Patients with chronic kidney disease (CKD) are known to have increased cardiovascular risk but there are few data on the risk of pediatric kidney transplant recipients. We aimed to assess the impact of pre- and post-transplant overweight on allograft function and to characterize the evolution of several cardiovascular risk variables over time and their impact.A retrospective analysis of the records of 23 children/adolescents followed at a tertiary center after kidney transplant was conducted. Data on anthropometry and cardiometabolic variables were analyzed before transplant, six and 12 months after the transplant, and at the last follow-up visit. The impact of the variables on allograft function (glomerular filtration rate (GFR)) was estimated by creatinine-based revised Schwartz formula (Cr-eGFR) and was evaluated using nonparametric tests. Results: The 23 patients included in the study had a median age of 6.3 (4.4-10.1) years. Both systolic and diastolic BP z-score values significantly decreased between BMI groups . During follow-up, GFR values decreased (Cr-GFR: 68.9 (57.7-76.8) vs. 58.6 (48.9-72.9), p=0.033 at 6-months and at the end, respectively). Significant negative correlations between triglycerides and cystatin C-based eGFR  and Cr-Cys-eGFR  at the end of the study were found.Our study showed a high number of overweight children undergoing kidney transplant. A negative correlation between triglycerides and GFR was found, which highlights the importance of managing nutritional status and regular blood lipids evaluation after kidney transplant. Better quality of life, optimized growth, and longer patient and graft survival are among the advantages of kidney transplant compared with other renal replacement therapies.Kidney transplantation has become the treatment of choice in both adults and children with kidney failure. In pediatric patients, early kidney transplantation was difficult but several advances have greatly improved outcomes in this age group. The higher risk in CKD patients is believed to be related to several concurrent traditional risk factors, such as obesity, hypertension, dyslipidemia, and sedentary lifestyle. Additionally, other factors directly associated with the CKD status, namely hemodynamic or metabolic stress, inflammation, increased renin-angiotensin-aldosterone activity, and endothelial dysfunction, are all together probably enhanced by the immunosuppression regimens used in the particular setting of transplant recipients patients. Thus, even after successful transplantation, there is an increased risk of CV disease. Besides the impact of donor-related factors and immunosuppression therapy, both pre- and post-transplant excessive weight gain, along with obesity-associated comorbidities, such as hypertension, dyslipidemia and insulin resistance, are increasingly recognized to significantly impact the renal graft function and morbidity of these patients. Moreover, obesity also seems to act as a risk factor for faster decline of allograft function, independently of the presence of other comorbidities.Patients with chronic kidney disease (CKD) are known to have increased risk of cardiovascular (CV) comorbidities and premature death throughout adulthood, thought to be due to the pediatric onset of end-stage renal disease (ESRD). Even in the absence of overweight, transplant patients are known to have an increased prevalence of both masked hypertension and nocturnal hypertension, with loss or reversed dipper pattern,, with an estimated one-third of patients being undiagnosed due to BP measurements performed in office only rather than ambulatory BP monitoring. Additionally, a positive association between body mass index (BMI) and systolic blood pressure (SBP) has been reported to remain evident years after transplant, with obesity contributing to even higher odds of masked and nocturnal hypertension after kidney transplant.Many patients already present elevated blood pressure (BP) before the transplant, but an even larger proportion will develop hypertension afterwards, during follow-up. Studies in adults showed inverse relationships between glomerular filtration rate (GFR) and serum triglycerides and total cholesterol and also that, at 12-months post-transplant, total cholesterol was an independent risk factor for mortality, but there are few data on the pediatric population after kidney transplant.In adults, dyslipidemia and insulin resistance are well-recognized risk factors for renal function decline, which are mainly associated with weight gain and immunosuppressants use after kidney transplantIn the present study, we aimed to assess the impact of pre- and post-transplant overweight status on the allograft function in all kidney transplant pediatric patients followed-up at a tertiary center. We also aimed to characterize CV risk variables such as BP, blood lipids, and insulin resistance and their evolution over time following kidney transplant, and to evaluate their impact on allograft function.In the present study, data of children and adolescents, aged 18 years or less at data collection (February 2020), who had undergone a kidney transplant and had their regular follow-up at the Pediatric Nephrology Unit, in Centro Materno-Infantil do Norte (CMIN), Centro Hospitalar Universitário do Porto (CHUPorto), were retrospectively evaluated. Two children were excluded for not having anthropometric data registered before kidney transplant. Finally, data of 23 children were analyzed; kidney transplants were performed between 2004 and 2019.A retrospective analysis of the clinical records of all included patients was performed. Data on sociodemographic features  were recorded. Data on clinical characteristics related to previous CKD  and kidney transplant  were also recorded.. Fasting insulin was evaluated, and insulin resistance was determined at the last follow-up visit using only the homeostasis model assessment for insulin resistance (HOMA-IR).Data on anthropometry  and on cardiometabolic variables  and high-density lipoprotein (HDL) cholesterol) were recorded immediately before the transplant (pre-transplant), approximately 6 and 12 months after the transplant, and at the last follow-up visit. Height and weight were used for BMI calculation and BMI-for-age values were classified according to the World Health Organization growth reference data for BMI z-score into the following categories: non-overweight (-2SD to +1 SD) and overweight ®) with an adequately sized cuff on the right arm. When available, the average of the second and third measurements  at each occasion was used for analysis. Hypertension and elevated BP were defined according to the 2017 American Academy of Pediatrics guidelines. The presence of high BP was considered when patients presented either elevated BP or hypertension.Office BP determinations were assessed with validated automated oscillometric devices  were gathered. Data on hemoglobin, serum creatinine, urea, cystatin C (Cys), glucose, insulin, total cholesterol, HDL cholesterol, LDL cholesterol and triglycerides was analyzed, whenever available. Serum creatinine was analyzed using a calibrator for automated system (Roche Diagnostics) and serum CysC was measured by a particle-enhanced nephelometric assay 2, the following formulas were used: creatinine-based formula - revised Schwartz formula (Cr-eGFR) = k x (height (cm)/serum creatinine (mg/dL), using a k constant of 0.413); cystatin C-based formula - Filler formula (Cys-EGFR) = Log (GFR) = 1.962 + [1.123 × log (1/cystatin C (mg/L))], and combined creatinine and cystatin C formula - Zappitelli combined formula (Cr-Cys-eGFR) = [(507.76 × e0.003×height(cm))/(cystatin C (mg/L)0.635 × serum creatinine (mg/dL)0.547) x 1.165].To estimate GFR in mL/min/1.73 mThe present study was approved by the Ethics Committee of Centro Hospitalar Universitário do Porto and complies with the Helsinki Declaration. Informed consent from children’s parents and verbal assent from children or adolescents for collecting information and biological samples was obtained.® SPSS® Statistics 26.0. Continuous variables are described as median and 25th and 75th percentiles and non-parametric testes were used, since data had a skewed distribution. Differences in independent continuous variables between groups were evaluated with Mann-Whitney test and paired variables were evaluated with Wilcoxon test. Differences in categorical variables were evaluated with Chi-square test. Bivariate associations between continuous variables were assessed by Spearman correlations. All p values were two-sided and considered statistically significant if <0.05.Statistical analysis was performed using IBMth-75th percentile, P25-P75) age of 6.3 (4.4-10.1) years at kidney transplant and 17 (74%) were male. Baseline characteristics of pediatric kidney transplant recipients according to pre-transplant BMI status, non-overweight  and overweight , are shown in 2 at 6 months post-transplant. All transplant recipients were initially maintained on standard immunosuppression therapy with tacrolimus (median dose 6.5 (5.49.6) mg/day), mycophenolate mofetil [median dose 600.0 (370.0-950.0) mg/day], and steroids [median dose 15.0 (10.0-15.0) mg/day]. At the end of the study, the immunosuppression therapy included for all patients a lower median dose of corticosteroids (2.5 mg/day) and tacrolimus 5.0 (4.4-6.0) mg/day.The 23 children and adolescents included in the study had a median  BMI and BMI z-score in the overweight group were 15.8 (15.0-16.9) and 1.4 (1.2-2.3), respectively. Patients in the overweight group had a shorter median follow-up time after transplant compared with the non-overweight patients . Regarding office BP data, no differences on SBP, diastolic BP (DBP), and respective z-scores were found between the BMI groups. Nine (39%) patients presented high BP and were being treated with anti-hypertensive drugs before kidney transplant .The distribution of patients by BMI classes during the study period is shown in During the follow-up period, creatinine increased and Cr-eGFR values significantly decreased . Cr-Cys-eGFR also significantly decreased over the follow-up period  . The comSpearman’s correlation between eGFR at the last follow-up visit and cardiometabolic variables during follow-up is shown in In the present study, we described the impact of pre- and post-transplant overweight status on the allograft function of pediatric patients following kidney transplant. We found a very high percentage of overweight children/adolescents before the transplant (around 35%) and this percentage was about 43.5% at the end of the study. Although, a decline in eGFR values was observed over time, no significant differences were found in the median values of eGFR between the non-overweight and the overweight group at 6 months, 12 months, or end of the study. Concerning the other cardiometabolic variables analyzed, we found that BP z-score values were significantly lower at the end of the study compared to the pre-transplant evaluation. Triglycerides were significantly lower at the end of the study and negatively correlated with Cys-eGFR and Cr-Cys-eGFR at that point.. A high percentage of children (35%) were overweight in before the transplant, and this number was even higher by the end of the follow-up period, although not significantly. The median BMI z-score remained stable during the follow-up period, with a slight increase in the 6-month evaluation. The prevalence of overweight/obesity found in our study was slightly higher than that reported in some previous pediatric studies. This difference might be explained by the use of different reference values for BMI classification. In fact, the WHO definition of pediatric obesity usually yields the highest estimations of