The purpose of this study was to determine whether maternal urinary phthalate metabolite concentrations are associated with the development of higher blood pressure or pregnancy-induced hypertension (PIH). Participants were women without chronic hypertension who enrolled in The Infant Development and the Environment Study, a prospective pregnancy cohort conducted at four U.S. academic medical centers from 2010–2012. Prenatal records were reviewed to obtain blood pressure measurements and diagnoses of PIH . Complete-case analyses used multivariable linear and logistic regression for analysis of blood pressure measurements and PIH diagnoses, respectively. In the final dataset (N = 668), higher concentrations of first-trimester monoethyl phthalate (MEP) and mono-3-carboxypropyl phthalate (MCPP) and third-trimester mono-isobutyl phthalate (MiBP) were significantly associated with a medical chart diagnosis of PIH. First-trimester mono-n-butyl phthalate (MBP) and MEP along with the sum of di-(2-ethylhexyl) phthalate metabolites (∑DEHP) were each associated with increased systolic blood pressure across pregnancy. In conclusion, several phthalate metabolite concentrations were significantly associated with PIH and greater increases in systolic blood pressure across pregnancy. Hypertensive disease in pregnancy represents a major contributor to maternal morbidity and mortality in the U.S. and worldwide, and the incidence of these diseases is increasing ,2,3. ThePhthalates are chemicals that are used to increase the flexibility of plastics and are ubiquitous in the personal care product and food packaging industries . CompareThere is growing literature indicating an association between maternal urinary phthalate concentrations and hypertensive disease in pregnancy , which mThis study aims to further elucidate the role of maternal urinary phthalate metabolites in pregnancy on blood pressure in the first and third trimesters, increases in blood pressure over the course of pregnancy, and the development of PIH. We used data from a multi-center observational pregnancy cohort study. We hypothesized that first-trimester maternal urinary phthalate concentrations would be associated with greater increases in blood pressure, higher maternal blood pressure in the third trimester, and increased odds of PIH diagnosis after the urine sample.The Infant Development and the Environment Study (TIDES) is a prospective cohort study of pregnant women recruited at four U.S. academic medical center sites, including the University of Minnesota, the University of California in San Francisco, the University of Washington, and the University of Rochester, between 2010 and 2012. Inclusion criteria included: gestational age less than 13 weeks, age of at least 18-years-old, able to read and write in English, no medical concerns for early pregnancy loss, and planning to deliver at the study site’s hospital. Participants with a diagnosis of chronic hypertension were excluded from the main analysis of this study but were included in the sensitivity analyses. Participants were asked to provide urine samples each trimester; for this study, only the first- and third-trimester phthalate values were measured. The women consented to the release of their pregnancy medical records for data abstraction. The primary aim of the prenatal TIDES was to determine the association between phthalates and anogenital distance; therefore, only pregnancies resulting in livebirths had their phthalates evaluated. Therefore, this study only includes women who delivered a livebirth. The study was approved by each site’s Institutional Review Board prior to the start of the study, and all participants signed written informed consent. Data abstraction from maternal medical records ascertained pregnancy information including maternal blood pressure values during the first- and third-trimester visits, ultrasound reports, pregnancy complication diagnoses, and details regarding delivery course and outcome.Maternal urine samples were collected in phthalate-free polypropylene cups, and all storage materials were phthalate-free. Specific gravity (SpG) was measured within 30 min of collection using a hand-held refractometer following calibration with de-ionized water. All samples were then stored at −80 degrees Celsius before the shipment of all of the samples to one of two laboratories: (1) the Division of Laboratory Sciences, National Center for Environmental Health, Center for Disease Control and Prevention (CDC) and (2) the Environmental Health Laboratory at the University of Washington (UW). Urine samples from the first trimester were then analyzed at each laboratory. All third-trimester urine samples were analyzed at the CDC. The CDC used enzymatic deconjugation of the metabolites from their glucuronidated form, automated online solid-phase extraction, separation with high performance liquid chromatography, and detection by means of isotope-dilution tandem mass spectrometry . The UW Maternal medical records were reviewed retrospectively by trained research staff to determine PIH diagnosis at any time during pregnancy and blood pressure measurements associated with the date of each study visit at which urine was collected (one visit each in the first and third trimesters). Any participant with a chronic hypertension diagnosis in the medical chart was excluded from the main analysis. Chronic hypertension diagnoses were identified via three mechanisms: (1) by ICD code during the pregnancy of interest, (2) as indicated by a provider’s note during the pregnancy of interest, or (3) if the participant reported taking antihypertensive medications every day for a week on their first-trimester survey. When a blood pressure value was not available at the date of urine collection, the subsequent visit’s blood pressure value was used. For visits with multiple blood pressure measurements taken, the last blood pressure measurement obtained on that date was used. This was to ensure an accurate resting blood pressure measurement and not a blood pressure measurement that was reflective of the patient’s exertion during their walk into the clinic.PIH was defined as a diagnosis of at least one of the following as denoted by ICD codes or by providers’ notes in the medical record: gestational hypertension (ICD10 O13), pre-eclampsia with or without severe features or HELLP  syndrome , or eclampsia  and the American Heart Association (AHA), which is defined as systolic blood pressure (SBP) ≥ 130 mmHg or diastolic blood pressure (DBP) ≥ 80 mmHg [Phthalate metabolite concentrations  were natControl variables were selected through the use of a directed acyclic graph DAG; , which wAfter assessing linearity through partial regression plots and partial residual plots, we used multivariable linear regression to analyze the continuous outcomes of interest, SBP and DBP, in both the first and third trimesters. We examined the association between blood pressure change  with first-trimester phthalates as well as the association of third-trimester blood pressures with (a) first-trimester, (b) third-trimester, and (c) the average of the first- and third-trimester maternal urinary phthalate metabolite concentrations. The average value acts as a surrogate for what may be average exposure across the span on the pregnancy, given that the half-life of most phthalate metabolites is <24 h ,36.We also considered two dichotomous outcomes: (1) diagnosis of PIH based on medical chart abstraction and (2) the 2017 ACC/AHA hypertension definition of SBP ≥ 130 mmHg or DBP ≥ 80 mmHg [Our final analysis set only included women who had data on all variables . Because we analyzed complete cases only, the model sample sizes ranged from 517 to 614, depending on the outcome variable, except for those considering the ∑DEHTP metabolite concentration, which had complete-case sample sizes of 436 to 472. All of the analyses were conducted using R software, Version 3.6.2.We performed several sensitivity analyses, including a series to assess for potential bias due to missing data. First, we assessed whether a missing urinary metabolite value was associated with any key covariates. Second, we compared covariates between groups with and without blood pressure measurements, which we restricted to measurements on or after the date of the respective trimester’s urine sample. Third, we estimated the relationship between hypertension during pregnancy and missing covariates, which were primarily provided through surveys.We also explored the extent to which this study’s phthalate metabolites associated differently when we included the women who had chronic hypertension, both including and excluding those who reported antihypertensive medication use in the first trimester. Finally, we evaluated whether the inclusion of the ICD9 code 642.3, “transient hypertension,” changed our results, as this diagnostic code included both individuals with actual transient hypertension (not a hypertensive disease of pregnancy) and gestational hypertension, which is included in the PIH definition.Live births were recorded for 805 TIDES participants, 67 of whom were excluded from our analyses due to chronic hypertension. Of the resultant 738 participants, 668 had complete data on race, age at delivery, education, marital status, income, smoking, pre-pregnancy BMI, and parity, and these women were included as participants in the current analyses. First- and third-trimester urinary phthalate metabolite concentrations for mono-isobutyl phthalate (MiBP), MEP, MBzP, MBP, MEHP, MCPP, and ∑DEHP were available for 631 and 635 participants, respectively. In addition, third-trimester concentrations for ∑DEHTP were available for 493 participants. A total of 539 participants had first-trimester blood pressure values available at or after the time of the first-trimester urine sample, and 566 participants had third-trimester blood pressure values available at or after the time of the third-trimester urine sample.Most of the sample was white (68.7%), had graduated college (73.6%), was married or living as married (83.4%), had a household income of at least USD 45,000 (64.3%), and did not smoke cigarettes (92.3%) . Of the p = 0.01 and adjusted OR 1.34, CI 1.05–1.7, p = 0.02; respectively for each ln-unit increase), as was the third-trimester concentration of monoisobutyl phthalate (MiBP) . Higher averages of the first- and third-trimester maternal urinary phthalate metabolite concentrations of MEP and MiBP were also significantly associated with PIH diagnosis  and mono-3-carboxypropyl phthalate (MCPP) were significantly associated with the diagnosis of PIH ; average MiBP was positively associated with third-trimester SBP . We also observed a significantly negative association between first-trimester MEP and first-trimester SBP .After controlling for covariates, first-trimester maternal urinary concentrations MBP, MEP, and ∑DEHP were positively associated with the difference between first- and third-trimester SBP  between the third and first trimesters. For the most part, this is not a clinically meaningful change in blood pressure, and it suggests that women may be vulnerable to environmental insults that in totality of all of her other risks may place her at greater risk of a hypertensive disorder in pregnancy. Notably, we believe our study is the first to observe significantly increased odds of PIH diagnosis as well as increased systolic blood pressure over the pregnancy, with higher first-trimester MEP levels being observed. This finding is particularly interesting because of its consistency across these two blood pressure outcomes.When we examined whether the timing and level of phthalate metabolites in pregnancy had an effect on PIH diagnosis in our multicenter cohort, we observed higher concentrations