Neuroepo is a new erythropoietin (EPO) formulation with a low sialic acid content with satisfactory results in animal models and tolerance in healthy participants and PD patients. In this study, 26 PD patients were assigned randomly to Neuroepo (n = 15) or placebo (n = 11) groups to test the tolerance of the drug. Outcome variables were neuropsychological tests and resting-state source qEEG at baseline and 6 months after administering the drug. Probabilistic Canonical Correlation Analysis was used to extract latent variables for the cognitive and for qEEG variables that shared a common source of variance. We obtained canonical variates for Cognition and qEEG with a correlation of 0.97. Linear Mixed Model analysis showed significant positive dependence of the canonical variate cognition on the dose and the confounder educational level . Additionally, in the mediation equation, we found a positive dependence of Cognition with qEEG for (p = < 0.0001) and with dose (p = 0.006). Despite the small sample, both tests were powered over 89%. A combined mediation model showed that 66% of the total effect of the cognitive improvement was mediated by qEEG (p = 0.0001), with the remaining direct effect between dose and Cognition (p = 0.002), due to other causes. These results suggest that Neuroepo has a positive influence on Cognition in PD patients and that a large portion of this effect is mediated by brain mechanisms reflected in qEEG.We report on the quantitative electroencephalogram (qEEG) and cognitive effects of Neuroepo in Parkinson’s disease (PD) from a double-blind safety trial ( Parkinson’s disease (PD) is one of the most common neurodegenerative disorders. The global burden of PD has doubled in 26 years – from 2 million patients in 1990 to 6 million patients in 2016 . The cliAlthough levodopa and dopamine agonists initially control and improve the motor symptoms of PD patients, there is still no effective intervention to slow down the progression of the illness, including cognitive deterioration. A contribution to the solution of PD disease burden might be neuroprotective drug therapy. However, despite keen interest in this approach, the issue of neuroprotection has proved to be complex because no fully demonstrated therapeutic agents are yet available . ContribErythropoietin was initially discovered as a hematopoietic growth factor. However, it has proved to be a promising molecule for treating neurological diseases . There in = 10) PD patients to evaluate the neuroprotective effect of Cuban recombinant human erythropoietin (ior-EPOCIM). They found that the drug was safe and well-tolerated , Cuba, collaborating with the Center for Molecular Immunology (CIM in Spanish). The study was registered at Participants were recruited in the outpatient Movement Disorders Clinic at CIREN from February 2015 to July 2016. Twenty-six patients with a clinical diagnosis of PD were selected from 46. The inclusion criteria for the selected sample met the criteria of the UK Brain Bank, severity stages of The 26 patients were randomly divided into two groups: One group consisted of 15 patients who received a 1 mL dose of intranasal Neuroepo per week for 5 weeks. Another group included 11 patients who took a placebo.The evaluation of the motor function was performed by a neurologist of the Movement Disorders Clinic at CIREN, using the Movement Disorder Society motor scale .We applied the levodopa equivalent dose (LED) method to standardize the intake of pharmaceutical agents by the patients. The LED was calculated using the conversion proposed by The EEG, neuropsychological, and motor evaluations were performed at two points: at the baseline and 6 months later. The patients were studied in the “ON” state for all the assessments planned during the early mornings. The patients were advised to take breakfast and their regular medication before attending the evaluations.Other assessments included clinical blood tests and blood pressure to follow the health status of the patients (data not shown).The project had ethics approval from the institutional review board at CIREN. Written informed consent was obtained from all patients and caregivers following the ethics standards at CIREN and CIM.Cognitive performance was assessed with a comprehensive neuropsychological battery for global cognitive screening, comprising 32 variables from 9 tests. The tests included the Mini-Mental State Examination  and the t-tests between the two measurement points for the Neuroepo and control groups. FDR set the threshold with both p and q levels set to 0.05. Consequently, the final six neuropsychological variables included are described in The initial 32 variables were screened to leave only those with a significant difference in The mood of the patients was assessed by the Hospital Anxiety and Depression Scale (HADS) validated for the Spanish population  only at 1 at the CIREN Neurophysiology Lab. For all electrodes, the impedance did not exceed 5 kΩ. EEG signals were amplified 10,600-fold, bandpass filtered from 0.5 to 30 Hz, and sampled by a 12-bit analog-to-digital converter at 200 Hz.Eyes closed resting monopolar EEG was recorded from Fp1, Fp2, F3, F4, C3, C4, P3, P4, O1, O2, F7, F8, T3, T4, T5, T6, Fz, Cz, and Pz using the International 10/20 system, all referenced to the linked earlobes [A1 (left)-A2 (right)]. The EEG was recorded using a Cuban neurometric system Medicid IV system and the Track Walker TM v5.0 softwaren = 15, placebo = 10, total n = 25, reduced from the original n = 26.The EEG was recorded at two assessment points: at baseline before the intervention and 6 months after administering the drug or placebo. We selected 2.56-s artifact-free segments selected by an expert (TVA) for the analysis using visual inspection. For the removal of other artifacts due to interfering physical or physiological activities, we employed different semi-automatic plugins based on EEGLAB  under thhttps://portal.cbrain.mcgill.ca.The topographic (qEEG) and tomographic (qEEGt) quantitative EEG methods have been explained elsewhere  and are For the Quantitative EEG analysis (qEEG), the EEG signals in time were re-reference to the Average Reference montage and corrected by the Global Scale Factor . This faFor the calculation of the PSD at the EEG sources, the VARETA (Variable Resolution Electromagnetic Tomography) methodology, as implemented in the Neuronic software  and CBRATo recap, the data analyzed comprised these measures:•The confounding variables for each patient were education, severity , and age when entering the trial.•The primary variables were measured simultaneously on two occasions (baseline and 6 months later) regarding their entry into the trial. These are considered repeated measures:a.Dose: the amount of Neuroepo received by each patient. At the baseline, all the patients had dose = 0. Six months later, only the Neuroepo group had received 5 mg. We do not use the group as a main or fixed effect in our analysis.b.Quantitative EEG variables for each subject: 3,244 log source spectra measured at 49 frequency points.c.Cognitive variables for each subject: MMSE, DRS, FAB, Sequency, Memory, and Recognition.To deal with the high dimensionality of data and small sample size, we employed probabilistic Canonical Correlation Analysis (pCCA) to obtain cognitive and qEEG cognitive latent variables reflecting common sources of variation. We then implemented a simple causal  mediation model with repeated measures to investigate the dose-effect on qEEG and cognitive variables using these latent variables.Whitening, or sphering, is a preprocessing step for data analysis and machine learning models. A set of random variables with a known covariance matrix is transformed into a latent space with identity covariance . WhiteniZ is the observed variable, Z is the latent whitened variable, and Wz is the whitening matrix or unmixing matrix. A recent study implemented pCCA as a whitening transform to integrate high-dimensional gene expression and methylation data for lung carcinoma  was used for the mediation analysis.We have implemented data whitening with pCCA to integrate qEEG and Cognitive variables using the whitening package in R . The firTo investigate if the effect of Neuroepo dosage on Cognition is mediated by qEEG, we implemented the mediation model shown in qEEG) and Cognition (Cog) are the mediator and outcome, respectively. The significance of the paths is analyzed using the following general repeated-measures, mixed-effect models:In this model Dosage of Neuroepo is the treatment variable. The latent variables qEEG , duration of illness (p = 0.98), familial antecedents of PD (p = 0.5), or severity of PD (p = 0.26.). Additionally, we found no significant differences between baseline and 6-months after intervention in both groups for the total score of the UPDRS “on” (p = 0.71) and “off” (p = 0.88), neither the LED (p = 0.77). There were no significant differences in mood between both groups at baseline.The average age of patients in the Neuroepo group was 56.4 years old (SD = 7.8), and the average age for the placebo group was 60.9 years old (SD = 7.2). The average duration of the disease for patients in the two groups was 5.4 years (SD = 3.2) and 5.8 years (SD = 4.1), respectively. Using the Hoehn and Yahr scale, we classified four patients in the Neuroepo group and one in the placebo group at stage I. We also identified eleven patients from the Neuroepo group and ten in the placebo group at stage II. Only nine patients had familial antecedents of PD (six patients in the Neuroepo group and three in placebo). No significant differences were found between the two groups concerning age  for each subject were used to compute the pCCA whitening transform. For this analysis, the six cognitive scores selected:  were included in calculating the latent cognitive scores. pCCA whitening was carried out to find a joint transform for the cognitive scores and the complete set of qEEG variables.The pCCA of these two datasets showed that the first latent dimension shows the strongest positive association between qEEG and Cognition. We restricted the further analysis to the first dimension, which was most highly associated with a canonical correlation of 0.97.WCog. The first column is the abbreviation of the cognitive variable and its respective loadings in the second column. Note that the loadings are roughly the same value. Thus, this latent variable is approximately an average of all the tests. The highest loadings are for DRS, followed by FAB, while the minimum loading is for Memory within this narrow range.The Cognitive latent variable is shown in WqEEG are shown in x-axis is the frequency in Hz with dashed vertical lines for each classical EEG band , and the y-axis is the standardized latent loadings. The red line shows the highest loadings, and the cyan line shows the minimum loadings for each frequency point. The latent factor maxima and minima are loads distributed over all frequency bands. This pattern suggests that this latent variable