Objective: To identify the frequency of congenital heart disease (CHD) in various Khyber Pakhtunkhwa (KPK) divisions.Materials and methods: To perform this research, we reviewed the medical records of pediatric cardiology patients hospitalized between January 2022 and July 2022. Data was taken from the cardiology department's computerized data system between January 1 and July 31, 2022. To prevent any errors in diagnosis and address them during input by the ward clerk, patients' addresses, diagnoses, and gender were verified with the computerized medical record. Data were analyzed, and frequency and percentages were calculated. Per the digital mapping of KPK districts, we stratified and examined the data among various KPK divisions.Results: Out Of the 371 patients with CHD who were admitted, 36.98% (137) were from the Peshawar division, 28.84% (107) from the Malakand division, 16.71% (62) from the Mardan division, 6.1% (23) from the Kohat division, 4.3% (16) from the Bannu division, 3.5% (13) from the Dera Ismail Khan division, and 3.5% (13) from the Hazara division. A total of 371 had CHD, of which 234 (63.07%) were cyanotic and 137 (36.92%) were cyanotic. The most prevalent acynotic congenital heart defect was patent ductus arteriosus (PDA) at 36.32% (85), followed by a ventricular septal defect (VSD) at 35.04 (82). The most frequent acyanotic congenital cardiac abnormality was tetralogy of Fallot (TOF) at 49.63% (68), which was followed by transposition of the great arteries (TGA) at 33.57% (46).Conclusion: In KPK, congenital heart disease is most prevalent in the divisions of Peshawar and Malakand, while it is least prevalent in Hazara. Congenital heart defects (CHD) are characterized as structural and functional cardiac deformities that, if not treated with the proper procedures, may result in a person's reduced quality of life and even early death . Nine-teChildren with CHDs have different types of presentation in the emergency department (ED): they may present in shock or cardiac failure or for murmur evaluation for the first time, or they may come to the emergency for management of spells or chest infection, or they may have a problem after cardiac surgery. Therefore, every child who presents in critical condition at the ED should have a suspicion of heart disease and be evaluated thoroughly for CHD as recommended by Bano et al. . OutsideThe lack of diagnostic facilities and access to healthcare in many regions of the globe contributes to the disparities in reported birth prevalence between high and low-income nations. Further research is required to customize the treatment of the global health issue of CHDs given that observed disparities may also be of genetic, environmental, socioeconomic, or ethnic origin . AlthougOur research's objective is to determine the prevalence of congenital cardiac disease throughout various KPK divisions. This will assist us in the future to focus our health resources on a particular demographic and geographic region while also allowing us to explore any disparities that we see that may have genetic, environmental, socioeconomic, or ethnic roots.Study designPatients hospitalized at the pediatric department of the Peshawar Institute of Cardiology (PIC) were recruited in this descriptive and prospective hospital-based research studyInclusion and exclusion criteriaAll patients from KPK with CHD admitted at the pediatric unit of our hospital were included in the study. All patients with acquired heart disease, syndromic babies with congenital heart disease, premature babies with patent ductus arteriosus or patients from other provinces were excluded from the study.Data collection Our intention was to utilize a well-designed data sheet to gather data for at least six months of our anticipated study. Between January 1 and July 31, 2022, data were extracted from the computerized data system of the cardiology department. Their residence, illness, and gender were checked against the computerized medical record to make sure there were no mistakes made when the ward clerk entered their information. We filtered and looked at the data among different KPK divisions in line with digital mapping of KPK districts. The essential data on the form was filled up using information from interviews with study participants and data from their hospital records. By including the hospital registration number, data duplication was avoided. Overall, 371 individuals were found, and data sheets were finished.Statistical analysis The collected data were entered and analyzed. Frequencies, means, and percentages are all components of calculated descriptive statistics.Ethical considerationThe ethical committee of Peshawar Institute of Cardiology granted approval for this study on 12/12/2022 .In our study, there were a total of 371 patients out of which 201 (55%) patients were female and 170 (45%) were male (Table Acyanotic CHD was diagnosed in 234 (63.07%) patients while cyanotic CHD was diagnosed in 137 (36.92%)  followed by the Malakand division 28.84%), Mardan division (16.71%), Kohat division (6.1%), Bannu division (4.3%), Hazara division (3.5%), and Dera Ismail Khan division (3.5%). Of the 371 patients, 137 (36.98%) were from Peshawar. Out of these 137 patients, 78 (56.93%) had acyanotic congenital heart abnormalities, whereas 59 (43.06%) had cyanotic ones. The most frequent acyanotic CHD was patent ductus arteriosus (PDA) followed by VSD, while the most frequent cyanotic CHD was TOF followed by transposition of the great arteries (TGA). Of the total number of patients, 107 (28.84%) were from the Malakand division, and among these patients, 78 (72.89%) had acyanotic CHD, and 29 (27.10%) had cyanotic CHD. The most frequent acyanotic CHD was VSD followed by PDA, while the most frequent cyanotic CHD was TOF followed by TGA and pulmonary atresia (PA). Out of 371 patients overall, 62 (16.71%) were from the Mardan division where 50% were cyanotic and 50 % were acyanotic. In this division of KPK, VSD was the most common acyanotic CHD followed by PDA, while the most prevalent cyanotic CHD was TGA followed by TOF. Twenty-three (6.19%) out of the 371 patients came from the Kohat division. Twenty (86.95%) of these patients were acyanotic, while three (13.04%) were cyanotic. The most frequent cyanotic CHD was TOF, whereas the most frequent acyanotic CHD was VSD followed by PDA. From the Bannu division, there were 16 patients (4.31 %). Six (37.5%) of them were cyanotic, whereas 10 (62.5%) were acyanotic. The most frequent acyanotic CHD in this division was PDA followed by VSD, while the most frequent cyanotic CHD was TOF followed by TGA and PA. From the Dera Ismail Khan division, there were 12 patients (3.2%). Among them, nine (75%) were acyanotic, and three (25%) were cyanotic. The most frequent acyanotic CHD here was PDA followed by VSD, while the most frequent cyanotic CHD was TOF followed by TGA. Twelve of the 371 total patients were from the Hazara division. In this group of 12 patients, four (33.33%) were cyanotic and eight (66.66%) were acyanotic. In this division of KPK, PDA was the most prevalent acyanotic CHD followed by VSD, while TGA was the most prevalent cyanotic CHD followed by TOF and PA  cases while cyanotic CHD was found in 137 (36.92%) cases making a ratio of 1:1.7, which means acyanotic is more common than cyanotic lesions. Similar results were obtained in a study conducted by Nicholas et al. in a tertiary referral center [Around the globe, 0.8% of newborns are born with congenital cardiac disease . The bulHistorically, early childhood was when most CHD patients passed away. However, this field of medicine has made amazing progress during the last four decades. With a consistent rise in age at death and a decline in mortality, death from CHD has shifted towards adults than from newborns . About 2In 2017, it was predicted that there were almost 1.8 occurrences of CHD per 100 live births worldwide . Heart dAccording to a study by Zahid et al., acyanotic CHD 52.8%) is more prevalent than cyanotic CHD (47.1%), which is similar to our study. However, their study did not examine the range of CHDs or the relative distribution of CHD in the various divisions of KPK . Our res% is moreOur research is distinctive since it is the first local study to concentrate on regional variations in CHD. And this will aid and direct us in the future towards more extensive research to help identify the many etiological and environmental elements contributing to CHD. According to our findings, CHD is more prevalent in urban regions than in non-urban areas.Our study has few limitations: it is a single-centered study, and patients seen in other centers across the province were not included. The results might have been different if data was collected at the division level as the patients might be referred to other nearby centers. According to our data, in KPK, congenital cardiac disease is more prevalent in the Peshawar and Malakand divisions, while it is least prevalent in the Hazara division. Acyanotic CHD is more common in KPK as compared to cyanotic CHD. Acyanotic PDA was the most common defect followed by VSD, while TOF was the most common lesion followed by TGA in the cyanotic group. Congenital heart disease is more prevalent in females as compared to males according to our study.


