Accurate continuous non-invasive blood pressure (CNIBP) monitoring is the holy grail of digital medicine but remains elusive largely due to significant drifts in signal and motion artifacts that necessitate frequent device recalibration. To address these challenges, we developed a unique approach by creating a novel intra-beat biomarker  to achieve highly accurate blood pressure (BP) estimations. We demonstrated our approach’s superior performance, compared to other common signal processing techniques, in eliminating stochastic baseline wander, while maintaining signal integrity and measurement accuracy, even during significant hemodynamic changes. We applied this new algorithm to BP data collected using non-invasive sensors from a diverse cohort of high acuity patients and demonstrated that we could achieve close agreement with the gold standard invasive arterial line BP measurements, for up to 20 min without recalibration. We established our approach's generalizability by successfully applying it to pulse waveforms obtained from various sensors, including photoplethysmography and capacitive-based pressure sensors. Our algorithm also maintained signal integrity, enabling reliable assessments of BP variability. Moreover, our algorithm demonstrated tolerance to both low- and high-frequency motion artifacts during abrupt hand movements and prolonged periods of walking. Thus, our approach shows promise in constituting a necessary advance and can be applied to a wide range of wearable sensors for CNIBP monitoring in the ambulatory and inpatient settings. Most commonly, BP is measured intermittently at the arm using a non-invasive sphygmomanometer . In high acuity medical settings, such as the operating room (OR) and intensive care unit (ICU), continuous BP monitoring is achieved via an invasive arterial catheter (A-line) placed in a peripheral artery2. While the A-line allows for the detection of sudden hemodynamic changes, since A-lines are highly invasive and associated with a number of medical complications, including hematoma, arterial thrombosis, and infection, their use is often limited to patients who are “high risk”6. In the U.S., it is estimated that only 36% of critically ill patients in the ICU receive an A-line7. Given the arm cuff’s relatively low precision compared to the A-line, and its tendency to overestimate low BPs and underestimate high BPs, its use as the sole instrument for measuring BP in most patients results in undetected critical hemodynamic changes that may have otherwise influenced patient care11. Additionally, recent studies have correlated continuous BP patterns with cardiovascular outcomes; for example, the variability in beat-to-beat BP measurements can be used to assess important physiological parameters, such as vascular tone, fluid responsiveness, and sympathetic autoregulation15.Blood pressure (BP) is an important physiologic metric that provides insights on a patient's cardiac function, volume status, organ perfusion, and overall hemodynamic stability18. Despite meeting the accuracy guidelines (mean average error ≤ ± 5 mmHg and standard deviation < 8 mmHg) cited by the Association of Advancement of Medical Instrumentation (AAMI) and U.S. Food and Drug Administration (FDA), their widespread use has been largely limited due to their bulkiness, high cost, and inconvenient form factor20.For this reason, continuous noninvasive BP (CNIBP) monitoring has garnered increasing interest over the past several decades yet remains an elusive unmet need. One of the first discovered CNIBP techniques was the volume-clamp method, which has been implemented in several commercial devices, including ClearSight , Caretaker , and CNAP 19. As they are susceptible to interference from ambient light, skin tone, changes in applanation pressure, and low-frequency baseline wander, PPG-based devices rely on a number of pre-processing steps, and often include moving average filters, frequency filters, and other noise-reduction techniques, such as discrete wavelet transformation (DWT) or empirical mode decomposition (EMD)26. Furthermore, since PPG requires high applanation pressures to achieve adequate morphologic resolution, many devices have transitioned to using the PPG signal’s temporal dimension via pulse wave velocity (PWV) to more reliably estimate BP27. PWV can be calculated from either the pulse transit time (PTT) or pulse arrival time (PAT). The former is defined as the time taken by a pressure wave to travel between two arterial sites and can be calculated by using two synchronized PPG signals at two different peripheral sites. The latter is defined as the PTT interval plus the pre-ejection period, which represents the delay between electrical depolarization of the left ventricle and the onset of ventricular ejection29. By using an additional nearby electrocardiogram (ECG) device, PAT was developed to overcome the significant challenge of calibrating two anatomically distant PPG devices.Photoplethysmography (PPG)-based devices have attracted attention for their smaller form factor compared to volume-clamp devices32. While both studies had initially shown satisfactory correlations to the radial A-line, McCarthy et al. demonstrated that Chen’s algorithm actually required recalibration every 4 minutes and tracked BP changes poorly33. Furthermore, in the context of vasoactive drugs, Payne et al. suggested that the calibration interval be further reduced to every 60 beats34. Conversely, Poon’s algorithm demonstrated improved BP tracking capabilities; however, it required recalibration every 45 seconds to stay within AAMI standards33. Indeed, since their inception, numerous variations of these algorithms have been developed with the aims of improving accuracy and reducing calibration dependency21. Moreover, pulse wave decomposition analysis and more complex models  have been implemented to improve measurement performance36. However, the external validity of these algorithms and their ability to perform in different clinical contexts has been difficult to assess, since most studies do not report their calibration intervals and data’s hemodynamic ranges.Many studies have described methods for estimating BP using PTT or PAT. Two of the most cited algorithms, developed under the basis of the Moens–Kortweg equation, were created by Chen et al. and Poon et al., and proposed quick calibration of PTT/PAT values by using a single reference BP value 37. While this approach was not validated against the A-line or an FDA-cleared device, a recent study demonstrated its ability to estimate systolic blood pressure (SBP) in the context of artificially generated baseline wander38. Most recently, Xu et al. proposed normalized STT (NSTT), which aimed to improve the stability of STT with normalization by PPG height39. Among 40 hemodynamically stable subjects, this approach demonstrated comparable results to an FDA-cleared tonometry device. However, since their technique relied on performing linear regression on their recorded waveform features, future investigation using clearly defined, distinct training and validation datasets are still needed in order to assess its accuracy.In 2016, Addison et al. proposed a single intra-beat PPG signal feature coined slope transit time (STT) as an alternative of PTT for tracking blood pressure41. Over the years, CAP sensors have grown increasingly popular due to their convenient form factor, high spatial resolution, quick response times, and low power consumption requirements42. Unlike PPG- and oscillometry-based devices, CAP sensors detect pulsatile flow from the artery by measuring the changes in capacitance that result from compression and expansion of the soft dielectric layer. Thus, similar to arterial tonometry, CAP sensors are placed directly over the artery, and with the use of an initial arm cuff measurement, can be calibrated to measure beat-to-beat BP43. Although CAP sensors were previously limited by their low sensitivities, recent advancements in sensor design have largely overcome this challenge45. While studies have previously demonstrated the potential for CAP sensors to correlate well with measurements from the A-line, similar to PPG, quality of the data is highly dependent on applanation pressures46. Additionally, due to respiratory variations and the stochastic behavior of the viscoelastic polymer sensors, they are highly susceptible to baseline wander47. Thus, as with PPG signals, scientists have had to employ a variety of filters to eliminate this low frequency baseline wander. While seemingly successful, these filters have been primarily tested on short signal segments where there were little to no changes in BP. For example, studies have often employed high-pass frequency filters with cut-offs of 0.25–0.5 Hz to reduce baseline wander; however, this approach may impede the ability to perceive slow physiological drifts in BP that fall below this frequency range49. Moreover, studies have not examined how these filters may alter interpretations of blood pressure variability (BPV). Therefore, the validity and safety of using such filters on physiological signals that are intended to inform medical decisions remains largely unknown.The advent of Microelectromechanical System (MEMS) technology has introduced the prospect of using small, wearable capacitive pressure (CAP) sensors for CNIBP monitoring50. Compared to other commonly employed signal processing techniques, including bandpass filter (BF), DWT, and STT, we demonstrated our approach’s superior performance in eliminating stochastic baseline wander, while maintaining signal integrity and BP estimation accuracy in the context of significant (> 10% from baseline) hemodynamic changes. We applied this novel algorithm in a demographically and medically diverse cohort of 15 OR patients and showed that we could achieve high correlations between the adjusted non-invasive CAP sensor data and gold standard A-line BP measurements in the context of stress- and drug-induced hemodynamic perturbations for as long as 20 min without re-calibration  to achieve highly accurate BP estimations. We defined DTT as the time from systolic peak to diastolic trough within a heartbeat. Unlike PTT or PAT that necessitate the use of multi-sensor systems, our algorithm utilizes the morphology of the hemodynamic waveform to enable single-sensor BP monitoringIn summary, our algorithm demonstrates several advantages to existing techniques, including: (1) enabling single-sensor BP monitoring, (2) removing stochastic baseline wander, (3) maintaining spatiotemporal signal integrity, (4) mitigating motion artifacts from sudden  or cyclic  movements, thereby (5) facilitating accurate BP measurements for patient monitoring. Thus, we introduce a unique and generalizable algorithm based on a novel intra-beat biomarker to correct raw BP data  obtained from various sensor sources to accurately estimate BP parameters, with significant implications in enhancing CNIBP technologies and overcoming challenges that have heretofore hindered their wide-scale adoption and usefulness.2. A total of 10,226 s of intra-operative BP recordings were extracted, with an average segment length of 204.5 (range: 60–1200) seconds. The ICU cohort consisted of 20 BP recordings, totaling 8405 s in duration, from different patients being treated at an ICU. The average segment length of the ICU recordings was 420.3 (range: 180–590) seconds. Due to the anonymized nature of the database, demographics were not available for the ICU patients.BP data was obtained from 15 surgical patients , DWT (4.70% ± 3.51), and STT (2.80% ± 1.10) algorithms . Moreover, average DBP errors were higher using the DWT  and STT  methods. While measurement errors from the DTT algorithm were consistently below 8%, significant deviations in accuracy were observed with the other algorithms during hemodynamic changes , with errors surpassing 15%.To compare our algorithm’s accuracy, calibration dependency, and BP tracking ability with those of other commonly employed methods, we utilized a 300-s segment of CAP sensor and A-line BP recordings from a hemodynamically unstable surgical patient Fig. . Based oUsing BP recordings from high acuity patients (OR and ICU), we evaluated our algorithm’s ability to correct raw BP signals and accurately measure critical cardiovascular parameters Figs.  and 4. OIn the OR cohort, we demonstrated strong linear correlations between CAP sensor estimations and gold standard A-line measurements, with Pearson coefficients of 0.987, 0.960, and 0.980 for SBP, DBP, and MAP, respectively Fig. a. The reTo demonstrate the generalizability of the DTT algorithm to other modalities, we further evaluated the accuracy of our approach by applying it to PPG measurements obtained from ICU patients. We similarly showed strong linear correlations to the A-line, with Pearson coefficients of 0.982, 0.958, and 0.952 for SBP, DBP, and MAP, respectively Fig. a. Moreovp = 0.351), DBP (p = 0.272), and MAP (p = 0.426).Assessment of beat-to-beat BPV can provide unique perspectives on important cardiovascular parameters and physiologic states. Thus, to verify that our approach maintained BPV integrity, we applied our DTT algorithm to the gold standard A-line measurements for all 15 OR patients and evaluated if BPV would be significantly altered. On average, the SDs of processed and unprocessed A-line measurements were 1.35 and 1.40 mmHg for SBP, 0.97 and 0.90 mmHg for DBP, and 1.02 and 1.01 mmHg for MAP, respectively. Overall, there was no statistically significant difference in BPV between these two groups for SBP . Finally, vascular disease was found to be associated with a significantly higher SBPV and DBPV .Hence, to uncover associations between BPV and cardiovascular health, OR patients were stratified into cohorts according to their age, history of hypertension, and history of vascular disease (VD). The systolic (SBPV) and diastolic BPV (DBPV) of subjects were subsequently evaluated and compared across groups Fig. . In the Intermittent motion artifacts present a significant challenge for ambulatory and outpatient CNIBP. To investigate our algorithm’s potential for future implementation into these settings, we assessed its performance in correcting CAP sensor measurements in the context of common arm/hand movements − 180° wrist rotation, 90° wrist flexion, hand closure, and wrist hit/impulse—and walking Fig. . MovemenOverall, the processed CAP sensor signals exhibited excellent agreement with Caretaker measurements. On average, the mean biases (SD) were 2.03 (2.55), 0.82 (2.83), 0.75 (2.6), and 2.10 (3.60) mmHg for SBP and 0.16 (2.09), 0.51 (1.86), 0.34 (2.16), and 0.84 (3.73) mmHg for DBP during wrist rotation, wrist flexion, hand closure, and wrist hit/impulse, respectively. Additionally, over the duration of three minutes of walking, our algorithm’s BP estimates agreed well with Caretaker measurements and demonstrated mean biases of 3.94 (5.49) and 1.03 (3.23) mmHg for SBP and DBP, respectively.53. For example, Kaisti et al. recently developed a non-invasive wearable MEMS pressure sensor that demonstrated remarkable temporal and morphological BP waveform accuracy; however, they were unable to measure BP amplitude due to reported baseline variations54. Some devices have attempted to circumvent this issue by requiring recalibration as frequent as every minute56. Naturally, this has made such devices often impractical and has stymied their adoption into clinical practice. Therefore, our algorithm’s ability to effectively remove this problematic drift and overcome this long-existing challenge can have significant implications in bringing existing and future CNIBP monitoring technologies closer to clinical use. Additionally, unlike many methods that require a posteriori signal processing, such as filters or regressions, or machine learning-based approaches that are computationally expensive and require training on large datasets, our DTT approach is algorithmically simple and may be more adaptable to real-time monitoring applications.In this study, we demonstrated the efficacy of our novel DTT approach in eliminating stochastic baseline wander to achieve accurate beat-to-beat BP measurements, well-within the limits demanded by AAMI/ISO standards, using noninvasive CAP and PPG sensor recordings from surgical and ICU patients. Despite their many advancements over the years, CNIBP monitors  all continue to face significant baseline drift and noise that prevent accurate, long-term continuous BP measurements53. Thus, by using a heterogenous and hemodynamically labile cohort of patients for our analyses, we were to evaluate our algorithm’s performance across a wide range of physiologic states and establish its validity for clinical use. However, nearly 52% of prior studies have reportedly used only normotensive patients for testing, severely limiting their external validity. Moreover, only 4% of studies have included hypotensive patients and fewer than 8% have included hypertensive patients in their analyses57. Therefore, this study serves as one of a select series of reports that have investigated CNIBP monitoring accuracy across a representative cohort of patients.Since a number of cardiovascular changes occur at varying BPs and heart rates, it is important for measurement techniques to be validated across a wide hemodynamic range before being considered sufficiently reliable for use in clinical practice26. However, since these methods are commonly applied to healthy, young subjects and their results reported as aggregate averages, it is often not possible to characterize their behaviors in the context of active BP changes. By utilizing a hemodynamically labile segment of BP measurements, we were able to characterize and compare our approach’s ability to track BP changes with other common techniques. As hypothesized, the accuracies of BF- and DWT-based methods faltered during changes in BP. This is likely due to the filters’ inability to distinguish between artificial  and physiological BP drift, since the basis of both methods rely on signal frequency without considering individual waveform characteristics. On the other hand, STT-based BP estimation exhibited slightly higher errors in SBP, but significantly greater deviations in DBP than our approach. As the BP waveform can be affected by many factors, it is possible that the STT method’s reliance on a single systolic feature limited its ability to the reflect changes in both SBP and DBP39.The ability for an algorithm to accurately track BP changes is also an important dynamic measure that is rarely assessed. Studies have frequently utilized pre-processing methods, such as BF and DWT, to reduce noise and baseline drift, with seemingly acceptable results59. Additionally, we observed that patients with hypertension exhibited higher ARVs and SDs for SBP and DBP than healthy individuals. This is consistent with Xia et al. findings, which suggested that hypertensive patients may possess compromised vascular elasticity, and hence elevated BPV60. While we did not observe a significant difference in coefficient of variation (COV) between the two groups, this may have been attributed to a type II error from a limited sample size or due to COV’s lower sensitivity for short-term changes than ARV62. Finally, we demonstrated a significantly higher SBPV and DBPV in vascular disease patients than healthy individuals. Interestingly, there was an observably larger inter-group difference in DBPV than SBPV. This was likely a result of the characteristic increase in arterial wall stiffness associated with vascular disease63.Validation experiments indicated that our DTT algorithm did not significantly alter BP signal variability, suggesting that our approach may be applied to future studies on short-term BPV. Our proof-of-concept experiments supported this conclusion, as we were able to identify several interesting associations between short-term BPV and cardiovascular health. Our findings demonstrated that older age was associated with increased SBPV and DBPV, in agreement with other studies that have suggested it to be due to increased arterial stiffness and impaired baroceptor function53. While several promising techniques have been recently developed, compensating for motion artifacts, especially those from “macro-motions” during walking or jogging, that possess an overlapping frequency spectrum with the BP signal remains a challenge65. In our experiments, we showed that our DTT algorithm was able to recover quickly from sudden baseline shifts caused by abrupt hand/arm movements. Additionally, we demonstrated our algorithm’s high tolerance to low-  and high-frequency  motion artifacts through its ability to accurately measure beat-to-beat BP during a prolonged period of walking. Importantly, these strong correlations were achieved without using any frequency filters or advanced signal processing techniques, as evidenced by the remnant signs of walking-induced enveloping in the DTT-processed BP signals. While additional testing during more intense activities is warranted, our DTT approach, nonetheless, shows potential as a means towards bringing CNIBP monitoring to the ambulatory setting.As the demand increases for wearable devices that enable continuous day-to-day biomonitoring, significant efforts have