th percentile). We eliminated patients with higher than 5 kg fluctuations in weight over the last 6 months. We also excluded all patients presenting with known contributors to secondary obesity , as wellChildren with primary obesity formed the study group. The control group was made up of normal-weight (BMI between the 5th and the 85th percentile), healthy, and age-matched children who were recruited as volunteers to be part of the study.2) was calculated, and the puberty development was assessed (Tanner stage). The Mobil-O-Graph device was utilized to determine the peripheral blood pressure values.All subjects were clinically examined: the weight , height , and waist circumference  were measured, the Body Mass Index , high density lipoprotein cholesterol , low density lipoprotein cholesterol , total cholesterol , triglycerides , non-HDL-cholesterol (mg/dL), triglycerides/HDL-c ratio, total cholesterol/HDL-c ratio, cortisol 8 am (ug/dL), thyroid stimulating hormone , aspartate aminotransferase , alanine aminotransferase , 25-OH-Vitamin D (ng/mL) and ionized Calcium (mg/dL). These parameters were measured after previous medical consults in our Pediatric Endocrinology Department, following a minimum 12 h time of fasting.® 24 h ABPM oscillometric device  with the Hypertension Management Software CS . It performs a brachial determination of the peripheral BP, followed by a Pulse Wave Analysis which includes the recording of the PWV, index of augmentation (AIx), mean arterial pressure (MAP), heart rate (HR), central pulse pressure (cPP) and the systolic and diastolic central BP . The device’s one-time measurement function was used. Details of the methodology and specifics of the device have been presented extensively in our previous work [The assessments were done through the Mobil-O-Graphous work .The manufacturer recommends the device for pediatric use, in children over three years old. Our experience confirms its operational reliability as well . The sofThe patients were instructed to avoid smoking for at least 4 h before to the examination, avoid consuming caffeinated beverages, and go to bed at 10 p.m. at the latest the night before our meeting. Each subject’s arm circumference was determined, and the appropriate cuff size was selected . We took the measurement after a 10-min period of supine rest. On the subject’s naked upper arm, the cuff was placed with the pressure tube facing up and the artery sign on the brachial artery. The patient must remain still and silent throughout the measuring process .The Mobil-o-Graph performs two separate measurements: Firstly, the measurement of the peripheral BP values, followed by a thirty-second intermission; secondly, the PWA, the central BP, and pulse pressure measurement; lastly, the software analyzes the measurement’s accuracy and advises on accepting the data or repeating the measurement. Each patient underwent one measurement. If the measurement’s accuracy was poor, we retook it after a five-min break .Data collection was carried out using Microsoft Excel and statistical analysis was conducted using MedCalc Statistical Software version 20.111 .n = 33) and a control group . Multiple subgroups were needed for statistical analysis based on sex, age, and puberty development. These groups were analyzed focusing on the parameters acquired through the oscillometer, which we called “the PWA parameters” in the Results section, for simplification: PWV (m/s), AI %, SBP (mmHg), DBP (mmHg), MAP (mmHg), HR (b/min), cSBP (mmHg), cDBP (mmHg), and cPP (mmHg).The 60 subjects formed two groups, according to the inclusion criteria: an obese group . In order to maintain a significance level of less than 0.05, one-way ANOVA post-hoc tests were run and Bonferroni corrections were made. The stepwise approach of multivariable regression analysis was used in MedCalc.The Shapiro–Wilk test divided the approach of the statistical analysis, splitting the data into normal and non-normal with regard to its distribution. Means, the Student’s The study respects the Helsinki Declaration and has received approval from the University of Medicine and Pharmacy Victor Babes Timisoara’s Ethics Committee for Scientific Research (No. 03/19.01.2021). We acquired the informed consent of all legal guardians and 18-year-old patients and the verbal consent of all minor patients.Sixty subjects between the ages of 6 and 18  were involved in the study. Based on their BMI, two groups of study were created, one of obese subjects (15 girls and 18 boys) and one of controls (14 girls and 13 boys). The majority of PWA markers significantly correlated with BMI as can be seen in Fifteen obese girls (45.45%) and 18 obese boys (54.54%), as well as 14 girls (51.85%) and 13 boys (48.14%) acting as controls were evaluated. The comparison of same-sex participants from the two groups revealed significant differences in arterial stifness parameters .p = 0.28), AIx (p = 0.81), SBP (p = 0.34), DBP (p = 0.06), MAP (p = 0.15), HR (p = 0.42), cSBP (p = 0.34), cDBP (p = 0.07), and cPP (p = 0.64)), or controls ((p = 0.81), DBP (p = 0.64), MAP (p = 0.056), HR (p = 0.82), cSBP (p = 0.64), cDBP (p = 0.19), and cPP (p = 0.27)). Under twelve years old, twelve to fifteen years old, and over sixteen years old comprised the three age subgroups for each study group. Following the Bonferroni adjustment, the one-way ANOVA tests failed to find any differences between the three subgroups for obese participants (PWV (p = 0.03), HR (p = 0.03), cSBP (p = 0.009), and cPP (p = 0.01) in obese subjects younger than 12, and PWV (p = 0.004), SBP (p = 0.02), cSBP (p = 0.002), and cDBP (p = 0.005) in obese subjects aged 12–15.Because the normal weight group only had four subjects and the obese group six, the analysis of the subjects ≥16-year-old is statistically inaccurate.According to Tanner’s stages of puberty, the research groups were split into three subgroups that included stage I, II and III, and IV and V. The ANOVA did not reveal considerable variations in arterial stiffness parameters between the three categories after applying the Bonferroni adjustment. Most parameters showed higher scores in Tanner IV and V patients .p = 0.017) and cSBP (p = 0.009) compared to their controls; for Tanner II and III, higher PWV (p = 0.03) and cSBP (p = 0.027) values; and for Tanner IV and V, higher cSBP (p = 0.014) and cDBP (p = 0.0095)  see .p < 0.01).For subjects who were obese, the average waist size was 98.3 cm . The resp < 0.01); When evaluating all subjects, the WC displayed a strong positive correlation with the PWV , as shown in The waist circumference has a strong correlation with MAP values as well  and heart rate levels than obese boys in this study (p = 0.039). Obesity considerably raises the scores of PWV, SBP, cSBP, and cDBP when evaluating PWA parameters within each sex. The fact that obese girls present increased markers for arterial stiffness compared to normal-weight girls, and that the same is valid for boys, is another argument that excess weight increases arterial stiffness, including peripheral and central BP values.It appears that sex has little to no impact on the vascular elasticity of obese children. Harbin et al. showed no variations between sexes concerning central BP values . In an aAge has an uncertain and difficult-to-measure impact on vascular stiffness in the pediatric and young-adult population. The main causes for vascular damage due to age are connected to the loss of collagen and elastin within the tissue of the vessels . In obesPuberty itself is not damaging to arterial elasticity, nor is it associated with increased velocity of the pulse wave or the index of augmentation in obese children . The expAbdominal adiposity represents a reliable marker of metabolic disruption and cardiovascular events , an esseThe analysis of blood parameters represents the particularity of the present study; as previously discussed, our previous work revealed similar results for clinical parameters .HDL-c is the anti-inflammatory component of the lipid panel, its main role being to transport excess cholesterol to the hepatic cells from the arterial walls . The metLDL-c is a major player in atherosclerotic plaque formation, especially when it is assocciated with low HDL-c . When a Tryglicerides, another component of the metabolic syndrome, reflects the individual proclivity to an unhealthy lifestyle, its values being under the direct influence of each individual’s diet . BecauseIn adult populations, the values of these blood lipids are clearly linked to vascular damage. The work of Wang et al. involving 909 adults revealed, after accounting for cardiovascular risks, that HDL levels are negatively correlated with PWV, while TG, LDL-c, and total cholesterol levels are positively correlated with PWV. The study also suggests that the otherwise healthy population displaying significant risk factors for arterial elasticity loss should take into account lipid-lowering therapy . TherefoStudies show the ratio between TG and HDL-c may be a more consistent and accurate indicator for cardiovascular, metabolic and dysglicemia risk ,78. ThisNon-HDL-c is at least as valuable in assessing cardiovascular risk as is LDL-c, being correlated to the risk of atherosclerotic progression and long-term cardiovascular events . In bothThe ratio between TC and HDL-c represents an independent predictor of ischemic coronary events in adults. Its power as a predictor grows when individuals with high TC/HDL-c ratio also present large waist circumferences, insulin resistance, and dyslipidemia . The anap = 0.01), only 6% of the obese presented a fasting glucose >110 mg/dL. Moreover, no correlations were detected in our analysis between fasting glucose and PWA parameters. These findings are in line with the above-mentioned observations. A far more accurate marker for insulin resistance is the HOMA-IR score, which in adolescents with weight excess is known to be a trustworthy proxy for estimating the resistance to insulin activity, powerfully predicting the risk of developing diabetes mellitus type 2 [High fasting glucose levels represent one of the earliest signs of glucose–insulin metabolism impairment in adults . Howevers type 2 . An impos type 2 . Hence, s type 2 , but unfs type 2 . Hemoglos type 2 . Hence, The most frequent liver issue associated with childhood obesity is non-alcoholic fatty liver disease, affecting almost 80% of these patients in various degrees of severity . It is aCortisol oversecretion is linked to cardiovascular conditions and thus, represents a significant contributor to morbidity and even death in Cushing’s disease . Obese cThe thyroid-stimulating hormone is linked to arterial stiffness, meaning higher values of the PWV, in overt or subclinical hypothyroidisms ,95. Weig25-OH-Vitamin D is involved in multiple intricate systems of the human organism, with great importance in phosphate–calcium metabolism, immune modulation, and vascular protection. Its involvement in the endothelial wall is controlled by the relationship of the endothelial cell vitamin D receptors and ligand vitamin D . It alsoThe primary benefit of this research is that the results managed to significantly support the main starting hypothesis that obese children present increased arterial stiffness and higher blood pressure values. Another strength is that the study succeeded in revealing the associations between the non-invasive markers of arterial stiffness and clinical parameters, and metabolic blood parameters, respectively. The limitations of this study include failing to perform ultrasonography measurements of the flow-mediated dilation, which is regarded as a standard for the early identification of damage in the arterial walls , as wellChildhood obesity promotes the loss of elasticity of large vessels by progressively aggravating arterial stiffness and increasing the values of peripheral and central blood pressure. A high BMI and an increased waist circumference are associated with a high PWV.Increased levels of LDL-c, triglycerides, non-HDL-c, as well as TG/HDL-c, TC/-HDL-c ratios, transaminase levels, and low titers of 25-OH-Vitamin D are significant to the progression of arterial stiffness in obese children. Cortisol and TSH levels are not significant to arterial stiffness in obese children without specific endocrine comorbidities and neither is fasting glucose in obese children without impaired glucose tolerance.We conclude that PWA contributes valuable data regarding patients’ vascular health, helping clinicians not only to evaluate and monitor patients at risk more accurately, but also to be more effective in their combat against obesity. Therefore, we believe that PWA should be considered a reliable instrument in the everyday evaluation of obese children.Future scientific endeavors will be required to better integrate the non-invasive markers of arterial stiffness with those of early endothelial dysfunction (flow-mediated dilation) and of subclinical atherosclerosis (carotid intima-media thickness) in obese children.