Positive correlations of MCACs and LCACs  with the left atrium size and volume, the right atrium volume, right ventricle, and the inferior vena cava sizes, as well as the pulmonary artery systolic pressure level were shown. A negative correlation between C18:1 and left ventricular ejection fraction  was found. However, a decrease in levels compared to referent values of ACs with medium and long chain lengths was 50% of the CHF-CHD cohort. Carnitine deficiency was found in 6% and acylcarnitine deficiency in 3% of all patients with chronic heart disease. Conclusions: ACs may be used in assessing the severity of the clinical manifestations and MR. ACs are an important locus to study in terms of altered metabolic pathways in patients with CHF of ischemic etiology and SD. Further larger prospective trials are warranted and needed to determine the potential benefits to treat patients with CV diseases with aberrate AC levels.Background: Progressive myocardial remodeling (MR) in chronic heart failure (CHF) leads to aggravation of systolic dysfunction (SD) and clinical manifestations. Identification of metabolomic markers of these processes may help in the search for new therapeutic approaches aimed at achieving reversibility of MR and improving prognosis in patients with CHF. Methods: To determine the relationship between plasma acylcarnitine (ACs) levels, MR parameters and clinical characteristics, in patients with CHF of ischemic etiology (n = 79) and patients with coronary heart disease CHD (n = 19) targeted analysis of 30 ACs was performed by flow injection analysis mass spectrometry. Results: Significant differences between cohorts were found for the levels of 11 ACs. Significant positive correlations (r > 0.3) between the medium- and long-chain ACs (MCACs and LCACs) and symptoms ; r = 0.31−0.39;  Chronic heart failure (CHF) is the final stage of cardiovascular disease (CVD). Coronary heart disease (CHD) remains to be one of the main causes leading to the progression of CHF and development of left ventricular (LV) systolic dysfunction. In CHD, chronic or acute ischemia of cardiomyocytes (CMC) and associated inflammation, hypertrophy, and apoptosis of CMC underlie the formation of structural and functional myocardial remodeling (MR) . At the Several authors note that against the background of ischemia, prolonged inhibition of β-oxidation of FA in CMC, the deficiency of carnitine as a substrate for FA oxidation and, consequently, accumulation of AC initiates lipotoxicity and intracellular acidosis, contributing to the inhibition of energy production in CMC, increased oxidative stress, which leads to organelle degradation, CMC apoptosis, and eventually death of viable myocardium ,5. In thIt is important to note that the severity of pathologic MR has a great influence on the further development of CHF of ischemic etiology . At the The prospective cohort study was conducted at the clinical bases of the Department of Hospital Therapy Sechenov University, Moscow, Russia, in the period from 2021 to 2022. The study included 2 comparison groups: the main group consisted of patients diagnosed with CHF of ischemic etiology and LVEF < 50% (CHF-CHD group); the control group included patients with CHD without signs of heart failure (CHD group). CHF was diagnosed according to current clinical recommendations , with de2), signs and symptoms of liver disease in the decompensation stage, portal hypertension, uncontrolled bronchial asthma and chronic obstructive pulmonary disease, gastric or duodenal ulcer in the exacerbation stage, chronic pancreatitis in the exacerbation stage, malignant neoplasms, thyroid diseases, Cushing’s syndrome, type 1 diabetes mellitus, thrombocytopenia, hemorrhagic syndrome, autoimmune diseases, mental illness, alcoholism, drug addiction, substance abuse, pregnancy and breastfeeding.The diagnosis of CHD was established if patients had stenotic lesions of coronary arteries according to coronary angiography/computed tomographic coronary angiography and/or a history of myocardial infarction (MI) not earlier than 3 months before sampling for metabolite level estimation. Exclusion criteria were the following: Secondary arterial hypertension, cerebrovascular disorders , acute renal failure, terminal renal failure  were used to assess structural and functional changes in the heart. TTE was performed using commercial stationary equipment . Linear dimensions, chamber volumes (including indexed by body surface area), ventricular wall thickness, and cardiac functional parameters ), as well as the dimensions of large vessels (inferior vena cava (IVC), pulmonary artery (PA), aorta) were evaluated according to the recommendations and considering sex differences.The study was approved by the local ethical committee of Sechenov University and was conducted in accordance with the set of ethical principles for medical research involving human participants set out in the Declaration of Helsinki. Study participants were verbally informed of the detailed protocol and provided written informed consent to participate in this study. g. Next, 40 μL of supernatant was transferred to the microtiter plate for analysis by flow injection using a tandem mass spectrometer (FIA-MS/MS). Analyses were performed in the positive electrospray ionization mode. Identification and quantification were achieved using multiple reaction monitoring (MRM).Plasma samples were collected after an overnight fast between 8 and 10 am from the vein into vacuum tubes containing ethylenediaminetetetraacetic acid tricalic salt dehydrate. Immediately thereafter, samples were centrifuged at 2000 rpm for 20 min and stored at −80 °C until analysis. The MassChrom Amino Acids and Acylcarnitines Non-Derivatized 57.000 Kit  was used. Five μL aliquots of each plasma sample were mixed with 50 μL of a solution of isotopically labeled internal standards (ISTD) in methanol in a microtiter plate to precipitate proteins. After 10 min of incubation, the microtiter plate was centrifuged for 5 min at 100× Standardization was performed by spiking isotope-labeled standards into the samples. The FIA-MS/MS analysis was performed on a Waters TQ─S-micro system equipped with an electrospray ionization source (ESI) and coupled to a Waters Acquity I high-performance liquid chromatography (HPLC) pump . Flow injection analysis (FIA) was performed using a mixture consisting of 50% acetonitrile–water with 0.1% formic acid added at an isocratic flow rate of 200 μL/min. Mass spectrometry was performed under the following conditions: residence time 0.019–0.025 sec; capillary voltage 2 kV; nitrogen was used as the collision gas medium, and the source temperature was 150 °C. Target mass spectrometry data were imported and preprocessed using MassLynx software v4.1 . Metabolite concentrations were calculated from the signal intensities of analytes and corresponding internal standards. Samples for both comparison groups were analyzed in the same batch. The intra-assay precision for the kit used ranged from 4.9% to 7.6% and the inter-assay precision ranged from 7.2% to 17.2%. The error for metabolites ranged from −12.3% to 16.0%.The normality of data distribution was checked using the Shapiro–Wilk criterion. The mean (M) and standard deviation (SD) in the format of M ± SD, if the indicator had normal distribution, or the median (Me) and interquartile range   were used; otherwise, ANOVA Kruskal-Wallis with Bonferroni posterior analysis was employed to compare groups of more than two. To analyze the strength of the correlation relationship between the studied features, Pearson’s correlation coefficient  and Spearman’s correlation coefficient  were used. Statistical analysis was performed using the programs STATISTICA 12.0 and IBM SPSS Statistics 23.0.Ninety-eight patients were included in the study. Seventy-nine patients were included in the group of CHF-CHD, 19 patients in the group of CHD. General characteristics of the comparison groups are presented in Significantly more patients in the CHF-CHD group had a history of MI compared to the CHD group . In the remaining patients who did not undergo MI, CHD was represented by proven coronary atherosclerosis with clinical manifestations of angina FC II-III according to Canadian classification. In contrast to patients in the CHF-CHD group in whom sinus rhythm was predominantly determined (73.7%), heart rhythm disorders (HRD) in the form of atrial fibrillation/atrial flutter (62%) of permanent form  prevailed in the CHF- CHD group. In addition, four patients with CHF had implanted devices—pacemakers .2), and relative wall thickness (RWT): in patients with CHD, the leading types were concentric and eccentric hypertrophy, represented equally (39.2% each); in patients without signs of CHF, concentric remodeling prevailed (63.1%)  .The comparison groups differ naturally in LVEF and volume size indices of the left heart cavities—left ventricle (LV) and left atrium (LA)—which significantly exceed the upper limit of the normal and are statistically significantly higher in patients with CHF of ischemic etiology. The CHF-CHD group was characterized by the presence of signs of right heart overload—increased right atrial volume and LA parameters: its size and calculated left atrial systolic pressure (LASP), as well as significantly larger basal right ventricular diameter (RVD) compared to the CHD group, although its value remained within the acceptable normal range .Carnitine deficiency was found in 6% and acylcarnitine deficiency in 3% of all patients with chronic heart disease . At the p < 0.05) were determined for 11 parameters, including those entered further into the correlation matrix (Table. 4): butyrylcarnitine (C4), decadienoylcarnitine (C10:2), dodecanoylcarnitine (C12), dodecanoylcarnitine (C12:1), tetradecanoylcarnitine (C14), tetradecanoylcarnitine (C14:1), tetradecadecadienoylcarnitine (C14:2), palmitoylcarnitine (C16), hexadecenoylcarnitine (C16:1), oleoylcarnitine (C18:1), linoleoylcarnitine (C18:2). According to these indices, the levels of all mentioned ACs were significantly higher in patients with CHF of ischemic etiology and LVEF <50% . In addition, decadienoylcarnitine  and short-chain glutarylcarnitine  also showed an association with decreased renal function characteristic of this patient cohort. Hydroxyoctadecanoylcarnitine (C18-OH) correlated with NT-proBNP levels .Correlations of moderate strength (r > 0.3 modulo) were revealed mainly between the level of AC with large and medium chain length and clinical characteristics of patients in the form of FC . Increasp < 0.05), and hydroxyisovalerylcarnitine—with FC . Also, the level of AC had a positive correlation of moderate strength with such echocardiographic parameters as LV size, volumes of both atria, dimensions of LV and vena cava inferior . The greAn intergroup comparison of AC levels was performed for this cohort of patients, with the grouping characteristic of FC I–IV . SignifiACs are of interest because in the field of metabolomic profiling, there is increasing evidence for the use of these metabolites as markers of CVD: insulin resistance , arteriaIn fundamental works devoted to the study of myocardial metabolism in CHF , it is nIndeed, several studies have shown an association of AC with CHF and systolic dysfunction. In experimental works on mouse models, the authors describe these changes in the framework of desynchronization of glucose and FA oxidation in CMC of hypertrophied myocardium with inhibition of mitochondrial enzyme CPT-1/2 and PPARα, PGC1α receptors directly by AC excess, which leads to the limitation of β-oxidation and formation of lipotoxicity . The autThe normal range of carnitine varies from 22 to 65 μM. The normal ranges of carnitine and its derivatives according to the Human Metabolomic Database (HMDB) are presented in However, if we refer to the basics of hemodynamics, it is known that myocardium of atria and RV is not able to resist prolonged overload , which iGiven the proven role of excessive accumulation of intracellular and circulating ACs in aggravation of cytotoxicity and, at the same time, the ambiguity of mechanisms explaining their accumulation in patients with CHF of ischemic etiology, it is necessary to conduct further prospective studies. It is important to study the peculiarities of metabolism and remodeling of both “right” heart departments and large vessels, such as PA and VCI. Such observations suggest the possibilities of therapy with carnitine in case of its deficiency. There are works where the effectiveness of supplements containing L-carnitine and its derivatives was analyzed in relation to patients with various CVD and positive effects, such as an increase in LVEF, a decrease in LV volumes, and a decrease in serum levels of sodium-uretic peptides. However, there are no studies among them that describe carnitine therapy in patients with LV and LVEF < 50%. Dambrova M. and co-authors reviewed existing data by 2022 on the effect of L-carnitine on the course of cardiovascular diseases: CHD, CHF, hypertension. The intended effect of these supplements is to increase the binding of fatty acids (acyls) and enhance their transport to the mitochondria for oxidative phosphorylation, thereby reducing the pool of circulating cytotoxic acylcarnitines . But it According to the results of our study, there are differences between the comparison groups in the levels of medium- and long-chain acylcarnitines in favor of relatively high levels of these fractions in patients with HF. At the same time, 50% of this cohort have AC values below the given reference values. In this regard, it is difficult to determine the clinical applicability of the data obtained.In addition, the question remains unresolved as to whether the levels of circulating ACs change with HFpEF or HF of non-ischemic etiology. Further studies of AC profiles in various HF phenotypes are needed to continue the search for new approaches to targeted therapy of rapidly spreading pathology.Limitations of our study included insufficient study power, different volumes of comparable samples, and the identification of plasma ACs in patients with comorbidities and multidrug therapy, which together may influence plasma metabolite levels. An improved epidemiologic design of follow-up studies, comparable samples of sufficient size, and a targeting study of CMC metabolites in human cardiac tissue may probably provide answers to outstanding questions on this topic.Heart failure of ischemic etiology remains a key problem in cardiology, and episodes of decompensation and progressive course of the disease, as well as myocardial remodeling—a significant burden for patients. At the same time, there is no doubt about the reversibility of cardiac remodeling and slowing of CHF progression with adequate drug therapy. According to the results of the study, despite the excess of carnitine levels, in patients with CHF of ischemic etiology and LVEF < 50% due to accelerated beta-oxidation of lipids, there is a deficiency of carnitine derivates with medium and long chain lengths. However, our work has shown that AC levels are associated not so much with cardiac remodeling in pure form but with many factors determining the severity of the course of CHF—congestion in both circulatory circles and overload of the right heart. All these results may have clinical significance if future studies confirm similar associations with changes in the profile of carnitine and derivatives. This, in turn, may allow further evaluation of the effectiveness of carnitine derivative deficiency therapy.


