Recent evidence suggests an association between hypertension and periodontitis, although the pathways and implications underlying both chronic conditions are still poorly understood. Therefore, the aim of this study was to evaluate the relationship between hypertension and periodontitis through an observational clinical study using periodontal, physical, and biochemical analyses in hypertensive and non-hypertensive individuals with periodontitis. A total of one hundred patients were divided into two groups. The first group was hypertensive patients with periodontitis. The second group was non-hypertensive patients with periodontitis. Periodontal parameters of probing depth, bleeding on probing, and clinical attachment level were evaluated. The systolic, diastolic, mean, and differential blood pressure were measured in the physical examination. In addition, body mass index and waist–hip ratio were verified. Biochemical tests for glycated hemoglobin, fasting blood glucose, estimated blood glucose, total cholesterol, high-density lipoprotein, creatinine, glutamate pyruvate transaminase, glutamic oxaloacetic transaminase, and C-reactive protein were evaluated. The data were submitted for statistical analysis (α = 0.05%). The results of this study demonstrated that patients with cardiovascular disease did not present with worse periodontal clinical parameters in the conditions studied. However, it is important to bear in mind that this cross-sectional study has some inherent limitations to its design; therefore, to study the relationship between hypertension and periodontitis further, an interventional randomized clinical trial should be conducted. Hypertension is defined as a chronic high blood pressure condition . In addiAdherence to antihypertensive medications is a key component to controlling blood pressure levels, though less than half of individuals are diagnosed . AdditioPeriodontitis is a multifactorial chronic inflammatory disease predisposed by a dysbiosis of oral microbiota ,10. It iPorphyromonas gingivalis ) was then calculated [Participants were weighed and measured with a balance and a stadiometer to obtain body weight in kilograms and height in meters; the body mass index . All patients received a previous explanation of the measurement at least five minutes before in a calm environment. In addition, they were instructed to not talk and not have a full bladder. Additionally, the patient should not have practiced physical exercise and should not have ingested alcohol, coffee, or food in an interval of fewer than sixty minutes.The blood pressure was measured with the patient seated, legs uncrossed, feet supported, back leaning, clothes not offering compression on the member, arm positioned at heart level and supported, with the palm facing upwards. The measurement was performed twice on both arms with an interval of one minute, and the highest value was recorded . The folIn the clinical examination, in addition to the number of teeth, probing depth (PD), bleeding on probing (BOP), and clinical attachment level (CAL) examinations were also performed at all six sites of each tooth in the oral cavity. All clinical periodontal parameters were obtained with a millimeter periodontal probe . The clinical examinations were performed by a calibrated and experienced examiner (JVSR). A series of blood tests were requested for all participants. The exams requested were complete blood count, C-reactive protein (CRP), fasting blood glucose and estimated blood glucose, glycated hemoglobin (HbA1c), total cholesterol, high-density lipoprotein (HDL), glutamate-pyruvate transaminase (GPT), glutamic-oxaloacetic transaminase (GOT), and creatinine. The determination of positive CRP was characterized by levels equal to or above 6 mg/L; levels below was considered negative .Examiner calibration was performed before the periodontal analyses. For the calibration, one hundred and twenty sites were randomly selected in three patients. PD and CAL parameters were obtained on two separate occasions with a 7 day interval. Data were tabulated and submitted to the Kappa  agreement-test for continuous variables  and by the χ2 test for categorical variables (gender and CRP). The Mann–Whitney test was used to assess the association between continuous variables . Demographic and clinical data were submitted for descriptive statistical analysis using GraphPad Prism v9.3.1 software . Demographic variables between hypertensive and non-hypertensive groups were compared by the Student’s The association between each study variable and hypertension was estimated as the odds ratio (OR) and 95% confidence interval (CI) by age-adjusted multiple logistic regression analysis using STATA v17.0 software . In addition, multiple linear regression analysis was used to assess the relationship of each quantitative study variable independently with the presence of hypertension through the β coefficient and 95% CI.p < 0.0001). There were no statistical differences in the gender of the groups. In periodontal parameters, the hypertension group had a lower number of teeth in the oral cavity when compared to the non-hypertension group (p = 0.016). The other periodontal parameters showed no differences. Interestingly, although there were no differences in the percentage of CAL among the CAL < 3 mm (6.6 and 4.9%), CAL 4–5 mm (64.9 and 68.8%), and CAL > 6 mm (27.9 and 25.6%) for the hypertensive and non-hypertensive groups, respectively, the CAL level of 4–5 mm presented with a trend to be statistically significant. This data correlated with a moderate severity of periodontitis for all the included patients. Higher percentages of HbA1c and fasting blood glucose were observed in the hypertension group, although without statistical significance . The estimated blood glucose values showed no significant difference between groups (n groups .p = 0.043). Regarding the physical data, higher values of WRI were observed in the hypertensive group (p = 0.001). There was no difference in the BMI. In the evaluation of the CRP data, there were a greater number of patients who were positive for CRP in the hypertensive group when compared to the non-hypertensive group . There was no difference detected between the groups in the diastolic pressure data . Regarding the glycemic profile, the regression indicated that hypertensive patients with periodontitis have higher levels of HbA1c  and fasting glucose . In addition, patients in the hypertension group had higher BMI rates . Multiple logistic regression also indicated an association between increases in systolic pressure levels , mean blood pressure , and differential pressure  in the hypertension group.The findings presented in p = 0.01). In addition, hypertension is also associated with higher levels of HbA1c  and fasting blood glucose , as well as higher BMI . Similar to logistic regression, linear regression indicated that the hypertension group had higher systolic, mean, and differential blood pressure indices .In Hypertension and periodontitis are both chronic inflammatory conditions with a high incidence and prevalence in the adult population. Although the impact of these conditions can have many clinical consequences, there is still a lack of investigations considering them altogether. The main findings of this study were that patients with cardiovascular disease did not present with worse periodontal clinical parameters. Therefore, our study showed, in the conditions studied, that hypertensive patients did not show a negative impact in the periodontal tissues and alveolar bone. However, it is important to bear in mind that this cross-sectional study has some inherent limitations to its design; therefore, to study the relationship between hypertension and periodontitis further, an interventional randomized clinical trial should be conducted evaluating the effects of periodontal treatment on the biochemical parameters to come to the conclusion that there is no relationship between periodontitis and hypertension.Tooth loss is an essential finding of periodontitis since periodontal disease progression results in the destruction of the periodontium . VariousA case-control study with 500 patients investigated the influence of periodontitis on blood pressure control . LikewisThe relationship between hypertension and periodontitis is associated with a chronic immune–inflammatory disorder increased mainly by periodontal inflammation . First, The renin–angiotensin system, in addition to controlling blood pressure, acts on periodontal tissues . A previThe CRP occurs primarily for an increased concentration of IL-6 . Our finIn the present study, the mean age of each group showed a more advanced age in individuals with hypertension. Thus, logistic and linear regression analyses were adjusted for age. Our data showed that there were no differences regarding periodontal and biochemical nor physical parameters when the data was adjusted for age. Therefore, the increased age in the hypertensive group was not an indicator of negative clinical periodontal outcomes. These results corroborate with the data in the literature, in which authors report a higher prevalence of hypertension in individuals with more advanced ages ,34, alth2. Obesity has been reported as a risk factor for hypertension and cardiovascular disease [Anthropometric data of BMI and WHR were higher in hypertensive patients. Nevertheless, logistic and linear regression analyses have not correlated hypertension and WHR. Regarding BMI, the hypertension group was 1.12 more likely to be obese with a BMI over 30 kg/m disease . Additio disease . This st disease . Present disease . Hence, The systolic but not diastolic blood pressure was elevated in the hypertensive group when compared to the non-hypertensive group. The correlation of hypertension with periodontitis was confirmed by the logistic and linear regressions. In addition, the blood pressure values registered in this research corroborate with the literature . ObservaAlthough this study adds more knowledge to the current literature on hypertension and periodontitis, some important caveats should be mentioned. The cross-sectional nature of the study design does not allow causal inferences regarding the relationship between cardiovascular disease and periodontitis to be made, and the assessment of disease incidence. Due to the need for a large and heterogeneous study population in cross-sectional studies, it is important to conduct future observational studies including a wider number of individuals, as well as studies analyzing the effect of periodontal treatment to assess the possible association between hypertension and periodontitis.The results of this study demonstrated that patients with cardiovascular disease did not present with worse periodontal clinical parameters in the conditions studied. However, it is important to bear in mind that this cross-sectional study has some inherent limitations to its design; therefore, to study the relationship between hypertension and periodontitis further, an interventional randomized clinical trial should be conducted. Therefore, it is suggested to conduct future observational studies including a larger number of individuals, as well as studies analyzing the effect of periodontal treatment to assess the possible association between hypertension and periodontitis.