overweight and obesity compared to other definitions. We should also consider that the prevalence of overweight and obesity in children is among the highest in Europe, so it is to be expected that the nutritional status of the pediatric CKD population follows this trend, at least in part. Another 2013 study reporting the prevalence of overweight/obesity in the European pediatric renal replacement therapy population reported a prevalence of overweight/obesity of over 30% in transplant patients, especially in those over 6 years of age, which is consistent with what we found in our study.Overweight is a common problem after renal transplantation, which can be explained by several factors, including increased appetite and improved taste sensation associated with the resolution of uremia and the use of steroids, a reduction in dietary restrictions due to improved renal function, and a sedentary lifestyle and poor physical fitness. Investigating this association was our main goal because contradictory findings are reported in the literature, especially in children, for which strong evidence is scarce. Due to the size of our sample, the power may not have been enough to find a significant difference between non-overweight and overweight patients in the eGFR estimations considered, regardless of the formula used to estimate GFR  and at different time points. Another possible explanation for this could be that, in our study, overweight patients had a shorter follow-up period than the non-overweight group. This might indicate that the problem of excessive weight gain in ESRD patients is more likely to affect those patients who have been transplanted in recent years. Previous studies with larger samples have found that GFR levels were significantly lower among overweight/obese patients, while other authors have found no significant differences in terms the effects of overweight on renal function, indicating the need for further studies in this age group.The finding of such a high prevalence of overweight among pediatric kidney transplant patients is particularly concerning since it has been increasingly acknowledged that overweight acts as an independent risk factor for decreased graft function and survival.CKD is known to be associated with increased CV risk in pediatric patients, which may be 3 to 5 times higher compared to their age-matched counterparts. Renal transplantation is thought to reverse some of the CV risk in these patients, but cardiometabolic factors continue to play an important role in the global risk of death in this population In our study, high BP, including patients with high or normal-high BP, was present in more than half of the patients before transplant but in a significantly lower percentage of patients at the end of follow-up (around 13%). Our results regarding BP values seem to indicate that effective efforts have been made towards BP control after kidney transplant. This is especially relevant considering that a higher percentage of patients were overweight at the end of the study, which could have contributed to higher BP values.The median SBP and DBP z-score values in our study were significantly lower at the end of the study compared to pre-transplant or even to the first evaluation after renal transplant, despite the difference at 6 months not being statistically significant. Hypertension is frequent among ESRD patients before transplant and usually persists after transplant, with a reported prevalence varying from 20% to almost 90%.. Multiple factors are known to be involved with post-transplant hypertension, and previous studies have reported a negative association between BP and GFR. In our sample, we found a marginally significant positive correlation between SBP at 6 months and Cr-eGFR and between SBP at 12 moths and Cr-eGFR, which is in contrast with previous findings, and might be explained by the low number of children with high BP in our sample. We did not have data on ambulatory blood pressure monitoring that would have helped us better assess the association with GFR, since transplant patients are known to have an increased prevalence of both masked hypertension and nocturnal hypertension, with loss or reverse dipper pattern, which may have escaped us in the present analysis. The benefits of using ambulatory blood pressure monitoring as a diagnostic tool to complement the study of hypertension and consequently increase graft survival have been shown in previous studies.The main reason for poor BP control after transplant seems to be the inappropriate use of anti-hypertensive drugs. After renal transplant, dyslipidemia is believed to contribute to a faster decline of the allograft function, especially when associated with proteinuria. Evidence suggests that total cholesterol concentration 12 months after kidney transplant is an independent predictor of mortality. Guidelines recommend early screening for dyslipidemia after transplantation, which should then be repeated at least annually. A negative correlation between triglycerides and eGFR was found at the end of the study, which reinforces the importance of this recommendation. Similar findings have been reported in a previous study in pediatric kidney transplant patients, with no significant association between eGFR and both total and LDL cholesterol concentrations but a negative association with plasma levels of triglycerides. Other previous studies failed to find an association between GFR and any lipid parameter after transplant, even when adjusting for age, BMI status, or primary kidney disease.The association between CKD and dyslipidemia is frequently reported in the literatureOur study had several limitations. Although it was a prospective longitudinal study design after transplant, data were obtained from medical records and retrospectively analyzed. Besides, our study was a single center study and included a relatively small number of patients. We could not access data from patients transplanted in the pediatric age but who were older than 18 years and followed-up in adult facilities at the time of the study. Another important limitation was that we considered the end of the follow-up as a temporal mark for several comparisons, but in fact the follow-up time after kidney transplant varied among patients and a difference between BMI classes may have been present. Additionally, we did not have access to waist circumference measurements during follow-up, thus precluding the analysis of the impact of abdominal obesity in the associations studied. Another important limitation was the fact that BP evaluation was solely based on office BP, measured in an oscillometric automated device, with data on ambulatory BP monitoring only being available for about half of the patients, which was not reported in the present study. Ambulatory BP monitoring would have provided us with more complete information, allowing the diagnosis of masked and nocturnal hypertension and perhaps for a more reliable association with renal function.Despite all limitations, our study showed that a high number of children and adolescents submitted to kidney transplant are overweight or obese. Considering the increasingly recognized impact of this risk factor on allograft function decline, our results should draw attention to the importance of better managing nutritional status in the high-risk group of ESRD patients. We observed a decline of eGFR over time, but we could not find differences in renal function between BMI groups probably due to a lack of power related to the sample size. Additionally, the negative association between triglycerides and GFR should also raise awareness to the importance of regular evaluation and management of blood lipids after kidney transplant. Although the number of studies on pediatric renal transplant have increased in recent years, more studies are needed to understand the best way to manage these patients. We believe that long-term studies, with larger samples and perhaps multicenter, are necessary to better assess the effect of obesity and its associated comorbidities on renal allograft function in children.We hope to be able to continue to follow this sample in the future by adding ambulatory BP monitoring to their regular screening visits to monitor not only the evolution of kidney function but also the impact of cardiometabolic risk factors, which are expected to become more significant as time progresses.


Although long-term smoking has been associated with chronic kidney disease, its effect on kidney function in early stages has not been clarified. Therefore, the proposed objectives were: (1) to identify subclinical kidney damage in smokers, through a panel of biomarkers; (2) to evaluate the progression of subclinical kidney damage after two years of consumption in these patients; and (3) study whether quitting smoking reduces kidney damage. A prospective study was carried out . Kidney function was assessed using a panel of biomarkers and compared between smokers and non-smokers, taking into account potential risk factors for kidney damage. These results show, for the first time in the literature, the relationship between smoking and early  kidney damage and provide a panel of biomarkers capable of detecting this condition . This study also indicates that subclinical damage is maintained when use continues, but can be reversed if patients stop smoking. The use of these biomarkers as diagnostic tools can be a preventive measure in the development of chronic kidney disease associated with smoking and in the prevention of acute events associated with potentially nephrotoxic pharmacological treatment in smokers. Trial registration number: NCT03850756. According to the World Health Organization, tobacco use leads to detrimental effects on public health and is responsible, directly and indirectly, for more than 7 million and 1.2 million deaths a year, respectively, worldwide [In recent years, tobacco has been proposed as a risk factor for the progression of chronic kidney disease (CKD) in patients who suffer from pathologies related to kidney deterioration and in the general population ,3,4. TheA large cohort study conducted in 2016 ,8,9, renSo far, no exhaustive evaluation has been carried out on the effect of cigarette smoking on renal function in early-stage kidney disease with more sensitive biomarkers to assess whether tobacco alone can cause kidney impairment . Although the mechanisms involved in such damage have not been precisely described, it has been proposed that oxidative stress may play a relevant role . ElucidaIn view of these facts, this study proposed to evaluate the association between tobacco use and kidney damage by (1) determining a panel of early biomarkers to detect subclinical renal damage in smokers as well as oxidative stress biomarkers to evaluate its involvement in kidney damage; (2) evaluating the progression of subclinical kidney damage associated with tobacco after two years of consumption; and (3) assessing whether smoking cessation reduces subclinical renal damage.The study protocol has been previously published .The study has been approved by the Clinical Research Ethics Committee (CEIC) of the Health Area of Salamanca . All participants signed an informed consent form prior to the study in accordance with the Declaration of Helsinki and World Health Organization standards for observational studies . During The patient recruitment procedure for each of the study’s objectives is explained below:Objective 1: to evaluate the association between tobacco use and subclinical kidney damage using a panel of early biomarkers as well as the possible role of oxidative stress in the development of such damage.A cross-sectional analysis using a prospective study’s baseline was conducted with