Endothelial dysfunction has a significant role in the pathogenesis of cardiovascular events in patients with kidney dysfunction. The present study aimed to compare the level of endothelial dysfunction in patients with chronic kidney disease (CKD) and acute kidney injury (AKI) by brachial artery flow-mediated dilation (FMD) technique. Also, we sought to find whether this non-invasive technique may assist in accurately distinguishing the acute or chronic nature of kidney failure in patients presenting with uremia for the first time.Demographic and medical characteristics, and laboratory and renal ultrasonography data of the patients with AKI and CKD were collected and compared with a control group. Brachial artery FMD was measured using a Toshiba aplio 300 device with a 7.5 MHz linear probe.P<0.001), serum Hb , Na , BUN  and Cr  was reported.In a total of 175 patients with a mean (SD) age of 55.96(15.54) years, FMD% was significantly lower in the CKD and AKI patients compared to the control group (Mean±SD: 16.28%±10.52%), 16.28 %±4.35%, and 24.24±5.71, respectively, p<0.001). Among the different causes of AKI, contrast-induced nephropathy (10.78%±1.75%), volume depletion (14.87%±1.22%), and post-renal AKI (15.96%±1.54%) had the lowest levels of FMD. Also, a significant correlation between FMD and eGFR (r=0.26, Compared to the control group, CKD and AKI patients showed greater levels of endothelial dysfunction as evidenced by lower brachial artery FMD. However, the FMD technique did not appear to be a practical method in differentiating CKD and AKI in patients presenting with uremia for the first time. Patients with chronic kidney disease (CKD) demonstrate an increased risk of cardiovascular mortality and morbidity even at earlier stages . In spitBesides mutual risk factors between CKD and CVD such as aging, hypertension, diabetes mellitus, hyperlipidemia, and smoking, CKD-specific non-classical risk factors including inflammation, volume overload, anemia, uremic toxins, renin-angiotensin, and sympathetic nervous systems, and oxidative stress highly contribute to CVD progression patients suffering from CKD . A vast  Although many factors, such as inflammation-mediated changes in vascular smooth muscle cell function and structural changes like vascular calcification, can contribute to the development of vascular impairment in CKD, endothelial cells dysfunction, which is primarily measured as impaired vascular dilation, is one of the most common concerns . Endothe FMD is a non-invasive technique that serves as a marker for an underlying atherosclerosis risk. After blocking the brachial artery for 5 minutes, the secretion of nitric oxide is stimulated, leading to dilation of the artery , 15. NotIn clinical practice, accurately diagnosing the acute or chronic nature of kidney failure in patients presenting with uremia for the first time is commonly required, particularly in developing regions without a good medical record system. In this regard, differentiating acute from chronic renal failure might be challenging when patients present with uremia and whose kidney function has been unclear for three months earlier . Given tStudy Protocol: The present cross-sectional study was conducted on patients with AKI and CKD referred to an outpatient clinic in Razi Hospital, Iran, in 2020. Patients with AKI and CKD were included and classified into two separate groups of AKI and CKD and were compared with the third group of patients with normal blood Cr level (control group) who did not have any history of kidney disease. Patients with the presence of either kidney damage or decreased kidney function for 3 months, were included in the CKD group irrespective of cause , laboratory information, and kidney ultrasonography data were collected from the patients' files. All ultrasound assessments were carried out by the radiologist of the team, blinded to the patients' clinical history. Patients were requested to abstain from caffeine, alcohol, vitamin supplementation consumption, and doing exercise for at least 10 hours before testing. Upon arrival, fasting participants laid down and rested in a supine position for 15 minutes in a temperature-controlled quiet room. Patients' blood pressure was measured using a mercury sphygmomanometer which was fit to the individual arm (80% of the diameter and 2/3 of the arm's length). Brachial artery FMD was measured non-invasively according to the standard protocol , median (range), or frequency (percent) statistics were used to describe the data. The normal distribution of the quantitative data was assessed using the Q-Q plot or Shapiro-Wilk test. To compare the measured variables in the studied groups according to the normality of the distribution of variables and homogeneity of variances, one-way analysis of variance (ANOVA), multiple comparison test (Turkey) or Welch test, and non-parametric tests  were used. To compare FMD in terms of quantitative and qualitative variables, Pearson correlation, independent t-test, and ANOVA test were applied. A p-value of less than 0.05 was considered significant. All data were analyzed using IBM SPSS 26 Version.A total of 175 patients with a mean (SD) age of 55.96(15.54) were studied (range: 14-88), of whom 125 patients were assigned to the CKD group (each stage of CKD=25 patients), 25 to the AKI group and 25 patients were studied as the control subjects. In total, 50.8% of the studied population were females. p<0.001). So, FMD in the control group was significantly higher than CKD and AKI patients . Also, when comparing every two groups, a significant difference was found in the mean FMD of the control group compared to the AKI (P=0.006) and CKD subjects (P= 0.001). However, no statistically significant differences regarding the mean of FMD between the CKD and AKI groups were observed (P=0.969). According to age subgroup analysis, in the group of patients < 45 years old, the mean of FMD in the control group  was significantly higher than AKI (n=4. Mean SD: 19.072.5) and CKD subjects . (p <0.001). Also, in the group of patients older than 45 years, the mean of FMD percentile in the control group  was found to be significantly higher than AKI (n=21. Mean SD: 15.744.45) and CKD patients . (p<0.017). In addition, in the comparison of FMD percentile between males and females, no differences were found (P=0.43). P=0.013, r=0.19, P=0.011, respectively). Also, serum urea  and creatinine  showed a weak negative correlation with FMD. Regarding the mean of FMD in stages of CKD, we classified CKD patients into two groups of GFR<30 and GFR≥30. Although FMD level was higher in patients with GFR≥30 (Mean±SD:19.36%±22.20%) compared to the group of patients with GFR lower than 30 (Mean± SD: 14.49%± 10.51%), the difference did not appear to be statistically significant between the two groups (P=0.61). Albeit, in the correlation analysis, a significant positive correlation between FMD percentile and eGFR was reported .P=0.012, P=0.02). Among AKI group, the mean of FMD with respect to the different causes of AKI  showed that the lowest level of FMD was seen in contrasted induced nephropathy (FMD percentile mean± SD: 10.78%±1.75%), volume depletion (FMD percentile mean± SD: 14.87%±1.22%), and post-renal AKI (FMD percentile mean± SD: 15.96%±1.54%), respectively. When comparing the FMD level between groups of patients having the traditional risk factors for CVD and those without CV risk or any comorbidities, except for individuals suffering from concurrent hypertension and CHF that had significantly lower FMD level compared with others, no significant differences were detected among those individuals with CV risk factors or comorbidities and those with no known underlying diseases . Also, iTo the best of our knowledge, this is the first study investigating and comparing endothelial dysfunction measured by FMD in 3 groups of CKD, AKI, and normal kidney function patients to survey whether FMD measurement could be considered as a valuable tool in further differentiation of these prevalent disorders and to predict the CVD prognosis of AKI and CKD patients.The present study showed that the mean of brachial artery FMD, which is representative of arterial vasodilation impairment, differed significantly between the CKD and AKI patients compared with the controls. So, CKD patients had the lowest mean of FMD percentile, suggesting that patients with CKD had more profound vascular dysfunction compared to the AKI and control groups; however, there was not found any differences in the mean of FMD percentile between the AKI and CKD groups. In the same vein, in a previous investigation, Tal Kopel et al. demonstrated that vascular function was impaired in patients with advanced chronic kidney dysfunction compared with individuals with no overt vascular disease. Also, SIn a case-control study in 2015, Ito et al. who aimed to determine the usefulness of FMD in CVD prognosis reported that FMD had a significant positive correlation with estimated glomerular filtration rate in diabetic patients with concurrent CHF -24. FMD In this study, the mean of brachial artery FMD in AKI patients was found to be reduced compared to the control group. Significant evidence exists that endothelial dysfunction is important to the etiology of acute renal damage. Also, acute kidney injury is associated with alterations in a vascular tone that contribute to an overall reduction in GFR . In thisWith regard to the mean of brachial artery FMD in different stages of the CKD severity, in the present study, although a negative correlation between serum Cr and BUN with the percentage of FMD was reported, with increasing CKD severity based on GFR (30 ≤GFR > 30), no significant decrease in the percentage of FMD was observed. Previous studies on FMD evaluation in different grades of CKD showed contrasting results. Similar to our finding, in the study by Thambyrajah et al., there was no significant difference in FMD between lower and upper quartiles of GFR in CKD patients . HoweverThe findings of this study have to be seen in the light of some limitations—first, the relatively small sample size of the study could underestimate the differences between studied groups. Second, the cross-sectional nature of the investigation inhibits inferences about causality. Also, our control subjects’ exclusion criteria for impaired kidney function were based on blood Cr rather than eGFR, and the control group may have included some people with reduced eGFR, which could have led to an underestimation of differences between kidney failure and control groups.In the present study, CKD and AKI patients were reported to have higher levels of vascular endothelial dysfunction, as evidenced by decreased brachial artery FMD compared to the control group. Despite low FMD in CKD patients, endothelial function was impaired equally in CKD subjects with and without traditional CV risk factors. Finally, although the FMD technique did not appear to be practical in differentiating CKD and AKI in the study subjects, it could be considered a helpful method in differentiating the causes of AKI by reporting the level of endothelial impairment.