is a contrast (weighted linear combination) between different cortical areas at each frequency.The marginal distributions of the loadings for the qEEG latent variables This impression is substantiated by We have implemented two mixed effect models with the latent variables for cognition and qEEG (mediator and outcome models).qEEG depends positively on dose and education with a p-value of 0.003 and 0.02, respectively. In contrast, the fixed effects for age showed a negative coefficient; however, the p-value was not significant. Results are given in The mediator model showed that Cog shows a positive dependency on qEEG and dose with a p-value of <0.0001 and 0.006, respectively  and 89.00% .The second model (outcome model) for ectively . The effMoreover, we combined these two models using the mediation package. We computed the estimates and quasi-Bayesian confidence intervals for the mediation models , the dirCog). The beta estimate for the total effect was 2.9 with 95% CI [1.7–4.1] and p-value < 0.0001. The 66% of the total effect was mediated by qEEGwith a p-value < 0.0001. The mediation analysis results are summarized in Cog , which is not mediated by qEEG. The results showed a positive association between dose and Cognition, meaning a higher value for dose results in higher values for the latent cognitive scores (n = 15) and the placebo group (n = 10). We attempted to answer two main questions: (a) does the administration of Neuroepo have a statistically significant effect on the cognitive outcome?; (b) is this effect, if present, mediated by the qEEG?This article presents a secondary analysis of a safety trial of the use of Neuroepo in PD patients where the outcomes were cognitive performance and quantitative EEG (qEEG) as a proxy for brain function. Two groups were studied that received a 5 mg dose of Neuroepo  sharing significant association with a correlation of 0.97. This result is not surprising since resting-state EEG has been previously strongly associated with cognitive performance in nondemented PD patients . This stFrom the pattern of the loadings shown in The frequency and spatial distribution of the qEEG latent variable are complex, indicating that widespread brain networks must be considered to obtain the optimal correlation with Cognition. The resultant qEEG latent variable is a complex ratio of qEEG source spectral power, a multivariate generalization of the power ratios of isolated frequency bands previously proposed as biomarkers. One example of the use of power ratios is the finding that delta/alpha 3 correlates highly with the MMSE . On the In analyzing latent variables and confounders of this 6-months longitudinal study, we note that the PD patients stayed at the same severity stage , maintaining the same medication dose. In any case, age, and severity, were introduced as confounding variables in all linear mixed-effects analyses (LMM). As shown in via the qEEG (as a proxy for brain function) is highly significant and explains 66% of the direct effect. This analysis indicates that some of the effects of Neuroepo dose on Cognition may be due to other factors, which are being explored in future studies.When broken down by the mediation analysis, we see that the effect of the dose A possible concern is whether the latent variable analysis might bias the mediation results. We do not consider this case since the pCCA only concentrates the shared variance of Cognition and qEEG and is independent of dose or confounder variables. This result begs the question of studying such a joint latent variate in other populations, normal or other neurodegenerative diseases. This type of latent variable might yield more powerful outcomes for clinical trials.More extensive clinical studies are needed to fully understand the mechanisms underlying the mediation that qEEG has on the effect of Neuroepo on Cognition. In addition, more preclinical studies on the neuroprotective effects of Neuroepo are required. A similar molecule, EPO, protects nigral dopaminergic neurons . NeuroepFirst, the clinical trial was designed to test Neuroepo tolerance, where safety and not efficacy were the primary outcome measure. However, phase I studies can have therapeutic potential, mainly in patients and not healthy volunteers .qEEG, when analyzed with dose, reached 89% , and analyzed with Cognition reached 100% .Second, the generalizability of our findings is limited because of the size of the sample. The phase I–II trials use small samples since they are testing novel drugs. However, the output was sufficiently powered. For example, Third, with such a short treatment and follow-up, we cannot entirely rule out that an underlying idiopathic change in PD progression causes the observed effects on Cognition. The LME contrast would eliminate a factor common to all subjects. This process would have to be distributed differentially in both groups. Larger sample sizes, longer follow-ups, and additional biological measurements would be needed to identify this process.2In conclusion, in this study, we demonstrated the potential of qEEG for distinguishing the differential effects of pharmacological intervention in PD. To verify these results and delve into the mechanics involved, we launched a phase II-III trial with a larger sample.https://openneuro.org/ with the doi: 10.18112/openneuro.ds003194.v1.0.0, for NeuroEPO group and (doi: 10.18112/openneuro.ds003195.v1.0.0) for placebo group. The file with the clinical, demographic and psychological variables is available in the Supplementary Material.The original contributions presented in the study are publicly available. The EEG data used in this study are stored in BIDS format at OpenNeuro repository: The project had ethics approval from the “Scientific Review Board” at the International Center for Neurological Restoration, from Spanish Centro Internacional de Restauracion Neurologica (CIREN), La Habana, Cuba. The patients/participants provided their written informed consent to participate in this study.IP recruited the patients at CIREN and led the whole clinical trial. LM collected the original EEG recordings at CIREN. TV, PG, and MZ performed the EEG visual inspection and quality control of the EEG datasets for further processing. JB-B, LG, and MZ were responsible EEG data for processing with qEEGt. FR did the new statistical analysis. CL converted the EEG files to BIDS and uploaded them to the OpenNeuro repository. PR and MJ contributed to the supervision of the work and revised the final version of the manuscript. PV-S and MB contributed to the research design and discussion of the analysis strategies and wrote the final version of the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Among those with non-dipper status, a higher high-sensitivity C-reactive protein level tended to be associated with incremental nighttime systolic blood pressure levels (p = 0.065). Conclusions: Hyperuricemia and micro-inflammation might be associated with attenuated nocturnal blood pressure dipping and incremental nighttime systolic blood pressure levels.Background: In patients with essential hypertension, a non-dipping blood pressure pattern is a strong risk factor for cardiovascular diseases. However, background factors associating with such a blood pressure pattern remain unknown. Methods: Untreated essential hypertensive patients without chronic kidney diseases who were admitted to our outpatient clinic were included. Blood sampling and 24 h ambulatory blood pressure monitoring were mandatorily performed. Non-dipper status was defined as a maximum decrease in nocturnal systolic blood pressure within 10%. Clinical factors associating with non-dipper status were investigated. Results: A total of 154 patients  were included. Among baseline characteristics, a higher serum uric acid level was independently associated with non-dipper status (odds ratio 1.03, 95% confidence interval 1.00–1.05,  Hypertension is one of the most common and major chronic diseases all over the world, and one of the most predominant risk factors for cardiovascular complications . Of noteThe detailed causality and mechanism of the development of non-dipper status remain uncertain. Although few studies have been reported, chronic inflammation, of which serum uric acid level is one of the indicators, might be associated with the progression of non-dipping of nocturnal blood pressure ,10. SuchConsecutive patients with untreated essential hypertension who were admitted to our outpatient clinic for the first time between January 2004 and December 2015 were retrospectively included. None of the patients had ever been admitted to any clinics to treat their hypertension beforehand. Blood pressures were measured in the interview room using automatic sphygmomanometers  several times at rest-sitting condition, according to the Japanese Society of Hypertension Guidelines for the Management of Hypertension . Two sta2 or urinary albumin excretion ≥300 mg/day, were excluded. Patients receiving anti-hyperuricemic agents were also excluded.Patients with chronic kidney disease (CKD), which was defined as an estimated glomerular filtration ratio <60 mL/min/1.73 mThe present study was approved by the institutional review board. The informed consents were wavered given the retrospective nature of this study and the opt-out of this study protocol. The study was conducted in accordance with the Declaration of Helsinki.Laboratory data were obtained from blood and urine samples on the same day of ambulatory 24 h blood pressure monitoring (ABPM) prior to the initiation of anti-hypertension treatment. Baseline demographics data, including laboratory and echocardiography data, were retrieved on the same day. Nitric oxide metabolites were measured by Griess test. The homeostasis model assessment of insulin resistance was calculated as follows: plasma fasting glucose (mg/dL) × immunoreactive insulin (μU/mL)/405. Serum leptin and adiponectin were measured by using an enzyme-linked immunosorbent assay kit.24 h ABPM was performed using a Takeda TM-2431 . On 24 h ABPM, blood pressure was recorded at 30-min intervals. The following parameters were calculated from 24 h ABPM: the average of systolic and diastolic blood pressure during 24 h, daytime (9:00 AM to 9:00 PM) and nighttime (0:00 AM to 5:00 AM). If >30% of the measurements were errors and missing, such cases were eliminated from the analyses.The percentage of nocturnal systolic blood pressure decline was calculated as follows: (daytime average systolic blood pressure − nighttime average systolic blood pressure) × 100/daytime average systolic blood pressure. According to the 24 h ABPM, non-dipper hypertension was defined as a decrease in nocturnal systolic blood pressure within 10% .A primary concern was the factors associated with the non-dipper status. A second concern was the factors associated with nighttime average systolic blood pressure among those with non-dipper status.Continuous variables are stated as mean and standard deviation. Categorical variables are stated as