patients recruited from the primary care centre, La Alamedilla , and a tobacco cessation clinic unit . The patients were divided into four groups based on their smoking habits and risk factors. Any person who had used tobacco either at the time of recruitment or during the previous year was considered a smoker. A person who had never used tobacco was considered a non-smoker. Diabetes mellitus, hypertension, and/or frequent use of non-steroidal anti-inflammatory drugs (>three days per week during the three months prior to recruitment) were considered risk factors for kidney disease. Considering these aspects, the experimental groups were distributed as follows: non-smokers with no risk factors (NS-NRF); non-smokers with risk factors (NS-RF); smokers with no risk factors (S-NRF); smokers with risk factors (S-RF) .Baseline urine samples were collected from the patients. A panel of biomarkers for kidney damage was determined for these samples. In addition, several oxidative stress biomarkers were analysed, as detailed later in Objective 2: to evaluate the progression of subclinical kidney damage associated with tobacco after two years of consumption.A prospective study was conducted with patients from the La Alamedilla health centre with a follow-up of two years. The patients remained in the same study group, implying that their smoking habits and risk factors had not changed in the two years.The increase in the urinary biomarkers of kidney damage was calculated as the difference between the values obtained at two years and the baseline values.Objective 3: to evaluate if smoking cessation reduces subclinical renal damage.A cross-sectional analysis using the baseline of a prospective study was conducted with patients recruited from the La Alamedilla health centre’s primary care consultation and a tobacco cessation clinic unit at the University Hospital, Salamanca. To meet this objective, a new group of patients was included: former smokers with no risk factors (FS-NRF) . Former Patients who were of legal age, had signed the informed consent form, and did not meet any of the following exclusion criteria were included in the study. Patients experiencing any of the following conditions were excluded from the study: those with terminal illnesses; those who had been previously diagnosed with kidney damage; those who had been treated during the previous week or at the time of recruitment with aminoglycosides, cephalosporins, tetracyclines, amphotericin B, cisplatin, cyclosporine, foscarnet, acyclovir, cidofovir, radiological contrasts, or any other potentially nephrotoxic drug.An encryption data system was established to protect the patients’ identities. The study data were collected and managed using the REDCap electronic data capture tools hosted at the University of Salamanca. A computerised database  was created using the date of sample collection, general data (age and sex), anthropometric measurements , biochemical parameters (plasma creatinine and urea), risk factors for kidney damage , and tobacco use (number of cigarettes/cigars consumed per day).g, 4 °C for 8 min), aliquoted, and stored at −80 °C until analysis.Urine samples were collected from all patients at the time of consultation. On the same day, the samples were centrifuged  biomarker was determined by western blotting. Briefly, 21 μL urine was separated by 4–20% gradient polyacrylamide gel electrophoresis . Proteins were then electrically transferred to an Immun-Blot PVDF Membrane  and incubated with anti-GM2AP (own production), followed by horseradish peroxidase-conjugated secondary antibody and chemiluminescent detection  with a ChemiDoc MP Imaging System . The bands were quantified by densitometry analysis using Image Lab software . Integral normalisation was conducted by referring to the band quantification data of the same positive control loaded in each gel.All biomarker values were factored by the urinary creatinine concentration to normalise the effect of urine concentration . The uriTo evaluate tobacco consumption, urine samples were analysed for cotinine (nicotine metabolite) concentration, for which the commercial kit “Cotinine ELISA kit”  was used. Data were normalised by the urinary creatinine concentration as explained previously.In the urine samples of the patients included in the first objective, a panel of oxidative stress biomarkers was also evaluated, for which the following commercial kits were used: “OxiSelect TBARS Assay Kit STA-330” for MDA quantification ; “OxiSelect Total Antioxidant Capacity Assay Kit STA-360” ; “8-Isoprostane ELISA kit 516351” ; and “Human Vanin RD-VNN1-Hu” .To evaluate the temporal evolution of kidney damage biomarkers over time, their absolute increase was calculated:Biomarker increase = Biomarker (2 years) − Biomarker .The percentages for all qualitative parameters were compared between groups using either Pearson’s chi-squared or Fisher’s exact test with Bonferroni post-hoc tests. The normality of the continuous quantitative data was evaluated with the Shapiro–Wilk (n ≤ 50) test or Kolmogorov–Smirnov test (n > 50). Pairwise comparisons were made using Student’s t-test  and Mann–Whitney U test . Three to four groups were compared using the Kruskal–Wallis test  and Bonferroni correction (post-hoc test). In addition, the correlation between urinary levels of cotinine, biomarkers of kidney damage, and biomarkers of oxidative stress was analysed using Spearman’s rank correlation tests  in the NS-NRF and S-NRF groups.p < 0.05. All statistical analyses were performed using the IBM SPSS Statistics software version 20 . The criterion for significance was set at To achieve the three objectives, patients were grouped according to their smoking habits and the presence of risk factors, as detailed in The groups were similar in terms of sex and weight. Patients’ age was higher in the groups that included risk factors (NS-RF and S-RF), which was expected because these pathologies  occur more frequently in older patients. The lower estimated glomerular filtration rates observed in these two groups were likely to have been associated with risk factors but were independent of smoking habits. However, there were no differences in plasma creatinine levels between the groups. Regarding patients with risk factors, the non-smokers (NS-RF) group had a higher percentage of hypertensive patients, whereas smokers (S-RF) had a higher percentage of diabetics and non-steroidal anti-inflammatory drug consumption.Finally, regarding tobacco use, patients without risk factors (S-NRF) stated that they smoked more cigarettes per day than those with risk factors (S-RF). As this information was provided by the patients—and may not have been entirely true in some cases—consumption was verified by measuring the biomarker cotinine, a metabolite of nicotine, in urine samples.To study whether tobacco causes early alterations in kidney function, the urinary excretion of a panel of kidney damage biomarkers was compared between smokers and non-smokers with and without risk factors. Biomarkers capable of detecting alterations during the early stages of damage were used . ProteinThe next step was to statistically determine whether patients who consumed more tobacco had greater renal impairment. Urinary cotinine levels were correlated with each evaluated biomarker of kidney damage . To avoiTo determine whether oxidative stress is involved in the nephrotoxic effects of tobacco, oxidative stress biomarkers were determined  in groupThe correlation between these biomarkers and urinary cotinine levels was also determined . There wRegarding the association between biomarkers of renal damage and oxidative stress, it was observed that oxidative alteration is directly proportional to kidney damage, which is more evident when total antioxidant activity is evaluated. This suggests that tobacco induces oxidative stress and that the body activates antioxidant defence mechanisms to combat it.To study the renal effect of tobacco use after two years, the evolution of the panel of renal function biomarkers was evaluated by calculating their absolute increases in groups without risk factors (NS-NRF and S-NRF). No difference was observed between any biomarkers except for transferrin, which was lower in smokers after two years of use. These results indicate that the biomarker levels were similar to baseline levels . TherefoTo achieve this objective, a new study group was included ) in which a panel of biomarkers of kidney damage was determined and compared with other groups of non-smokers and smokers without risk factors . Again, only groups without risk factors were included so that the results obtained could be attributed more directly to tobacco consumption and not to other factors. For all the analysed biomarkers , it was Although long-term smoking has been associated with CKD , the effSmoking-related renal injury shares pathophysiological mechanisms with diabetic nephropathy and hypertension, such as insulin resistance and increased sympathetic nervous activity , which iIn recent decades, several biomarkers of kidney injury have been identified in urine and blood to address the well-recognised limitations of creatinine as an indirect biomarker of kidney damage. These biomarkers are either produced directly by the kidney or accumulate because of tubular cell dysfunction after kidney injury. Our results indicate an increase in the urinary excretion of NGAL, KIM-1, NAG, transferrin, and GM2AP, confirming subclinical damage in smokers (with and without risk factors). When the initial kidney injury is induced in the epithelial cells of the renal tubules, subtle changes occur, releasing specific proteins such as NGAL, KIM-1, or NAG into the urine and systemic circulation ,25,26. SBased on the evidence from these studies, our results suggest that the urinary excretion of these biomarkers can indicate early damage to the renal tubules. To the best of our knowledge, this is the first time that tobacco use has been associated with subclinical damage at the tubular level. It has been established that subclinical damage can create a condition of susceptibility that degenerates into acute kidney damage in certain circumstances; for example, when the patient is treated with potentially nephrotoxic drugs (such as aminoglycosides and platinum compounds) or is subjected to diagnosis tests with contrast media ,33,34,35In contrast, the correlation between the excretion of these biomarkers and cotinine suggests a relationship between the level of consumption and the degree of kidney damage. Although this study has a limitation in that each smoker was different both in terms of the time of consumption and the number of cigarettes smoked per day, cotinine, as a biomarker of recent consumption, supports our argument.The principal determinants of CKD development and progression are cardiometabolic risk factors, such as age, elevated blood pressure, dyslipidaemia, obesity, diabetes, and smoking . It has Oxidative stress is one of the main mechanisms involved in kidney damage associated with tobacco. Chronic exposure to nicotine and free radicals in tobacco smoke has been shown to increase oxidative stress biomarkers ,39. Our Finally, in relation to the cessation of tobacco consumption, there is evidence indicating that it is one of the most effective measures to prevent the progression of renal failure ,9,41. InIn conclusion, the novelty of our results lies in presenting evidence of subclinical (possibly tubular) kidney damage in tobacco users. This study provides a panel of biomarkers capable of detecting this condition that can be used to implement preventive measures against the development of CKD and possible acute events derived from potentially nephrotoxic treatment in smokers.