The incidence of DCI was 5 out of 6 in Class 1 and 1 out of 13 in Class 2 (p < 0.001). These results suggest that the acute (<90 min) DCS-measured CBF response to IT nicardipine is associated with intermediate-term (up to 3 weeks) development of DCI.One of the common complications of non-traumatic subarachnoid hemorrhage (SAH) is delayed cerebral ischemia (DCI). Intrathecal (IT) administration of nicardipine, a calcium channel blocker (CCB), upon detection of large-artery cerebral vasospasm holds promise as a treatment that reduces the incidence of DCI. In this observational study, we prospectively employed a non-invasive optical modality called diffuse correlation spectroscopy (DCS) to quantify the acute microvascular cerebral blood flow (CBF) response to IT nicardipine (up to 90 min) in 20 patients with medium-high grade non-traumatic SAH. On average, CBF increased significantly with time post-administration. However, the CBF response was heterogeneous across subjects. A latent class mixture model was able to classify 19 out of 20 patients into two distinct classes of CBF response: patients in Class 1 ( Subarachnoid hemorrhage (SAH) is an uncommon cause of stroke that disproportionately contributes to increased mortality and morbidity. Globally, SAH affects ~8:100,000 people annually, with a mortality rate of ~30% . One of Calcium channel blockers (CCBs), which act on smooth muscle cells to dilate the vasculature, have been long investigated for their potential role in the treatment of large-artery vasospasm and the prevention of DCI. Indeed, the only guideline-recommended treatment for the prevention of DCI is the oral administration of dihydropyridine CCB nimodipine . InteresRecent data suggest that the intrathecal (IT) delivery of the CCB nicardipine may have a role in a reactive (rather than a preventative) treatment approach to address cerebral vasospasm and avoid DCI . This apvia pericytes regulating capillary size)  , 21, IT ry size) , 21. Furry size) , 13 and ®) have the inherent disadvantage of their invasive nature. Other indirect measures of microvascular flow, like non-invasive near-infrared spectroscopy measurements of hemoglobin oxygen saturation, are poor surrogates of CBF , positron emission tomography (PET), and/or computed tomography (CT) can quantify microvascular CBF, the cost, need for patient transport, and a lack of continuous monitoring limit their feasibility for capturing transient hemodynamic changes at the bedside. Brain tissue oxygen monitors , that is fit to simple analytical models, to extract a blood flow index (BFI) (2/s) differ from the traditional units of blood flow (ml/min/100 g), numerous validation studies demonstrate that BFI correlates with CBF measured by other “gold-standard” modalities   to measure regional microvascular CBF . In DCS,ex (BFI) . Althougg., MRI) , 25.Herein, we use DCS to test the hypothesis that IT nicardipine increases microvascular CBF from pre-administration levels in the absence of systemic changes. We also explore factors that are associated with the microvascular flow response, including patient characteristics, systemic hemodynamic response, baseline macrovascular flow velocities, and the development of DCI. Finally, we determine the correlation between microvascular CBF measured by DCS and macrovascular flow velocities measured by transcranial Doppler ultrasound (TCD).Adult patients with non-traumatic SAH in the neurocritical care unit at Emory University Hospital  who had an external ventricular drain (EVD) placed as part of their usual care were enrolled. This observational study was approved by the Emory University Institutional Review Board (IRB00107474). Written and informed consent was obtained prior to study initiation from all patients or their surrogates.Once consented, patients were included for monitoring only if (1) they developed large-artery vasospasm and (2) they were deemed to require IT nicardipine by the treating clinical teams  as part of their usual care. Diagnosis of large-artery vasospasm was confirmed by either TCD, CT angiography, or digital subtraction angiography, according to accepted definitions . TCD wasPatients received 4–5 mg of nicardipine mixed with 2 ml of NaCl 0.9% intrathecally through an existing EVD. After administration, the EVD was clamped for up to 30 min to promote the uptake of nicardipine by the local tissue microenvironment. Treatment dose, frequency, and length were determined by the attending physician and were not influenced by study enrollment.Patient outcome was defined by the presence or absence of DCI on the recent imaging available within 6 weeks from admission, according to the consensus criteria . SpecifiTo quantify the cerebral hemodynamic effects of IT nicardipine, continuous measurements of microvascular CBF were made with DCS during the first dose of IT nicardipine treatment.2 (τ), with a custom software correlator , eight photon-counting avalanche photodiodes , and a counter/timer data acquisition board  . Detecterrelator   and a head strap  spaced 2.5 cm from a bundle of seven 4.4 μm single-mode detection fibers  . All fibad strap , C. If lg2, at time, t, and delay time, τ, were fit for a blood flow index [BFI(t)] using the semi-infinite solution to the correlation diffusion equation >1.2 to increase sensitivity to the cerebral layer  over the 5-min baseline immediately prior to IT nicardipine administration.where delineator function , as well as any influence of intracranial pressure (ICP), on the cerebral hemodynamic response to IT nicardipine, we simultaneously captured blood pressure, HR, and ICP. As per standard clinical care, continuous arterial blood pressure was measured with a transducer in the radial artery leveled at the heart. Blood pressure was captured at 125 Hz with an analog-to-digital converter board (NI USB-6343) beginning 5 min before the first dose of IT nicardipine and continuing for up to 90 min post-administration. These data were time-synced with DCS measurements of CBF. Beat-to-beat values of systolic, diastolic, and mean blood pressure (MAP), as well as HR, were derived from the arterial blood pressure waveform in post-processing using the function  in MATLAIntracranial pressure was measured with a transducer in the EVD . In general, the EVD was opened to allow for spontaneous CSF drainage; thus, continuous ICP measurements were not available. However, the EVD was clamped for the first 30 min after the administration of IT nicardipine, as well as briefly before and after this 30-min window. Thus, ICP was stochastically captured by hand every 1–15 min for up to 90 min post-administration.MAP(t) = MAP(t)−MAPbaseline, where MAPbaseline is the temporal mean of MAP(t) over the 5-min baseline immediately prior to IT nicardipine administration.To quantify the effect of IT nicardipine on HR, MAP, and ICP, we estimated the change in each parameter from pre-administration levels, e.g., ΔTo investigate the relationship between microvascular and macrovascular perfusion, we compared the average DCS-measured BFI in 5 min prior to IT nicardipine administration to TCD measures of mean CBF velocity in the middle cerebral artery (MCA) and anterior cerebral artery (ACA). We focused our investigation on these vessels because our DCS sensor was positioned near the intersection of the MCA and ACA vascular territories . TCD dat2 was used to determine the goodness of fit. Furthermore, because we observed a heterogeneous response of rCBF to nicardipine, we used a latent class mixture model  based on the class with the highest posterior probability of class membership. We used chi-square and Wilcoxon rank sum tests to determine the differences between these empirically derived classes in age, sex, SAH grade, time to treatment initiation, the total number of IT nicardipine doses, intracranial and mean arterial pressure pre-administration, TCD velocities pre-administration, and incidence of DCI.To test our hypothesis that IT nicardipine increases microvascular CBF in the absence of systemic changes, we first graphically explored rCBF, MAP, HR, and ICP as a function of time after nicardipine administration. Data were downsampled to 10-min intervals to aid in visualization. Next, a linear mixed-effects model was applied to the downsampled data to determine significant trends in each measured variable with time, where we accounted for repeated measures within participants . This model satisfies the assumptions of normality. For the outcomes MAP, HR, and ICP, we modeled subject-specific intercepts and slopes. For outcomes that were relative to time zero , we modeled subject-specific slopes. The model Rre model  (LCMM) trs, was used to assess the extent to which a linear model explains the variability in the relationship between BFIbaseline and mean blood flow velocities in the MCA and ACA.To determine the relationship between microvascular CBF measured with DCS and macrovascular CBF velocity measured with TCD, Spearman's rank coefficient, rproject.org); all other analyses were performed in MATLAB. Statistical significance was assessed at the 0.05 level.Data are reported as mean ± standard deviation unless otherwise stated. LCMM analysis was performed with the LCMM package in R , failure to properly secure the DCS sensor on the forehead (n = 3), or co-administration of oral nimodipine at the time of DCS monitoring that induced confounding effects on CBF (n = 1). The average duration of DCS monitoring post-nicardipine was 82.7 ± 23.2 min.Between 1 April 2019 and 31 October 2021, 57 patients with non-traumatic SAH  admitted to the neurocritical care unit at Emory University Hospital consented. Of 57 patients, 37 developed clinically significant large-artery vasospasm that required treatment with IT nicardipine, as determined by the treating-attending physician. The CBF response to the first dose of IT nicardipine was monitored in 27 out of 37; the remaining 10 were excluded due to the availability of the research-based DCS device. Of those 27 monitored with DCS, 20 (74%) were included in our final analysis; the remaining 7 datasets were excluded due to measurement duration of <15 min. Of these seven discarded datasets, premature discontinuation was caused by patient discomfort related to IT administration and EVD clamping , with a mean ± standard deviation age of 48.5 ± 10.1 years . Aneurysp > 0.05, p > 0.05); ICP remained unchanged from IT nicardipine administration during the monitoring session .The average MAP prior to IT nicardipine administration was 103 ± 16 mmHg; the average HR was 80 ± 14 bpm. After administration, no significant trends with time were observed for MAP or HR (both p < 0.001), although appreciable response heterogeneity was noted across subjects . Patients in Class 1 were mostly female  and tended to have a higher pretreatment MCA velocity in the hemisphere of DCI monitoring . Most strikingly, the frequency of DCI was significantly different between classes (p < 0.001); 5 out of 6 subjects in Class 1 had DCI, 4 of whom developed new DCI, despite treatment with IT nicardipine, on the recent imaging available up to 6 weeks post-bleed, and 1 of whom started with DCI prior to nicardipine, while only 1 out of 13 subjects in Class 2 had DCI  . Average pretreatment MCA and ACA maximal mean blood flow velocities were 132.3 ± 34.2 cm/s and 98.9 ± 28.5 cm/s, respectively. In this subset of patients, we observed a significant positive correlation between mean resting-state blood flow velocity in the MCA and baseline, pretreatment BFI measured by DCS ( 0.0014) . A similHere, we used DCS to quantify the microvascular CBF response to IT nicardipine administration in SAH patients with large-artery cerebral vasospasm. On average, microvascular CBF increased over 90 min of monitoring. This CBF increase was observed in the absence of systemic changes in blood pressure or HR, suggesting that the cerebral hemodynamic response is likely due to a local drug effect rather than systemic influences and further strengthening the plausibility of microvascular effects on top of the macrovascular effects, as previously reported , 13. Howp = 0.02, Several possible mechanisms may explain the lack of CBF response to nicardipine in the Class 1 subset. MCA velocity was higher in Class 1 compared to Class 2 (p = 0.082). Of note, the sensor was positioned over the watershed area between the ACA and MCA territories. This positive correlation between resting-state microvascular and macrovascular flow is seen in healthy adults, including by DCS vs. TCD  DCS monitoring sessions were discarded from the analysis. While this incidence is appreciable, we anticipate a significantly lower discard rate with continued future enrollment as we continually make improvements to the research device that enhances SNR. Third, based on previous reports of a short half-life of nicardipine , 45, we In summary, we use DCS to characterize the cerebral hemodynamic response to IT nicardipine treatment in patients with large-artery cerebral vasospasm after SAH. We observed the following two distinct classes of microvascular CBF response: (1) minimal-to-no change and (2) a steady increase. We found that 83% of patients whose CBF failed to respond to nicardipine developed DCI, while 8% of patients whose CBF increased developed DCI. These results suggest that the acute (< 90 min) DCS-measured CBF response to IT nicardipine is associated with intermediate-term (up to 3 weeks) development of DCI. If these findings are corroborated with future, larger-scale prospective, randomized control trials, they suggest that DCS, alongside TCD, may provide a valuable biomarker to better inform clinical decisions, diminish the development of DCI, and improve functional outcomes following SAH.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 Emory University Institutional Review Board (IRB00107474). The patients/participants provided their written informed consent to participate in this study.Data acquisition: ES, KC, AL, SL, and ZF. Data analysis: ES. Data interpretation, discussion, and writing—reviewing and editing: ES, CM, FA, OBS, PK, OS, and EB. Statistical analysis and writing—original draft preparation: ES, CM, OS, and EB. Supervision: OS and EB. All authors have read and agreed to the published version of the manuscript.