numbers and percentage. Continuous variables were compared between the two groups using an unpaired t-test. Categorical variables were compared between the two groups using the Fisher’s exact test.p < 0.10 in the univariable analyses were included in the multivariable analyses with frothed method following the confirmation of their variance inflation factors <10.Factors associated with the existence of non-dipper status were investigated using logistic regression analyses among potential clinical parameters . Among those with non-dipper status, factors associated with nighttime systolic blood pressure were investigated using linear regression analyses among potential clinical parameters. In both regression analyses, variables with Before conducting this retrospective study, we analyzed the required sample size for the primary statistics. We estimated the odds ratio of 2, alpha error of 0.05, and 1-beta value of 0.80. The required sample size was calculated as 113.p-values < 0.05 were considered statistically significant. Analyses were performed using R software version 3.5.2 .Two-sided A total of 154 patients were included. Mean age was 55.7 ± 11.9 years old and 88 (57%) were men. No patients had active infection, malignancy, collagen disease, and cardiovascular diseases. Two patients had type 2 diabetes mellitus and 11 patients had dyslipidemia. The duration of hypertension was 4.9 ± 6.7 years. Mean 24 h systolic blood pressure was 142 ± 16 mmHg. Baseline demographics, laboratory data, and urinary data were summarized in There were 56 patients (36%) with non-dipper status. Patients with non-dipper status were characterized by elevated average systolic blood pressure during 24 h and nighttime, increased body mass index, serum uric acid, and high-sensitivity C-reactive protein (CRP), and decreased plasma nitric oxide metabolites compared with those with dipper status. The amount of alcohol intake was not statistically different between the two groups.p < 0.05 for all; p > 0.05 for all).Among laboratory data, uric acid, high-sensitivity CRP, and low-density lipoprotein cholesterol were higher, and high-density lipoprotein cholesterol and nitric oxidative metabolites were lower in the non-dipper status than the dipper status .Among potential clinical parameters, uric acid and high-sensitivity CRP, as well as body mass index, were associated with the existence of non-dipper status . We display here a representative patient with non-dipper status, presenting 8.2 mg/dL of uric acid, 0.175 mg/dL of high-sensitivity CRP (There were no statistically significant determinants of nighttime average systolic blood pressure in the dipper cohort (vity CRP .A 54-year-old woman with non-dipper status with a nocturnal systolic blood pressure decline = 9.6%, presenting 8.2 mg/dL of uric acid, 0.175 mg/dL of high-sensitivity CRP. BP, blood pressure.This study investigated factors associated with non-dipper status in patients with essential hypertension. Hyperuricemia was independently associated with non-dipper status. Among those with non-dipper status, high-sensitivity CRP tended to be associated with incremental nighttime average systolic blood pressure.Patients with essential hypertension often have comorbid hyperuricemia , which iIn patients with hypertension, the stimulated renin-angiotensin system and sympathetic nerve system both decrease the blood flow of renal medulla, accumulating serum uric acid levels. Furthermore, when activated, these systems stimulate reabsorption of uric acid via the urate transporter 1, which is located on the proximal tubule . Thus, tIn another study, the serum uric acid level was higher in those with non-dipper status compared with those with dipper status ,16, whicOn the contrary, it is unclear whether hyperuricemia itself would contribute to the development of hypertension. Some experimental studies showed controversial findings ,19. OtheWe can at least hypothesize that the existence of hyperuricemia would be a surrogate of non-dipper status. Strict management of 24 h blood pressure might be encouraged if we find such patients. Whether intervention to hyperuricemia would ameliorate non-dipper status remains uncertain.Among those with non-dipper status, some patients had further incremental 24 h blood pressure. An elevated high-sensitivity CRP was independently associated with it ,10.High-sensitivity CRP is one of the major indexes of chronic inflammation, which impairs endothelial function and facilitates microvasculature remodeling. Progression of microvasculature remodeling increases vascular resistance and causes essential hypertension . The levAccording to experimental studies, hyperuricemia stimulates the release of various cytokines ,25. The Some comparisons might not reach statistical significance given the moderate sample size. We used the expected odds ratio of 2.0 to estimate the required sample size. However, given the lack of any similar studies, we cannot show robust references to validate our estimation. Of note, obesity and nitric oxide might also have associations with non-dipper status, although their impacts did not reach statistical significance. We performed 24 h ABPM only once per patient. We assessed the association among variables and causality remains uncertain. We did not measure several potentially important clinical factors, including the existence of sleep apnea and waist circumference, which might also affect our findings. We excluded those with CKD, given that CKD is a well-known strong contributor of non-dipping pressure pattern . We hypoHyperuricemia and micro-inflammation might be associated with attenuated nocturnal blood pressure dipping and incremental nighttime systolic blood pressure levels. Their detailed causality and associated therapeutic strategy remain the next concern.


Microcirculation plays a vital role in scleroderma physiopathology and the mechanism of fat survival.This study aims to assess the blood perfusion change after fat grafting and evaluate the relationship between blood perfusion and fat graft retention in patients with localized scleroderma (LS).A pilot study was conducted in patients with LS receiving autologous fat grafting (AFG). Fat graft retention measured by magnetic resonance imaging (MRI) analysis and blood flow perfusion measured by laser speckle contrast imaging 6 months postoperatively were noted. PUMC Localized Scleroderma Facial Aesthetic Index was used to assess the improvement of facial aesthetic impairment.p = 0.010). The blood perfusion at follow-up increased by an average of 1.15 ± 0.14 times before the operation. No association between the increase in the blood flow perfusions and fat graft retention was found .The fat retention at the 6-month follow-up was 34.56 ± 11.89 percent. At the 6th month of follow-up, the relative blood perfusion at the lesion area was 115.08 ± 14.39 PU, significantly higher than 100.42 ± 10.62 PU at the pre-operation (Local blood perfusion in the lesion area relatively increased after AFG, but no direct relationship was found between fat retention and increased blood supply. Localized scleroderma (LS) is a rare autoimmune connective tissue disorder characterized by inflammation and fibrosis of the skin and subcutaneous adipose tissues in the affected area , 2. PresA prospective pilot study approved by the institutional ethical committee was conducted in patients with LS seeking AFG to correct facial atrophy at Peking Union Medical College Hospital. All candidates were evaluated for suitability to be enrolled in the study by the criteria as follows. Inclusion criteria: (1) Patients with LS in the stable phase (documented by dermatologists); (2) Desire for correcting facial atrophy; (3) Signed informed consent. Exclusion criteria: (1) Absence of the lower abdomen fat donor site; (2) Undergoing steroid, anti-fibrotic or anti-scarring treatment ; (3) Unstable or advanced phases of LS; (4) Chronic diseases that require to take long-term medication; (5) BMI > 2 points during the study.The primary outcomes were the fat graft retention measured by magnetic resonance imaging (MRI) analysis and blood flow perfusion measured by laser speckle contrast imaging 6 months postoperatively. The secondary outcome was the improvement of facial aesthetic impairment of LS patients using PUMC Localized Scleroderma Facial Aesthetic Index.At study entry, the facial atrophy volume of the individual was measured by MRI analysis. By comparing the volume difference of the subcutaneous adipose tissue between the target lesion site and the unaffected symmetry site, the graft volume was noted for each participant . LiposucPreoperative variables included age, gender, duration, and BMI. Six months postoperatively, the participants were asked to return for follow-up assessments where surgical complications and BMI change were recorded, and the participants were photographed. Clinical assessment of facial deformity was separately evaluated by two plastic surgery experts using PUMC Localized Scleroderma Facial Aesthetic Index (PUMC LSFAI) preoperatively and postoperatively . PUMC LSMagnetic Resonance Imaging (MRI) scan with a 3.0 Tesla MR scanner  was performed pre-operation, post-operation, and follow-up, using a thirty-two-channel head and neck coil. The MRI scan was conducted from the frontal bone to the neck base, excluding the supraclavicular region. Axial TSE T1-FLAIR weighted  was used with a slice thickness of 4mm . The perThe presence of complications was also assessed . All imaBlood flow is a significant indicator to monitor the activity of LS and evaluate the efficacy of treatment , 13. Blot-test was used to assess normally distributed continuous variables, and results are presented as mean and standard deviation. Ordinal categorical variables were assessed using the Wilcoxon signed rank sum test, and results are presented as median and interquartile range. Spearman’s rank correlation coefficient was used to measure the association of non-normally distributed continuous variables or categorical variables. Significance was set to the level of p < 0.05.The sample size was estimated to be significant with 10 participants with an alpha of 0.05 and a beta of 0.8 by using PASS Statistical Software . Statistical analyses were conducted using SPSS 26.0 . Shapiro–Wilk test was used to assess continuous variables for normality. Paired 2 (Twenty-three patients (thirteen women and ten men) were enrolled in the study and retained throughout the 6 months to study completion, whose average age was 24.82 ± 5.93 years, and average BMI was 21.52 ± 1.77 kg/m2 . Seventep = 0.010). The blood perfusion at follow-up relatively increased by an average of 1.15 ± 0.14 times before the operation. Results from the univariable and multiple variable regression analyses on fat retention are presented in r = −0.082, p = 0.811). Clinical outcome assessment further showed the dyspigmentation, skin thickness, soft tissue atrophy, facial symmetry, facial proportion, facial profile, and PUMC LSFAI scores of the