been made towards developing systems that support long-term ambulatory recording. However, despite many advancements in CNIBP monitoring technologies over the years, ambulatory BP monitoring continues to be an elusive undertaking. The presence of motion-related artifacts and abrupt changes in signal baseline introduce an especially complex confounding factor in BP estimation algorithms that make accurate and precise ambulatory BP monitoring a significant challenge67, it is still susceptible to the confounding effects incurred by changing applanation pressure. Quantitative characterization of pulse waveforms shows promise as a method of automatically assessing signal quality and detecting perturbations in applanation68. Several groups have also demonstrated the feasibility of using a secondary pressure sensor or force transducer as a feedback mechanism within their system to account for changes in contact pressure71. For the purposes of demonstrating our DTT approach, we manually excluded segments of data with visibly low-quality waveforms and utilized a moving median filter as a coarse method to remove remaining intermittent disruptions in signal quality. Future iterations of our algorithm will benefit from a machine learning classification model  to automatically assess signal quality and more precisely exclude corrupt waveforms73. Additionally, while we tested our algorithm against a wide and dynamic range of cardiovascular parameters, further testing of this technique against a larger sample of patients would better elucidate its generalizable efficacy. Moreover, future investigations are warranted to directly compare the accuracy and tracking performances of our DTT algorithm with multi-sensor approaches using PTT or PAT. Nonetheless, our DTT approach shows promise in constituting a necessary advance for wearable sensors for CNIBP monitoring in the ambulatory and inpatient settings.Although our approach overcomes several critical obstacles in CNIBP monitoring, there are still limitations that warrant future study. While our DTT algorithm mitigates much of the challenges associated with baseline wander and motion artifacts, as with existing CNIBP technologies75. Ambulatory BP measurements used for motion artifact analysis were obtained from one healthy subject using an FDA-cleared CNIBP monitoring device  and a noninvasive CAP sensor placed at the contralateral radial artery. Informed consent was obtained from all OR and ambulatory subjects, and experimental protocols were approved by and conducted in accordance with the UCI Institutional Review Board (IRB no. 2019-5251 and 2016-2924). Usage of the ICU recordings was IRB exempt due to the anonymized and deidentified nature of the public database.BP data was acquired from subjects in the OR, ICU, and ambulatory settings. The OR cohort consisted of 15 intraoperative patients receiving treatment at the University of California, Irvine (UCI) Medical Center between June 2020 and March 2021. All patients were under general anesthesia and received intravenous medications  whenever clinically indicated. BP recordings from surgical patients were simultaneously obtained invasively via radial A-line and noninvasively using a CAP sensor placed on the contralateral radial artery  of sensors could not be controlled for in the OR and ICU setting, an unsupervised algorithm was developed to objectively identify and exclude segments of data that contained significant deviations in applanation. Since perturbations in contact pressure alter signal amplitude, a change in BP waveform contractility, defined as the maximum of the first derivative of the systolic upstroke, was used as a surrogate marker of changing applanation. Hence, for a given pair of noninvasive and invasive BP signals, regressions of the change in normalized contractility were calculated and compared using a hypothesis test. The sensors were considered to have significant deviations in applanation if the pair of regressions were statistically different (p < 0.05). A 30-s sliding window was utilized in this step to minimize the amount of excluded data.All collected BP signals were pre-processed in MATLAB  prior to analysis. Using the devices’ integrated clocks, noninvasive BP measurements (via CAP or PPG sensors) were synchronized with the recordings from reference devices (A-line or Caretaker) to a precision of one second. Next, BP recordings were manually determined by the authors to exclude sections of data with low-quality signal based on the following criteria: (1) signals were at least 30 s in length and (2) consisted of at least 30 s of continuous BP waveforms possessing clearly visible systolic peaks, dicrotic notches, and diastolic troughs. Since inconsistent applanation pressure is a major source of measurement error in CNIBP monitorsBP_annotate package in MATLAB to identify the peaks and troughs in our raw BP signal and extract each BP waveform76. Once extracted, these waveforms were used by our algorithm to calculate beat-to-beat DBP based on an initial calibration measurement and each waveform’s distinct morphology  hemodynamic waveforms, as shown in Fig. logy Eq. . These “logy Eq.  and baseeDBP was the estimated DBP, t was time, SBP0 was the initial SBP cuff measurement, m0 was a calibration factor, and C was waveform contractility. The factor, m0, was calculated as an average of the first five recorded beats:PP0 was the initial pulse pressure obtained by cuff measurement, PPs was the sensor pulse pressure, SBPs was the sensor SBP, and DBPs was the sensor DBP.Using an initial BP measurement from a standard BP cuff, beat-to-beat diastolic blood pressure (DBP) was calculated as a function of DTT, defined as the time from systolic peak to diastolic trough, and waveform contractility Fig. :1\docume0 [mm Hg/s], served two purposes: (1) to convert the raw signal into pressure measurements [mm Hg] and (2) to track changes in DBP relative to the initial DTT. Beat-to-beat change in contractility was included as a dynamic transformation factor to adjust for stress- or drug-induced physiological changes in left ventricular contractility that can modify contraction and relaxation times and, consequently, alter BP waveform morphology78.Thus, the calibration factor, mSince our algorithm calculated DBP using intra-beat parameters that were independent of the confounding effects introduced by low-frequency noise, by comparing the estimated DBP to raw DBP, we were able to empirically model the baseline wander in our recordings, which served as an offset for the raw BP signals Fig. b. The ca79. COV is a normalized measure of SD and was defined by dividing by the mean BP80. ARV, which aims to account for the temporal order of measurements and reduce the errors produced by signal noise, was defined by the mean of the absolute differences between adjacent BP measurements82. Each BPV measurement represented an average over a 30-beat window. Since intraoperative infusion of vasoactive medications could artificially increase BPV, this confounding factor was mitigated by excluding BPV measurements from segments that exhibited BP ranges exceeding 10 mmHg.Since there is currently no well-established standard for measuring BPV, short-term (beat-to-beat) SBPV and DBPV were quantified using three different metrics: SD, COV, and ARV. SD is the most commonly used index and represents the global fluctuation of BP measurements around the meanp-value less than 0.05 was considered statistically significant. A t-test or Wilcoxon signed rank test was used for continuous variables to evaluate differences between the means of two samples. Shapiro–Wilk tests were used to assess for normality. Brown–Forsythe tests were used to determine statistical differences in BPV between two sets of measurements. Pearson linear correlation coefficients were calculated to assess how well beat-to-beat noninvasive sensor measurements correlated with those of the A-line. Mean bias, SD, and 95% confidence intervals (CIs) were also calculated, which in combination with the Bland–Altman method of paired measurements, were used to assess agreement between noninvasive (CAP or PPG sensor) and invasive (A-line) BP monitoring methods. The benchmark for acceptance was based on AAMI/ISO 81060-2 standards (mean bias: 5 ± 8 mmHg), which are used for FDA clearance of non-invasive sphygmomanometers84.All statistical analyses were performed in MATLAB. A Supplementary Information 1.Supplementary Information 2.


Crescent formation indicates severe glomerular pathology, and hypothyroidism usually predicts poor prognosis for severe diseases. However, the relationship between thyroid function and the progression of chronic kidney disease (CKD) is unclear. This study analysed the prognostic predictive value of the serum free triiodothyronine (FT3) to free thyroxine (FT4) ratio and its correlation with renal function in patients with CKD with crescent formation.This single-centre study included 162 CKD patients with glomerular crescents confirmed by renal pathology between March 2012 and December 2014. According to the first tertile (0.284) of FT3/FT4 ratio, the patients were divided into high and low FT3/FT4 ratio groups. Kaplan-Meier and Cox regression analyses were performed to evaluate the prognostic value of the FT3/FT4 ratio.The age, haemoglobin, eGFR, urinary albumin-to-creatinine ratio, cardiac troponin T, N-terminal brain natriuretic peptide precursor, FT3, FT4, percentage of total crescents in non-globally sclerotic glomeruli, prevalences of hypertension, moderate to severe renal tubulopathy and crescentic nephritis, and proportion of patients receiving glucocorticoids and immunosuppressants were significantly different between high and low FT3/FT4 ratio groups (P < 0.05). Multivariate Cox regression analysis showed that when compared with patients with a high FT3/FT4 ratio (>0.284), those with intermediate and low FT3/FT4 ratios (≤0.284) had an increased risk of the long-term composite endpoint (P < 0.05 for various adjustment models).A low FT3/FT4 ratio is associated with increased mortality and worse outcome risk in CKD patients with crescent pathology. Glomerular crescent formation is a hallmark of severe glomerular injury and can present in patients with primary and secondary glomerulonephritis. The presence of extensive glomerular crescents  is the main pathological feature of rapidly progressive glomerulonephritis. Several studies , 2 have ‘Non-thyroidal illness syndrome’ (NTIS) is a syndrome of abnormal thyroid hormone metabolism that is general in critically ill patients and has been also reported in patients with CKD. Thyroxine (T4) is the main secreted and