Hypotension after cardiac arrest could aggravate prolonged hypoxic ischemic encephalopathy. The association of circulatory shock at hospital admission with outcome after cardiac arrest has not been well studied. The objective of this study was to investigate the independent association of circulatory shock at hospital admission with neurologic outcome, and to evaluate whether cardiovascular comorbidities interact with circulatory shock. 4004 adult patients with out-of-hospital cardiac arrest enrolled in the International Cardiac Arrest Registry 2006–2017 were included in analysis. Circulatory shock was defined as a systolic blood pressure below 90 mmHg and/or medical or mechanical supportive measures to maintain adequate perfusion during hospital admission. Primary outcome was cerebral performance category (CPC) dichotomized as good, (CPC 1–2) versus poor (CPC 3–5) outcome at hospital discharge. 38% of included patients were in circulatory shock at hospital admission, 32% had good neurologic outcome at hospital discharge. The adjusted odds ratio for good neurologic outcome in patients without preexisting cardiovascular disease with circulatory shock at hospital admission was 0.60 [0.46–0.79]. No significant interaction was detected with preexisting comorbidities in the main analysis. We conclude that circulatory shock at hospital admission after out-of-hospital cardiac arrest is independently associated with poor neurologic outcome. The early phase after cardiac arrest can be complicated by circulatory shock, due to low systemic vascular resistance and/or myocardial dysfunction2, potentially aggravating HIE through prolonged cerebral hypoperfusion. The reported incidence of circulatory shock at presentation after OHCA is 15–68%6. In studies circulatory shock is defined as hypotension, clinical signs of hypoperfusion, or the need for supportive measures to maintain an acceptable perfusion pressure. The lack of a universally accepted definition of circulatory shock and differences in patient selection could explain the large variation in the incidence reported. Outcomes after cardiac arrest include survival and/or neurologic recovery, dichotomized as favorable or poor, according to the International Liaison Committee of Resucitation (ILCOR)7. Observational studies have failed to prove an association between increased cardiac output post-cardiac arrest and improved long-term outcomes11. Current guidelines based on observational studies recommend a mean arterial pressure (MAP) above 65 mmHg during the initial phase of critical care13. Impaired autoregulation of cerebral perfusion has been reported in 35% of post resuscitation patients and is overrepresented in patients with preexisting arterial hypertension14. This may explain lack of beneficial effects in interventional trials targeting increased blood pressure for patients with hypotension post OHCA16. Despite the many studies on the association between circulatory shock on admission and outcome after OHCA the data are conflicting19. In this observational study of a large international cardiac arrest database, our hypothesis was that circulatory shock at hospital admission after OHCA is independently associated with neurologic outcome. As a secondary analysis, we explored the relative contribution of circulatory shock in patients with cardiovascular comorbidities, on neurologic outcome.The main driver of poor long-term outcome after out-of-hospital cardiac arrest (OHCA) is hypoxic ischemic encephalopathy (HIE)This is a retrospective registry study of patients enrolled from 2006 to 2017 in The International Cardiac Arrest Registry (INTCAR), a large North American/European post cardiac arrest registry containing a defined core dataset. Ethical Review Boards (ERB) in each country approved data collection and participation. Informed consent was waived from all participants in line with the Helsinki declaration, by approval of the Ethical Review Board in Lund, reference number: REPN Lund Dnr 2007/272.All patients in the INTCAR registry were screened for eligibility. Exclusion criteria were the following: in-hospital cardiac arrest (IHCA); Patients awake on admission defined as Glasgow Coma Score motor component equal to 6; Age below 18 years; Missing records on the presence or absence of circulatory shock on admission or Cerebral Performance Category (CPC) at hospital discharge. Subgroup analysis was performed in patients with continuous explanatory variables linearly associated with outcome.20, the primary outcome was dichotomized as good (CPC 1–2) or poor (CPC 3–5) at hospital discharge. The CPC scale ranges from 1 to 5, with 1 representing good cerebral performance or minor disability, 2 moderate disability, 3 severe disability, 4 coma or vegetative state, and 5 brain death21. By default, poor neurologic recovery according to this definition, is correlated with mortality. Circulatory shock was defined as systolic blood pressure < 90 mm Hg and/or the need for supportive measures, such as inotropes, vasoactive drugs, mechanical circulatory support devices to maintain a systolic blood pressure ≥ 90 mmHg or end-organ hypoperfusion. Hospital admission was defined as the first unit the patient presented at after the OHCA, emergency department (ED), the intensive Care Unit (ICU) or coronary angiography lab, depending on the routines of the including hospital. Time to start of advanced life support (ALS) was defined as time from witnessed cardiac arrest or, in the event of unwitnessed arrest, time from emergency call to start of advanced life support by medical personnel. Return of spontaneous circulation (ROSC) was defined to have occurred when chest compressions were not required for 20 consecutive minutes and signs of circulation persisted. Predefined co-morbidities were registered if they involved current pharmacological or prior surgical treatment or were under active medical supervision at the time of arrest. Obesity was defined as body mass index > 35.According to the International Liaison Committee of Resucitation, core outcome recommendations22. All continuous variables were scaled to standard deviations (SD) and centered22. Analysis of variables with more than 5% missing did not reveal any evidence for systemic mechanism of missingness. Final analyses were based on the pooled estimates, using Rubin’s rules, from 24 datasets imputed by chained equations with predictive mean matching for continuous variables and logistic regression for categorical data, using all modelled variables and outcomes. Imputation was done under the assumption of missing at random. The association between circulatory shock and outcome was estimated using generalized additive methods (GAM) with smooth functions fitting continuous data to cubic restricted splines using 5 knots. Fit of the smooth functions for continuous data were visually checked by plotting residuals for the explanatory variables versus the log odds of the dependent variable, and by estimating the k-index. Models were adjusted for: first monitored rhythm: Pulseless Electrical Activity (PEA), asystole or either pulseless ventricular tachycardia or ventricular fibrillation (VT/VF); Presence of ST-Elevation Myocardial Infarction (yes/no); witnessed arrest (yes/no); bystander cardiopulmonary resuscitation (yes/no); time to start of ALS (square root transformed minutes); sex ; time to ROSC (ordered quantiles transformed minutes); age (ordered quantiles transformed years); circulatory shock on presentation at hospital (yes/no), presence of the following comorbidities(present/not present): Neuro-vascular disease, Chronic obstructive pulmonary disease, obesity, diabetes, chronic kidney disease, hypertension, coronary artery disease, congestive heart failure, arrhythmia; interaction between comorbidities and circulatory shock on presentation. Results from GAM models are presented as odds ratios (OR) with 95% confidence interval (CI). To estimate the association with outcome for the continuous variables in our model, subgroup analysis was performed on a patient group defined by continuous variables linearly associated with neurologic outcome at hospital discharge. Cutoffs for the variables in subgroup analysis was empirically tested and confirmed linear. Complete cases models confirmed concurvity for continuous data < 0.01, and variance inflation index (VIF) for categorical data < 3, indicating no significant concurvity or multicollinearity. Goodness of fit was confirmed with Hosmer–Lemeshow test. Sensitivity analysis was performed comparing our results with that of data imputed with a span of 75–125% of originally imputed using a calibrated-∂ adjustment23 data for variables with missingness more than 5%. Because of the exploratory nature of this analysis, no correction was done for multitesting.Continuous descriptive data are presented as medians with interquartile (IQR) range. Differences in baseline variables were tested using Chi-square test for categorical data, while continuous data were tested using Student’s t-Test or Mann–Whitney test as appropriate. Variables with less than 20% missing were considered as candidates for explanatory variables in analyses. Pairwise correlation was estimated for all combinations of variables. The least relevant variable, from the perspective of our main hypothesis, was dropped from analysis if Pearson correlation coefficient was over 0.75 or less than -0.75. Skewed continuous explanatory variables were transformed to normal distribution, choosing the method yielding the lowest Pearson P statistic/degrees of freedomOut of 5943 enrolled patients in the INTCAR registry 4004 were eligible for analysis Fig. . Of the The explanatory model revealed a nonlinear association between age, ROSC and outcome. The association with time to ALS was linear , explanatory continuous variables were linear .In this large retrospective cohort study of unconscious adult survivors of OHCA admitted to the intensive care unit, the main finding is that circulatory shock at hospital admission is independently associated with poor neurologic outcome at hospital discharge.34. Seven of these studies analyzed blood pressure levels within the first hour after hospital admission35, three of them reporting conflicting evidence regarding blood pressure as an independent predictor of outcome34. Contrary to our findings, a single center study consisting of a mixed cohort of IHCA/OHCA cases not treated with targeted temperature management (TTM), found that MAP five minutes after ROSC was not associated with neurologic outcome in adjusted analysis34. Less than 15% of patients in this study had recorded 5-min MAP levels < 65 mmHg, which might reflect a lingering adrenaline effect, which could have confounded the results. In an Australian registry study, systolic arterial blood pressure < 90 mmHg at admission after OHCA was found to be independently associated with lower hospital survival only in the subgroup of patients with an initial shockable rhythm17. Patients in that study were aggressively resuscitated with fluid loading and prehospital vasopressors, suggesting that the relative contribution of circulatory shock on outcome might decrease in patients with the worst physiologic characteristics. In a study of a mixed cohort of IHCA/OHCA patients, a systolic arterial blood pressure < 90 mmHg within one hour of ICU admission was found to be independently associated with higher in-hospital mortality19. This is in line with our findings, but the authors found a higher relative contribution on outcome, possibly due patient selection and model not adjusted for time to ROSC.The use of hypotension as a surrogate definition of circulatory shock, complicates the interpretation of the underlying cause(s), since blood pressure is the product of cardiac output and systemic vascular resistance. A number of observational studies have previously investigated blood pressure levels during the early phase of critical care, leading up to the European resuscitation council 2021 guidelines recommendation of a MAP > 65 mmHg for unconscious survivors of cardiac arrest2 at 12 h post ROSC10. In two other studies, no such association was found9; another study found an association between higher CI time integral and poor neurologic outcome at 28 days11. Two randomized controlled trials have published neutral results on surrogate markers for neurologic outcome using circulatory interventions to optimize cerebral oxygen delivery in the acute phase post OHCA16. The results of our subgroup analysis suggest an interaction between circulatory shock on admission and pre-arrest hypertensive disease. This finding is in line with previous studies36; the effect was not significant in the full cohort. The results of the exploratory subgroup analysis should be cautiously interpreted in the context of multi-testing and should be seen as hypothesis generating.Our results suggest that hypotension and/or circulatory shock may contribute to subsequent neurologic outcome. However, the association between circulatory shock  and neurologic outcome has, to our knowledge, not been studied. A few small observational studies report the influence of low cardiac output in the setting of the subacute phase of OHCA. Huang et al. report increased hospital survival, but no difference in neurologic outcome among patients with a cardiac index (CI) > 2.5 l/min/m37. The lower limit of autoregulation, however, is right shifted after cardiac arrest38. This leaves cerebral blood flow reliant on blood pressure, rendering cerebral oxygenation vulnerable in hypotension. This process is further aggravated by cerebral hypoperfusion caused by microcirculatory injury39, potentially explaining our findings. Results also suggest that individually optimized blood pressure targets should be investigated in future studies, as some patients may benefit from higher post-arrest blood pressure targets. This could explain why hemodynamic interventional trials have failed to improve outcome in the context of cardiac arrest. Comparing the point estimates in our study, the relative influence of the presence of circulatory shock at the time of hospital admission on neurologic outcome at hospital discharge is minor as compared to some of the other explanatory variables in our model, specifically first documented rhythm, age, and time to ROSC. Explained variance is low, indicating the need for further studies targeting the pathophysiologic mechanism of circulatory shock in this context and how individual physiological characteristics may affect the trajectory of circulatory shock and outcomes.This study adds to the previous conflicting evidence that early circulatory shock in the context of OHCA is independently associated with poor neurologic outcome. Autoregulation is the innate mechanism regulating cerebral blood flow over a wide range of perfusion pressures, mitigating ischemia and hyper perfusionDefinitions of circulatory shock, timing and duration of circulatory shock, patient selection, sample size, TTM-levels and timing/choice of endpoints make comparison of studies cumbersome. We acknowledge a number of limiting factors in our study, the most obvious ones being: (1) The lack of a universally accepted definition of circulatory shock; (2) The sensitivity and specificity for circulatory shock with the predefined definition used in the INTCAR database has not been published. (3) Additional signs normally associated with the clinical diagnosis of circulatory shock, e.g. lactate, was not included in the INTCAR database. (4) Neurologic outcome in this study was evaluated at hospital discharge, which may be too early for complete neurologic recovery. (5) Additional outcome measures of neurologic recovery or neurologic injury, eg neuropsychiatric/cognitive testing and biomarkers indicating cerebral injury , was not available in the predefined dataset. Due to the correlation between dichotomized neurologic outcome with mortality, our results also should be interpreted within the context of survival. Further, the study population represents a convenience sample and registered data were not monitored, which introduces potential bias. The influence of circulatory shock on outcome in the setting of cardiac arrest is inherently difficult because of competing risk of poor outcome due to the initial hypoxic/ischemic insult. We lack data on cause of arrest, biomarkers and physiological parameters, which could account for the low explained variance in our models. Analyses were made on a large predefined dataset, and although the sensitivity analysis over a wide range was similar to the results of the imputed dataset, there is no guarantee that missing data did not affect the results. By virtue of design, causal inferences cannot be made.Circulatory shock at hospital admission after OHCA is independently associated with poor neurologic outcome at hospital discharge.Supplementary Information.