participants significantly improved at follow-up, except for the surface area of the lesion item .The fat retention at the 6-month follow-up was 34.56 ± 11.89 percent. At the 6th month of follow-up, the blood perfusion at the lesion area was 115.08 ± 14.39 PU, significantly higher than 100.42 ± 10.62 PU at the pre-operation (ion item . SpearmaLocalized scleroderma is a chronic benign inflammatory connective tissue disease that manifests as various plaques of different shapes and sizes with signs of skin inflammation, sclerosis, and atrophy , 2. A coMany studies have shown that local blood perfusion in the plaque is positively correlated with the activity of scleroderma; therefore, it can be used to predict disease progression and disease activity , 20, 21.In this study, we found that the blood perfusion in the lesion area relatively increased after AFG, which has never been reported in the literature. We reckon this result should not be interpreted as the reactivation of the disease as the patients’ symptoms did not worsen, and no occurrence of new lesions. The increase in local blood perfusion should be considered as a consequence of fat grafting, which is consistent with other studies . To dateAnother finding in this study was that AFG significantly improved facial aesthetics in many aspects, including soft tissue volume, skin thickness, pigmentation, facial symmetry, proportion, and profile. The increase in soft tissue volume directly results from AFG and further improves the overall facial aesthetics. In contrast, the skin texture and pigmentation changes may come from the regenerative effects of fat grafting . The regFurthermore, previous studies on LS have shown ASCs had multiple advantages of immunomodulatory effects to limit inflammation and reduce fibrosis. By providing potent anti-inflammatory cytokines, such as interleukin-10, indoleamine 2,3-dioxygenase, and nitric oxide, ASCs have been proved to effectively disrupt the inflammatory response, inhibit the release of proinflammatory mediators, and decrease antigen presentation and phagocytosis, suppressing LS progression , 33. MeaOne of the limitations of this article is the small sample size. In addition, the measurement of the skin fibrosis and skin thickness of patients with LS was not achieved in this study. These indicators may represent the severity and prognosis of the disease, thereby facilitating the assessment of the outcome or reactivation of the disease after fat grafting.Autologous fat grafting significantly improved the impaired facial aesthetics, including soft tissue atrophy, skin thickness, dyspigmentation. Local blood perfusion in the lesion area relatively increased after AFG, but no direct relationship was found between fat retention and increased blood supply.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Peking Union Medical College Hospital. The patients/participants provided their written informed consent to participate in this study.HW and XL: conceptualization and supervision. HW: methodology, validation, and writing – original draft preparation. HW, YL, ZJL, LW, and ZML: formal analysis and investigation and resources. XL: writing – review and editing and funding acquisition. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Two major studies of structural changes associated with aging in human kidneys are reviewed and new information presented. The studies are the Monash University stereologically analyzed series of 319 autopsy kidneys from the United States in which 44% were white and the Mayo Clinic CT angiogram/biopsy analysis of 1,388 US kidney donors in which 97% were white. Hypertension rates in the Monash series were 48% and included moderate and severe hypertension. In the Mayo Clinic study, 12% had mild hypertension. The studies showed no relationship between glomerular number and hypertension except for a weak relationship with older white women in the Monash series. An inverse relationship was present between glomerular number and glomerular volume, a reciprocity that tended to enhance glomerular mass and by inference filtration capacity with lower nephron numbers. This relationship seemed to be present whether low nephron numbers were intrinsic or acquired. In the Mayo Clinic studies, pretransplant iothalamate clearances demonstrated that single nephron (SN) glomerular filtration rates (GFR) were similar throughout the range of glomerular number in subjects younger than 70 years, but that increased SNGFR correlated with nephron hypertrophy and increased nephrosclerosis particularly at 70 years of age and over. Hypertension at least through middle age cannot be related to a deficiency of glomeruli, but glomeruli are lost with later aging in association with adaptive nephron hypertrophy that can maintain GFR near normal. These studies help define an age‐related nephropathy that overlaps with hypertension as a potential cause of end‐stage renal disease when glomerulosclerosis is advanced. The disector/fractionator is used primarily at autopsy, whereas the CT/biopsy method can be conducted on living persons. These studies have clinical significance because low nephron endowment may help define patients at high risk for progressive chronic kidney disease who may benefit from early clinical intervention to prevent ESRD  yielding the second “slice” sampling fraction. The location of the samples from the cortex can be determined by the subsequent histologic sections showing capsule, a rim of upper medulla, or none.The selected sample blocks are embedded in glycol methacrylate to avoid the shrinkage of processing into paraffin and then completely serially sectioned at a thickness of 20 μm to produce approximately 100–150 section pairs per kidney. Every 10th and 11th paired sections are selected producing a “section” sampling fraction. The 10th (“reference” section) is examined with the 11th “look‐up” section. Identical regions of the section pairs are projected onto unbiased counting frames (grids) from tandem microscopes  in the kidney is calculated. The glomerular tuft areas are calculated from the points that they overly on the grid. The average glomerular volume (Vglom) is derived from the volume density divided by the numerical density of glomeruli in the kidney. Multiplication of Nglom by Vglom provides an estimate of the total glomerular volume of the kidney .The number of disappearing glomeruli in the serial sections represents the number of glomeruli in the block. From the individual blocks representing a known fraction of the whole cortex, the total number of glomeruli . For this reason, counts are often referred to as “unbiased,” but this is only the case if the technique is used correctly.The percent of glomerulosclerosis, the severity of arteriosclerosis, and the percent of interstitial fibrosis and tubular atrophy were analyzed morphometrically as planar data with Image ProPlus software as described previously  was calculated. The causes of death among this autopsy cohort closely resemble that of the general Mississippi population with approximately one‐third of deaths being caused by CVD  of 29–51 years. To prevent excessive glomerular loss due to renal scarring from interfering with glomerular counting, the collection excluded diseased kidneys or kidneys with any more than moderate arteriolonephrosclerosis. This restriction resulted in the collection of only 20 subjects 65 years or older. Clinical information on the subjects included cause of death, hypertension history, and height and weight from which body mass index  with a more than 9‐fold range from 210,332 to 2,702,079. There was no significant racial difference (P = 0.29), but females had significantly fewer glomeruli than males .The median NP = 0.66) but with females having lower birth weight than males (P = 0.04). For subjects 18 years or older, there was a significant direct correlation between birth weight and Nglom  with each 1 kg increase in birth weight predicting an increase of 132,446 glomeruli   with each kilogram increase in birth weight predicting an increase of 4.8 cm in height  and between height and Nglom  with each 1.0 cm increase in height predicting an increase in 3,737 glomeruli   with no significant difference by race (glom increased with age and reached adult size at about 20 years of age. The median adult Vglom was 7.1 μm3 × 106 (IQR 5.5–8.9) with a more than 6‐fold range from 2.7 to 17.0 μm3 × 10,6 and with African Americans having significantly larger Vglom than whites (P < 0.001). There was an inverse correlation between Nglom and Vglom  with each decrease of 46,067 Nglom predicting an increase of 1.0 μm3 × 106 in Vglom   with every 1.0 cm increase in height predicting an increase of 0.89 cm3 of Vglomtotal  and was not significantly different than the median Nglom of either non‐hypertensive (P = 0.75) or hypertensive African Americans (P = 0.65).Birth weight had no association with hypertension in either race, and Table P < 0.001) and female sex  but not BMI  or Nglom . For sex alone, lower Nglom was significant for 13 hypertensive females (P = 0.02) but not for 35 hypertensive males (P = 0.15). When age was examined as a single variable, hypertensive white women were significantly older than those without hypertension . The findings suggest that the lower Nglom in hypertensive white women was likely to be an age‐related nephron loss and probably not a primary factor in the elevated blood pressure.White hypertensives had significantly fewer glomeruli than non‐hypertensives Table . In logiglom was determined by African American race , male sex , higher BMI , hypertension , and lower Nglom . African American race, hypertension, obesity, and aging are significantly related to chronic kidney disease  and the Mayo Clinic study (CT/biopsy method). These estimates are compared by age range using non‐paired These are minor age differences that do not detract from important similarities that include a direct correlation between height and glomerular number, an inverse correlation between glomerular volume and glomerular number, and an increased glomerular volume with increased BMI. The Monash series found that birth weight was related to both height and glomerular number suggesting that birth weight was essentially “right sizing” the number of glomeruli in a kidney for an individual's adult height. The Mayo Clinic study showed an absence of a relationship between glomerular number and mild hypertension, while the Monash series findings showed no significant association between glomerular number and hypertension among African Americans of either sex nor among white males.The substantial loss of glomeruli with aging that was found in the Mayo Clinic donor kidneys helps explain the large population of older persons, classified as having “ vascular disease”, but without any elevation of blood pressure or with only mild hypertension that are second only to diabetes as a cause for entry into US ESRD programs . Persons 70–75 years old had a substantial loss of glomeruli and SNGFR increased presumably as an