MMP-9-1562C>T polymorphism, MMP-9 serum levels and nephrolithiasis risk.The role of matrix metalloproteinase 9 (MMP-9) in the pathophysiology of chronic kidney disease (CKD), which is associated with a nearly two-fold greater risk for urinary calculi compared to people without CKD, has been demonstrated. The aim of the research is to evaluate the association between MMP-9-1562C>T polymorphism. The serum MMP-9 was measured in 105 kidney stone patients and 77 controls by enzyme-linked immunosorbent assay.A hospital-based case-control study involving 302 kidney stone patients and 408 controls without kidney stone from southern China was conducted. Sanger sequencing was used to genotype the p < 0.001). The serum MMP-9 levels of patients with CT/TT genotypes of MMP-9-1562C>T were significantly higher than those with CC genotype .Compared to the control group, the CT genotype was more frequent in nephrolithiasis patients . Moreover, there was also a higher frequency of CT/TT genotypes among patients with nephrolithiasis . The risk remained for the subgroups of patients aged >53, smokers with pack-years of smoking >20, non-drinkers, non-diabetic patients, patients with hypertension, recurrent episodes and calcium oxalate stones . Biochemical parameters did not differ between genotypes. Compared to controls (18.57 ± 5.80 ng/mL), nephrolithiasis patients had significantly higher serum MMP-9 levels (30.17 ± 6.78 ng/mL, MMP-9-1562C>T polymorphism in association with its soluble protein increased the risk of kidney stone, thus suggesting it could be used as a susceptibility biomarker for nephrolithiasis. Further functional studies and larger studies that include environmental exposure data are needed to confirm the findings.The  Nephrolithiasis is a worldwide disease that seriously threatens human health with a global prevalence rate of 9% in adults . MoreoveNumerous causes have been suggested for nephrolithiasis, including a family history of the disease, environmental exposure, hypercalciuria and dietary habits. Despite many researches, it was still not clear about the etiology of nephrolithiasis formation. A study has demonstrated that twins who were monozygotic had a higher concordance rate of kidney stones than twins who were dizygotic, suggesting genetic susceptibility factors may play a role .MMP-9 mRNAs increase as a result of abnormal activation and interaction of multiple cell signaling pathways  account for a family of zinc metalloendopeptidases which have been correlated to both pathological and physiological events involving the breakdown of extracellular matrix (ECM) and the induction of fibrosis . An impopathways , 12. In pathways .MMP-9 gene has 13 exons and 12 introns and is located on the long arm of chromosome 20 (20q11.1–13.1)  . Researcd sepsis .MMP-9-1562C>T polymorphism and nephrolithiasis risk in Malaysians. The researchers discovered that individuals with TT genotypes were more likely to develop nephrolithiasis  × (years of smoking) were calculated. Drinking more than 3 times a week for at least half a year was identified as habitual drinkers, while the rest were identified as none-drinkers. Face-to-face interviews were conducted to collect individual demographic information, followed by the collection of a 5 mL venous blood sample from each participant.MMP-9-1562C>T polymorphism was genotyped by Sanger sequencing.A Concert DNA Blood Extraction kit was used to extract genomic DNA from blood cells . The An analysis of serum samples from 105 kidney stone patients and 77 controls was performed. We centrifuged the serum for 10 min at 2000 rpm after it clotted for half an hour at 4°C. The serum plasma samples were isolated and stored at −80°C before enzyme-linked immunosorbent assay (ELISA) testing. We used MMP-9 ELISA kits following the manufacturer’s instructions . The concentration of MMP-9 was obtained based on the comparison the O.D. of the samples with standard curves.LILR-20  was used to assess stone composition. A skilled technician interpreted FT-IR spectra to identify specific absorption peaks to determine the qualitative composition of stone samples. When a stone was made up of multiple compounds, we calculated the ratios of different absorbencies at fixed wave numbers, and quadratic equations were used to determine relative abundances of compounds from mixtures that had known compositions , 20. It t-test, Pearson’s χ2 test or Fisher’s exact test were applied to detect the differences in the selected variables and distributions of demographic characteristics between cases and controls. Using adjusted odds ratios (ORs) and 95% confidence intervals (CIs) from unconditional logistic regression, we estimated the association between the nephrolithiasis risk and genotypes. All ORs were adjusted for age, sex, pack-years of smoking, drinking, hypertension and diabetes status. Among controls, genotype frequencies were calculated using Hardy–Weinberg equilibrium (HWE). All statistical analyses were performed with Statistics Analysis System software  and the differences were considered statistically significant when two-sided p was <0.05.The student’s p = 0.997). Among the two groups, there was a similar sex composition (p = 0.181). The BMI values, proportions of hypertension, diabetes, smoking, and alcohol drinking were also similar between these two groups. However, the cases had a larger proportion of high BMI (BMI >24 kg/m2) individuals than the controls . Furthermore, 18.54% of cases had a positive family history of urolithiasis, significantly higher than controls (9.37%) (p < 0.001).As shown in the MMP-9-1562C>T polymorphism among nephrolithiasis patients and controls, along with its association with nephrolithiasis risk. In the control group, genotype frequencies were consistent with HWE (p = 0.082). The frequencies of the CC, CT, and TT genotypes were 77.81%, 21.52%, 0.67%, respectively, among the cases; and they were 83.82%, 14.71%, 1.47%, respectively, among the controls (p = 0.048). Compared to the control group, the CT genotype was more frequent in nephrolithiasis patients . Moreover, there was also a higher frequency of CT/TT genotypes among patients with nephrolithiasis . However, there was no difference in allele distribution between the two groups (p = 0.105).p = 0.003), smokers with pack-years of smoking >20 , non-drinkers , patients with hypertension  and non-diabetic patients .Furthermore, stratified analyses of age, sex, BMI, pack year of smoking, drinking habits, hypertension status, diabetes status and family history were conducted. As presented in To better understand the association between the polymorphism and clinical risk factors, biochemical parameters including urine pH, serum calcium, uric acid, phosphorus and creatinine were analyzed. As shown in p = 0.027: the risk of developing nephrolithiasis in individuals with CT/TT genotype compared to CC genotype)  with the risk of multiple stones was found. Compared to the control group, the CT/TT genotypes were more frequent in patients with recurrent episodes of nephrolithiasis  .MMP-9-1562C>T genotypes and chemical stone composition was performed. Compared with the control group, the frequency of CT/TT genotypes was significantly higher in patients with calcium oxalate stones   .p < 0.001) (p = 0.037)  (< 0.001) . When th< 0.001) . In addi= 0.037) .MMP-9-1562C>T SNP (rs3918242) and the risk of nephrolithiasis in a southern Chinese population in this hospital-based case-control study. Comparing CT and CC genotypes frequencies between nephrolithiasis patients and controls, we found that CT genotype was significantly more prevalent in the nephrolithiasis patients; also it was revealed that the variant T allele (CT/TT) was significantly more frequent in the lithiasis population. Further stratification revealed that the risk remained for the subgroup of patients aged >53, smokers with pack-years of smoking >20, non-drinkers, non-diabetic patients, patients with hypertension, recurrent episodes and calcium oxalate stones. Compared to controls, nephrolithiasis patients had significantly higher serum MMP-9 levels. Moreover, patients with nephrolithiasis who had the CT/TT genotype had significantly higher serum MMP-9 levels than those who had the CC genotype. To the best of our knowledge, no studies have yet examined the association between the MMP-9-1562C>T polymorphism and nephrolithiasis in Chinese individuals.We investigated the relationship between the MMPs are zinc-dependent endopeptidases that can degrade ECM components, including collagen, which was essential for tissue repair and reconstruction during inflammation , 22. TheMMP-9 gene at position 1,562, which is close to the transcription start site. The polymorphism increases mRNA, protein expression, and MMP-9 activity in T allele carriers, whereas the C allele causes a decrease in these activities  has been identified in the tivities , 30. ConMMP-9-1562C>T polymorphism has synergistic effect with CSE in nephrolithiasis by up-regulating the expression of MMP-9. Further studies on the mechanism of MMP-9 and CSE in the formation of nephrolithiasis are warranted in the future.According to our findings, heavy smokers with more than 20 pack years of smoking seem to be more susceptible to developing nephrolithiasis with the variant T allele. Cigarette smoke is a complex mixture of chemical compounds, most of which has been proven to be cytotoxic, mutagenic, and oncogenic. Research has shown that cigarette smoke extract (CSE) can up-regulate the production of MMP-9 in rat vascular smooth muscle cell . In addiMMP-9-1562C/T polymorphism increased the risk of nephrolithiasis in patients with hypertension. Basic studies on hypertension have revealed that MMP-9 expression was significantly higher in conduct vessels with thicker intimas and media and the process could be blocked by MMP inhibitor (doxycycline) treatment . However, there was no significant difference in the smoking rate of diabetic patients between the two groups (p = 0.239). Multiple studies have shown that CSE or smoking can increase MMP9 expression in vitro and in vivo  in the 3′ untranslated region of e stones . Cell exe stones . Taken tMMP-9-1562C>T polymorphism and nephrolithiasis risk in Malaysians. Mehde et al. (p = 0.483). Between the two study populations, these discrepancies