Introduction: Contrast-induced acute kidney injury (CI-AKI) is a common and potentially serious complication of percutaneous coronary intervention (PCI) procedures, as it induces acute kidney injury (AKI), especially in previously diagnosed chronic kidney disease (CKD) patients, particularly in those who also have diabetes. Adequate hydration and using a minimal volume of contrast media are the recommended measures to decrease CI-AKI in CKD patients. A combination of sodium bicarbonate and N-acetylcysteine (NAC) may be a superior strategy for preventing CI-AKI. This study is aimed to evaluate the safety of PCI in moderate to severe CKD patients.Method: This was a prospective, single-center study, from 2019 to 2021. We included all chronic kidney disease who undergo PCI procedures. The kidney level was measured on admission and 24 hours after the PCI procedure. The patients received 75 meq/500 mL of sodium bicarbonate one to six hours before procedures, oral acetylcysteine 600 mg bid for three days, and rehydration with 1000 ml of normal saline infusion for eight hours in patients without congestive heart failure. SPSS Version 23.0  was used to input and process the data.Results: This study included 118 subjects, with baseline characteristics of age 58.77 ± 9.08 years, 80.5% male, 47.5% diabetic, 50% hypertension, and 59.5% congestive heart failure. From the coronary angiogram, we found most of our subjects (57.6%) had three-vessel disease, 28.8% had two-vessel disease, and 15.6% had one-vessel disease. About 67.8% of subjects used <50 ml of low molecular contrast. The baseline creatinine level was 2.46 ± 1.04 mg/dL and the estimated glomerular filtration rate (eGFR) was 30 ± 12.65 mL/min. There were 19 (16.1%) patients with stage 3A CKD, 45 (38.1%) stage 3B, 41 (34.7%) stage 4, and 41 (34.7%) stage 5. The kidney function test after 24 hours of contrast admission showed a creatinine level of 2.37 ± 1.20 mg/dL (P<0.05) and the eGFR of 34.74 ± 16.10 mL/min. There was no significant difference in creatinine levels between stage 3A and stage 5 CKD. There was a significant reduction in creatinine in stage 3B CKD, from 1.917 ± 0.22 to 1.71 ± 0.37 mg/dL (P = 0.001); and stage 4 CKD, from 2.77 ± 0.55 to 2.72 ± 0.94 mg/dL (P = 0.013).3 exerts a better antioxidative effect, which reduces the harmful short-term and long-term consequences of contrast media. Previous studies revealed the use of low-to-zero contrast media was safer in CKD patients who had undergone PCI. By applying these measures, our study showed a good outcome of PCI with no worsening renal function in CKD patients.Discussion: CKD is a risk factor for developing CI-AKI after PCI, which is a marker of poor long-term outcomes. The development of CI-AKI is a strong predictor of post-PCI bleeding, which aggravates hemodynamic instability. The combination of NAC and NaHCOConclusion: With good prophylaxis measures, such as using minimal volume contrast media, adequate rehydration, and the combination of sodium bicarbonate and acetylcysteine, it is safe to do PCI in moderate to severe CKD patients. Contrast-induced acute kidney injury (CI-AKI) is a potentially life-threatening complication of percutaneous coronary intervention (PCI) procedures. According to the acute kidney injury network (AKIN), CI-AKI is diagnosed if at least one of the following criteria is met: 1) absolute increase in serum creatinine (SCr) by >0.3 mg/dL from baseline; 2) relative increase in SCr by >50% from baseline; and (3) urine output is reduced to <0.5 ml/kg/hours for at least six hours [ absolute relativeVarious studies reported that CI-AKI occurred in up to 30% of patients receiving intra-arterial contrast media . In a prIodinated contrast (tri-iodinated benzene) is used in the coronary angiography procedure. Cytotoxicity occurs after the contrast administration and the endothelial cells produce vasoactive mediators ), which later cause prolonged renal vasoconstriction, impaired renal perfusion, and ischemia . The renStudy populationThis was a single-center, prospective cohort study, which was conducted at Primaya Hospital, Tangerang City, Banten, Indonesia. Study participants were taken using the consecutive sampling method. We included patients over 18 years old who had a history of CKD stage 3 or over, a history of coronary arterial disease (CAD) (stable), underwent the PCI procedure and were checked for serum creatinine level on admission and 24 hours after the procedure. Patients with unstable hemodynamics were excluded from the trial.Study protocolAll patients received 75 meq/500 ml bicarbonate sodium one to six hours before procedures, oral acetylcysteine 600 mg bid for three days, and rehydration with 1000 ml for eight hours (given two hours pre-contrast and six hours after contrast). Kidney function measurement was assessed on admission and 24 hours after PCI procedures to see any kidney function decline within the first 24 hours. This study was approved by the ethics committee of Primaya Hospital Tangerang , with reference number 001/KOMED-EXT/RSABT/IX/2019.Data collection and definition of variable2 is classified as stage 1, 60-90 ml/min/1.73 m2 is classified as stage 2, 45-59 ml/min/1.73 m2 is classified as stage 3A, 30-44 ml/min/1.73 m2 is classified as stage 3B, 15-29 ml/min/1.73 m2 is classified as stage 4, and less than 15 ml/min/1.73 m2 is stage 5 [The patients were classified by sex , a history of previously diagnosed hypertension, diabetes mellitus, and heart failure was obtained. The contrast volume used was classified as less than 50 ml or over 50 ml. From the coronary angiogram, we described the number of vessels affected (1/2/3 vessel disease). We used the 2012 Kidney Disease Improving Global Outcomes (KDIGO) CKD classification to group the CKD patients, whereas CKD is defined as a function or structural abnormalities of the kidney presented at least three months. Glomerular filtration rate (GFR) is used for the classification of CKD, of which over 90 ml/min/1.73 m stage 5 . The kidThis study included 118 subjects, with baseline characteristics  . Both meThe usage of low or minimal contrast volume, adequate hydration, and the use of high-dose statins have been recommended in CI-AKI prevention. Creatinine monitoring should be done once daily for the first five days after the injection of the contrast medium . A previAdequate hydration should be ensured in all patients undergoing coronary angiography because it prevents CI-AKI ,14. The 3 group 2 days after the contrast exposure [Intravenous bicarbonate sodium and acetylcysteine, as we gave to our subjects, have been in debate. Theoretically, bicarbonate sodium decreases urine acidification  on the renal tubule and it may help reduce free radical injury . A previexposure .Our subjects had been given a limited volume of contrast media, received intravenous normal saline for hydration pre- and post-procedure, and also received both intravenous bicarbonate sodium and N-acetylcysteine, which have antioxidative effects. In our study, we found there was no worsening serum creatinine in the first 24 hours after the procedure in the CKD patients, but further study should be done assessing the 48 hours renal function. We suggest comparing the first 24 hours and 48 hours post-contrast serum creatinine to see if the first 24 hours' creatinine level may predict the incidence of CI-AKI. This study was not compared between CKD patients and non-CKD patients because we aimed to see if these prevention measures may be an option for CKD patients to prevent CI-AKI. The limitation of this study is that we did not assess the daily serum creatinine, as per the previous study protocols, to assess the decline in renal function per day. We also did not compare the outcome of each comorbidity with the effect of CI-AKI prevention.With good prophylaxis measures, such as using minimal volume contrast media, adequate rehydration, and the combination of sodium bicarbonate and acetylcysteine, worsening renal function was not found in the first 24 hours in CKD patients. Further studies with larger samples and assessing the 48 hours serum creatinine and the long-term outcome of kidney function with these measures of prevention should be done.