adaptation to glomerular loss (Denic et al., glom, the reciprocity between lower glomerular number and larger volume enhances glomerular mass and supports increased glomerular filtration. Additionally, the larger glomerular volume attenuates the perfusion pressure of individual glomeruli and the potential for glomerular hypertension. This has been studied in transplant donors, where despite increased SNGFR in the remaining kidney, glomerular hypertrophy compensated for the reduction in glomerular mass, and estimates of glomerular capillary pressure remained constant (Blantz and Steiner, In kidneys with low NThe convergence of BMI and glomerular number may be a factor in the development of obesity‐related glomerulopathy. With low glomerular number, a threshold may be reached in the capacity of glomeruli to adaptively enlarge with larger BMI, and increased glomerular perfusion may eventually result in glomerular hypertension. A similar phenomenon may occur with aging, where the enlargement of remaining, non‐sclerotic glomeruli may be limited and eventually reach a point recognized as decompensated hypertensive injury (Hughson et al., 4These two studies of the US subjects showed that there was a wide range in the number of nephrons in normal kidneys and that lower glomerular number was associated with an increased mean glomerular volume. The studies also showed a decline in glomerular number with age and nephrosclerosis that is quite marked in the Mayo Clinic subjects after 70 years of age. Among Mayo Clinic subjects, an increased SNGFR was observed with acquired glomerular loss in the over 70‐year‐old group, but among younger subjects what appeared to be intrinsic differences in glomerular number and volume were not associated with alterations in SNGFR. Exceptions were seen in subjects with obesity and height ≥190 cm where SNGFR did increase in association with larger glomerular volume (Denic et al., These findings have important implications for understanding the risk of ESRD among the large population of kidney patients that are neither diabetic nor have any defined type of kidney disease. As many as 55% of persons entering the US ESRD programs fall into this category and are diagnosed as mildly hypertensive or have never been recognized as being hypertensive at all (Klag et al., Obesity‐related renal disease consists of diabetic changes, glomerulomegaly with proteinuria, and focal segmental glomerulosclerosis (Kambham et al., in utero to meet the metabolic demands of an also predetermined adult body size, albeit without the burden of obesity. Both birth weight and adult height are predictive of glomerular number, but because of the wide variance in glomerular number throughout the range of body height or birth weight, this requires robust numbers of subjects to demonstrate. The Monash series and Mayo Clinic studies provide those numbers and are showing that glomerular number is unlikely to be related to the initiation of hypertension, at least in young‐ and middle‐aged adults. It is doubtful that this will be regarded as a completely settled question, but interest is shifting toward the relationship between low glomerular number with its attendant large glomerular size on the risk for progressive nephrosclerosis.The kidney is composed of a highly redundant system of nephrons whose numbers seem to be predetermined The Mayo Clinic studies show that large numbers of glomeruli disappear from the aging kidney and that kidney donors having family members with ESRD have reduced numbers of glomeruli (Elsherbiny et al.,


Nitric oxide (NO) is important to cardiovascular health (CVH), and its bioavailability could be regulated by the antioxidant effect of polyphenols, improving endothelial function and consequently blood pressure (BP). However, scant research has been carried out on NO and CVH correlates in adolescent populations. Therefore, our aim was to investigate the association between NO and the CVH status and other health factors in adolescents. NO, total polyphenol excretion (TPE), anthropometric measurements, BP, blood lipid profile, blood glucose, diet, physical activity, and smoking status were recorded, while CVH score was classified as ideal, intermediate, and poor. Negative associations were observed between NO and body mass index, body fat percentage, BP, and triglycerides; and positive associations between NO and skeletal muscle percentage, HDL-cholesterol, fruit and vegetable intake, and TPE was observed. To capture more complex interactions among different factors, multiple linear regression was performed, obtaining a significant association between NO and fruit and vegetable intake (β = 0.175), TPE (β = 0.225), and systolic BP (β = −0.235). We conclude that urinary NO levels are positively associated with the consumption of fruits and vegetables rich in antioxidants such as polyphenols and negatively associated with systolic BP. Approximately one third of global deaths in 2019 were caused by cardiovascular diseases . As a shIn addition, fruits and vegetables are sources of antioxidants such as polyphenols, which could improve the bioavailability of NO ,10. As aSome studies have evaluated the relationship between NO and nitrate intake in adult populations, showing a reduction in blood pressure after a dose of nitrate whether in concentrated solutions or in the form of vegetable-based products ,8. HowevOn the other hand, tobacco contributes to a decrease in the activity of NO synthase , which decreases NO production in smokers ,14. MoreThe American Heart Association defines cardiovascular health (CVH) as the presence of four health behaviors: smoking status, BMI, physical activity, and diet status, and three health factors: blood glucose levels, total cholesterol (TC), and BP . Due to In this section, we describe the study design, sample selection, anthropometric, and cardiovascular measurements, urinary biochemical and statistical analyses. ClinicalTrials.gov: NCT03504059, accessed on 3 October 2022). This study enrolled a total of 1326 adolescents from 24 public secondary schools in Spain (seven in Madrid and 17 in Barcelona). All participants signed an informed consent form. All the details of the recruitment and design of the trial have been previously published [A cross-sectional analysis of baseline data was performed in a sub-sample of participants enrolled in the SI! Program for Secondary Schools trial (registered at ublished . For the2). Waist circumference was measured three times with a Holtain tape to the nearest 0.1 cm [All anthropometric measurements were performed by trained nutritionists. Height was measured with a Seca 213 portable stadiometer (0.1 cm of precision). Body weight, body fat percentage, and skeletal muscle percentage were measured using an OMRON BF511 electronic scale with 0.1 Kg of precision  after overnight fasting, with participants wearing light clothes and no shoes. BMI was calculated as body weight divided by height squared  was calculated based on the 7 cardiovascular metrics  using the cut-off points proposed by Steinberger et al., 2016 . Each coAll participants in this study provided a fasting spot urine sample, collected in the morning. The urine was aliquoted and stored at −80 °C for subsequent analysis . NO conct test was used to identify variables that exhibited sex-related differences: Kruskal–Wallis test with Dunn–Bonferroni correction was used to ascertain for differences between CVHs categories, and to identify differences in NO levels among CVHs, and eta-squared was used to identify effect size; correlation between NO levels and each study variable was assessed with simple linear regression and Spearman’s correlation coefficients. Fourth, principal component analysis was used to eliminate collinearity among variables. Fifth, to identify the most important variables associated with NO, the forward stepwise selection method was used. This method was fed with the statistically significant variables  from the analysis of differences between sexes (Student t test), variables with different median values in the CVHs categories , and correlated variables  with NO. Finally, with the subset of variables selected by the forward stepwise method, a multiple linear regression model, adjusted by confounding factors, such as sex, age, smoking status, and BMI, was used to determine the influence and global association of study variables with NO additionally. Data were analyzed with R software version 4.1.0 . In all tests, a p-value < 0.05 was considered statistically significant.A six-step process was followed to identify the association among NO and CVH status and other healthy factors. First, to prevent variables from having unequal weights, all variables were standardized (z-scores) prior to the statistical analysis. Second, the Kolmogorov–Smirnov test was used to determine normality of variables. Third, candidate predictor variables were identified using a variety of statistical methods: Student The general characteristics of the study population are presented in Most of the variables correlated with NO levels according to the Spearman correlation test  showed sNo collinearity was found among the variables, which was tested using principal component analysis. Skeletal muscle percentage, SBP z-score, TC, TPE, and intake of fruit and vegetables, whole grains, and sugar-sweetened beverages were identified by the forward stepwise method as the most important variables associated with NO.p = 0.025), TPE  and SBP z-score  showed a statistically significant association with NO, whereas TC , skeletal muscle percentage , and the intake of sugar-sweetened beverages and whole grains  were not significantly associated with NO in the multiple linear regression model adjusted by confounding factors , and the health status of the population, as due to their early stage of life, most participants were healthy. Due to age and ethical issues, it was not possible to obtain a blood sample, which would have allowed a more comprehensive knowledge of NO. The cross-sectional design was another limitation of our study.The results of the present study are promising. However, a deeper understanding of the relationship between NO and CVH factors in early life stages is necessary. Our results may contribute to a better understanding of the relationship between NO and CVH factors in early life stages . They may also contribute to health promotion  and the prevention of cardiovascular disease development in adolescents, thus improving quality of life in adulthood. However, deeper studies might be required to understand more complex interactions between the aforementioned factors.In conclusion, our results show that NO is positively associated with fruit and vegetable intake and TPE and negatively associated with SBP. Our results, along with those exhibited in related research works, suggest that NO and polyphenol levels could come from the consumption of fruits and vegetables, and the combination of the effects of NO and polyphenols could produce a decrease in BP.