can be attributed to differences in environmental exposure, detection methods, and ethnic background. For example, the frequencies of the CC, CT, and TT genotypes in our control were 83.82%, 14.71%, 1.47%, respectively, which were different from theirs . On the other hand, the research by Mehde et al. contains 120 cases and 120 controls. The sample size was relatively small, with insufficient statistical test efficacy to explore the real association. Furthermore, we performed stratified analyses based on age, sex, BMI, pack year of smoking, drinking habits, hypertension status, diabetes status, family history, multiple stones, recurrence, and chemical stone composition to get more precise results.To date, there has only been one published report of the association between e et al.  showed tMMP-9 gene, which have not yet been found, increased the risk of nephrolithiasis. Third, the role of MMP-9 in nephrolithiasis is not completely understood and further experimental studies are nevertheless necessary to explore the specific mechanisms for MMP-9 polymorphism and nephrolithiasis. Fourth, given that our study was hospital-based, selection bias was inevitable and our control population might not be accurately representative of the general population. However, in this study, incident patients were recruited. Moreover, in our Chinese control subjects, genotype distribution was similar to that reported for other diseases in the literature. For example, the frequencies of CC, CT, and TT genotypes in our controls were 83.82%, 14.71%, 1.47%, respectively, which resembles those discovered by Li et al. , the Changshu Medical Science and Technology Youth Program (cswsq202102), Clinical Key Subject Construction Project Foundation of Changshu (CSZDXK202001) and Introduction Project of Clinical Medicine Expert Team for Changshu (CSYJTD202001).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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Background and objectivePatients with neurogenic bladder (NB) are at a higher risk of developing chronic kidney disease (CKD). Due to their lower muscle mass, the estimated glomerular filtration rate (eGFR) based on creatinine (Cr) may be overestimated and delay the diagnosis of renal failure. This study compared eGFR calculated with different equations based on Cr and/or cystatin C (CysC) in children with NB, and the differences between patients with lower muscle mass (underdeveloped lower limbs) and those with independent gait (less muscle depletion).MethodsWe calculated the eGFR in pediatric patients with NB and CKD stages 1 and 2 by using the following equations: Chronic Kidney Disease in Children equation for serum creatinine (CKiD-Cr), CKiD-CysC, CKiD combined-Cr/CysC, Zappitelli-CysC, and Zappitelli combined-Cr/CysC.ResultsWe evaluated a total of 47 patients, 74.5% with CKD stage 1, with a median age of 14.1 years. Of these participants, 59.6% had lipo/myelomeningocele. The CKiD-Cr and CysC-based equations led to significantly lower calculated eGFR (p<0.05), specifically CKiD-CysC (p<0.001), Zappitelli-CysC (p<0.001), CKiD-Cr/CysC (p<0.001), and Zappitelli combined-Cr/CysC (p<0.05). When CKiD-CysC was used, 68% of the patients moved to a more advanced CKD stage. In patients without independent gait, with lower muscle mass (55.3%), the median eGFR calculated using the CKiD-Cr and CKiD combined-Cr/CysC equations was significantly higher (p<0.05). However, there were no differences between the two groups when using the other CysC-based equations.ConclusionIn patients with NB and poor muscle mass, the CKiD-Cr equation may overestimate renal function. CysC-based equations seem more reliable in these patients, especially in those with greater muscular atrophy. Neurogenic bladder (NB) is defined as a lower urinary tract dysfunction ranging from detrusor underactivity to overactivity, either associated with sphincter detrusor dyssynergia or not, and resulting in inadequate storage capacity, urinary incontinence, and/or ineffective emptying capability. It is caused by a congenital or acquired injury or disease at any level in the central or peripheral nervous system -3.In the pediatric population, the most common cause of NB is spinal dysraphism such as myelomeningocele, lipomeningocele, meningocele, and occult lesions. Other etiologies of NB include sacral agenesis, cerebral palsy, traumatic spinal cord injuries, tumors of the brain or spinal cord, muscular dystrophy, and other neuromuscular diseases ,4-9. MosChronic kidney disease (CKD) is three times more prevalent in patients with NB than in the general population; it affects 25-50% of these patients and is a major cause of morbidity and mortality . Kidney It is critical to reach an early diagnosis and to better identify risk factors, in order to prevent kidney disease progression and preserve lifetime kidney function. Thus, accurately measuring kidney function is crucial to identify patients in the early stages of kidney dysfunction and to monitor its progression closely ,7,14-17.Cr is a simple and practical renal function marker. It is produced at a fairly constant rate and eliminated mostly by the glomeruli. However, as it is produced from the nonenzymatic degradation of muscle creatine, its level is highly dependent on the patient’s muscle mass, resulting in low sensitivity and accuracy. Besides, it is also affected by age, sex, diet, some drugs, malnutrition, and chronic illness ,19,20. OSeveral equations based on Cr and/or CysC have been created to improve the accuracy of the eGFR calculation and are widely used: CKiD-CysC, Zappitelli-CysC, CKiD combined-Cr/CysC, and Zappitelli combined-Cr/CysC ,20. In pIn this study, we compared the eGFR calculated by different equations based on Cr and/or CysC in children with NB in the early stages of CKD (stages 1 and 2). We also compared the eGFR calculated with these equations between patients with motor neurological injury (MNI) - patients unable to walk independently, patients with underdeveloped lower limbs and poorer muscle mass - and patients without MNI - with independent gait and with more typically developed lower limb musculature.This article was previously posted to the Research Square preprint server on 20 April 2023: Menezes C, Costa T, Brás C, et al.: Estimating Glomerular Filtration Rate in Pediatric Patients With Neurogenic Bladder: a comparison between Creatinine- and Cystatin C-Equations. Res Square. DOI: 10.21203/rs.3.rs-2778544/v1.Study design and sampleWe conducted a cross-sectional observational retrospective study by analyzing the clinical records of all pediatric patients (aged <18 years) with NB and CKD stages 1 and 2, based on the eGFR calculated with the CKiD-Cr (bedside Schwartz) equation, and followed up between January 2009 and April 2022 at an outpatient multidisciplinary NB clinic of the pediatric nephrology unit of a tertiary pediatric hospital in Portugal.Variables definition and data collection2, with evidence of kidney structural damage, and stage 2 is defined as an eGFR level between 60 and 89 mL/min/1.73 m2  compared to the patients without MNI [0.67 (0.5-0.9)] mg/dL, (p<0.001). However, the median CysC value was similar in the patients with MNI [0.89 (0.8-1.2) mg/L] and those without MNI [0.95 (0.75-1.2) mg/L; p = 0.764)  in the patients with MNI compared with the patients without MNI [118.52 (101.21-152.14) and 91.97 (72.82-115.01) vs. 91.23 (64.25-112.16) and 82.80 (63.59-88.60) mL/min/1.73 mThe importance of early diagnosis of kidney disease in patients with NB and the risk of CKD progression is paramount. An early diagnosis enables the implementation of the best therapeutic plan and the optimal follow-up strategy to prevent progressive kidney damage. Earlier detection of CKD in this population also allows a timely referral to pediatric nephrology care and closer monitoring ,26. ReguThe eGFR calculated with the CKiD-Cr (bedside Schwartz) equation is the most commonly used method to assess kidney function in children. However, the reduced muscle mass in patients with NB turns Cr into a less accurate marker, as reported in several previous studies ,22,23,27The National Institute for Health and Care Excellence guidelines (UK) recommend not using serum Cr and Cr-based eGFR equations alone to monitor renal function in patients with NB . Our stuDangle et al.  publisheZhou et al.  conducteOur results are also in line with those of Morgan et al. , who evaMorrow et al.  comparedOur study has a few limitations. As it was a retrospective study, we did not confirm the accuracy of Cr- and/or CysC-based eGFR calculation by using a clearance method that measures exogenous filtration markers, which is the gold standard, or by using nuclear-medicine-based GFR evaluation or 24-hour urine Cr and/or urea clearance. Additionally, this was a single-center study, and hence the generalizability of the results might be limited. Despite these limitations, to our knowledge, this is the first Portugal-based observational retrospective study comparing GFR estimated based on Cr and CysC in pediatric patients with NB-associated kidney disease as well as the differences between patients with and without MNI, and with very different degrees of muscle mass reduction.As creatinine is highly dependent on patient muscle mass, Cr-based formulas may overestimate eGFR in children with NB, especially in those with greater muscle atrophy. This may delay CKD diagnosis or even prevent a correct disease staging, leading to several therapeutic and prognostic implications. Hence, since CysC is unaltered by body size and composition, and muscle mass, CysC-based formulas may be a more reliable method to assess kidney function in these patients. Further studies need to be conducted in the pediatric population with NB, including multicentric studies with a larger number of patients, which compare Cr- and CysC-eGFR calculations with a GFR standard measuring method such as nuclear medicine-based GFR evaluation or 24-hour urine Cr and/or urea clearances. It would also be important to compare eGFR calculated with different formulas based on Cr and/or CysC in children with NB and in a control group of children without NB and muscle depletion, to identify a more accurate tool to estimate kidney function in these patients and to support consensus recommendations.