Introduction: Not much is known about the significance of nutritional status and support in transplant surgery, least of all in simultaneous pancreatic and kidney transplantation. Malnutrition in the context of simultaneous pancreatic–kidney transplantation seems to be complex and a still poorly investigated problem. Since SPKTX is highly qualified and also has a small volume procedure, it is difficult to obtain data from large cohorts of patients. The aim of this article is to gather existing evidence and information about the subject, as well as to elicit some questions and goals for the future. Methods: We searched through the Pub-Med database using the keywords “pancreas and kidney transplantation” combined with “nutritional risk”, “nutritional status”, “malnutrition”, “nutritional intervention”, and “frailty”, finding a total of 4103 matching results. We then narrowed it down to articles written in English with the full text available. We also researched through the references of articles most accurately matching our researched terms. Results: There are numerous tools that have been investigated for the screening of malnutrition, such as the NRI index, PNI index, NLR, SGA scale, and NRS-2002 scale, each of which proved to be of some use in predicting patient outcomes in different surgical settings. Since all of them differed in components and assessed parameters and, in the absence of more sensitive or infallible indicators, the most reasonable approach seems to evaluate them jointly. Conclusion: It is important to underline the necessity of nutritional screening and the subsequent introduction of adequate therapy while awaiting transplantation in an attempt to improve results. Considering the complexity of surgical procedures and the severity of underlying diseases with their intense metabolic components, the patient’s nutritional status seems to significantly influence results. Consequently, nutritional risk assessments should be a part of the routine care of patients qualified for transplantation. Assessing nutritional risk and the subsequent implementation of nutritional support has a well-established place in the peri-operative care of patients undergoing major gastrointestinal surgery . There aIt has been largely proved that malnutrition is a risk factor for complications in abdominal surgery. It compromises the healing of anastomoses and surgical incisions on the abdominal wall. Malnourished patients are at risk of increased postoperative morbidity and mortality, lengthened hospital stays, and impaired wound healing ,4.There is also evidence of malnutrition compromising the outcomes of transplantation of solid organs, such as the liver, lungs, or kidney ,6,7,8,9.The prevailing indication for SPKTX is autoimmune diabetes followed by end-stage diabetic nephropathy, with special consideration for brittle diabetes, resulting in hypoglycemia unawareness, frequent severe metabolic complications, or the failure of exogenous therapy to prevent metabolic complications ,11. AlsoThere is evidence that SPKTX is more beneficial for these patients than a kidney transplant alone, presumably thanks to better metabolic control ,14,15. NThe complexity of the procedure itself and the severity of underlying diseases leading to transplantation in the first place require special attention when qualifying for this treatment. A risk assessment and ability to predict outcomes and distinguish groups of patients that could benefit most from the procedure compared to those whose risk profile is too high seems to be of the utmost importance. Patients’ functional impairment, most commonly assessed using the Karnofsky scale, has been described as an important factor when predicting the outcomes of treatment in many medical fields, including simultaneous pancreas–kidney transplantation .Since SPKTX is a highly qualified and small-volume procedure, the aim of this article is to gather existing evidence and information about this subject as well as to elicit some questions and goals for the future.We searched through the Pub-Med database using the keywords “pancreas and kidney transplantation” combined with “nutritional risk”, “nutritional status”, “malnutrition”, “nutritional intervention”, and “frailty”, finding a total of 4103 matching results. We then narrowed it down to articles written in English with their full text available. We also researched through references of articles most accurately matching our researched terms. The summary of our research, divided into subsections discussing pathophysiology, laboratory markers, risk scales, and nutritional intervention, is as follows.According to ESPEN , malnutrition is “a state resulting from lack of intake or uptake of nutrition that leads to altered body composition (decreased fat-free mass) and body cell mass leading to diminished physical and mental function and impaired clinical outcome from disease” .Different forms of malnutrition can be distinguished according to leading pathophysiological pathways. One of them is disease-related malnutrition with inflammation. Inflammatory response, elicited by disease-specific mechanisms, leads to anorexia, reduced food intake, weight loss, and muscle catabolism ,22,23,24Depending on whether the disease is chronic or acute, the inflammatory response might be milder or stronger. Consecutively, apart from the above-mentioned malnutrition in relation to chronic disease, another form of malnutrition caused by the catabolic state is acute disease- or injury-related ones, and major surgical procedures are considered one of its triggers. Stress metabolic response, consisting of high pro-inflammatory cytokine activity, increased corticosteroid and catecholamine release, and insulin resistance, can lead to fast nutrient storage, which is additionally exacerbated by immobilization and reduced food intake .Therefore, there are many reasons for patients prepared for simultaneous pancreatic–kidney transplantations to have compromised nutritional status.4+ production, resulting in complement activation [First of all, chronic kidney disease is proven to induce a state of chronic inflammation through various pathways. The kidneys’ compromised ability to excrete acid leads to excess NHtivation . Alterattivation ,28. Lasttivation . Taking tivation ,31.Metabolic acidosis that is present in the state of CKD activates proteolysis by activating the ubiquitin–proteasome system and caspase-3, which causes other organ muscle proteins to degrade . AcidosiThe mode of renal replacement therapy might contribute to malnutrition not only by inducing inflammation but also through other mechanisms. Two main modalities are peritoneal dialysis (PD) and hemodialysis (HD). There is evidence that patients undergoing HD have greater muscle mass and mid-arm circumference . It is eThe non-inflammatory mechanisms of malnutrition additionally contribute to its development in CKD patients. Patients with insufficient kidney function (CKD 5 stage) but not yet requiring renal replacement therapy have additional risk factors of decreased protein levels due to dietary limitations . Also woOne of the complications of diabetes is gastroparesis, which is delayed gastric emptying that occurs due to neuronal damage caused by chronic hyperglicemia. The result of this might be early satiety, nausea, and vomiting, all of which additionally impair the patient’s nutritional status ,39. AccoOverweight or obese patients are a group requiring special concern. First of all, elevated BMI (body mass index) is a known risk factor in pancreatic transplant surgery ,42. ObesAs a result of inadequate protein intake and excessive catabolic state, sarcopenia might be present. It is defined as a loss of skeletal muscle mass, strength, and function, leading to increased mortality and worse outcomes in surgical treatment . DiagnosSarcopenias exacerbate obesity-associated insulin resistance and impair glycemia . The medSarcopenia might also be considered as a surrogate of frailty, which has recently been brought to attention as a risk factor for increased mortality and morbidity . The conAlthough the general concept of frailty seems to be widely accepted, tools for its diagnosis are yet to be established. In the literature, there have been numerous scales developed for assessing patients’ frailty in various conditions ,64. SomeDue to the persistent increased awareness of the prevalence and importance of frailty in transplant settings, the American Society of Transplantation developed a working group designed to discuss the problem of frailty in accordance with different organ transplantation, including the kidney, liver, heart, and lung . Apart fThere have been several attempts to establish laboratory markers of malnutrition. One of the first was serum albumin, a protein produced by hepatocytes, with its main function as a carrier molecule for the maintenance of the oncotic pressure of blood. Due to its long half-life time (14–20 days) and its distribution along fluid compartments , daily protein intake did not significantly influence its levels . It has Other possible serum markers of malnutrition might be prealbumin, which is affected by an inflammatory state as well as albumin; however, it acts as a more reliable indicator of decreased protein intake because of its significantly shorter half-life time and its smaller total amount ,76,77. HApart from visceral proteins, total lymphocyte count has also been assessed as a potential malnutrition marker . HoweverSerum lipoproteins might also be a meaningful indicator of nutritional status. Total cholesterol  and non-There is no clinically established scoring system concerning recipient-related factors that are designed specifically for SPKTX transplantations. Tools designed to predict outcomes, such as P-PASS (Preprocurement Pancreas Suitability Score) and PDRI (Pancreas Donor Risk Index), analyze donor-related factors. However, there are still conflicting results regarding their clinical usefulness ,83. TherThe Nutrition Risk Index (NRI) is a diagnostic tool designed to predict surgical outcomes with correlation to malnutrition using the serum albumin level and comparing a patient’s actual weight with the usual one . Among tThe comparison of parameters assessed in the aforementioned index and scales is presented in the table below .Thanks to growing knowledge and evidence of the influence of nutritional status on the results of surgery, much has been said regarding nutritional support as a part of prehabilitation protocols. Prehabilitation, considered a way of improving the patient’s overall health status prior to elective surgery in order to induce the best possible systemic response for injury, consists of exercise, nutrition, and psychosocial components .We can hardly call transplantation either elective or emergency surgery. When considering deceased donation, as is almost exclusively the case in pancreatic transplantation, the exact time of the procedure cannot be perceived for obvious reasons . TherefoEarly enteral nutrition, described as an enteral feed initiated within 24 h of surgery, is one of the main parts of enhanced recovery after surgery (ERAS) protocols in abdominal surgery, regarding, for example, esophageal, gastric, pancreatic, or bowel surgery ,97,98,99The main concern about introducing early enteral nutrition in pancreas transplant patients concerns the presence of high small bowel anastomosis. However, there have not been RCTs evaluating early enteral nutrition in these patients. Retrospective studies indicate the safety of these modes of nutrition, as well as demonstrating better nutritional support and increasing postoperative albumin levels; however, it has to be underlined that there is no clear evidence of benefits in these exact groups of patients . ESPEN gApart from concerns about the influence of enteral input on the healing of anastomoses, there is also the possibility of limited tolerance toward early enteral nutrition due to intestinal dysfunction and gastroparesis, especially in the early postoperative phase, as pancreatic transplantation consists of severe surgical injury to the abdominal cavity. As already mentioned, diabetic patients are at risk of delayed gastric emptying. Altogether, the decreased motility of the small intestine due to an autonomic nervous system might be present . If limiLactobacillus plantarum have also been proven to decrease the rate of infections [It is important to notice that enteral nutrition does not compromise tacrolimus absorption or blood levels . Enteralfections . HoweverThere are some data concerning immuno-modulatory substrates available, although they are limited, and there are no recommendations regarding this subject . In the Malnutrition in the context of simultaneous pancreatic–kidney transplantation seems to be complex and still a poorly investigated problem. Since SPKTX is highly qualified and also has a small volume procedure, it is difficult to obtain data from large cohorts of patients. Considering the complexity of this surgical procedure and the severity of underlying diseases with their intense metabolic component, the patient’s nutritional status seems to significantly influence results. Consequently, nutritional risk assessments should be a part of routine care in patients who qualify for transplantation. There are numerous tools calculating malnutrition, differing in their components and assessed parameters; therefore, the most reasonable approach seems to be joint evaluation. Its usefulness and predictive value in patients undergoing simultaneous pancreas–kidney transplantation requires further investigation.