With a median follow-up of 36.7 months post-transplant, kDGF was associated with a significantly increased risk of developing more severe postoperative complication(s) (p < 0.000001), poorer renal function , and worse death-censored graft (p = 0.00004) and patient survival (p = 0.0002). kDGF may be responsible for remarkable negative effects on immediate and potentially longer-term clinical outcomes after CLKT. Understanding the important risk factors for kDGF development in CLKT may better guide recipient and donor selection(s) and improve clinical decisions in this increasing group of transplant recipients.Combined liver–kidney transplantation (CLKT) improves patient survival among liver transplant recipients with renal dysfunction. However, kidney delayed graft function (kDGF) still represents a common and challenging complication that can negatively impact clinical outcomes. This retrospective study analyzed the incidence, potential risk factors, and prognostic impact of kDGF development following CLKT in a recently transplanted cohort. Specifically, 115 consecutive CLKT recipients who were transplanted at our center between January 2015 and February 2021 were studied. All transplanted kidneys received hypothermic pulsatile machine perfusion (HPMP) prior to transplant. The primary outcome was kDGF development. Secondary outcomes included the combined incidence and severity of developing postoperative complications; development of postoperative infections; biopsy-proven acute rejection (BPAR); renal function at 1, 3, 6, and 12 months post-transplant; and death-censored graft and patient survival. kDGF was observed in 37.4% (43/115) of patients. Multivariable analysis of kDGF revealed the following independent predictors: preoperative dialysis ( Combined liver–kidney transplantation (CLKT) was first described as a treatment modality to overcome the development of end-stage liver disease (ESLD) concomitantly with end-stage kidney disease (ESKD) by transplanting both grafts from the same donor. CLKT has been increasingly performed since the Model for End-stage Liver Disease (MELD) liver allocation system was introduced in 2002 , prioritFor ESLD patients on dialysis at the time of transplant, graft and patient survival has been higher among CLKT recipients compared with patients undergoing liver transplant alone (LTA) or kidney after liver transplant (KALT), i.e., among those receiving a KT from a different donor at some point following the LTA ,4. IndeeNevertheless, kidney delayed graft function (kDGF) is a common and challenging postoperative complication in CLKT, with a reported incidence ranging from 7–50% in single-center studies ,9 and laAt our center, hypothermic pulsatile machine perfusion (HPMP) has been used prior to transplant in all CLKT recipients. The few existing reports comparing HPMP vs. static cold storage (CS) of the donor kidney in CLKT have documented a significantly lower kDGF incidence when HPMP is applied ,13, a reDelaying implantation of the renal allograft in CLKT is also an approach that we take at our center. As previously described by others, stabilization of the patient’s coagulopathy and hemodynamics by weaning vasopressor support are benefits of the delayed strategy compared with performing a simultaneous liver–kidney (SLK) transplant ,13. The The purpose of this observational study was therefore to determine which subset of baseline variables were most influential in predicting kDGF development as well as to determine the prognostic impact of kDGF development in our unique CLKT cohort .A retrospective cohort study was conducted on 115 consecutive adult patients undergoing CLKT at the Miami Transplant Institute between 1 January 2015 and 28 February 2021. The decision to include patients transplanted since 2015 was based on adoption of uniform and homogenous criteria for CLKT listing at our Institute, also in agreement with those introduced by UNOS in 2017 [Data were obtained from a prospectively maintained electronic database and complemented by a review of clinical charts and donor data. The study was in accordance with the University of Miami Institutional Review Board and Helsinki Declaration. Written informed consent was obtained from all subjects or a legal surrogate. Last follow-up date for this study was 31 July 2021.The primary study endpoint was the incidence of kDGF, defined as the requirement for dialysis during the first week post-kidney transplant . SecondaIn accordance with the Clavien–Dindo classification , a singlInternational Club of Ascites (ICA) criteria were used for the diagnosis and staging of acute kidney injury (AKI), regardless of the cause . ® , a type of non-oxygenated hypothermic machine perfusion. Renal allografts were arterially cannulated and perfused with Kidney Perfusion Solution® (KPS-1). KPS-1, having the same composition as UW® Machine Perfusion Solution, originally formulated at the University of Wisconsin, is a clear, sterile, non-pyrogenic, non-toxic solution with an osmolality of 300 ± 15 mOsm/kg, a sodium concentration of 100 mEq/L, a potassium concentration of 25 mEq/L, and a pH of 7.4 ± 0.1 at room temperature. Based on the sodium/potassium ratio, the composition is thus consistent with that of an extracellular solution [Following kidney recovery, all deceased donor kidneys were connected to the LifePort Renal Preservation Machinesolution .Perfusion temperature was set at 4 °C, and systolic perfusion pressure was initially fixed at 30 mm Hg, with adjustment made after 30 min to obtain a flow goal of >100 mL/min. Pumping flow (mL/min) and resistive indices (RIs) (mmHg/mL/min) were serially monitored. Kidneys were maintained under these conditions at a centralized holding facility at the Miami Transplant Institute until the time of transplant, in order to facilitate the logistics related to CLKT, independent of whether the delayed or simultaneous strategy was used .Hypothermic perfusion was not applied to liver allografts.All LT recipients at our center undergo a second post-transplant operation between postoperative days 2–3 (only the skin is closed at the time of LT). During the second-look operation, the liver allograft is evaluated, a biopsy is generally obtained, and an accurate washout of the abdomen is performed to evacuate any existing fluid collection or hematoma along with final closure of the abdominal wall. This method aims at minimizing the risk of developing graft congestion/abdominal compartment syndrome in the immediate post-reperfusion period, and in assessing the early occurrence of bile duct necrosis (or leak) and/or other unrecognized bowel injuries or obstructions .By performing the standard second-look operation after LT as described above, it was not automatically included among the postoperative complications, as this approach represents a surgical protocol at our Institute. However, if any other procedures in addition to those listed above were performed, then the second look operation was classified as a grade IIIb postoperative complication, according to the Clavien–Dindo scale.All LT cases in our series were performed using the piggyback hepatectomy technique without employing a veno-venous bypass.KT was always performed using the conventional extra-peritoneal approach. The right iliac fossa was the site for all primary kidney allograft implantations; re-transplant operations were completed contralaterally. After completing the vascular anastomoses, a modified extravesical ureteroneocystostomy technique was used in all recipients .Primary fascia closure was always accomplished at the end of KT. In all cases of delayed KT, continuous veno-venous hemodialysis (CVVHD) was used during the time transpiring between performance of the LT and KT.All recipients received immunosuppressive therapy according to our center protocols, with induction consisting of at least one dose of intravenous antithymocyte globulin (ATG) (1 mg/kg) and basiliximab (20 mg) plus 3 or 4 doses of methylprednisolone (500 mg) ,35. The The dual induction therapy with ATG and the IL2rAb basiliximab, compared with ATG alone, results in a prolonged depletion, extended to 3 months post-transplant of CD25 cells that represent the alloantigen-stimulated effector T cells ,37,38,39Achieving early and effective lymphocyte depletion with dual induction therapy may allow for the delayed introduction of calcineurin inhibitors, early withdrawal or complete avoidance of maintenance steroids, possible lower daily dosages of maintenance immunosuppressive agents, and reduced costs ,37,38,392 × 1 dose) was also given. For highly sensitized recipients, i.e., those with a calculated panel reactive antibody ≥80%, low level positive flow crossmatch and/or high levels of preformed donor specific antibodies (MFI ≥ 6000), Rituximab  were calculated for baseline continuous variables (with geometric mean and corresponding SE being used for baseline continuous variables having skewed distributions). t-tests for continuous baseline variables . Tests of association between kDGF development and various outcome variables were performed using Pearson (uncorrected) chi-squared tests for dichotomous outcomes, standard t-tests for continuous outcome variables, and log-rank tests for time-to-event outcomes. Time-to-event graphs were performed using the Kaplan–Meier technique.Tests of association between baseline variables and kDGF development (No: kIGF (immediate graft function)/Yes: kDGF) were performed using Pearson (uncorrected) chi-squared tests for dichotomous baseline variables and standard 2 at various times post-transplant; thus, for the purpose of achieving greater statistical precision and power, all eGFR values ≥120 were capped at 120 mL/min/1.73 m2 in the statistical analyses. Of note, there were some patients that had eGFR values much larger than 120 mL/min/1.73 mMultivariable analysis was performed using stepwise logistic and linear regression. In the attempt to avoid the selection of potentially spurious associations into these multivariable models, a more stringent type I error of 0.025 was used. All of the statistical analysis was performed using the Statistical Analysis System (SAS) software, Version 9.4, SAS Institute, Inc., Cary, NC, USA.Overall, the mean (±SE) recipient age was 59.6 (±0.9) years; the percentage of male recipients was 60.0% (69/115). Recipient race/ethnicity included: 52.2% (60/115) being Hispanic, 31.3% (36/115) being white, 13.9% (16/115) being African-American, and 2.6% (3/115) being Asian.n = 39, 33.9%), chronic hepatitis C , and alcoholic hepatitis  represented the most frequent indications for LT, followed by cryptogenic cirrhosis including autoimmune hepatitis, primary sclerosing cholangitis, and primary biliary cirrhosis ; autosomal dominant polycystic liver disease ; and chronic hepatitis B . Hepatocellular carcinoma was diagnosed in the explant pathology in 15 patients (13.0%). A combination of at least two different etiologic agents of ESLD was reported in seven patients (6.0%). Non-alcoholic steato-hepatitis  followed by HRS , autosomal dominant polycystic kidney disease , and chronic glomerulonephritis . HCV-associated glomerulonephritis, HIV-associated nephropathy, calcineurin-inhibitor induced