transported form of thyroid hormone. Its free form can be transported into cells to be de-iodinated and converted into free triiodothyronine (FT3), which regulates energy metabolism and protein synthesis and stimulates tissue growth, maturation, and differentiation. Impaired FT4-FT3 conversion is a major characteristic of NTIS, and the decreased FT3/FT4 ratio is therefore its biomarker. NITS is associated with decreased renal function in non-dialysis CKD patients , 6 and aTherefore, to clarify the association between the degree of T4-T3 conversion and the progression of CKD with crescents, the severe glomerular pathological changes suggesting high disease activity and rapidly progression, our study assessed the association of the FT3/FT4 ratio with a composite endpoint in a retrospective cohort of CKD patients with crescent formation in our centre.We analysed 227 consecutive patients who underwent kidney biopsy and showed glomerular crescent pathology at the Department of Nephrology, Zhongshan Hospital, Fudan University, between March 2012 and December 2014. Demographic variables (age and sex), clinical variables, laboratory tests results, kidney pathology results, and pharmacological treatment were obtained from electronic medical records. The inclusion criteria were as follows: (i) age ≥18 years at biopsy and (ii) renal biopsy-proven crescent formation (including cellular/fibrocellular/fibrous crescents). The exclusion criteria were as follows: (i) unavailable thyroid functional test results within 1 week before kidney biopsy; (ii) past history of kidney disease; (iii) past history of thyroid disease or hypothalamic-pituitary disease; (iv) immunosuppressive therapy before kidney biopsy; (v) administration of medication that may affect thyroid hormone secretion and metabolism within 1 month of the thyroid function test; (vi) renal replacement therapy (RRT) at kidney biopsy; and (vii) no follow-up data available. This study was approved by the ethics review committee of Zhongshan Hospital, Fudan University. The overall design of this study is shown in Hypertension was defined as systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg at repeated examinations on different days in the hospital, self-reported history of hypertension, or use of antihypertensive medications .The estimated glomerular filtration rate (eGFR) was calculated using the 2009 CKD-EPI creatinine formula .Kidney biopsy reports were based on independent grading by two histopathologists. Glomerular crescents were defined as hyperplastic lesions involving >10% of the circumference of the Bowman’s capsule, including cellular, fibrocellular, and fibrous crescents. A ‘cellular crescent’ was defined as extracapillary hypercellularity of >2 cell layers composed of >75% cells with or without fibrin and <25% fibrous matrix. A composition of 25–75% cells with or without fibrin and the remaining fibrous matrix was defined as a ‘fibrocellular crescent’, and a composition of >75% fibrous matrix and <25% cells with or without fibrin was defined as a ‘fibrous crescent’ . The extIn this cohort, normal FT4 levels ranged from 12 to 22 pmol/L, and thyrotropin (TSH) from 0.27 to 4.20 μIU/mL. Thyroid function status was defined using these cut-off values, as follows: (i) overt hypothyroidism was defined as elevated TSH levels in combination with reduced FT4 levels; (ii) subclinical hypothyroidism was defined as elevated serum TSH levels in combination with normal FT4 levels; (iii) euthyroidism was defined as TSH levels within the specific reference range; (iv) overt hyperthyroidism was defined as decreased TSH levels with elevated FT4 levels; and (v) subclinical hyperthyroidism was defined as decreased TSH levels without elevated FT4 levels.Renin-angiotensin-aldosterone system (RAAS) blocker use was defined as treatment with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, spironolactone, or any combination. Immunosuppressive treatments, including glucocorticoids and other immunosuppressants, were recorded based on the intention to treat.Serum creatinine levels were examined at least every 3 months. The primary composite endpoint included a ≥50% reduction in the eGFR, RRT initiation, or death from any cause. The eGFR and time to initiation of RRT or death were retrospectively obtained from electronic medical records.t−test or Mann-Whitney U-test; categorical variables were compared using the chi-square test or the Fisher exact test. Kaplan-Meier curves were used to assess event-free survival, and the log-rank test was used to evaluate differences between groups. Univariate and multivariate Cox regression models were used to assess the association of the FT3/FT4 ratio with the composite endpoint, and crude and adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were reported. All variables in the univariate analysis were entered into the forward conditional Cox regression model for the multivariate analysis. Statistical analyses were performed using SPSS Statistics  and GraphPad Prism 8.00 . P-values less than 0.05 were considered statistically significant.Continuous variables were described as mean with standard deviation (SD) and median with interquartile ranges (IQR) according to normal and non-normal distributions, respectively. Categorical variables were expressed as frequencies and constituent ratios. Depending on the distribution type of values, continuous variables were compared between groups using the Student’s P=0.036). The incidence of the events composing the composite endpoint based on the FT3/FT4 ratio, separated by tertiles, is shown in P < 0.01); it was not significantly different between patients with intermediate and low FT3/FT4 ratios (P = 0.828). Therefore, patients were divided into high (>0.284) and low (≤0.284) FT3/FT4 ratio groups according to the first tertile.Between March 2012 and December 2014, 227 patients underwent renal biopsy at our centre and had pathological findings of glomerular crescents. After excluding 65 patients Figure 1P < 0.01); however, there were no significant differences in the TSH level or the prevalence of overt or subclinical hypothyroidism between the two groups. There were also no significant differences in sex, 24-hour urine protein, albumin, haemoglobin A1C (HbA1c), or the proportion of RAAS blocker application between the low and high FT3/FT4 ratio groups.P = 0.001) (P = 0.024). The HR of the primary endpoint increased significantly with lower haemoglobin, eGFR, and FT3; higher cTnT, NTproBNP (Ig), and %Cres; hypertension; and moderate to severe tubulopathy  , whereas an elevated eGFR-EPI was an independent protective factor   Figure 2In this observational retrospective cohort study of patients with glomerular crescents, a low baseline FT3/FT4 ratio was associated with higher renal function exacerbation and a greater risk of mortality. This prognostic association remained after multivariate adjustment for confounding factors, such as age, concomitant disease, laboratory and pathological parameters, and treatment strategy. In addition to the FT3/FT4 ratio, the presence or absence of hypertension and the eGFR at kidney biopsy were independent risk factors for the long-term composite endpoint, suggesting that baseline hypertensive comorbidity and renal function may be valuable for assessing the prognosis of CKD patients with crescent formation.Previous studies on thyroid function in CKD patients mainly focus on the relationship between hypothyroidism and renal function and its role in renal prognosis –16. ThyrNTIS is highly prevalent in patients with CKD, and it has value as a predictor of CKD exacerbation  and poorThere is still no consensus on the optimal cut-off point to define a high and low FT3/FT4 ratio. Most studies categorise patients into tertiles , 29, as Age, comorbid hypertension, haemoglobin, eGFR, cTnT, NTproBNP, %Cres, moderate-to-severe tubulopathy, and administration of glucocorticoids combined with other immunosuppressive therapies are classical prognostic factors for CKD; the results of our univariate Cox analysis also showed these factors to be related to the composite endpoint. These prognostic indexes were significantly different between the high and low FT3/FT4 ratio groups. The eGFR is usually inversely associated with the severity of tubulointerstitial injury , and simIn conclusion, we found that a low FT3/FT4 ratio was associated with poor long-term outcomes in patients with CKD with glomerular crescents. This finding suggests that the FT3/FT4 ratio is a risk factor in these patients. However, there are some unresolved questions. The mechanism by which the metabolic variation in thyroid hormones affects the progression of CKD remains to be elucidated by further basic and clinical studies. Another question is whether patients with a low FT3/FT4 ratio would benefit from a more aggressive etiological treatment or thyroid hormone replacement. Additionally, our study had several limitations. First, there were only baseline data on the FT3/FT4 ratio, and the effect of variations in this ratio during follow-up on prognosis could not be assessed. Second, it should be noted that the participants in this study were patients with CKD with crescent formation; therefore, the conclusions of this study may not be generalizable to all CKD populations. Third, information on some potential confounders, such as established cardiovascular disease or obesity, was not documented in this study; however, we had a large number of other relevant confounding variables for adjusting multivariate models.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, Zhongshan Hospital, Fudan University. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.LZ and YW were responsible for the study design. LZ, YW, YN and WL were responsible for data collection. LZ, YL and BZ were responsible for analysis and interpretation of data. LZ, SJ, ZS, FL and HL were responsible for writing the manuscript. YF and XD were responsible for supervision or mentorship. All authors were involved in writing the paper and had final approval of the submitted and published versions.This study was supported by the National Natural Science Foundation of China (grant 81900699), Shanghai Municipal Key Clinical Specialty (shslczdzk02501), Shanghai Municipal Hospital Frontier Technology Project supported by Shanghai ShenKang Hospital Development Center (SHDC12018127), Shanghai "science and technology innovation plan" technical standard project (19DZ2205600) and Shanghai "science and technology innovation plan" Yangtze River Delta scientific and technological Innovation Community project (21002411500).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.