The mechanisms that explain the cardio-renal benefits of sodium glucose co-transporter 2 (SGLT-2) inhibitors are unknown. The effect of SGLT-2 inhibitors on arterial aging, measured by Aortic Pulse Wave Velocity (Ao-PWV) and Soluble Klotho (s-Klotho), a circulating anti-aging biomarker of arterial health are also unclear.A 24-week single center randomized controlled trial (registry number/ EudraCT Number: 2013-004042-42) comparing Dapagliflozin and Ramipril (D+R) versus Ramipril (R) on the primary endpoint of urine albumin excretion rate (AER) and pre-specified secondary endpoints of Ao-PWV and biomarkers of arterial aging [s-Klotho and Fibroblast Growth Factor 23 (FGF-23)]. People with type 2 diabetes who had estimated glomerular filtration rate (eGFR) > 60 ml/min and residual microalbuminuria on maximum tolerated renin angiotensin system (RAS) inhibition were included in this study.n = 17) or R (n = 16) arms. After 24 weeks of treatment, Ao-PWV (mean ± SD) did not change significantly from baseline D +R [9.06 ± 1.91 m/s to 9.13 ± 2.03 m/s], and R [9.88 ± 2.12 m/s to 10.0 ± 1.84 m/s]. AER fell significantly by 43.5%  in people in the D+ R arm only. We do not observe any significant changes in FGF-23 or s-Klotho. HbA1c and Angiotensin 1–7 fell significantly only in D + R arm.In total, 33 participants  were randomized to either D+R (The combination of Dapagliflozin and Ramipril had no effects on Ao-PWV and s-Klotho which are biomarkers of arterial aging and cardio-renal risk. Our data suggest that the early cardio-renal benefits observed with SGLT-2 inhibitors are unlikely to be related to an improvement in arterial aging. Sodium-glucose co-transporter-2 (SGLT-2) inhibitors have demonstrated cardio-renal benefits in large randomized controlled trials in people with diabetic kidney disease (DKD) and residual albuminuria all on renin angiotensin system (RAS) inhibition –3. HowevArterial stiffness as measured by aortic pulse wave velocity (Ao-PWV) is an independent predictor of cardiovascular and renal outcomes and a biomarker of arterial aging. We have previously demonstrated a close positive association between Ao-PWV and albuminuria, a biomarker of vascular endothelial dysfunction and independent predictor of cardio-renal outcomes. Adding SGLT-2 inhibitors to RAS blockers reduces albuminuria and prevents cardio-renal disease in people with albuminuric DKD , 7.Soluble Klotho (s-Klotho) and Fibroblast Growth Factor 23 (FGF-23), are involved in the pathogenesis of vascular disease through regulation of endothelial function and vascular calcification . SGLT-2 To further evaluate the role of SGLT-2 Inhibitors on albuminuria, Ao-PWV and other markers of arterial aging, we performed a pre-specified secondary analysis of people with type 2 diabetes (T2DM) with preserved renal function and residual microalbuminuria despite maximum tolerated RAS inhibition who participated in a 24-week randomized controlled trial comparing Dapagliflozin and Ramipril (D+R) vs. Ramipril (R) only.This was a pre-specified secondary analysis of people with T2DM and residual albuminuria despite RAS inhibition who participated in a 24-week prospective randomized trial comparing treatment with D+R to R only.Inclusion criteria included age between 35–75 years, residual albuminuria defined as urine albumin creatinine ratio (ACR) > 3 mg/mmol in the preceding 12 months on a maximum tolerated and stable dose of ACE-inhibitor or angiotensin receptor blocker (ARB). All participants needed to have an estimated glomerular function rate (eGFR) more than 60 ml/min. People with history of a CVD event within the past 6 months, on loop diuretics or medications, which could affect sodium balance were excluded. Other exclusion criteria included non-diabetic renal disease, recent or current use of SGLT-2 receptor inhibitor, history of connective tissue disease or inflammatory arthritis, uncontrolled hypertension , pregnancy and lactation, HbA1c > 12%, recent history of (within 3 years of screening visit) of active malignancy, one or more severe hypoglycaemic episodes within 6 months of screening, New York Heart Association class 3 or 4 cardiac disease and abnormal liver function tests defined as ALT or AST levels > 3 times the upper limit of normal at screening. People with previous hypersensitivity to the active substance, a history of pancreatitis or diabetic ketoacidosis were also excluded.The trial was conducted in compliance with the principles of the Declaration of Helsinki (1996), and in accordance with all applicable regulatory requirements. Clinical trial registry number / EudraCT Number: 2013-004042-42. The study was approved by Guy's Research Ethics Committee and the Medicines and Healthcare Products Regulatory Agency UK. All participants provided informed consent and were recruited from the outpatient diabetes clinics. The study was funded by a research grant from Astra Zeneca.Following a 5-week run in phase, participants were randomized by a means of a computer- generated random sequence to either Dapagliflozin 10 mg once daily (OD) and Ramipril 10 mg OD (D+R) or Ramipril 10 mg (R). In the 5-week run in period people who were on RAS inhibition other than ramipril had their ACE inhibitors or ARBs discontinued and replaced by Ramipril.The primary endpoint of the trial was change in albuminuria as measured by albumin excretion ratio (AER) from timed urine collections from baseline to week 24. Secondary endpoints included Ao-PWV (by applanation tonometry), central aortic blood pressure, components of the RAS  and biomarkers of arterial aging . Other secondary endpoints included changes in Hemoglobin A1c (HbA1c), changes in serum electrolytes , urine electrolytes  and urate, lipids , haematocrit and hemoglobin. All measurements and procedures were performed with the patients in the fasted state and having refrained from nicotine, alcohol, and caffeine for at least the previous 10 h. Brachial blood pressure was measured in triplicate in the supine position by an automated sphygmomanometer . Ao-PWV was determined from carotid and femoral pressure waveforms obtained non-invasively by applanation tonometry  using the Sphygmocor system  as previously described . CentralUrine albumin concentration was measured by immunoturbidimetry using a CobasMiras Plus analyzer  from three timed overnight urine collections, and the median AER was calculated. Serum total cholesterol (enzymatic colorimetry) and creatinine levels were also measured using a Cobas Mira Plus analyzer. Plasmas-Klotho  and plasma C-terminal FGF-23  were measured in duplicate by enzyme-linked immunoassay from samples stored at −80 °C –12. Bloot test , Mann–Whitney test  and χ2 test . The change in primary and secondary endpoints was analyzed using an analysis of covariance (ANCOVA) with the respective baseline value as covariate. The primary population used in this assessment was the intention to treat population. Endpoint was defined as the last available post-randomization measurement of endpoints. Variables were tested for normality by Shapiro test and Q-Q plots and further on mean, standard deviation and 95% confidence intervals were calculated for the normally distributed variables and median and interquartile range for the non-normally distributed variables. Student's t-test for normally distributed variables or Mann-Whitney for non-normally distributed variables were used to compare variables between the two groups. All statistical analysis was done within Rstudio (version 1.3.1073) under R version 4.0.2 . A two-tailed p value < 0.05 was considered significant.Descriptive statistics were used for the analysis of demographic and clinical features. Data were compared using an unpaired n = 24) were males and 27.3% females (n = 9) with T2DM, mean age of 58 years (range 42 to 75 years) and of African-Caribbean 48.5 % (n = 16), Caucasian 42.4 % (n = 14) and Asian 9.1 % (n = 3) ethnicity . Of the cohort, 72.7% , p 0.81]. p < 0.01) in people in the D + R arm as opposed to 5%  in the R arm. As expected, mean HbA1c decreased only in D +R treatment arm [mean difference [−1.03% ]. There was however no association between changes in HbA1c and Ao-PWV observed.p < 0.001) and urine magnesium that fell by 2.19 mmol/day  in D +R arm. In contrast no significant changes in components/markers of the RAS were observed  and , respectively, albeit not to a statistically significant level. We also did not observe any significant changes in either group in urinary sodium, phosphate or calcium excretion (from timed urine collections) or serum levels of calcium or phosphate ; p = 0.042], HbA1c , fasting plasma glucose  and angiotensin 1–7 , which were all lower in the D +R arm as compared to the R , respectively. Overall, dapagliflozin was well tolerated with no serious adverse events (SAE) related to the drug reported  with residual albuminuria despite RAS inhibition. In contrast to other studies, we standardized the RAS inhibition used with all people being on ramipril during trial. Furthermore, we evaluated arterial stiffness using the gold standard measure of Ao-PWV. The 24-week treatment period with dapagliflozin is longer than many other similar proof of concept trials and indeed changes in Ao-PWV and sKlotho have been observed with other interventions of shorter duration , 23.We have demonstrated that the combination of dapagliflozin and ramipril treatment does not influence Ao-PWV, measures of central arterial stiffness or sKlotho as compared to ramipril alone in people with type 2 diabetes and residual microalbuminuria despite optimal RAS blockade. Our results suggest that the observed early cardio-renal benefits of SGLT-2 inhibitors are unlikely to be related to improvements in arterial stiffness or arterial aging.Requests for access to data should be addressed to the corresponding author.The study was approved by Guy's Research Ethics Committee and the Medicines and Healthcare Products Regulatory Agency UK. The patients/participants provided their written informed consent to participate in this study.JK and LG designed the research study, interpreted the data, and drafted the article. NF, DS, MF, GM, AP, and AC collected and interpreted the data and contributed to the manuscript. AM and SA contributed and led on data analysis and interpretation. All authors have reviewed the article and approved the final draft.This work was funded by a research grant from Astra Zeneca. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitive cardiac-specific troponin T (hs-cTnT) are associated with abnormal cardiac structure and function and an increased risk of cardiovascular death in chronic kidney disease (CKD) patients. There is limited knowledge about these cardiac markers in pediatric CKD patients.2) and 26 transplanted patients . Follow-up was scheduled after 1 and 3 years. Longitudinal patterns and associations to kidney function, cardiovascular risk markers, and echocardiographic parameters were assessed.Longitudinal levels of NT-proBNP and hs-cTnT were analyzed in 48 pediatric patients, 22 with CKD  and elevated left ventricular mass index . The strong association to LVMI remained when using GFR-adjusted NT-proBNP in similar analysis. Patients with left ventricular hypertrophy (LVH) also had higher NT-proBNP (235 [146–301] ng/L) than patients without LVH (86 [11–477] ng/L), p = 0.02. High hs-cTnT over-time was also associated with low GFR  and a low cc-TDI e´/a´, indicating a worse LV diastolic function . This association did not persist for GFR-adjusted hs-cTnT.High NT-proBNP was present in 27% of CKD and 11% of CKD-T patients. Similarly 32% of CKD and 8% of CKD-T patients had elevated hs-cTnT levels. In longitudinal multivariate analyses, high log NT-proBNP was associated with low GFR (NT-proBNP and hs-cTnT are elevated in pediatric CKD and CKD-T patients. GFR-adjusted NT-proBNP was associated with longitudinal levels of elevated LVMI suggesting this might be a marker for early subclinical myocardial damage.A higher resolution version of the Graphical abstract is available as The online version contains a graphical abstract available at 10.1007/s00467-022-05481-w. Cardiovascular disease (CVD) represents one of the most important causes of death in chronic kidney disease (CKD) patients . SeveralTroponins T and I (cTnT and cTnI) are widely used in adult cardiology to diagnose patients with acute myocardial infarction (AMI) , while NImportantly, patients with advanced CKD reveal elevated levels of these cardiac biomarkers, despite no obvious signs of AMI or heart failure. Two possible mechanisms are discussed, either continuous subclinical myocardial damage related to CKD comorbidities and/or reduced renal clearance per se , 8. NT-pUnfortunately, the risk of CVD and cardiac-related death is increased already in pediatric CKD . While tThe present study set out to analyze associations between longitudinal levels of high-sensitive (hs)-cTnT, hs-cTnI, and NT-proBNP and structural and functional cardiac abnormalities assessed by echocardiography in a cohort of pediatric CKD patients and kidney transplant recipients. Previously published algorithms to correct levels of NT-proBNP and hs-cTnT for kidney function based on adult studies were also assessed in this pediatric cohort, and in a sub-analysis, two different methods used to assess hs-cTnI were also compared.The study was designed as an observational prospective cohort study of children with CKD, either non-dialysis CKD stage 2–5 patients (CKD) or kidney transplant recipients (CKD-T). All patients were treated at the outpatient Pediatric Nephrology Clinic at Astrid Lindgren Children’s Hospital, Karolinska University Hospital Huddinge in Sweden, with recruitment taking place between 2007 and 2008. The final study population consisted of 22 CKD and 26 CKD-T patients. The patients were seen at baseline, after 1 year and after 3 years. Seven CKD patients were transplanted during the follow-up period.Medical records were reviewed for etiology of kidney disease, duration of CKD, time after kidney transplantation, and records of medication. Clinical data were collected including values for height, weight, body mass index (BMI), and office blood pressure.Standard deviation scores (z-scores) for systolic and diastolic blood pressures as well as height, weight, and BMI were obtained , 21. HypBlood was drawn in a standardized manner during a clinical visit in the morning and following an overnight fast. Serum analyses of hemoglobin, creatinine, cystatin C, calcium, phosphate, intact (i)-PTH, albumin, and high-sensitive (hs)-CRP were performed in all study participants. Early morning spot urine was also collected to assess albuminuria, with a cut-off set at urinary albumin ≥ 20 mg/L. GFR was assessed by using iohexol or inulin/PAH clearances in most assessments (92.4%). In the remaining patients (7.6%), GFR was estimated from cystatin C, or in a few patients where cystatin C values were not analyzed, GFR was assessed using creatinine levels .The prevalence of anemia (hemoglobin < 5th percentile for age) , hypercaSerum hs-cTnT and NT-proBNP were analyzed using electrochemiluminescence (ECL) immunoassays on the Cobas e 411 . Serum hs-cTnI was also analyzed and compared using two methods: STAT High Sensitive Troponin I immunoassay on the Architect Plus analyzer  and Access hs-cTnI on the DxI 800 system . Elevated levels were defined as > 97.5th percentile for age and sex for hs-cTnT and NT-proBNP , 26 and 1,892 – 0.025 × GFR and GFR adjusted hs-cTnT = (GFR/90) × hs-cTnT. Depending on GFR, concentrations of the assessed GFR-adjusted hs-cTnT may be lower than the detection limit of the assay, 3 ng/L.Due to the strong association to GFR for both NT-proBNP and hs-cTnT, we also assessed GFR-adjusted levels based on adult data , 30. The2.7) . Univariate analyses at baseline were performed using For univariate and multivariate longitudinal analyzes, linear mixed models with a restricted maximum likelihood (reml) approach were used, which includes a random subject effect taking into account that a subject is measured several times. Non-normally distributed outcome variables were log-transformed before analyses.p-values < 0.10 in univariate models were tested in the multivariable models to fit the best model. Due to potential confounding, patient group (CKD or CKD-T), age at baseline (years), and GFR (ml/min/1.73 m2) were forced into the model. A p-value < 0.05 was considered statistically significant.The primary outcomes in the linear mixed models were log NT-proBNP, log GFR-adjusted NT-proBNP, log hs-cTnT, log GFR-adjusted hs-cTnT, and log hs-cTnI. The models included both baseline and follow-up measurements for the independent variables. In a sub-analysis, two different methods (Architect and DxI) for analyzing hs-cTnI were also assessed. Secondary outcomes were markers of cardiovascular morbidity; LVMI, LVH, cc-TDI e´ z-score, and PWD E z-score, as well as cc-TDI e´/a´ and PWD E/cc-TDI e´. Variables with U test.Subjects initiating kidney replacement therapy  during the study were analyzed separately following transplantation, resulting in potential bias due to nonrandom missing values as subjects with the most advanced disease were “lost to follow-up.” These patients were assessed to estimate the immediate effect of transplantation using a Mann–Whitney p = 0.42. There were no dropouts during the study among CKD-T patients, but in total, 7 (32%) CKD patients were transplanted during the follow-up period. Data obtained after transplantation in this subgroup of patients were analyzed separately.The baseline clinical characteristics of 22 CKD and 26 CKD-T patients are summarized in Table p = 0.02) and hs-cTnT  were higher in CKD compared with CKD-T patients. In contrast, while GFR adjusted levels were generally lower in both groups, GFR-adjusted hs-cTnT was instead higher among CKD-T patients than for CKD patients , while GFR-adjusted NT-proBNP levels were similar in the two patient groups (p = 0.47). The levels for hs-cTnI (Architect and DxI) were lower than for hs-cTnT, and no patient had hs-cTnI (Architect or DxI) levels above the upper reference limit.Cardiovascular risk was assessed according to the presence of anemia, inflammation, and deranged calcium–phosphorus balance as presented in Table Cardiac data at baseline show a prevalence of LVH of 21% in CKD and 28% in CKD-T patients Table . While nβ = 1.01, p = 0.30), while mean GFR declined with an annual rate of 2.4 mL/min/1.73 m2 in CKD-T patients (p = 0.002). Systolic and diastolic blood pressure z-scores as well as BMI z-score, inflammatory profile, and hemoglobin levels remained unchanged during the 3-year follow-up period in all study participants (data not shown). Calcium–phosphorus balance changed significantly in both groups, where phosphate  and i-PTH  decreased in CKD patients and albumin-adjusted calcium  and phosphate  decreased in CKD-T patients over time.In univariate analyses of changes during follow-up, mean GFR was stable over time in the CKD group , but none of the other cardiac biomarkers, changed significantly during the follow-up period in CKD patients. There was no significant change in cardiac biomarkers in the CKD-T group (data not shown). Regarding cardiac status, none of the measured echocardiographic markers changed over time in CKD-T patients and only PWD E/cc-TDI é decreased significantly in the CKD group; β =  − 0.17, p = 0.05.Only log hs-cTnI  and log hs-cTnT   and CKD-T patients . In contrast, log hs-cTnI was not associated with GFR (p = 0.78 for DxI and p = 0.18 for Architect).Multivariate analyses of follow-up data reveal a strong association between kidney function and both log NT-proBNP 1) Table . To visu Table . 