In multivariate analysis, age  and significant fibrosis  remained independently associated with GH, regardless of the presence of metabolic alterations and nephrotoxic drugs. GH, an early marker of renal damage, is highly prevalent in MASLD and is associated with hepatic fibrosis. GH may be considered an early marker of both liver and renal disease and its recognition could prompt the management of risk factors aimed at preventing the progression of both hepatic and renal disease.Glomerular hyperfiltration (GH) is an increase in the glomerular filtration rate, possibly progressing to chronic kidney disease (CKD). Metabolic-associated steatotic liver disease (MASLD) is linked to an increased risk of CKD, especially if fibrosis is present; however, the association between GH and MASLD has not been explored. To evaluate GH prevalence in MASLD and its possible correlation with liver fibrosis. 772 consecutive patients with ultrasound MASLD  were enrolled. GH was defined as estimated glomerular filtration rate (eGFR) greater than the upper quartile of values in the cohort. Liver stiffness measurement (LSM) by FibroScan ≥ 7.2 kPa suggested liver fibrosis. GH was present in 20% of patients, liver fibrosis in 30%. In total, 53.4% of the cohort was obese, 40.9% hypertensive, 36.3% diabetic and 70.8% dyslipidaemic. GH patients compared to non-GH were significantly younger (38.4 ± 8.3 vs. 49.5 ± 7.7,  Glomerular hyperfiltration (GH) can be defined as a supraphysiological elevation in the glomerular filtration rate (GFR) that occurs when the single-nephron glomerular filtration rate (SN-GFR) increases in all or some kidney nephrons. Persistent increases in the SN-GFR can eventually lead to proteinuria, glomerulosclerosis and decline in kidney function . TherefoIn addition, GH has also been associated with other pathological conditions, such as dementia , sleep dThe metabolic alterations related to GH also predispose to the accumulation of fat in the liver, configuring the condition of hepatic steatosis . In JuneMASLD includes several stages of liver disease, possibly progressing towards metabolic-associated steatohepatitis (MASH), cirrhosis and end-stage liver disease ,10. FurtAs GH and MASLD share the same cardiovascular and metabolic risk factors, a possible association between these two conditions could have been expected. Nevertheless, data in literature on this topic focus on the previous definition of NAFLD, are scarce and include heterogeneous and small cohorts, usually using non-invasive scores for the diagnosis of hepatic steatosis.Therefore, the aim of our study is to evaluate the prevalence of GH and its associated factors in a wide multicentric adult population of ultrasound-proven MASLD subjects, as well as a possible positive correlation between GH and advanced forms of liver disease.Out of 1497 MASLD patients evaluated, 772 subjects were enrolled according to the selection criteria .> 110 mL/min) was present in 152 (19.6%) patients, with mean GFR of 96.6 ± 14.8 mL/min, according to the CKD-EPI formula. As for metabolic comorbidities, more than half of the cohort was obese, 40.9% presented hypertension, 36.3% T2DM and 70.8% dyslipidaemia. As for liver disease, 29.5% of the cohort presented a severe grade of steatosis at US and the mean CAP values were 316 ± 56 dB/m, while presence of liver fibrosis by LSM  was present in 234 (30.3%) patients, with a median value of 7.6 kPa (IQR 2.2–52.2).The general characteristics of the whole population are described in p < 0.001), whereas no difference was observed concerning smoking status or ethnicity. Similarly, prevalence of all metabolic comorbidities, except for presence of hypertension (higher in non-hyperfiltrating subjects), was superimposable between the two groups, as well as use of any antihypertensive drugs, including angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs), diuretics or statins.As reported in p = 0.007), as well as increased LSM values  were observed in the GH group compared to its counterpart. Similarly, a higher prevalence of fibrosis by LSM > 7.2 kPa was present in hyperfiltrating patients compared to those who did not .As for liver disease, a significantly higher prevalence of severe steatosis   were independently associated with the presence of GH, whereas no association of other metabolic features was found. Interestingly, the independent association with LSM was consistent even after adjusting for ACEi/ARBs or diuretic therapy.As reported in When considering the presence of liver fibrosis by FibroScan  instead of LSM expressed as linear variable, fibrosis remained independently associated with the presence of GH  , the Metabolic and Liver Disease Centre of the Policlinico Hospital of Milan  and the Royal Free London NHS Foundation Trust, Sheila Sherlock Liver Centre  were enrolled according to inclusion and exclusion criteria.® technical limitations.Inclusion criteria were age >18 years and ultrasound (US)-proven MASLD. Exclusion criteria were GFR < 60 mL/min, age > 65 years (we arbitrarily chose this age threshold for possible confounders linked to a high burden of comorbidities in elderly population), other causes of liver disease except MASLD , use of steatosis-inducing drugs and decompensated cirrhosis. Similarly, patients with congestive heart failure, free abdominal fluid or pregnancy were also excluded, according to FibroScanThe study protocol was approved by the Institutional Ethics Committee of Verona and Milan  (2524CESC for Verona and N-0006778-U for Milan), while in London (UK) it was a retrospective evaluation as part of an audit. All patients provided written informed consent to participate to the study according to the ethical guidelines of the 1975 Declaration of Helsinki.At enrolment, anthropometric measurement, medical history, smoking habits and use of current therapy (including antihypertensive agents and statins) were recorded for each participant.2 defined the presence of overweight and obesity, respectively. Hypertension was diagnosed by blood pressure ≥140/90 mmHg or use of any antihypertensive drug and dyslipidaemia by low-density lipoprotein (LDL)-cholesterol > 100 mg/dL, triglycerides > 150 mg/dL and/or high-density lipoprotein (HDL)-cholesterol < 40 mg/dL for men and 50 mg/dL for women, or use of lipid-lowering drugs. Type 2 diabetes was diagnosed by fasting glucose > 126 mg/dL in more than two consecutive measurements or a single value of >200 mg/dL or a glycated haemoglobin (HbA1c) > 6.5% (48 mmol/mol), as well as therapy with insulin or oral/injective hypoglycaemic agents . The equation has been validated in populations with normal as well as low GFR [2 * BSA)/1.73 m2 [The estimated glomerular filtration rate (eGFR) was calculated using the new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, developed in 2021 ,30. The  low GFR . Accordi/1.73 m2 . BSA was/1.73 m2 .Glomerular hyperfiltration was defined as eGFR ≥ the upper quartile of our population, as reported in previous studies .Abdominal US was performed at enrolment by three (one for each centre) experienced sonographers using a 3.5 MHz convex-array probe. Hepatic steatosis was classified as absent, mild, moderate or severe according to the following accepted criteria: hepatorenal echo contrast, liver brightness, deep attenuation and vascular blurring ,35.®, Echosens, Paris, France), using the XL probe for indeterminate measurements with the M one. Results were expressed as liver stiffness measurement (LSM) in kPa and were considered valid if the interquartile range did not exceed 30% of the median value [Liver stiffness measurement was assessed using transient elastography , which is used to quantify hepatic steatosis and is expressed as dB/min, was obtained simultaneously to LSM.During FibroScan10. Categorical variables were compared using the Chi-square test. Logistic multivariate regression analyses were performed to determine if any anamnestic or clinical variables could be independently associated with hyperfiltration (odd ratio (OR), with a confidence interval (CI) of 95%). The variable selection was performed through sequential replacement (a stepwise method), which consists of a combination of backward and forward techniques. If the p-value was less than 0.05 or above 0.1, the covariates were, respectively, included and excluded from the regression model. Jamovi 2.2.5 solid version was used for all data analyses. All tests were 2-sided, and p-values < 0.05 were considered statistically significant.Continuous variables are presented as mean ± standard deviation or median (interquartile range) based on data distribution. Categorical variables are expressed as percentages. Variables with non-normal distribution were transformed in Log®, was independently associated with GH, a marker of early renal damage. This would open a new prospective in the diagnostic scenario of patients with MASLD. In fact, if, on the one hand, indication to screen MASLD patients for CKD, defined by a decline in GFR, is established, on the other hand, no attention has been paid to date to hyperfiltration, which often precedes CKD. Therefore, screening MASLD subjects for abnormally elevated GFR values could foster an earlier recognition of a possible risk of CKD development. On the other hand, detection of increased GFR in outpatient clinics, may allow the prompt referral of patients to a hepatology setting, prompting actuating intervention strategies able to prevent the occurrence of advanced hepatic and renal damage. This could have an impact either on health or economic aspects given the high burden of cardiovascular morbidity and mortality driven by both MASLD and CKD. Given the retrospective nature of this study, further prospective studies are necessary to validate our findings.In conclusion, this is the first study demonstrating the relationship between hepatic fibrosis and renal dysfunction in precocious stages defined by GH in a wide cohort of MASLD subjects. We have further demonstrated that hepatic fibrosis, diagnosed by FibroScan