A prospective, observational study in a single academic center was conducted from March 2019 to March 2022. Plasma levels of angiopoietin (Ang)-2, Vascular Endothelial Growth Factor-C (VEGF-C), Vascular Cell Adhesion Molecule-1 (VCAM-1), Copeptin (CPP), beta-trace protein (BTP), brain natriuretic peptide (BNP), and cardiac troponin I (cTnI) were all measured. Lung ultrasound (US) B-lines, bioimpedance, and echocardiography with global longitudinal strain (GLS) were recorded. The study outcome was the initiation of chronic dialysis  during 24 months of follow-up. A total of 105 consecutive patients with a mean eGFR of 21.3 mL/min/1.73 m were recruited and finally analyzed. A positive correlation between Ang-2 and VCAM-1 and BTP was observed. Ang-2 correlated positively with BNP, cTnI, sCr, E/e′, and the extracellular water (ECW)/intracellular water (ICW) ratio (ECW/ICW). After 24 months, a deterioration in renal function was observed in 47 patients (58%). In multivariate regression analysis, both VCAM-1 and Ang-2 showed independent influences on risk of renal replacement therapy initiation. In a Kaplan-Meier analysis, 72% of patients with Ang-2 concentrations below the median (3.15 ng/mL) survived without dialysis for two years. Such an impact was not observed for GFR, VCAM, CCP, VEGF-C, or BTP. Endothelial activation, quantified by plasma levels of Ang-2, may play a key role in GFR decline and the need for dialysis initiation in patients with CKD 3b, 4, and 5.Volume status, congestion, endothelial activation, and injury all play roles in glomerular filtration rate (GFR) decline. In this study, we aimed to determine whether the plasma endothelial and overhydration markers could serve as independent predictors for dialysis initiation in patients with chronic kidney disease (CKD) 3b-5 (GFR < 45 mL/min/1.72 m Chronic kidney disease (CKD) affects about 13.4% (11.7–15.1%) of the population worldwide. Traditional risk factors for CKD development and progression, such as diabetes mellitus (DM), hypertension, and obesity, are already well-constituted . The cliThe potential to become such a microvascular biomarker is present in several molecules. Among those analyzed in this study, angiopoietin-2 (Ang-2), a modulator of endothelial dysfunction , earns a2 and a preserved ejection fraction could be predictive for renal impairment progression and initiation of renal replacement therapy.We aimed to assess which of the circulating biomarkers, including angiopoietin, in CKD patients with eGFR < 45 mL/min/1.73 m2) who met the inclusion criteria. A total of 35 patients were in stage 3b, 34 patients were in CKD 4, and 36 were in stage 5. The mean age at enrollment was 52.6 (±14.8) years, and 68 (64.8%) of the patients were male. Of all participants, 79% were hypertensive and 24% were diabetic mellitus. There were 22 patients with heart failure enrolled in the study. Ten of them were in the dialysis group. Regarding the etiology of CKD, the following causes were recorded: chronic glomerulonephritis (GN)—24; diabetes—22; hypertensive nephropathy—19; autosomal dominant polycystic kidney disease (ADPKD) -10; interstitial—8; urologic complication—6; unknown—11. However, we did not find a specific relation between circulating biomarkers and any of the above etiologies. We analyzed a total of 105 patients with CKD stages G3b-5 , deteriorated renal function (progressors), and undergoing maintenance hemodialysis. Comparative data between the groups are displayed in Over a follow-up period of 24 months, deterioration of renal function was observed in 47 patients (progressors), and 31 presented stable or ameliorated renal function. Twenty-two maintenance dialysis patients formed a control group .Between the two groups, progressors versus nonprogressors, we observed a difference in concentration of angiopoetin-2, but also of VCAM and B-trace protein. Moreover, differences in urine and blood osmolality and procalcitonin, as well as in traditional clinical measures such as lung ultrasound B-lines and BNP were observed .In a Kaplan-Meier analysis, a significant impact of Ang-2 on renal survival, described as a need for RRT commencement, a hard endpoint, was found . Namely,In our study, we showed that Angiopoetin-2, unlike other examined potential biomarkers and eGFR, helps to predict the need for renal replacement therapy commencement within a two-year span. Although the concentration of B-trace protein and VEGF-C also differed significantly in the progressors and nonprogressors groups, they did not show such a predictive value.In the angiopoietin family, Angiopoietin-1 (Ang-1) and Angiopoietin-2 (Ang-2) are crucial. Ang-1 maintains vascular quiescence, prevents vessel leakage, and promotes endothelial cell survival via activation of the endothelial cell receptor Tie-2. Ang-2 competitively inhibits the effects of Ang-1 on Tie-2, leading to vessel instability and eventual capillary rarefaction. Ang-2 plays a role in many diseases related to vascular permeability . Regarding the association of Ang-2 with adverse renal outcomes, our study is consistent with results obtained by Tsai et al. , who dis2. In this study, Ang-2, Ang-1, and VEGF levels, as well as echocardiography parameters, were all measured. Ang-2 was significantly associated with left ventricle mass index and hypertrophy. Although in pathophysiology VEGF-A plays an important role in Ang-2 mediated signaling modulation, the study did not reveal a significant correlation with cardio vasculature. The same team  conductOn the basis of a model of CKD development in mice, the first therapeutic strategy directly addressing renal endothelium via Ang-2 inhibition as a CKD therapy was established. Chang et al.  showed tIn a small study, Bontekoe et al.  hypothesAccording to our study, there is a moderate link between Ang-2 and the E/e′ ratio, which is a measure of the LV filling pressure . DiastolThe evaluation of renal function is mostly focused on calculating GFR using creatinine calculations. Lipocalin-type prostaglandin D2 synthase (prostaglandin H2-D-isomerase), also known as beta-trace protein (BTP), is a low molecular weight (LMW) protein. It catalyzes the conversion of prostaglandin H2 (PGH2) to prostaglandin D2 (PGD2). BTP—as LMW protein shares with Cystatin-C (CysC) biochemical features exceptionally useful in GFR estimation. Beta-trace protein  has been nominated in the last few years as a potential new biomarker of renal function decline . BTP is It is highly likely that the combination of Ang-1 and Ang-2 tests will greatly enhance the risk stratification for CKD development and dialysis commencement. In a recent prospective multicenter investigation, the prognostic value of angiopoietins (Ang-1:Ang-2 ratio) for future renal disease in patients with acute kidney injuries was determined . We hypoThe limitation of our study was lack of evaluation of the interaction between the therapeutic intervention and the biomarker. All patients were ambulatory, and we considered them as clinically compensated, receiving the standard of care medication . Furthermore, only half of the study patients had urine albumin creatinine ratio (UACR) results (properly taken morning sample) available, and all of them showed positive results (UACR >  30 mg/g). Nevertheless, ranges were similar in the majority of the patients (no patients showed nephrotic or nephritic syndrome), and in this study we focused on CKD patients who would start dialysis in near future. Future research should analyze how currently used medication changes the levels of angiopoietins. 2, left ventricle ejection fraction (LVEF) >45%, age above 18 years, and informed consent. The exclusion criteria were liver cirrhosis, an active malignancy, severe lung disease, LVEF < 45%, and NYHA III or IV. The observational study was conducted at the University Hospital Wroclaw between March 2019 and March 2022. The study group included 105 patients with chronic kidney disease in stages G4–5, including kidney transplantation recipients. Patients undergoing hemodialysis were used as a control group. The decision to start dialysis was based on GFR < 15 mL/min and at least one of the uremic symptoms . CKD was staged according to to Kidney Disease Improving Global Outcomes (KDIGO 2012) GFR categories and the eGFR was calculated using the simplified four-variable Modification of Diet in Renal Disease (MDRD) Study formula . The incDiagnosis criteria for heart failure were based on echocardiography (EF < 50% and/or left ventricular end-diastole diameter greater than 5.5 cm) and/or BNP levels: over 500 pg/mL for patients with CKD stages 3b; over 800 pg/mL for stage 5. In the dialysis group there were six patients with HF with preserved EF (HFpEF), EF > 50%; four patients had HF with mildly reduced EF (HFmrEF), EF 45–49%.One patient died due to COVID-19 infection, and four others were lost in the follow-up period. The patients were assessed at the enrollment, which took place between March 2019 and November 2020. Demographic and clinical data included age, body mass index (BMI), presence of diabetes mellitus, and hypertension (HTN). The follow-up data were collected based on medical documentation and telephone contact with patients 24 months after the enrollment. The observation ended in March 2022. In each participant we performed a lung ultrasound (LUS) examination with a B-lines (ultrasound B-lines) assessment, echocardiography with global longitudinal strain evaluation, a pulse wave velocity measurement, bioelectrical impedance analysis (BIA), and a six-minute walk test (6-MWT) for evaluating physical functional capacity. All the exams and measurements, despite echocardiography, which was performed by a cardiologist, were performed by the same nephrologist. Blood and urine samples were collected for standard laboratory tests  and for potential novel markers of renal insufficiency. An accredited local laboratory performed measures of concentration using Enzyme-Linked Immunosorbent Assay (ELISA) for Angiopoetin-2, Vascular Endothelial Growth Factor-C, Vascular Cell Adhesion Molecule-1 (CD106), Copeptin, and Prostaglandin D- Synthase (B-trace protein). A standard (3.0-MHz) echocardiography probe  was used for the chest ultrasound. The test protocol encompassed detecting extravascular lung water (LW) by visualizing B-lines, as these are the US equivalent of standard chest X-ray Kerley B-lines . The exaThe transthoracic echocardiography examination was performed with a high-resolution ultrasound machine . On the basis of the measurements, the LV mass (LVM) was calculated and then indexed to the body surface area (BSA). For the diastolic function evaluation, we used the ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e′) visualized in pulse-wave (PW) and tissue Doppler, respectively. Ejection fraction of the left ventricle was calculated by the Simpson biplane method. GLS was measured using a two-dimensional speckle tracking echocardiography. Three apical views were obtained, and then the average peak systolic longitudinal strain was provided by the software. The bioelectrical impedance analysis was measured with a single-frequency (SF) analyzer BIA-101 . The measurements were conducted according to the manufacturers’ instructions, at one frequency of 50 kHz at 0.8 mA. Every patient was examined in a supine position. The single-use dedicated electrodes were attached to one hand and ipsilateral ankle. After being acquired, the resistance and reactance values, together with other basic characteristics of the patient, were analyzed by dedicated software. Extracellular water and intracellular water were obtained, and then the ECV/ICV ratio was counted. The 6-MWT is an accessible and easy-to-perform test with wide indications . For theFor VCAM-1, VEGF-C, and Angiopoietin-2 concentration measurements, the Quantikine™ ELISA  solid-phase sandwich technique was used. For prostaglandin D synthase, the sandwich ELISA  was also used. For Copeptin (CPP), a Competitive-ELISA  set was applied. After the sequence of reactions of each biomarker in 96-well polystyrene microplates precoated with proper antibodies, the color change was measured spectrophotometrically at a wavelength of 450 nm. The concentrations of each biomarker in the examined samples were then determined by comparing the optical density of the samples to the standard curve. The sensitivity for Ang-2, expressed as mean minimum detectable dose (MDD), was 8.29 pg/mL.Based on renal function after 24 months, patients were divided into three groups: with stable/ameliorated renal function; with deteriorated renal function; and undergoing hemodialysis as a control group. 2 test. Univariate and multivariate regression analyses were performed to identify clinical factors influencing the risk of dialysis starting. Kaplan-Meier survival analysis was used to analyze the impact of plasma biomarkers, e.g., Ang-2, on renal replacement therapy (RRT) commencement. Statistical significance was set at a two-sided p-value of less than 0.05.Statistical analysis was performed using Statistica ver. 13 software . Data in tables are expressed as the mean and median with interquartiles (IQR). The distribution was tested with the use of the Kolmogorov–Smirnov test. Differences between the two groups were assessed with the use of a t-test or median U test. Categorical variables were expressed as absolute (N) and percentage (%) values and compared using the χIn conclusion, our study demonstrated that among other new potential biomarkers, unlike GFR, elevated Angiopoetin-2 concentration shows predictive properties regarding the necessity to commence RRT in CKD patients in Stages 3b-5. Understanding of the pathomechanism underlying the link between adverse renal outcomes and increased circulation of Ang-2 can help not only due to its predictive value, but maybe also in developing future therapeutic strategies.


