SD: 16.3]) were included. TT reduced the incidence of exacerbations by 16.7% (p < 0.044) and the number of patients with exacerbations by 8.5% (p < 0.001) compared to previous DT. The rate of patients with severe exacerbations requiring systemic corticosteroids and their hospitalization rates significantly decreased by 22.5% and 29.5%. TT significantly improved FEV1, FVC, and FEV1/FVC, saving €571/patient for society. Younger patients with asthma (18–44 years old) and patients with severe asthma (FEV1 < 60%) performed better upon the initiation of TT. Conclusions: TT reduced asthma exacerbations, improved lung function and reduced healthcare costs vs. DT, particularly in patients requiring systemic corticosteroids to treat severe exacerbations.Introduction: Adding LAMA to LABA/ICS is recommended to improve control in patients with persistent asthma. Methods: This observational, retrospective, before-and-after study considered patients diagnosed with asthma who started LABA/ICS + LAMA treatment  between 1 January 2017 and 31 December 2018 and had been treated with LABA/ICS  in the year before. Changes in lung function and exacerbation rates, healthcare resource utilization, and healthcare and non-healthcare costs (€2019) were estimated in patients with asthma in clinical practices in Spain. Data from computerized medical records from seven Spanish regions were collected ±1 year of LAMA addition. Results: 4740 patients (64.1 years old [ Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation. It is defined by a history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough, that change in intensity over time, and a varying airflow limitation . GeneticAsthma is often found to coexist with pulmonary  or extrapulmonary  comorbidities . The tre1], peak expiratory flow and impulse oscillometry parameters, and multiple pulmonary function tests) , PrimoTinA [n = 912], MezzoTinA [n = 2103], TRIMARAN/ TRIGGER , IRIDIUM [n = 3092], ARGON [n = 1426], and CAPTAIN [n = 2439]) showed that adding LAMA increased lung function, decreased exacerbations, and, in some cases, ameliorated asthma control  and median [P25–P75]), forced vital capacity  and FEV1/FVC . Eosinophil counts in cells/μL (mean [SD] and median [P25–P75]) in blood were also measured. The number and percentage of patients with ≥300 cells/μL were also provided.Lung function was estimated using the forced expiratory volume in first, second , hospitalizations , diagnostic/therapeutic tests . On the other hand, quantitative data were described using means and standard deviations (SD) in symmetrical distributions and medians and interquartile ranges  for asymmetrical distributions. The 95% confidence intervals (CI) were calculated to estimate population parameters. Descriptive univariate statistical analyses were carried out. The baseline characteristics of patients were summarized using descriptive statistics. For continuous variables, the number of patients, means and standard deviations, were reported. Frequency distributions with quantities and percentages were reported for categorical variables using absolute and relative frequencies , the techniques of statistical significance for paired groups were used. McNemar’s tests and Student’s t-tests were conducted to compare treatments, severe exacerbation rates, use of healthcare resources, and costs between the study cohorts (before and after the addition of LAMA to the LABA/ICS therapy). A generalized linear model (GLM) repeated measures procedure was also carried out to compare dependent variables (intra-subject), such as the severe exacerbation rates and the use of SABA and oral corticosteroids, before, and after, the addition of LAMA to the LABA/ICS therapy. A complete factorial model  was developed and the criteria to apply it was the Mauchly’s sphericity test with orthonormalized data transformation. In addition, the impact of the covariates’ inter-subjects  in severe exacerbation rates were analyzed. 1, severe exacerbation rates and costs, per age group , asthma severity (patients with FEV1 at the index date <60% or ≥60%) and having an additional diagnosis of chronic obstructive pulmonary disease (COPD). Subgroup analyses were developed to estimate the changes in FEVThe treatment persistence/duration was analyzed using a Kaplan–Meier survival analysis (procedure: log-rank test). Data were censored in the absence of the event. p < 0.05.The SPSSWIN version 25 statistical program was used. Statistical significance was set at This study was carried out in line with the Helsinki Declaration. Patient consent was not obtained since Spanish legislation excludes existing data that are aggregated for analysis. Personal data were de-identified as specified in the Spanish Law 15/1999, of 13 December, on Personal Data Protection, and the Organic Law 3/2018, of 5 December, On the Protection of Personal Data and Guarantee of Digital Rights ,48. The In conclusion, our results showed that the addition of LAMA to the ICS/LABA therapy improved the clinical outcomes of patients with asthma, including lung function and severe exacerbation rates, particularly in younger patients and those with more severe asthma. These improvements led to a decrease in the use of concomitant medications and other healthcare resources, along with cost savings for the Spanish National Health System and society.


So far, quite a few studies have revealed that systemic iron levels are related to asthmatic inflammatory reactions. And most studies have focused on the correlation between systemic iron levels and asthma, with inconsistent findings. Yet, few studies have investigated the connection between serum iron and blood eosinophil counts. Hence, we have explored the connection between serum iron and blood eosinophil counts in asthmatics by utilizing data from NHANES.A total of 2549 individuals were included in our study after screening NHANES participants from 2011 to 2018. The linear regression model and XGBoost model were used to discuss the potential connection. Linear or nonlinear association was further confirmed by the generalized additive model and the piecewise linear regression model. And we also performed stratified analyses to figure out specific populations.In the multivariable linear regression models, we discovered that serum iron levels were inversely related to blood eosinophil counts in asthmatic adults. Simultaneously, we found that for every unit increase in serum iron (umol/L), blood eosinophil counts reduced by 1.41/uL in model 3, which adjusted for all variables excluding the analyzed variables. Furthermore, the XGBoost model of machine learning was applied to assess the relative importance of chosen variables, and it was determined that vitamin C intake, age, vitamin B12 intake, iron intake, and serum iron were the five most important variables on blood eosinophil counts. And the generalized additive model and piecewise linear regression model further verify this linear and inverse association.Our investigation discovered that the linear and inverse association of serum iron with blood eosinophil counts in asthmatic adults, indicating that serum iron might be related to changes in the immunological state of asthmatics. Our work offers some new thoughts for next research on asthma management and therapy. Ultimately, we hope that more individuals become aware of the role of iron in the onset, development, and treatment of asthma. Asthma Asthma is a complex inflammatory disease of the airways with numerous pathophysiological features . Type 2 It is thought that dietary changes may have contributed to the development of asthma over the past few decades as a result of society’s ongoing evolution . A consiQuite a few studies to date have focused on the correlation between systemic iron levels and asthma. Yet, few research have examined the relationship between eosinophil counts and serum iron levels in asthmatics. Using National Health and Nutrition Examination Survey (NHANES) data, we investigated the connection between serum iron concentrations and blood eosinophil counts in American adults with asthma to gain insight into the role of serum iron in asthma.22.1Every two years, the National Health and Nutrition Examination Survey (NHANES), sponsored by the Centers for Disease Control and Prevention, collected data on the health and nutritional status of the U.S. population. NHANES uses a complex, multistage probability design to sample the civilian, noninstitutionalized population residing in the 50 states and D.C. The NCHS Institutional Review Board authorized the NHANES database in conformity with the revised Helsinki Declaration. Before the data collecting procedures and exhaustive health tests, the informed consent forms were completed. Details of the design and content of NHANES are available on the NHANES website.2.2The data from the 2011-2018 NHANES from were utilized in our investigation. For the second analyses, these data comprised demographic information, examination information, dietary information, laboratory information, and questionnaire data. During 2011 to 2018, the NHANES collected an aggregate of 39156 samples. We eliminated populations who were (1): younger than 18 years old (n=15331); (2) lost data on blood eosinophils (n=2147); (3) lost data on serum iron (n=450); (4) without asthma (n=17999); (5) lost data on more than one of following covariates(n=680): educational background, marital state, poverty to income ratios (PIR), body mass index (BMI), smoking state, alcohol intake, folate intake, vitamin A intake, vitamin B12 intake, vitamin C intake, iron intake, hypertension history, diabetes history, steroid use. Eventually, a large, nationally representative sample (n=2549) of asthmatic adults in the U.S. was recruited for our investigation. 