CKD experiences a decrease in 24-h UCaE as early as stage 1, with a significant decline in stage 4. CKD and non-CKD patients with lower UCaE levels are at an increased risk of renal decline, regardless of other variables.This study investigated the impact of 24-h urinary calcium excretion (UCaE) on renal function decline in hospitalized patients with and without chronic kidney disease (CKD). This study enrolled 3815 CKD patients in stages 1–4 and 1133 non-CKD patients admitted to the First Center of the Chinese PLA General Hospital between January 2014 and July 2022. The primary outcome for CKD patients was a composite of CKD progression, defined as a 40% decline in estimated glomerular filtration rate (eGFR) or end-stage kidney disease. Annual eGFR change was the secondary outcome. For non-CKD patients, the primary outcome was an eGFR decline of ≥20% or CKD incidence, while annual eGFR change was the secondary outcome. The association between UCaE and kidney function decline was assessed using Cox proportional hazards and generalized linear models. Primary outcomes were observed in 813 CKD patients and 109 non-CKD patients over a median follow-up of 3.0 and 4.1 years, respectively. For CKD patients, every 1-mmol/d increase in UCaE was associated with a 15% decreased risk of CKD progression. The hazard ratio (HR) was 0.85, with a 95% confidence interval (CI) of 0.77–0.93. For non-CKD patients, the risk of renal function decline decreased by 11%. The multivariate models indicated that there was an annual decrease in eGFR in both CKD and non-CKD patients, with a reduction of 0.122 mL/min/1.73 m To account for missing data (missing rate < 6%), we used the random forest-based estimation method, which does not assume normality or require specification of the parametric model. Specifically, we utilized the ‘missForest’ package. To visualize the correlations between baseline 24-h UCaE and kidney function, we employed ‘ggridges’ and ‘ggplot2’.3 supplement, calcium-free phosphorus binders, calcitriol, and vitamin D supplement application. Other vitamin D receptor activators, calcimimetics, and bisphosphonate are rarely used in our medical center, so we did not conduct statistical analysis of these drugs. Non-CKD models were adjusted for age, sex, BMI, MAP, DM, diuretics, serum calcium, eGFR, and 24-h proteinuria. In the current study, serum calcium was found to have a stronger association with UCaE than albumin-corrected calcium. Therefore, serum calcium was used as the co-variable in this study  when using the ‘cox.zph’ function in the ‘survival’ R package. This assumption was, however, demonstrated in non-CKD patients. To investigate the risk of outcomes based on UCaE in CKD patients, time-dependent Cox regression models were utilized. The multivariate adjustment strategies were designed to account for potential confounding factors between UCaE and decreased renal function based on clinical plausibility. Models of CKD were adjusted for the following baseline covariates: age, sex, current smoking habit, body mass index (BMI), mean arterial pressure (MAP), CKD etiology, DM, CVD, eGFR, 24-h proteinuria, hemoglobin, serum albumin, serum calcium, serum phosphorus, alkaline phosphatase, total cholesterol, triglyceride, urinary sodium excretion, urine potential of hydrogen, angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB), glucocorticoids, diuretics, statins, CaCOis study .p was tested using Jonckheere’s trend method.Linear mixed models were used to estimate the decline slope of eGFR using all eGFR values prior to the initiation of renal replacement therapy. The models included random intercept and random slope for each individual. The generalized linear regression model was utilized, with the annual eGFR change analyzed as either a continuous or binary dependent variable. Follow-up time was stratified to describe the eGFR decline slope in the four UCaE groups. The most recent creatinine recorded minus baseline time was used to calculate follow-up time. 2), HTN, DM, and diuretic usage to explore the relationship between UCaE and composite outcomes (primary and secondary outcomes). All statistical tests were 2-sided; a p-value < 0.05 was considered statistically significant. R software, version 4.1.3, was used for the analyses .To test the linearity assumption between UCaE and eGFR decline, we utilized restricted cubic splines through the ‘rms’ package. Specifically, we used 4 knots located at the 5th, 35th, 65th, and 95th percentiles in our models. Additionally, we conducted subgroup analyses and expressed the results through a forest plot using the ‘forestploter’ package. We categorized the patients by age (≥60 or <60 years), sex, BMI (≥25 or <25 kg/m2) than in non-CKD patients (94.7 mL/min/1.73 m2). Additionally, the UCaE was lower in CKD patients (1.7 mmol/d) compared with non-CKD patients (5.0 mmol/d). The median 24-h urine volume was slightly lower in CKD patients (2.0 L/d) compared with non-CKD patients (2.1 L/d). p < 0.001, The ridge map a indicatUntil July 2022, 3815 CKD and 1133 non-CKD patients were followed up for 13,455 and 4856 person-years, respectively. Of the CKD patients, 21.3%  developed the primary outcome, while 9.6%  of non-CKD patients had a sustained change in kidney function.p < 0.0001 and p = 0.0045, respectively)  and a p-value of 0.001.The Kaplan–Meier analysis indicated that patients with the lowest calcium excretion had a significantly lower probability of not experiencing a decline in renal function compared with those with the highest excretion, regardless of whether they had CKD or not  years. p < 0.001). The study found that for every 1-mmol/d increase in UCaE, the annual eGFR decline decreased by 0.122 mL/min/1.73 m2/year. Additionally, when the dependent variable was binomial, the risk of RKFD (≥5 mL/min/1.73 m2/year) was reduced by 10% for each 1-mmol/d increase in UCaE, with an odds ratio of 0.903 (95% CI 0.843–0.969). In non-CKD patients, those with the highest quartile of UCaE had a 60.7% lower risk of rapid eGFR decline than those in the lowest quartile . For each 1-mmol/d increase in UCaE, the risk of eGFR decline in non-CKD patients decreased by 0.046 mL/min/1.73 m2/year.During a median eGFR follow-up of 3.22 (1.93–5.19) years, the study observed a decline rate of at least 5 mL/min/1.73 mp value = 0.478; p value for UCaE < 0.001) and non-CKD patients . When OR was 1, UCaE in CKD and non-CKD patients was 1.73 and 4.93 mmol/d, respectively.p = 0.064, p = 0.019), had a BMI < 25 kg/m2 (p = 0.003), did not have hypertension (p = 0.020), diabetes mellitus (p = 0.017), or used diuretics (p = 0.003), there was a significant association between UCaE and the decline in kidney function.In the subgroup analysis of CKD patients, a significant association was found between 24-h UCaE and composite outcomes, except in those with normal blood pressure (p < 0.001).Lower UCaE was found to be significantly associated with a faster annual decline in eGFR in patients with CKD, irrespective of the duration of follow-up, as shown in The study found that the 24-h UCaE in patients with CKD began to decline as early as stage 1 and was severely reduced in stage 4. Patients with early-to-moderate CKD had a UCaE of 1.73 mmol/d, almost one-third of the UCaE in patients without CKD. The study also found that an increase in 24-h UCaE was linked to a lower risk of CKD or CKD progression during the follow-up, regardless of whether the patients had CKD. These associations remained stable even after adjusting for important co-variables for CKD. Sensitivity analyses determined the robustness of these findings. In addition, there was a significant linear trend between UCaE and prognoses. These results suggest that a lower UCaE, rather than a higher one, is a feature and predictor of CKD progression.2D3 leading to inadequate absorption of calcium from the gastrointestinal tract and increased PTH stimulating enhanced renal tubule calcium reabsorption has been disproven by studies on vitamin D supplementation or decreased PTH, which have failed to alter UCaE in humans [2D3, recent studies have found that FGF-23 and Klotho are also linked to UCaE. CKD patients with fasting normophosphatemia and normocalcemia have been found to have higher levels of FGF-23 compared to healthy subjects, but a lower fractional excretion of calcium [2D3. Decreased levels of vitamin D can impair the absorption of calcium in the intestines and its excretion in urine. In addition, PTH, 1,25(OH)2D3, FGF-23, and Klotho can stimulate TRPV5 activity, leading to increased reabsorption of calcium in the kidneys. This mechanism will be further discussed below.The initial theory that reduced UCaE during the progression of kidney disease was due to decreased renal production of 1,25(OH)n humans ,17,18. W calcium . FGF-23 2D3 remained unchanged [UCaE is significantly impacted by dietary habits, particularly animal protein, potassium alkali salts, and sodium intake. A clinical study conducted on premenopausal women demonstrated that a decrease in dietary protein intake from 1.1 g/kg to 0.8 g/kg while maintaining similar levels of calcium, phosphorus, and sodium resulted in a 32% reduction in UCaE. However, the levels of serum calcium, PTH, and 1,25(OH)nchanged . Consuminchanged ,22. Undenchanged . Patientnchanged . In norm2+ via claudin 16 (CLDN16) and CLDN19, which form heterodimeric paracellular divalent cation channels. The paracellular transport of cations is driven by the lumen-positive voltage generated by Na-K-2Cl cotransporter 2 (NKCC2) activity and luminal K+-recycling via the renal outer medullary potassium channel (ROMK) [2D3 enhances the expression of TRPV5 through increased binding of the vitamin D receptor to response elements in the gene promoters to increase respective mRNA concentrations of TRPV5 [Changes in the expression of calcium channels, calcium-binding proteins, calcium pumps, and exchangers in tubules may directly affect UCaE. Calcium reabsorption in the proximal convoluted tubule occurs in parallel with that of sodium and water, mainly through passive paracellular diffusion and solvent drag. The thick ascending limb (TAL) of the loop of Henle are the site of paracellular reabsorption of Cal (ROMK) . CLDN14 l (ROMK) . Kidney-l (ROMK) . In addil (ROMK)  also sugl (ROMK) . The firl (ROMK) . 1,25 and calbindin-D28K mRNA abundance, causing calcium accumulation in epithelial cells which may lead to a toxic concentration and cause cell damage. Wei Y et al. [2+ influx to promote chondrocyte apoptosis in osteoarthritis. However, this apoptosis in tubular cells has yet to be proved. Further research is needed to determine whether increased urinary calcium reabsorption after activation of TRPV5 contributes to renal loss.Kidney damage resulting in hypocalciuria has also been noted in animal models ,43,44. Istration . EndotoxDespite remarkable progress in UCaE, the complex mechanism of calcium metabolism and its effects on renal failure remain unclear. Whether reduced UCaE in CKD or CKD higher-risk individuals are in a state of positive calcium balance or reduced net calcium absorption, the mechanism for long-term renal impairment warrants further investigation. There are some limitations to be aware of. First, although the participants in this study broadly represented hospitalized patients with and without CKD regarding age, eGFR, and UCaE, we cannot rule out inherent bias due to the recruitment process, which specifically targeted patients with information on repeated visits. Moreover, the study population may have been selected differently from patients not meeting the inclusion criteria. Second, because PTH, vitamin D, and FGF-23 were not routinely checked in hospitals until the late stages of CKD, we did not have enough information on calcium-regulatory hormones. Despite these, we have adjusted the variables highly correlated with the above hormones, such as serum calcium, phosphorous, and eGFR. In addition, Taylor J et al.  reportedIn patients with CKD, the 24-h UCaE levels began to decline as early as stage 1 and showed a significant decrease in stage 4 when compared with non-CKD patients. Furthermore, the risk of renal decline was found to be higher in both CKD and non-CKD patients with lower 24-h UCaE levels, regardless of other variables.