of first-trimester MEP and MCPP, and higher concentrations of third-trimester MiBP were significantly associated with a medical chart diagnosis of PIH. In addition, when averaged over the pregnancy, the MEP and MiBP metabolites were also associated with PIH diagnosis. This is consistent with prior studies that showed that increased urinary MCPP was associated with PIH and with serum concentrations of PAPP-A, a marker associated with PIH ,26. InteSimilar to two of the three other pregnancy cohort studies on this topic, we did not find an association between a ∑DEHP-induced diagnosis of PIH or incident maternal blood pressure values, though we did find an association with the increase in SBP ,25,26. Ip < 0.01) for MBzP, MEHP, MCPP, MiBP, ∑DEHP, and ∑DEHTP. The main effects of the phthalates were not significant in these models, though, and the direction (positive or negative) of the association between phthalate exposure and blood pressure or PIH among women on antihypertensives was not consistent.Our primary aim was to determine the odds of incident PIH, but we also explored the extent to which these phthalate metabolites associated differently in the subsample of pregnant women who had chronic hypertension and who were excluded from our primary analyses. In the sensitivity analyses that included the 67 participants with chronic hypertension, certain urinary phthalate concentrations, including MEHP, MEP, and ∑DEHP, were associated with PIH diagnoses . The assWe were also interested in examining the timing and the phthalate level on changes in blood pressure over the course of the pregnancy. In doing so, we observed that only first-trimester exposures were significantly associated with increased systolic blood pressure between the first and third trimesters. Specifically, we found that MBP, MEP, and the sum of the di-(2-ethylhexyl) phthalate metabolites (∑DEHP) were each associated with a significant but slight increase in systolic blood pressure across pregnancy. There were no significant findings for changes in blood pressure (systolic or diastolic) when examining any of the third-trimester or averaged phthalate metabolite levels.The strengths of this study include the large sample size, the diversity of the participants from across the U.S., and its multisite design. There are three previously published studies of PIH in relation to phthalates in pregnancy. The Werner et al.  study inSome limitations in our study design may affect the interpretation of our results, such as the variation in the detailed documentation inherent to the chart review and the missing urine samples and blood pressure values in some cases. However, our sensitivity analyses showed little effect of these missing values. Single spot urine samples may poorly reflect phthalate metabolite concentrations across a whole trimester due to their short half-life. On the other hand, the average concentration might serve as a proxy for typical phthalate exposure during pregnancy. In fact, we estimated larger coefficients for the average than for the concentration at either trimester in the analyses for MiBP, which could indicate a broad window of susceptibility during pregnancy. Future studies should consider taking more frequent measurements of both phthalate metabolite concentration and blood pressure to confirm whether there are critical windows for phthalate exposure with regard to hypertension in pregnancy. Lastly, we excluded ICD9 code 642.3, “transient hypertension,” which includes some participants diagnosed with gestational hypertension. This decision was made because otherwise, individuals with a diagnosis of true transient hypertension in pregnancy, which is not considered a hypertensive disease in pregnancy, might have been included and thus would have affected the strength of our findings. However, in the sensitivity analysis, our results were relatively unchanged by inclusion of this ICD9 code. This could be because transient hypertension is often the first diagnosis prior to a diagnosis of full-fledged pregnancy-induced hypertension due to the nature of the disease. A transient hypertension diagnosis would be met if a single measurement had SBP ≥ 140 mmHg or DBP ≥ 90 mmHg, whereas to meet the criteria for gestational hypertension, a patient must have two separate elevated blood pressures more than four hours apart.In conclusion, our multicenter cohort found that the urinary MEP, MCPP, and MiBP levels of pregnant women were positively associated with PIH, and that pregnant women’s first-trimester urinary MBP, MEP, and ∑DEHP were associated with an increase in systolic blood pressure from the first to third trimester. Our results add to the body of literature in support of the association between phthalates and elevations in blood pressure in pregnant women. Given the significant maternal and fetal morbidity and mortality associated with pregnancy-induced hypertension, the identification of modifiable risk factors that are present at a population-level, such as environmental exposure to phthalates, has serious public health implications. The physiologic pathway that may explain this finding has yet to determined, and therefore, more research on the temporal pathway of the timing of phthalate exposure on the onset of higher blood pressure in pregnancy is warranted.


Acute kidney injury (AKI) and chronic kidney disease (CKD) are common events after radical nephrectomy (RN). In this study we aimed to predict AKI and CKD after RN relying on specific histological aspects. We collected data from a cohort of 144 patients who underwent radical nephrectomy. A histopathological review of the healthy part of the removed kidney was performed using an established chronicity score (CS). Logistic regression analyses were performed to predict AKI after RN, while linear regression analysis was adopted for estimated glomerular filtration rate (eGFR) variation at 1 year. The outcomes of the study were to determine variables correlated with AKI onset, and with eGFR decay at 1 year. The proportion of AKI was 64%. Logistic analyses showed that baseline eGFR independently predicted AKI . Moreover, AKI , baseline eGFR , and the presence of arterial narrowing  were independently associated with eGFR decline. Our findings showed that AKI onset and eGFR decline were more likely to occur with higher baseline eGFR and lower CS, highlighting that RN in normal renal function patients represents a more traumatic event than its CKD counterpart. Acute kidney injury (AKI) and chronic kidney disease (CKD) are two possible sequelae following radical nephrectomy (RN) . Post-suAlthough numerous efforts have been made by clinicians to better understand and predict the development of AKI and CKD after RN, several problems remain unsolved. One of the most intriguing arguments is that AKI and CKD occurring after surgery should be considered differently in respect to other clinical settings when renal function decline is sharply compromised but not related to an acute loss of nephron mass . At the Thus, to address these points, we carried out an in-depth analysis on the clinical and pathological characteristics of 144 consecutive RN cases in predicting AKI and CKD.2 (G1), 60 mL/min/1.73 m2 (G2), and 45 mL/min/1.73 m2 (G3a and G3b-4). The study consists in two different but related parts. In the first one, the primary outcome is to identify clinical variables correlated with the AKI onset after radical nephrectomy; in the second one, the primary outcome is to determine the eGFR decay after one year from surgery. In both cases subsequent analysis was carried out to model the eGFR decay  with respect to the clinical variables.We performed a retrospective cohort study of patients who underwent RN due to the presence of a kidney mass suspected of malignancy. The following data were considered: age, gender, body mass index (BMI), TNM staging, Fuhrman grading, hypertension, diabetes, and medical therapy (ACE inhibitors (ACEi), angiotensin II receptor blockers (ARBs), calcium antagonists, beta blockers, and diuretics). Serum creatinine (s-Cr) values (Kinetic Picrate standardized COBAS C 800) for IDMS) were collected before surgery (t0), at 24 and 48 h after surgery, and at dismissal , as well as after one year (ty) to detect renal function fluctuations and the subsequent risk of AKI, which usually presents within 48 h of surgery ,10. Base00 for IDThe cohort consisted of 144 consecutive patients diagnosed with a kidney mass who were candidates for elective radical nephrectomy (2009–2019). Exclusion criteria were as follows: (a) age < 18 years, (b) CKD category G5 according to KDIGO guidelines , (c) solPostoperative AKI was diagnosed according to s-Cr increase 72 h after surgery based on the KDIGO criteria . AccordiHistological evaluation was performed on two dedicated specimens of kidney tissue derived from the unaffected part of the removed kidney (at least more than 3 cm away from the tumor). All histological samples were examined by the attending pathologist in order to identify signs of medical nephropathy. A slide with a specimen of approximately 15 × 20 mm containing both the medulla and cortex from normal tissue was prepared from histology. Then, two parallel lines were drawn on the normal kidney tissue with a marking pen to simulate biopsies using a 16-gauge biopsy core. A Nikon Eclipse 80i microscope  with Pan Fluor was used at different power to evaluate an area of about 20 × 1.3 mm that was randomly chosen from one side of the line.All samples were buffered, formalin fixed, paraffin embedded, and 4 mm thick kidney sections were stained with hematoxylin and eosin. We then analyzed samples for each subject using the chronic lesions score described by Remuzzi et al. in 1999 . This scAnalyses were carried out to detect potential correlations between the outcomes of interest  and other independent variables. A linear regression model was used to predict continuous variables , while we adopted the non-parametric Wilcoxon test (two groups) and Kruskal–Wallis test (more than two groups) for comparisons of continuous variables between groups. Wilcoxon test with Holm’s correction was used for post hoc test comparisons and Fisher’s exact test was performed for comparisons between categorical variables. Binomial logistic regression was used to identify possible predictors of AKI onset. The significance level for all the analyses was set at 0.05. All analyses were performed using programming language for statistical computing R version 3.6.3  , R packaDescriptive characteristics of the patient population are reported in p = 0.7) or Fuhrman grade (p = 0.3). The median hospital stay after the surgery was 3 days (3–3). After surgery, 69% of patients demonstrated a rise in serum creatinine, which classified them as affected by AKI, according to KDIGO criteria. It is important to underline that the majority of these patients were classified as stage 1 (58%), with only a small percentage of stage 2 (8%) and 3 (3%). For the purposes of our analysis, we considered AKI onset as the outcome and investigated for predictors among clinical data and comorbidities. We did not observe any correlation with age, gender, intraoperative blood loss, presence of hypertension (considering the use of specific drugs), diabetes, BMI, TNM staging, Fuhrman grading, and histopathology. Logistic regression predicting AKI onset showed that baseline eGFR was a significant predictor for the CKD-EPI formula, as shown in Overall, 21% of patients had CS = 0, 35% had CS = 1, 26% had CS = 2, and 18% had CS ≥ 3. No correspondence was observed with the TNM score  1.04 for CKD-EPI). Evaluation of the eGFR trend after nephrectomy showed that patients who developed AKI had a higher pre-surgery eGFR, as shown in Linear regression