2.3post-hoc analyses. On the NHANES website, you can find a thorough overview of laboratory procedures.The serum iron concentration was measured using the DcX800 method, which is a timed-endpoint method. Acetic acid releases iron from transferrin, which is then reduced to the ferrous form by hydroxylamine and thioglycolate. The ferrous ion is complexed instantly with the FerroZine Iron Reagent. At a predetermined time period, the system measures the change in absorbance at 560 nm. This variation in absorbance is related to the iron concentration in the sample. Using a Becker Coulter MAXM analyzer, complete blood counts with 5-part differential measurements were done on whole blood samples obtained over the NHANES 2011–2018 cycles. The 5-part differential measure yielded cell counts of lymphocytes, monocytes, segmented neutrophils, eosinophils, and basophils (103 cells/L), which were utilized for 2.4Covariates comprised demographic information, examination information, dietary information, and questionnaire data. Demographic information involved sex, age (years), race , educational background , poverty to income ratios , marital state . Next, we also comprised examination information and diet information, such as body mass index (kg/m2), smoking state (whether smoked over 100 cigarettes in a lifetime), intake of alcohol, vitamin A, vitamin B12, vitamin C, folate and iron , hypertension history , diabetes history , and steroid drugs use history . The assessment of asthma was predicated on information obtained from the questionnaire segment of the National Health Interview Survey conducted in the United States. To evaluate the presence of asthma, the participants were queried with the following question: “Have you ever been diagnosed with asthma by a healthcare professional?” If the respondent answers affirmatively, they were classified as an individual with asthma. On the NHANES database website, you may find more comprehensive explanations of all variables.2.5We performed statistical analyses of serum iron concentrations and blood eosinophil counts in accordance with the NHANES database’s guidelines. Mean ± SD and percentage were used to illustrate continuous and categorical variables, individually. Initially, blood eosinophil counts were transformed into four quartiles. We calculated the p-value of categorical variables using the weighted chi-square test, and the p-value of continuous variables using the Kruskal Wallis rank sum test. The link of serum iron with blood eosinophil counts was then determined using three types of weighted linear regression models . The model 1 adjusted no covariates; the model 2 adjusted sex, age, and race; and the model 3 adjusted gender, age, race, educational background, marital state, PIR, BMI, smoking state, alcohol intake, vitamin A intake, vitamin B12 intake, vitamin C intake, folate intake, iron intake, hypertension history, diabetes history, and steroid drug use. Next, we utilized the machine learning of XGBoost algorithm model to discuss the relative importance of selected variables on the effect of blood eosinophil counts. And, the stratified analyses were then undertaken to determine the stratified correlation between serum iron concentrations and blood eosinophil counts. To analyze the potential linear link of serum iron with blood eosinophil counts, we created a smooth curve according to the penalty spline approach using the generalized additive model. In addition, the segmented regression model was employed to confirm the linear or nonlinear association between serum iron concentrations and blood eosinophil counts. If a non-linear association was found, a two-piecewise linear regression model was used to assess the threshold influence of serum iron levels on blood eosinophil counts. When the ratio between serum iron levels and blood eosinophil counts became apparent in a smoothed curve, the recursive technique automatically estimates the inflection point at which the maximum model likelihood will be applied. R software (Version 4.2.0) with the R package was used to conduct all statistical analyses. In our research, a p-value of less than 0.05 indicated statistical significance.33.1Weighted distributions of the baseline characteristics, comprising demographic information, examination information, laboratory information, and questionnaire information from the 2011-2018 NHANES survey, were displayed in 3.2We utilized three weighted linear regression models to examine the relationship between serum iron and blood eosinophil levels in persons with asthma Table 2.3.3We further analyzed stratification connection of serum iron and blood eosinophil counts in different subgroups by sex, age, race, education background, marital state, PIR, BMI, smoking state, hypertension history, diabetes history, and steroid drugs use to ensure that the results of the linear regression analysis were reliable Figure 23.4In the stages of model development and verification, we implemented the XGBoost algorithmic model of machine learning to assess the relative significance of selected variables associated with blood eosinophil counts. The selected variables consisted of age, poverty-to-income ratio, body mass index, alcohol consumption, intake of vitamin A, vitamin B12, vitamin C, folate, iron, and serum iron. On the basis of the outcomes of each variable’s contribution by XGBoost model, we discovered that vitamin C intake, age, vit B12 intake, iron intake, and serum iron were the five most influential factors in the blood eosinophil counts Figure 33.5The general additive model (GAM) is extremely sensitive to determining whether a correlation is linear or nonlinear. We performed GAM to explore the linear or nonlinear connection of serum iron and blood eosinophil counts to validate the trustworthiness of regression analysis results. We generated a smooth fit curve based on model 3 Figure 44In recent years, there has been a significant increase in allergic illnesses, which has accompanied with a remarkable increase in interest in the potential link between micronutrients and asthma , 31, 43.As a result, we evaluated the relationship between serum iron levels and blood eosinophil counts in 2,549 adults with asthma who took part in the NHANES survey in the United States from 2011 to 2018. To our knowledge, our investigation is the first study to discuss the connection between serum iron levels and blood eosinophil counts in adults with asthma and one of the most extensive cross-sectional studies. In multiple linear regression models, we observed the negative correlation between serum iron levels and blood eosinophil counts in American adults with asthma. Simultaneously, we discovered that for every unit increase in serum iron (umol/L), blood eosinophil counts reduced by 1.41/uL in model 3, which controlled for sex, age, race, educational background, marital state, PIR, BMI, smoked state, alcohol intake, vitamin A intake, vitamin B12 intake, vitamin C intake, folate intake, iron intake, hypertension history, diabetes history, and steroid drug use. Furthermore, we created a machine learning XGBoost model to estimate the relative importance of selected variables, and found that vitamin C intake, age, vit B12 intake, iron intake, and serum iron were the five most influential factors on blood eosinophil counts. Then, we determined the linear and negative association between serum iron levels and blood eosinophil counts by the generalized additive model and the two-piecewise linear regression model. As shown by the findings discussed above, the correlation between serum iron and blood eosinophil count in American adults with asthma was linear and negative.The majority of asthma cases are caused by type 2 inflammation, which is mediated by respiratory epithelium and type 2 T-helper lymphocytes. Inflammation of the airway is most likely caused by a combination of changes in geographical location, environmental factors, and dietary patterns , 48. It Quite a few published studies reported the connection between asthma and iron intake. A case-control study found that iron supplementation improved chronic cough and bronchial hyperreactivity . Haim BiCompared to past studies, ours has some advantages. Our study presents a rather large, nationally representative sample of individuals with asthma and involves quite a few potential confounders. Second, we use stratified analysis to determine the connection between serum iron and blood eosinophil counts in the different population because confounders may affect the results. Then, we use the XGBoost algorithm model’s machine learning to determine the relative importance of selected variables. And the linear and inverse relationship between serum iron and blood eosinophil counts is further confirmed by generalized additive model and segmented regression model. Our work offers some new thoughts for next research on asthma management and therapy. More studies will be required in the future to clarify the connection between serum iron and blood eosinophil counts and to determine the underlying mechanism.Despite this, we recognize that our study has some limitations. Due to the limitations of the NHANES database, we included asthmatic individuals based on questionnaire data as opposed to the lung function test. And the pharmaceuticals included in our study that altered blood eosinophils were predominantly cortisol drugs and other anti-allergy medications, but no biologics. Owing to constraints in the NHANES database, our analysis includes only serum iron but not iron binding capability, transferrin saturation, and information of pre and peri-birth nutrition. The XGBoost algorithm remains an algorithm, created by humans, and as such is not guaranteed to be 100% objective. And participants’ physical conditions at the time of blood collection, such as whether they have acute or stable asthma, are not known. Therefore, additional prospective studies will be necessary to shed light on the potential role of serum iron in the control, progression, and treatment of asthma and to uncover potential mechanisms of action.5Our investigation discovered that the linear and inverse association between serum iron and blood eosinophil counts in asthmatic adults, indicating that serum iron might be related to changes in the immunological state of asthmatics. Our work offers some new thoughts for next research on asthma management and therapy. Ultimately, we look forward to more people recognizing the role of iron in the onset, development, and treatment of asthma.http://www.cdc.gov/nchs/nhanes/.Publicly available datasets were analyzed in this study. This data can be found here: The studies involving humans were approved by NCHS Research Ethics Review Board. The studies were conducted in accordance with the local legislation and institutional requirements. The human samples used in this study were acquired from The NHANES protocol was approved by the NCHS Research Ethics Review Board. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements.JW performed the study design, data extraction, statistical analysis, drafted the manuscript, and revised the manuscript. CW performed the study design, data extraction, and drafting of the manuscript. JX re-collected, cleaned and analyzed the data, participated in the revision of the manuscript, and played an important role in the revision of the manuscript. MG performed data extraction and statistical analysis and revised the manuscript. SG participated in the study’s design and management and revised the manuscript. All authors read and approved the final manuscript.