Atrial fibrillation (AF) and chronic kidney disease (CKD) often coexist and share an increased risk of thrombo-embolism (TE). CKD concomitantly predisposes towards a pro-haemorrhagic state. Our aim was to evaluate the prognostic value of CKD in patients undergoing percutaneous left atrial appendage occlusion (LAAO).n = 1089), CKD stage 3 (n = 796), CKD stage 4 (n = 170), and CKD stage 5 (n = 69) based on the estimated glomerular filtration rate at baseline. The primary endpoint included cardiovascular (CV) mortality, TE, and major bleeding. The expected annual TE and major bleeding risks were estimated based on the CHA2DS2-VASc and HAS-BLED scores. A non-significant higher incidence of major peri-procedural adverse events (1.7 vs. 2.3 vs. 4.1 vs. 4.3) was observed with worsening CKD (P = 0.14). The mean follow-up period was 13 ± 7 months (2226 patient–years). In comparison to CKD stage 1+2 as a reference, the incidence of the primary endpoint was significantly higher in CKD stage 3 , CKD stage 4 , and CKD stage 5 . Left atrial appendage occlusion led to a TE risk reduction (RR) of 72, 66, 62, and 41% in each group. The relative RR of major bleeding was 58, 44, 51, and 52%, respectively.A total of 2124 consecutive AF patients undergoing LAAO were categorized into CKD stage 1+2 (Patients with moderate-to-severe CKD had a higher incidence of the primary composite endpoint. The relative RR in the incidence of TE and major bleeding was consistent across CKD groups.  We report the largest, real-world, multicentre cohort of LAAO patients categorized based on baseline kidney function.Left atrial appendage occlusion procedural success was high, irrespective of the severity of kidney dysfunction at the time of LAAO procedure.Left atrial appendage occlusion led to a relative risk reduction in the incidence of TE and major bleeding that was consistent across CKD groups, irrespective of their very different risk profiles at baseline.2DS2-VASc and HAS-BLED scores.Left atrial appendage occlusion may provide an effective TE and bleeding prevention, irrespective of the baseline kidney function, when compared with the expected rates for patients with similar CHAFuture randomized studies comparing the efficacy of LAAO vs. oral anticoagulation in patients with CKD are warranted.1 The benefit of left atrial appendage (LAA) exclusion from systemic circulation has been further corroborated by the results of the recent Left Atrial Appendage Occlusion during Cardiac Surgery to Prevent Stroke (LAAOS III).2 This randomized trial showed a significant beneficial effect on thrombo-embolic (TE) risk in cardiac surgery candidates with AF undergoing concomitant appendage exclusion.In high-risk patients with non-valvular atrial fibrillation (AF), stroke prevention via percutaneous left atrial appendage occlusion (LAAO) has been demonstrated to be non-inferior to oral anticoagulation with either vitamin K antagonists and direct oral anticoagulants (DOACs).3–5 LAAO has now become a widespread therapy for stroke prophylaxis. Atrial fibrillation patients currently eligible for LAAO have multiple comorbid conditions, chronic kidney disease (CKD) being one of the most prevalent. Indeed, AF and CKD often coexist and are both associated with an increased risk of TE events and mortality, as they share common risk factors, including hypertension, coronary artery disease (CAD), and diabetes mellitus.6–9 Renal functional impairment concurrently contributes to an increase in haemorrhagic risk as kidney function declines. Chronic kidney disease-related haemorrhagic diathesis has a multifactorial pathophysiology .As a result of a growing body of evidence on the efficacy of LAAO and the remarkable safety profiles of currently available percutaneous devices,10 The objective of this registry was to elucidate the impact of CKD on procedural success and clinical outcomes after LAAO.This bleeding tendency raises a therapeutic conundrum in patients with concomitant AF, as the potential benefit on stroke prophylaxis conferred by oral anticoagulation may be outweighed by an increased risk in major bleeding. In this perspective, LAAO may be a particularly attractive approach in this population, as it may confer TE protection without increasing the risk of bleeding.2 score of ≥2 or a CHA2DS2-VASc score of ≥3.The registry included 2192 consecutive patients with non-valvular AF scheduled for percutaneous LAAO with a Watchman 2.5 device  at eight different international centres  between December 2014 and June 2020. Eligibility criteria included ≥18 years of age with non-valvular AF who were unsuitable for long-term oral anticoagulation  and had a CHADS12 Written informed consent was obtained from each patient before every interventional procedure.Clinical characteristics, procedural variables, and follow-up data were extracted from Institutional Review Board-approved, locally maintained, prospective databases. The Watchman implantation technique has been previously described elsewhere.2) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation: 141 × minα × max − 1.209 × 0.993Age × 1.018 [if female] × 1.159 [if black], where serum creatinine and Age are expressed in mg/dL and years, respectively, κ is 0.7 for females and 0.9 for males, and α is −0.329 for females and −0.411 for males.Patients were categorized according to the estimated glomerular filtration rate (eGFR) at the time of implantation. The eGFR (mL/min/1.73 m2), CKD stage 3 (eGFR 30 to 59 mL/min/1.73 m2), CKD stage 4 (eGFR 15 to 29 mL/min/1.73 m2), and CKD stage 5 .Patients were divided into 4 study groups: CKD stage 1+2 , peripheral embolism, major peri-procedural bleeding, myocardial infarction, device embolization, acute heart failure, pericardial effusion requiring surgery or percutaneous drainage, retroperitoneal haematoma or other major vascular complications requiring surgical repair.Overall peri-procedural adverse event rate was calculated including all the above-mentioned major peri-procedural complications plus groin haematoma and pericardial effusion not requiring intervention.The primary efficacy endpoint included a composite of cardiovascular (CV) death, stroke, TIA, peripheral embolism, clinically significant bleeding during follow-up.13 and included major and clinically relevant minor events.Clinically significant bleeding was defined according to the International Society of Thrombosis and Haemostasis criteriaThe incidence of acute kidney injury (AKI) was assessed in all patients not receiving regular dialysis before the procedure and with creatinine assessment within 7 days before and between 24 and 48 h after the procedure.Post-implant antithrombotic regiment and follow-up strategies were left to each operator’s preference.13 Major bleeding included: fatal bleeding, symptomatic bleeding in a critical area or organ , and/or bleeding causing a fall in haemoglobin ≥2 g/dL or requiring transfusion of ≥2 units of packed red blood cells or whole blood. Clinically relevant minor bleeding included bleeding requiring a clinical response, such as hospital admission, physician guided medical or surgical treatment, or need for antithrombotic therapy changes.Bleeding events were classified according to the International Society of Thrombosis and Haemostasis criteria as major, clinically relevant minor, and non-clinically relevant minor bleeding.χ2 tests for categorical covariates; non-parametric test of Kruskal–Wallis was used to compare non-normally distributed continuous variable. For all tests, a P-value < 0.05 was considered statistically significant. Association between CKD stage and clinical endpoints was examined using the Cochran–Armitage trend test.For continuous variables, descriptive statistics were provided , while median (interquartile range) was used for non-normal data. Categorical data were described as number (percentage). Comparisons among groups were performed using Pearson’s bivariate test and P-value < 0.10) in the univariate analysis were included in the multivariate analysis.Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to estimate the association between CKD and other clinical findings  using logistic regression analysis. Univariate and multivariate analyses were performed, and all the variables with a significant association . Further details are reported in the The Kaplan–Meier method was used to estimate cumulative event rates in the four groups. Differences in each group were compared using log-rank tests. CKD stage 1+2 was used as a reference to calculate the prognostic values of baseline renal function using a Cox regression hazard model. The expected annual TE and major bleeding risks were estimated based on the CHATables S1 and S2.We enrolled 2192 consecutive patients with an indication to percutaneous LAA occlusion. Device implant was unsuccessful in 68 (3.1%) patients; baseline characteristics and predictors of implant success are reported in 2DS2-VASc: 4.7 ± 1.4; HAS-BLED: 3.5 ± 1.0). Among them, 51.3% (n = 1089) were categorized as CKD stage 1+2, 37.5% (n = 796) as CKD stage 3, 8.0% (n = 170) as CKD stage 4, and 3.2% (n = 69) as CKD stage 5. Of those with end-stage CKD, 72.5% (n = 50) were on haemodialysis.The final study cohort with successful Watchman implantation included 2124 patients , and other risk factors for stroke and bleeding were statistically significant. These variations in baseline characteristics led to significant differences in CHA2DS2-VASc (P < 0.001) and HAS-BLED (P < 0.001) among groups.Baseline and procedural data are depicted in Table 2) significantly increased in parallel with CKD severity among groups .Procedural duration .A non-significant higher incidence of major peri-procedural adverse events (1.7 vs. 2.3 vs. 4.1 vs. 4.3) was observed with worsening baseline kidney function  and HAS-BLED ≥5  were the only independent predictors of major complications (Table 3).At multivariate analysis, history of CAD .Among minor complications, the incidence of groin haematoma in each group was 0.6, 1.3, 2.4, and 2.9, respectively (P = 0.01).Overall peri-procedural complications (major and minor) were significantly different among groups . There were 170 (8.3%) patients who met the primary composite endpoint of CV death, stroke, TIA, peripheral embolism, clinically significant bleeding for a total of 177 clinical events (8.0 events/100PY) (see Table S5). The incidence of the primary endpoint at 1 year and 2 years significantly increased with worsening CKD across the four study groups . In comparison to CKD stage 1+2 as a reference, the incidence of the primary endpoint over the entire follow-up period was significantly higher in CKD stage 3 , CKD stage 4 , and CKD stage 5 .Follow-up data were available in 2039 patients. The mean follow-up period was 13 ± 7 months  and was not different among groups (Table 4), CKD stage 3 , CKD stage 4 , CKD stage 5 , as well as AKI  were associated with an increased risk of the primary endpoint in the multivariate model. The influence of different post-procedure antithrombotic strategies on the composite outcome is reported in Table S6.12In the Cox regression analysis .A linear increase in event rates for TE events, stroke/TIA, and clinically relevant bleeding was observed among the four groups; however, the differences were not significant (Table S5). The comparison between the expected annual TE and major bleeding risks and the annualized observed risk are reported in the supplemental results and in Figure S2.The annualized rates of TE events were 2.5% in CKD stage 1+2, 3.1% in CKD stage 3, 4.0% in CKD stage 4, and 6.6% in CKD stage 5, respectively (see Table S5) increased in parallel with CKD severity among groups . A significant difference in CV mortality was observed among CKD stage 4 and CKD stage 5 , compared to CKD stage 1+2 patients .The annualized CV mortality rates .Minor bleeding occurred in 2.8% of patients with CKD stage 1+2, 4.4% with CKD stage 3, 5.8% with CKD stage 4, 9.2% with CKD stage 5  of our cohort; among them, 239 (23.1%) patients had severely decreased renal function or organ failure.Left atrial appendage occlusion patients with eGFR < 60 mL/min/1.73 mThe burden of cardiovascular comorbid conditions was significantly higher in patients at more advanced stages of CKD; nonetheless, procedural success was high, irrespective of the severity of kidney dysfunction at the time of LAAO procedure.A higher incidence of major peri-procedural adverse events was observed with worsening baseline kidney function; however, the differences were not statistically significant.Chronic kidney disease classification