analysis between the pre-surgery value of eGFR and its decay at 24 h, 48 h, and 72 h exhibited significant results . p = 0.02) and with the presence of tubular atrophy (p = 0.006) or interstitial fibrosis (p = 0.02). The results confirmed that already damaged tissue correlates with a milder eGFR decay  was found between baseline eGFR and renal function decay over 1 year. The higher the baseline value, the greater the eGFR decline. (p < 0.001). Indeed, patients who developed AKI during hospitalization showed a greater than 17% decline , and 2% of patients were classified (according to the CKD-EPI equation) as G1, 26% as G2, 58% as G3a, and 14% as G3b-4. No significant correlations regarding hypertension, diabetes, and overweight or obesity at time zero were observed. A significant correlation (decline. . AKI ons decline .p = 0.003). The post hoc test enlightened that eGFR decay for patients with CS ≥ 3 had a milder reduction of the renal function than patients with CS = 0 and 1. The four components of the CS were correlated with eGFR decline, as reported in We also observed that the eGFR decay after 1 year correlated with the CS of the removed kidney (2 displayed a median eGFR decay of 29 mL/min/1.73 m2 (20–34) and a 74% rate of AKI development. In parallel, another significant association was reported between lower CS, meaning the absence of histological damage, and a higher eGFR decline. These results are hypothesis generating. First, the absence of a strong correlation between pre-existing hypertension and AKI development could be related to good compliance with anti-hypertensive therapy by patients before surgery. Regarding obesity, a possible explanation could be that this condition likely leads to a compensation mechanism given its known effect on glomerular hyperfiltration. As far as diabetes is concerned, none of the patients had diabetic nephropathy with clear signs of kidney dysfunction and gross proteinuria or progressive kidney injury. Furthermore, the absence of correlation between AKI development and the aggressiveness of the tumor may be linked to the inability of cancer tissue to affect overall renal function, while the remaining “healthy” parenchyma tends to compensate. Conversely, the surprising association between a “healthier” kidney status before surgery and the greater risk of developing surgical AKI could be unexpected at first glance. However, as the literature has already demonstrated, this result could be explained by a compensatory mechanism already present in patients who had a previously compromised kidney status with an eGFR < 60 mL/min/1.73 m2. Hyperfiltration in the remaining kidney seems to occur progressively in the advanced stages of CKD and, thus, the acute loss of nephrons does not represent a severe traumatic event on overall renal function in comorbid patients. On the contrary, as demonstrated in the literature by the comparison between LKDs and oncological patients, surgical AKI is more likely to occur in healthy individuals with no histological damage because the total renal function is still carried out by both organs. The same observations were reported by Martini et al., who showed that partial nephrectomy induces more strain in patients with normal baseline eGFR [p < 0.001). We observed that at 12 months, 85% of AKI patients fell into a lower eGFR category with respect to their baseline, while only 15% remained within the same category. Interestingly, the median eGFR decay in patients who developed AKI was greater among those whose eGFR was ≥60 mL/min/1.73 m2. As a matter of fact, the greater the impairment of baseline renal function, the lower the median decline in eGFR over time. In addition, none of the patients with baseline eGFR < 60 mL/min/1.73 m2 developed ESRD at 1 year. Conversely, patients with normal renal function had a median decay of 28 mL/min/1.73 m2 (21–34) one year after RN. Finally, it is also important to underline that the eGFR value at discharge after RN did not correlate with the decay at one year. The chronicity score evaluated the healthy part of the removed kidney at the time of surgery and demonstrated that the absence of histological damage (CS0–CS1) was prognostically related to a greater decline at 1 year, with worsening of the eGFR category in 87% of cases. Regarding the absence of arterial narrowing, 88% of patients developed CKD, while for kidney fibrosis, this finding occurred in 81% of patients. The correlation between AKI development and eGFR decay at 12 months confirmed the hypothesis that in some cases the remnant contralateral kidney is likely unable to compensate for the removed one in the short- to mid-term, especially if eGFR was higher and no histological damage was present at baseline. These results suggest that, before surgery, both kidneys were correctly filtrating in these patients and that the remaining kidney was not able to achieve the same eGFR total value on its own, neither immediately nor at 1 year. On the contrary, when baseline eGFR was <60 mL/min/1.73 m2, most of the overall renal filtration was being performed by the contralateral kidney, and so, acute and chronic decline remained low because the contribution of the tumoral kidney was negligible. These results can be compared to those reported by Bachrach and colleagues, who quantified the contribution of the removed kidney to overall filtration ranging from 50% to less than 20% in a study involving 136 patients who underwent radical nephrectomy or nephroureterectomy and had a preoperative renal scan with calculated differential function. The compensation of the remaining kidney exceeded 12% of the expected value in the entire population and almost 15% in patients with eGFR < 60 mL/min [In the last decade the concepts of surgical post-operative AKI and CKD caused by the acute loss of nephrons have been proposed in order to distinguish them from the pathological medical conditions of AKI and CKD . In factine eGFR . Our resine eGFR . Conside0 mL/min . These d0 mL/min . We can 0 mL/min ,25. Howe2 values (for both models) indicate low accuracy and are mainly due to two factors: the small number of patients involved in the creation of the model and the biological variability that plays a key role compared to external elements [The main limitations of the study are due to its retrospective nature. The use of serum creatinine values for classifying AKI was due to the lack of other biomolecular marker levels ,26,27,28elements .Predicting AKI and eGFR decay after RN should take into consideration a combination of clinical, laboratory, and pathological features. The pathological analysis should be routinely performed in the healthy part of the removed kidney and combined with the other clinical parameters to provide tailored multidisciplinary counseling. Finally, both surgically derived AKI and CKD should be considered and classified differently with respect to their medical alter egos.


Using serum creatinine leads to an overestimation of kidney function in patients with primary neuromuscular disorders, and reduced kidney function may remain undetected. Cystatin C (CysC) could provide a better estimation.To evaluate the precision, accuracy, and bias of two creatinine-, one cystatin C-based and one combined equation to estimate glomerular filtration rate (eGFR) in patients with primary neuromuscular disease.2) with primary neuromuscular disease. Kidney function was measured by iohexol clearance, and blood samples for serum creatinine and CysC were drawn simultaneously. Bias was defined as the mean difference between eGFR and measured iohexol clearance, and accuracy as the proportion of eGFRs within ± 10% (P10) of measured clearance.Of the 418 patients initially identified at the out-patient clinic, data on kidney function was obtained for 145 adult patients  ml/min/1.73m2 also at all levels of kidney function we evaluated (at 30–59 ml/min/1.73m2 bias was 27 (95% CI 21–35), at 60–89 it was 25 (95% CI 20–28) and at ≥ 90 it was 12 (95% CI 7–22)). eGFR CysC also had the best accuracy in patients with reduced kidney function (P10 was 5.9% at 30–59 ml/min/1.73m2).Kidney function (iohexol clearance) was 81 ± 19 (38–134) ml/min/1.73mCystatin C-based estimations of kidney function performed better than creatinine-based ones in patients with primary neuromuscular disease, but most importantly, all evaluated equations overestimated kidney function, especially in patients with reduced kidney function. Therefore, kidney function should be measured by gold-standard methods when precision and accuracy are needed.The online version contains supplementary material available at 10.1007/s40620-021-01122-x. Five.0 mL of iohexol  was administered intravenously. After 4 h a second blood sample was drawn from the contralateral arm for analysis of iohexol concentration. The distribution volume was estimated using a function related to body weight, and another method was used to correct for the lack of complete uniform distribution and non-immediate mixing. The analysis and calculations of iohexol clearance were performed at the Department of Clinical Chemistry at Sahlgrenska University Hospital/Mölndal. This department participates in inter-laboratory comparison schemes from Equalis and has been certified  were calculated using the following equations:−1,154 + age0.203 + 1.212 (if patient is black) × 0.742   × body surface area (m2)/1.73(m2) and the body surface area (BSA) was calculated with the DuBois and DuBois formula; body area (m2) = 0.20247 × length (m) 0.725 × weight (kg) 0.425 , partial Spearman's Rho method was used and ρ is the partial correlation coefficient. Bias was assessed as the mean difference (eGFR-measured clearance), with negative values indicating lower eGFR than measured kidney function (underestimation) and positive values indicating overestimation. Accuracy was defined as the proportion of eGFRs within ± 30% (P30) and ± 10% (P10) of measured clearance. The 95% confidence intervals (95% CIs) were calculated as measures of the statistical uncertainty when estimating bias and accuracy using bootstrap with 1000 replications, which gives good estimates of confidence intervals. Bias and accuracy P30 and P10 were evaluated in relation to the kidney function levels 30–59, 60–89 and ≥ 90 ml/min/1.73mgreement . In thesgreement , but thi2 with no difference between men and women (not shown). Only 18 patients had a measured clearance below 60 ml/min/1.73m2. Unindexed kidney function (measured clearance) and eGFRs are shown in Supplementary Table 1.Clinical and biochemical characteristics of the study participants n = 145) are shown in Table 45 are shThe correlations between BSA-indexed measured clearance and eGFRs are shown in Table 2, with eGFR CysC having the smallest bias (22), followed by CKD-EPI (27), MDRD (32) and eGFR CysC + CKD-EPI (26) . When comparing bias at different kidney function levels different patterns were found for the equations. eGFR CysC had the lowest bias at all levels of kidney function (clearance) and overall eGFR CysC had a significantly lower bias than MDRD and eGFR CysC + CKD-EPI. All equations had a larger bias in patients with reduced kidney function, i.e. measured clearance below 60 ml/min/1.73m2.Table . When comparing the accuracy at different levels of kidney function MDRD and eGFR CysC had a low P10 in patients with reduced kidney function . At P30 all creatinine-based equations improved their performance overall but the 95% CIs were wide. Among the creatinine-based equations, MDRD had the best performance in patients with reduced kidney function (22%) and CKD-EPI in patients with normal kidney function (56%). eGFR CysC had the best accuracy in patients with normal kidney function, significantly higher than both MDRD and eGFR CKD-EPI but the P30 in patients