In this paper, we aimed to review the past, present, and future opinions on AKI kidneys. (2) Methods: A PubMed search was conducted for topics relevant to AKI kidney transplantation. (3) Results: Current short- and long-term data on AKI kidneys have demonstrated good outcomes including favorable graft function and survival. The role of procurement biopsies is controversial, but they have been shown to be beneficial in AKI kidneys by allowing clinicians to differentiate between reversible tubular injury and irreversible cortical necrosis. Machine perfusion has also been applied to AKI kidneys and has been shown to reduce delayed graft function (DGF). The incidence of DGF increases with AKI severity and its management can be challenging. Strategies employed to counteract this have included early initiation of dialysis after kidney transplantation, early targeting of adequate immunosuppression levels to minimize rejection risk, and establishment of outpatient dialysis. (4) Conclusions: Despite good outcomes, there continue to be barriers that impact AKI kidney utilization. Successful strategies have included use of procurement biopsies or machine perfusion and expectant management of DGF. With increasing experience, better use of AKI kidneys can result in additional opportunities to expand the donor pool. Acute kidney injury (AKI), an acute decline in renal function, is observed in upwards of 25% of deceased donors ,2. WhileEarly transplant data on AKI kidneys have suggested a higher risk for graft loss, delayed graft function (DGF), primary nonfunction, and lower estimated glomerular filtration rates (eGFR) compared to non-AKI kidneys . AlthougThe use of preimplantation (procurement) biopsies is commonly described in current AKI data experiences. Although the general use of procurement biopsies is controversial and debated, the science supporting procurement biopsy use for AKI donors has established criteria guiding safe utilization ,8,9. UseIt is well known that the demand for kidney transplantation far exceeds the number of available donor kidneys. Between 2015 and 2017, only 39% of the patients on waitlists received transplants. For the remaining individuals, 20% of the patients were removed due to various reasons such as being too ill, 6% of the patients died, and 35% of the patients are still waiting for a transplant 3 years after being listed . Within As a result, there have been many efforts by the transplant community to identify reasons for discard and to improve utilization . The rolWith the availability of long-term data on AKI kidney outcomes, there has been increasing consideration and use of these kidneys by more transplant centers . InitialThe success that our transplant center program has had in utilizing severe AKI kidneys is multifactorial, beginning with careful consideration of a donor’s clinical history and cause of death. The etiology of a donor’s AKI and an indication for renal replacement therapy is also pertinent. The duration of renal replacement therapy and anuria can provide insight into the severity of AKI. When possible, minimization of CIT and use of machine perfusion is ideal; however, this is not always modifiable due to late allocation offers and logistical complexity. Prior to proceeding with a transplantation, per our center’s protocol, all kidneys with AKI undergo a preimplantation procurement biopsy. All efforts are made to review these biopsies by our transplant center’s on-call pathologist, nephrologist, and transplant surgeon. Historically, this has largely involved physical review of the slide at the time of kidney allograft arrival. If the slide could not be provided by the organ procurement organization, then a second preimplantation biopsy was performed. These practices have been, at times, challenging with the addition of incremental CIT as well as unnecessary resource utilization if the biopsy read proved to be unsuitable for kidney transplantation . More reReported data on kidney allograft biopsies, as a whole, have been heterogenous, in part, due to variability in reporting. Prior studies have shown that chronic changes in formalin-fixed paraffin-embedded postreperfusion biopsies correlate with inferior outcomes following deceased-donor kidney transplantations ,24,25. AThe evaluation of a preimplantation biopsy by a pathologist is controversial. In some part, this is related to variability in performance and reporting. To improve the standardization of preimplantation kidney biopsy procurement, the Organ Procurement and Transplantation Network has proposed new guidelines, wherein a procurement biopsy is performed on a specific subset of organ donors . With thThe value of procurement biopsies continues to be controversial, and some organ procurement organizations have opposed implementation of the updated minimal donor criteria policy because they believe the additional requirements for kidney biopsies will adversely impact kidney utilization. We do not recommend routinely using a procurement biopsy in younger, low-risk donor kidneys. However, in our center’s experience with transplanting kidneys from AKI donors, we have found that a procurement biopsy can be valuable. Transplant centers must try to safely utilize all available organs, pair the correct organ with the correct recipient, and ensure that that they are attaining appropriate short- and long-term quality goals. In some circumstances, procurement biopsy data add valuable information to this decision-making process. By comparison, a primary goal for organ procurement organizations is to increase successful placement of donor organs. In this context, the metrics by which transplant centers and organ procurement organizations are held are not always congruent.At our institution, a standardized online fillable form is utilized within pathology for all requested preimplantation biopsies . The bioPost-perfusion biopsies are used in concert with preimplantation biopsies and provide additional insight. The presence of similar pathologic findings in both pre and post implantation biopsies from a patient allow for the deduction that the process is donor derived, as opposed to de novo. Additionally post-perfusion biopsies of AKI kidneys allow pathologists to assess for any acute progression of tubular injury/necrosis and provide a well processed paraffin-embedded formalin-fixed piece of tissue for more complete histologic evaluation and for additional work-up, should this be necessary in the future.Static cold storage (SCS) is the most common method of preservation of organs due to its ease of availability and low cost. Marginal and high-risk kidneys are being increasingly accepted and used by transplant centers to meet the demands of ongoing organ shortage and recipients on waitlists. Such kidneys are more susceptible to ischemia-related reperfusion injury, along with higher rates of DGF and incremental risk for primary nonfunction . Over thIn an international randomized controlled trial that randomized one kidney to HMP and the other kidney to SCS, kidneys undergoing HMP had reduced risk and duration of DGF and higher one-year graft survival . Other sA single-center observational study at the Miami Transplant Institute (MTI) reported outcomes comparing the use of SCS-preserved kidneys with kidneys preserved with SCS at procurement and hypothermic machine perfusion (HMP) on arrival. The results showed an overall decrease in DGF, as well as slow graft function rates and low acute rejection rates compared to the use of only static cold storage . In thisSince discard is often common with severe AKI kidneys due to concern for prolonged DGF, normothermic machine perfusion may help to decrease the DGF duration in AKI kidneys . NormothOxygen carriers are supplied with a crystalloid/colloid solution, oxygen, insulin, and various other nutrients to support metabolism ,45,46. NAKI kidneys have a higher risk of DGF than non-AKI kidneys, and the severity of AKI further increases this risk ,11. A reThe data on the impact of DGF on graft function and rejection are conflicting, likely due to variations in study populations, the center practices of induction agents, and timings for initiating calcineurin inhibitors. In non-AKI kidneys, the studies in the United Kingdom and the Australian and New Zealand Dialysis and Transplant Registry have reported increased graft loss with longer DGF duration ,58. ThesIn a single center study of 1018 patients with DGF, the use of AKI kidneys was not associated with poor graft survival or increased risk of fibrosis at the 4-month protocol biopsy compared to 696 allografts without DGF . The graThe management of DGF after kidney transplantation can be challenging and involves consideration of many factors including immunosuppression and volume status . ImmunosThe management of DGF after kidney transplantation is variable across transplant centers. A recent survey study of U.S. and Canadian transplant centers showed 20–40% DGF, with most centers reporting longer length of hospital stay . Muth etTransplant centers should develop a clinical protocol for managing patients who develop DGF. It is important to counsel patients on the likelihood of DGF based on risk factors. Careful assessments of urine output, volume status, and electrolytes are necessary early after transplantation to determine the need for initiation of dialysis. Anticipation of the need for vascular access for dialysis in DGF patients is important. Beta-blockers and clonidine should be restarted at a lower dose to prevent rebound phenomenon and avoiding ACE-inhibitors (ACE-i) and angiotensin receptor blockers (ARB) immediately after kidney transplantation is usually advisable. Early initiation of calcineurin inhibitors and maintaining an adequate calcineurin inhibitor trough level should decrease the risk of acute rejection. If available, the utilization of machine perfusion may be considered in donors with a longer CIT to decrease the risk of DGF .At our center, we have adopted a clinical protocol for discharging patients with DGF on post-transplant Day 2 or Day 3. We follow these patients with outpatient assessments that include laboratory investigations three times a week and outpatient dialysis until DGF resolves. We start discharge planning on the day of transplant with the assistance of nursing staff and case management. The reduction in length of hospital stay translates to a cost reduction resulting from decreased utilization of hospital resources. Dialysis management should include careful assessment of post-transplant target weight based on clinical findings in order to avoid an abrupt drop in blood pressure. We advise that patients with DGF lasting more than 14 days should receive an ultrasound and biopsy of the allograft to rule out rejection or other unexpected complications.AKI in donors is increasingly common, and despite good long-term outcomes, there continue to be significant barriers impacting discard and utilization. Careful screening of donors with AKI is important. Reviewing donor clinic history, procurement biopsies, and machine perfusion parameters have been strategies employed by transplant centers to avoid unfavorable outcomes. DGF frequently occurs with AKI kidneys and its incidence and duration increase with donor AKI severity. The success of normothermic machine perfusion in other solid organs presents an opportunity for more standardized access to machine perfusion for kidney transplantation. In addition to donor selection, post-transplant management plays an important role in successful outcomes for AKI kidney allografts. This includes patient counseling, early initiation of immunosuppression to reduce risk for rejection events, and frequent assessment of volume status. With increasing experience, there are additional opportunities to further expand the donor pool by using AKI kidneys. Future opportunities include ongoing standardization of procurement biopsy reporting, increasing availability of machine perfusion, and improving the definition and reporting of DGF.