In a significant proportion of pregnant women, elevated blood pressure may first present during the intrapartum period. This phenomenon, intrapartum hypertension, is often overlooked as blood pressure during delivery is attributed to labour pain, analgesic agents and haemodynamic changes. Thus the true prevalence and clinical significance of intrapartum hypertension remains unknown. This study sought to define the prevalence of intrapartum hypertension in previously normotensive women, identify associated clinical characteristics, and its impact on maternal and fetal outcomes.In this single-center retrospective cohort study, all available partograms were reviewed over a 1-month period at an outer metropolitan hospital in Sydney . Women with diagnosed hypertensive disorders of pregnancy during the incident pregnancy were excluded. A total of 229 deliveries were included in the final analysis. Intrapatum hypertension (IH) was defined as two or more systolic blood pressure (SBP)⩾140 mmHg or diastolic blood pressure (DBP)⩾90 mmHg during the intrapartum. Demographic data at the time of the first antenatal visit for the incident pregnancy as well as final maternal outcomes (intrapartum and post-partum) and fetal outcomes were collected. Statistical analyses were carried out using SPSSv27 with adjustments for baseline variables.p = 0.02), higher body mass index (p < 0.01) and higher diastolic blood pressure at the first antenatal visit (p = 0.03) were associated with intrapartum hypertension. A longer second stage of labour (p = 0.03), intrapartum non-steroidal anti-inflammatory medications (p < 0.01) and epidural anaesthesia (p = 0.03) were associated with intrapartum hypertension, while IV syntocin for labour induction was not. Women with intrapartum hypertension had a longer inpatient admission following delivery (p < 0.01), and elevated postpartum BP (p = 0.02) with discharge on antihypertensive medications (p < 0.01). Intrapartum hypertension was not associated with poor fetal outcomes, though subgroup analyses showed that women who had at least a single elevated blood pressure reading during the intrapartum experienced poorer fetal outcomes.Amongst 229 deliveries, 32 women (14%) had intrapartum hypertension. Older maternal age (In previously normotensive women, 14% developed intrapartum hypertension during delivery. This was associated with postpartum hypertension, longer maternal admission and discharge with antihypertensive medications. There was no difference in fetal outcomes.The online version contains supplementary material available at 10.1186/s12884-023-05386-y. Hypertensive disorders of pregnancy are an important cause of maternal and neonatal morbidity worldwide, and there has been an increasing focus during antenatal care to initiate appropriate treatment and reduce poor perinatal outcomes . In womeDespite the incongruency in reported prevalence, the limited existing literature suggests an association with poor outcomes. Lao et al.  reportedThus, the objective of this study was to define the prevalence of IH in women who were previously normotensive throughout their pregnancy. The study also sought to identify the clinical characteristics associated with IH, and the consequences for maternal and fetal outcomes.A single-center retrospective cohort study was conducted. All available electronic and paper partograms were reviewed over a 1-month (October 2019) period at an outer metropolitan hospital in Sydney. Campbelltown Hospital is a teaching hospital in South Western Sydney with over 3400 births annually. Women more than 32 weeks gestation are able to deliver at Campbelltown Hospital as it has a special care nursery but no neonatal intensive care.All women with a partogram who delivered during the study period were included. Partograms without any blood pressure readings recorded were excluded. Women with a diagnosis of a hypertensive disorder of pregnancy  prior tLabour partograms were reviewed and IH was defined as two or more either systolic blood pressure (SBP) measurement ⩾140 mmHg or diastolic blood pressure (DBP) ⩾90 mmHg during the intrapartum period, at least 30 minutes apart. For labouring women without a pre-existing diagnosis of HDP, blood pressure is checked every 2 h using an automated blood pressure device. Hospital policy encourages women to adopt positions that enhance labour and uteroplacental perfusion, and women are not repositioned to check blood pressure. For women undergoing a caesarean section, continuous non-invasive blood pressure monitoring occurs intraoperatively using an automated blood pressure device, in the supine position.https://intergrowth21.tghn.org).A subgroup analysis was also undertaken for women with a single SBP measurement ⩾140 mmHg or DBP measurement ⩾90 mmHg during labour. The length of each stage of labour, total number of readings measured, total number of elevated readings and medication charts were reviewed. The post partum course was assessed for episodes of hypertension, medications commenced, length of stay and adverse maternal or fetal outcomes . A mateElectronic documentation were reviewed for a total of 6 weeks follow-up to assess for re-admissions due to uncontrolled or symptomatic hypertension, in addition to the hypertensive complications listed above. Readmissions for other causes were not included unless they had concomitant hypertensive complications, or were noted to have elevated blood pressure during their admission requiring medication changes.Ethics for this study was approved by the South Western Sydney Local Health District Research Ethics committee (2020/ETH00824). Statistical analyses were carried out using SPSSv27 with adjustments for baseline variables. Data that is normally distributed was analysed with parametric tests and non-normally distributed data was analysed with non-parametric tests. Significance was set at 0.05.During October 2019, there were 316 births at Campbelltown Hospital, with 300 labour partograms available for review. Fifty-three partograms (18%) had no blood pressure readings documented during the intrapartum period. A further 18 women were excluded due to having a diagnosis of a hypertensive disorder of pregnancy. The flow of patients is outlined in Fig. p < 0.001). Figure The median (±IQR) number of blood pressure readings per patient was 4 ±21), with caesarean sections recording more blood pressure readings than a vaginal delivery , higher body mass index (p < 0.001) and higher DBP at the first antenatal visit (p = 0.03) , and this was associated with higher maternal age  had an intrapartum systolic blood pressure reading ⩾140 mmHg, 7 (3%) had intrapartum systolic blood pressure reading ⩾160 mmHg, and 16 (7%) had an intrapartum diastolic blood pressure reading ⩾90 mmHg.p < 0.01) and have a longer second stage of labour (p = 0.03).Table p < 0.01) and epidural anaesthesia (p = 0.03) were associated with IH, however administration of intravenous syntocin for labour induction was not associated. Seven women were treated with antihypertensive agents during the intrapartum period . Intravenous antihypertensive agents were required in 3 women . The median (± IQR) number of antihypertensive doses received was 2 (± 2).Administration of intrapartum non-steroidal anti-inflammatory medications (NSAIDs) (p = 0.02), require a longer hospital admission following delivery (p < 0.01) and be discharged on regular antihypertensive medications (p < 0.01). No woman in either group suffered a stroke, seizure, acute coronary event, pulmonary oedema or other end-organ hypertensive complications. Three women were readmitted in the first 6 weeks post partum with uncontrolled hypertension, and none of these women had IH. Median (±IQR) time after discharge to readmission was 6 (±4) days, with the median (±IQR) readmission length 2 (±2) days.Women with IH were more likely to have elevated blood pressure postpartum  after controlling for the other variables in the model.Regression analysis was conducted to examine the relationship between IH and various potential predictors. Having 2 or more raised blood pressure readings during the intrapartum period was predictive of postpartum hypertension  and higher SBP at the first antenatal visit (p = 0.04).Ninety-one women (39.7%) had at least a single raised blood pressure in the intrapartum period (SBP⩾140 or DBP⩾90), and this was associated with a higher body mass index (p = 0.03), as well as the need for an emergency caesarean section (p < 0.01). Administration of intrapartum non-steroidal anti-inflammatory medications (NSAIDs) (p < 0.01) and epidural anaesthesia (p < 0.01) were associated with IH.There was an association between raised blood pressure during the intrapartum, and a longer second stage of labour (p = 0.03 and p = 0.02 respectively), birthweight <10th centile (p < 0.01) and the need for high level neonatal care (p = 0.02). The group with at least a single raised blood pressure reading during the intrapartum was more likely to have a fetal composite outcome (p = 0.03).Fetal outcomes and maternal post-partum outcomes differed between the two groups Table . Intrapap < 0.01), and elevated postpartum blood pressure readings (p < 0.01) with discharge on regular antihypertensive medications (p = 0.01).Women with at least a single raised intrapartum blood pressure reading also had a longer maternal inpatient admission following delivery (p = 0.04) was predictive of raised blood pressure during the intrapartum after controlling for the other variables of body mass index, intrapartum medications and duration of labour in the model.Regression analysis revealed that higher systolic blood pressure at the first antenatal visit  prior to delivery , and 83% of this group had hypertension during labour. Compared to previously normotensive women, the HDP group were more likely to have significantly higher initial antenatal visit, intrapartum, postpartum and discharge systolic and diastolic blood pressures (p < 0.01). They were more likely to require intrapartum intravenous antihypertensive medications, as well as have antihypertensive medications on discharge (p < 0.01). This group had a significantly higher rate of preterm deliveries (p = 0.03), maternal ICU admissions (p < 0.01), maternal re-admissions (p < 0.01) and length of stay > 3 days (p < 0.01) compared to the previously normotensive population (Supplementary Table Hypertensive disorders of pregnancy (HDP) had been diagnosed in 6% of women  developed systolic BP > 160 mmHg, though only seven were treated with antihypertensive agents, 3 of which required intravenous delivery. This is mirrored in other studies, where low rates of treatment of severe hypertension was common , 9. The In addition to defining the clinical characteristics of IH, this work sought to report on the consequences of IH for maternal and fetal outcomes. Two previous separate studies found that in more than half of eclampsia cases and intrapartum strokes, hypertension developed for the first-time during labour , 5. In tThis study is the first to assess fetal outcomes in the context of IH. There was no difference in fetal outcomes between the two groups. However, in the subgroup analysis of women with at least a single elevated BP reading, there was a higher rate of APGAR scores < 9, birthweight <10th centile, the need for high level neonatal care and a significant fetal composite outcome. The reason for this is unclear though may be in part explained by the higher rate of caesarean sections in this group, and larger studies are necessary to explore this association further.Another possible explanation for the higher rate of fetal birthweight <10th centile is that these women had undiagnosed HDP.There are several limitations to this study. Firstly, as a retrospective cohort study, the technique of measuring blood pressure that was utilised, nor the accuracy of recorded data within the medical record is not able to be validated. Secondly, this study had a small sample size, with no severe maternal events such as stroke or eclampsia occurring in this cohort.Finally, there are sources of bias that arise from the disproportionate incidence of IH in women undergoing caesarean sections. There is potential selection bias as women may undergo a caesarean section because of IH. Additionally, women undergoing a caesarean section exclusively receive intrapartum NSAIDs, a practice undertaken by many anaesthetists locally to reduce post-operative pain , and tenAlmost 14% of women without pre-existing hypertension, developed IH, while 3% developed severe hypertension (systolic BP ⩾160). Traditional vascular risk factors such as older maternal age, higher BMI and higher diastolic blood pressure at the first antenatal visit was associated with IH. Within this cohort, IH was associated with a longer maternal inpatient admission following delivery, elevated postpartum blood pressure readings, and discharge with regular antihypertensive medications. These findings suggest that IH may represent a late manifestation of a hypertensive disorder of pregnancy, rather than normal physiology of delivery.Additional file 1: Supplementary Table 1. Baseline demographics, intrapartum details and maternofetal outcomes for women two or more elevated blood pressure readings. Supplementary Table 2. Baseline demographics, intrapartum details and maternofetal outcomes for women with and without HDP.