with reduced kidney function was only 12%. Unindexed kidney function (measured clearance) and eGFRs are shown in Supplementary Table 3 and commented on below.Accuracy was evaluated as measured clearance ± 10% (P10) and ± 30% (P30) and the overall accuracy for the different equations varied, P10 from 5.6 to 21% and P30 from 20 to 49%. Overall eGFR CysC had a significantly higher overall P10 than MDRD and eGFR CysC+CKD-EPI2, respectively. Thus, MDRD exhibited the largest bias. The largest overestimations using eGFRs were found in patients with reduced kidney function. Figures using unindexed kidney function (measured clearance) and eGFRs are found in Supplementary Fig. 2a–d.The bias for different equations are also illustrated by Bland–Altman diagrams displayed in Fig. 2). Important to note is that the use of unindexed measured clearances and eGFRs also resulted in a change in number of subjects in the different kidney function-level categories, in 30–59 ml/min 18 to 16, in 60–89 ml/min 79–61 and in > 90 ml/min 48–67. When using unindexed measured clearance and eGFRs the overall difference in bias between eGFR CysC and eGFR CKD-EPI and the differences in accuracy between P10 eGFR CysC and eGFR CysC + CKD-EPI, and P30 eGFRCys and eGFR CysC + CKD-EPI, respectively, became significant. Figures and tables using unindexed measured clearances and eGFRs are found in the Supplementary section.Overall, only minor changes were observed when unindexed measured clearances, i.e. absolute values (ml/min) were used instead of BSA-indexed and eGFRs, i.e. relative values  close to the BSA used for normalization (1.73 m2) of kidney function.The convention of indexing glomerular filtration rate to BSA attempts to normalize kidney function across populations of differing body size but may be inappropriate when a more precise estimation of kidney function is needed or in patients with extreme body sizes. Adding to the complexity, there is a disproportionate relation between extracellular volume (ESV) and BSA , and a hA weakness when using cystatin C-based estimations of kidney function has previously been the lack of an international calibrator resulting in analytical bias and inability to compare cystatin C analysis carried out using different assays. Recently, an international cystatin C calibrator was used to develop an assay-independent cystatin C-based equation for estimation of GFR (CAPA) . It is hThe findings of our study should however be interpreted in light of its strengths and limitations. The strengths include that the study population is larger than in previous corresponding studies, the measurements of serum creatinine and cystatin C were done using standardized and calibrated assays, and the analysed blood samples were drawn simultaneously with the measurements of iohexol clearance. However, there are also some limitations. One is that we pooled patients with different primary neuromuscular diseases who may have had different disease characteristics, and that from the initial 418 patients identified at the outpatient clinic data on renal function was obtained only in 145 cases in CKD stage I–IIIa, thus few participants had severe kidney failure or an advanced neuromuscular disease with very low muscle mass. The generalizability to all patients with reduced muscle mass should thus be further evaluated. The calibration of measured and estimated kidney function by BSA has been questioned in patients with altered body composition, i.e. both low and high body mass index, however, this concern is not specific for this study , 43 but Another limitation and potential concern is that plasma clearance of iohexol used to measure kidney function in this study has not been validated specifically in patients with primary neuromuscular disease or in other populations with low body mass index and reduced muscle mass, i.e. sarcopenia, but there are studies ongoing to assess this matter .Another potential explanation for part of the results in this study may thus be that both the MDRD and the CKD-EPI equation were developed using urinary clearance of iothalamate as a measurement of kidney function; GFR. This is in contrast with our study but also in the development of the cystatin C -based estimation using CAPA where plasma clearance of iohexol was used. A recent paper has shown that there may be an approx. 15% difference between urinary clearances for the two tracers . Since pIt should also be highlighted that Pearson's correlation coefficient does not take into account any differences in values between compared groups and thus the correlation can be quite good even when eGFR values differ from measured clearance values by twofold or more. To explain the difference between agreement and correlation it is therefore important to depict bias and the limits of agreement using Bland–Altman diagrams.In conclusion, our findings indicate that a cystatin C-based estimation of kidney function may be more accurate in patients with primary neuromuscular disease and low muscle mass. However, even though it provides better accuracy, it varies within a wide range and should thus not be considered good enough for use in patients in whom better accuracy is warranted, for example when contrast media and potentially toxic drugs are administered.Another important finding is that both creatinine- and cystatin c-based equations systematically overestimated kidney function, especially in patients with reduced kidney function. This is clinically relevant, since detecting and diagnosing patients with reduced kidney function is extremely important as they are at risk of developing secondary metabolic  complications and/or end-stage kidney disease, and the reduction of kidney function may affect drug dosing. Further studies are necessary both to validate currently used techniques for measuring kidney function in patients with low body mass index and reduced muscle mass, as well as to evaluate diagnostic strategies for estimating kidney function in patients with reduced muscle mass and altered body composition.Supplementary file1 (DOCX 204 KB)Below is the link to the electronic supplementary material.


Elevated blood pressure (BP) in acute ischemic stroke is common. A raised BP is related to mortality and disability, yet excessive BP lowering can be detrimental. The optimal BP management in acute ischemic stroke remains insufficient and relies on expert consensus statements. Permissive hypertension is recommended during the first 24-h after stroke onset, yet there is ongoing uncertainty regarding the most appropriate blood BP management in the acute phase of ischemic stroke. This study aims to develop a decision support tool for improving the management of extremely high BP during the first 24 h after acute ischemic stroke by using machine learning (ML) tools.This diagnostic accuracy study used retrospective data from MIMIC-III and eICU databases. Decision trees were constructed by a hierarchical binary recursive partitioning algorithm to predict the BP-lowering of 10–30% off the maximal value when antihypertensive treatment was given in patients with an extremely high BP (above 220/110 or 180/105 mmHg for patients receiving thrombolysis), according to the American Heart Association/American Stroke Association (AHA/ASA), the European Society of Cardiology, and the European Society of Hypertension (ESC/ESH) guidelines. Regression trees were used to predict the time-weighted average BP. Implementation of synthetic minority oversampling technique was used to balance the dataset according to different antihypertensive treatments. The model performance of the decision tree was compared to the performance of neural networks, random forest, and logistic regression models.In total, 7,265 acute ischemic stroke patients were identified. Diastolic BP (DBP) is the main variable for predicting BP reduction in the first 24 h after a stroke. For patients receiving thrombolysis with DBP <120 mmHg, Labetalol and Amlodipine are effective treatments. Above DBP of 120 mmHg, Amlodipine, Lisinopril, and Nicardipine are the most effective treatments. However, successful treatment depends on avoiding hyponatremia and on kidney functions.This is the first study to address BP management in the acute phase of ischemic stroke using ML techniques. The results indicate that the treatment choice should be adjusted to different clinical and BP parameters, thus, providing a better decision-making approach. Machine learning (ML) applications in healthcare have significant potential for improving clinical decision-making diagnoses, treatment effectiveness, and healthcare management, including lowering the costs for both healthcare providers and patients . ML applAn elevation in BP is common in the acute phase of a stroke and occurs early at the time of arrival to the emergency room. In two-thirds of the patients, elevated BP was transient and resolved within 2 weeks from symptom onset . ObservaHigh BP in acute stroke can decrease blood perfusion to areas of ischemic brain tissue, which, in turn, can cause neurological damage . An extrThere are therapeutic strategies for elevated BP that are not included in the current acute stroke guidelines. In most hypertensive emergencies, intravenous (IV) drug administration is considered, although oral therapy with ACEI/ARBs or beta-blockers is effective in the acute setting of hypertensive emergency because of the activation of the renin system. Besides the medications mentioned above for BP lowering in acute ischemic stroke, other treatment options are utilized in various hypertensive emergencies including metoprolol, esmolol, nitroglycerine, clonidine, and enalaprilat. The duration of action of these treatments ranges from several minutes to several hours and enables dose adjustment according to clinical judgment . The useFew randomized clinical trials have examined the impact of BP reduction immediately after acute stroke with antihypertensive agents , 15. TheSeveral randomized clinical trials have examined the use of specific antihypertensive agents , 17. TheIn many clinical trials evaluating BP-lowering, markedly elevated BP ranges  were excluded –16. Howehttps://github.com/OritMazza/BP_managment_AIS.The source codes for the analyses can be found at: https://github.com/MIT-LCP/mimic-code.The MIMIC Code Repository is open source and available online. It was used with minor changes for the variable extraction tasks and can be found at the following link: We used two large, public, and freely accessible intensive care unit (ICU) databases of de-identified patients: the eICU Collaborative Research Database (eICU-CRD) and the Medical Information Mart for Intensive Care III (MIMIC-III) database in a diagnostic accuracy study based on retrospective multicenter data. Adult patients admitted to critical care units at the Beth Israel Deaconess Medical Center between 2001 and 2012 with acute ischemic strokes were selected from the MIMIC-III v1.4 Critical Care Database . SimilarThe cohort included adult patients aged 18–88. Older patients were excluded because of the de-identification process of the MIMIC-III and eICU databases, which obscured the identities of patients above 89 years old to comply with the Health Insurance Portability and Accountability Act (HIPAA) regulations , 22.treatment table with the treatmentString variable and the keyword “thrombolytics.” Table I in the The ICD-9 codes were identified for acute ischemic stroke as follows: 433 , 434 , and 436 (acute but ill-defined cerebrovascular disease). The ICD-9 codes were selected according to their highly predictive values for actual cases of acute ischemic stroke, as previously described . The 433A time window of 24 h from hospital admission was selected for patients who did not receive EVT/tPA. According