AGXT variant, which imparts a relatively favorable outcome, little is known about determinants of kidney failure. Identifying these is crucial for disease management, especially in this era of new therapies.Primary hyperoxaluria type 1 (PH1) has a highly heterogeneous disease course. Apart from the c.508G>A (p.Gly170Arg) In this retrospective study of 932 patients with PH1 included in the OxalEurope registry, we analyzed genotype-phenotype correlations as well as the impact of nephrocalcinosis, urolithiasis, and urinary oxalate and glycolate excretion on the development of kidney failure, using survival and mixed model analyses.P = 0.003). Poor outcomes were found in patients with other potentially vitamin B6-responsive variants. Nephrocalcinosis increased the risk of kidney failure significantly . Urinary oxalate and glycolate measurements were available in 620 and 579 twenty-four-hour urine collections from 117 and 87 patients, respectively. Urinary oxalate excretion, unlike glycolate, was higher in patients who subsequently developed kidney failure (P = 0.034). However, the 41% intraindividual variation of urinary oxalate resulted in wide confidence intervals.The risk of developing kidney failure was the highest for 175 vitamin-B6 unresponsive (“null”) homozygotes and lowest for 155 patients with c.508G>A and c.454T>A (p.Phe152Ile) variants, with a median age of onset of kidney failure of 7.8 and 31.8 years, respectively. Fifty patients with c.731T>C (p.Ile244Thr) homozygote variants had better kidney survival than null homozygotes (AGXT null variants and nephrocalcinosis were the strongest determinants for kidney failure in PH1.In conclusion, homozygosity for   Nevertheless, few studies have investigated these associations and their findings require confirmation in larger patient groups.PH1 is a genetic metabolic disease, with an estimated prevalence of 1:152 000 in Europe and North America,AGXT variants are known to cause PH1.AGXT variants, c.731T>C (p.Ile244Thr) and c.121G>A (p.Gly41Arg), lead to protein aggregation and accelerated degradation, combined with partial mitochondrial mistargeting.More than 200 pathological ,Little is known about other potential determinants of kidney failure in PH1. Nephrocalcinosis has been associated with a higher risk of developing kidney failureIn this study, we used the OxalEurope registry to describe genotype-phenotype correlations, including potentially vitamin-B6 responsive missense variants that were previously only described in very small numbers. In addition, we investigated if nephrocalcinosis and urolithiasis were related to kidney outcome. Finally, we explored the association between urinary oxalate and glycolate excretion and the development of kidney failure.AGXT genotype, symptoms), age at diagnosis, 24-hour urinary oxalate and glycolate excretion, and kidney outcome at follow-up. The STROBE checklist was used as a guideline for reporting  homozygous B6+, (ii) compound heterozygous B6+/missense, (iii) homozygous missense, (iv) compound heterozygous B6+/null, (v) compound heterozygous missense/null, and (vi) homozygous null. The AGXT variants c.508G>A (p.Gly170Arg) and c.454T>A (p.Phe152Ile) were referred to with the term “B6+”, based on their DNA sequence change (missense), pathophysiological consequence  and evidence of in vivo vitamin B6 response.2).2 or treatment by dialysis. This study did not include patients on RNA-interference therapy.For descriptive statistics and for comparing the risk of kidney failure between patients with different P-values, and 95% CI were provided. Mixed model analysis was performed to investigate the longitudinal outcome trajectory of urinary oxalate and glycolate excretion between patients with and without kidney failure at last follow-up, excluding measurements after onset of kidney failure. The mixed model was fitted on logarithmically transformed data, taking group, age, and their interaction as fixed effects; and patient-specific intercept and slope of time as random effects. Outcomes were back transformed to original scale for graphical interpretation. The method of calculating intraindividual variation was adapted from Clifford-Mobley et al.P < 0.05, using IBM SPSS version statistics version 28  and RStudio version 3.6.1 . The following R packages were used: ggplot2, survival, linear mixed-effects models, regression modeling strategies.Categorical variables were presented as percentages and between-group differences were assessed using the chi-square test. Continuous variables were expressed as median (range or interquartile range [IQR]) and between-group differences were evaluated using Mann-Whitney U test and Kruskal-Wallis test. Cumulative survival rates were calculated from “date of birth” to “date of kidney failure” or censored at last follow-up date. Survival analysis was performed with Kaplan-Meier curves and log-rank test. The event of interest was kidney failure. Factors associated with kidney outcome were estimated by Cox-regression analyses. To meet the proportional hazards assumption, patients with infantile oxalosis were excluded from Cox-regression analyses for genotype. Patients with kidney failure at time of diagnosis were excluded from Cox-regression analyses for nephrocalcinosis and urolithiasis. Urinary oxalate and glycolate excretions determined after onset of kidney failure or after transplantation were excluded too. HRs, We obtained data of 932 patients  with PH1. Patients from France, the United Kingdom, Germany, the Netherlands, and Italy accounted for 76.0% of the cohort . The cliAGXT genotype was known for 760 patients . Allelic frequencies of all individual missense variants are given in s 81.5%, . There wAGXT genotype , but occurred in a quarter of null homozygotes . B6+ homozygotes were significantly older at time of first presentation, diagnosis, and onset of kidney failure (P < 0.001) as compared to other genotype groups. Nearly half of patients (47.2%) presented with kidney failure at the time of diagnosis. At last-follow-up, 473 patients (63.9%) had kidney failure.Kidney outcome was known for 740 patients. Clinical presentation of PH1 was related to genotype . InfantiA total of 198 patients with PH1 were diagnosed in adulthood. Seventy-three of them (41.0%) were B6+ homozygotes. A smaller number of patients were missense homozygotes (20.2%), B6+/null heterozygotes (14.6%), null homozygotes (9.0%), missense /null heterozygotes (7.3%), and B6+/missense heterozygotes (6.2%). They developed symptoms at a median age of 20.7 years and received the diagnosis at a median age of 37.7 years. At the time of diagnosis, the majority of adult patients with PH1 (71.5%) experienced kidney failure. The median age at onset of kidney failure was 35.4 years. Thirty patients died at a median age of 47.2 years. There were 362 (47.2%) patients whose diagnosis was missed until the onset of kidney failure. The percentages of patients in each genotype-based group were similar to those of the entire cohort. There was a large gap between median age at first symptoms (5.6 years) and median age at diagnosis (15.8 years). Patients who developed kidney failure had a median age of 15.3 years (IQR 0.9–34.1) at onset of kidney failure. This was not significantly different between patients who developed kidney failure prior to the establishment of the diagnosis or during follow-up . In 39 patients (4.2%), the diagnosis was only established after a failed kidney transplantation.P < 0.001) and missense/null heterozygotes , but also the case for B6+/null heterozygotes  and missense homozygotes . In B6+/missense heterozygotes, the risk of kidney failure was not significantly higher than in B6+ homozygotes . Comparing null homozygotes to missense homozygotes, the risk of developing kidney failure was significantly higher in the first group . The median age at onset of kidney failure was 31.8 years for B6+ homozygotes, 29.6 years for B6+/missense heterozygotes, 15.4 years for missense homozygotes, 18.7 years for B6+/null heterozygotes, 15.0 years for missense/null heterozygotes and 7.8 years for null homozygotes  years. The median age at diagnosis was 28.1 years (range 0.2–63.4) years. There were 56 patients who presented with kidney failure. Twelve patients developed kidney failure during follow-up. The median age at onset of kidney failure was 31.6 (range 0.4–62.7) years. Fifteen patients died at a median age of 51.5 (range 0.7–67.6) years.Eleven patients were c.454T>A homozygotes, most of them from Western European countries. The median age at symptom onset was 19.6 (range 0.4–57.9) years and 30.9 years (range 8.4–59.3) at diagnosis. Ten patients had a history of urolithiasis at the time of diagnosis and nephrocalcinosis was found in 4 patients. In 2 patients, the diagnosis was only established after onset of kidney failure. Another patient had recurrent stone events from childhood on, but the diagnosis was only established in her 40s, and despite missing treatment with pyridoxine until then, kidney function had remained normal. There were no cases with infantile oxalosis. At the last follow-up, 6 patients had progressed to kidney failure at a median age of 44.7 (range 16.2–74.4) years. Three of them died at ages of 17, 45, and 62 years.n = 24) presented with kidney failure; 9 of them with infantile oxalosis. Four additional patients developed kidney failure during follow-up. The median age at onset of kidney failure was 12.9 (range 0.2–70.1) years. Six patients with kidney failure died at a median age of 25.5 (range 1.4–49.8) years. Kidney survival curves were not significantly different between c.731T>C and c.508G>A homozygotes but were borderline significant when comparing c.731T>C to c.454T>A homozygotes (P = 0.051). Comparing c.731T>C homozygotes to null homozygotes, kidney survival rates were significantly higher in c.731T>C homozygotes (P = 0.003).Kidney outcome was known for 50 of 64 c.731T>C homozygotes . This vaAGXT missense variants, that are potential candidates for in vivo vitamin B6 responsiveness, are presented in n = 5), nephrocalcinosis (n = 4), and kidney stones (n = 11) to kidney failure . Vitamin B6 response was seen in 2 patients carrying c.121G>A variants and 1 patient heterozygous for c.139G>A. At last follow-up, 2 patients had developed kidney failure and 4 patients had died.Clinical characteristics and kidney outcome of patients with other P < 0.001) whereas urolithiasis did not .Nephrocalcinosis increased the risk of developing kidney failure  were reported in 84 patients . The med2. Twenty-three B6+ homozygotes had lower excretion rates than 12 missense homozygotes and 24 null homozygotes . For urinary glycolate ratios, CVintra was 49.2% and for 24-hour urinary glycolate, CVintra was 57.4%.Median intraindividual variation was expressed as a coefficient of variation (CVintra = SD/mean). For urinary oxalate, CVintra was 43.1% for urinary oxalate ratios and 41.0% for 24-hour collections  and potential candidates (e.g. c.731T>C) according to a recent review that comprehensively summarized the current body of evidence for vitamin B6 responsiveness for several pathogenic variants.in vitro and in vivo.,AGXT missense variants are scarce and are reported in detail in this study. Patients with c.454T>A variants may have better kidney survival than c.508G>A homozygotes, but this was not statistically significant in our cohort. This confirms previous findings in smaller cohorts.in vitro;in vitro results, it has been suggested that pyridoxal and pyridoxamine could better counteract the protein misfolding, caused by the c.731T>C variant, than pyridoxine. In their cellular study, Oppici et al.in vitroin vitro,in vitro studies, the c.139G>A, c.167T>A, c.481G>A, and c.481G>T variants potentially impart vitamin B6 responsiveness,In this study, we focused on genotype-phenotype correlations for 8 in which baseline characteristics were comparable to those of the current study cohort.We found that nephrocalcinosis was associated with a three-fold higher risk of developing kidney failure, whereas urolithiasis was not. This is in line with an international cohort study of 170 patients with PH1,Oxalate/creatinine ratios were not significantly higher in patients who developed kidney failure, possibly related to the higher percentage of B6+ homozygotes in the group with favorable kidney outcome. Examining absolute urinary oxalate excretions, we did find significantly higher urinary oxalate in patients with kidney failure at last follow-up. However, the effect was small and the CI was wide. Only 1 previous study has investigated the impact of urinary oxalate on kidney outcome and found that urinary oxalate excretion at diagnosis, stratified by quartile, was strongly associated with the risk of