was a strong predictor of the primary composite endpoint of CV mortality, stroke, TIA, peripheral TE events, and major bleeding.2DS2-VASc and HAS-BLED scores.Left atrial appendage occlusion provided an effective TE and bleeding prevention, irrespective of the baseline kidney function, when compared with the expected rates for patients with similar CHA14–19In our cohort, Watchman implantation procedure was highly successful (96.9%); this finding is concordant with other recent reports on the same occlusion device.P = 0.14). This observation is consistent with a previous study in 1014 patients undergoing LAAO with an Amplatzer Cardiac Plug.21 Although major complications were similar among CKD groups, the rate of overall complications was significantly higher in patients with more advanced stages of CKD. A similar significant increment associated with CKD severity was also observed for minor vascular complications/groin haematoma, which was likely the main determinant for the higher prevalence of total peri-procedural complications. Two large studies have recently reported higher procedural complications and longer hospital stays in CKD patients included in the National Inpatient Sample and Nationwide Readmissions Databases.23 The partial discrepancy among our findings and these previous observations may be attributed to the high level of experience with LAAO of the operators involved in our study. Additionally, these studies were limited to first generation devices; next generation LAA occluders (e.g. Watchman FLX) have recently demonstrated a remarkable safety profile25 and may be particularly beneficial in frail populations, such as those with severe/end-stage CKD.Additionally, Watchman implantation was a fairly safe procedure, as demonstrated by a mean major complication rate of 2.2%. Chronic kidney disease severity predicted neither successful device deployment nor major peri-procedural complications. Notably, despite a different cardiovascular and metabolic risk profile at baseline, the differences in major complications were not statistically significant . The resulting concomitant predisposition to both thrombosis and bleeding in AF patients with CKD emphasizes the need for a better understanding of the risk/benefit ratio of currently available pharmacological and non-pharmacological strategies for stroke prophylaxis.7Chronic kidney disease affects approximately 13–15% of the population worldwide and is a well-known, independent risk factor for cardiovascular disease and all-cause mortality.10Percutaneous LAAO has been proven to be non-inferior to oral anticoagulation for preventing AF-related major TE and bleeding events; furthermore, recent long-term data showed a significant reduction of non-procedural bleeding with LAAO.30 Two large studies using the Nationwide Readmissions22 and National Inpatient Sample23 Databases have recently investigated the association between kidney function and in-hospital/short-term outcomes; however, no data were provided on the incidence of TE events and bleeding in the long-term. Other studies have previously attempted to assess the association between kidney function and LAAO efficacy but their observations were limited by the small number of patients with more advanced stages of CKD.30However, there have been only a few studies assessing the impact of kidney function on peri-procedural and clinical outcomes in patients undergoing LAAO; their main limitations are the small number of patients with more advanced forms of kidney dysfunction and the relatively short follow-up duration.2); Among them, 239 (23.1%) patients had severe CKD or failure (eGFR < 30 mL/min/1.73 m2), 50 (20.9%) of whom in chronic dialysis. On average, patients were followed for 13 ± 7 months. The degree of kidney dysfunction was associated with mid/long-term prognosis of patients undergoing LAAO. Specifically, the incidence of the primary endpoint over the entire follow-up period was significantly higher in CKD stages 3, 4, and 5, compared to CKD stage 1+2. Baseline kidney function was also associated with a significantly higher incidence of CV mortality in advanced-stage CKD (stages 4 and 5).The present analysis included 1035 patients with at least moderate loss of kidney function  independently predisposing to cerebrovascular events, irrespective of the presence of AF. In patients on OAC, either DOACs or vitamin K antagonists, a paradoxical increased rate of ischaemic stroke has been described among patients with a moderate/severe decrease in eGFR, as well as end-stage renal disease.post-hoc nature of this analysis introduces all the inherent limitations related to its design. (2) Our observations on the prevalence of peri-procedural AKI were based on a single creatinine assessment at 24–48 h after the procedure, which might have led to an underestimation of the incidence of AKI. (3) All patients included in the study received a Watchman device; therefore, our findings cannot be generalized to other occlusion devices. (4) The calculation of eGFR using the CKD-EPI equation may be limited by age; however, this method proved superior to other equations in terms of both kidney function estimation and risk prediction. (5) The number of patients with advanced CKD was small, compared to the other groups. Nonetheless, this study includes the largest cohort of patients with severe and end-stage CKD. (6) Our cohort included only patients with LAAO, and no comparison was performed with other pharmacological strategies for stroke prophylaxis.(1) Although data were extracted from a database of prospectively collected data, the In this real-world, multicentre cohort of LAAO patients categorized based on baseline kidney function, CKD was associated with a higher incidence of overall, but not major, peri-procedural complications. Patients with moderate-to-severe CKD also had a higher incidence of the primary endpoint of CV mortality, stroke, TIA, peripheral TE, and major bleeding. The relative RR in the incidence of TE and major bleeding was consistent across CKD groups. Future randomized studies comparing the efficacy of LAAO vs. oral anticoagulation in patients with CKD are warranted.euad315_Supplementary_DataClick here for additional data file.


Hemodynamic monitoring is imperative for patients with cardiogenic shock undergoing Intra-aortic Balloon Pump (IABP) therapy. Blood pressure monitoring encompasses non-invasive, invasive peripheral arterial pressure (IPAP), and invasive central aortic pressure (ICAP) methods. However, marked disparities exist between IPAP and ICAP. This study examined the discrepancies between IPAP and ICAP and their clinical significance.A retrospective analysis was conducted on cardiogenic shock patients who underwent IABP therapy and were admitted to the Coronary Care Unit (CCU) of a tertiary hospital in China from March 2017 to November 2022. The Bland–Altman plot illustrated the discrepancy between IPAP and ICAP. A clinically significant difference between ICAP and IPAP measurements was defined as ≥ 10 mmHg, which could necessitate alterations in blood pressure management according to current guidelines that recommend maintaining a mean arterial pressure (MAP) ≥ 70 mmHg.p = 0.013) and age ≥ 60 years  were associated with an increased likelihood of a clinically significant MAP discrepancy. Conversely, a history of coronary heart disease was associated with a decreased likelihood .In total, 162 patients were included in the final analysis. In patients without vasopressors, the difference between ICAP and IPAP was 5.73 mmHg , whereas, in patients with vasopressors, it was 4.36 mmHg . ICAP measurements exceeded IPAP in patients undergoing IABP therapy. However, the difference was not statistically significant between the two groups. Multivariate logistic regression revealed that higher serum lactate levels (Odds ratio [OR], 1.14; 95% confidence interval [CI], 1.03–1.27; Notable discrepancies between ICAP and IPAP measurements exist in cardiogenic shock patients undergoing IABP therapy. ICAP exceeds IPAP, and factors such as age ≥ 60 years, elevated lactic acid levels, and absence of coronary heart disease contribute to this discrepancy. Enhanced vigilance is warranted for these patients, and the consideration of peripheral invasive monitoring in conjunction with IABP therapy is advised.The online version contains supplementary material available at 10.1186/s12872-023-03479-2. Cardiogenic shock (CS) constitutes a critical condition characterized by the heart’s inadequate contractility, which compromises the maintenance of sufficient cardiac output due to insufficient myocardial oxygenation and elevated cardiac workload . ConsequGlobally, over 4.5 million cases have been managed using IABP, including more than 300,000 in China alone, and the usage rate is witnessing an annual escalation between 13 and 20%. IABP entails the deployment of a balloon catheter within the descending aorta, which is regulated by an external device. During diastole, balloon inflation elevates diastolic pressure, which fosters improved coronary circulation. Conversely, deflating the balloon prior to systole diminishes the resistance against systolic output, consequently enhancing myocardial oxygenation and reducing oxygen consumption by mitigating cardiac workload.Efficient management of IABP necessitates the monitoring of numerous parameters, among which the assessment of hemodynamic status is of utmost importance –9. HealtStudies indicate that SBP and DBP measurements can exhibit a discrepancy of 10–15 mmHg when obtained from central versus peripheral sites. This variance arises as the pulse travels through the arterial system, leading to increased SBP and potentially decreased DBP due to the reflection of the pressure wave. For instance, peripheral SBP, as measured from the radial artery, is usually higher than aortic SBP, a phenomenon termed the physiological amplification of central pulse pressure . HoweverAccurate blood pressure monitoring is indispensable for CS patients undergoing IABP therapy, as it imparts critical insights into the hemodynamic status and informs therapeutic decision- making . NotablyIn our study, we aimed to investigate the discrepancy between peripheral blood pressure and CAP in a large patient population undergoing IABP therapy with vasopressors, compared to a control cohort treated with IABP without vasopressors. We hypothesized that the administration of vasopressors might be associated with amplified discrepancies between IPAP and ICAP measurements, potentially impacting clinical management strategies for patients receiving IABP.This study was approved by the ethics committee of Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology(TJ-IRB20220955). Informed consent was waived due to the retrospective nature of the study and the utilization of anonymized data from electronic medical records.This was a single-center, retrospective study conducted at the CCU of a tertiary-level general hospital in China, which predominantly serves patients with severe coronary heart disease (CHD), severe arrhythmia, cardiac insufficiency, cardiomyopathy, fulminant myocarditis and other severe cardiac ailments. Upon admission to the CCU, attending physicians promptly initiate electrocardiogram (ECG) monitoring. Typically, patients