1) Table . Both lop = 0.02) and NT-proBNP levels (p = 0.01) following kidney transplantation, corresponding to the rise in GFR (p < 0.001). While this trend was unchanged for GFR-adjusted NT-proBNP that decreased after transplantation (p = 0.03), GFR-adjusted hs-cTnT increased instead (p = 0.002), .Cardiac biomarkers and GFR were also assessed in the 7 CKD patients who were transplanted during follow-up, comparing levels before and after transplantation Fig. a–c. Thisn p = 0.0, GFR-adj2), Fig. . There wβ = 0.02, p = 0.05) .Multivariate analyses of longitudinal associations for cardiac biomarkers show that elevated log NT-proBNP was associated with increased LVMI (5) Table . Indeed,02, Fig. . To furtβ =  − 0.09, p = 0.05). As for NT-proBNP, we also assessed correlations for GFR-adjusted levels of log hs-cTnT. In this multivariate model, the significance for TDI e´/a´ noted previously disappeared . As for log hs-cTnI (Dxl), a significant association was seen for both high LVMI  and low cc-TDI e´/a´  in univariate analyses, but this did not remain after adjustments in the multivariate model , troponin I (hs-cTnI), and NT-proBNP and early subclinical pathological changes in cardiac structure and function in a cohort of pediatric CKD and CKD-T patients. Echocardiography was used to analyze the presence of increased LVMI and affected LV diastolic function as early markers of cardiac disease.The results of this study suggest that levels of NT-proBNP and hs-cTnT are elevated in pediatric CKD and CKD-T patients and support previous studies revealing a strong correlation with GFR , 39. IndHs-cTnT was in this study not correlated to LVMI but with a decreased LV diastolic function revealed as low TDI e´/a´. Similar findings have been reported in large-scale cross-sectional and longitudinal studies of adult healthy populations as well as CKD patients , 41, butIn line with previous pediatric studies and in contrast to the other cardiac biomarkers, hs-cTnI was not associated with kidney function . SimilarThat findings vary for the three cardiac biomarkers analyzed in this study could be explained by the limited number of patients analyzed, which affect the possibility to reach power and statistical significance in all analyses. Another reason could be explained by their different physiological actions. For example, cardiac-specific troponins are peptides released from cardiac muscle cells activated during muscle contraction, while BNP is a hormone secreted by cardiomyocytes in response to stretching of the ventricles due to increased intravascular volume. Increased troponin levels are detected in cases with cardiomyocyte damage like myocardial ischemia and necrosis in acute coronary syndromes , 46, andThere are some important limitations to this study. First, while we had only 3% missing data for hs-cTnT and hs-cTnI, we had 25% missing values for NT-proBNP over follow-up. We also had 13% missing values for the echocardiographic measurements, which might have affected the results on the outcome analysis. Finally, we have important bias in the CKD group as seven (32%) patients were transplanted during follow-up, being those with the worst kidney function who dropped out.In summary, we report that NT-proBNP and hs-cTnT are strongly associated with GFR with increasing levels as kidney function deteriorates. Both cardiac biomarkers are closely related to abnormalities of left ventricular structure (increased LVMI) or function (decreased TDI e´/a´) in pediatric CKD and CKD-T patients, but the correlation only remains for NT-proBNP after adjustments for GFR. Importantly, it is possible that these cardiac biomarkers are more markers of disease than causally linked to CVD in these patients. Therefore, future studies need to assess whether and which GFR-adjusted values should be used when interpreting cardiac biomarkers in pediatric nephrology research. Further, it is important to increase knowledge of the underlying biological mechanisms and to explore whether targeting these biomarkers with therapy might reduce the risk of future CVD.Graphical Abstract 5481 (PPTX 284 KB)Below is the link to the electronic supplementary material.


Of 14,673 AKI surviving patients, 10.18% had PNR and 14.33% showed NR. Compared with no AKI, PNR and NR of AKI were associated with an increased risk of composite adverse outcomes (adjusted subdistribution hazard ratio (SHR) 4.55; 95% CI, 4.05–5.11; SHR, 3.54; 95% CI, 3.18–3.94, respectively). Patients with NR showed a greater risk of adverse outcomes than those with non-rapid recovery at 3 months after hospital discharge. The AKI recovery pattern within 6 months following inpatient care revealed an increasing continuum of risk of long-term adverse kidney outcomes. Risk stratification and a kidney function monitoring plan at discharge are needed to improve post-AKI care.Timing and extent of kidney function recovery after an acute kidney injury (AKI) episode are associated with chronic kidney disease onset and progression. This study aimed to categorize AKI recovery patterns within 6 months after index hospital discharge and associate them with kidney outcomes. This was a retrospective cohort study of 234,867 patients, hospitalized between 2010 and 2017, and classified as AKI or no AKI. Kidney function recovery from pre-hospitalization baseline within 1.5× serum creatinine (SCr) were evaluated at 3 and 6 months after hospital discharge and categorized as persistent non-recovery (PNR: SCr not recovered at 3 and 6 months), non-recovery (NR: SCr not recovered at 6 months), and recovery (SCr recovered at 6 months). A composite of incident chronic kidney disease, kidney replacement therapy, and estimated glomerular filtration rate reduction >30% from baseline and <15 mL/min/1.73 m The incidence of acute kidney injury (AKI) is rapidly increasing worldwide, with an associated increase in direct medical costs and worsening long-term outcomes ,2,3,4,5.It is important to mention that the extent of kidney function recovery is dependent upon the timing of the baseline kidney function assessment . Most previous AKI recovery studies investigated kidney function recovery from the peak SCr during hospitalization, limited to hospital-acquired AKI (HA-AKI) , withoutThe 22nd Acute Disease Quality Initiative AKI Advisory Group suggested that the initial step toward quality improvement of AKI care starts with primary AKI prevention in an outpatient setting to avoid CA-AKI-associated hospitalization and a continuum of care after hospital discharge post-AKI . ClarifyThis retrospective cohort study included hospitalized adults of the Acute Kidney Injury Recovery Evaluation Study cohort from the network of Chang Gung Memorial Hospitals in Taiwan. Data from the Chang Gung Research Database (CGRD), an integrated electronic health records dataset that has been described in previous articles , were utThe AKI Recovery Evaluation Study included a cohort of patients aged 20 years or older hospitalized between 1 January 2010 and 31 December 2017 from the network of Chang Gung Memorial Hospitals. Patients who did not have SCr values both at admission and ≤90 days prior to the index hospitalization were first excluded, and then patients who had a kidney transplant or received maintenance dialysis therapy before the index hospitalization, or who were younger than 20 years at the index admission date, were also excluded. To assess patient kidney function recovery from AKI, hospitalized patients who had data of at least one SCr value both at admission and ≤ 90 days prior to the index hospitalization, survived to 6 months following the index hospital discharge, and had at least one SCr within 3- and 6 months after the discharge were included in this retrospective cohort of Acute Kidney Injury Recovery Evaluation Study . AKI wasOur study concept is illustrated in −1.154 × age (years)−0.203 × 0.742 , with the averaged eGFR value over a 3-month interval  were included in this study; of that total, 65,056 patients  remained in the study for the 6-month kidney function recovery assessment  showed recovery, 10.2% (n = 1493) had PNR, and 14.3% (n = 2102) were NR. Excluding 16,999 patients who developed an outcome event within 6 months post-AKI discharge  years; however, patients with recovery AKI were older (mean age of 63.46 years) than those without AKI and those in the other AKI groups. A larger percentage of patients with recovery AKI and non-AKI were male, and fewer of them had a CCI score > 3  than other AKI groups. Importantly, more patients with PNR- and NR-AKI experienced CA-AKI only  and both CA- and HA-AKI (10.85% vs. 4.04%) than patients with recovery AKI . On the n = 65,056). Patients with PNR- or NR-AKI had a higher mean eGFR (86.72 vs. 72.03 mL/min/1.73 m2) at baseline than that in those with recovery AKI, but showed a low and sustained eGFR at the 3- (40.70 vs. 64.51 mL/min/1.73 m2) and 6-month follow-up (42.15 vs. 51.04 mL/min/1.73 m2) (1.73 m2) .n = 48,357), the overall unadjusted in-hospital mortality rate was 18.37% ; patients with and without CKD showed a similar mortality rate of 6/100 PY following the index hospital discharge  than in those with recovery AKI and non-AKI  .p < 0.0001). Overall, patients with PNR- or NR-AKI had substantially higher rates of composite adverse kidney outcomes than patients with recovery AKI and no-AKI over the 7-year follow-up period  indicated that PNR-AKI  was significantly associated with a greater risk of adverse kidney outcomes, and the degree of association was 5-fold higher in patients with CKD at baseline  . CompareIn the sensitivity analyses, the dose–response association between AKI recovery patterns and adverse kidney outcome risk was consistent between the 3- and 6-months recovery pattern and between those with and without CKD at baseline . The risThe present hospitalized cohort study results are novel in AKI literature and demonstrate that kidney function recovery patterns at 6 months after index AKI hospital discharge are associated with long-term adverse kidney outcomes compared with those of hospitalized patients with no AKI. Partial and persistent non-recovery of kidney function in the 6-month AKI cohort after hospital discharge was considered high in the study cohort. Although 86% of the patients experienced a full recovery of kidney function within the first 3 months after the AKI discharge, extending the observation period to 6 months is important for stratifying the risk of sustained non-recovery and short-term recovery with poor long-term kidney outcomes.AKI non-recovery has been associated with a higher risk of major adverse kidney outcomes; however, duration of non-recovery kidney function and its association with long-term patient outcomes have yet not been systematically studied. In the Alberta healthcare system, 3231 AKI survivors (vs. 880 patients without AKI) were assessed 90 days after discharge ; AKI survivors without recovery from kidney function had a four-time higher risk of recurrent AKI (adjusted HR 4.13 (3.38–5.04)) and 26% higher risk of