developing kidney failure (HR 3.4 [1.4–7.9]).et al.10 it remains to be established what percentage reduction in urinary oxalate excretion will actually prevent progression to kidney failure. More insight into this will probably come from long-term follow-up data clinical trials with RNA-therapeutics, that effectively reduce urinary oxalate excretion.It is known that the variation in urinary oxalate excretion in healthy volunteers is high (42.5%).AGXT genotype. Considering that glycolate excretion is highly influenced by diet and that normal glycolate excretion rates do not exclude PH1, we recommend proceeding with genetic testing in case of high clinical suspicion of PH1 but normal urinary glycolate excretion, as proposed in the recent European guidelines.An association between urinary glycolate excretion and kidney outcome was not found in this study. This biomarker, with a very high CVintra, was not necessarily elevated in every sample of patients with PH1, regardless of AGXT genotypes, whereas we now focus on the absence or presence of kidney failure at last follow-up. Besides genotype-phenotype correlations, there are several other factors assumed to influence the disease course, such as conservative treatment methods, which were not considered in our analyses. Even patients with unfavorable genotypes may thus experience a stable disease course if adequately treated, given that this (conservative or RNA-interference) treatment significantly influences outcome.The OxalEurope registry is the largest database available worldwide, comprising real-world observational data. The main strength of this study is the availability of data on genotype-phenotype correlations, with kidney failure as phenotypic outcome. The parallel weakness of this study is the lack of other phenotypic outcomes. Potential additional clinical outcomes include kidney function or chronic kidney disease stage, number of stone events, and grade of nephrocalcinosis. Including those outcomes would have given more information on the course of the disease in patients with different AGXT variants with evidence for in vivo vitamin B6 responsiveness (c.508G>A and c.454T>A).Several limitations are inevitable and inherent to the partly retrospective nature of the OxalEurope registry. Not all data were available in all patients. When analyses were performed in a subgroup of 932 patients for that reason, this was indicated in the manuscript or tables. Center-specific supply could have influenced the results if the provided care differs from center to center, for example with regard to monitoring adherence to vitamin B6 treatment. However, we think this effect is not significant because the main participating centers are located in Western Europe and would monitor their patients in the same way. Historically, OxalEurope did not consistently capture all variables of interest, such as the response and compliance to hyperhydration, urine alkalizers or vitamin B6 treatment. Vitamin B6 efficacy to reduce urinary oxalate excretion per patient was not routinely tested by standardized methods and only sporadically captured. Therefore, the term ‘B6+’ did not indicate actual biochemical vitamin B6 response; however, it was rather used to refer to patients with The main focus of this study was genotype-phenotype correlations; an unparalleled number of c.731T>C homozygotes was studied, revealing similar outcomes in this group as compared to c.508G>A or c.454T>A homozygotes. In addition, we found that nephrocalcinosis at time of diagnosis increased the risk of kidney failure 3 times. Urinary oxalate excretion was significantly higher in patients who developed kidney failure as compared to those with a favorable kidney outcome. Urinary glycolate was not associated with kidney outcome and repeated 24-hour urine collections were needed to reveal elevated excretion rates in some cases. Intraindividual variation was high for both biomarkers. A continued contribution of follow-up data will keep the OxalEurope registry updated, providing information on the prognosis of patients with PH1 in the era of new therapies.JWG, MJSO, SFG, LJD, and ELM have received an unconditional grant from both Alnylam Pharmaceuticals and Dicerna (Novo Nordisk) Pharmaceuticals to fund the OxalEurope Registry. SFG received a PhD scholarship from the Amsterdam University Medical Centers. SAH and SHM have received consultation fees from Alnylam Pharmaceuticals and Dicerna Pharmaceuticals. BBB, CA, GM, JB, JHa, JHo, LC, MJSO, and PMF have received consultation fees from Alnylam Pharmaceuticals. CMH has received consultation fees from Dicerna Pharmaceuticals and funding from Fundación Disa. All the other authors declared no competing interests.


PbtO2 was studied over the entire monitoring period. Thresholds were analysed in relation to outcome based on median and mean values, percentage of time and dose per hour below critical values and visualised as the combined insult intensity and duration.A total of 239 TBI patients with data on clinical outcome (GOS) and intracranial pressure (ICP) and pbtO2 was slightly, but not significantly, associated with outcome. A pbtO2 threshold at 25 and 20 mmHg, respectively, yielded the highest x2 when dichotomised for favourable/unfavourable outcome and mortality/survival in chi-square analyses. A higher dose and higher percentage of time spent with pbtO2 below 25 mmHg as well as lower thresholds were associated with unfavourable outcome, but not mortality. In a combined insult intensity and duration analysis, there was a transition from favourable towards unfavourable outcome when pbtO2 went below 25–30 mmHg for 30 min and similar transitions occurred for shorter durations when the intensity was higher. Although these insults were rare, pbtO2 under 15 mmHg was more strongly associated with unfavourable outcome if, concurrently, ICP was above 20 mmHg, cerebral perfusion pressure below 60 mmHg, or pressure reactivity index above 0.30 than if these variables were not deranged. In a multiple logistic regression, a higher percentage of monitoring time with pbtO2 < 15 mmHg was associated with a higher rate of unfavourable outcome.Median pbtO2, under 25 mmHg and particularly below 15 mmHg, for longer durations and in combination with disturbances in global cerebral physiological variables were associated with poor outcome and may indicate detrimental ischaemic hypoxia. Prospective trials are needed to determine if pbtO2-directed therapy is beneficial, at what individualised pbtO2 threshold therapies are warranted, and how this may depend on the presence/absence of concurrent cerebral physiological disturbances.Low pbtO PRx was calculated as the moving Pearson correlation coefficient of 30 consecutive 10-s average values of ABP and ICP and updated every minute [Collection of physiological data including ICP, ABP, and pbtOy minute , 20. Miny minute .2 were defined based on five different methods and analysed in relation to favourable/unfavourable outcome and survival/mortality. The first definitions were cruder, whereas the latter allowed for more granular ways to study pbtO2 insults. In the first insult definition, differences in median and mean values over the entire monitoring time were tested in relation to the outcome groups. In the second definition, we used a similar approach as Sorrentino et al. [2 values from the normal to lower range and divided it into 5 mmHg-intervals. These dichotomisations were compared to the patients’ outcome  using a chi-square test. The threshold with the highest x2 was considered as optimal for outcome dichotomisation. In the third insult definition, the percentage of good monitoring time  below the same critical values as mentioned above was calculated for pbtO2  [Regions with insufficient data (less than 20 patients per pixel/correlation) were not included in the maps, i.e. they were coloured white.2 below 15 mmHg for 20 min was specifically counted as one insult only for the pixel representing 20 min, but was not counted as an accumulated insult in pixels with lower durations that had already been exceeded (e.g. 19 min). The intensity was still cumulative in this study.For each pixel of the insults image, the duration was not cumulative, i.e. an insult with e.g. pbtOThe insults of pbtOo et al.  and expl40 mmHg) . In the 40 mmHg) . In the 40 mmHg) , which w40 mmHg) –29. For 40 mmHg) . PositivIn addition, prior to analysis, shorter gaps in the data (10 min or less) were closed via a linear approximation between the value just prior to and after the gap. The gaps were closed to avoid breaking up longer insults because of a small number of missing values. Insults where the duration was determined by a gap in the data, or the start or end of the recording were excluded from the analysis since their true duration could not be determined.2 below 15 mmHg (the %GMT threshold most strongly associated with unfavourable outcome as an isolated insult) in combination with other perfusion-related variables: ICP > 20 mmHg, PRx > 0.30, CPP < 60 mmHg, or ∆CPPopt < −5 mmHg. The ICP and CPP thresholds were chosen in accordance with the management protocol. Although PRx is not a direct measure of brain perfusion, we chose to include this variable since positive PRx indicates that the vascular reactivity is impaired and the brain is deprived of the protective mechanism that could stabilise CBF over a certain range of CPP and thus prevent ischaemia or hyperaemia. We chose PRx above 0.30, which has previously been strongly associated with poor outcome and may reflect approximately when the limit of autoregulation is exceeded [The %GMT was calculated for pbtOexceeded , 30. ∆CPexceeded .2 with ICP, PRx, CPP, and ∆CPPopt, respectively, in relation to outcome were visualised using the metric of %GMT fulfilling both thresholds criteria (for pbtO2 and for the other variable) in relation to GOS in heatmaps [2  together with ICP , PRx , CPP , and ∆CPPopt  yielded a grid of 1 400 cells (35 * 40) for the plots with pbtO2 vs ICP- and PRx and 1 050 cells (35 * 30) for the two other plots. For each coordinate/pixel (combination of two thresholds) the %GMT was calculated for all patients and correlated with GOS using the Spearman test. To produce smoother images, each pixel was divided into 3 by 3 subpixels followed by application of a Gaussian kernel filter (standard deviation of 2 pixels). The final values for each pixel were then translated into the jet colour scale (red to blue) with red/blue colour indicating an association with unfavourable/favourable outcome (GOS). Due to the moderate correlation strength (r within ± 0.3), the jet colour scale was limited to this correlation coefficient range. Pixels with less than 5 patients with at least 5 min of monitoring time for the corresponding combination of pbtO2 with ICP, PRx, CPP, or ∆CPPopt were excluded, i.e. coloured as white. In addition, a density plot was generated to visualise the frequency of the %GMT for certain combinations of pbtO2 with ICP, PRx, CPP, or ∆CPPopt. The resulting numbers were normalised (divided) by the highest count within the grid to yield density values ranging from 0 to 1 for each cell in the grid. A Gaussian smoothing, similar to the above procedure, was applied here as well and the final values were then transformed to colours using the jet colour scale.In addition, the interactions of pbtOheatmaps . The hea2 insults  with favourable/unfavourable outcome and survival/mortality was analysed with the Mann—Whitney U test and/or the chi-square test. Similar outcome analyses were done with the pbtO2-%GMT threshold most strongly associated with outcome in combination with ICP > 20 mmHg, PRx > 0.30, CPP < 60 mmHg, and ∆CPPopt < −5 mmHg. Multiple logistic outcome regressions were conducted with unfavourable outcome and mortality, respectively, as the dependent variable. Age and GCS together with the %GMT of ICP > 20 mmHg, PRx > 0.30, CPP < 60 mmHg, and the most significant pbtO2 threshold from the univariate insult-analyses were used as independent variables in these regressions. In similar, but separate regressions of unfavourable outcome and mortality, the %GMT of ∆CPPopt < −5 mmHg replaced CPP < 60 mmHg as an independent variable, to determine the role of the autoregulatory rather than the absolute, fixed CPP targets. A p-value below 0.05 was considered statistically significant. We abstained from adjustment for multiple testing since this was an exploratory study and many of the significance tests overlapped to a high degree.The statistical analyses were conducted in RStudio software (version 2022.12.0) . ContinuIn this TBI cohort of 239 patients Table , the med2 was 27 (IQR 21–33) mmHg. The median number of days with available data of ICP and pbtO2 from the NCC