In the latest reports, atherogenic indices have been related to acute coronary syndromes, stable coronary artery disease, heart failure and future cardiac events. Conventional atherosclerosis risk factors have been associated with mitral annular calcification (MAC), but data on the relationship between atherogenic indices and MAC are lacking. We aimed to investigate a possible relationship between MAC and atherogenic indices.In total 741 patients (n = 427 with MAC and n = 314 without MAC) who were examined in our cardiology clinic from February 2016 to October 2021 were recruited in the study. Mitral annular calcification was diagnosed by transthoracic 2-dimensional echocardiography. The atherogenic coefficient (AC), Castelli risk index 1 (CRI-1), Castelli risk index 2 (CRI-2) and atherogenic index of plasma (AIP) were calculated by utilizing standard lipid test values.There was no statistically significant difference in sex, age, diabetes and hypertension status between the patient and the control groups. Serum triglyceride level, AIP, Hs-CRP, smoking and BMI were independently significantly associated with MAC in multiple regression analysis (p < 0.001).Higher AIP was related to the existence of MAC and also predict the presence of MAC independently. Studies evaluating the modification of these indices are needed.The online version contains supplementary material available at 10.1186/s12872-022-02891-4. Mitral annular calcification (MAC) is described as calcification of the fibrous structures of the mitral valve . This chAtherogenic dyslipidemia, which is involved in the pathological process of atherosclerosis, is defined as coexistence of increased circulating triglycerides (TG) and decreased high-density lipoprotein cholesterol (HDL-C) . While eThe atherogenic index of plasma (AIP), calculated according to log10 (TG/HDL-C) formula, has been proposed as a strong marker in prediction of the atherogenicity and cardiovascular events in addition to individual lipid risk parameters –18. CompIn the retrospective study, we scrutinized the data of 66,575 patients who had transthoracic echocardiography (TTE) between February 2016 and October 2021 at our outpatient clinic. The patients were chosen arbitrarily from our clinic TTE database and patient files. We excluded the patients who had missing data on admission. After applying the exclusion criteria, 427 patients with MAC and sex and age-adjusted 314 patients without MAC as control were enrolled in the study , myocardial infarction, more than 50% occlusion of the carotid arteries, carotid artery surgery and/or stenting, history of valve surgery, decompensated heart failure, familial lipid metabolism disorders and patients who were receiving any lipid lowering medications  were excluded. In addition, we defined stroke, transient ischemic attack, peripheral arterial disease (occlusive disease of low extremity arteries with angiographic or Doppler ultrasound evidence or with history of revascularization or amputation), chronic obstructive pulmonary disease, malignancy, chronic inflammatory disease, autoimmune disease, chronic renal failure, thyroid dysfunction as exclusion criteria.Blood pressure was measured after 5 min rest in the morning and the mean value of two separate measurements was recorded. Hypertension was defined when the SBP was higher than 140 mmHg and/or DBP was higher than 90 mmHg or was on antihypertensive therapy. Diabetes mellitus was defined if the fasting blood glucose level was exceeding 126 mg/dl or receiving any diet or medications to reduce blood glucose. Patients were assigned as current smokers who continued smoking currently or ex-smoker who have quit smoking in the last six months. Body mass index was calculated using the formula; weight (kilogram)/square of height  and TG values were tested by standard laboratory methods. LDL-C was measured directly by LDL-C tests. AIP was calculated following the formula; logarithm of the TG to HDL-C ratio. Rest of the indices investigated in this study were calculated as; CRI-1 = TC/HDL-C; CRI-2 = LDL-C/HDL-C and AC non-HDL-C/HDL-C.Data were analyzed using SPSS 22.0 for Windows. Normality distribution of variables was assessed by using Kolmogorov Smirnov//Shapiro-Wilk test. For comparison, Student t test, chi-square test, and Mann-Whitney U test were used as appropriate. Results were reported as mean ± standard deviation for continuous variables which were normally distributed, median (min-max) for continuous variables without normal distribution and percentages for qualitative variables. The receiver operating characteristic curve analysis was used to determine predictive values of risk factors for MAC. We performed multivariate regression analysis adjusted for the variables that were of statistical significance in the univariate analysis. A multivariable logistic regression model with backward selection (P > 0.1 as exit criterion) was used to evaluate variables associated with MAC. Odd’s ratio and 95% confidence intervals for each variable were calculated. The statistical significance level was accepted as p-value < 0.05 in all analyses.We included 427 MAC (+) patients and 314 control subjects. The clinical, laboratory and demographic features of the patients are summarized in Table When we compared echocardiographic parameters Table , left veROC curve analysis revealed a cut-off level of 0.56 for AIP to predict MAC with 71% sensitivity and 70% specificity   and ongoing inflammation accompanying lipid accumulation were the main pathological mechanisms of MAC –22. AlsoAs a prominent index of atherogenicity in recent publications, AIP that is formulated as log10 (TG/HDL-C) showed higher correlations with cardiovascular diseases and stronger predictive power for future cardiovascular outcome when compared to simple lipid measurements in previous studies , 17. As In the study of Allison et al., patients with MAC have had higher non-HDL-C levels, lower HDL-C levels and higher TC to HDL-C ratios than age and sex matched controls while there was no significant difference in TC levels . NonetheWe have reported that increased smoking status, BMI and Hs-CRP levels were independently associated with MAC like some previous studies . AlthougOur study has some restrictions. Firstly, current study was designed retrospectively which emerged a structural limitation. Secondly, we did not evaluate the severity of MAC by echocardiography or any other imaging modalities. Thirdly, the echocardiography evaluation may have limitations due to imaging quality of echocardiography imaging method itself, but all the patients tested by the same device. Next, hypertension was diagnosed after two separate measurements of blood pressure on one visit though 2–3 office visits at 1–4-week intervals are suggested to confirm the diagnosis of hypertension. Lastly, our analysis based on a spot blood measurement so the alterations of those parameters during long periods could not be assessed meaning that lack of prognostic role in those patients.Elevated atherogenic indices have been associated with the existence of MAC, which has an increased risk for mitral valvular disease, conduction system delays and atrial fibrillation. Future investigations are warranted to elucidate whether lipid lowering medication could prevent the mitral annular calcification.Below is the link to the electronic supplementary material.Supplementary Material 1: Mac raw dataSupplementary Material 2: Supplement file for ROC curve analysisSupplementary Material 3: Legends of supplementary file


Patients after kidney transplantation need to take long-term immunosuppressive and other drugs. Some of these drug side effects are easily confused with the symptoms of Fanconi syndrome, resulting in misdiagnosis and missed diagnosis, and causing serious consequences to patients. Therefore, improving awareness, early diagnosis and treatment of Fanconi syndrome after kidney transplantation is critical.This retrospective study analyzed 1728 cases of allogeneic kidney transplant patients admitted to the Second Xiangya Hospital of Central South University from July 2016 to January 2021. Two patients with Fanconi syndrome secondary to drugs, adefovir dipivoxil (ADV) and tacrolimus, were screened. We summarized the diagnostic process, clinical data, and prognosis.The onset of Fanconi syndrome secondary to ADV after renal transplantation was insidious, and the condition developed after long-term medication (>10 years). It mainly manifested as bone pain, osteomalacia, and scoliosis in the late stage and was accompanied by obvious proximal renal tubular damage  and renal function damage (increased creatinine and azotemia). The pathological findings included mitochondrial swelling and deformity in renal tubular epithelial cells. The above symptoms and signs were relieved after drug withdrawal, but the scoliosis was difficult to rectify. Fanconi syndrome secondary to tacrolimus has a single manifestation, increased creatinine, which can be easily confused with tacrolimus nephrotoxicity. However, it is often ineffective to reduce the dose of tacrolomus, and proximal renal failure can be found in the later stage of disease development. There was no abnormality in the bone metabolism index and imageological examination findings. The creatinine level decreased rapidly, the proximal renal tubule function returned to normal, and no severe electrolyte imbalance or urinary component loss occurred when the immunosuppression was changed from tacrolimus to cyclosporine A.For the first time, drug-induced Fanconi syndrome after kidney transplantation was reported. These results confirmed that the long-term use of ADV or tacrolimus after kidney transplantation may have serious consequences, some of which are irreversible. Greater understanding of Fanconi syndrome after kidney transplantation is necessary in order to avoid incorrect and missed diagnosis. Kidney transplantation is currently considered as the most effective treatment method for end-stage renal disease. Compared with long-term dialysis treatment, patients who received kidney transplantation have achieved longer survival and better quality of life –3.After kidney transplantation, a large amount of immunosuppressive drugs and other drugs are regularly taken for a long time that can cause drug toxicities, numerous side effects, and complications.Fanconi syndrome, is a clinical syndrome of a variety of small and medium molecular substance reabsorption disorders caused by the impairment of proximal renal tubular function caused by congenital or acquired factors. It is rare in clinical practice. Fanconi syndrome was first described by Lignac in 1924, and in 1936, Fanconi first characterized children with Fanconi syndrome as having rickets, growth retardation, and diabetes (Transplanted patients with hepatitis B or hepatitis B virus (HBV) carriers need to take long-term medication. The nucleotide analogue adefovir dipivoxil (ADV) is widely used in the treatment of chronic hepatitis B , 8. HoweThis study aimed to review and summarize the clinical processes of diagnosis, treatment, and prognosis of Fanconi syndrome secondary to ADV and tacrolimus after kidney transplantation in the Second Xiangya Hospital of Central South University.From July 2016 to January 2021, a total of 1728 cases of allogeneic kidney transplantation were performed in the Department of Kidney Transplantation, the Organ Transplantation Center of the Second Xiangya Hospital of Central South University. During this period, five post-renal transplant patients were diagnosed with Fanconi syndrome. The flowchart for the screening of studied