mortality (adjusted HR 1.23 (1.10–1.43)) in the 5-year follow-up . SimilarThis study is one of few, long-term follow-up studies to elaborate kidney function trajectory after an episode of AKI. Previously, the kidney function trajectory in the post-AKI recovery period was primarily based on a hypothetical model. Rather than directly measuring patient outcomes after an episode of AKI, this longitudinal analysis of the hospitalized adults who had repeated SCr measurements in practice further provided us with a better understanding of a full course of AKI recovery from baseline kidney function  and its role in the development of adverse kidney outcomes. Kidney function recovered at 3 months after hospital discharge was suggested to decrease AKI-associated risk of heart failure and all-cause death in the ASSESS-AKI study for evaluating AKI-associated with mortality, and cardiovascular and kidney outcomes among hospitalized patients who survived ≥3 months after discharge . In addition, this study extended the observation time frame of AKI recovery from 3 months to 6 months after the index hospital discharge, enabling us to elaborate the effect of slow recovery of AKI on adverse kidney outcomes. The results of the current study showed that 10.2% patients with sustained unrecovered kidney function after AKI discharge (PNR-AKI) was associated with an approximate 5-fold risk of a composite outcome of kidney disease; on the other hand, patients with prior CKD whose kidney function at 6 months recovered to the baseline pre-hospitalization level had a nearly similar risk of composited adverse kidney outcome as patients with no AKI. Although the observed associations need to be validated in further research, these study results supported the need for continuous long-term monitoring for at least 6 months post-AKI to clarify the modifiable prognostic factors of AKI recovery , and thus decrease morbidity and adverse sequelae of AKI as recommended by the Acute Disease Quality Initiative . Following the currently recommended AKI criteria , this laPrevention of incident CKD and management of CKD progression has been a target in AKI literature. The findings of this study provide valuable insight into the continuity of post-AKI care and complement previously published short-term (≤90 days) kidney recovery trajectory data. Regarding baseline kidney function and multi-comorbidities populations, such as diabetes, glomerular kidney disease, surgeries, or intensive care , continu2, decrease in eGFR by ≥35% or increase in SCr by >50% within 3 months, and/or structural kidney damage  [2 for longer than 3 months) or patients who were in the post-AKI recovery period and had an eGFR < 60 mL/min/1.73 m2. The full spectrum of kidney damage  is beyond the scope of this AKI recovery evaluation study. However, more research is needed to map these causes and clinical characteristics of AKD patients with and without AKI to long-term major adverse kidney outcomes. Recently, KDIGO recommends using the term acute kidney disease (AKD) to cover patients with abnormal kidney function and/or structure with the functional criteria: AKI, eGFR < 60 mL/min/1.73 mThere are limitations in this study that should be addressed. First, the 6-month AKI recovery patterns after hospital discharge only included patients with a sufficient number of SCr measurements . A considerable proportion of AKI survivors were excluded due to missing SCr values in the follow-up period, which may limit its generalizability to patients who received a certain degree of medical care. However, this study is unique in that it focuses on the pre-and post-AKI kidney function kinetics and compares them to patients without AKI in the index hospitalization in routine care practice. Second, time-varying residual confounding in the post-AKI follow-up cannot be completely excluded and resulted in the bias toward a higher extent association of patients with PNR-AKI with adverse kidney outcomes. Non-AKI factors, such as non-regular nephrologist follow-up, comorbidities, and nephrotoxins, might accelerate kidney function deterioration. Third, the results may be applicable only in the Taiwanese or populations with universal access to a healthcare system, and may have limited generalizability to the overall population of AKI patients. Last, the duration of AKI dialysis therapy following the index hospital discharge was not assessed, which requires further research to investigate the effect of dialysis therapy on AKI-related outcomes. Nevertheless, the dose-relationship between timing kidney function recovery spectrum and adverse kidney outcomes in the present study could help improve the understanding of risk prevention for AKI-related adverse kidney outcomes. In summary, periodic continuous kidney function assessment and modifiable risk management for at least 6 months after hospitalization of AKI could be beneficial for patients with slow or temporal AKI recovery of kidney function in the real world setting. Patient’s pre-hospital kidney function, etiology of AKI, and time to evaluate eGFR recovered to baseline should be considered in the risk stratification strategy. A better AKI stratification will lead to risk ascertainment on an individual patient basis and ultimately to personalized approaches for AKI care and follow-up.


Diabetic nephropathy (DN) is one of the most serious complications of diabetes. Therefore, delaying and preventing the progression of DN becomes an important goal in the clinical treatment of type 2 diabetes mellitus. Recent studies confirm that sodium-glucose cotransporters 2 inhibitors (SGLT2is) have been regarded as effective glucose-lowering drugs with renal protective effect. In this review, we summarize in detail the present knowledge of the effects of SGLT2is on renal outcomes by analyzing the experimental data in preclinical study, the effects of SGLT2is on estimated glomerular flitration rates (eGFRs) and urinary albumin-creatinine ratios (UACRs) from clinical trials and observational studies, and renal events  in some large prospective cardiovaslucar outcomes trials. The underlying mechanisms for renoprotective activity of SGLT2is have been demondtrated in multiple diabetic and nondiabetic animal models including kidney-specific effects and secondary kidney effects related to amelioration in blood glucose and blood pressure. In conclusion, these promising results show that SGLT2is act beneficially in terms of the kidney for diabetic patients. Type 2 diabetes (T2D) is a rapidly increasing global health concern throughout the world. According to the 2021 International Diabetes Federation (IDF) statistics, the number of diabetic patients among the age group of 20-79 years worldwide is 537 million. This number is predicted to rise to 643 million by 2030 and 783 million by 2045 (2 of body-surface area (Sodium-glucose cotransporters 2 (SGLT2) inhibitors are a new class of oral anti-diabetic drugs that have played an increasingly important role in the management of type 2 diabetes in recent years –11. Undeace area .In addition to the attenuated antihyperglycemic effects, the enhanced urinary glucose excretion also contributes to body weight loss and blood pressure reduction , 16. PerThe SGLT2i are proposed as promising candidates for treating hyperglycemia, and the prevention of the onset and progression of renal adverse events in diabetes despite the kidney-protective mechanism deserves more investigation. Therefore, this review summarizes the evidence of renal outcomes with SGLT2i from basic animal studies, human clinical trials and recent large prospective randomized controlled studies. Moreover, the current review focuses only on the six commercially available SGLT2i , and does not include SGLT2i that are still under development.All studies evaluating the association between SGLT2 inhibitors and kidneys were selected.The review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Studies were initially screened on the basis of their title or abstract. Studies that seemed to meet the qualification criteria were selected for full text review. Studies that did not include data on SGLT2 inhibitors and kidneys were excluded.Dapagliflozin exerts renoprotective effects in various animal models, including progressive diabetic nephropathy rats , 35, 41,Some mechanisms may explain this kidney-protective effect of dapagliflozin, among which are reductions of inflammation and oxidative stress , 37, 42,However, inconsistent with these studies, a study in progressive chronic kidney disease (CKD) rats with 5/6  nephrectomy did not show any renoprotective effects with dapagliflozin treatment. Additionally, neither the decreased eGFR nor the extent of glomerulosclerosis and tubulointerstitial fibrosis was improved, thus suggesting that dapagliflozin does not attenuate disease progression in the classical kidney model of non-diabetic CKD .Numerous studies have verified that the reduction in albuminuria with dapagliflozin treatment appears to be independent of changes in HbA1c, eGFR or systolic blood pressure (SBP). In two multicenter randomized controlled trial (RCT) studies, patients with T2DM and hypertension were assigned to either dapagliflozin 10 mg/day or placebo added to an ongoing RAS blockade therapy . After 1In a real-world study with 17,258 T2D patients who received dapagliflozin or other glucose-lowering agents, the albumin excretion rate was reduced in the dapagliflozin group and remained unchanged in the other groups. Although dapagliflozin resulted in a mild decline in eGFR, there was no evidence of worsening renal function . Anotherpost-hoc analysis of an RCT, dapagliflozin significantly reduced albuminuria in patients with T2D, and changes in albuminuria were correlated with the reduction in eGFR, as well as with the decrease in urinary tubular marker-kidney injury molecule-1 (KIM-1) (In a  (KIM-1) . Thus, t (KIM-1) . These f2) were randomized to dapagliflozin (10 mg once daily) or placebo groups for 24 weeks (In the DERIVE study (NCT02413398), patients with T2D and CKD 3a -TIMI 58 trial, 17,160 T2D patients both with and without established atherosclerotic cardiovascular disease (CVD) and creatinine clearance of at least 60 mL/min were randomly assigned to 10 mg dapagliflozin