Furthermore, therapies that modify medullary tPO2 produce corresponding changes in bladder PuO2. Clinical studies have shown that bladder PuO2 correlates with cardiac output, and that it increases in response to elevated cardiopulmonary bypass (CPB) flow and mean arterial pressure. Clinical observational studies in patients undergoing cardiac surgery involving CPB have shown that bladder PuO2 has prognostic value for subsequent AKI. Thus, continuous bladder PuO2 holds promise as a new clinical tool for monitoring the adequacy of renal medullary oxygenation, with its implications for the recognition and prevention of medullary hypoxia and thus AKI.Acute kidney injury (AKI) is common in the critically ill. Inadequate renal medullary tissue oxygenation has been linked to its pathogenesis. Moreover, renal medullary tissue hypoxia can be detected before biochemical evidence of AKI in large mammalian models of critical illness. This justifies medullary hypoxia as a pathophysiological biomarker for early detection of impending AKI, thereby providing an opportunity to avert its evolution. Evidence from both animal and human studies supports the view that non-invasively measured bladder urinary oxygen tension (PuO Acute kidney injury (AKI) is a frequent complication in intensive care units, affecting 30–60% of critically ill patients . The rolE. coli resulting in reduced creatinine clearance [2) is seen. A similar fall is demonstrated upon initiation of CPB [2 may provide a means for early detection of risk of AKI and for guiding therapies in order to avoid exacerbating that risk. However, it is not clinically feasible to directly monitor renal medullary tPO2 in patients. Our research group has proposed that continuous measurement of bladder urinary oxygen tension (PuO2) could provide a non-invasive surrogate measure of renal medullary tPO2 and thus could be an appropriate pathophysiological biomarker of AKI [2 in the renal pelvis equilibrates with renal medullary tPO2, (iii) that oxygen diffusion across the epithelium of the ureter and bladder only partially confounds the relationship between medullary tPO2 and PuO2 and that (iv) bladder PuO2 provides reliable prognostic information. A selection of studies separated into animal and human data is presented below as support for these assertions.Serum creatinine is used to estimate glomerular filtration rate and diagnose patients with AKI. Other plasma and urinary biomarkers, including neutrophil gelatinase-associated lipocalin and cystatin C, have demonstrated promise in the early detection of AKI . Howeverlearance , 16 or olearance , a fall n of CPB , 19. Morr of AKI . The ratr of AKI ): that  or fluid resuscitation was found to reverse medullary tissue hypoxia in ovine septic AKI back to healthy physiological levels [2. Norepinephrine further worsened renal medullary tissue hypoperfusion and hypoxia, an undesirable effect; but this was not seen when vasopressin was used as primary vasopressor [2 in ovine septic AKI [2 in healthy sheep [2 also increased.Renal medullary tPOion rate . Consequl levels , 26. On opressor , 24. Angptic AKI  but was hy sheep , 33, med2, they all appear to mirror changes in bladder PuO2 in sheep (e.g. during resuscitation with fluids [2 (vasopressin V1-receptor activation or blockade of nitric oxide synthesis) were administered to anesthetised rabbits, the changes in bladder PuO2, measured using the same technique as used in sheep, mimicked changes in medullary tPO2 [2 varied linearly with medullary tPO2 under normoxic or slightly hypoxic conditions [Despite the variable effects of various resuscitative measures on medullary tPOh fluids , norepinh fluids  and angih fluids ; as wellh fluids ). Similaary tPO2 . Furthernditions .2 may be a clinically feasible technique to estimate renal medullary tPO2, and therefore vulnerability towards developing AKI, as well as a tool to gauge the impact of resuscitation strategies on medullary tPO2.Together, these preclinical observations indicate that measurement of bladder PuO2 in humans had been reported previously  [2, presumably due to the increased medullary oxygen consumption associated with salt loading [2 and bladder PuO2 were reported to rise with increasing inspired fraction of oxygen, although the response was sluggish in disease states such as pyelonephritis or azotemia [2 was altered with agents that affect sympathetic tone, in a manner independent of urine flow [2 to changes in FiO2 could be an index of medullary blood flow at periods of stable oxygen consumption, with a slower response time indicating poorer medullary blood flow, in a manner analogous to an indicator dilution technique for determining flow [Although PuOly e.g. , 35), th, th2 in ly (e.g. –39. Thisary tPO2  as well der PuO2 . Furtherr shock) , whilst azotemia . Additioine flow . Leonharing flow .2 largely focused on measuring effects of various interventions on bladder PuO2, given the ease of sampling. These included demonstration of the reduction in PuO2 with sevoflurane and isoflurane [2 with the renal vasodilatory effects of dopamine, prostaglandin E1 and fenoldopam [2 in critically ill patients, which was attributed to attenuation of cardiac output and thus renal blood flow and medullary perfusion [2 in otherwise well patients after relief of urologic stones [2 in septic patients [Continued reports of the use of PuOoflurane , and thenoldopam , 42. Dexerfusion . Furosemc stones , but waspatients . Whilst patients  and humapatients , 47, furpatients , 49, whi2 have included examination of the effects of red cell transfusion and the relationship between bladder PuO2 and cardiac output. In a small study involving eight patients, red cell transfusion was seen to increase bladder PuO2 as measured by a blood gas analyser [2 and cardiac output (as measurement by Swan-Ganz catheter) were positively correlated [2) is relevant for determining PuO2.Studies of the effects of non-pharmacological interventions on bladder PuOanalyser . Additiorrelated . These i2 and PuO2 or kidney outcomes has been further explored in patients undergoing CPB. During CPB, it is notable that increasing pump flow results in a more favourable renal oxygen supply relative to demand, with a lower oxygen extraction ratio [2 > 280 ml/min/m2 was found to result in fewer patients developing Acute kidney Injury Network (AKIN) Stage 1 compared with usual care  [2 was successfully raised in response to higher CPB pump flow (and therefore systemic DO2) and mean arterial pressure (MAP) compared with normal CPB pump flow and MAP  [2 during CPB with increasing pump flow and MAP, with a response time of 17 min  . Furtherctively) . This de2 is at least somewhat contributory to PuO2 (or improved kidney outcomes), the preceding discussions describing the association of PuO2 with medullary tPO2 in both animal and human studies suggest that it is medullary perfusion (and thereby oxygenation) that is the key variable that is altered. This is particularly relevant because the medullary circulation is poorly autoregulated and is determined by factors that are distinct from cortical or global renal perfusion [Whilst it is possible that the concomitant increase in renal perfusion or cortical perfusion with increased systemic DOerfusion .2 and AKI [2 was observed upon initiation of CPB, and a slower rate of rise of PuO2 after weaning from bypass [2 in the post bypass period [2 values [2 using a blood gas analyser six hours after admission to ICU had modest discrimination in detecting patients who later developed AKI [Further support for the association between renal medullary tissue hypoxia and AKI comes from observational studies involving patients undergoing cardiac surgery requiring CPB that examined the association of bladder PuO and AKI –59. In tm bypass  or a lows period  or a low2 values  were assWhilst bladder PuO2 is more convenient and less invasive for approximating medullary tPO2 than ureteric measurement, potential confounders abound. These include oxygen from the presence of blood in urine, which would be expected to contaminate samples with arterialised oxygen tension . This is2 measurements can also be altered by the diffusion of oxygen between urine and the wall of the bladder and ureter, or exposure of urine to atmospheric oxygen [2 in a way that minimises the opportunity for diffusion of oxygen from these sources, and (ii) through use of computational models to estimate the magnitude of this diffusion and correct for it.Bladder PuOc oxygen . The unc2 can be measured continuously using a fibre optic probe inserted into the bladder catheter  [Bladder PuOter Fig.  so that 07 mmHg) , 58 was 07 mmHg) . However2 can also potentially be measured by collecting urine from a Foley catheter for analysis in a blood gas machine [2 in humans using this approach [2 was measured in the bladder [Urinary PO machine , 51, 59.approach –65 were  bladder   [2 and bladder PuO2 appear to be the patient’s systemic oxygenation and their rate of urine flow. Thus, as urine flow becomes greater, the error in the estimate of medullary PO2 generated by measurement of urinary PO2 becomes less. In contrast, as urine flow becomes less and a patient becomes progressively hyperoxemic or hypoxemic, the error becomes greater [2 is probably most useful when patients have a normal or high urine flow. But even when such conditions are not entirely met, computational models can account for variations in urine flow and systemic oxygenation. The most sophisticated model developed to date predicts the existence of a family of linear relationships between bladder PuO2 and pelvic ureteric PuO2 for any given set of input conditions of urine flow and systemic arterial PO2 in human patients  . Consequ greater . Therefo2 has been noted in established hydronephrosis and could also occur with renal cysts, due to medullary thinning and the influence of renal cortical oxygenation on measurements [2 could still be useful as a reflection of the adequacy of medullary oxygenation.Finally, the implications of disease states of the kidney for measurements of bladder PuO2 remain to be fully elucidated, as recent clinical studies have been performed largely on patients without established kidney disease –58. Furturements . Neverth2 promise to provide a non-invasive method for estimating medullary tPO2 and have prognostic value. Furthermore, it is a physiological variable that can be manipulated by pharmacological and other non-pharmacological interventions, making it an ideal candidate for targeted therapies to maintain or restore its value and thereby protect the kidney from injury. Sources of error or confounding variables remain a challenge, although many of these can be overcome by appropriate sampling and computational modelling. Harnessing the value of continuous bladder PuO2 monitoring appears promising in critical care environments.AKI is common in critical care units, and attenuating its severity or even preventing its development is a key therapeutic target. There is increasing evidence that the inadequacy of renal medullary oxygenation is linked with its development. Furthermore, medullary tissue hypoxia appears to precede other evidence of AKI. Continuous measurements of bladder PuO