to guidelines, tPA is administered at the hospital up to 3–4.5 h from ischemic stroke symptom onset and, therefore, is usually administered at a time window of 24 h from admission to the hospital . A time icustay_id) for each patient resulted in 1,142 ICU admissions (icustay_id) and 1,061 hospital admissions (hadm_id). The extraction of the selected time window of 24 h from hospital admission (admittime) to the ICU admission time (intime) resulted in a unique ICU stay for each patient in the selected cohort.The KDD process is divided into three major steps, which we followed in our study and are illustrated in The second step after preparing the data is the use of ML techniques. According to the research question and the data available, the ML approach is selected (either supervised or unsupervised learning). When the predicted outcome is well-defined and can be labeled, supervised learning is preferred. The selection of specific algorithms is guided by the dependent variable of the prediction task. When the dependent variable is of continuous type, a regression algorithm is typically selected. When the dependent variable is of categorical type, a classification algorithm is typically selected. Some algorithm types, for example, random forest and artificial neural networks, fit both classification, and regression problems. An unsupervised learning approach is considered when the prediction task is unknown. In such cases, pattern identification and recognition techniques can be applied.The processed data were divided into training and validation datasets. The training dataset is used to produce a trained and fitted model that generalizes well to unknown data. When a large amount of data is available, a sample of the original dataset—the validation dataset—is held back from the training model and is used to evaluate the model performance to obtain an unbiased result of the model's effectiveness. Typically, in this step, different algorithms are compared to identify the best model that fits the prediction task. The final step entails the evaluation of the patterns and their presentation. This step is essential to ensure that useful knowledge is derived from the data.Further evaluation of the time-weighted average (TWA) of SBP and DBP was calculated and used as a continuous outcome variable in the prediction of algorithms. The TWA provides a less biased and more accurate estimation of BP than a simple average  and can diagnoses_icd, patients, admissions, icustays, chartevents, labevents, and prescriptions) and eight different tables in the eICU database .The MIMIC-III (v1.4) relational database contains 26 different tables relating to unique patients, unique admissions to hospitals, and unique admissions to ICUs . The eICvent variable in table apacheApsVar, which contains information on whether the patient was ventilated at the time of the worst respiratory rate. Similar to the mechanical ventilation variable, we used the absence or persistence of central venous pressure (CVP), cardiac output (CO), and cardiac index (CI) as covariates in both databases because of their high prevalence of missing values, and the importance of including them as indicators of the need for more intensive monitoring care.We extracted 91 variables as possible attributes for prediction algorithms. The variables were divided into four groups: demographic, hemodynamic and vital signs, laboratory results, and comorbidities. We included 91 out of 103 predictors used by Wang et al.'s pipeline for the MIMIC-III database . Becausehttps://mor.nlm.nih.gov/RxMix/) to identify the members of each antihypertensive drug class. Then, we extracted prescriptions for antihypertensive medications in the first 24 h in the ICU or from the time of onset of the tPA treatment. The output for each drug class was stored as a binary result, namely, whether the medication from the specific drug class was administered (1) or not (0). We included 106 antihypertensive medications, which were divided into eight different drug classes. Comorbidities in the MIMIC-III and eICU databases were selected according to Quan et al. and enhanced the ICD9-CM coding algorithm, which is also provided in the MIMIC-III repository , 31. We chartevents table. To ensure that a single maximum value is not subjected to outliers or erroneous measurements, we added a variable that counts the number of times that the BP values elevated beyond the thresholds and excluded the BP values that were only elevated once in the selected time window. Different itemids for laboratory results or vital signs were grouped according to their clinical taxonomy to reduce missingness and duplicate measures, similar to other studies  ≤ 1) for better performance according to the following formula:where Z(i) is the normalized variable, and x(i) is the original variable at index i=1, 2, …, 91.step  function from the MASS package in R  were treated with tPA or EVT. Of the ICU-stay cases, 694 (10%) met the criteria for “Success” of the primary outcome. p < 0.05) and have a better handle on the overfitting problem and selection bias toward covariates with many possible splits  and continuous outcomes (regression trees). The minimum criterion for each split was selected as p < 0.05, and the input variable with the smallest p-value was used for the next division  method examines whether the covariates and the response variable are statistically significant . The different drug classes were replaced by the drug that induced the greatest reduction, as shown in p < 0.001) is the maximum DBP. The splitting criteria for the first node are based on whether the maximum DBP that was observed in the 24-h time window was above 120 mmHg (left branch) or equal to or below 120 mmHg (right branch). p = 0.048). When the DBP was below 105 mmHg (node 15), patients who received beta-blockers (BetaB = 1) had a probability of 0.7 to manage the treatment successfully when the SBP was above 180 mmHg . Two effective treatments from the beta-blocker class were identified. Metoprolol with a 0.9 probability of reducing BP to the selected interval when the SBP was above 181 mmHg , and the DBP was between 106 and 120 mmHg. Labetalol had a probability of 1 when the DBP was between 97 and 120 mmHg.In p < 0.001). However, the treatment of Hydralazine  was found to be less effective in predicting BP reduction to the selected interval (0.4 probability). Patients who received EVT/tPA had a very low probability of BP reduction when ACE-I (node 9), CCBs (node 11), or diuretics (node 14) were administered (p < 0.001). On the left side, patients who did not receive EVT/tPA with SBP above 220 mmHg (node 3) and those who received beta-blockers (node 4) had a probability of 0.8 for the prediction of the primary outcome (p < 0.001). The most significant treatment from the beta-blocker drug class was labetalol , with the same probability of BP reduction.Patients who received EVT/tPA and were treated with vasodilators  had a probability of 0.8 for predicting the primary outcome . For patients with SBP below or equal to 202 mmHg (node 33) and sodium levels higher than 129 mEq/L, using beta-blockers lowered the BP with a probability of 0.9 . In comparison, for sodium values lower than 129 mEq/L, the probability of lowering the BP was 0.5 , that is, random probability, and, thus, does not contribute to hypertension management.*, node 22). When labetalol is administered, the probability of reducing BP is 0.9  if the SBP is below or equal to 200 mmHg. However, when BP is above 200 mmHg, the probability is 0.6 . When metoprolol (node 40) is administered, the probability is 0.7 .The subtree for the beta-blocker class is shown in p < 0.001). Patients who received diuretics (node 24) had a high probability, 1, when the SBP was equal to or below 197 mmHg (node 26); however, when the SBP was above 197 mmHg, the probability of BP reduction was incredibly low and equal to 0.3 (p = 0.002).On the right, patients who did not receive beta-blockers  but received ACE inhibitors (node 29), direct vasodilators (node 23), and CCBs (node 31) had a probability of 1, 0.8, and 0.8, respectively (***), with the same probability of 1 to reduce BP to the interval. Amlodipine  was the most significant drug treatment from the CCB class and resulted in the reduction of BP with a higher probability (0.9). Furosemide  lowers BP with a probability of 0.8  when the SBP (node 27) is below or equal to 204 mmHg. However, when the SBP is above 204 mmHg, the probability to lower BP to the selected interval is very low and equal to 0.1 . Hydralazine  lowers BP with a probability of 0.9  if the SBP is above 225 mmHg and lisinopril is not administered.As evident in The decision trees presented in p < 0.001).We further evaluated the TWA of SBP and DBP with regression trees to assess the effect of the different antihypertensive drugs on BP reduction during the first 24 h of treatment. This additional assessment provided information regarding the level of BP achieved with the use of the different treatments. The diastolic  and systTreatment with Labetalol predicted a TWA BP of 138.5/72.6 mmHg. When Hydralazine was used, the predicted TWA BP was 140.9/80 mmHg. The predicted TWA SBP for patients who received tPA was 134.7 mmHg.Both regression trees showed a prediction of BP according to different sodium levels. When the sodium levels were higher than 132 mEq/L, the predicted TWA SBP was 131.6 mmHg, and for lower sodium levels, the predicted TWA SBP was 126 mmHg. When the sodium levels were higher than 133 mEq/L, the predicted TWA DBP was 70 mmHg, while for lower sodium levels, the predicted TWA DBP was 67.5 mmHg.The RMSE of the TWA SBP regression tree model was 19.72 mmHg, and the MAE was 15.9 mmHg. Regarding the TWA DBP regression tree model, the RMSE was 24.6 mmHg, and the MAE was 10.22 mmHg.p = 0.024, terminal nodes 14 and 13, respectively). When Labetalol is administered, the probability is 0.7 . This means that in high levels of BPs, there is a 70% probability that BP will be lowered by Labetalol to the selected interval, but in the other 30%, whether BP is decreased is unknown. When Hydralazine is administered, the probability is 0.6 . When lisinopril is administered, the probability of lowering BP to the interval depends on the sodium levels: above 138 mEq/L, the probability is 0.9, while for lower sodium levels, the probability is much lower and equals 0.5. The probability of lowering BPs with nicardipine depends on the BP levels, kidney function, and sodium levels, and accordingly, is equal to 0.9 when the SBP is below 195 mmHg, the creatinine levels are below 1.47 mg/dL, and the sodium levels are 133 mEq/L. However, when the sodium levels are lower, the probability of lowering the BP to the interval is 0. The probability of lowering BP when the DBP is below 120 mmHg with metoprolol is low and equals 0.6 . The probability of lowering BP with furosemide depends on the SBP levels. When the SBP was above 200 mmHg, the probability was 0.83. However, for SBP <200 mmHg, the probability was 0 . The performance of the balanced tree yielded high accuracy, F-score, and kappa values of 0.94, 0.8, and 0.75, respectively.The results of the decision tree analysis based on the balanced dataset are shown in randomForest  neural network algorithm was implemented using the R package nnet . As showComparing the different classification models, the highest performance was found for the random forest model with accuracy, kappa, and F-score values of 0.984, 0.91, and 0.901, respectively, for the original dataset, and 0.972, 0.843, and 0.864, respectively, for the reduced dataset. The results of the performance of the different models are listed in The moderate model performance of the logistic regression model is shown by lower