The MBOAT7 rs641738 (C>T) variant has demonstrated an association with non-alcoholic fatty liver disease (NAFLD) in both adult and pediatric patients, while few studies have been conducted in elderly populations. Hence, a case–control study was undertaken to assess their correlation in elderly residents in a Beijing community.A total of 1,287 participants were included. Medical history, abdominal ultrasound, and laboratory tests were recorded. Liver fat content and fibrosis stage were detected by Fibroscan. Genotyping of genomic DNA was performed using the 96.96 genotyping integrated fluidics circuit.Of the recruited subjects, 638 subjects (56.60%) had NAFLD, and 398 subjects (35.28%) had atherosclerotic cardiovascular disease (ASCVD). T allele carriage was associated with higher ALT (p=0.005) and significant fibrosis in male NAFLD patients (p=0.005) compared to CC genotype. TT genotype was associated with reduced risk of metabolic syndrome  and type 2 diabetes  in NAFLD population when compared to the CC genotype. In addition, TT genotype was also associated with reduced risk of ASCVD  and less obesity  in the whole population.MBOAT7 rs641738 (C>T) variant was associated with fibrosis in male NAFLD patients. The variant also reduced risk of metabolic traits and type 2 diabetes in NAFLD and ASCVD risk in Chinese elders. Given that the prevalence of non-alcoholic fatty liver disease (NAFLD) covers higher than 25% of the population, it has become the most common chronic liver disease worldwide , 2. The Membrane bound O-acyltransferase domain containing 7 (MBOAT7) is a multi-transmembrane protein and an important member of the “Lands’ Cycle” of membrane phosphatidyl chain remodeling . In 2015The clinical significance of MBOAT7 rs641738 C>T variant on NAFLD has been evaluated in various races and age groups; however, its impact on the elderly population remained unclear. In the current study, the relationship between MBOAT7 rs641738 variant with the risk of NAFLD and hepatic fibrosis in an elderly population. Meanwhile, the correlation of the rs641738 T allele with metabolic traits and ASCVD was also analyzed. Furthermore, we explored the effect of rs641738 variant on serum ANGPTL3 level in order to explain the link between MBOAT7 with ASCVD.Elder citizens in Beijing Mentougou community who participated in annual free physical examination was recruited from 1/11/2020 to 30/9/2021. The study protocol was approved by the individual Ethics Review Committee of Beijing Youan Hospital . All study subjects provided written informed consent.The study was carried out in Menkuang Hospital, Beijing Jingmei Group General Hospital. The inclusion criteria were (1) patients with fatty liver diagnosed by ultrasound and (2) who signed informed consent. The exclusion criteria were (1) excessive alcohol consumption (≥30g/day in men or 20 g/day in women); (2) lack of medical history or lab results; (3) inability to obtain reliable abdominal ultrasound results due to specific reasons, such as intestinal gas interference; (4) malignant tumors, HIV, and other serious diseases that may affect the nutritional status or organ function; and (5) comorbidity with other liver diseases, such as viral hepatitis and autoimmune hepatitis. The controlled groups were residents without fatty liver examined by ultrasound.Usually, 10–20 residents took part in the routine examination every morning. If a patient is diagnosed with fatty liver by ultrasound, he/she is transferred to an isolated room to be recruited and further examined. The next resident without fatty liver following the previous NAFLD patients was recruited as control. Eventually, 1,287 residents were examined, and 1,128 residents were recruited in the study Figure 1The routine free examination included abdomen ultrasound examination, routine blood test, routine urine test, liver function, renal function, fasting blood sugar (FBS), glycosylated hemoglobin (HbA1c), and lipid profile. Extra blood sample was obtained and tested for hypersensitive C-reactive protein (hs-CRP) and fasting insulin (FINS) in addition to the routine examination. All laboratory tests were carried out in the central lab of Menkuang Hospital or Beijing Jingmei Group General Hospital.Two trained investigators carried out the whole study. They were responsible for recruiting patients, performing anthropometric examinations, and determining liver fat content and liver stiffness (LSM) by FibroScan 502 touch device . The demographic indicators and medical histories were extracted from the community health records and checked again on site.Fatty liver was diagnosed by ultrasound, and participants were divided into two groups, NAFLD and non NAFLD. Body mass index (BMI) was calculated as weight (kg) divided by the square of the height (m). Waist-to-hip ratio (WHR) was calculated as waist circumference divided by hip circumference. Homeostasis model assessment insulin resistant (HOMA-IR) was calculated as (FINS (pmol/L) × FBS (mmol/L))/22.5. Additionally, non-invasive liver fibrosis score formulas fibrosis-4 index (FIB-4)  and AST-2 . In brief, hypertension is diagnosed when systolic blood pressure ≥130mmHg or diastolic blood pressure ≥85mmHg or when taking antihypertensive drugs. T2DM is diagnosed when FBS ≥7.0 mmol/L, HbA1c ≥ 6.5%, OGTT 2 h blood sugar ≥ 11.1mmo/L, or taking hypoglycemic drugs. MetS was defined in accordance with the criteria, which was based on the presence of at least three of the following components: (1) elevated waist circumference (≥90cm for men or ≥80 cm for women); (2) elevated triglycerides (≥1.70 mmol/L) or drug treatment for elevated triglycerides; (3) reduced HDL-C (<1.0 mmol/L for men and<1.3 mmol/L for women) or drug treatment to reduce HDL-C; (4) elevated blood pressure (≥ 130/85 mmHg) or drug treatment for hypertension; and (5) elevated FBS (≥5.6 mmol/L) or drug treatment for elevated glucose. ASCVD w2 .Genomic DNA was extracted from the patient’s blood specimens . DNA concentration and quality were determined by spectrophotometry  and standardized to approximately 50 ng/ml before genotyping. Next, genomic DNA has genotyped with the usage of a 96.96 genotyping integrated fluidics circuit (IFC) with customized SNP-type assays on the Juno™ system  and quantification on the Biomark™  in accordance with the manufacturers’ instructions. All genotyping was blinded to clinical variables. The Fluidigm SNP Genotyping Analysis program, version 4.5.1, was used to analyze the data .Serum ANGPTL3 levels were determined in 120 patients who were randomly selected from subjects with the three genotypes, each group containing 40 patients. ANGPTL3 was quantified by ELISA according to the instructions . The intra- and inter-assay coefficients of variation of ANPTL3 were<8% and 10%, respectively.2 test was also used if indicated. All comparison tests between the two groups were two-tailed with a 95% confidence interval. Univariate and multivariate logistic regression analyses were performed to assess the independent predictors for NAFLD, ASCVD, hypertension, and MetS. The statistical significance was set at p-value<0.05. The Statistical Package for Social Science for Windows, version 19.0 , GraphPad Prism (version 2.0), and R language (version 3.4.3) were used for data analyses.Clinical characteristics were compared between the rs641738 T allele carriage and non-T carriage or among the three genotypes. Descriptive values were expressed as mean ± standard deviation (SD) or medians and interquartile ranges (IQRs) depending on the distribution of the data. Student’s t-test or Mann–Whitney–Wilcoxon test was used to assess continuous variables according to value distributions. Frequencies and percentages were used to summarize categorical variables, and data were compared by using Pearson’s chi-square when appropriate. The χA total of 1,128 subjects were enrolled in the study. Characteristics of the NAFLD and non-NAFLD populations are provided in Among the NAFLD patients, carriage of the rs641738 C >T polymorphism accounted for 47.81% (305/638). These patients presented significantly higher TC, HDL, LDL, and FINS than non-T carriage p<0.05, Table 2.The demographic and clinical characteristics of NAFLD patients according to C→T genotypes are listed in Gender is an important modified factor of NAFLD. Gender differences in clinical characteristics are listed in To further investigate this observation, we compared the characters according to the genotypes in male and female patients separately. In male NAFLD patients, T allele carriage was associated with significantly higher levels of ALT, FINS, WHR, and significant fibrosis than non-T allele carriage , thereby producing the main molecular species of phosphatidylinositol (PI) in the cell membrane . Thangapep mouse . The treep mouse . Furtherep mouse . The aboep mouse , 48. Theep mouse . Howeverep mouse . Gender In our study, the association of the rs641738 variant with higher serum HDL was found but not TC and LDL-C. In a Spanish study, MBOAT7 variants were found to be associated with higher TC, LDL, and TG . Data fr2 cholesterol and protein levels in obese individuals by comparing HDL concentrations in 68 age-matched obese individuals with controls  can be found below: The study protocol was approved by the individual Ethics Review Committee of Beijing Youan Hospital . The patients/participants provided their written informed consent to participate in this study.XX, HX and XL participated in the acquisition, analysis, and interpretation of data; prepared the manuscript; and had equal contribution to the study. SZ, GW, and LZ reviewed the literature and built the databases. ZC, and LQ contributed to the analysis and interpretation of the data and provided important scientific input. XD and YL statistically analyzed the data and wrote the first draft of the manuscript. JZ and YZ supervised the whole study. All authors collaboratively discussed key decisions throughout the course of the review, provided critical feedback on preliminary manuscript and interpretation of results. All authors contributed to the article and approved the submitted version.