was 5 (IQR 3–8) and 5 (2–7) days, respectively. The median percentage of time with available pbtO2 and ICP data during the NCC was 69% (IQR 45–85) and 77% (IQR 60–89), respectively.During NCC, the median ICP was 13 (IQR 10–17) mmHg, the median PRx was 0.01 (IQR −0.08–0.15), the median CPP was 75 (IQR 72–80) mmHg, the median ∆CPPopt was 0 (IQR -1–2) mmHg, and the median pbtO2 was significantly higher in patients with favourable as compared to unfavourable outcome, butthere was no difference related to mortality  pbtO x2 Fig. , when di2 was below rather than above 15 mmHg . Furthermore, low pbtO2 without concurrent disturbances in the global cerebral physiological variables did not correlate with worse outcome. The association between low pbtO2 and outcome was more pronounced when any of the other global variables, i.e. ICP, PRx, CPP, or ∆CPPopt, was concurrently deranged. This supports the notion that low pbtO2 in combination with disturbances in global cerebral physiological variables indicate detrimental spatially widespread ischaemic hypoxia. However, pbtO2 is a focal measure and normal values do not exclude ischaemic hypoxia elsewhere.In this study, including 239 TBI patients, we found that pbtO2 was associated with unfavourable outcome and to some extent with mortality , consistent with several previous studies [2-probe is focally restricted to monitor a small brain region, it conveys clinically important information that is relevant for long-term recovery. It appeared that the %GMT and dose per hour below certain pbtO2 thresholds (e.g. 15 mmHg) were more strongly associated with outcome than median/mean values. This was expected considering the crude nature of median/mean values to capture brief, but dangerously low values.First, low pbtO studies –10. This2 went below 25 mmHg. The transition started slightly higher for the dose concept, which was expected since it also takes into account the cumulative magnitude (mmHg below the threshold being explored). The transition around 25 mmHg may be considered a relatively high value, since pbtO2 has similarly been shown to be around 20–25 mmHg in otherwise healthy patients undergoing elective neurosurgery [2. Previous, smaller (n ≈ 100), TBI studies have reported similar thresholds for outcome associations as compared to this study. The threshold for mortality/survival has been reported to fall between 10 and 29 mmHg [2, but also explored the potential time-dependent effect of exceeding an insult intensity. This was done both by investigating the accumulated burden of exceeding a certain threshold (%GMT and dose of pbtO2 below e.g. 15 mmHg) and for specific durations for individual insult intensities (e.g. pbtO2 below 15 mmHg for exactly 15 min in the heatmap). The heatmap was particularly important to visualise the role of pbtO2 deteriorations, since it is acknowledged that pbtO2 trends may exhibit different patterns [2 is only occasionally associated with high ICP and low CPP [2 deteriorations were clinically relevant as they were associated with poor outcome. Furthermore, the heatmap indicated that what defines a dangerously low pbtO2 could depend on the duration of the insult. Altogether, in comparison to the traditional fixed 20 mmHg pbtO2 threshold [2 go below 15 mmHg even for shorter durations and preferably to keep it above 25 mmHg.Second, regarding mmHg thresholds, in the statistical analyses, including the percentage of GMT, dose per hour, and the insult intensity/duration heatmap, there was a transition towards unfavourable outcome when pbtOosurgery . However 29 mmHg , 10 and  29 mmHg , 7, 9. Ipatterns , such as low CPP , 9, it ihreshold , our res2 below 15 mmHg in combination with disturbances in any of the global physiology-related variables ICP, PRx, CPP, or ∆CPPopt, were rare and only occurred in less than 1% in most patients. The limited overlap between insults in global cerebral physiological variables and pbtO2 was to some extent expected, as there is a significant intra-individual spatial variability in CBF [2 was typically monitored in a non-eloquent brain area , an isolated pbtO2-insult would then also not be expected to have a major effect on a global outcome measure such as GOS. However, when both global cerebral physiological variables and focal pbtO2 were disturbed at the same time, it was more likely that the entire brain was affected by ischaemic hypoxia, which could explain why even though this was rare it correlated with worse outcome. Although such combined insults only occurred in median in less than 1% of monitoring time, more than 50% of the patients exhibited such combined deranged values at least at some point in the NCC, indicating that they were infrequent but detrimental. In this scenario, it is expected that therapies oriented towards CBF augmentation would be beneficial. Furthermore, low pbtO2 alone without concurrent disturbances in global cerebral physiological variables was not associated with worse outcome. Thus, it is possible that therapies targeted to improve isolated pbtO2 insults may have somewhat limited clinical value due to the reasons mentioned above. However, further insights in this matter will be revealed when the three ongoing RCTs on pbtO2-oriented management have been completed.Third, it was clear that events of pbtOy in CBF  and it hy in CBF , 12, whi2 insults were weakly associated with outcome, we found that %GMT of pbtO2 below 15 mmHg was independently associated with unfavourable outcome, even after adjustment for %GMT of ICP > 20 mmHg, PRx > 0.30, and CPP < 60 mmHg. We speculate that this finding reflects the times when low pbtO2 indicated cerebral decompensation of widespread ischaemic hypoxia due to hypoperfusion. However, this association was attenuated when CPP < 60 mmHg was replaced by the autoregulatory target ∆CPPopt < −5 mmHg, which might be an even stronger indicator of global cerebral hypoperfusion.Fourth, despite that isolated pbtO2-directed treatments in addition to ICP and CPP [2 threshold at 20 mmHg; however, it is possible that considering both thresholds of pbtO2 intensity and duration could be an alternative approach, since values below 25 mmHg may be detrimental for the brain if the insults persist over longer time periods. In another, more individualised, approach, pbtO2-directed therapies could be guided by the concurrent use of microdialysis monitoring, since the latter could indicate when energy metabolic decompensation starts to occur due to pbtO2 deterioration for the individual patient [2 therapies based on if such deteriorations translate into increases in blood-based biomarkers of global brain damage [Fifth, there are now three ongoing phase III trials on the role of pbtO and CPP , which m patient . Yet anon damage .2 carries clinically relevant information for outcome and pbtO2 appears to be a valuable multimodality monitoring tool for making patient prognosis and possibly guiding treatment. In the clinical interpretation of pbtO2, not only the absolute intensity level, but also the duration of exceeding certain threshold ranges should be taken into account, since lower intensity levels may be tolerated for a slightly longer time, whereas higher intensities may be very dangerous even for brief periods. The absolute pbtO2 level should also be viewed in relation to the global cerebral physiological variables ICP, PRx, CPP, and ΔCPPopt. If the focal pbtO2 measure and any of these global variables are deranged at the same time, this is a particularly ominous brain state and management should be devoted to control ICP and augment CPP/improve ΔCPPopt. The clinical implications of isolated pbtO2 disturbances are less clear and it remains to be determined if it adds any value to treat this condition by e.g. augmentation of CBF or arterial oxygen content.Lastly, the clinical implications of this study are that low pbtOn = 239) of TBI patients with high-frequency data of ICP and pbtO2. We also used an extensive approach to study insult-thresholds from different angles. Particularly, the heatmaps visualised in a novel way how the effects of exceeding insult intensities may be time dependent and the importance of combined perfusion-related vs. isolated pbtO2 insults.The main strength of this manuscript was a relatively large cohort size (2 measured close to focal traumatic lesions is lower than in normal-appearing tissue [2 probe was typically inserted in the non-dominant frontal lobe while direct placement in lesions was avoided according to protocol. However, unfortunately, we were unable to access the radiological images to confirm this. This also prohibited us from proceeding with sub-analyses on the influence of pbtO2 from a peri-lesional vs normal-appearing probe location in relation to outcome. Third, this was a single-centre study with a selection of those patients who received both ICP- and pbtO2 monitoring. This limits the external validity of our findings. Fourth, the reliability of PRx and CPPopt has been questioned for EVD based ICP measurements and for patients with decompressive craniectomy. We attempted to address this issue with careful signal processing as explained in part I. Fifth, clinical outcome is a complex measure that is related to many factors, such as age, injury patterns, NCC treatments, and rehabilitation, which may have influenced the relative importance of pbtO2 derangements in relation to GOS. Sixth, the heatmaps were to some extent sensitive to noise, particularly for insults that were rare, which reduced the reliability of these areas in the plots. Seventh, we explored several pbtO2 thresholds; however, it was inevitable that they overlapped to some extent, since exceeding a certain value for a certain duration also implied that an even higher intensity might have been exceeded for some time during that period. Consequently, this makes it to some extent challenging to determine at what specific intensity and duration secondary brain injury occurred. Lastly, the data analysed in this retrospective study reflects more than just physiological or pathophysiological dynamics; it represents the intricate interplay of a dedicated NCC team striving to optimise brain physiology and physiological variables. The strength of their predictive prognostic values observed in the study are influenced not only by the patients' physiological responses but also by the collective efforts and expertise of the healthcare professionals involved in their care. Therefore, while the study findings may suggest a limited association between pbtO2 and outcomes, it is crucial not to interpret this as a justification for a laissez-faire approach. The proactive and tailored interventions implemented by NCC teams remain essential in optimising brain function and ensuring the best possible outcomes for patients.There were also some limitations. First, demographic and clinical data could not be retrieved in some cases. Second, previous studies indicate that pbtOg tissue , 37. In 2 below 20–25 mmHg was fairly common and there was a gradual transition towards unfavourable outcome for longer periods of time below these values and even more pronounced below 15 mmHg. Interestingly, pbtO2 below 15 mmHg was particularly associated with poor outcome when ICP, PRx, CPP, or ∆CPPopt were also deranged, but not when these variables were controlled. This suggests that pbtO2 should be considered in combination with the global physiology-related variables to indicate detrimental ischaemic hypoxia. However, isolated pbtO2 insults may have somewhat limited clinical value.In TBI patients treated in NCC, pbtO