accuracy, kappa, and F-score values of 0.93, 0.52, and 0.557, respectively, for the original dataset, and 0.928, 0.531, and 0.569, for the reduced dataset. After the random forest and decision tree, the neural network algorithm showed high accuracy, F-score, and kappa values.This study assesses whether a patient who receives antihypertensive treatment, according to recommended thresholds, is an effective treatment that lowers BP in the range of 10–30% below the maximum BP value in the first 24 h after the acute ischemic stroke onset. In comparison to randomized clinical trials that were tested in conventional methods, one or two medications in each clinical trial and compare the results to a placebo group, our study simultaneously examined over 100 antihypertensive medications using ML techniques.This study has three major findings:Blood pressure (BP) management in the first 24 h after a stroke should be managed according to different BP levels and other clinical variables, mainly kidney functioning and sodium levels. Diastolic blood pressure (DBP) is the main variable predicting the probability of BP reduction in the first 24 h after acute ischemic stroke.For patients receiving tPA/EVT, labetalol and amlodipine are effective treatments when antihypertensive treatment is administered in cases where SBP > 180 mmHg and DBP <120 mmHg.Monitoring and treating low sodium levels (<133 mEq/L) is important for successful BP reduction in the first 24 h after the acute ischemic stroke in patients with very high BP (DBP> 120 mmHg). The independent regression analysis predicting the TWA BP supports the relationship between sodium levels and BP.p = 0.004). These results are supported by the analysis of both balanced and imbalanced datasets. Labetalol also lowers BP with a probability ranging between 0.6 and 0.7 when the BP is above 200/120 mmHg, that is, in 30–40% of cases, and the goal of BP reduction to the interval is not reached. This may reflect the difficulty of lowering BP with labetalol in patients with excessively high BP. Treatment with labetalol predicted a TWA BP of 138.5/72.6 mmHg (p < 0.001) in the hyper-acute phase after a stroke. Unlike current recommendations, patients receiving EVT/tPA with DBP <120 mmHg had a low probability of BP reduction over the prescribed range with CCB therapy (p < 0.001) as a class group. However, the balanced dataset analysis showed very good results with the use of amlodipine. The use of amlodipine for patients receiving tPA/EVT should be further studied as a potential antihypertensive treatment in this group of patients. This is a novel finding that emerged from this study and has practical importance.In accordance with the AHA/ASA recommendations, we found that the group of patients receiving tPA would benefit from beta-blockers when DBP ranges from 105 to 120 mmHg with a high probability of reducing BP to the selected interval with Labetalol (p < 0.05) for lower levels of sodium.Another important finding is the significance of electrolyte balance, especially sodium levels, in BP management. In patients with DBP above 120 mmHg, successful BP management is related to sodium levels. According to the balanced results, both lisinopril and nicardipine treatments depend on avoiding hyponatremia. Sodium levels lower than 129–133 mEq/L do not contribute to hypertension management in acute stroke because the probability of BP reduction is 0–0.5. Nicardipine is also effective only when kidney functioning is normal or only slightly elevated (creatinine <1.47 mg/dl) and when the SBP is below 195 mmHg. Above an SBP of 195 mmHg, the probability of lowering BP to the interval with nicardipine was very low. However, we cannot exclude a temporary response to a lower BP with nicardipine. According to the analysis of the imbalanced dataset, nicardipine was not included in the results of the decision tree algorithms. This might have resulted from the relatively lower number of observations with nicardipine treatment. The balanced dataset corrected the bias of minority representation of nicardipine, which can be attributed to different protocols that were used in different ICU units and found to be statistically significant for the prediction task. Similar results for the regression trees indicated a significant relationship between BP and sodium levels. The regression trees predicted higher DBP and SBP for higher sodium levels above 132 mEq/L and a modest reduction in BP of 5.6/2.5 mmHg  and salt-wasting syndrome, as well as to non-stroke-related causes, such as comorbidities, the use of certain medications, and iatrogenic causes . The difIn accordance with the AHA/ASA recommendations to use CCBs  and the INWEST trial that showed a significant decrease in SBP and DBP with nimodipine , we founp < 0.001. These results are supported by the analysis of both balanced and imbalanced datasets. According to the imbalanced dataset, Lisinopril showed a low probability of reducing BP when the DBP was lower than 120 mmHg. Treatment with lisinopril was not included in the results of the balanced dataset for DBP <120 mmHg  had a lower p-value and contributed more to the prediction task.Similar to the CHHIPS trial that showed a significant decrease with lisinopril , our res** in When DBP was above 120 mmHg, both hydralazine and metoprolol showed a low probability of lowering BP (0.6). The imbalanced dataset showed that treatment with Hydralazine was effective when SBP was above 225 mmHg. However, for lower BPs, hydralazine lowered BP with a very low probability. This is not reflected in the balanced dataset analysis. This might result from the fact that the imbalanced dataset also included patients who received more than one antihypertensive treatment. Therefore, we can see that subtreeThe algorithm shows that BP reduction with furosemide is effective when the SBP is below 200 mmHg with a high probability, 0.8, which will reduce BP. However, in patients with SBP > 200 mmHg, the probability of lowering BP is very low. This might be related to the fact that furosemide inhibits the Na-K-Cl cotransporter, resulting in the increased secretion of sodium in the urine. This explanation is suggested because the results indicate that effective treatment depends on avoiding low sodium levels for certain medications (nicardipine and lisinopril).We emphasize that the analysis with ML techniques to predict outcomes indicates the relationships between predictors and outcomes rather than causality.p < 0.05. These results are consistent with the trials that showed a significant decrease of <10/6 mmHg when compared to placebo  and random forest algorithms have very high accuracy, kappa, and F-score values. We chose a subset of features by using a bidirectional stepwise algorithm that selected the most relevant features from the original dataset and, thus, decreased the model complexity without significantly reducing the prediction accuracy. The high kappa and F-score values indicate the high validity of the models. The moderate model performance of the logistic regression model vs. the decision tree algorithm is evident by the lower kappa and F-score values. Similar results of better accuracy performance when tree algorithms were compared to logistic regression were found when tested on large datasets . The neuThis study has several limitations. Our study reflects the current general recommendations and current practices for hypertension management after acute stroke. However, the two databases that were used included data that were collected during 2001–2012 (MIMIC-III) and 2014–2015 (eICU) and may reflect the management of stroke patients before the up-to-date recommendations that replaced the 2013 guidelines for the early BP management of patients with acute ischemic stroke. In addition, the exact range of BP lowering in extremely high BP is not well-established yet. Patients with severe hypertension (> 220/120 mmHg) were usually excluded from studies that examined the clinical outcomes related to BP lowering after acute ischemic stroke. Thus, whether a lowering of 10–30% from the maximum BP for highly elevated BP is too drastic should be further studied. Another important issue that clinicians should take into consideration is that the decision-making in hypertension management after acute stroke should not guide treatment alone, and clinical judgment is cardinal, especially for patients with acute concomitant comorbidities  in whom treatment should be individualized. In addition, it is important to pay attention to the contraindications of certain antihypertensive drug classes. The use of beta-blockers in acute decompensation of heart failure or the use of beta-blockers in patients with asthma exacerbation are some of the examples. Further research is needed to examine the outcomes of BP lowering in the acute phase after ischemic stroke, especially in patients with severe hypertension (>220/120), who are underrepresented in clinical trials. Outcomes according to different BP-lowering intervals should be further examined.This is the first study to address BP management in the acute phase following ischemic stroke using ML techniques. The study shows that the choice of antihypertensive treatment in the context of acute ischemic stroke should be adjusted to different BP levels and clinical features of the patient, thus providing a better decision-making approach. Further work will clarify whether there are different subgroups of patients for whom specific BP management options are better, and might include additional outcomes such as morbidity levels, mortality, readmission to hospitals, and recurrent stroke. ML techniques are used to discover hidden patterns from data and to apply robust interrogation to datasets; however, there is a risk of overfitting. However, the potential improvement in BP management in acute ischemic stroke suggested in this study should not be ignored. Rather, follow-up studies should further examine the strategies to reduce inherent ML risks and attempt to replicate the results of clinical studies.https://doi.org/10.13026/C2HM2Q. The eICU Collaborative Research Database, a freely available multi-center database for critical care research. Pollard TJ, Johnson AEW, Raffa JD, Celi LA, Mark RG, and Badawi O. Scientific Data (2018). http://dx.doi.org/10.1038/sdata.2018.178. Available from: https://www.nature.com/articles/sdata2018178.Publicly available datasets were analyzed in this study. This data can be found at: Johnson, A., Pollard, T., & Mark, R. (2019). MIMIC-III Clinical Database Demo (version 1.4). PhysioNet. MIMIC-III and eICU databases have received ethical approval from the Institutional Review Boards (IRBs) at BIDMC and MIT and because the database does not contain protected health information, a waiver for the requirement for informed consent was included in the IRB approval. Researchers using those databases are required to formally request access. There are two key steps that must be completed before access is granted: the researcher must complete a recognized course in protecting human research participants that includes Health Insurance Portability and Accountability Act (HIPAA) requirements. The researcher must sign a data use agreement, which outlines appropriate data usage and security standards, and forbids efforts to identify individual patients. Access was granted to OM on July 28, 2019. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.All authors made substantial contributions to the conception, design of the work, contributed to revising it critically for important intellectual content, and gave their final approval of the version to be published. OM was also responsible for the extraction, analysis of the data, and manuscript drafting.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.