Among the possible causes of hypertension in adolescence, electrolyte imbalances and environmental pollutants are drawing increasing attention. We aimed to examine the relationship between bisphenol A (BPA), phthalate metabolites, and serum electrolytes and blood pressure.Eighty-six participants aged 12–15 years were included in the study. Body mass index (BMI), office blood pressure and 24-h ambulatory blood pressure measurements (ABPM), and carotid intima-media thickness were determined. Blood samples were taken for hemogram, renal function tests, and serum electrolytes. Free- and total-BPA and phthalate metabolites were analyzed from urine samples.p = 0.004). Associations between MBzP and ABPM- hypertension and WCHT were remained after confounding factor adjustment. Adolescents with detectable MBzP levels had also higher “albumin-corrected calcium” and lower serum phosphate and “albumin-corrected calcium x phosphate product” compared to others. Adolescents with detectable urinary MBzP levels had higher blood pressure profiles in some 24-h , daytime (systolic blood pressure-SDS), and night-time  measurements, compared to others. WCHT was found to be associated negatively with monomethyl phthalate and the sum of dibutyl phthalate metabolites and ABPM-HT with MCPP. There was no significant association between blood pressure profiles and free- and total-BPA status.Of the participants, 34 were evaluated as normal blood pressure profile, 33 as white-coat hypertension (WCHT), and 19 as ABPM-hypertension. Adolescents in ABPM- hypertension groups had higher BMI-standard deviation score (SDS), leucocyte, platelet count; but lower serum chloride, compared to the normal blood pressure profile group. The percentage of adolescents with detectable urinary mono-benzyl phthalate (MBzP) was higher in ABPM-hypertension (42.1%) and WCHT groups (33.3%), compared to the normal blood pressure profile group (5.9%, MBzP was associated with adverse blood pressure profiles in adolescence. Additive follow-up studies are necessary for cause-effect relations.The online version contains supplementary material available at 10.1186/s12882-022-02774-y. The worldwide increase in the incidence of hypertension (HT) and obesity in the pediatric population have critical long-term cardiovascular effects . StudiesCalcium, phosphate, magnesium, sodium, potassium, and chloride have crucial roles in patients with various diseases, and even in the general population –10. HighPhthalates, one of the man-made pollutants, are environmental chemicals that are widely used in consumer goods and personal care products today. Since these substances are not covalently bonded to the polymer, they can affect the environment and people by mixing with the atmosphere, food product, or directly into body fluids in various ways . PhthalaSince bisphenol A (BPA) is widely used in the manufacture of polycarbonate plastics, epoxy resins and thermal paper, it is found in many products such as plastic bags, water bottles, toothpastes, electronic equipment, paper and toys . In addiPrevious studies evaluated the effects of pollutants such as BPA and phthalates on the cardiovascular system or kidney diseases, regardless of the micronutrient balances of the cases –18, 20. Most studies about HT were performed by office blood pressure measurement. However, ambulatory blood pressure monitoring (ABPM) has a higher reproducibility and a better correlation with end-organ damage, compared to office blood pressure . TherefoWe aimed to investigate how serum electrolytes and urinary levels of 14 phthalate metabolites and BPA, including free and total are associated with (a) blood pressure profiles , and (b) carotid intima-media thickness (cIMT) in a group of asymptomatic adolescents who are not on antihypertensive medication. Understanding the relation between serum electrolytes, pollutants and blood pressure may be important to define risk groups for HT and to take preventive measures. The detection of possible associations for HT and management of these factors during childhood period could be important to prevent cardiovascular disease in adolescents and adults.The target population of the study was adolescents aged 12–15 years who were evaluated in the Child Health Checkup Study (CHCS) at the Hacı Sabancı Secondary School and Ticaret Odası Secondary School between December 2017 and March 2018. Adolescents who were newly diagnosed with HT in CHCS and following healthy growing age-appropriate (±1 years) adolescents were enrolled for the study. Exclusion criteria included any cardiac, renal or endocrine disorders, and taking any medicine that can alter blood pressure.The study protocol was approved by the Provincial Directorate of National Education and Hacettepe University Ethics Committee (GO:16/582). Written informed consent was obtained from the participating children and their families before enrollment in the study.All participants’ physical examinations including office blood pressure and anthropometric measurements (height and weight) were taken as part of the CHCS. With the WHO-Anthro Plus database, standard deviation scores (SDS) of height and body mass index (BMI) were estimated . ObesityCases with high blood pressure and control cases were called to the hospital for further evaluation. From adolescents admitted to hospital, age, sex, history of diseases and medication usage, and parental age and HT were taken with a questionnaire. Then, venous blood and urine samples were taken on admission to the hospital, and 24-h ABPM and ultrasonography for cIMT were performed the next day.A venous blood sample was taken into EDTA containing tube for complete blood count  and plain tube for protein, albumin, urea nitrogen, creatinine, sodium, potassium, chloride, calcium, magnesium. Then, urine samples were taken into glass containers and divided into two 10-mL aliquots into amber glass vials and tops packed with aluminum foil; and one stored at − 20 °C until analyses for phthalates metabolites and BPA levels. The second aliquot was used for urinary creatinine, albumin, protein, and beta-2 microglobulin. Laboratory analyses were performed at a reference laboratory with appropriate kits.Albumin-corrected calcium (ACCa) was defined as the formula given below.Urinary albumin, protein, and beta-2 microglobulin levels were adjusted for urinary creatinine. Estimated glomerular filtration rate (eGFR) was calculated with Schwartz formula .ABPM measurements were made from the patient’s non-dominant arm with the cuff of the appropriate size and the Spacelabs Monitor 90,207 device . Measurements were made every 15–20 min during the waking period and 30 min during the sleep period; ABPM data were evaluated with a measurement time of at least 18 h without interruption; at least 20 measurements during wakefulness and at least 7 measurements during sleep; at least one measurement was made per hour, including the sleep period , 37. SDSDefinitions of ABPM profiles including normal ABPM profile, ABPM-HT, WCHT, masked HT and dipping were given in Fig. Ultrasound examination for cIMT measurement was performed with an Affiniti 70G ultrasound system  using 5-18 MHz linear probe according to Mannheim consensus . Five meFree BPA (fBPA) and total BPA (tBPA) levels were measured using the MyBioSource Human fBPA ELISA kit  and the Human tBPA ELISA Kit (Cat no: MBS109499) by the user manual.Of phthalates, 14 metabolites  were explored in urine sample using the ‘Waters ACQUITY UPLC-MS/MS System ’ device using the Acquity UPLC BEH Phenyl Column , 43 in CThe determination of urinary creatinine (Cre) levels was based on Jaffe’s colorimetric method with an automatic biochemical analyzer to correct urine dilution (Beckman Coulter ORS61780 21). The concentrations of urinary phthalate metabolites and BPA were determined as both unadjusted  and creatinine corrected values (μg/g-cre).ΣDEHP [the sum of di (2-ethylhexyl) phthalate (DEHP) metabolites] was estimated by adding the molar concentrations of five metabolites: MEHP (MW = 278), MEHHP (MW = 294), MEOHP (MW = 292), MECPP (MW = 308) and MCMHP (MW = 308) and multiplied by the MW of MECPP , 45. ThePrimary/secondary DEHP metabolites calculated by dividing the molar concentration of MEHP by the sum of MEHHP, MEOHP, MECPP, and MCMHP.Detectable rates were fBPA 12.8, MBzP 24.4%, MEP 95.3%, MEHP 97.7%, MCINP 77.9%, MCPP 80.2%, MMP 89.5%, MiNP 11.6%  or mean and standard deviation as appropriate. Urinary phthalate metabolites having p value < 0.2 for either WCHT or ABPM hypertension in Model 2.Multinominal logistic regression analyzed the differences in rates of selected urinary phthalate metabolites having ≥ median value or detectable levels among groups of blood pressure profiles  with four models. Model 0 was crude model. Model 1 included adjustment for age, sex, BMI-SDS. Model 2 included WBC, platelet, Cl, alb-adj-CaXP, eGFR, U-cre in addition to Model 1. In addition to parameters of Model 2, Model 3 covered five phthalate metabolites having Logistic regression were used for the differences in rates of urinary phthalate metabolites having ≥ median value or detectable levels among groups of “day or/and night HT” vs normal profile with four models. Model 0 was crude model. Model 1 included adjustment for age, sex, BMI-SDS and parental HT. Model 2 included platelet, eGFR, U-cre in addition to Model 1. Model 3 covered phthalate metabolites having p value < 0.2 with confounding factors in Model 2. Besides, cases were divided into 4 groups according to MEP  and MBzP (detectable or not) and association with day-time and/or night-time HT were evaluated with logistic regression.The association of the rates of the high ΣDEHP metabolites with cIMT SDS higher than 95th percentile were analyzed with logistic regression in crude model, after adjustment for age, sex and BMI-SDS, and after controlling for age, sex, BMI-SDS, eGFR, U-cre.The Odds ratio (OR) and 95% confidence interval (CI) were calculated for logistic regressions.P-values < 0.05 were accepted as statistically significant.SPSS version 22  was used for statistical analyses. n = 34), WCHT (n = 33) and ABPM-HT (n = 19). Since the number of adolescents with masked-HT was low, they were not analyzed separately and were included in the ABPM-HT group; i.e. ABPM-HT included adolescents with office and ABPM-HT (n = 15) and masked-HT (n = 4).After repeated office blood pressure measurements 57 adolescents with office HT and 46 adolescents with normal office blood pressure were admitted to the hospital for further evaluation. Three had Hashimoto thyroiditis, two did not give urine and four had no ABPM and eight had attention deficit hyperactivity disorders and they were excluded from the study. At the end, 48 adolescents with office HT and 38 adolescents with normal office blood pressure completed the study. Following 24-h ABPM, adolescents were