Among renal replacement therapies, preemptive kidney transplantation (PKT)presents the best clinical, social, and economic results. However, it is stillinfrequently chosen as first therapy for patients with irreversible kidneyfailure. Initiatives in different parts of the world were developed to identifythe reasons why PKT is still not widely used and to facilitate the access ofpatients with end-stage kidney disease to the advantages associated with it.This article addresses the main advantages and difficulties of PKT and discusseswhen it should be indicated and how to prepare potential recipients for PKT. One of the most significant advantages of PKT is the avoidance, or at leastdelay of dialysis-related risks. It also offers better post-transplant clinical outcomes and lower medium- and long-term financial costs.Preemptive kidney transplantation (PKT), defined as a kidney transplant performedbefore the start of maintenance dialysis, may be considered the optimal therapy formost patients with end-stage kidney disease (ESKD). The rate of PKT is even lower in other countries, such as Spain (5%),Uruguay (5.4%), or Indonesia (2.7%). Although the Transplantation Registry in Brazil does not officially countPKT, data from Hospital do Rim – the largest kidney transplant center in Brazil andthe world – indicate that 16.67%  of all living donor kidneytransplants between 2011 and 2016 were performed preemptively.However, PKT is not commonly performed around the world. For instance, in the UnitedStates (US), only 9.3%  of all kidney transplants performedbetween 2000 and 2018 were in the preemptive modality.There are several reasons for the low PKT rate, some of which are quite complex.Policies for allocating organs, ethical issues, patient and care team education,late referral to the nephrologist, and a time- and energy-consuming donor evaluationprocess are some of the barriers to PKT. Similar initiatives have been observed in other countries. Their goal is tooffer the clinical advantages of PKT to a greater number of patients, and itseconomic and social benefits, beyond reducing the overall waiting list for kidneytransplantation.In 2007, the National Kidney Foundation convened a Kidney Disease Outcomes QualityInitiative (NKF/KDOQI) conference to discuss a “Transplant First” approach as aprimary goal in the care of ESKD patients. This initiative aimed to identify keydifficulties for PKT and what could be done to overcome these barriersThe present narrative review aims to discuss advantages related to PKT, why it isinfrequently performed, when is the best moment to perform it, and how patientsshould be prepared for this therapy.. From a clinical point of view, PKT provides a lower risk of allograftfailure and acute rejection, higher allograft survival, and less need forpre-transplant blood transfusions – since dialysis patients tend to have lowerhemoglobin levels than non-dialysis ESKD patients under conservative care.PKT has several advantages over transplantation performed after the start ofdialysis. These advantages are independent of kidney transplant recipients’characteristics, such as age and gender.A retrospective study with data from the U.S. Renal Data System evaluated 8,481patients who received a living donor kidney transplant. When compared with livingdonor kidney transplantation after dialysis, PKT with living donors was associatedwith a 52% lower risk of allograft failure during the first year aftertransplantation , an 82% decrease in the second year, and an 86% decrease in subsequent years .In addition, PKT patients are spared of the potential risks associated with dialysistherapy, such as catheter-related infection, cardiovascular adverse effects such asleft ventricular hypertrophy, hypertension, and intradialytic complications such as hypotension2)and PKT (49.5 ± 5.7 mL/min/1.73 m2). Although PKT showed indeed a‘modestly’ slower annual decline in GFR than non-PKT, the superior allograftsurvival of PKT could not be justified by preservation of native renal function orby differences in the rate of loss of renal function in that study.Despite all the clinical benefits, it is unclear what the reasons for theseadvantages are. A 2004 study compared glomerular filtration rate (GFR) six monthsafter transplantation and the subsequent rate of loss of renal function in 34,997non-PKT with 5,966 PKT recipients. The mean GFR after six months of transplantationwas similar among recipients from non-PKT , and the fact that it was asingle-center study, the study results were somehow unexpected. However, the authorsexplain that kidney transplants may not dramatically improve the quality of life ifthe patient had not experienced the burden of dialysis. Contrarily, patients caneven feel uncomfortable after transplantation due to the regular intake ofimmunosuppressive drugs. Non-PKT patients may have improved quality of life becausethey had previous experience with dialysis. A 2018 US study that compared costs of kidney transplantation with dialysisshowed that the predicted costs per quality-adjusted life-years over ten years wasUS$ 39,939 for HLA-compatible living donor transplantation compared with US$ 72,476for dialysis.From an economic perspective, PKT might have higher initial costs than dialysis dueto surgical procedure, hospitalization, and immunosuppressive drug therapy. However,there is a medium-term compensation for these costs, as PKT has a smaller impact onannual expenses per patient when compared to expenses with dialysis in the long run. Some barriers, mainly related to ethical issues and patient education, makeit difficult to increase the use of PKT.However, even with clinical, social, and economic advantages, PKT is still rarelyperformed in the worldSome aspects are relevant when choosing the most appropriate therapy for ESKDpatients. There are ethical issues that must be addressed, mainly related todeceased donor PKT. In these cases, government and public policy makers seek toprovide as equal chances as possible to patients on the waiting list throughequitable organ allocation.To do so, several ethical principles are considered: equity, priority , medicalurgency, efficiency, utility, therapeutic outcomes, autonomy, and responsibility.The great challenge lies in balancing these principles, respecting the hierarchy ofimportance, without disregarding any principle. With this goal in mind, severalethical models can be adopted, depending on the prioritized criteria.. The prioritarianism theory, on the other hand, defends the prioritization ofthe most seriously ill patients (worst-off), while the beneficiality model considers criteria such as longer lifeexpectancy and greater number of lives saved. Perhaps the best known of all ethical theories in medicine, the equity modeladvocates equal chances for all patients. However, some authors criticize this model, arguing that this proposal isimpossible to apply in practice.The social utility model (utilitarianism theory), for example, gives priority to thepatients most useful to the community21,24. Waiting list time isused by most policies for allocating organs while life expectancy has beenincreasingly valued. In general, it is recommended to consider urgency and probability of success. The main purpose of policies for allocating organs is to balance thejustice-based system and the utility-based system.Following the justice-based system, many theories prioritize impartial criteria . It is a therapy that offers several benefits to the recipient, but alsoprolongs the waiting time on the list for patients who are already on dialysis,which might result in an increase in some of their risks, such as mortality.However, achieving this balance is challenging as deceased donor PKT is a principleof dual effect. Also, according to these authors, to be morally acceptable, preemptivetransplantation needs to meet the following criteria: the principal aim of the act, and the act itself, are good;the harmful effects are not intentionally pursued;the harmful effects are not the aim of the act and the good effect is nota direct cause-and-effect result of the harmful effect;the intended good effect is as great as or greater than the harmfuleffects and proportionate to them.Because of this ethical complexity, some authors suggest that deceased donor PKTshould only be performed in places with high transplantation rates and reduced timeon the waiting list. Because of these controversies, national transplant policies in somecountries have restrictions that prevent a larger adoption of PKT worldwide. InThailand, for example, PKT can only be performed in live kidney transplantrecipients. In Spain, deceased donor PKT is usually available only after depletionof the waiting list.Indeed, ethical issues of PKT have been widely discussed in the last decades: ≤ 18 years old and eGFR < 15 mL/min/1.73 m2 or;2 or;> 18 years old and eGFR < 10 mL/min/1.73 m2Diabetic patients and eGFR < 15 mL/min/1.73 mIn Brazil, PKT can be legally performed not only for living donor kidney transplantsbut also for deceased donor kidney transplantation. According to the Ordinance2600/2009, the in-state donation rate must be equal to or greater than the nationalaverage donation rate to allow deceased donor PKT within the respective Brazilianstate. In Brazilian states where deceased donor PKT is permitted, the recipient muststill meet one of the following criteriaLate referral to the nephrologist, which makes PKT not a possible treatment optionfor many ESKD patients, is another significant barrier. A careful clinicalevaluation before kidney transplantation is mandatory, including not onlycomorbidities and possible contraindications, but also the patient’s lifestyle, pastclinical history, family history, and associated risks. This assessment usuallytakes time, and when there is a late referral, the patient and transplant team donot have enough time to perform a careful PKT evaluation before renal replacementtherapy is formally indicated.Therefore, the patient and medical team must be aware of the path to be followed fromdiagnosis of chronic kidney disease (CKD) to the possibilities of choosing renalreplacement therapies. It is also crucial that transplant centers are accessible toall patients and that their protocols are well clarified for professionals whoassist these patients with CKD under conservative treatment.We must consider that excluding PKT from therapeutic possibilities may mean deprivingthis patient of a valuable treatment alternative and all its advantages. Therefore,the first step is to invest in measures that address the main barriers, such asadequate education and training for patients and healthcare professionals. .Due to the aforementioned benefits, one may believe that PKT should be performed assoon as clinically and ‘ethically’ possible. However, it is not easy to define thebest moment for PKT. Although ‘early’ PKT could be theoretically desirable in orderto maximize benefits for patients, we have to avoid initiating renal replacementtherapy before irreversible kidney failure. A few studies have tried to answer thisquestion and define the best moment to perform a PKT2 , Group 2: 10.0–14.9mL/min/1.73 m2 , and Group 3: ≥15.0 mL/min/1.73m2 . This study concluded that PKT in the groupwith the most preserved GFR did not improve allograft survival after kidneytransplantation compared to PKT with lower pre-transplant GFR.A study evaluated 671 PKT (first and kidney-only) performed between 1984-2006 at twoUS centers and showed that higher pre-transplant kidney function was associated withbetter kidney function after transplantation. However, the difference in kidneyfunction decreased over the first year. Higher allograft survival was not evidencedin recipients with higher pre-transplant GFR. Patients were divided in three groupsbased on pre-transplant kidney function estimated by MDRD equation: group 1:<10.0 mL/min/1.73 m. A study enrolling 19,471 PKT recipients