Severe pulmonary hypertension (PH) is associated with poor operative outcomes; however, guidance for perioperative management of this population is lacking. Mechanical ventilation has known deleterious effects on right ventricular preload and cardiac output. Meanwhile, pneumoperitoneum results in further cardiopulmonary insults. We report the successful case management of a patient with severe PH scheduled for elective cholecystectomy. While patients undergoing this surgery typically benefit from the less invasive, laparoscopic approach, the risk-benefit ratio may tilt towards risk in the setting of severe PH. A multidisciplinary approach to optimize outcome included the decision to perform an open rather than laparoscopic procedure, which resulted in a favorable outcome. Severe pulmonary hypertension (PH) is associated with poor operative outcomes, and guidance for perioperative management of this high-risk population is lacking ,2,3,4. MA 74-year-old man (consent acquired) with recurrent right heart failure with RV systolic pressure >80 mmHg, preserved left ventricular ejection fraction with diastolic dysfunction, previous lower extremity deep venous thrombosis and pulmonary embolism no longer on anticoagulation due to recurrent falls, coronary artery disease, untreated severe sleep apnea (apnea-hypopnea index of 96.5), chronic obstructive pulmonary disease on supplemental oxygen, and BMI of 38 kg/m2, chronic kidney disease (estimated glomerular filtration rate 46 mL/min) presented for cholecystectomy in the setting of chronic cholecystitis after multiple failed therapies over the course of a year including percutaneous drainage and endoscopic retrograde cholangiopancreatography.American Society of Anesthesiologists (ASA) physical status classification was IV with metabolic equivalents less than four. He was able to transfer from his wheelchair to his chair at home but was unable to walk more than several feet due to joint pain, neuropathy, and dyspnea. The revised cardiac risk index was four, and New York Heart Association functional classification was three. His pulmonary hypertension was thought to be multifactorial, with at least components of WHO group two (left heart disease), three (hypoxemic lung disease), and four .Cardiology and pulmonary consultants familiar with the patient emphasized the high-risk nature of the surgery and felt that no further evaluation or changes in medical management were necessary. The anesthesiologist and surgeon similarly described an approximately 20% risk of perioperative death ; the patient insisted on proceeding. The same anesthesiologist and surgeon then developed a plan addressing patient comorbidities that included modifying the usual surgical approach. Whereas 90% of cholecystectomies at our institution are performed laparoscopically, an open procedure was elected in this case, given the possibly catastrophic pathophysiologic effects of pneumoperitoneum.On the morning of surgery, a T 7/8 thoracic epidural and radial arterial catheter were placed under local anesthetic. A 3 milliliter (mL) epidural test dose of 1.5% lidocaine with 1:200,000 epinephrine was negative for signs and symptoms of intravascular or intrathecal injection, resulting in an appropriate sensory level to ice.Inhaled nitric oxide at 40 parts per million (ppm) and vasopressin 0.02 units per minute (units/min) were initiated, followed by an inhalational induction with sevoflurane and fentanyl 100 micrograms (mcg) in divided 25 mcg doses. Once the patient became unresponsive with loss of lid reflex, rocuronium 100 milligrams (mg) was administered, and an uneventful rapid sequence intubation was performed. Following intubation, a pulmonary arterial catheter (PAC) and transesophageal echocardiography probe were inserted.Anesthesia was maintained with sevoflurane, titrated to bispectral index  value of 50-60, and rocuronium dosed as needed to maintain paralysis. Peak end-tidal sevoflurane was 1.1% at the time of induction and was gradually tapered down to 0.0% during closure. Epidural infusion of 0.0625% bupivacaine with 10 mcg/mL hydromorphone was begun at 8 mL per hour after removal of the gall bladder but terminated after 30 minutes due to concern for its contribution to the hemodynamic deterioration described below. No additional opioids were administered. Ventilation was maintained in a pressure-regulated volume control mode, and peripheral oxygen saturation (SpO2) was maintained in the low-to-mid-90s on a fraction of inspired oxygen (FiO2) 0.8 and positive end-expiratory pressure 5 cmH2O. A recruitment maneuver to 20 cmH2O performed between induction and incision and intended to maximize and maintain alveolar patency caused a transient decrease in systemic blood pressure from 110s/60s mmHg to 60s/30s mmHg. At the 90-minute mark of surgery, systemic pressures decreased to 80s/40s mmHg despite the increase in vasopressin infusion to 1.4 units/min and twelve 1-unit vasopressin boluses. Furthermore, IV milrinone at 0.4 mcg/kg/min and nitric oxide continued at 40 ppm; pulmonary pressures increased from the 50s/30s mmHg to within 20% systemic pressures. With epinephrine boluses (2.5 mcg x 5), systemic pressures elevated without widening the systemic to pulmonary gradient. Echocardiography revealed moderately to severely reduced RV fractional area change, indicating a severely reduced RV ejection fraction.The closure was completed two hours after incision, at which time neuromuscular blockade was reversed with sugammadex and pressure support weaned to spontaneous unassisted ventilation with continuous positive airway pressure (CPAP) 5 cmH2O. The estimated blood loss was 100 mL. His hemodynamic profile improved with a widened systemic to pulmonary pressure gradient and satisfactory systemic (90s/50s mmHg) and pulmonary (60s/40s mmHg) pressures. He was extubated to nasal CPAP and transferred to the ICU stable, awake, and comfortable. Intraoperative hemodynamic trends are shown in Figure Increased postoperative complications and mortality rates in PH patients are well described. Lai HC et al. reported a mortality rate of approximately 10% in non-cardiac surgery patients with pulmonary arterial systolic pressures >70 mmHg compared to 0% in case-matched controls . In a prFor PH patients, mechanical ventilation presents a twofold decrement in RV stroke volume and cardiac output with decreased RV preload  . IncreasAlthough minimally invasive technologies facilitate procedures in many patients, clinicians must always consider the risks and benefits of the case at hand. Regarding laparoscopy, there is no explicit agreement at which point along the spectrum of PH disease severity the potential harm of pneumoperitoneum begins to outweigh the expected benefits. In the case of intraabdominal surgery for patients with severe pulmonary hypertension, the risk assessment by the surgical and anesthesia team should consider the possible harms of laparoscopy versus alternative approaches as part of their risk mitigation strategy.


The data were collected from January 2022 to December 2022 and randomly divided into modeling and validation groups at a 7:3 ratio. The Lasso regression model was used for data dimensionality reduction, feature selection, and clinical test feature construction. Multivariate logistic regression analysis was used to build the prediction model.The application of the nomogram in the verification group showed good discrimination, with an AUC of 0.9205 (95% CI: 0.8471–0.9527) and a good calibration effect. Decision curve analysis demonstrated that the predictive model was clinically useful.This study presents a nomogram prediction model that incorporates age, waist-height ratio and elevated density lipoprotein cholesterol (HDL-CHOLESTEROL), which can be used to predict the risk of codeveloping diabetes in hypertensive patients. Hypertension and diabetes are common chronic diseases with steep rates. It has been reported that the number of elderly people suffering from hypertension has reached 250 million , which pTherefore, how to implement effective diversified health education for every primary care staff member is worth considering. By actively improving the awareness of residents, we can help reduce the incidence of hypertension, thereby reducing the risk of cardiovascular diseases . Among tDyslipidemia is an essential risk factor for hypertension and HDC, and enhanced daily lipid monitoring is particularly critical in this population. The risk of cardiovascular disease and death can be significantly reduced through the quantitative management of lipid levels . Among tA common feature of prehypertensive patients and prediabetic patients is insulin resistance, and insulin resistance is an early stage that can develop into two different diseases . StudiesBased on the above, it is necessary to include BMI, WC, WHtR and other indicators in the analysis of influencing factors of the HDC of residents in jurisdictions, use a new method to describe the change trajectory of their respective association intensity with the HDC of residents in jurisdictions, and further analyze their relationship with the HDC of residents in jurisdictions to judge their respective prediction efficiency of the HDC risk of residents in jurisdictions. It would also be of strong practical interest if the population studied were targeted at the residents of the jurisdiction.Nomogram prediction models are methods used to assess the probability of occurrence of certain diseases. Due to its superior reliability, it has been widely used in cancer and other research fields –12. It c(1) To determine the relationship between BMI, WC and WHtR of residents in the jurisdiction and HDC while controlling for as many confounding factors as possible;(2) The dose‒response relationship between BMI, WC and WHtR and HDC was described for residents of different sexes and ages.(3) Construct the HDC prediction model of district residents based on BMI, WC and WHtR and other factors and obtain the prediction efficiency of BMI, WC and WHtR;(4) The direct effect of obesity on the HDC of residents in the jurisdiction was obtained, and the mediating effect size in the relationship between sociodemographic factors, lifestyle and HDC was obtained.This study aims to achieve the following objectives:This study is expected to explore the relationship between BMI, WC, WHtR and HDC among residents of the jurisdiction from multiple perspectives. The results of this study can provide theoretical guidance for the prevention of HDC and encourage people to improve their lifestyle, focus on weight and WC control, and reduce the burden of the disease.Ethical approval was obtained for this retrospective analysis. Clinical data on 7,200 hypertension patients in his study were collected at a community health service center in Hongshan District, Wuhan City, from January 2022 to December 2022. All patients were randomly divided into a modeling group and a validation group at a 7:3 ratio. At the same time, the model population was divided into two groups based on whether hypertension and diabetes comorbidities occurred, namely, the comorbidity group and the noncomorbidity group.Baseline clinical data included questionnaires, physical examinations, and clinical tests. The questionnaire includes:①Basic information, including gender, age, education level, marital status, occupation type, family type, etc.② Behavior and lifestyle: including inhaling (active or passive smoking), alcohol consumption, labor intensity, physical exercise, daily static behavior time , salt consumption, oil consumption, etc. ③Knowledge related to chronic diseases: excess salt will affect health, the standard of salt intake per person per day (< 6 g), the standard of edible oil intake per person per day (< 25 g), understanding the characteristics of people at high risk of chronic diseases ; chronic illness, family history, etc.1. Questionnaire survey: All staff received standardized training and conducted face-to-face questionnaire surveys on subjects one by one, including basic sociological information such as gender, age, marital status, education level and household registration.2. Measurements of blood pressure: Three investigators monitored the subjects' blood pressure in a resting state for three consecutive sessions, and the mean blood pressure over the three sessions was taken as the final blood pressure.3. Measurements of glucose and lipids: The subjects were given nonsmoking alcohol and a high-sugar, high-fat diet for 24 h, and after eight hours of fasting, venous blood from the elbow was collected. Blood samples are tested as soon as they are sent to the laboratory on the same day.4. Measurement of WC: According to the method recommended by the World Health Organization (WHO), the measurement is carried out using a standard tape measure that is nonelastic, anti-tensile, and does not deform when subjected to gravity within 100 g. Half of the connecting length between the lower edge of the 12th rib in the middle auxiliary line and the iliac crest was taken as the measuring point, and the measuring edge of the tape measure passed the measuring point on both sides of the body of the study object to measure WC.The blood pressure was monitored 3 times on different days without taking antihypertensive drugs, and the diastolic blood pressure was ≥ 90 mmHg (1 mmHg = 0.133 kPa) or systolic blood pressure was ≥ 140 mmHg each time or a previously diagnosed high blood pressure.The diagnostic criteria for diabetes were as follows : fastingDiagnostic criteria for dyslipidemia were as follows : serum tAfter completing the questionnaire, Epidata3.1 was used to build the database. The data were input via double-check and processed in SPSS19.0. Based on the values for height and WC, the value of WHtR and its 25th percentile (P25), 50th percentile (P50), and 75th percentile (P75) were calculated.P < 0.05 was considered statistically significant.SPSS 