Importantly, Hcy/eGFR ratio was an independent risk factor for CKD progression event . The risk of CKD progression events continuously increased with the Hcy/eGFR ratio, but reached a plateau when Hcy/eGFR ratio was >1.79. Our findings suggest that elevated Hcy/eGFR ratio may be an early marker of poor renal outcome in IgAN.Hyperhomocysteinemia (HHcy) is very common among patients with chronic kidney disease (CKD), and related to the risk of cardiovascular events and mortality in these patients. However, the prevalence of HHcy in primary causes of CKD and its role in kidney disease progression are not well-understood. In this study, we investigated the prevalence of HHcy in different CKD stages in 221 patients with IgA nephropathy (IgAN) and 194 patients with other primary glomerular diseases. We also evaluated the association of homocysteine (Hcy) [after adjusted for estimated glomerular filtration rate (eGFR)] with CKD progression event, defined as ESKD or 50% decline in eGFR, in a cohort of 365 patients with IgAN. The prevalence of HHcy was 67.9% (150/221), 53.5% (76/142), 51.5% (17/33), and 42.1% (8/19) in patients with IgAN, membranous nephropathy, minimal change disease, focal segmental glomerulosclerosis, respectively. The Hcy/eGFR ratio was significantly associated with pathologic features of IgAN, including the proportion of global glomerulosclerosis ( Primary glomerular diseases (PGD)—glomerular diseases that are not caused by a systemic disease—account for about 20% of chronic kidney disease (CKD) in most countries . A greatHomocysteine (Hcy) is a sulfur-containing intermediary amino acid produced following the metabolic conversion of methionine to cysteine. Hyperhomocysteinemia (HHcy) is a condition characterized by the increase in plasma levels of Hcy—total plasma levels of Hcy >15 μmol/L. Hcy can reduce the utilization activity of nitric oxide, increase oxidative stress, induce endothelial dysfunction, and promote the proliferation of vascular smooth cells , 5. RaisIn this study, we enrolled 221 cases with IgAN and 194 cases with other PGD to investigate the prevalence of HHcy in different CKD stages in these patients. We also evaluated the association of Hcy/eGFR ratio with disease severity and CKD progression in a cohort of 365 patients with IgAN.The cross-sectional study was based on data obtained from medical records from the renal division of Peking University First Hospital. We included participants with PGD who underwent comprehensive health examinations, including renal biopsy and plasma concentrations of total Hcy from January 2016 to December 2020. We excluded individuals with gout, pyuria, or nephritis secondary to systemic disease or cancer, as well as other factors that influence the plasma Hcy levels. Individuals with gastrointestinal diseases, alcoholic addiction, vegetarian lifestyle, and regular consumption of folic acid and vitamin supplements were also excluded. Finally, 221 cases with IgAN were recruited in the observational study. The diagnosis was based on renal biopsy by light microscopy, immunofluorescence, and electron microscopy. At the same time interval, 142 patients with membranous nephropathy (MN), 33 patients with minimal change disease (MCD), and 19 patients with focal segmental glomerulosclerosis (FSGS) were enrolled served as disease controls.In addition, to explore the role of Hcy in disease progression, a total of 365 patients with biopsy-proven IgAN diagnosed between 2009 and 2020 were selected from the prospective IgAN database at Peking University First Hospital. Patients in the database were followed up regularly every 3–6 months.This study was approved by the Ethics Committee of Peking University First Hospital and informed written consent was obtained from all patients.Clinical manifestations at the time of renal biopsy, including age, sex, homocysteine, serum creatinine, 24-h urine protein excretion, uric acid, and other biochemical characteristics were collected from the medical records. The definition of HHcy was referred to as the presence of homocysteine concentrations >15 μmol/L. The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation . The Oxft-test. A Mann-Whitney U-test was used to compare the differences between two independent samples when the sample distributions are not normally distributed. Differences among categorical variables were analyzed using the chi-squared test.Continuous variables were presented as mean ± standard deviation for normally distributed variables or median with interquartile range for non-normally distributed variables. Categorical variables were summarized as frequency with percentage. For continuous variables, the significance of differences between groups was determined using independent sample Cox proportional hazards models were adopted to evaluate the relationship between Hcy/eGFR ratio and risk of end point. Sex, age, eGFR, proteinuria, mean arterial pressure, and use of steroids and/or other immunosuppressive agents were adjusted in multivariable-adjusted Cox proportional hazards models. Receivers operating characteristic (ROC) curves were constructed at the most discriminating cut-off point value to predict the disease progression. Kaplan-Meier analysis was used to derive cumulative kidney survival curves. The division between the groups of participants was on the basis of the cut-off value in the ROC curves, and difference between curves was analyzed using a log-rank test. The association between Hcy/eGFR ratio and end point was also evaluated on a continuous scale with restricted cubic spline curves based on Cox proportional hazards models. Knots for the cubic splines were placed with default parameters.p-values were 2 tailed, and values < 0.05 were considered statistically significant. Analyses were performed using SPSS software v20.To investigate correlations between Hcy/eGFR ratio and clinicopathological parameters in IgAN patients, Pearson's correlation coefficients were used for continuous variables and Spearman's correlation coefficients for binary and ordinal variables. Partial correlation analysis was used to quantify the correlation between two variables after removing the effects of other variables. All 2 and the median proteinuria level was 1.4 g/24 h .The characteristics of the patients with PGD at the time of kidney biopsy are described in p < 0.001) and uric acid levels (p < 0.001), and lower eGFRs (p < 0.001) than those without HHcy, which was not specific to any kind of PGD.The mean homocysteine level in IgAN was 23.2 ± 15.3 μmol/L . HHcy was detected in 150 (67.9%) of the 221 patients in IgAN group. Whereas, the prevalence of HHcy was 53.5% (76/142), 51.5% (17/33), and 42.1% (8/19) in MN, MCD and FSGS groups, respectively. As shown in p = 0.02). In CKD stages 3–5, the prevalence of HHcy was 89.8, 80.0, 85.7, and 77.8% in IgAN, MN, MCD, and FSGS, respectively (p = 0.38). Specifically, the prevalence of HHcy in CKD stages 1–2 in IgAN was 36.2% (21/58) and 63.1% (41/65), respectively. Thus, HHcy is very common in IgAN cases of normal or mildly reduced renal function (about 1/3 in CKD 1 and 2/3 in CKD 2), which may be of clinical importance. In line with expectations, the prevalence increased with decreasing renal function, which was 84.4% (54/64), 100.0% (28/28), and 100.0% (6/6) in CKD stages 3, 4, and 5 in IgAN, respectively  in IgAN and disease controls . In CKD ectively .r = −0.65, p < 0.001), and remained significant after controlling for cardiovascular risk factors, including age, sex, hypertension, and total cholesterol levels . The Hcy/eGFR ratio was also positively correlated with serum creatinine , serum uric acid , proteinuria , systolic blood pressure , and diastolic blood pressure . In addition, the Hcy/eGFR ratio was significantly associated with pathologic features of IgAN, including the mesangial hypercellularity , the segmental glomerulosclerosis , the proportion of global glomerulosclerosis , the proportion of ischemia originated glomerular sclerosis , the severity of tubular atrophy/interstitial fibrosis , and the presence of crescent . These results suggest that Hcy might contribute to the progression of IgAN.Then, we explored the correlations between Hcy (after adjusted for eGFR) and clinicopathological parameters in patients with IgAN . The Hcy2 and the median proteinuria level was 1.1 g/24 h . The mean homocysteine level in IgAN was 23.7 ± 19.4 μmol/L . Overall, 238 participants (65.2%) received steroids or other immunosuppressive agents. After a median follow-up of 34 months , 32 (8.8%) participants reached the composite kidney disease progression event, including 27 kidney failure events. Compared with other patients, these patients showed a higher prevalence of HHcy  and more severe histological lesions, including higher prevalence of M1 , S1 , and T1/T2  according to the Oxford classification  (As shown in gression . The are< 0.001) .The association between Hcy/eGFR ratio and end point was also evaluated on a continuous scale with restricted cubic spline curves based on Cox proportional hazards models . The risIn this study, we investigated the prevalence of HHcy in 221 patients with IgAN and 194 patients with other primary glomerular diseases, and found that patients with HHcy tended to present with more severe disease than those without HHcy. Among the four kinds of PGD, IgAN had the highest prevalence of HHcy, especially in patients with CKD stages 1–2. Notably, our study demonstrated that Hcy/eGFR ratio was associated with the chronic changes in kidney biopsy specimens in IgAN. On the basis of our follow-up data, we found that elevated Hcy/eGFR ratio was independently associated with increased risk of kidney disease progression in IgAN.The prevalence of HHcy in patients with CKD has been reported . NeverthMoreover, we found that Hcy/eGFR ratio was significantly associated with eGFR, proteinuria, and multiple chronic pathologic features of IgAN, which are important markers for the development and progression of CKD. Thus, the Hcy/eGFR ratio may be a potential marker for predicting the prognosis of IgAN. Consistently, participants reached the CKD progression event presented more severe histological lesions, including mesangial hypercellularity, segmental glomerulosclerosis, and tubular atrophy/interstitial fibrosis. Chronic changes in kidney biopsy specimens have a major bearing on predicting prognosis of CKD and guiding treatment . EndocapA previous study has reported the association between Hcy levels and renal function decline in hypertensive adults . To our In conclusion, HHcy was more prevalent in IgAN patients than in patients with other primary glomerular diseases, especially in the early stages of CKD. Hcy/eGFR ratio was significantly associated with markers of poor renal outcome in IgAN. Importantly, we use a cohort study demonstrating that elevated Hcy/eGFR ratio was independently associated with increased risk of disease progression in IgAN. Further high-quality trials of early intervention of HHcy in IgAN to prevent progression to CKD and ESKD are warranted.