necessitating regular arterial blood gas analyses or intensive hemodynamic monitoring are subjected to invasive arterial pressure monitoring. Furthermore, as stipulated by the CCU’s clinical protocol, critically ill patients must have blood pressure measurements and vital sign documented at a minimum hourly frequency.The study population comprised patients admitted between March 2017 and November 2022, who underwent arterial blood pressure monitoring. Inclusion criteria entailed: (1) age over 18 years, (2) a confirmed diagnosis of cardiogenic shock, and (3) treatment with IABP with a counterpulsation ratio of 1:1, ensuring the equipment functioned optimally. Exclusion criteria encompassed patients diagnosed with hypertensive emergencies  , severe IABPs were percutaneously inserted through the femoral artery under fluoroscopic guidance by an interventional physician. Following IABP treatment in the catheterization room, patients were transferred to the CCU. The system was calibrated to zero at the level of the right atrium, along the midaxillary line, and then secured. Prior to data collection, the arterial pressure measurement device underwent a routine "square wave test". ICAP data were acquired from the IABP console , with the most recent three measurements being selected post-successful implantation . The average of these three measurements was compared.IPAP monitoring was conducted using a multi-function monitor  and a disposable pressure sensor set . Experienced nurses performed arterial punctures with a 20G arterial indwelling needle . It is imperative to ensure the absence of air bubbles in the pressure measurement system and to prevent the pipeline from twisting or folding. The system was calibrated to zero at the level of the right atrium, along the midaxillary line, and then secured. A "square wave test" of the arterial pressure measurement device was routinely performed before data acquisition. Exclusion criteria included: (1) an unsmooth catheter with incomplete needle sleeve insertion, and (2) more than two punctures in the same area or the presence of local hematomas at puncture and catheter placement sites. Blood pressure data were collected concurrently with the CAP measurements.Data were extracted from electronic medical records. We first collected demographic data such as age, gender, diagnosis, past medical history, and body mass index. The laboratory information system provided serum lactate and left ventricular ejection fraction (LVEF) values, which were extracted from the first medical records at the time of admission. Clinical data included three measurements each of CAP and peripheral arterial pressure, heart rate, vasopressor administration, duration of IABP treatment, and arterial catheterization. Additionally, data regarding catheterization complications during hospitalization were extracted. Complications of peripheral arterial catheterization were defined as infection, bleeding at the puncture site, hematoma and aneurysm. IABP-related complications included limb ischemia, thrombosis, bleeding and hematoma at the puncture site, infection, etc. Details of the data extraction form see Supplemental file The primary outcome of this study was an analysis of the discrepancies between ICAP and IPAP measurements. The secondary outcome concerned the clinical relevance of the discrepancies between ICAP and IPAP. Clinical relevance was defined by: a) a difference of 10 mmHg or more between the two measurements, and b) potential alterations in blood pressure management in accordance with current guidelines . For exaDescriptive analyses were performed to present continuous variables as mean ± standard deviation (SD) or median with interquartile range (IQR), and categorical variables as percentages. The paired t-test was used to assess the difference between ICAP and IPAP within the same group. To evaluate differences between two groups (patients with or without vasopressor treatment), independent t-tests or Mann–Whitney U tests were employed. Categorical data comparisons were conducted using Chi square tests.p-value > 0.05 indicating a good fit.The Bland–Altman plot was used to graphically depict the discrepancies between ICAP and IPAP. Forward stepwise multivariable logistic regression was employed to ascertain if independent variables could predict the outcomes of interest. Various independent variables potentially associated with blood pressure were controlled in the regression analysis. Additionally, probit regressions were conducted to estimate the proportion of patients exhibiting the primary outcome per unit change in continuous variables. The fit of the multivariate logistic regression models was assessed using Hosmer-Leeshawn tests, with a p value < 0.05 was deemed statistically significant.Analyses were performed using Minitab version 19  and GraphPad Prism 8.3 . A two-tailed A total of 320 patients who underwent IABP between March 2017 and November 2022 were initially enrolled in this study. Of these, 162 patients were included in the final analysis, comprising 71 patients who did not receive vasopressors and 91 patients who did  of the participants were male. No statistically significant differences were observed in demographic characteristics such as age, gender, and body mass index, or in clinical factors associated with the location of the arterial catheter   of the patients exhibited clinically relevant MAP differences (≥ 10 mmHg) that could necessitate alterations in clinical management. Among the patients requiring vasopressors, 20% (18/91) had clinically relevant MAP differences, in contrast to 13% (9/71) of those not requiring vasopressors (7/162 of p = 0.013). Furthermore, patients aged 60 years or older had 13 times higher odds compared to those younger than 45 years . Conversely, patients with CHD were less likely to have clinically relevant MAP differences . The logistic regression model demonstrated a good fit (Hosmer–Lemeshow p = 0.65), and no collinearity was detected as the variance inflation factors for the final variables were below 10  of patients would present a clinically relevant MAP difference at a serum lactate level of 2 mmol/L , whereas patients with CHD were less likely . The model did not exhibit collinearity (Hosmer- Lemeshow p = 0.13). The results are shown in Table Of the study population, 40% (64/162) demonstrated a MAP difference of 10 mmHg or greater between the two blood pressure measurement methods. Multivariate logistic regression analysis indicated that patients aged over 60 years were significantly more likely to have such MAP differences  of the patients demonstrating a variance in MAP between ICAP and IPAP measurements. According to the Bland–Altman plot, the IPAP-derived MAP was consistently lower than that obtained through ICAP, irrespective of vasopressors administration. Consequently, in scenarios where IABP monitoring is infeasible due to sensor failure, transducer malfunctions, or console screen visibility issues, clinicians should remain vigilant to the possibility of underestimating blood pressure by up to 10 mmHg when using invasive MAP measurements as an alternative.1 receptors, while dopamine acts on α, β, and dopamine receptors. The discrepancy in findings between our study and prior research may be attributed to differences in study populations and the fact that our study did not differentiate between various types of vasopressors. Moreover, a recent study by Kim et al. suggested that the severity of vasopressor usage plays a role [Furthermore, our study contradicts previous research regarding the influence of vasopressors on the discrepancy between ICAP and IPAP. Tran et al. suggested that vasopressors contributed to a 6.4-fold increase in clinical MAP compared to cases without vasopressors . Contrars a role . Our cohThe logistic regression analysis revealed a positive association between higher serum lactate levels, age ≥ 60 years, and the absence of CHD with an increased likelihood of a clinically relevant difference in MAP as measured by IPAP and ICAP. There is a scarcity of research investigating the factors associated with this clinically relevant difference in MAP among CS patients undergoing IABP therapy. In terms of serum lactate, our study corroborates the findings of Tran et al., where serum lactate levels were identified as a common independent risk factor for clinically relevant MAP differences in septic patients . MoreoveAdditionally, we observed a 7% complication rate associated with IPAP (11/162), while it was 6% for ICAP (10/162). These findings align with previous reports, which state that the complication rate for patients undergoing IABP therapy ranges from 4.7% to 31.0%, with access site bleeding being the most prevalent complication . ChristeDespite providing important insights into the differences between ICAP and IPAP measurements under various conditions and their potential impact on clinical management, this study has limitations. First, this was a retrospective study and data were derived from electronic medical records. It does not confirm causal relationships. Second, being a single-center study with a limited sample size, the findings may not be generalizable. Additionally, propensity score matching was not feasible, and the heterogeneity between patients requiring vasopressors and those who did not may induce bias due to different vasopressor mechanisms. Third, capturing only the three most recent blood pressure measurements post-IABP implantation might not reflect longitudinal trends. Other clinical factors not included in the current study might also influence the results, and the clinical relevance of these differences concerning patient outcomes remains unclear. Future multi-center randomized controlled trials with larger sample sizes, encompassing a broader range of variables and extended follow-up periods, are warranted to solidify the evidence.In conclusion, it is crucial to accurately monitor blood pressure for patients with CS undergoing IABP therapy. However, the consistency between IPAP and ICAP measurements is suboptimal. The current study revealed no statistically significant differences in MAP measurements between the groups treated with or without vasopressors. It is essential for physicians to comprehend the underlying technology and engage in dialogues with providers . In managing CS patients undergoing IABP therapy, particular attention should be paid to individuals aged 60 years or above, exhibiting elevated serum lactate levels, and without a history of CHD, by judiciously adjusting vasopressor dosages and tailoring therapeutic regimens. Furthermore, this study highlight the importance of healthcare professionals employing peripheral invasive monitoring for patients receiving IABP therapy until additional research becomes available. It is vital to avoid premature withdrawal of vasopressors, which may result in insufficient organ perfusion, and to remain vigilant to the risks associated with arterial catheterization.Additional file 1: Supplementary file 1. Data extraction form.Additional file 2: Supplementary file 2. List of independent variables that were included in the multivariate logistic regression that measured the association between clinical factors and clinically relevance of blood pressure monitoring of IABP patients.