Kidney fibrosis is the hallmark of chronic kidney disease (CKD) and is characterized by an imbalanced extracellular matrix (ECM) remodeling. Collagen type III is one of the main ECM components of the interstitial matrix of the kidney. We hypothesized that measuring three biomarkers of collagen type III reflecting different aspects of this protein turnover  may provide different information about the fibrotic burden in patients with IgA nephropathy (IgAN). We examined a cohort of 134 patients with IgAN. The three collagen type III biomarkers were measured in serum (S) and in urine (U) samples taken on the same day before kidney biopsy was performed. Biopsies were evaluated for interstitial fibrosis and tubular atrophy, according to the Banff and MEST-C scores. S-PRO-C3 and S-C3C correlated with the degree of fibrosis in the biopsy, whereas U-C3M/Cr had an inverse correlation with fibrosis. U-C3M/Cr had the highest discrimination ability for advanced fibrosis, which was maintained after adjustment for the other collagen type III biomarkers, proteinuria, and serum creatinine. The data presented in this study indicate that measuring the different fragments of the same ECM protein and in different matrices provides a variety of information regarding pathological kidney tissue alterations in patients with IgAN. IgA nephropathy (IgAN) is the most common primary glomerulonephritis ,2 and ocThe two ECM biomarker assays C3M and C3C measure the degradation of collagen type III by targeting neo-epitope fragments generated by specific protease cleavage . The PRO-C3 biomarker assay measures collagen type III formation by targeting the pro-peptide secreted during protein maturation. The concept of ECM degradation and formation as well as the pathological value of measuring ECM protein turnover are reviewed elsewhere ,7. C3M aOther collagen biomarkers, including the collagen type VI assay PRO-C6 (measuring collagen type VI formation and levels of endotrophin), have previously been associated with the degree of histological fibrosis in kidney biopsies from the same group of IgAN patients . RecentlA total of 134 patients with biopsy-proven primary IgAN diagnosed at Charles University and General University Hospital in Prague, Czech Republic, were included in this study, and 10 healthy volunteers were enrolled as controls. All consecutive patients with IgAN diagnosed between 2011–2015, with a representative biopsy sample, available specimens in local biobank and who were willing to participate in this research study were included.For the IgAN patients, blood and urine samples were taken on the same day before kidney biopsy was performed. Blood and urine samples from the healthy controls were collected in the same hospital following the same procedures. Informed consent was obtained from all participants and the study was conducted in compliance with the Declaration of Helsinki principles.Clinical and laboratory data were collected or measured in the laboratories of the General University Hospital. The data included sex, age, serum creatinine (sCr), proteinuria (PU), and C-reactive protein (CRP)  as well as whether the IgAN patients had diabetes mellitus or/and hypertension. The eGFR levels were calculated using the chronic kidney disease epidemiology collaboration equation , and theUltrasound-guided kidney biopsies were collected, evaluated for the percentage level of fibrosis (continuous variable), and classified according to the MEST-C and Banff classification for interstitial fibrosis and tubular atrophy (as previously described ). The BaTM Creatinine kit (BioAssay Systems) and the levels of the collagen type III biomarkers measured in urine were normalized for urine creatinine .The collagen type III biomarkers, C3M, C3C, and PRO-C3, were measured in serum  and urine  from IgAN patients and healthy controls using competitive enzyme-linked immunosorbent assays . Monoclonal antibodies were used to target one of the sequences listed in 10-transformed data were used for parametric statistical analysis. Univariate and multivariate (with backwards elimination) linear regression analyses were performed with log10-transformed data to analyze the association of biomarkers with the level of fibrosis as a quantitative measure. Statistical analyses were performed using GraphPad Prism version 8.4.3  and MedCalc version 20.121 . p < 0.05 were considered significant.Spearman’s rank correlation was used to assess the association between clinical parameters and biomarker levels. The statistical differences between groups were analyzed with the Kruskal–Wallis test. Receiver operating characteristic (ROC) curve analysis was used to evaluate the discriminatory power of biomarkers for advanced fibrosis defined as a biopsy scored as ci3 (advanced fibrosis), according to the Banff score, from patients with a biopsy scored as ci0–ci2 (low–moderate fibrosis). The comparison of C-statistics was used to evaluate the superiority of the ROC curves. LogA total of 134 patients with IgAN and 10 healthy controls were included in this study. The IgAN patients and healthy controls were not significant different regarding age, but the healthy control group had a higher representation of females (we do not expect the difference in age representation to influence the results). The clinical characteristics are summarized in The serum levels of the collagen type III biomarkers seemed to increase in late-stage kidney disease, even though this was only significant for S-C3C and S-PRO-C3 C,E. Therp < 0.0001), S-C3C , and S-PRO-C3   B,D,F. U-< 0.001) B.p < 0.01–0.0001, p < 0.01, p < 0.05, The IgAN patients were stratified into groups based on two fibrosis evaluation schemes: the Banff score and the T-score from the MEST-C classification. U-C3M/Cr levels were significantly lower in patients with biopsies scored as ci2–ci3 compared to ci0, according to the Banff system (p < 0.0001) and S-C3C  were able to separate IgAN patients into advanced vs. low–moderate fibrosis groups. However, their discriminatory power was not superior to that of sCr  (The IgAN patients were divided into two groups based on the Banff score: low–moderate fibrosis (ci0–ci2) vs. advanced fibrosis (ci3). A total of 111 patients were included in the low–moderate fibrosis group and 22 patients in the advanced fibrosis group. U-C3M/Cr  .The association of the collagen type III biomarkers with the level of fibrosis on a continuous scale were compared to the biomarkers of kidney function sCr and PU and hypertension and diabetes. In the univariate models, sCr, U-C3M/Cr, S-C3C, U-C3C/Cr, and S-PRO-C3 were significantly associated with the level of fibrosis, whereas PU, S-C3M, U-PRO-C3/Cr, hypertension, and diabetes were not . U-C3M/Cpartial = 0.29, p<0.01) and U-C3M/Cr   from the univariate models in  = 0.01) .Kidney fibrosis is a hallmark of CKD and a strong predictor of progression to end-stage kidney disease . To undeIn our study, we showed that the three collagen type III biomarkers, measured in serum and in urine, had a unique association with the degree of fibrosis in kidneys as well as with other clinical parameters. All the biomarkers  were associated with kidney function (sCr or eGFR), with U-C3M presenting the strongest correlation. S-C3C and S-PRO-C3 had a positive correlation and U-C3M/Cr had an inverse correlation with the level of fibrosis. S-C3C and S-PRO-C3 were also associated with inflammation (CRP) but not with PU, whereas U-C3M/Cr had an inverse association with PU but was not related to inflammation. This could indicate that the association of urinary level of C3M with kidney function may reflect the fibrotic burden in the kidneys, while the increased levels of C3C and PRO-C3 in circulation are related to the inflammatory state.U-C3M/Cr was the ECM biomarker with the highest discrimination power for advanced fibrosis. It independently reflected the fibrotic burden after adjustment for markers of kidney functions. The fact that U-C3M/Cr and sCr were the only biomarkers retained in a final model for the fibrotic burden in biopsies from patients with IgAN may indicate that these markers are both strongly related to the fibrotic burden but describe different processes, and thus, U-C3M/Cr adds to the information provided by sCr. This will need to be evaluated in larger cohorts and in CKD patients with different etiologies.This presented study are limited by the lack of data for the expression of collagenases and their association with fibrosis in the kidney. This study is further limited by the relatively small number of IgAN patients and the fact that the association of the biomarkers with the degree of fibrosis was only investigated in patients with IgAN. The association of the biomarkers with the degree of fibrosis, especially U-C3M/Cr, needs to be confirmed in a larger IgAN cohort and in cohorts with other etiologies of CKD.The presented data indicate that measuring different fragments of the same ECM protein and in different matrices provide different information regarding pathological kidney tissue alterations in patients with IgAN. This highlights the importance of measuring the right epitope in different organs and diseases. Among the investigated biomarkers, U-C3M/Cr appears to be a promising non-invasive biomarker of fibrosis that could be used as a supplement to kidney biopsies.