or placebo once daily . After aEmpagliflozin has demonstrated renoprotective effects in both diabetic and non-diabetic animal models. In T1D mice, empagliflozin was found to attenuate diabetes-induced oxidative stress, apoptosis and inflammation, thus leading to the renoprotective actions of empagliflozin , 46. In In a retrospective observational study, 110 Japanese T2D patients who received empagliflozin (10 mg daily) were divided into two groups: a non-elderly subject group age ≤ 65 years) and an elderly subject group (age ≥ 65 years). At 6 months, eGFR, urinary protein excretion and blood pressure were significantly reduced only in non-elderly patients, and both the ΔeGFR and ΔUP were considerably associated with changes in systolic blood pressure, thus suggesting that the renoprotective effect of empagliflozin was correlated with blood pressure reduction, whereas this effect was limited in elderly patients because of the decreased arterial elasticity . Regardi years anIn patients with T2D, the kidney-protective mechanism of empagliflozin may be to provide more renal fuel energetics by decreasing hyperfiltration and improving renal oxygenation , 66. Mor2 were assigned to empagliflozin 10 mg, 25 mg or placebo once daily. In addition to the cardiovascular benefits, empagliflozin also exerted a significant decline in important renal endpoints compared with the placebo. Empagliflozin significantly reduced the risks of incident/worsening nephropathy, including the progression to macroalbuminuria, the doubling of serum creatinine, the initiation of renal replacement therapy or renal death compared with the placebo (2) and UACR  at baseline and across the two examined doses (P ≥ 0.05 for the interactions) across the subgroups defined by age   trial, T2D patients with CVD and eGFR ≥ 30 mL/min/1.73m placebo , 68. Theed doses . In addi5 years) .In terms of renal function, patients in the empagliflozin group had an initial decrease in eGFR (within 4 weeks), which remained stable within 188 weeks, and the eGFR was fully reversible after the discontinuation of empagliflozin treatment. However, placebo-treated recipients had a gradual, irreversible decrease in eGFR . MoreoveIn exception of the favorable results in the EMPA-REG OUTCOME trial, future studies in CKD patients both with and without diabetes are underway to provide important insights into the renoprotective effects of empagliflozin . Until now, the EMPEROR-Reduced study has found that the effect of empagliflozin on the decrease in eGFR and on the risk of the composite renal outcome was consistent in patients with or without CKD, regardless of the degree of kidney impairment at baseline, which reinforces the beneficial effects of empagliflozin on delaying the progressive development of renal function decline , 73.via the β-hydroxybutyrate mediated reduction of nicotinamide adenine dinucleotide phosphate oxidase proteins (NOXs) and oxidative stress  (These results were confirmed by a RCT with canagliflozin (100 mg or 300 mg), which identified 269 patients with T2D and with a subset of stage 3 CKD (defined as eGFR ≥ 30 and < 50 mL/min/1.73m2) . eGFR ha2) Table 3.2)   clinical trial, 1,450 T2D patients receiving metformin were assigned to canagliflozin 100 mg or 300 mg and glimepiride 6-8 mg . The eGF2 were randomly assigned to canagliflozin or placebo , and the mean UACR was 18% lower (95% CI: 0.16-0.20) in participants treated with canagliflozin compared to those treated with placebo (In the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, a total of 10,142 participants with T2D and eGFR >30 mL/min/1.73m placebo , 78. The placebo . Additio placebo Table 4.2, 71.6% of whom had a history of CVD. The effect of canagliflozin on the primary outcome, which was a composite of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke, with other cardiovascular, renal and safety outcomes, was similar in people with CKD and those with preserved kidney function (P = 0.08). Most cardiovascular and renal outcomes were also similar across eGFR subgroups (eGFR < 60 and ≥ 60 mL/min/1.73m2)  subjects had an eGFR less than 60 mL/min/1.73m/1.73m2)   can play an important role in delaying the development of diabetic nephropathy because the renal outcomes have been confirmed and assessed in this trial.2 and substantial albuminuria) (2) and baseline UACR   trial further assessed whether canagliflozin can slow renal failure in T2D patients with established kidney disease (eGFR of 30 to < 90 mL/min/1.73mminuria) , 79. The00 mg/g) , 61   . During Another study investigated the differences between two low-dose SGLT2is (canagliflozin and ipragliflozin) in patients with T2DM. Both demonstrated improved UAE (P < 0.05) and no changes in eGFR after the administration with SGLT2is for 24 weeks, which was different from previous studies .In the Long-Term ASP1941 Safety Evaluation in Patients with Type 2 Diabetes with Renal Impairment (LANTERN) study, patients with T2DM and mild to moderate renal impairment (RI) were assigned to 50 mg ipragliflozin or placebo once daily for 24 weeks and continued the treatment for a 28-week extended time period  . IpragliTofogliflozin exerted renoprotective properties by suppressing renal injury. Treatment with tofogliflozin for 8 weeks significantly attenuated glomerular hypertrophy and decreased UACR in db/db mice compared with untreated db/db mice . It has 2) and gradually increased from 4 to 52 weeks (+6.1 mL/min/1.73m2), thus demonstrating a considerable increase from baseline to week 52 (+2.4 mL/min/1.73m2). Additionally, a greater increase in eGFR at week 52 was significantly correlated with lower basal HbA1c and DSI levels. Thus, this open-label study suggested that the effect of tofogliflozin on eGFR may be closely associated with the handling of both glucose and sodium through SGLT2 in the renal tubule.A pooled analysis evaluated the effects of daily sodium intake (DSI) on eGFR in 775 Japanese T2D patients administrated with tofogliflozin . During P < 0.0001). Except for the lowest eGFR subgroup, the HbA1c values of the other eGFR subgroups were significantly decreased (P < 0.0001) and body weight decreased by -2.95 kg from baseline to week 104 (P < 0.0001) (In the Japanese Study of tofogliflozin with T2DM Patients/Long Term (J-STEP/LT), 6,897 T2D patients were randomized to receive tofogliflozin  . After t 0.0001) . UnfortuLuseogliflozin showed renoprotective effects in various animal models, including a non-diabetic model of renal ischemia/reperfusion injury  and a tyIn a retrospective study, 238 patients with T2D were divided into 3 groups based on the eGFR levels and administrated with 2.5 mg luseogliflozin once daily . In all At present, the choice of anti-diabetic medications for clinicians is not limited to glucose-lowering efficacy, but needs to consider other aspects, such as the risk of hypoglycemia, the impact on body weight and blood pressure, the effects on the heart and kidney, safety and cost , 11, 94.P = 0.0028)  , 97. The 0.0028) , 99. Hen 0.0028) –103. How 0.0028) , 105, th 0.0028) , 107 and 0.0028) . The LEA 0.0028)  showed t 0.0028) , 107 or  0.0028) . This ma 0.0028) , 110. HoRecent trials with the effects of SGLT2 on the kidney seem to be even more impressive, especially the EMPA-REG OUTCOME trial for empagliflozin, the CANVAS trial for canagliflozin and the DECLARE-TIMI 58 trial for dapagliflozin. These studies showed a significant reduction in a composite of renal outcomes  in T2D patients with CVD compared with in the placebo group. As has been previously mentioned, these effects can be explained neither by a mild improvement in blood glucose control (a scheme aimed at achieving blood glucose equipoise)  nor by aThe favorable renal effects of large-scale clinical studies with SGLT2is have been published or are currently underway, with the goal of identifying a new treatment strategy for T2DM. The preliminary results of several clinical trials have shown a significant reduction in proteinuria and eGFR, the need for renal replacement therapy or death due to renal disease. Experimental data from animal models have shown that SGLT2is exert renal protection through various mechanisms other than glucose control. Although more studies are needed, the current results are likely to provide a foundation for the application of SGLT2is in patients with diabetic nephropathy, as well as for the prevention of renal dysfunction, and for the management of renal disease in patients without diabetes.As a new class of antihyperglycaemic medications, SGLT2i is increasingly being used in the treatment of T2D. Preliminary findings from multiple clinical studies and large-scale clinical studies with cardiovascular endpoints devoted to SGLT2is have consistently shown significant decrease in albuminuria and stable eGFR that was independent of changes in glucose control. In animal studies, SGLT2i can protect kidney by suppressing RAS, decreasing intraglomerular pressure, improving mitochondrial dysfunction, alleviating oxidative stress, improving fibrosis, and inhibiting apoptosis, and eventually it is proposed to have a potential impact on DN. According to the fingdings, SGLT2is can be considered as a promising agent for the prevention, attenuation or even reversal of DN. However, studies specifically for renal endpoints with SGLT2is are still lacking and more clinical trials and pre-clinical studies are required.XS collected data, analyzed data, and wrote the manuscript. GW reviewed and edited the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Background/Aims: Some previous observations have noted that after six months of peritoneal dialysis (PD) treatment with icodextrin solutions, blood pressure (BP) and NT-proBNP tend to return to baseline values. This may be due to accumulation of icodextrin products that exert a colloid osmotic effect, which drives water into the bloodstream, causing the rise in blood pressure. Since icodextrin is metabolized by α-Amylase and its gene copies are lower in females than in males, we hypothesized icodextrin metabolites reach higher concentrations in females and that cardiovascular effects of icodextrin are influenced by sex.Methods: Secondary analysis of a RCT comparing factors influencing fluid balance