This study aims to explore the correlation between central and peripheral thyroid resistance indices and diabetic retinopathy(DR) in patients with type 2 diabetes mellitus (T2DM), so as to provide a clinical basis for the prevention and treatment of diabetic retinopathy.This study retrospectively analyzed 1249 euthyroid patients with T2DM hospitalized in the Department of Endocrinology, Peking University International Hospital from January 2017 to June 2022, including 852 males and 397 females, with an average age of 54.73 ± 13.40 years. According to the degree of DR, the patients were divided into three groups including the no diabetic retinopathy (NDR) group, non-proliferative diabetic retinopathy (NPDR) group and proliferative diabetic retinopathy (PDR) group.p < 0.05). Logistic regression showed that after adjusting for age, body mass index (BMI), sex, diabetes duration, blood pressure, blood lipid, HbA1c, lower level of FT4 was an independent risk factor for DR, high level of TSH, TFQI, TSHI and TT4RI were independent risk factors for DR. Central and peripheral thyroid sensitivity indices have predictive value for DR, the overall predictive accuracy of FT3/FT4 was 0.61 , the overall predictive accuracy of TFQI was 0.66, the overall predictive accuracy of TSHI was 0.66, the overall predictive accuracy of TT4RI was 0.63 .Free thymidine (FT4), thyroid stimulating hormone (TSH), thyroid feedback quantile index (TFQI), thyrotropin-T4 resistance index (TT4RI), thyroid stimulating hormone index (TSHI) and free triiodothyronine/free thyroxine (FT3/FT4) levels among the three groups were significantly different, with the NDR group having lowest TSH, TFQI, TT4QI, TSHI and the highest in the PDR group (all The reduction of central and peripheral thyroid hormone sensitivity is an independent risk factor for DR. These results can help predict the risk of the occurrence and development of DR, which may provide a clinical basis for the prevention and treatment of DR in T2DM patients. In 2019Previous studies have established a clear connection between DM and its associated complications with thyroid hormones (THs). Compared with healthy people, the prevalence of thyroid disease (TD), especially hypothyroidism, in DM patients is higher . CurrentCurrently, there is limited research both domestically and internationally regarding the correlation between impaired TH sensitivity and diabetic complications. Particularly, there is a lack of studies investigating the connection between impaired TH sensitivity and DR. Therefore, this study aims to assess the relationship between THs, central and peripheral TH sensitivity, and DR among euthyroid patients with T2DM. The findings of this research endeavour will offer valuable clinical insights into the prevention and management of DR.2.2.1.The study was approved by the Ethics Committee of Peking University International Hospital and was conducted in accordance with the ethics standards of institutional and national research committees and the 1964 Helsinki Declaration and its later amendments or comparable ethics standards. As the study involved the retrospective analysis of clinical data, the requirement for written informed consent was waived. The number of the ethics approval is 2022-KY-0030-01.2.2.This study retrospectively analyzed 1249 T2DM patients hospitalized in the Endocrinology Department of Peking University International Hospital from January 2017 to June 2022, including 852 males and 397 females. All patients were accorded the diagnostic criteria for diabetes of the World Health Organization (WHO) in 1999 , includi2.3.2.3.1.2) =weight (kg)/body height2 (m2).The data of 1249 patients were retrospectively analyzed, and the general conditions of the patients, including sex, age, height, weight, diabetes duration, systolic blood pressure (SBP), diastolic blood pressure (DBP) and hypoglycemic medications were all recorded. The body mass index (BMI) was calculated using the formula: BMI , fasting blood glucose (FBG), postprandial blood glucose (PBG), triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), serum creatinine (sCr), uric acid (UA), free thymidine (FT4) and free triiodothyronine (FT3) and TSH (thyroid stimulating hormone). HbA1c is determined by high-performance liquid chromatography.The assessment index of THs sensitivity is as follows:(1) TFQI Index:TFQI=CDFFT4-(1-CDFTSH); First rank the FT4 and TSH from the minimum to the maximum. Then, according to the principle of empirical cumulative distribution function (CDF), transform the probability distribution of FT4 and TSH into the probability quantile between 0 and 1. After calculating, the range of TFQI is from − 1 to 1. TFQI is negative, indicating that HPT axis is more sensitive to the change of FT4; a positive value indicates that the HPT axis is relatively insensitive to the change of FT4; 0 indicates that the sensitivity of HPT axis to FT4 is normal.(2) TT4RI: TT4RI was calculated as the formula: TT4RI=FT4×TSH.(3) TSHI: TSHI was calculated as the formula: TSHI = LnTSH + 0.1345 × FT4.The higher the TSHI and TT4RI values, the lower the central sensitivity to THs.(4) FT3/FT4: the higher the FT3/FT4 value, the higher the peripheral sensitivity to TH.2.3.3.All subjects were examined for DR. According to the results, the patients were divided into three groups: no DR (NDR) group, non-proliferative retinopathy (NPDR) group and proliferative retinopathy (PDR) group. The criteria are as follows: NPDR includes the first stage in which small bleeding spots or micro angiomas are found, the second stage in which hard exudation was found and the third stage in which soft cotton sample was found. PDR includes the fourth in which blood accumulation and neovascularization of the retinal vitreous body were found, the fifth stage in which fibrovascular hyperplasia and subsequent vitreous tissue were found and the sixth stage in which traction retinal detachment leads to blindness.2.3.4.p < 0.05 was considered to be statistically significant.Statistical analysis was performed with the SPSS Version 22.0 software . The data were analyzed using the Kolmogorov-Smirnov test, and all variables had a normal distribution and were expressed as the mean ± standard deviation. Multi-group comparisons of the data were compared with the one-way analysis of variance (ANOVA). The statistical description of counting data is based on constituent ratio or rate and comparisons among groups were made using χ2 test. Unconditional logistic regression models were used for univariate and multivariate analysis of the factors, and OR and 95%CI were calculated. The receiver operating characteristic (ROC) curves were plotted and the area under the ROC curve (AUC) was calculated. All statistical tests were performed with two-sided tests, and 3.3.1.p < 0.05). The UA, UACR and eGFR levels among the three groups were significantly different, with the PDR group having the highest UACR and lowest eGFR levels . The HbA1c, FBG and PBG levels among the three groups were significantly different, with NDR group having the lowest HbA1c, FBG and PBG among the three groups . In addition, the FT4, TSH, TFQI, TT4QI, TSHI and FT3/FT4 levels among the three groups were significantly different, with the NDR group having lowest TSH, TFQI, TT4QI, TSHI and the highest in the PDR group . The SBP, DBP, TC, TG, LDL-C, HDL-C, FT3 were not significantly different among the three groups . There was no significant statistical difference in hypoglycemic drugs among the three groups   .3.2.Taking DR as a dependent variable and THs as independent variables, a univariate logistic regression model was established. The results showed that after adjusting for age, BMI, sex, diabetes duration, blood pressure, blood lipid and HbA1c, the indices including TSH, TFQI, TSHI and TT4RI were independent risk factors for DR .3.3.Taking PDR as the dependent variable and THs as the independent variables, a univariate logistic regression model was established. The results showed that after adjusting for age, BMI, sex, duration, blood pressure, blood lipid and HbA1c, the indices including TSH, TFQI, TSHI and TT4RI were independent risk factors for PDR .3.4.The model for predicting the risk of DR with variables including THs and THs sensitivity indices showed that the AUC of the models ranked TSHI (0.66) = TFQI (0.66) > TT4RI (0.63) > TSH (0.62) > FT3/FT4 (0.61) > FT4 (0.59) > FT3 (0.55). The corresponding cut-off points of FT4, FT3, TSH are 16.95 pmol/L, 4.35 pmol/L and 2.38uIU/ml respectively. The corresponding cut-off points of FT3/FT4, TFQI, TT4RI and TSHI are 0.24, 0.44, 44 and 3.57 .3.5.The model for predicting the risk of PDR with variables including THs and THs sensitivity index showed that the AUC of the models ranked TSHI (0.63) =TFQI (0.63) > TT4RI (0.62) > TSH (0.59) > FT4(0.58) > FT3/FT4 (0.54) > FT3 (0.51). The corresponding cut-off points of FT4, FT3, TSH are 18.05 pmol/L, 3.65 pmol/L and 2.36uIU/ml respectively. The corresponding cut-off points of FT3/FT4, TFQI, TT4RI and TSHI are 0.28 0.44,46.18 and 3.29 .3.6.The multivariate predictive model was established with DR as the dependent variable and age, duration, UA, Egfr, HbA1c, FT3/FT4, TFQI, TT4QI and TSHI as independent variables. The regression equation is logit (DR) = −3.23727 − 0.00934 × age +0.07810 × duration +0.00170*UA −0.00148 × eGFR +0.07341 × HbA1c + 0.38299*TFQI +0.00358 × TT4RI +0.69236 × TSHI −4.47422 × FT3/FT4, the AUC is 0.73 , a specificity of 78.85%, a sensitivity of 55.74 P% and an accuracy of 72.21% .3.7.The multivariate predictive model was established with PDR as the dependent variable and age, duration, UA, eGFR, HbA1c, FT3/FT4, TFQI, TT4QI and TSHI as independent variables. The regression equation is logit (PDR) = 0.11446 − 0.00897*age +0.01095*duration +0.00306*UA −0.00649*eGFR −0.00028*HbA1c + 1.27457*TFQI +0.01356*TT4RI −0.27423*TSHI −2.32958*FT3/FT4, the AUC is 0.69 , a specificity of 51.93%, a sensitivity of 80.00% and an accuracy of 62.84% .4.THs increase energy consumption and heat production , increasSeveral biological changes associated with TH levels have been found, substantiating the influence of THs on microvascular complications. These changes include the impact of THs on metabolic processes within the body, the development of chronic inflammation due to decreased TH levels, and the impairment of vascular endothelial function . At presThe correlation between TH sensitivity and retinopathy has been extensively studied using animal models. These studies have provided valuable insights into the underlying pathophysiological mechanisms linking THs and retinopathy. Kocaturka found that rats with hypothyroidism exhibited reduced levels of sirtuin 2 protein expression in the retinal ganglion cell layer. This finding suggests that the significant deficiency of THs adversely impacted the normal development of the retinal cell structure . SeveralAt present, there are limited studies on the incidence of DR in patients with T2DM complicated with subclinical hypothyroidism (SCH). However, a meta-analysis investigating the association between DR and SCH has revealed that SCH was linked to an increased risk of DR. Specifically, individuals with SCH had a 2.13 times higher likelihood of developing DR . A recenMultiple studies have indicated that certain oral antidiabetic drugs can impact the level of THs. In an animal study, the effects of metformin on external symptoms and biochemical indicators related to thyroid function were assessed in rats. The findings revealed that metformin administration led to alterations in thyroid function in male rats, characterized by clinical manifestations of hyperthyroidism. The role of metformin in inhibiting TSH levels and increasing FT3 and FT4 levels highlights the importance of clinical awareness regarding the therapeutic intervention of metformin in thyroid-related conditions . Also, aTT4RI  is a simRegarding the correlation between TH sensitivity and T2DM, recent studies have shown that higher TH resistance indices are associated with obesity, metabolic syndrome, diabetes, and diabetes-related mortality. Hence, it is proposed that TH resistance can serve as an indicator of the energy balance in individuals with T2DM. These resistance indices may offer valuable insights into monitoring the energy balance of T2DM patients . In our At the same time, in this study, we also analyzed the correlation between the sensitivity of peripheral organs and tissues to changes in THs and DR. The results showed that FT3/FT4 levels in the NPDR and PDR groups were significantly lower compared to the NDR group. In contrast to our research findings, a recent cross-sectional study reported no statistically significant association between the sensitivity of TH indices and the risk of DR in euthyroid patients with T2DM after adjusting for covariates in the logistic regression model . HoweverThere are some limitations in this study. Firstly, due to the cross-sectional design, further research is required to investigate whether modulating thyroid function can potentially improve the severity and prognosis of DR. Secondly, the subjects of this study consisted exclusively of hospitalized patients, potentially limiting the generalizability of the findings to T2DM patients in outpatient settings, specifically concerning the correlation between THs and DR. Additionally, the single measurement of DR examination and TH levels due to the limited duration of hospitalization may introduce deviation, so it is necessary to further study the samples on a large scale in the future. Finally, as this study was conducted retrospectively, certain functional alterations, such as color vision defects, which can be observed in diabetes without evident retinopathy, were not examined. In future studies, it is essential to incorporate some functional parameters among patients with T2DM, as these indicators are also believed to be associated with thyroid homeostasis.In summary, this study observed that patients with NPDR and PDR exhibited significantly lower sensitivity levels of central and peripheral thyroid hormones compared to NDR patients, despite having normal thyroid function. After adjusting for factors such as age, sex, duration, blood pressure, blood lipid, and blood glucose, the decreased sensitivity of central and peripheral thyroid hormones was an independent risk factor for the occurrence of DR. These findings have important implications for predicting the risk of development and progression of DR, which may lay the groundwork for conducting large-scale cohort studies. Furthermore, these provide valuable insights for developing strategies related to the prevention, treatment, and management of DR in patients with T2DM.