nephropathy, and chronic rejection were the other etiologies of CKD in 20.9% of recipients (n = 24). A combination of at least two different etiologic agents of ESKD was reported in 40 patients (41.1%). The most common indication for KT was diabetic and/or hypertensive nephropathy  and five (4.3%) CLKT recipients already underwent previous isolated liver and isolated kidney transplants, respectively. p = 0.0002).Mean BMI at listing was significantly higher in recipients with NASH cirrhosis (30.0 ± 0.8) compared to recipients with alcoholic cirrhosis (24.5 ± 0.9) and other causes of ESLD (27.4 ± 0.6) , while the physiologic MELD score at the time of CLKT was 28.5 (±0.7), with a median time on waitlist of 65 (range: 2–2405) days. Sustained isolated AKI, AKI on CKD, and isolated CKD were the criteria justifying the KT in 12 (10.4%), 34 (29.6%), and 69 (60.0%) recipients, respectively. Delayed implantation of the renal allograft was performed in 69.6% (80/115) of cases, with a mean delayed time among these 80 cases of 20.7 (±0.9) hours after the LT. Vasopressor support was required during the operation in 71 (61.7%) patients, while in 64 (55.7%) patients, it was used within the first 6 h after the LT. CVVHD was administered preoperatively in 22 (19.1%) cases with a geometric mean duration of 6.8 (*/1.3) days, intraoperatively in 78 (67.8%) cases, and postoperatively (after the KT) in 30 (26.1%) cases. Mean liver and kidney CITs were 5.3 (±0.1) and 23.8 (±1.1) hours, respectively. Mean donor age was 38.4 (±1.4) years, and DCD donors were used in 19 cases (16.5%). Mean Kidney Donor Profile Index (KDPI)  was 40.9Regarding HPMP, the mean time lapse to initiation of HPMP was 3.93 (±0.22) hours, whereas the mean duration of pumping was 19.84 (±1.07) hours. The mean initial flow and RIs were 55.2 (±4.1) mL/min and 0.7 (±0.04) mmHg/mL/min, respectively, while mean final flow and RIs were 152.1 (±2.4) mL/min and 0.21 (±0.01) mmHg/mL/min, respectively. n = 12). Most of the patients received 3 doses of antithymocyte globulin and 2 doses of basiliximab as induction treatment . Postoperative hospital-acquired infections were reported in 56 (48.7%) recipients. In total, 67 recipients (58.3%) experienced a postoperative complication of Clavien–Dindo grade ≥3, while mean CCI was 51.4 (±2.5). Geometric mean hospital length of stay was 24.0 (*/1.1) days. In total, 43 patients (37.4%) developed kDGF. Eight patients (7.0%) had kPNF, while RAF was observed in 10.4% of recipients (A first BPAR episode was observed in 7 (6.1%) and 13 (11.3%) cases of the renal and hepatic allografts, respectively. All first episodes of kidney and liver acute rejection were T-cell mediated, grade IA and mild, respectively.During a median follow-up of 36.7 (range: 3.8–74.7) months post-transplant, death-censored hepatic allograft failure was documented in 5 patients (4.3%), with a median time-to-occurrence of 2.9 (range: 1.8–45.1) months post-transplant. Death-censored renal allograft failure occurred in 14 patients (12.2%) with a median time-to-occurrence of 3.0 (range: 0.03–51.6) months post-transplant. Death was reported in 21 patients (18.3%) with a median time-to-occurrence of 8.1 (range: 0.7–58.6) months post-transplant, of whom 9 (42.9%) died with functioning allografts. n = 13, 61.9%), followed by cardiopulmonary failure , liver allograft failure , hemorrhagic stroke , and an unknown reason .The leading cause for recipient mortality after CLKT was sepsis with multiple organ system failure , a result that was consistent across the etiology of ESLD (specific results not shown), while patients on hemodialysis before transplant  were more likely to develop kDGF  (Tests of association of recipient baseline variables with kDGF development found that the mean recipient BMI was significantly lower in the kDGF group (ctively) . p = 0.002 and 0.01, respectively)   differedctively) . p = 0.02) (p = 0.0002 each), as displayed in the HPMP and operative variable comparisons (p = 0.03). Among the other operative variables analyzed, a significantly higher mean number of PRBC units were transfused during LT in patients with kDGF (p = 0.006).Among HPMP parameters analyzed, mean final RIs were significantly higher in the kDGF group ( = 0.02) . Mean tiparisons . Likewisp < 0.000001 each) and 3 months (p = 0.004 and 0.0004) post-transplant, respectively. Significant differences in geometric mean sCr at 6 and 12 months post-transplant showing poorer renal function in the kDGF group were observed, while similar but nonsignificant trends existed for mean eGFR (2), significantly higher percentages were observed in the kDGF group at each time point .In comparing postoperative outcomes by group , recipieean eGFR . Howeverp = 0.000002 and 0.0001, respectively). Freedom-from-death-censored renal allograft failure and patient survival were also significantly less favorable for patients who developed kDGF , as shown in Similarly, percentages developing RAF and kPNF were significantly higher in the kDGF group  (p < 0.000001) in the kDGF group, and length of hospital stay was significantly longer (p < 0.000001). Regarding overall postoperative morbidity, the percentages of patients developing a major complication as classified by Clavien–Dindo grade ≥3 and any hospital-acquired infection were significantly higher in the kDGF group (ctively) . Consequp = 0.27), even as recipients with kDGF received significantly fewer doses of anti-thymocyte globulin as induction treatment (p = 0.002), and the third dose (p = 0.0009) in particular , receiving preoperative dialysis (p = 0.0003), a prolonged time from LT to KT (p = 0.0003), use of a DCD graft (p = 0.007), and older donor age (p = 0.003)  . Note thp < 0.000001 for each pairwise test of linear correlation). Thus, it was statistically impossible to determine which of these three baseline variables was the most appropriate multivariable predictor of kDGF development , it appeared that, biologically, Time from Liver to Kidney Tx (hr) was the most appropriate variable to be selected into the kDGF logistic model, as Time from Liver to Kidney Tx (hr) clearly reflects the patient’s clinical status at the time of LT.Of note, three of the baseline variables were highly correlated/confounded: longer Time from Liver to Kidney Tx (hr), longer CIT Kidney, and longer HPMP Pump Time (pment in . Given tp = 0.007), delayed implantation of the renal allograft (p < 0.000001), a greater number of units of PBRCs transfused during LT (p = 0.007), and postoperative vasopressor support within the first 6 h post-LT (p = 0.01)  .p < 0.000001, p = 0.05, 2), even after controlling for the 2 other significant multivariable predictors of this outcome  and with routine use of HPMP for all donor kidneys. Among all the baseline variables assessed, we were able to identify specific risk factors for developing kDGF in CLKT recipients . The use of kidneys from donors after circulatory death and older donors was significantly associated with kDGF in the multivariable analysis, confirming several previous reports ,12,14. T and withWhile the time elapsed between performing the LT and KT was observed to be a highly significant predictor of kDGF in our study, this finding should not lead one to conclude that delaying the kidney transplant might actually increase kDGF risk. In fact, a major consumption of blood products during the LT and the use of vasopressor support immediately after the LT were significant predictors of a longer time between the two operations in multivariable analysis, suggesting that higher degrees of surgical complexity during LT and recipient hemodynamic instability immediately following LT strongly support the approach of delaying the kidney transplant, at least for the sicker patients, an approach which has been promoted in other studies ,13. ThusSimilar conclusions regarding risk factors for kDGF were reached by Korayem et al. , stressiWith the exceptions of our study and Ekser et al. , we are Recent evidence from a large randomized controlled trial  togetherRegarding the HPMP parameters recorded in our series, though the final resistive index was significantly higher in univariable analysis of kDGF risk, this association was not confirmed in multivariable analysis. Thus, its clinical significance might be limited here, as the final pumping indices reported were excellent in both groups . Other iLower recipient BMI was associated with a significantly higher risk of developing kDGF in our study. While the causes of ESLD were not directly associated with kDGF risk, patients with alcoholic cirrhosis had a significantly lower BMI. Thus, the association found here between lower recipient BMI and higher kDGF risk could be related to the clinical status of the patient at the time of LT. Clearly, it would be preferable to have included a measure of sarcopenia  before dIn terms of secondary endpoints, patients with kDGF had significantly worse renal function at 1, 3, 6, and 12 months post-transplant, in agreement with previous series conducted in isolated KT ,51 and CThere are several limitations to this study, particularly that of cause and effect. As previously described, patients with a difficult LT procedure might first have to be stabilized before they can receive the KT; thus, a longer time between LT and KT by itself might not be a risk factor, but a result of a complicated situation. Secondly, although the data were prospectively collected and stored in our hospital database, the analysis performed was a single-center retrospective cohort study. However, the recent time period in which all patients were transplanted (since 2015) and the use of well-established criteria for CLKT listing markedly reduced the likelihood that an “era effect” and/or selection bias would exist. Additionally, the same primary surgical team performed these CLKT transplants with few (if any) differences in transplant protocols, as the study period was relatively short. Single-center studies also allow for the collection and investigation of a larger number of potentially relevant baseline variables, which may contribute to a more accurate assessment of the associations between those variables and prespecified study outcomes.Currently, at the Miami Transplant Institute, we do not have a standard protocol in place that determines the optimal timing of KT after LT during CLKT. By performing this retrospective study, our hope was to identify potential variables (such as the requirement for PBRCs during LT and post-LT requirement of vasopressor support) that could subsequently be used in establishing a more uniform approach to this growing group of solid organ transplants recipients.The incidence of kDGF remains high among CLKT recipients that are known to have a high MELD score. Longer time from LT to KT resulted the strongest multivariable predictor of higher kDGF occurrence, followed by pre-transplant dialysis, older donor age, lower recipient BMI, and use of DCD grafts. Additionally, kDGF was associated with inferior post-transplant outcomes and lower graft and patient survival in this class of solid organ transplant recipients. Further prospective studies with larger number of patients undergoing CLKT are required to validate and confirm these findings.