between 1995 and 2009 from theUnited Network for Organ Sharing (UNOS) cohort evaluated patterns and implicationsof transplant timing in PKT. Again, this study did not find differences in patientsurvival or death-censored allograft survival between patients with different GFR atPKT – either in the entire cohort or in subgroup analyses of patients that couldpotentially benefit from ‘early’ PKT.Studies have consistently failed to demonstrate advantages in allograft survival with‘early’ PKT.It is worth noting that the studies mentioned above did not consider the benefits ofnot having the patient undergo maintenance dialysis. Patients who remain on dialysisfor a long period have higher mortality than transplanted patients2 for most patients,but the final decision must consider several factors, such as the clinicalcondition, the rate of decline of the native kidney function, and ethical issues. Anindividualized approach and a shared decision-making process whenever possible arehighly recommended.Taken together, the studies suggest that ‘early’ PKT does not provide benefits topatients. In contrast, it might anticipate potential surgical risks to bothrecipients and donors. Therefore, the ideal time to perform PKT seems to be whenpatients have the lowest level of kidney function that keeps them without uremic orcongestive signs and symptoms. Although preparation should indeed be started early,we must avoid performing a PKT when there is still a significant residual kidneyfunction. This threshold is usually 15 mL/min/1.73 m. Therefore, kidney transplantation, preemptive or not, should always beencouraged, except when the procedure is contraindicated or refused. The patientshould start its preparation from the moment of CKD diagnosis.Kidney transplantation is superior to dialysis for most patients and provide betterquality of life and survival advantages. Diabetics and children are often the most favored groups. However, the indication for PKT should not be restricted to thesepatients.PKT has the advantage of eliminating risks associated with long-term dialysis2 if the irreversibility of kidney damage is confirmed. Some studies suggest there is no benefit in transplanting a patient witheGFR >15 mL/min/1.73 m2, except in those who already have uremic signsand symptoms, which might occur among patients with diabetes.Most policies of organ allocation accept the preemptive listing of patients with eGFR<15 mL/min/1.73 m. Echocardiography is always indicated for suspected or confirmed cases ofheart failure or valvular heart disease. For patients at increased risk of coronaryartery disease, investigation of peripheral vascular disease through Doppler shouldbe considered.PKT can be performed with a living or a deceased donor, and preparation for PKTusually follows the same recommendations and protocols for non-PKT. Theinvestigation of PKT candidates aims to identify conditions that increase thepatient’s surgical risk and/or that may reduce the chances of the procedure’ssuccess. It is important to carry out a careful anamnesis, investigating data suchas family history and medical history. For patients at high risk, cardiovascularassessment is necessary. There is no consensus regarding the indication forpre-transplant catheterization. In general, it is recommended for high-riskpatients, including those with diabetes and a history of ischemia. Chest radiography should be ordered to investigate active infections or todetect, in combination with other exams, latent infections such as tuberculosis.Upon admission for transplantation, active acute infections must beinvestigated.Infectious diseases should also be part of the investigation while preparingpotential PKT recipients. It is recommended that at least serology be performed toinvestigate for hepatitis B, hepatitis C, and HIV. Other serologies, such ascytomegalovirus and toxoplasmosis, are useful in post-transplant follow-up and arerecommended by many transplant centers. In some countries, such as Brazil, theseserologies are mandatory exams. Additional investigation to exclude arbovirusinfection can be necessary in case of clinical suspicion, especially in endemicregions and during outbreaks. Information regarding miscarriages in women or other events suggestive ofcoagulation abnormalities should not be ignored. Although they are not a barrier fortransplantation, the existence of these pathologies changes pre-, intra-, orpostoperatively management. The contraindications are summarized in Simultaneous pancreas-kidney transplantation should be considered for diabetic patientsIt is noteworthy that, although there are mandatory exams in the preparation ofcandidates for transplantation, patient assessment must be individualized andcarried out according to comorbidities and risks. Transplantation centers usuallyhave their own protocols, which include a list of exams to ensure safe investigationin compliance with local government regulations and policies, and consider theepidemiology of infections and structural difficulties of each service. 2) at the time of transplantation do not appear to have additionalbenefits. The nephrology community must encourage global initiatives to betterunderstand the barriers and facilitate access to PKT.PKT provides better post-transplant clinical outcomes, a better quality of life, andeconomic benefits than dialysis. However, the percentage of preemptive transplantsperformed annually worldwide remains low. There are several for this, such asethical issues, late referral to the nephrologist, patient and medical teameducation, and a time-and energy-consuming donor evaluation process. Preparingpatients for PKT is similar to non-PKT ones, but defining the right moment toperform it is not trivial. Avoiding PKT when there is still a significant residualkidney function is recommended as patients with higher GFR (>15 ml/min/1.73m


Aims/Introduction: Diabetic kidney disease (DKD) is defined as diabetes with impaired renal function, elevated urinary albumin excretion, or both. DKD is one of the most common microvascular complications of diabetes and plays an important role in the cause of end-stage renal disease (ESRD). About 5% of people with type 2 diabetes (T2DM) already have kidney damage at the time they are diagnosed, but other triggers of renal insufficiency, such as obesity, hyperlipidemia, glomerular atherosclerosis are often present, making it difficult to define “diabetic kidney disease” or “diabetic nephropathy” precisely in epidemiology or clinical practice. Therefore, the aim of this study is to identify diabetic patients with CKD at an early stage, and evaluate the value of tubular injury markers including α1-microglobulin (α1-MG), β2-microglobulin (β2-MG), N-acetyl-beta-D-glucosaminidase (NAG) and Urinary retinol binding protein (URBP) in the development of diabetes to DKD.Materials and methods: We recruited a total of 182 hospitalized patients with T2DM in the First Affiliated Hospital of Zhengzhou University from February 2018 to April 2023. We collected basic clinical characteristics and laboratory biochemical parameters of the patients. Based on their levels of urinary albumin creatinine ratio (UACR) and glomerular filtration rate (GFR), patients were divided into DM group  and DKD group  excluding other causes of chronic kidney disease. We further developed diagnostic models to improve the ability to predict the risk of developing DKD by screening potential risk factors using univariate and multivariate logistic regression analysis. Calibration plots and curve analysis were used to validate the model and clinical usefulness. Next, we screened patients with relatively normal estimated glomerular filtration rate (eGFR) (≥90 mL/min/1.73 m2) to investigate whether tubular injury markers could accurately predict the risk of DKD in patients with normal renal function. We defined the rate of GFR decline as a prognostic indicator of renal function in patients and collected the information of the re-hospitalized DKD patients to determine whether the relevant indicators had an impact on the renal prognosis.Results: The patients with DKD had higher levels of tubular injury markers than patients with DM. URBP, α1-MG, eGFR were statistically different in both univariate and multivariate logistic regression analyses and displayed great predictive power after modeling with an area under curve of 0.987. The calibration curve showed medium agreement. Decision curve showed it would add more net benefits for clinical decision. After adjusting eGFR and serum creatinine (Scr), URBP was demonstrated to be associated with early renal function impairment.Conclusion: Tubular injury markers play an important role in early diabetic renal function impairment. About 30%–40% of patients with both type 1 diabetes (T1DM) and type 2 diabetes (T2DM) experience renal impairment  and apprIn clinical work, the only gold standard for the diagnosis of diabetic nephropathy is still renal biopsy. However, it cannot be done in some individuals. As an invasive tool, renal biopsy can only be performed in those who do not have contraindications. On the other hand, renal biopsy is relatively expensive. As a result, it is still diagnosed based on its clinical presentation in most clinical work. According to relevant guidelines, screening and staging of early diabetic kidney disease is based on levels of albuminuria and eGFR . EspeciaAs low molecular weight proteins, α1-microglobulin (α1-MG) and β2-microglobulin (β2-MG) has properties that are readily filtered by glomeruli and reabsorbed and catabolized by proximal tubular cells and as a marker of tubular function injury has also been studied in other types of diseases . In one Therefore, the aim of this study was to evaluate the role of tubular injury markers including α1-MG, β2-MG, NAG and URBP in the development from diabetes to diabetic kidney disease. By assessing individual risk factors, physicians and patients can take more timely measures on lifestyle management such as low-salt and low-fat diabetic diet and medical intervention.2, n = 63) and DKD group . A total of 182 patients including 63 DM and 119 DKD were enrolled in this study.In this retrospective analysis, we screened all diabetic patients who were hospitalized at the First Affiliated Hospital of Zhengzhou University from February 2018 to April 2023. Criteria for inclusion were as follows: 1) complete four markers of tubular injury, 2) age 18–80 years, 3) diagnosed as T2DM.The exclusion criteria were severe liver disease, malignancy, autoimmune disease such as systemic lupus erythematosus and schizophrenia. According to the level of UACR, they were divided into DM group , systolic blood pressure (SBP) and diastolic blood pressure (DBP). The laboratory indices included Serum potassium, Serum sodium, Serum calcium, Urea nitrogen, Serum creatinine (Scr), uric acid (UA), total cholesterol (TC), high density lipoprotein (HDL), low density lipoprotein (LDL), albumin (ALB) levels, triglyceride (TG), eGFR, red blood cell (RBC) count, white blood cell (WBC) count, platelet (PLT) count, hemoglobin (Hb), 24-hour uric total protein (24-hour TP), urinary α1-MG, β2-MG, NAG, and RBP levels.n = 35) and a training group (n = 147). Because the distribution of some continuous variables in this study was not normal, and the difference between the two groups was too large, we performed natural logarithm transformation of α1-MG, β2-MG, and URBP before analysis to reduce the error caused by the analysis. We used descriptive statistics of variables to describe the characteristics of each group. Continuous variables were described by mean and standard deviation if the data followed a normal distribution, or median and interquartile range if they did not. Data analysis was performed using R software (version 4.3.0) and SPSS 25.0.Patients with DKD or DM were randomly assigned to a validation group  and the area under the curve (AUC) was