Oxidative stress contributes to the progression of chronic kidney disease (CKD) and CKD-related mortality. The nuclear factor erythroid 2-related factor 2 (Nrf2) is essential in the regulation of cellular redox status, and Nrf2-activating therapies are under evaluation in several chronic diseases, including CKD. It is therefore inevitable to understand how Nrf2 behaves in advancing CKD. We analyzed Nrf2 protein concentrations in patients with varying extents of CKD but without renal replacement therapy, and in healthy subjects. Compared to healthy controls, Nrf2 protein was upregulated in mild to moderate kidney function impairment (G1–3). Within the CKD population, we found a significant positive correlation between Nrf2 protein concentration and kidney function (estimated glomerular filtration rate). In severe kidney function impairment , Nrf2 protein was reduced compared to mild to moderate kidney function impairment. We conclude that Nrf2 protein concentration in severe kidney function impairment is reduced relative to the mild to moderate kidney function impairment where increased Nrf2 protein concentrations prevail. With respect to the implementation of Nrf2 targeted therapies, it will be necessary to explore in which population of patients with CKD such therapies are able to effectively add to the endogenous Nrf2 activity. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a central component in the regulation of cellular redox status and has gained considerable interest as a therapeutic target in many chronic diseases ,2. In chNrf2 (molecular weight ~95–110 kDa) is ubiquitously expressed and functions as a transcription factor that responds to reactive oxygen species (ROS) production. It belongs to the cap “n” collar subfamily of basic-region leucine zipper transcription factors. Nrf2 binds to DNA in an acidic region, thereby regulating transcriptional activity. The Kelch-like ECH-associated protein 1 (Keap1) is a negative regulator of Nrf2 and mediates its degradation via proteasomes . Upon ROIn human kidney disease, the Nrf2 system seems to display different functional states relating to the extent of kidney failure and comorbidities ,4,8. In Preclinical studies showed that pharmacological Nrf2 activation could attenuate kidney injury ,17,18. TThe endogenous status of Nrf2 in human CKD is a key component for the context of potential Nrf2-targeting therapies. Therefore, we investigated Nrf2 protein concentration in stages of progressive kidney failure and compared the results to healthy control subjects. Furthermore, we tested the relation of Nrf2 protein to glomerular filtration rate as a measure of kidney function. We found a significant positive association between the glomerular filtration rate and Nrf2 protein concentration in our patient population with CKD. Our results showed a biphasic behavior of Nrf2 protein concentration. While Nrf2 protein was increased in mild to moderate kidney function impairment compared to healthy subjects, we found a significant reduction in Nrf2 protein in severe kidney function impairment.We enrolled 75 patients with non-dialysis-dependent CKD from the outpatient clinic of the Department of Nephrology, Odense University Hospital. Patients were approached consecutively as they came to the nephrological outpatient clinic on the days of blood sampling. Inclusion and exclusion criteria were prespecified and uniformly applied to the study participants. The inclusion criteria were being legally competent, age > 18 years, and verified CKD according to the 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease [The study enrolled 21 healthy control subjects. These persons were recruited by personal contact among students and staff at the University of Southern Denmark in the same time period as the CKD patients. Inclusion and exclusion criteria were prespecified and uniformly applied to the study participants. The inclusion criteria were being legally competent, age > 18 years, and absence of chronic disease in the medical history. The exclusion criterion was no written informed consent.The study was approved by the Regional Ethics Committee (S-20110061) and written informed consent was obtained from all study participants before inclusion into the study.Clinical data were obtained from medical records on actual medical status and medical history. This included the record of age, sex, height, weight, cause of kidney disease, comorbidities, and routine blood biochemical analyses. Venous blood samples were drawn in the morning from study participants. Serum was separated and stored at −80 °C until the batch analysis of samples for Nrf2. The eGFR was calculated using the 2009 CKD-EPI creatinine equation. All biochemical analyses, including the determination of Nrf2 protein were performed by laboratory staff blinded to the clinical characteristics of the study participants, including eGFR categories.Serum concentrations of Nrf2 were measured by enzyme-linked immunosorbent assay (ELISA) using kits from Invitrogen, ThermoFisher Scientific, Göteborg, Sweden  that can be utilized to analyze human Nrf2 in serum, plasma, and cell culture supernatants. The kit was run according to the manufacturer’s instructions. The lowest detectable Nrf2 serum concentration was 21 pg/mL. Samples with an Nrf2 concentration below the detection limit (DL) were set to 0.5 DL, hence 10.5 pg/mL in the statistical analyses. This applied to 10 out of 21 healthy control subjects, 8 out of 37 patients with CKD G1–3, and 19 out of 38 patients with CKD G4,5. The coefficient of variation (%CV) of the standards was below 22.6 with an average %CV of 10.8.p < 0.05 was considered statistically significant.The data distribution was tested using the D’Agostino and Pearson omnibus normality test. Continuous variables are given as medians and interquartile ranges, and categorical variables are given as counts and percentages. Groups were compared using the Kruskal–Wallis test or the Mann–Whitney test, as appropriate. Differences in categorical variables between groups were analyzed by Fisher’s exact test. A non-parametric bivariate correlation analysis (Spearman) was performed. The relation between a continuous and a binary categorical variable was assessed by comparison of the respective two groups containing the continuous data using the Mann–Whitney test. Data were analyzed using GraphPad prism software . All statistical tests were two-sided and a two-sided value of Clinical and biochemical characteristics of the study subjects are given in We analyzed the relation between Nrf2 protein concentration and clinical parameters that might be related to Nrf2 according to the literature. p = 0.009). We did not detect a significant association of Nrf2 protein with the presence of diabetes, proteinuria, and C-reactive protein. A summary of the relations of Nrf2 protein to clinical parameters is given in Our analyses showed a significant positive correlation between eGFR and Nrf2 protein concentration in the CKD population in our study , and severe kidney function impairment . p = 0.003). As shown in Nrf2 protein concentrations between the three groups differed significantly  in healthy control subjects, 454.4 pg/mL (interquartile range 30.9–1082 pg/mL) in mild to moderate kidney function impairment, and 12.8 pg/mL (interquartile range 10.5–247.4 pg/mL) in severe kidney function impairment.From our results, we conclude that in the population of patients with CKD a significant positive association between glomerular filtration rate and Nrf2 protein exists. Compared to healthy controls, an upregulation of Nrf2 protein was found in mild to moderate kidney function impairment, while the Nrf2 protein concentration in severe kidney function impairment  was significantly lower compared to less advanced CKD stages.We report a biphasic behavior of Nrf2 protein concentration in CKD. In our study, mild to moderate kidney function impairment was characterized by higher Nrf2 protein concentration than in healthy subjects. As lower glomerular filtration rates were associated with lower Nrf2 protein concentration within the CKD population, Nrf2 protein concentration in severe kidney function impairment was significantly reduced compared to mild to moderate kidney function impairment. Nrf2 protein concentration was comparable between CKD G4,5 and healthy subjects. The latter result is in line with findings on Nrf2 gene expression in peripheral blood mononuclear cells reported from patients with CKD G3–5 . On the The higher Nrf2 protein concentration, seen in our study in mild to moderate kidney function impairment, might be expected, as the Nrf2 accumulation with adjacent translocation to the nucleus and induction of antioxidant target genes is the adequate response to an oxidative challenge to sustain or regain redox homeostasis . Such upAn interesting point is the high number of samples with very low serum Nrf2 protein concentrations, below the limit of detection, in both the healthy control subjects and in patients with very advanced CKD. While in healthy subjects this might reflect lower requirement for stimulation of the Nrf2 system, in patients with very advanced CKD this could hint to a reduced capacity for Nrf2 system activation.We also investigated the relation between Nrf2 protein and clinical characteristics in our CKD population. The relation between the presence of diabetes and Nrf2 protein concentrations was analyzed since a significantly higher plasma concentration of the Nrf2 target NQO1 had been reported in plasma from diabetic patients , pointinAnother important parameter with respect to Nrf2 is proteinuria. A positive correlation between the Nrf2 target heme oxygenase 1 (HO-1) and proteinuria has been reported , and in The significant interplay between inflammation and oxidative stress in CKD has been stressed ,36,37,38An important question that arises from our study is how the consequences of both the upregulation of Nrf2 in mild to moderate kidney function impairment and the downregulation of Nrf2 in severe kidney function impairment can be assessed. We suggest that it is necessary to perform prospective cohort studies that investigate CKD progression and CKD-related morbidity in relation to Nrf2 concentration. To assess Nrf2 efficiency in these prospective studies, measurements of Nrf2 concentration and markers of oxidative damage should be combined. Such analyses could guide the design of clinical studies with Nrf2-activating substances in CKD subgroups defined by CKD stage and comorbidities.An assessment of plasma Nrf2 protein as a surrogate for Nrf2 protein concentration in different cell types and tissues needs to be established in human CKD. On the one hand, factors such as systemic inflammation, uremic toxins or comorbidities exert their effects on all cell types. We recently found, in a systematic review, that the state of Nrf2 system components depended mainly on CKD stage, comorbidities, and investigated Nrf2 target rather than investigated cell type . On the Study limitations: The low number of study participants is a limitation of our study. Furthermore, a biochemical characterization of healthy study participants would be advantageous. In addition, healthy control subjects were significantly younger and had a lower BMI compared to patients with CKD. We suggest that future studies be performed to reinforce our results, especially with respect to an analysis of Nrf2 protein concentration separately for each stage of CKD.In conclusion, we found that Nrf2 protein concentration in severe kidney function impairment was reduced relative to the mild to moderate kidney function impairment. In the earlier stages of CKD with mild to moderately reduced kidney function (CKD G1–3), Nrf2 protein concentrations were increased compared to healthy control subjects. With respect to the implementation of Nrf2 targeted therapies, it will be important to analyze in which CKD stages or kidney diseases Nrf2-activating or Nrf2-modifying therapies can effectively support the endogenous Nrf2 activity and/or Nrf2 targets.