26.0 and R 4.1.3 software were used for statistical analysis. All data are presented as categorical variables, and logistic regression was used for both univariate and multivariate analyses. Subjects included in the study were randomly divided into modeling and validation groups at a 7:3 ratio. Variables were initially screened by a single-factor analysis and LASSO regression, and then the predicted variables were finally included in the model by a multifactor regression analysis to construct the columnwise model. The nomogram model was evaluated in terms of differentiation, calibration and clinical net benefit. The differentiation was evaluated by the C-index, receiver operator characteristic (ROC) curve and area under the curve (AUC). The degree of calibration was assessed by the calibration curve. Clinical benefit was assessed by decision curve analysis. In this study, the SPSS statistical software package was used to perform unbiased randomization on 7200 samples. The specific operations are as follows: The software package automatically obtains the formula "partition variable" = 2*re.bernoulli(0.6)-1 according to the initializing value of the activity generator, sets it to the probability parameter 0.6 of the Bernoulli variable and assigns the partition value of 1/-1. The partition value of "1" can allocate 70% of the samples (5040 cases); the partition value of "-1" allocates 30% of the sample (2160 cases). Bernoulli (0.3) resets the partition variable according to the formula "partition variable" = "partition variable" -re.bernoulli(0.3). Twenty percent (1008 cases) of the partition value "1" is set as the test sample with the value "0". The sample value of 80% (4032 cases) is still "1", which is set as the training sample. A total of 2160 cases of the original partition value "-1" are set as persistent samples, as shown in Table P > 0.05, as shown in Table There were 5040 cases in the modeling group and 2160 cases in the verification group, and there was no statistical significance in clinical data between the two groups (P < 0.05), as shown in Table In the modeling group, the subjects were divided into an HDC group (672 cases) and a non-HDC group 4368 cases) according to whether they had hypertension and diabetes. Through univariate analysis, it was found that sex, age, marriage, education level, family category, BMI, static behavior time, TG, TC, HDL, LDL, WHtR, WC and other differences between the two groups were statistically significant (68 cases P < 0.05), as shown in Table With the diagnosis of diabetes comorbidity as the dependent variable and the five predictors screened by LASSO regression as the independent variables, the multivariate regression analysis showed that age, WHtR and HDL-C were independent risk factors for hypertension-diabetes comorbidity  and 0.8530 (0.8328 ~ 0.8732), respectively.The AUC of the modeling group was 0.91325 (95% CI: 0.8572–0.9403)  of the modeling group  The results of this study come from a single institution; therefore, multicenter verification is needed to expand the universality of the experimental results. (2) This study is a retrospective study, and there may be inevitable selection bias. In summary, this study establishes a clinical-lab nomogram that can be used as a clinical tool for individualized hypertension-diabetes comorbidities to assist clinical treatment decision-making and enable precision medicine.Hypertension and diabetes are mutually progressive, and both are closely linked to insulin resistance. To facilitate the management of chronic diseases in the community, a simple and accessible clinical-laboratory nomogram was constructed. With this scoring system, the risk of comorbidity in hypertensive patients is generated, allowing grassroots clinicians to individually predict the risk of comorbidity in hypertension and diabetes, in line with the current trend of individualized precision medicine.The high accuracy of the nomogram prediction model for hypertension-diabetes comorbidities developed in this study not only enables early identification and prediction of HDC risk in hypertensive patients but also provides more favorable clinical guidance for grassroots staff and patients in medical interventions and lifestyle monitoring and is worth promoting.


High blood pressure, also known as hypertension, is a major risk factor for cardiovascular disease. Salt intake has been shown to have a significant impact on BP, but the mechanisms by which it influences the blood pressure dipping pattern, and 24-h blood pressure remains controversial. This literature review aims to both summarize the current evidence on high salt diet induced hypertension and discuss the epidemiological aspects including socioeconomic issues in the United States and abroad. Our review indicates that a high salt diet is associated with a blunted nocturnal blood pressure dipping pattern, which is characterized by a reduced decrease in blood pressure during the nighttime hours. The mechanisms by which high salt intake affects blood pressure dipping patterns are not fully understood, but it is suggested that it may be related to changes in the sympathetic nervous system. Further, we looked at the association between major blood pressure and circadian rhythm regulatory centers in the brain, including the paraventricular nucleus (PVN), suprachiasmatic nucleus (SCN) and nucleus tractus solitarius (nTS). We also discuss the underlying social and economic issues in the United States and around the world. In conclusion, the evidence suggests that a high salt diet is associated with a blunted, non-dipping, or reverse dipping blood pressure pattern, which has been shown to increase the risk of cardiovascular disease. Further research is needed to better understand the underlying mechanisms by which high salt intake influences changes within the central nervous system. Across the United States, cardiovascular disease (CVD) including hypertension is the leading cause of death amongst men and women, and almost all ethnic groups. In 2020, CVD claimed the lives of 697,000 individuals; 1 in 5 deaths were attributable to CVD . ConditiAs our nation quickly progressed into a fast paced, work around the clock society, Americans have begun resorting to convenient food options that are packed with sodium, trans fats, and other unhealthy, unnatural substances . DespiteAccording to the American Medical Association, hypertension is an abnormally increased arterial blood pressure, greater than 130/80 mmHg. Some causes of hypertension include a diet with processed foods with salt, fat, and cholesterol . Among hHypertension is not only an issue in the United States, however. Shockingly, the United States does not even fall within the top 10 countries with the highest prevalence of hypertension. According to Zhou et al., prevalence of hypertension in men reached as high as 62% in Paraguay and 56% in Hungary in 2019 . About 5Although the physiological mechanisms underlying hypertension are still not completely understood, it is widely accepted that a high salt diet greatly influences the body’s ability to regulate blood volume due to electrolyte imbalances . In thisAt the most basic level, it is well understood that the consumption of a high salt diet alters the body’s homeostatic electrolyte balance, specifically the amount of extracellular sodium in circulation which in turn alters the body’s ability to clear extra circulatory volume . Within The Baroreflex feedback pathway is the body’s primary means by which it regulates small fluctuations in blood pressure. Studies suggest that these baroreceptors have the capacity to regulate blood pressure even in patients with chronic hypertension through a mechanism termed “resetting,” allowing them to modulate changes in blood pressure over a wide range of pressures, rather than pressures confined to a certain range . Due to Baroreflex dysfunction is associated with hypertension in humans, and in various models of diet-induced hypertension including the Dahl-Salt Sensitive (DSS) rat, deoxycorticosterone acetate (DOCA)-salt and spontaneously hypertensive rat (SHR). Other rat models also displayed similar disruptions in baroreceptor activity in response to high salt diets. In SHR, salt loading similarly lead to accelerated hypertension as well as increased renal sympathetic nerve activity and impaired central baroreceptor reflex activity . HoweverThe regulation of blood pressure by the baroreceptors is primarily aimed at inhibiting large variations in blood pressure throughout the day. However, in normal individuals, there is a circadian mediated decrease in blood pressure at nighttime. A term coined “nocturnal blood pressure dipping” has been used to describe the physiologically normal decrease in mean arterial pressure by approximately 10–20% at night . Some reThe normal dip in blood pressure is in part regulated by a suppression of the sympathetic nervous system mediated by circadian rhythm . The autAlthough the loss of this normal dipping pattern is not entirely understood, it is well accepted that a high salt diet greatly increases an individual’s risk of developing a non-dipping pattern. Salt-sensitive hypertensive patients tend to exhibit non-dipper-type nocturnal hypertension . This isAnimal studies have greatly contributed to our understanding of the effects of high salt diet on circadian blood pressure disruption. The effects of salt loading on the circadian blood pressure rhythms of Dahl-Salt Sensitive (DSS) rats vs. Dahl-Salt Resistant (DSR) rats was studied by Witte et al. examined the relationship between the suprachiasmatic nucleus (SCN) and these dipping patterns in rat models . Interes2+-ATPase in the endoplasmic reticulum, leading to a depletion of intracellular Ca2+. A study by Another brain region known to be involved in regulation of blood pressure is the paraventricular nucleus (PVN) of the hypothalamus. In A study by Although there are several areas of the brain that have been closely studied for their role in blood pressure regulation, the nTS is one of great importance that has yet to be completely understood. The nTS, being the initial site for the coordination for the baroreflex, is essential in blood pressure regulation . MaintaiAlthough hypertension affects all types of individuals, there are undeniable health disparities across the United States that puts certain groups of individuals at a greater risk. In a cohort study by Neufcourt et al., they aimed to investigate the independent association of wealth, education, and income with incident hypertension among older adults living in the United States . Their fExtensive time and research have unveiled a wealth of knowledge regarding the body’s intrinsic mechanisms for blood pressure control. We discussed the body’s first line of surveillance in blood pressure regulation, the baroreceptor reflex, and how its projections to the nTS modulate autonomic output to the heart to compensate for the changes in peripheral pressure. Further, the PVN and SCN are two critical brain regions responsible for blood pressure modulation. We discussed the implications of a high salt diet on the body’s innate abilities to modulate blood pressure, and looked towards recent research that proves how these increased salt concentrations are directly impacting the intrinsic pathways responsible for the maintenance of circadian blood pressure dipping patterns. Lastly, we identify the significant socio-economic imbalances that indirectly increase the risk of CVD amongst underrepresented minorities and low-income communities likely related to structural racism. There are still more questions that need to be answered to fully understand this complex process. Further research should investigate exactly how a high salt diet is correlated to a loss of nocturnal blood pressure dipping, and whether hypertension or loss of blood pressure dipping patterns is the preceding symptom. Specifically, studies to determine the role of high salt diet on modifying the central mechanisms directly related to blood pressure regulation, such as the baroreflex, and how these are reflected in dipping patterns is necessary to develop further therapeutics. Lastly, the root of the high salt diet in our country in relation to food manufacturing processes should also be a topic of discussion.DM conceived and designed the study. DM, JV, and DC wrote the first draft of the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by American Heart Association 23AIREA1057412 to DM; NIH LRP 1L40HL165612-01 to DM; and Cooper Biomedical Sciences Internal Competitive Funds to DM. Funding for open access provided by Rowan University Libraries’ Open Access Publishing Fund.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.