control in diabetic PD patients with high or high average peritoneal transport receiving icodextrin (n = 30) or glucose (n = 29) PD solutions. Serum icodextrin metabolites, osmolality, body composition and Inferior Vena Cava (IVC) diameter were measured at baseline, and at 6 and 12 months of follow-up.Results: After six months of treatment, icodextrin metabolites showed higher levels in females than in males, particularly G5-7 and >G7, serum osmolality was lower in females. In spite of reduction in total and extracellular body water, ultrafiltration (UF) was lower and IVC diameter and BP increased in females, suggesting increment of blood volume.Conclusion: Females undergoing PD present with higher levels of icodextrin metabolites in serum that may exert an increased colloid-osmotic pressure followed by less UF volumes and increment in blood volume and blood pressure. Whether this could be due to the lesser number of α-Amylase gene copies described in diabetic females deserves further investigation. It does not easily diffuse through the peritoneal membrane which allows longer permanence in the peritoneal cavity exerting a sustained and more efficient peritoneal ultrafiltration (UF) (Icodextrin is a specific fraction of dextrin (a starch-derived water-soluble glucose polymer) that has been successfully used as a ion (UF) . Since 1ion (UF) . All theion (UF) . Icodextion (UF) , and facion (UF) . These cion (UF) .In spite of its notably advantages, some less favorable changes were noted in patients treated with icodextrin solutions. Over six months of continuous use, patients show trend of blood pressure back to baseline levels, as well as increments in the circulating levels of atrial and brain natriuretic peptides, markers of expansion of blood volume and myocardial damage . FurtherIcodextrin leaves peritoneal cavity and reaches blood stream via the lymphatic circulation, this account from 20 to 40% for the longer dwell of 8–16 h. In the circulation, icodextrin is hydrolyzed by circulating α-Amylase, yielding oligosaccharides  such as maltose (G2), maltotriose (G3), maltotetraose (G4) and maltopentaose (G5) and these molecules may accumulate over the long term . Based oIn this study, we address the hypothesis that icodextrin metabolites reach higher concentrations in female than in male diabetic patients undergoing Continuous Ambulatory Peritoneal Dialysis (CAPD) and those cardiovascular effects of icodextrin are influenced by sex.n = 29) received at least one bag of 2.5% dextrose  and patients in the icodextrin group (n = 30) received 7.5% icodextrin . Liberal use of 2.5% or 4.25% dextrose solutions was allowed in both groups in order to reach the treatment goal. The study protocol was approved by the Local Research Committees of all the participating hospitals, and the National Commission for Scientific Research of the Instituto Mexicano del Seguro Social (IMSS).A secondary analysis was performed with data from a prospective, multicenter, randomized controlled trial of diabetic patients undergoing CAPD with high and high average peritoneal transport type in whom icodextrin-based solutions were compared with glucose-based solutions as regards ability to control hypertension and edema as signs of fluid overload and metabolic control . BrieflyPatients were included if they had end stage renal disease secondary to diabetic nephropathy, if they had high or high average peritoneal transport type, and signed a written informed consent. Patients were excluded when seropositive for hepatitis B or HIV, if they had malignancies, or were receiving immunosuppressive medication. Patients who had had a peritonitis episode 1 month or less before being screened were also excluded. There was no selection by age, gender, residual renal function or time on dialysis. Patients were followed-up for 12 months .Clinical and demographic data were collected at baseline from medical records. In-office blood pressure was measured every month; 24-h ambulatory blood pressure; body composition by electrical bioimpedance  and echocardiogram with Doppler  were taken at baseline, at 6 and 12 months, and inferior vena cava diameter calculated . Biochem+K+Cl− system, Lexinton, MS, USA).Plasma α-Amylase activity was measured using an adapted routine method using p -nitrophenol maltoheptaoside as a substrate . Plasma Data are expressed as percentages or mean ± SD according characteristics of variables. For statistical analysis, patients of each group were divided by gender and differences were analyzed by repeated comparisons over time. Pearson´s correlations were done between biochemical indices and cardiovascular variables. All statistical analysis was done with SPSSw v24.A complete description of data at baseline is in the original paper . Table 1Data herein presented show measurable quantities of icodextrin metabolites in blood of diabetic patients treated with icodextrin PD solutions. Concentrations of icodextrin metabolites are higher in female than in male patients and were related with increments in the inferior vena cava diameter, a marker of blood volume. Changes in diameter of vena cava were in parallel with a trend back to baseline of systolic blood pressure after six months of treatment but were not followed by increments in LVMI or NT-proBNP values. These data suggest that icodextrin dose used may be excessive for women size, may be insufficiently metabolized by diabetic women, perhaps reflecting a smaller number of α-Amylase gene copies in this population , and/or Icodextrin PD solutions have been successfully used since the 1990s. The colloid osmotic properties of icodextrin allows a sustained peritoneal ultrafiltration rate without the risk of excessive exposition to high glucose concentration in patients with fluid overload, a condition often seen in diabetic patients with high/fast peritoneal solute transport rate .In spite of its clinical value, some unexpected findings have been reported in patients treated with icodextrin solutions, among them increments in atrial natriuretic peptide, a cardiac hormone related with volume overload, and brain natriuretic peptide, another cardiac hormone related with volume and stretch overload as well as abnormal myocardial remodeling. Increments in LVM have also been reported. A plausible explanation for these findings is the accumulation of icodextrin metabolites in blood, which might exert a colloid osmotic effect and promotes expansion of blood volume .Data from this secondary analysis are in line with the proposed explanation, icodextrin metabolites concentration increases along time. Small but significant increments were seen in all the measured size fragments. It is important to mention that only concentration and not the whole pool were measured since increments in blood volume was estimated indirectly. Early increments in icodextrin metabolites could be masked by increment in blood volume and be detectable until they accumulate along time and reach threshold of the technique used for the analysis. However, the decline observed in osmolality is an indirect support of the increment of icodextrin products, this mean displacement of other active molecules and ions accounting for osmolality .Explanations for the higher increments of icodextrin metabolites in women are not clear. Icodextrin pharmacokinetics follows a simple, single-compartment model that can be approximated by zero-order absorption and first-order elimination , this meAnother explanation derives from the efforts to find prognostic markers for the future development of obesity and diabetes. Biochemical and genetic research suggest that small number of genes copies encoding salivary and pancreatic α-Amylases confers higher susceptibility for this disease. Less number of α-Amylases genes copies is present in obese and diabetic patients compared with normal subjects. Furthermore, the number is even small in women than in men, which match with epidemiological studies showing higher prevalence of obesity and diabetes in women than in men . DiffereAnd additional but not proved explanation is related enzyme activity. Macroamylase is an enzymatically active circulating complex of amylase bound noncovalently to immunoglobulins or to polysaccharides which is cleared from circulation by the kidney. Its size, interferes the bound of large substrates and consequently total activity decreases . ContribWe do not know whether the observed concentrations of icodextrin metabolites completely explain increments in blood volume represented by increased inferior vena cava diameters. Calculations of the colloid osmotic pressure generated by icodextrin fragments indicates that 76% of pressure is generated by fragments larger than 8.5 kDa and small fragments of 2.1 kDa generates only 3% . As was Changes in blood pressure and Left ventricle mass index move according to concentrations of icodextrin metabolites; however, differences between sexes were not clear. Small sample size may explain the lack of statistical difference.The study has some limitations including a small sample size. In spite of that, significant differences were seen in the most important findings. Other refers to indirect measurements of blood volume; inferior vena cava diameter has significant correlation with measurements with dilution methods and repeated measurements in the same patients reduce variability. Measurement of number of α-Amylase gene copies was not done; this evaluation requires complex technologies since the number of copies should be accompanied with evaluation of gene expression and the kinetic characteristics of the enzyme, particularly with its susceptibility of inhibition by icodextrin.In summary, these data suggest that females are more susceptible to accumulation of icodextrin metabolites during long term PD treatment with standardized PD solution volumes, and that this might cause blood volume expansion, and return of blood pressure and Left ventricle mass index to baseline values. Further studies are necessary for the adequate evaluation of genetic and biochemical characteristics of α-Amylase as a possible determinant of icodextrin metabolites. Adjustments of icodextrin prescription on basis of diabetes, gender, and body size need also be analyzed.