used to evaluate the diagnostic efficiency of the model. Calibration curves were used to evaluate the calibration of the DKD incidence risk nomogram. Next, we used the meaningful variables to draw nomograms for clinical application. Decision curve analysis (DCA) was used to verify the clinical utility of the nomogram . Baseline characteristics for all patients are presented in All screened T2DM patients were divided into DKD and DM groups according to the UACR levels. Among all patients, there were 121 males (66.5%) and 61 females (33.5%). The mean age was 54.2 ± 10.4 years in DM group and 51.6 ± 11.2 in DKD group (range 18–80 years). Tubular injury markers were significantly increased in the DKD group compared with the DM group (n = 147) and a validation group (n = 35). There were roughly no statistically significant differences between these variables, illustrating the similar clinical profiles between the two groups in All patients with DKD and DM were randomly divided into a training group  in the DKD group and matched eGFR and creatinine in both groups so that there was no statistically significant difference of those two indicators. The basic characteristics between the DM and DKD groups is shown in p < 0.05) play an important role in early prediction of renal impairment.To investigate whether tubular injury markers could accurately predict the risk of DKD in patients with normal renal function, we screened patients with relatively normal eGFR  may play an important role in early prediction of renal impairment with normal renal function. We also collected follow-up information from part of patients, compared the decrease of eGFR over a period time. And we found the level of tubular injury markers did not correlate with renal prognosis which were rarely studied in related fields.In this retrospective case–control study, we collected and analyzed the laboratory examination of 182 patients with DM and DKD. We established a clinical diagnostic model using three indicators including eGFR, and URBP and improved ability to predict risk of DKD. In addition, we found that URBP  . Therefop < 0.001). Besides, our study found that NAG did not correlate greatly with the rate of glomerular decline. Furthermore, a similar study from Japanese showed that in a cohort of patients with DKD confirmed by renal biopsy, assessment of urinary NAG levels did not add prognostic value (This study found that NAG was the risk factor for DKD in patients with T2DM. N-acetyl-b-D-glucosaminidase (NAG) is a lysosomal brush border enzyme that is localized in the microvilli of renal tubular epithelial cells. Because NAG has a large molecular weight (>130 kD), it does not filter through the glomeruli unless tubular injury occurs . Urine Nic value .p < 0.01)  , which iα1-MG is a low-molecular-weight glycoprotein, which is a hydrophobic ligand-binding protein. Like RBP, the free form is easily filtered by the glomerulus, but almost all of it is absorbed and metabolized by the renal tubules. Thus, increased urinary excretion of α1-MG suggests impaired proximal renal tubule function . There i2) compared with nondiabetic control subjects. These data illustrate that tubular markers have an important role in the early development of renal function impairment in diabetic patients (β2-MG is a 99 amino acid single chain polypeptide with a molecular mass of 11,800. Its filtration in the glomeruli and reabsorption in the renal tubules are like to RBP that can be filtered freely from glomeruli and almost completely absorbed by renal tubules . Xu Jianpatients . In othepatients . Althougpatients . But in The decision curve showed the clinical utility of our model, indicating it may be beneficial for clinicians to diagnose the disease by using our model. The results of decision curves suggest the good clinical application value of our model.In summary, our model can improve the ability to predict the risk of DKD in clinical work. Through the estimation of individual risks, clinicians and patients can take more precise measurements in lifestyle monitoring and medical intervention. Compared to renal biopsy, our nomogram is noninvasive and does not have any contraindications. In addition, laboratory parameters in nomograms are easily measured. There are also several limitations in our current study. First, our sample size is not large. Second, it is a single-centered study. Third, the diagnosis of diabetic nephropathy is based on clinical criteria and is not as precise as renal biopsy.


The use of a distributional regression method and precise methods for measuring exposure and outcome were necessary to detect an unfavorable association between BP and GFR in this study of the general population.The results of randomized controlled trials are unclear about the long-term effect of blood pressure (BP) on kidney function assessed as the glomerular filtration rate (GFR) in persons without chronic kidney disease or diabetes. The limited duration of follow-up and use of imprecise methods for assessing BP and GFR are important reasons why this issue has not been settled. Since a long-term randomized trial is unlikely, we investigated the association between 24-h ambulatory BP (ABP) and measured GFR in a cohort study with a median follow-up of 11 years. The Renal Iohexol Clearance Survey (RENIS) cohort is a representative sample of persons aged 50 to 62 years without baseline cardiovascular disease, diabetes, or kidney disease from the general population of Tromsø in northern Norway. ABP was measured at baseline, and iohexol clearance at baseline and twice during follow-up. The study population comprised 1589 persons with 4127 GFR measurements. Baseline ABP or office BP components were not associated with the GFR change rate in multivariable adjusted conventional regression models. In generalized additive models for location, scale, and shape (GAMLSS), higher daytime systolic, diastolic, and mean arterial ABP were associated with a slight shift of the central part of the GFR distribution toward lower GFR and with higher probability of GFR < 60 mL/min/1.73 m Whereas randomized controlled trials (RCTs) have established hypertension as a cause of cardiovascular disease beyond a reasonable doubt, similar high-quality evidence does not exist for the prevention of chronic kidney disease (CKD) by treating primary hypertension in persons without diabetes6. Indeed, at least two RCTs have found an adverse effect of intensified antihypertensive treatment on the glomerular filtration rate (GFR)5. Although this may have been caused by short-term hemodynamic changes that may ultimately lead to beneficial long-term effects, this remains unproven because of the limited duration of follow-up in the RCTs5.High blood pressure (BP) is the leading risk factor for death and loss of disability-adjusted life years globally and is an important risk factor for end-stage kidney disease (ESKD)7. In the longitudinal population-based Renal Iohexol Clearance Survey (RENIS), we did not find an association between elevated BP and accelerated mean GFR decline in the general middle-aged population over a median follow-up of 5.6 years9. We hypothesized that additional genetic and environmental factors are necessary for elevated BP to cause CKD in some individuals after an even longer observation period.The lack of definitive evidence for the causal association between high BP and loss of kidney function has raised doubts about whether nonmalignant primary hypertension is a cause of CKD in persons without diabetes. In a study of kidney biopsies from live kidney donors by Denic et al., mild hypertension was not associated with the number of nephrons, the single-nephron glomerular filtration rate (GFR), or the total GFR10.In the present study, we investigated this hypothesis by analyzing baseline 24-h ambulatory blood pressure (ABP) as a risk factor for change in the GFR measured as iohexol clearance after a follow-up of more than ten years. Since conventional least squares regression methods only analyze changes in the mean of the GFR distribution while assuming its other properties to be constant, we used distributional regression to analyze the associations between ABP and the time change of different percentiles of the GFR distribution11. The RENIS cohort was recruited from all persons between 50 and 62 years of age examined in the sixth Tromsø Study. All persons without self-reported cardiovascular disease, kidney disease or diabetes mellitus were invited, and 1627 persons were included in random order until a prespecified target was met. The cohort underwent measurements of plasma iohexol clearance at baseline in 2007–2009 (RENIS-T6), in 2013–2015 (RENIS-FU) and in 2018–2020 (RENIS-3)  is a substudy of the Tromsø Study. The Tromsø Study has invited random samples of the general population of the municipality of Tromsø in northern Norway to a series of repeated health surveysThis study complied with the Declaration of Helsinki and was approved by the Regional Committee for Medical and Health Research Ethics of Northern Norway. All subjects provided a written informed consent.The investigations were performed at the Clinical Research Unit of the University Hospital of North Norway. The participants answered questionnaires that included questions about previous diseases, alcohol use, smoking habits, and current medication. Alcohol use was analyzed as a dichotomous variable for the weekly use of alcohol or not. Smoking was analyzed as the number of cigarettes per day currently used. Antihypertensive medication was analyzed as separate dichotomous variables for the use of ACE inhibitors, A2 receptor blockers, beta-blockers, calcium blockers, diuretics or other antihypertensives.14 and has been described in detail previously15. Five millilitres of iohexol were injected intravenously and a sample obtained for iohexol measurement at the optimal sampling time for each person calculated by Jacobsson’s equation16. GFR was calculated by a numerical solution of Jacobsson’s three equation 16. To avoid confounding from changes in body size, absolute GFR in mL/min was used. Body surface area-indexed GFR was analyzed in a sensitivity analysis17. Body surface area was estimated by the equation of DuBois and DuBois17.GFR was measured as single-sample plasma iohexol clearance, which has been validated against gold standard methods18. The criteria for a valid ABP measurement were adopted from the International Database on Ambulatory Blood Pressure in Relation to Cardiovascular Outcome study19. Attended office BP was measured after 2 min of rest in the seated position with an automated device  by a study nurse18. The daytime to nighttime systolic and diastolic dips were analyzed as one minus the ratio of the mean nighttime to daytime systolic BP (SBP) or diastolic BP (DBP). Ambulatory mean arterial pressure (MAP) was defined as DBP + ((SBP − DBP)/3).Twenty-four-hour ABP was initiated at the day of the baseline GFR measurement using the Spacelab 90207  as described previously20.Office hypertension was defined as office SBP ≥ 140 mmHg or office DBP ≥ 90 mmHg or the use of antihypertensive medication according to the guidelines of the European Society of Hypertension18. The urine albumin-creatinine ratio (ACR) was measured as the median of ACR measured on three separate days21. Serum creatinine was measured using an enzymatic assay standardized to the isotope dilution mass spectrometry method . Cystatin C was measured by a particle-enhanced turbidimetric immunoassay  calibrated to the international reference ERM-DA471/IFCC as described previously22. Estimated GFR (eGFR) was calculated using the original Chronic Kidney Disease Epidemiology Collaboration equations published in 2009 and 2012 24.Fasting serum glucose, creatinine, cystatin C, triglycerides, and LDL- and HDL-cholesterol were measured with standard methods as described previously20. Differences across the