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Committee of Peking University First Hospital. The patients/participants provided their written informed consent to participate in this study.X-JZ and HZ designed the study. Y-NW carried out experiments and data analysis. HX and Z-RS contributed to sample collection and performed clinical characterization. All authors contributed to the manuscript and approved the submitted version.This work was supported by the National Natural Science Foundation of China , Natural Science Foundation of Beijing Municipality (Z190023), Chinese Academy of Medical Sciences Research Unit (2019RU023), Clinical Medicine Plus X-Young Scholars Project of Peking University (PKU2020LCXQ003), Fok Ying Tung Education Foundation (171030), and Beijing Nova Program Interdisciplinary Cooperation Project (Z191100001119004).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. 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Background: Immunoglobulin A nephropathy (IgAN) is the most common primary aetiology of glomerulonephritis worldwide, and it is the most important type in terms of morbidity and mortality. IgAN involves the deposition of immune bodies in the mesangial cells of the kidney, which causes renal glomerular damage, haematuria, proteinuria, and various other symptoms. Previous studies have mainly focused on the East Asian population, with few studies conducted in Saudi Arabia, particularly in the western region. The diagnosis requires a biopsy, which should be examined by an expert and classified according to the Oxford classification system.Objectives: Analyze the clinical, pathological, and laboratory features of male and female patients diagnosed with IgAN at King Abdulaziz University Hospital (KAUH).Methods and materials: This was a retrospective record review conducted at KAUH in Jeddah, Saudi Arabia between May-June 2021. The study included 18 patients diagnosed with IgAN by biopsy, and their clinical, laboratory and pathological data were evaluated and classified according to the Oxford classification system.Results: Demographic data revealed a male predominance of 66.7%. The most common pathological finding was mesangial proliferation, and the most common presentation was haematuria. For treatment options, corticosteroids were the most prescribed drugs. A significant relationship was found between IgAN with increased serum creatinine and male sex (P = 0.017). Additionally, a significant relationship was observed between decreased estimated glomerular filtration rate (eGFR) in IgAN and the male sex (P = 0.006).Conclusions: We found a difference in terms of pathological, clinical and laboratory presentations of IgAN between males and females. Men generally had worse kidney function at presentation and advanced Oxford classification in their kidney biopsies compared to women. Immunoglobulin A nephropathy (IgAN), often referred to as Berger's disease, is an autoimmune glomerulonephritis, with a predominance of IgA deposits in the glomerular mesangium, either alone or in combination with IgG, IgM, or both -3. It isA study conducted by the International IgA Nephropathy Network and the Renal Pathology Society reported that pathologists had classified their patients' renal biopsies and taken into account their clinical data to have a reference set of pathological variables to be used as indicators for renal survival . The patThis single-center retrospective record review study was conducted at KAUH, a tertiary care centre in Jeddah, Saudi Arabia.This research was authorized by the Institutional Review Board of KAUH (Ref: 38-21). The procedures followed were in accordance with the ethical standards of the responsible committee based on the Good Clinical Practice Guidelines. Informed consent was waived due to the retrospective nature of the study. We collected and analysed the data of 67 patients diagnosed with primary IgAN by biopsy between 1989 and 2021. The number of patients who fulfilled the inclusion criteria was 18, and we included patients of all ages diagnosed with IgAN by biopsy. Patients with no documentation of laboratory investigations, secondary IgAN due to other diseases such as Henoch Schonlein purpura, and those with established end-stage renal disease (ESRD) at the time of the first diagnostic biopsy were excluded.Clinical dataThe clinical data of all patients diagnosed with IgAN on biopsy was acquired through a review of the hospital records. Data retrieved included information about gender, nationality, age, weight (Kg), height (cm), and first clinical presentation, including the presence of nephrotic syndrome, isolated haematuria, isolated proteinuria, acute kidney injury, and hypertension. The following concomitant morbidities were also considered: diabetes, ischemic heart disease, chronic heart failure, malignancy, cerebrovascular disease, autoimmune disease, thyroid disease, chronic liver disease, peripheral vascular disease, respiratory disease, and CKD. Blood pressure (BP), blood urea nitrogen (BUN), total cholesterol, triglycerides, and microhaematuria, defined as the presence of >3 red blood cells per high power field (HPF), serum creatinine (sCr) at the time of biopsy, haemoglobin level, proteinuria (g/dL) and estimated glomerular filtration rate (eGFR) (mL/min/1.73 m2). eGFR was measured using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for adults , in whicPathological dataThe results of each renal biopsy were classified by an expert pathologist using the updated Oxford classification: mesangial hypercellularity ; endocapillary hypercellularity , segmental glomerulosclerosis , tubular atrophy/interstitial fibrosis , and cellular or fibrocellular crescents  .Statistical analysisMicrosoft Excel was used for data entry and the Statistical Package for Social Sciences (SPSS) version 21  was used for statistical analysis. Mean and standard deviation (SD) were calculated to describe continuous variables, while frequencies and percentages were used for categorical variables. Student’s t-test and chi-square test were used to evaluate the differences between continuous and categorical variables, respectively. Statistical significance was set at P < 0.05.Eighteen patients were enrolled in this study, of which 66.7% were men Table . The meaThe most common presenting symptoms were isolated haematuria (44.4%), nephrotic syndrome (38.9%), hypertension (38.9%), isolated proteinuria (22.2%), nephrotic syndrome (5.6%), and acute kidney injury (5.6%). The most prevalent concurrent morbidities were respiratory disease (16.7%), followed by thyroid disease (11.1%).As shown in Table The laboratory findings are shown in Table The histopathological features are shown in Figures In our study, a significant relationship was observed between the male sex and increased serum creatinine levels (P = 0.017). This could be because men have a higher proportion of muscle mass and are generally more physically active, which in turn leads to increased muscle breakdown leading to an increased amount of creatinine produced in the body. Similar findings were reported in a study conducted in Brazil by Baxmann et al. , in whicAnother sex-related difference was found in our study; males had lower eGFR than females, and a significant relationship between decreased eGFR and male sex was noted (P = 0.006). This is probably due to the protective effect of oestrogen on kidney function in females. Males, in general, are more prone to renal disease and tend to have a higher rate of progression of renal disease, possibly due to this phenomenon. Moreover, females produce lesser creatinine than males, which, in general, protects the kidneys from the increased workload. Several studies support these hypotheses. In a study conducted in China, Deng et al. reported that men were more likely than women to have a low eGFR . AnotherHaematuria was the most common presentation in our cohort, which could indicate that it is one of the hallmarks of IgAN. Among the two types of haematuria, macroscopic and microscopic haematuria, the former might be overlooked . The preCorticosteroids were the most common drugs prescribed in our study. This is not surprising because of the well-known immunosuppressive effect of corticosteroids. IgAN, being an immune-mediated disease, is effectively controlled with steroids, which explains their widespread use in patients with IgAN. According to a recent study conducted by Wang et al., corticosteroid therapy is likely to be effective and safe for patients with IgAN . AnotherRegarding the histopathological features according to the Oxford classification, men had a higher score than women. Additionally, no tubular atrophy (T) or crescents (C) were recorded in female patients, and only one female patient had segmental sclerosis, which might indicate that males usually have worse histopathological findings and rate of renal damage than females, possibly due to the lack of renal protective properties of oestrogen seen in females. As mentioned above, the probable processes underlying the renal protective effect in females appear to be linked to oestrogen . AdditioThe most prevalent histopathological finding was mesangial proliferation (M1). Several studies have also reported mesangial proliferation (M1) as the most common histopathological finding in IgAN ,12,21. TStudy limitations include a single study location , only one ethnic group included, small sample size, poor documentation of data for some patients, especially clinical presentations and laboratory findings. Although this study uses a more recent classification to describe the clinical, pathological, and laboratory features of IgAN in a Saudi cohort, a multicentre and multiethnicity study is recommended to make more relevant comparisons.We conclude that there is a difference in the pathological, clinical, and laboratory findings in IgAN between men and women. Men generally have worse laboratory and pathological findings; therefore, we strongly suggest changes in the diagnostic, treatment and follow-up guidelines to accommodate these differences. Moreover, national screening programs focusing on the most common presentations, such as haematuria and hypertension to detect IgAN at an early stage, are important to minimize long-term deterioration in renal function. Finally, we strongly recommend conducting a multicentre and multi-ethnic study to explore the ethnic variability in IgAN in terms of presentations and findings.