To evaluate the link between the neutrophil to HDL-C ratio (NHR) and the degree of coronary stenosis in patients with stable coronary artery disease (CAD).Totally 766 individuals who attended our clinic for coronary angiography between January 2019 and January 2021 were included in this study. The participants were divided into two groups, including the CAD group and control group. Spearman correlation analysis was used to investigate the association between NHR and Gensini score and logistic regression analysis was performed to determine the influence of NHR on CAD and severe CAD. Receiver operating characteristic (ROC) curve was constructed to analyze the predictive value of NHR for severe CAD.P < 0.01). There was a positive correlation between NHR and Gensini score, as well as the frequency of coronary artery plaques. Logistic regression demonstrated that NHR was an independent contributor for CAD and severe CAD. In ROC analysis, the area under the ROC curve (AUC) for NHR was larger than that for neutrophil, HDL-C or LDL-C/HDL-C, and the differences were statistically significant . The NHR limit that offered the most accurate prediction of severe CAD according to the greatest possible value of the Youden index, was 3.88, with a sensitivity of 62.6% and a specificity of 66.2%.The CAD group had a substantially higher median NHR than the control group (3.7 vs. 3.2, NHR was not only associated with the occurrence and seriousness of CAD, but also a better predictor of severe CAD than neutrophil, HDL-C or LDL-C/HDL-C. Coronary artery disease (CAD) is a global epidemic disorder with high morbidity and mortality . With inTraditional inflammatory parameters such as White blood cell (WBC) and its subtypes, including neutrophil to lymphocyte ratio (NLR), monocyte to lymphocyte ratio (MLR), platelet to lymphocyte ratio (PLR), monocyte to high density cholesterol ratio (MHR) and mean platelet volume to lymphocyte ratio (MPVLR) –13 are cAs mentioned above, atherogenesis is facilitated by several factors, including neutrophils and HDL-C, therefore, it was hypothesized that the neutrophil to HDL-C ratio (NHR) is an integrated biomarker more relevant to atherosclerosis as it would offer information about both inflammation and lipid metabolism. For this reason, our study investigated the connection between NHR and CAD and develop the projected value of NHR for the grading of coronary stenosis in individuals with stable CAD.n = 492), whereas controls had no luminal stenosis or lower than 30% (n = 274)  .The study was approved by the institutional review board of Shanghai University of Traditional Chinese Medicine’s Putuo hospital and was conducted according to the principles articulated in the second version of the Helsinki Declaration. All participants provided written informed consent and their individual information was kept strictly confidential.2). All patients were required to fast the previous night before having peripheral venous blood samples taken for measurement of CRP, FBG, PBG, TC, TG, HDL-C, LDL-C, WBC, neutrophils, and serum creatinine automatically using a Beckman Colter AU5800 biochemical analyzer . The CKD-EPI formula was used to derive estimated Glomerular Filtration Rate (eGFR) (9/l) by HDL-C (in mmol/l).At the time of admission, the patient’s anthropometric measurements and biochemical variables were recorded. After subjects had rested for 10 min and been seated, their blood pressure was measured twice. The mean blood pressure was then calculated. All patients’ height and weight were measured to calculated the body mass index (BMI) by the formula of weight/height2 (kg/me (eGFR) . HbA1c w1c ≥ 6.5% or the subjects who are using glucose-controlling medicines.Systolic blood pressure (SBP) ≥ 140 mmHg and/or diastolic blood pressure (DBP) ≥ 90 mmHg  were usen = 178), double-vessel (n = 154), and triple-vessel (n = 160) forms based on the number of affected coronary arteries. The Gensini score was utilized to determine the degree of CAD intensity, which was calculated by summing the values for the location and luminal narrowing of each lesion (n = 180), tertile 2 from 24–45 points (n = 149), and tertile 3 had a score ≥ 45 points (n = 163). Patients with a Gensini score ≥ 45 points were considered to have severe CAD.All participants underwent coronary angiography with the cardiologist blinded to the patient’s details. At least 50% stenosis in one of the four main coronary arteries  was required to diagnose CAD. The coronary artery stenosis disorders were classified as single-vessel  test was performed according to the nature of the variables. Chi–square test was used to analyse the statistical significance of differences between groups of categorical variables. The relationship between NHR and CAD was investigated using multivariable logistic regression and a ROC curve was used to evaluate the sensitivity and specificity of NHR’s ability to predict severe CAD. The maximum Youden index was utilized to establish the optimal cut-off for the NHR. MedCalc was used to compare the AUCs for NHR, neutrophil, HDL-C and LDL-C/HDL-C. The level of statistical significance was determined to be a two-tailed P < 0.05.All statistical analyses were performed using SPSS version 22.0. The Kolmogorov–Smirnov test was used to validate the distribution of continuous variables. The mean and SD of regularly distributed variables are presented, whereas the median is provided for non-normally distributed data (interquartile range). Categorical variables are represented numerically and statistically in numbers and percentages. The independent samples P < 0.01). Besides, subjects with CAD were of older age and had higher SBP, serum creatinine and poorer glycemic management than their counterparts . When comparing CAD patients with non-CAD patients, the total WBCs and neutrophil counts were higher, whereas levels of TC, TG, HDL-C, and LDL-C were lower in the former group. The CAD group also had higher median NHR levels . BMI, DBP, CRP, LDL-C/HDL-C, and frequency of alcohol consumption were not different between the two groups.P for trend was calculated with each tertile of Gensini score taken as a unit. The participants with the highest tertile of Gensini score had higher levels of BMI, WBCs, neutrophils, CRP, HbA1c, Cr, NHR, and higher prevalence of diabetes, but lower levels of HDL-C and less alcohol drinkers, compared to those with the lowest tertile of Gensini score .P < 0.01) after controlling for characteristics such as gender, age, BMI, smoking status, diabetes and hypertension (Model 2), or after accounting for LDL-C, creatinine, HbA1c, and CRP levels (Model 3), and after accounting for medications (Model 4). In the unadjusted model, each 1SD increase in NHR level was significantly associated with 1.73-folds (95% CI 1.44–2.08) increased risk of CAD and 1.85-folds (95% CI 1.52–2.25) increased risk of severe CAD. The adjusted ORs (95% CI) for CAD and severe CAD were 1.55 (1.27–1.91) and 1.84 (1.50–2.26) in Model 2, 1.50 (1.21–1.86) and 1.86 (1.50–2.30) in Model 3, 1.41 (1.12–1.77) and 1.85 (1.50–2.29) in Model 4 .It was established that NHR is a separate risk factor for CAD and severe CAD. P < 0.05). According to the tertiles of Gensini score, median NHR levels from low tertile to high tertile groups were 3.42 (2.75–4.25), 3.64 (2.64–5.05), and 4.28 (3.28–6.03), respectively. The high tertile group also had NHR levels that were noticeably higher than the middle tertile group as well as the low tertile group (P = 0.000). The scatter diagram was shown in P = 0.000), LDL-C/HDL-C  and HDL-C , with the Gensini score (As shown in le group . In addini score .P < 0.05). Analysis of ROC curve indicated that 3.88 was the optimal threshold of NHR in detecting severe CAD, which accorded with 62.6% sensitivity and 66.2% specificity.According to the reports, CAD accounts for 44.60% of all deaths in rural areas and 42.51% in urban areas, respectively , leadingThere was a correlation between high NHR and severe CAD, possibly because inflammation is involved in the pathogenesis of atherosclerosis, which is largely mediated by circulating neutrophils . The rolP < 0.01).A negative correlation between both myocardial infarction (MI) and CAD with HDL-C was observed . A moderAccording to the above analysis, neutrophil increases and HDL-C level decreases in CAD patients, suggesting that the comprehensive indicator NHR may make more contribution for CAD. Chen et al.  found thThe Gensini score is one of the most regularly used CAD severity markers, with varied weight coefficients , 47. We In summary, we believe that NHR is an effective serological biomarker to predict CAD and assess the degree of coronary stenosis. Nonetheless, our research was not without its caveats. First, because our study was conducted at a single center, the findings cannot be generalized. Second, it was a retrospective and observational study, so the causal relationship between NHR and CAD could not be determined. Finally, we only collected NHR levels at admission and did not investigate the prognostic value of NHR on adverse cardiovascular outcomes. Further multi-center and prospective studies are needed to confirm these findings.The high ratio of neutrophils to HDL (NHR) was related to an increased risk of serious CAD. Unlike many other biological parameters, NHR may be inexpensively calculated from a complete blood count on admission, so has the potential as a simple clinical marker for the assessment of CAD.The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by the Institutional Review Board of Shanghai University of Traditional Chinese Medicine’s Putuo hospital. The patients/participants provided their written informed consent to participate in this study.JG wrote the manuscript. JL and WS performed the statistical analysis. CZ, HW, and JX participated in the data collection and checked the data. BX contributed to the discussion. HZ evaluated the severity of coronary artery disease. TL and WT participated in the design of this study and edited the manuscript. All authors have participated in the work and have reviewed and agreed with the content of the article.