classified as normal office blood pressure and ABPM .On the other hand, WBC and platelet count in both normal blood pressure profile and WCHT groups were remained to be significantly lower than that the ABPM-HT group when controlled for BMI-SDS .The differences for urinary levels of tBPA and other phthalate metabolites according to blood pressure groups did not reach to statistical significance Table . The perp = 0.004).The percentage of adolescents with urinary MBzP above detectable level was higher in ABPM-HT (42.1%) and WCHT groups (33.3%), compared to the normal blood pressure profile group .The percentage of adolescents having ΣDBP metabolites > 40 μg/L, was lower in WCHT groups (30.3%), compared to the normal blood pressure profile group . When these five metabolites  were included in analysis, this correlation for WCHT persisted only for detectable MBzP , ΣDBP metabolites , and MMP . MCPP and MEHHP did not remain in the final model. There was a negative association between high MCPP and ABPM-HT, whereas, positive association between detectable MBzP and ABPM-HT in model 2 and model 3  had normal daytime and night-time blood pressure, 13 (15.1%) had daytime or night-time HT and 12 (14.0%) had sustained HT (i.e. daytime and night-time HT). Adolescents with sustained HT had higher BMI-SDS and counts of platelets, compared to those with normal daytime and night-time blood pressure  and daytime or night time HT group 46.2%), compared to normal daytime and night-time blood pressure group , compared to normal daytime and night-time blood pressure (Supplementary Table p = 0.011), ACCa to phosphate ratio , and lower serum phosphate  and ACCa x phosphate product , compared to group with urinary MBzP below detectable level . There was no association between clinical characteristics and cIMT  in urine, in boys a 1-ng/ml revealed that an increase in MEP concentration was associated with a 0.016 mmHg decrease in systolic blood pressure .Except for urinary MBzP and MEP levels, other phthalate metabolites showed no significant positive association with blood pressure profiles in our study. This is the first study evaluating WCHT with these pollutants. A recent cross-sectional study from Isfahan  included 108 children (6–18 years) observed a positive relationship between systolic blood pressure and some metabolites including urinary MnBP and MEHP; no association with MEHHP, MEOHP, and MMP . A recenIn our study a negative association was detected between ΣDBP metabolites and WCHT. In a mouse model, Xie et al. showed an increase in the levels of angiotensin-converting enzyme (ACE) and angiotensin II (AngII) in the DEHP treatment group without a significant change in estradiol level; on the other hand, there was an increase in the level of estradiol in the DBP treatment group, and the expression of ACE, AngII, AT1R, and eNOS in the DBP treatment groups showed no significant change. They suggested that different effects of DEHP and DBP on blood pressure could be related with the different estradiol levels induced with DEHP and DBP .We showed a negative association between MMP and WCHT. In a study conducted by Yao et al. in children, a positive relationship was reported between MMP and high blood pressure . In addiIn our study, we also showed a negative relation between MCPP and ABPM hypertension. Although higher MCCP concentrations in the first-trimester was found to be associated with pregnancy induced hypertension , MCPP waThe results of the studies are inconsistent, the number and type of metabolites studied are not standardized. Differences might also be due to sample matrix, age groups, exposed dosage, and whether the metabolite level is used directly or corrected by urinary creatinine or urine density. In addition, exposure to multiple contaminants is present at the same time and this might cause interaction between pollutants.In our study, there is no interaction between carotid IMT-SDS and MBzP. We have also shown that phosphate was significantly lower in adolescents with urinary MBzP equal to or greater than the detectable level. Interestingly, a previous study detected both damage in liver and kidney and abnormalities in the trace element and mineral levels DEHP-administered rats . TherefoCarotid IMT-SDS was found to be associated with ΣDEHP metabolites in our study. Similarly, matrix metalloproteinases-2 and -9 expression which are inducers of atherosclerosis was reported to be increased in rats exposed to DEHP compared with control rats . In addiAlthough it is not known exactly how phthalates cause changes in blood pressure, it is thought that oxidative damage may be responsible. Interestingly, a positive association between MBzP and increased oxidative stress and impaired vascular function was reported in the pediatric age group . There ap = 0.081). Although there was no significant association, further studies are needed with a larger sample size. fBPA is considered to be more toxicologically active than the conjugated BPA [In our study, we did not find a significant relationship between the tBPA levels and blood pressure profiles. Similarly, a study conducted with 471 Dutch children aged 6–10 years reported that there was no significant relationship between blood pressure and BPA after multiple testing corrections . Howeverated BPA . There aWe identified a higher percentage in parental HT in adolescents with HT. Similarly, familial aggregation with an increased liability of childhood-onset essential HT with parental essential HT is known . BesidesIn our study, we focused on asymptomatic adolescents detected in school screening, without antihypertensive medication. Patients with heart disease and having any drug therapy were excluded to avoid bias. In patients, different treatment interventions may affect the exposure level. The inclusion of asymptomatic adolescents without hypertensive medication might influenced the results and only statistically significant association could be detected with the phthalate MBzP. The small sample size might also affect the detection of associations. The cross-sectional design, relatively small study group, lack of detailed data for exposure, a single measurement of urinary metabolites were the limitations of the study. To some extent, these features might limit the generalizability of the current findings. Fetal origins of HT could not be evaluated in our study due to the single-exposure design. However, prenatal pollutant exposure might have an additive role in childhood blood pressure . To the Blood pressure profiles were related with BMI-SDS, WBC, platelets, some serum electrolytes , carotid IMT-SDS, and one of the studied phthalate metabolites (MBzP). MBzP was associated with parental HT, serum albumin and phosphate level, ACCa-phosphate product, and some blood pressure profiles. Interaction between MBzP and blood pressure profiles remained significant after adjusting confounding factors. Further studies in a large sample size with serial measurement are necessary to validate our results.Additional file 1


Background and Objectives: The recommended therapeutic management in renal cell carcinoma (RCC) with supradiaphragmatic inferior vena cava/right atrial thrombus (IVC/RA) is surgery. Extracorporeal circulation is required. Acute kidney injury (AKI), a frequent complication after nephrectomy and cardiac surgery is associated with long-term kidney disease. This study aims to identify the risk factors involved in the occurrence of the severe postoperative AKI (AKI3) and to analyse various preoperative validated risk scores from cardiac and noncardiac surgery in predicting this endpoint. Materials and Methods: The medical data of all patients with RCC with supradiaphragmatic IVC/RA thrombus who underwent radical nephrectomy with high thrombectomy, using extracorporeal circulation, between 2004–2018 in the Prof. C. C. Iliescu Emergency Institute for Cardiovascular Diseases, Bucharest, were retrospectively analysed. The patients who died intraoperatively were excluded from the study. The predefined study endpoint was the postoperative AKI3. Preoperative, intraoperative and postoperative data were collected according to the stratification of study population in two subgroups: AKI3-present and AKI3- absent patients. EuroSCORE, EuroSCORE II, Logistic EuroSCORE, NSQIP any-complications and NSQIP serious-complications were analysed. Results: We reviewed 30 patients who underwent this complex surgery between 2004–2018 in our institute. Two patients died intraoperatively. Nine patients (32.14%) presented postoperative AKI3. Age , preoperative creatinine clearance  and intraoperative arterial hypotension  were risk factors for AKI3 . Intraoperative arterial hypotension emerged as the only independent risk factor in multivariable analysis . Logistic EuroSCORE  best predicted the endpoint. Conclusions: An integrated team effort is essential to avoid intraoperative arterial hypotension, the only independent risk factor of AKI3 in this highly complex surgery. Some risk scores can predict this complication. Further studies are needed. Although renal cell carcinoma (RCC) represents around 3% of all cancers ,2, its iIn RCC with supradiaphragmatic IVC/RA venous thrombus, the surgery consists of radical nephrectomy with thrombus removal, often under extracorporeal circulation, with or without cross-clamping the ascending aorta arresting the heart. Hypothermia or IVC reconstruction may be sometimes required.This type of surgery is highly complex. Urologists, cardiac surgeons, cardiologists, anaesthesiologists, perfusionists and many others work together to ensure the perioperative care of these patients. The intraoperative complications can be very serious: massive blood losses with significant transfusion and major embolic events. These can lead to postoperative organ dysfunction or death. One frequent postoperative complication is acute kidney injury (AKI). The radical nephrectomy alone presents a high incidence of AKI, of 53.9% , which hThat is why it is vital to find the risk factors that influence the occurrence of the most severe stage of AKI (AKI3), especially the modifiable ones, in order to avoid the chronic dialysis requirement. Preoperative risk assessment is also very important  in this In this study, we retrospectively analysed all consecutive patients who underwent radical nephrectomy with supradiaphragmatic IVC/RA thrombectomy using extracorporeal circulation between 2004–2018 in the Prof. C. C. Iliescu Emergency Institute for Cardiovascular Diseases, Bucharest, Romania. We have already shown that intraoperative arterial hypotension was associated with AKI3 in this setting . The preThis single-centre retrospective study reviewed the medical data of all consecutive patients who underwent radical nephrectomy with supradiaphragmatic IVC/RA thrombectomy using extracorporeal circulation between 2004–2018 in the Prof. C. C. Iliescu Emergency Institute for Cardiovascular Diseases, Bucharest, Romania. The exclusion criteria was intraoperative death. The approval of the Research