ABP levels were analyzed with two-sample t-tests, Wilcoxon rank-sum tests or tests of proportion as appropriate.The baseline characteristics of the cohort are given as the mean (standard deviation) or median (interquartile range) for ABP < or ≥ 130/80, the threshold for hypertensive 24-h ABP according to the European Society of Hypertension26. GAMMs are a generalization of linear mixed models where nonlinear effects of the independent variables can be modeled. The reason for using GAMMs and not linear mixed models was that a previous investigation in the RENIS cohort found sex-specific nonlinear relationships between mean GFR and time12. Accordingly, we adjusted for these relationships in the GAMMs.We first investigated the relationship between mean GFR and the BP components with general additive mixed models (GAMM)28.The GAMMs had GFR as the dependent variable and a linear term for each BP component as the independent variable in separate models. The models included a random intercept and slope and an unstructured covariance matrix. We analyzed office and ambulatory daytime and nighttime SBP, DBP, and MAP as well as the systolic and diastolic nighttime BP dips. We included both the linear main effects of these BP components and their interaction with time. The coefficient for this interaction represented the association between the component and the GFR change rate. A negative sign for the coefficient signified a steeper GFR decline. The time variable was defined as years since baseline. In addition to the sex-specific nonlinear time variables, we included two sets of linear baseline adjustment variables, including their interactions with time: Model 1: sex and sex-specific variables for baseline age, body weight, height, and dichotomous variables for each class of antihypertensive medication. Model 2: As Model 1 with the addition of pulse frequency, fasting glucose, triglycerides, LDL- and HDL-cholesterol, number of cigarettes currently smoked per day, and a dichotomous variable for weekly alcohol use. Model 3: As Model 2 with the addition of ACR. All study participants were included in the GAMM analyses regardless of whether they were examined at follow-up because mixed models allow for missing observations at one or more points in time29. The GFR distribution used in this investigation was the sinh-arcsinh (SHASH) distribution30, which is specified by the four parameters location, scale, skewness, and tailweight. Variations of these four parameters permit greater flexibility in the probability distribution that can be modeled than the usual normal distribution . Conventional least squares regression methods analyze the effect of exposures on the mean of outcomes, whereas other aspects of their probability distributions are assumed to be independent of the exposures. GAMLSS relaxes these assumptions and analyzes the effects of the exposure on the total outcome distribution31. The p-value for the nonlinear interaction between the ABP component and time for each SHASH parameter in each best-fitting model was used to judge whether there was a time-dependent association between the ABP component and the development of the GFR distribution. The finding of an association implied that the corresponding ABP component was a risk factor for time change in the GFR distribution. The p-value for the nonlinear main effect of an ABP component in each best-fitting model was used to judge whether there was a time-independent cross-sectional association between the BP component and GFR.To find the simplest model consistent with the data, we compared the fit of models with the four SHASH parameters specified above with models where one or more of the nonlinear functions for scale, skewness or tailweight were replaced by a constant. Models with all eight possible combinations of replacement by a constant for these three parameters were examined. The Akaike Information Criterion (AIC) was used to compare the fit of the modelswww.stata.com) and R version 3.6.3 (www.r-project.org) were used for the analyses in this study. The mgcv and mgcViz packages of R were used for the analyses with GAMM and GAMLSS26. Statistical significance was set at p < 0.05.STATA/MP 17.0 (12. The median (IQR) (range) follow-up was 10.7 (6.4–11.3) (0–12.8) years.Valid ABP measurements were obtained for 1608 (99%) of the 1627 persons included at baseline. Because of missing values for some of the adjustment variables for 38 persons Table , the stucrea, eGFRcys, eGFRcyscrea, smoking, alcohol use or LDL-cholesterol.Most baseline characteristics Table , includiThere were no statistically significant linear associations of any of the investigated BP components with the mean GFR change rate in the GAMMs in the fully adjusted model Table . SensitiGAMLSS with nonlinear functions for location, scale, and skewness, but with a constant tailweight parameter, had the lowest AIC and best fit for all of the ABP components except nighttime DBP  Table . AccordiIn contrast, all of the ABP components demonstrated cross-sectional time-independent associations with the location and scale parameters (p < 0.05) Table . The dayThe corresponding predicted time change of the 10th, 25th, 50th, 75th and 90th percentiles of the GFR distribution for daytime ABP at the mean of the adjustment variables are shown in Fig. At baseline, Fig. Sensitivity analyses with office BP components in the best fitting GAMLSS in Table 2 are shown in Fig. 25. For women, the difference in probability between the 95th and 5th percentiles for daytime SBP was 0.05 (95% CI 0.03 to 0.09), for daytime DBP 0.03 (95% CI 0.002 to 0.07) and for daytime MAP 0.05 (95% CI 0.02 to 0.09). For men, the same differences were 0.04 (95% CI 0.02 to 0.07), 0.02 (95% CI -0.01 to 0.04) and 0.03 (95% CI 0.01 to 0.06).Based on the best fitting GAMLSS for daytime ABP, the predicted ten-year probabilities of a GFR lower than 60 mL/min/1.73 mWe compared the fit of GAMLSS for daytime ABP in Table crea, eGFRcys or eGFRcyscrea for GFR as the dependent variable in the fully adjusted GAMM and GAMLSS models demonstrated substantial differences between measured GFR and eGFR, and between the three different eGFRs (see Supplementary Results, Tables Substituting eGFRThis study found no association between elevated baseline BP and long-term mean GFR in the multivariable-adjusted conventional regression models Table . With a crea32. The authors found no association between SBP and incident CKD but did not report results for DBP. Several differences between the study population and methodology may account for the differences from our study, of which the most important were a low participation rate, the use of estimated GFR and the lack of any adjustment for antihypertensive medication32.To our knowledge, the only other longitudinal investigation of ABP and kidney function in a population-based study was McMullan et al.’s study of ABP and eGFR52, there is no conclusive evidence from RCTs that antihypertensive treatment prevents kidney dysfunction, except in patients with CKD or diabetes5. In a meta-analysis of RCTs with 78,931 participants, BP-lowering treatment had no effect on the risk of kidney failure6. However, the short median follow-up of only 3.4 years of the included studies was a major limitation, which may explain why beneficial effects were difficult to detect.Considerable uncertainty exists about the effects of BP on GFR. Although most longitudinal observational studies have found an association between BP and subsequent GFR decline, incident CKD or ESKD12. Because this effect was included as an adjustment in the GAMLSS in this investigation, its predictions differed between the two sexes due to the nonlinearity of the models, although the overall pattern of changes was the same.We found different predicted time changes in the GFR for women and men Figs.  and 5, e53, there is also evidence of an association between hypertension and hyperfiltration from a recent Mendelian randomization study54 and from the initial drop in GFR when antihypertensive treatment is started in RCTs57. This drop has been interpreted as a beneficial effect of reducing hyperfiltration58. Our results suggest that hyperfiltration may persist longer than previously thought in some persons. The ultimate consequences of this are unclear.The time change in the GFR distribution showed a paradoxical high GFR with an increasing trend for high daytime ABP Fig. . In addi59. The associations between ABP and GFR in younger people could have important implications for antihypertensive therapy and should be explored further.Whereas the aim of this study was to study the time change in the GFR distribution, there were statistically significant cross-sectional time-independent associations between all of the ABP components and SHASH parameters Table . This in65. Accordingly, caution should be applied when using eGFR in studies of BP and GFR. Also, office BP did not identify time-dependent associations with the GFR distribution (Table 67 and in CKD patients68.The current study illustrates how different methods influence the results of an observational study of BP and GFR. In addition to the regression model, the method for assessing GFR is decisive: the results when using the eGFRs differ from the measured GFR and between each other Tables  and S8. on Table . This su52. Comorbidities that could mediate an indirect effect of BP on GFR may inflate the BP effect, but few previous studies excluded subjects with CVD or diabetes or adjusted for these conditions38. We studied a representative sample of the general population without CVD or diabetes, which is a further strength of our investigation.The most important strengths of the present study are its use of iohexol clearance and ABP, which are gold standard methods for assessing GFR and BP. To our knowledge, the duration of follow-up also exceeds all previous observational studies and RCTs studying the association between BP and GFR decline, except for two studies with a follow-up of 30 years69. Although there were no linear associations between BP and GFR change in fully adjusted GAMMs, a larger study with greater statistical power may have been able to detect the small effects found with GAMLSS. ABP was only measured at baseline, and we did not consider changes in BP during follow-up. A sensitivity analysis after excluding observations with antihypertensive medications did not indicate that changes in antihypertensive medication during follow-up were important for the results. The study participants were of European ancestry, limiting the generalizability. Since we are not aware of any other population-based cohorts with ABP and serial measurements of GFR, external validation of our findings is currently not possible.The main limitation of this study is that inferences about causality cannot be made from observational studies. The direction of any causal connection between ABP and GFR is also uncertain, as subclinical kidney damage has been suggested as a cause of primary hypertensionWe conclude that investigations of the relationship between BP and kidney function depend critically on the methods for assessing BP and GFR as well as on the statistical methods. By using measurements of GFR and ambulatory BP in a model that relaxes the restrictive assumptions of conventional regression methods, we found that elevated daytime ABP was associated with a shift in the GFR distribution toward lower GFR. This will only be associated with a modest acceleration of GFR decline in most people but increases the risk of CKD. The genetic and environmental causes of low GFR in a minority of persons with high ABP are clinically important and should be the subject of further research. The potential for preserving GFR in these persons through antihypertensive treatment should also be explored, ideally in a long-term RCT with change in measured GFR as the endpoint.Supplementary Information.