patients is presented in All recipients were routinely given methylprednisolone intravenous infusion and oral mycophenolate mofetil before kidney transplantation. Regarding the induction therapy, deceased-donor (DD) kidney transplant recipients were given anti-thymocyte globulin induction before surgery, and living-donor (LD) kidney transplant recipients were given baliximab before surgery. All recipients were treated with triple immunosuppressive therapy after surgery, including tacrolimus , mycophenolate mofetil , and methylprednisolone . The tacrolimus concentration was measured regularly and maintained at 6–9 ng/mL within 1 year post-renal transplant patients and no less than 6 ng/mL thereafter. Once the diagnosis of tacrolimus-induced Fanconi syndrome was confirmed, tacrolimus was immediately replaced with 3 mg/(kg d) cyclosporin A. The plasma concentration of cyclosporin A was monitored with a valley concentration target concentration of 80–120 ng/mL and a peak concentration target concentration >400 ng/mL.All kidney transplant recipients were routinely treated with antibiotics to prevent infection, and DD recipients were routinely treated with a “big siege” infection prevention program (anti-Gram-negative bacteria in conjunction with anti-Gram-positive bacteria and caspofungin) for 10 days to prevent infection. Donor kidney lavage fluid, wound drainage fluid, and urine were collected for culture. The anti-infection regimen was adjusted according to the negative culture results. LD recipients routinely used second-generation cephalosporins for infection prevention after surgery, and quinolones were used to prevent infection for 1 week in case of allergy. If the renal function recovered well within half a month after the operation, compound sulfamethoxazole was added to prevent Pneumocystis jirovecii pneumonia(PJP) up to 9 months after the operation. If there was no obvious bone marrow suppression such as leukopenia within half a month after the operation, ganciclovir/valganciclovir was added to prevent cytomegalovirus(CMV) infection until 9 months after the operation. If the patient was positive for hepatitis B surface antigen (HBsAg), intravenous hepatitis B immunoglobulin was administered for 5 days after the operation, followed by long-term oral nucleotide drug anti-HBV treatment and regular monitoring of HBV-DNA level. The patient was treated with long-term oral ADV against HBV due to positive HBsAg after operation.2) at the posterior anterior position of the left proximal femoral neck and lumbar spines L1-L4 . Whole-spine splicing X-ray anterior and lateral views, whole-body single-photon emission computed tomography bone scan, and transplanted kidney biopsy pathological examination were performed, and other clinical data were collected.Retrospective analysis was used to observe and evaluate the general information of patients, including the primary disease before transplantation, type of dialysis, duration of dialysis, type of kidney donation, number of human leukocyte antigen (HLA) mismatches, whether or not it was the primary transplant, the time of Fanconi symptoms, main symptoms and conditions, time from symptom discovery to diagnosis, type and dosage of causative drugs, and duration of medication. Comparative statistical analysis was performed after kidney transplantation from the time of increased creatinine level, bone pain, and osteomalacia symptoms to the day of diagnosis of Fanconi syndrome. Laboratory tests related to Fanconi syndrome, including blood creatinine, blood urea nitrogen, blood uric acid, blood bicarbonate, blood phosphorus, blood potassium, blood calcium, blood glucose, urine β-2 microglobulin, urinary phosphorus, urinary potassium, urinary calcium, urinary glucose, and estimated glomerular filtration rate (eGFR) value, were performed at 2, 7, 18, 500 and 1825 days after diagnosis of Fanconi syndrome. Laboratory tests of bone metabolism and molecular markers included 25 hydroxy-vitamin D (25-OH-VitD), N-terminal mid-fragment (N-MID), procollagen type 1 N-terminal peptide (P1NP), β-isomerized cross-linked C-telopeptide of type 1 collagen (βCTX), alkaline phosphatase (ALP), and intact parathormone (iPTH). Dual-energy x-ray absorptiometry was performed to determine the bone mineral density  until the diagnosis of Fanconi syndrome. Even so, after immediate drug withdrawal and active symptomatic treatment, the eGFR of the two patients recovered significantly, and they were followed up for approximately 5 years (1825 days) and 1 year (500 days). The eGFR of the two patients increased to 41.45 and 40.25 mL/min/1.73 m2, respectively (Before the diagnosis of Fanconi syndrome (>10 months), the eGFR of patients with ADV and tacrolimus remained at approximately 65 and 40 mL/min/1.73 mectively Figure 22 before the diagnosis of Fanconi syndrome, which reached the lowest level (0.574 g/cm2) >12 months after the diagnosis. It gradually recovered to 1.017 g/cm2 at the current follow-up at approximately 60 months after drug discontinuation. The bone mineral density score also changed from severe osteoporosis (−2.53) and gradually increased and reached a normal level (0.3). The bone mineral density of the femoral neck ranged from 0.922 g/cm2, before the diagnosis of Fanconi syndrome, to 0.387 g/cm2, at more than 12 months after the diagnosis and gradually recovered after drug withdrawal, and the bone mineral density was 0.446 g/cm2 at the most recent follow-up (approximately 60 months). The bone mineral density score was −2.53 in severe osteoporosis, and it was −2.7 at the current follow-up at 60 months. Although the bone mineral density of the femoral neck improved after drug withdrawal, severe osteoporosis remains during the long-term follow-up. Owing to the timely diagnosis of the tacrolimus patient, no changes in the lumbar spine or bone mineral density have occurred yet, and the bone mineral density and score were normal until follow-up at 12 months.The patients’ laboratory tests of bone health-related metabolism before the diagnosis of Fanconi syndrome (>10 months), at the diagnosis of Fanconi syndrome, and during follow-up are presented in The transplanted kidney biopsy of the ADV patient revealed the following light microscopy results: shedding of renal tubular epithelial, exposed basement membrane, regeneration of some renal tubular epithelial cells, red blood cells in the lumen, and scattered inflammatory cells in the interstitium, chemotherapy drugs (such as cisplatin and cyclophosphamide), anti-nucleotide drugs (such as ADV and tenofovir), valproate, and Chinese herbal medicines containing reported . In partreported . There aIn our study, the ADV patient was found to be positive for HBsAg after kidney transplantation; thus, long-term anti-HBV treatment , was given, which is very common in kidney transplant patients. Chronic viral hepatitis B is a disease characterized by chronic liver inflammation caused by persistent HBV infection. The low immunity after kidney transplantation can easily cause explosive hepatitis. Long-term anti-HBV drug treatment is needed to control the HBV-DNA at a low level. More than 350 million people worldwide are HBV carriers. China is a high-incidence area of HBV infection. Currently, there are approximately 93 million cases of chronic HBV infections, accounting for almost one-third of worldwide HBV cases –25. DrugOsteopenia and osteoporosis are the common complications after kidney transplantation. At the same time, kidney transplant recipients are most susceptible to bone diseases due to various chronic kidney diseases before surgery, which manifest as hyperphosphatemia, hypocalcemia, increased parathyroid hormone, abnormal vitamin D levels, increased alkaline phosphatase levels, and metabolic acidosis. Although kidney transplantation improves the recipient’s renal function and quality of life, abnormal bone metabolism persists. More than 15% of kidney transplant patients develop osteoporosis in the first year after transplantation , and theHowever, post-renal transplant patients who take glucocorticoids for a long time may have accompanying chronic viral hepatitis that requires long-term ADV treatment. Osteomalacia and skeletal deformities are not yet present in the early stage of the disease. At this stage, bone pain and bone loss are the main symptoms, which are easily confused with osteoporosis caused by hormones, leading to misdiagnosis . In thisTacrolimus is a calcineurin inhibitor, which is a macrolide immunosuppressant extracted from the fermentation broth of Streptomyces tsukubaensis. It was approved by the FDA in 1994 for solid-organ transplantation. At present, it is widely used in the prevention and treatment of rejection after various organ transplantations, which is an important part of the immunosuppressive regimen after kidney transplantation . RelevanIn this study, the patient regularly took tacrolimus  for a long time after kidney transplantation, and the tacrolimus trough concentration was regularly monitored to be no less than 6 ng/mL. Except for long-term combined use of mycophenolate mofetil and methylprednisolone to maintain immunity, no other drugs were taken, and there was no occurrence of heavy metal poisoning. Ten years after kidney transplantation, the patient had an increase in creatinine, which may be initially considered as nephrotoxicity caused by tacrolimus. We adjusted the dosage of the drug to reduce the trough concentration of tacrolimus, but the patient’s creatinine gradually increased from normal to 490 μmol/L, and fatigue occurred. There were no other specific manifestations, and the urine output did not decrease. The population-reactive antibodies showed negative results, and other related antibody investigations showed no abnormality. The ultrasound Doppler of the transplanted kidney showed that the blood flow of the transplanted kidney was abundant, and the renal vascular resistance index was not high. Based on the findings, the possibility of rejection and prerenal damage was not considered. We found that the patient had obvious evidence of proximal tubular injury, increased serum creatinine, and azotemia, but the serum uric acid was significantly decreased, and the patient developed severe hypophosphatemia, severe hypokalemia, severe hypocalcemia, severe metabolic acidosis, and urine β-2 microglobulin, which met the diagnostic criteria for Fanconi syndrome . The tacThis study focused on the characteristics of Fanconi syndrome after kidney transplantation, which can reduce incorrect and missed diagnosis and thus benefit transplant patients. The limitations of our study is that number of patients is limited and tacrolimus patient have no kidney allograft biopsy. Exploring potential spectific biomarkers to identify Fanconi syndrome in the early stage deserves further research.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 Ethics Committee of the Second Xiangya Hospital of Central South University. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.ZT, TL and HD drafted the manuscript. ZT, CHF, MN, XY, YF, JP, SS, MZ and CF collected data. JP and MZ generated the figures. XX, HZ, FP, GL, SY, YW and XT performed the surgery. XZ and XJ made and analyzed the biopsies. LP, HD, ZT and TL designed the outline of the manuscript and revised the manuscript. All authors contributed to the article and approved the submitted version.This work is supported by the National Science Foundation of China , Excellent Youth Foundation of Hunan Province of China (2021JJ10076) and Huxiang Young Talents of Hunan Province (2019RS2013).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.