Ethics Committee (REC) of our institute (12425/15.04.2019) was obtained to access the data and to use it in this study. The requirement for written informed consent was waived by the REC. The predefined study endpoint was the postoperative AKI3. Kidney Disease Improving Global Outcomes (KNIGO) criteria of AKI definition [All the patients were diagnosticated with nonmetastatic RCC with supradiaphragmatic venous thrombus by the urologists. The surgery consists of radical nephrectomy  and high thrombectomy (cardiac time) using extracorporeal circulation, in a multidisciplinary approach, under general anaesthesia, with standard and invasive monitoring . The postoperative care of the patients was taken in the Department of Cardiovascular Anaesthesiology and Intensive Care of our Institute.The studied preoperative variables were: age, sex, extent of the thrombus, preoperative creatinine clearance, body mass index (BMI), preoperative nutrition status, preoperative haemoglobin concentration, obesity, kidney involved, the presence/absence of other comorbidities. The extent of the thrombus was determined using transoesophageal echocardiography. The preoperative creatinine clearance was evaluated using the last preoperative value of serum creatinine in the Cockcroft–Gault Equation. We used the last preoperative serum creatinine value and haemoglobin concentration in our analysis. BMI classified the patients according to their nutrition status. The presence/absence of preoperative diabetes mellitus, arterial hypertension and heart failure were identified according to the diagnosis recorded in the preoperative medical evaluation.The studied intraoperative variables were: duration of extracorporeal circulation, intraoperative blood loss, minimum intraoperative haemoglobin concentration, units of packed red blood cell transfused intraoperatively, units of fresh frozen plasma transfused intraoperatively, usage of cross-clamping of ascending aorta, duration of cross-clamping of ascending aorta, using of ultrafiltration during the extracorporeal circulation, temperature management during extracorporeal circulation (moderate hypothermia/normothermia) and intraoperative arterial hypotension. The presence of the intraoperative arterial hypotension was defined as the mean intraoperative arterial blood pressure (MAP) below 60 mmHg for more than 20 min before, during and after extracorporeal circulation. All the patients had continuously monitored invasive arterial pressure via an arterial catheter such that the anaesthesiologist could document MAP in the anaesthesia sheet at 5–15 min intervals.The postoperative variables were: haemostasis reintervention and systemic inflammatory response syndrome (SIRS). SIRS was retrospectively evaluated according to the postoperative medical data, using the recognized definition .We reviewed EuroSCORE, EuroSCORE II, Logistic EuroSCORE, NSQIP any-complications and NSQIP serious-complications for the two subgroups of patients and expressed them as quantitative variables. We have chosen EuroScore, Logistic EuroScore and EuroScore II to be assessed to our endpoint because our surgery consists of a cardiac time  beside the abdominal time .p < 0.05). The quantitative variables were displayed with their mean/median and standard deviation (SD) and analysed using the independent t-test or Mann–Whitney test depending on the variable distribution (the Shapiro-Wilk test). The categorical variables were analysed using the exact Fisher test (for 2 × 2 contingency tables) or Kendall tau b test (if chi test cannot be applied). Receiver operator characteristic (ROC) analysis was used to assess the quantitative variables to the endpoint . The cut-offs with their sensitivity and specificity were presented. ROC analysis was also used to asses and to compare the risk scores. The statistically significant variables have been tested in univariable binary logistic regression (Exp(B), OR, CI 95%, p). After testing for multicollinearity, the statistically significant variables were introduced in the multivariable binary logistic regression to identify the independent risk factors for AKI3 .We used IBM SPSS Statistics 26 in our analysis with a threshold of statistical significance of 95% . A cut off value of 60.5 years predicted the endpoint .The nine AKI3-present patients were significantly older (63.33 ± 7.01 years) than the others (54.42 ± 9.83 years old) . The ROCp 0.006, CI95%: 0.630–0.954). A cut-off value of 62.50 mL/min predicted the outcome .The preoperative creatinine clearance was significantly lower (59.44 ± 21.57 mL/min versus 82.10 ± 17.83 mL/min) in AKI3-present patients  as shownp = 0.311). Using cross-clamping of ascending aorta, the duration of extracorporeal circulation, ultrafiltration or different temperature management on extracorporeal circulation did not influence the endpoint  predicted the endpoint with good discrimination , but NSQIP any-complications did not present significant AUC, also its value is more than 0.7 .Age, preoperative clearance creatinine and intraoperative arterial hypotension were the risk factors for postoperative AKI3 in our univariable analysis. But intraoperative arterial hypotension emerged as the only independent risk factor. This was defined as MAP under 60 mmHg for more than 20 min pre, during and post extracorporeal circulation The result emphasizes the previous findings of our group that demonstrated a significant association between intraoperative arterial hypotension and the postoperative complications, including AKI3 . Our preThe patients included in our study underwent radical nephrectomy with supradiaphragmatic IVC/RA thrombectomy using extracorporeal circulation. Both radical nephrectomy and cardiac surgery present high risk for AKI, but our studied surgery is a combination of them in oncological patients.AKI definition and staging were elaborated by KNIGO . Some faRadical nephrectomies had a high AKI risk . Male seThe high incidence of the AKI in radical nephrectomy would be due to the loss of nephrons in the resected kidney, an unmodifiable factor, but also to damage of the other kidney. It is already known that in donor nephrectomy compensatory hypertrophy develops in the contralateral kidney and, thus, the kidney function remains almost normal ,25. The Intraoperatively, maintaining the optimum renal perfusion of the remaining kidney seems to be the most important action in preventing AKI and especially AKI3. The multidisciplinary team must avoid the hemodynamic instability and manage the low cardiac output states, rationally using the vasopressors and inotropes. Hypovolemia, anaemia and vasoplegia must be also addressed in order to optimise the arterial renal perfusion of the remaining kidney . The incThe diabetes mellitus, arterial hypertension or heart failure, preoperative haemoglobin concentration, the extend of thrombus, sex, kidney involved or preoperative nutritional status did not associate in our study with AKI3. Intraoperative blood loss, the level of required transfusion, the duration of extracorporeal circulation, minimum haemoglobin concentration, use of ultrafiltration, temperature management, hemostatic reintervention or SIRS have the same characteristics. Using the cross-clamping of the aorta and its duration did not influence AKI3 in our study.Considering other studies results, it is not a surprise that in our study intraoperative arterial hypotension, age and preoperative creatinine clearance were significantly correlated with AKI3. Thus, we emphasize the importance of the close invasive monitoring of the arterial pressure and of the multidisciplinary as well to minimize the magnitude and the duration of the intraoperative arterial pressure, but also to optimise preoperatively the renal function of the patients.In noncardiac surgeries, the maintenance of sufficient MAP is the most important hemodynamic parameter to preserve perioperatively . The 201Since 1999, EuroSCORE, has been demonstrated to be a tool for predicting mortality in cardiac surgery ,31. UsinRegarding the risk scores for AKI, Toumpoulis et al. raised the question since 2004 if EuroSCORE can predict anything else than mortality . They shNSQIP was proposed to predict the risk of postoperative complications. Both NSQIP serious and any-complications refer to progressive renal insufficiency and acute renal failure . Some stIn our study, in nephrectomy with high thrombectomy using extracorporeal circulation, all the variants of the cardiac surgery risk scores predicted AKI3. Logistic EuroSCORE, followed by EuroSCORE had the highest predictive value (AUC > 0.800). EuroSCORE II and NSQIP serious-complications also predicted AKI3, but with AUC < 0.800. That is why we propose the three variants of EuroSCORE, especially Logistic EuroSCORE and EuroSCORE, as a tool to predict AKI3 in this kind of surgery. EuroSCORE may be even easier to use, comparing to its logistic formula. We must take into consideration the calculated cut off of EuroSCORE of 3.5. This mean that an EuroSCORE more or equal to four, not a high value, highlights the risk of postoperative AKI3. NSQIP serious-complications may be also used, but probably together with another risk score. To the best of our knowledge, this is the first study to assess these risk scores in predicting AKI3 in this complex surgery.Study limitation. This study is a single-centre retrospective study, with a relatively small number of patients, due to the reduced incidence of this pathology, renal cell carcinoma with supradiaphragmatic venous extension. Our Institute, the Prof. C. C. Iliescu Emergency Institute for Cardiovascular Diseases, Bucharest, represents the most experienced hospital in this field in Romania. Almost all the studies regarding this complex surgery are single-centre and retrospective. The most experienced centre worldwide, Cleveland Clinic, reports 101 cases of this kind in a 28 years-experience . Even ifThe radical nephrectomy with supradiaphragmatic inferior vena cava/right atrial thrombectomy performed using extracorporeal circulation for safe removal of the high thrombus in patients diagnosticated with nonmetastatic renal cell carcinoma is a complex surgery. Acute kidney injury, a frequent complication both in radical nephrectomy and in cardiac surgery, presents a high incidence in this setting. Preoperative risk assessment and renal function optimisation are useful, as we demonstrated that preoperative creatinine clearance, a partially modifiable risk factor, determined AKI3 in univariable analysis. Some validated risk scores from cardiac surgery can predict this complication, especially Logistic EuroSCORE and EuroSCORE. NSQIP serious-complications may be used to complete preoperative evaluation. Intraoperatively, all the effort must be made to maintain the optimal perfusion pressure of the remaining kidney especially monitoring the invasive blood pressure and avoiding prolonged periods of arterial hypotension. Of course, due to the limitations of our study, further studies are needed to confirm our results.