The endotracheal cuff pressure depends on the airway pressure during positive-pressure ventilation. A high endotracheal cuff pressure may be related to intraoperative coughing, which can be detrimental during neurosurgery. We investigated the incidence of intraoperative coughing and its association with peak inspiratory pressure (PIP) during neurosurgery under general anesthesia without neuromuscular blockade.2O, n = 318) and low  PIP groups. After propensity score matching, 206 patients were selected in each group. Demographic, preoperative, surgical, and anesthetic data were collected retrospectively from electronic medical records and continuous ventilator, infusion pump, and bispectral index data from a data registry.This retrospective study divided 1656 neurosurgical patients who underwent total intravenous anesthesia without additional neuromuscular blockade after tracheal intubation into high (PIP > 21.6 cmHIntraoperative coughing occurred in 30 (1.8%) patients, including 9 (0.5%) during the main surgical procedure. Intraoperative coughing was more frequent in the high PIP group than in the low PIP group before  and after  propensity score matching. In multivariable logistic regression analysis after propensity score matching, a high PIP , tidal volume divided by predicted body weight , and surgical duration  predicted intraoperative coughing.The incidence of intraoperative coughing was 1.8% in neurosurgical patients undergoing general anesthesia without neuromuscular blockade and might be associated with a high PIP.The online version contains supplementary material available at 10.1186/s12871-023-02080-6. An endotracheal tube is commonly inserted and maintained for mechanical ventilation during surgery under general anesthesia. However, it can induce some discomfort secondary to tracheal mucosa irritation, resulting in coughing or bucking. During neurosurgery, the risk for intraoperative coughing is relatively high, because the use of neuromuscular blocking agents (NMBAs) is often restricted to enable intraoperative motor evoked potential monitoring . MoreoveCauses of intraoperative coughing under general anesthesia include too light anesthesia, inadequate local anesthesia in the larynx, insufficient neuromuscular blockade, movement of the endotracheal tube or patient’s head, inflation or deflation of the endotracheal cuff, and endotracheal or endobronchial suction . HoweverThe endotracheal cuff pressure is positively correlated with the airway pressure during positive-pressure ventilation . Increas(primary outcome measure) in neurosurgical patients undergoing general anesthesia without neuromuscular blockade.Therefore, this retrospective study investigated the incidence and timing of intraoperative coughing and evaluated the association between a high PIP and intraoperative coughing Prior to data collection, the Institutional Review Board of Seoul National University College of Medicine/Seoul National University Hospital approved this study  and waived the requirement for informed consent. This paper adhered to the Strengthening the Reporting of Observational Studies in Epidemiology statement and all methods were carried out in accordance with the Declaration of Helsinki.This retrospective study involved patients who underwent neurosurgery under total intravenous anesthesia (TIVA) with tracheal intubation and should not have received neuromuscular blockade after tracheal intubation between December 2017 and November 2019. Patients who had no data from the ventilator in the registry file, underwent relatively light anesthesia  for deep brain stimulation, or received additional NMBAs during surgery were excluded.All data were collected retrospectively. Demographic , preoperative , surgical , and anesthetic (administration of NMBAs) data were obtained from electronic medical records. Continuous data from the ventilator , infusion pumps (effect site concentration [Ce] of propofol and remifentanil), and BIS monitor  were obtained from a data registry  that stores these data automatically with a temporal resolution of 500 Hz . In patiIntraoperative coughing was usually documented in the anesthetic records. Intraoperative coughing was identified by checking the anesthetic records for a record of intraoperative coughing and comprehensively analyzing several waveforms  recorded in the registry files . The registry files of all patients were screened to find any intraoperative coughing that was missing from the anesthetic records. When screening intraoperative coughing in the registry file, we first checked whether there was a moment when PIP increased rapidly during surgery. If present, then we checked for irregular changes in several waveforms  at that point. When it was difficult to determine whether intraoperative coughing was present by analyzing the waveforms, another anesthesiologist was asked to make a decision by analyzing the waveforms. The time point at which PIP began to rise abruptly was regarded as the onset of intraoperative coughing.If intraoperative coughing occurred, mechanical ventilation was stopped to avoid additional dyssynchrony with the ventilator and intravenous delivery of propofol and remifentanil was checked. After that, the target Ce of propofol and remifentanil was raised to suppress intraoperative coughing. Administration of NMBAs was not allowed because of motor evoked potential monitoring.2O. The endotracheal cuff pressure was not measured again or adjusted unless cuff leak was suspected. Mechanical ventilation was routinely maintained in volume-controlled mode with a TV of 8 mL/kg based on the predicted body weight (PBW) and a PEEP of 5 cmH2O [Without premedication, patients were monitored with noninvasive blood pressure measurement, peripheral pulse oximetry, and electrocardiography in the operating room. TIVA was induced with a target-controlled infusion of remifentanil (Ce = 4 ng/mL) and propofol (Ce = 4 µg/mL) using the Minto and Schnider models, respectively. Rocuronium (0.6–0.8 mg/kg) was administered only once during anesthetic induction to facilitate tracheal intubation and was not administered thereafter, in order to monitor intraoperative motor evoked potentials. The upper airway including larynx was not topically anesthetized. A reinforced endotracheal tube with an inner diameter of 7.5–8.0 mm was inserted in males and 7.0 mm in females. The endotracheal cuff was inflated to a manometer pressure between 20 and 30 cmH 5 cmH2O –12. ArteThe primary outcome measure was the association between high PIP and intraoperative coughing. The incidence, timing, and other perioperative predictors of intraoperative coughing were also investigated.To determine whether PIP is independently related to intraoperative coughing, patients were divided into high and low PIP groups based on the optimal cutoff value of PIP for intraoperative coughing, which is defined as a value maximizing the sum of sensitivity and specificity in receiver operating characteristic (ROC) analysis. Then, propensity score matching was performed in a 1:1 ratio to minimize biases resulting from imbalance in covariate distribution between the high and low PIP groups. All variables investigated in this study were used for propensity score matching except for PIP, BIS value, and fEMG. The variables included in propensity score matching were sex, age, body mass index, American Society of Anesthesiologists physical status, hypertension, diabetes mellitus, asthma, chronic obstructive pulmonary disease, smoking, obesity, cardiac disease, pulmonary disease, hepatic disease, renal disease, surgical type, surgical position, surgical duration, BIS monitoring, Ce of propofol and remifentanil, PEEP, and TV/PBW. Estimation and matching algorithms for propensity score matching were logistic regression and nearest neighbor, respectively, and caliper was 0.01.2 test or Fisher’s exact test according to the expected frequency of cells. Data for continuous variables are expressed as mean (standard deviation) or median (interquartile range) and compared using the Student’s t-test or Mann–Whitney U-test according to the normality of their distribution. To identify independent predictors of intraoperative coughing, four , and TV/PBW) and three , and TV/PBW) variables with P values < 0.05 in the univariable logistic regression analysis were entered into a multivariable logistic regression analysis before and after propensity score matching respectively. ROC analysis was used to evaluate the discriminative power of predictors, which was categorized into five grades based on the area under the curve (AUC): 0.5–0.6, fail; 0.6–0.7, poor; 0.7–0.8, fair; 0.8–0.9, good; 0.9–1.0, excellent. [The normality of data distributions was evaluated using the Shapiro–Wilk test. Data for categorical variables are expressed as number of patients (proportion) and compared using the Pearson’s χcellent.  The optiThis study considered 2182 patients who underwent neurosurgery under TIVA with tracheal intubation  patients, once in 29 (1.8%) patients and twice in 1 (0.1%) patient. Intraoperative coughing occurred before, during, and after the main surgical procedure  in 14 (0.8%), 9 (0.5%), and 7 (0.4%) patients, respectively. There were nine patients who needed additional assessment of the registry file by another anesthesiologist to confirm intraoperative coughing, and intraoperative coughing was finally identified in four patients of them.2O. Patients were divided into high  and low  PIP groups. After propensity score matching, all included variables matched well (P = 0.929) and no variables differed significantly between the high and low PIP groups (both n = 206), except for higher fEMG  in the high PIP group (n = 80) than the low PIP group  and its optimal cutoff value was 21.6 cmH2O, P = 0.007) and TV/PBW  were significantly higher and surgical duration  was significantly longer in patients with intraoperative coughing than in those without  and intraoperative  variables can help elucidate the exact mechanism of intraoperative coughing. Third, because the patients in this study underwent TIVA without additional administration of NMBAs during surgery, it is difficult to apply our results to neurosurgical patients who received NMBAs during surgery or patients who undergo inhalational anesthesia. Fourth, because the endotracheal cuff pressure was not measured continuously or strictly controlled throughout the surgery in this study, whether a high PIP results in intraoperative coughing by increased endotracheal cuff pressure is not fully investigated. The incidence of intraoperative coughing was 1.8% in neurosurgical patients under general anesthesia without neuromuscular blockade. A high PIP may be associated with intraoperative coughing in such patients.Below is the link to the electronic supplementary material.Supplementary Material 1