We thank Salama S et al. for their evaluation of noninvasive positive-pressure ventilation (NPPV) strategies in patients with chronic obstructive pulmonary disease (COPD) and who are suffering an acute exacerbation thereof . We woulFirstly, higher HACOR  scores, as well as the trend in the scores, better predicts NPPV failure when assessed within 24 h . We wondSecondly, they evaluated patient comfort and quality of mask-fitting using a visual analogue scale to determine overall acceptance, as well as tolerance to NPPV, using the iVAPS mode. iVAPS is a novel dual-hybrid mode of NPPV which offers continuous automatic breath-to-breath adjustment of the level of pressure support to achieve a desired target alveolar ventilation . Hence, Thirdly, only the height of patients was used to predict physiological dead space which was used to calculate target alveolar ventilation in the iVAPS group. Ideally, body weight and height, and hence, body mass index, might have been used. They are known to affect functional residual capacity and respiratory mechanics .Fourthly, although the groups were comparable regarding the duration of NPPV use and intensive care unit (ICU) stay, it is not clear what criteria the authors used to guide the discontinuation of NPPV or discharge from the ICU. This warrants clarification.2/FiO2) as criteria for detecting NPPV failure and the subsequent need for re-intubation, as well as the initiation of invasive mechanical ventilation (IMV). The respiratory rate oxygenation (ROX) index, on the other hand, can evaluate the combined impact of oxygenation (PaO2/FiO2) as well as respiration [Finally, the authors used the ratio of partial pressure of arterial oxygen tension and the fraction of inspired oxygen concentration (PaOpiration . ROX monIn the study in question, the authors did not find any differences in the outcomes or satisfaction scores between the iVAPS and S/T modes of NPPV in acute exacerbations of COPD during weaning from IMV. We think clarity on the above-mentioned points might aid the overall evaluation of the outcome of this study. Further well-designed, higher-powered studies are perhaps warranted to identify the subset of patients who might benefit most from the use of this innovative NPPV mode.


To evaluate the association among andrological diseases at the first outpatient visit and the medications taken by patients for other comorbidities, as well as the differential impact between specific medication and relative comorbidities.This is a single-center retrospective study based on subjects who referred to the Andrology Unit with a well-defined andrological diagnosis.p < 0.001) were: ED and (a) antihypertensives; (b) antihyperglycemics; (c) lipids-lowering; (d) psychotropics. The univariate and multivariate regression analyses confirmed the association. All the related comorbidities were also significantly associated with the univariate analysis, and all remained significantly associated with multivariate analysis. A multivariate analysis was also conducted to analyze the association between ED and the following pairs of variables “DM-antihyperglycemics”, “dyslipidemia-lipids-lowering”, and “hypertension-antihypertensives”. In all cases, the pathology, but not the specific treatment, was significantly associated with ED.A total of 3752 subjects were studied (mean age ± DS 46.2 ± 16.5 years). A total of 19 categories of andrological diseases and 110 type of medications for other comorbidities were identified. ED was the most frequent andrological pathology at the first andrological examination (28.7%), followed by infertility (12.4%). The couple of variables that were statistically significant in the univariate association analysis (ED is significantly associated with antihypertensive, antihyperglycemic, lipid-lowering, psychotropic drugs’ intake. Anyway, ED appears to be more related to the diseases than to the specific therapies. The definitive cause/effect relationship should be established based on future prospective studies. The disorders that lead patients to carry out an andrological evaluation can be various and heterogeneous, i.e., sexual and ejaculatory dysfunction, infertility, hypogonadism, and infections; frequently, an etiopathogenetic cause cannot be identified. Several studies have hypothesized a correlation between certain medications and andrological diseases –3.Considering sexual dysfunction, the classes of drugs most associated with these disorders are psychotropics and antihypertensives , 4. ConsAnyway, anti-androgens, luteinizing hormone-releasing agonists, and antagonists used to treat prostate cancer, anti-ulcer drugs, opiates, and digoxin have also been linked with ED .Considering male fertility, several medications have been shown to have adverse effects, acting through different mechanisms, including direct effects on germ cells, effects on the hypothalamus pituitary gonadal axis as well as effects on erectile or ejaculatory function . In factIn addition, several studies have shown that the intake of psychotropic drugs can determine alteration of semen quality, mainly a significant impairment of progressive motility and sperm morphology . FinallyThe purpose of this study was to evaluate the association among the andrological diseases at the first outpatient visit and the medications taken by patients for other comorbidities, as well as the differential impact between specific medications and relative comorbidities.In this single-center retrospective study, male subjects, Caucasian, aged between 18 and 45 years, who referred to the Andrology Unit of Sant’Andrea University Hospital from January 2013 to December 2020 were evaluated. All patients with an andrological diagnosis were considered eligible for statistical analysis, using a specific electronic database adapted to the Andrology Unit. The prevalence of first diagnosed andrological pathology and ongoing chronic medications for non-andrological comorbidities were assessed.p value < 0.05 was considered statistically significant.Categorical variables were expressed as an absolute number and percentage. Continuous variables as mean ± standard deviation (SD). The Chi-squared test was performed to identify associations between different variables. A p value, and 95% confidence interval [95% CI].A logistic regression model was adopted to evaluate the impact of classes of medications on andrological diseases Table , consideA univariate analysis and a multivariate analysis were also conducted to evaluate the effect of medications and the related comorbidities on andrological disease which resulted significantly associated.Statistical analysis was performed using the IBM-SPSS 25 version .The study adhered to the Hospital’s Ethics Committee guidelines and to the Ethical Principles for Medical Research Involving Human Subjects as adopted at the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the 55th WMA General Assembly, Tokyo, Japan, October 2004 and subsequent modifications when enforced .The study was approved by the Ethics Committee of the Hospital (Protocol n. RIF. CE 6559_2021).The study population included 3752 subjects; the mean age ± DS was 46.2 ± 16.5 years. The occupational status was available for 1427 patients, of which 34.9% were self-employed/freelancers, 32.9% employees, 13.6% retirees, 10.1% unemployed, and 8.5% students. The marital status was available for 2464 patients, of which 57.1% were married/cohabitant, 29.5% were in a relationship, and 13.3% were single.n 110 drugs grouped into n 69 categories)  Fig.  were idep < 0.001).ED was the most frequent andrological pathology at the first andrological examination (28.7%), followed by infertility (12.4%). The mean age ± SD of ED patients was significantly higher than the remaining population , followed by lipid-lowering (9.0%) and antihyperglycemic (7.0%).p < 0.001) were: (a) antihypertensive and ED; (b) antihyperglycemic and ED; (c) lipid-lowering and ED; (d) psychotropics and ED.The couple of variables that were statistically significant in the univariate association analysis , lipid-lowering , antihypertensive , and psychotropic . All these drug categories remained significantly associated with the multivariate analysis: antihyperglycemic , lipid-lowering , antihypertensive , and psychotropic drugs . None of the other variables resulted significantly associated.Specifically, antihyperglycemic (p < 0.5)  metformin, insulin, glinides, DPP4 inhibitors, and sulfonylureas among antihyperglycemic; (ii) statins among lipid-lowering; (iii) beta-blockers, calcium channel antagonists, ACE inhibitors, angiotensin receptor antagonists (sartans) among antihypertensive, and (iv) benzodiazepines and SSRI among psychotropic (5) Table .Table 2An 332 patients; OR 3.5, 95% CI 2.76–4.45, p < 0.001), dyslipidemia , hypertension , psychiatric disorders , and all remained significantly associated with multivariate analysis: DM , dyslipidemia , hypertension , and psychiatric disorders .All the related comorbidities were also significantly associated with the univariate analysis: DM (p = 0.03)—antihyperglycemic ; dyslipidemia —lipid-lowering ; hypertension —antihypertensives .A multivariate analysis was also conducted to analyze the association between ED and the following pairs of variables “DM-antihyperglycemics”, “dyslipidemia-lipids-lowering”, and “hypertension-antihypertensives”. In all cases, the pathology, but not the specific treatment, was significantly associated to ED: DM  and ED is accompanied by a similar statistically significant association between ED and underlying comorbidities . Furthermore, the multivariate analysis of the association between ED and the pairs of variables consisting of a specific comorbidity and the respective drug therapy , highlighted statistical significance of the association between ED and comorbidity, but not with therapy. Nevertheless, the analysis could be affected by a collinearity bias given the relationship between each comorbidity and the related drug treatment.Finally, regarding the model that considers the interactions between different drugs, interesting results were found for what concern the interaction between antihypertensives, lipids-lowering, and antihyperglycemic drugs. This could be due to that the simultaneous consumption of drugs, and consequently of the underlying pathologies, increases the risk of developing the ED itself.The main limitations of the study are the retrospective nature that cannot allow to evaluate the specific molecules of individual drug class categories for all patients, and the difficulty to identify the direct causality between drug intake and ED, since ED shares the same pathogenetic mechanisms as DM, dyslipidemia, arterial hypertension, as well as psychiatric pathologies.In conclusion, ED appears to be the most prevalent pathology in the andrological population. Furthermore, ED was significantly associated with antihypertensive, antihyperglycemic, lipid-lowering, psychotropic drugs’ intake; the simultaneous use of several categories of these drugs was associated with an increased risk of developing ED itself. Anyway, our results highlighted that ED is more related to the diseases than to the specific therapies. The definitive cause-and-effect relationship between these medications and ED can be established based on future prospective studies.