IgAN as primary kidney disease and interval from transplantation to conception were associated with HIP . The 20-year graft survival or prevention of CKD stage 5 in group with IgAN was lower than that in the group with other primary disease (p < 0.01). KT recipients should be informed of the risk of HIP and possibility of long-term worsening of postpartum renal function.Pregnancy in kidney transplantation (KT) recipients has been challenging because of the high risk of maternal, fetal, and renal complications. Although patients with immunoglobulin A nephropathy (IgAN)-chronic kidney disease (CKD) are at a high risk for hypertension in pregnancy (HIP), the maternal risk in KT recipients with IgAN as the etiology remains unclear. We retrospectively reviewed the medical records of pregnant KT recipients who delivered at our hospital. The incidence of maternal and fetal complications and the impact on kidney allografts between the group with IgAN as the primary kidney disease and the group with other primary diseases were compared. The analysis included 73 pregnancies in 64 KT recipients. The IgAN group had a higher incidence of HIP than the non-IgAN group (69% vs. 40%,   Female patients with end-stage kidney disease (ESKD) are known to have lower fertility rates due to disruption of hypothalamic-gonadal axis . EarlierHowever, pregnancy in KT recipients remains challenging because it might severely affect graft kidney function, fetal development, and maternal health; in particular, the risk of deterioration of allograft function and/or occurrence of antibody-mediated rejection exists throughout pregnancy . MohammaImmunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis, which is one of the leading causes of ESKD in the younger generation. Therefore, IgAN would also be the common primary disease of ESKD for KT recipients , in partIn general, for pregnant women (non-KT patients), IgAN is considered as a risk factor for adverse outcomes. A systematic review by Piccoli et al. has revealed that the incidence of adverse pregnancy-related outcomes, including HIP or PE, was ten-fold higher in pregnancy with IgAN (non KT patients), than in control groups . In thisThis study was conducted to evaluate pregnancies in KT recipients and their impact on the mother, fetus, and graft function after delivery in our hospital. We focused on the difference in the incidence of maternal/fetal complications and the impact on kidney allograft, depending on the presence or absence of IgAN as primary kidney disease. We also examined the factors related to HIP in KT recipients.This retrospective cohort study examined post-KT pregnant women who were on regular prenatal care and delivered at our hospital from 1 January 2001 to 31 December 2019. This study, conducted at a single center , was approved by the Institutional Review Board of the Tokyo Women’s Medical University Hospital (#2022-0084). This study retrospectively collected data from the medical records; therefore, informed consent was waived by the Institutional Review Board of the Research Ethics Committee of the Faculty of Medicine of Tokyo Women’s Medical University Hospital. All methods of research procedures were performed in accordance with the Declaration of Helsinki. The exclusion criteria were as follows: 1) follow-up period from delivery of <3 years; 2) pregnancies resulting in birth at <22 weeks of gestation; 3) miscarriage; 4) abortion; and 5) stillbirth. Stillbirth was defined as the intrauterine death of a fetus at ≥22 weeks of gestation.The basic information of patients, pregnancy, and neonates  were collected from the patients’ medical records. Latent IgA deposition from donor was not considered IgAN as primary disease.Calcineurin inhibitors (tacrolimus or cyclosporine), mycophenolate mofetil (MMF) and prednisolone were used as maintenance immunosuppressants at our hospital. MMF was discontinued at least 6 weeks prior to the planned pregnancy and replaced with azathioprine (AZA), considering a risk of the teratogenicity. The date of preparation for pregnancy was defined as the date when MMF was discontinued or replaced with AZA on medical charts.Pregnancy data included the incidence of HIP, gestational diabetes , APGAR-score , and umbilical cord blood pH at delivery. The maternal indications for cesarean section include severe HIP, deterioration of kidney graft function, prolonged labor . The assay was also conducted according to the manufacturer’s instructions as previously described. Positive DSA was defined as a mean fluorescence intensity >1000.The Luminex single antigen beads assay  was used to detect de novo (either PE or GH), according to the ISSHP guidelines.This study compared the incidence of HIP between patients with IgAN as the primary kidney disease and those with other primary diseases. HIP is defined as chronic (predating pregnancy or diagnosed before 20 weeks of pregnancy) or 2) within 20 years postpartum. The occurrence and date of the first observed outcome postpartum were also investigated. For recipients who underwent twice deliveries, the duration from the first delivery was included in the analysis. Patient survival was examined at graft loss, the date when CKD stage 5 was detected, or the date of the last follow-up.The primary outcome was the composite of all-cause graft loss and chronic kidney disease (CKD) stage 5 . Continuous data were expressed as mean ± standard deviation or median (interquartile range). Student t-tests or Mann–Whitney U-tests were used to compare continuous variables. The chi-square test or Fisher’s exact test was used to compare the categorical variables. Univariate and multivariate logistic regression analyses were performed to examine significant factors associated with HIP. The Kaplan-Meier method and log-rank test were used to compare differences in graft survival or CKD stage 5 within 20 years postpartum between groups. A paired-samples t-test was used to compare kidney function at each point . Values for which p was less than 0.05 were inferred as significant.All statistical analyses were conducted using software , followed by glomerulonephritis  , and congenital anomalies . All the patients were recipients of living related KT, and most donors were the recipients’ parents.Of the 110 pregnancies during the study period, a total of 73 births in 64 patients were included in the analysis . Nine rede novo hypertension. As presented in The average interval from transplantation to conception was 6.4 ± 4.0 years, and 60% of pregnancies were observed ≥5 years after transplantation. The average period from the date of preparation for pregnancy (discontinuation of MMF or replacement with AZA) to pregnancy was 1.1 ± 1.1 years. However, there were six cases, in which MMF was suspended or changed after pregnancy was confirmed. The mean maternal age at delivery was 34.9 ± 4.22 years old. No significant difference in mean maternal age was observed between the two groups. HIP occurred in 37 patients (50%), of which 14 patients had hypertension before pregnancy, and 23 patients developed p = 0.02) and significantly lower gestational age and birth weight  than the other primary diseases group. Additionally, more neonates in the IgAN group had a low APGAR score <7 at 5 min after birth.The IgAN group had a higher incidence of HIP  had proteinuria (quantitative test 1+) before pregnancy , it recovered to baseline level within 1 year postpartum  of them had de novo DSA postpartum. No significant difference in the rate of de novo DSA was detected between the two groups (p < 0.01)  .n = 2, 20%), recurrent IgAN , calcineurin inhibitor toxicity , and secondary (FSGS)  and unknown causes . Compared to the non-IgAN group, the IgAN group had a higher rate of graft loss or incidence of progression to CKD stage 5  (p < 0.01).Among the patients in this study population, 10 recipients eventually experienced graft failure or progression to CKD stage 5 within 20 years postpartum. The causes of graft loss or CKD stage 5 included rejection  Thus, it is presumed that these findings might reflect the high incidence of HIP in the group with IgAN.The prevalence of PIH in generally reproductive-aged women is approximately 7%–10% . HIP remReportedly, the risk of GH or PE was 10 or 11 times higher in women with IgAN despite relatively well preserved kidney function . AccordiAlthough the underlying pathophysiology of HIP has not been elucidated to date, placental ischemia and imbalance of angiogenic factors seem to be responsible for it . First, As for the activity or severity of IgAN before pregnancy, no significant differences in creatinine level and rate of proteinuria before pregnancy were observed between the groups with and without IgAN. Moreover, whether recurrent IgAN occurred in the kidney allograft in all pregnancy cases with IgAN remains unclear. Since 2019, we have routinely performed pre-pregnancy kidney biopsies to detect whether pregnancy was possible. However, the biopsy results before 2018 were insufficient because they were not determined in our hospital. Only 3 of 8 cases with pre-pregnancy biopsy results in the IgAN group had recurrent IgAN. Altogether, no evident mechanism between IgAN in KT recipients and HIP can be inferred from the results of this study.p < 0.01), independent of maternal age. The optimal timing of pregnancy after KT remains controversial. The American and European guidelines for advising transplant recipients suggest that conception could be considered as early as 1–2 years post-transplantation, under a stable general condition . This trend is similar as that previously reported . Buren ep = 0.01). However, we cannot insist that recipients with IgAN are prone to rejection postpartum, because only 36 of 64 patients underwent kidney biopsy postpartum. Second, on whether IgAN as the primary disease affects graft survival, several studies have revealed that comparatively short-term graft survival (within 10–12 years) for IgAN patients was similar to that of patients with other primary disease (p = 0.66). Collectively, whether IgAN as a primary kidney disease has a higher likelihood of deteriorating kidney function or graft loss after delivery is difficult to be explained. Pregnant recipients with IgAN should be paid special attention for kidney function postpartum.The rate of graft loss or CKD stage 5 within 20 years postpartum was significantly higher in the IgAN group than in the other primary disease. What is the rationale behind this result? First, the rejection rate in the IgAN group was higher than that in the group with other primary diseases (50% vs. 12.5%,  disease , 26, but disease , 27. Gra disease , 27. In The present study has several limitations. First, we might not have investigated or collected sufficient data on the unknown factors affecting the relationship between IgAN and HIP. Second, as mentioned above, the severity or activity of IgAN before delivery was not sufficiently considered because of the lack of data on kidney biopsy. We only had data on urinary protein as a qualitative test because quantitative tests are not routinely performed for general follow-up in outpatient clinics. Moreover, the race-dependent difference in IgAN was not considered as this study was performed in a single Japanese medical facility, which enrolls only Asian patients. Third, the generalizability of the results remains unconfirmed because this retrospective study was conducted in a single institution. Hence, larger studies including other facilities or different races are needed in the future to test our findings.Within these limits, our study presents several clinical implications. Our findings suggest that female recipients of childbearing age wishing to consider pregnancy should be informed of the complete maternal risks and influence on kidney function by an expert multidisciplinary team. The best outcomes could be likely achieved under careful pre-pregnancy evaluation, planning, and perinatal management. We hope that our findings may guide periconceptional counseling on clinical decision-making and quality of life in KT patients.