Diabetic donors are recognized as a reliable source of organs, although the discard rate of kidneys is still high. Few data are available on the histological evolution of these organs especially on kidneys transplanted into non-diabetic patients who remain euglycemic.We describe the histological evolution of ten kidney biopsies performed on non-diabetic recipients of diabetic donors.Mean donor age was 69 ± 7 years, 60% were males. Two donors were treated with insulin, eight with oral antidiabetic drugs. Mean recipient age was 59.9 ± 7 years, 70% were males. The pre-existing diabetic lesions identified in the pre-implantation biopsies, encompassed all histological classes, and were associated with mild IF/TA and vascular damages. The median follow-up was 59.5 [IQR 32.5–99.0] months; at follow-up, 40% of cases did not change histologic classification, two patients with class IIb downgraded to IIa or I and one with class III downgraded to IIb. Conversely, three cases showed a worsening, from class 0 to I, I to IIb or from IIa to IIb. We also observed a moderate evolution of IF/TA and vascular damages. At follow-up visit, estimated GFR was stable (50.7 mL/min vs. 54.8 at baseline) and proteinuria was mild (51.1 ± 78.6 mg/day).Kidneys from diabetic donors show variable evolution of the histologic features of diabetic nephropathy after transplant. This variability may be associated to recipients characteristics such as euglycemic milieu, in case of improvement, or obesity and hypertension, in case of worsening of histologic lesions. Diabetic donors (DD) are recognized as a reliable source of organs. In fact, Cohen et al. demonstrated that patients that received a DD kidney had a considerable survival benefit compared with patients who remained on the waitlist . NeverthThe available literature is mainly focused on the functional evaluation of the graft, while scarce is the histological evaluation of the lesions from diabetes comparing the pre-implantation versus the follow-up biopsies. Khan et al. analyzed the clinical and histological outcomes of diabetic or ND kidneys transplanted in recipients with or without diabetes. They focused their attention on the presence of mild diabetic nephropathy changes in post-perfusion biopsies and on the evolution towards stable or progressive nephropathy, identified in for-indication biopsies , 6. MoreOf note, all the studies mentioned above describe a population of donors relatively young and with low Kidney Donor Profile Index (KDPI), an index routinely used in the United States for the allocation of organs, that reflects the comorbidities of the donors and has a relationship with the outcome of the kidney, the higher (> 80%) the KDPI the lower the outcome. Indeed, data on the histological evolution and clinical outcomes of kidneys from DD with comorbidities that worsen KDPI, such as age or cardiovascular diseases, are still lacking.On our part, although in a small series of cases, this contribution is the first that addresses the histological evolution of diabetes and chronic lesions in a series of ND recipients of kidneys from diabetic donors.The aim of our study was to evaluate the changes in diabetic histological features in kidney transplant patients that received a diabetic donor organ. We performed a retrospective analysis of electronic medical records of deceased donors enrolled from 2004 to 2015 at the Sant’Orsola Hospital–University of Bologna, Italy. Among them, we selected all those with a diagnosis of type 1 and type 2 diabetes (T2D) prior to expiration and with an available pre-implantation kidney biopsy. We identified a case series of 10 kidney transplants whose recipients, at the time of analysis, had not a history of diabetes, were still on follow-up and had executed at least one biopsy, either for cause or per protocol , 11. CliClinical information on donors was obtained through the electronic medical records provided by the Regional Transplant Center of Emilia Romagna, based in Bologna, Italy. The clinical information recorded were age, sex, body mass index (BMI), history of hypertension, cardiovascular events, diabetes and relative drugs, type of death, KDPI, cold ischemia time, creatinine, GFR calculated using the CKD-EPI formula, proteinuria determined on urine spot collections. Clinical information on recipients was collected through the medical records available at the Kidney Transplant Center of Sant’Orsola Hospital–University of Bologna, Italy. The clinical information recorded were age, sex, BMI, original nephropathy, history of hypertension, cardiovascular events, diabetes and relative drugs, HLA matches, delayed graft function (DGF), creatinine, GFR calculated using the CKD-EPI formula, proteinuria determined on 24-h collection, immunosuppressive regimens. The study was authorized by the internal Ethical Committee (185/2020/Sper/AOUBo).The renal tissue was fixed in Serra solution and embedded in paraffin. Slices were cut at 3-µm thickness and stained with hematoxylin–eosin, periodic acid-Shiff and Masson’s trichrome stains. Transmission Electron Microscopy (TEM) was executed to measure the thickness of the Glomerular basement membrane (GBM). TEM was performed on specimens of renal tissue fixed in glutaraldehyde and was available for 7 patients. For the examination we used a Philips CM10  TEM equipped with Gatan camera; for each sample, five digital images were randomly acquired using the FEI proprietary software Olympus SIS-Megaview-SSD digital camera. GBM thickness was measured in twelve different positions, at 13,500 of magnification. Renal tissue specimens were scored by two pathologists not in contact with each other and unaware of the patient’s clinical data. Agreement between pathologists was calculated by means of Kappa Cohen coefficient of agreement. The discordant cases were discussed collegially. Samples were scored in accordance to the established histopathological classification of diabetic nephropathy (DN) . The DN Among the kidney recipients from diabetic donors, we isolated 10 patients that were non-diabetic neither pre- nor post- transplantation. The characteristics of donors and recipients are summarized in Tables 2; 70% of them were hypertense and 50% had a history of cardiovascular disease (CVD). All patients were T2D, on insulin therapy in two cases, and half of them were on oral antidiabetics. Mean serum creatinine at donation was 0.9 ± 0.2 mg/dl, eGFR 75.8 ± 18.9 ml/min/1.73 m2, urinary protein 10 ± 13 mg/dl, all ECD-DBD donors with a mean KDPI 95.7 ± 6.6% and mean cold ischemia time 13:19 ± 3:10 h.The mean age of donors was 69 ± 7.2 years-old, 60% of them were male, the mean BMI was 29.8 ± 5 kg/m2 at baseline  Diabetic nephropathy classThe coefficient of agreement was high as testified by the Kappa Cohen coefficient (K = 0.85). The evaluation of the biopsies according to the Banff classification  showed m(b) Interstitial fibrosis and tubular atrophy evaluationAccording to implantation biopsies, the most frequent DN class was IIa (50% of cases), IIb was present in two cases, and classes 0, I and III in the others. At follow-up, 40% of cases remained stable in class IIa , while two class IIb cases were downgraded to IIa and I patients 1 and 6), respectively, and one class III case to IIb (patient 4). We observed a worsening in three cases: from class 0 to I (patient 7), from class I to IIb (patient 10) and from class IIa to IIb (patient 9)  Vasculature evaluationInterstitial Fibrosis and tubular atrophy (IF/TA) scores showed not uniform changes. As shown in Table The DN arteriolar hyalinosis score improved in five patients, remained stable in three and worsened in two Table . The artDiabetic donors’ potential to expand the donor pool has been extensively analyzed in large cohort studies; it has been ascertained that receiving a kidney from a DD does assure a survival benefit, compared to remaining on the waiting list and that patient and graft survival depend on the status of the recipient. Indeed, the worst outcomes are seen when diabetes is present in both the donor and the recipient, and the diabetic recipient of a non-diabetic kidney has a worse evolution then a non-diabetic recipient , 12, 13.The degree of chronic injury by IF/TA was evaluated in allocation biopsies and the damage was substantially mild or absent, while arterio-nephrosclerosis was of mild-to-moderate entity in the same samples. Aside from DN, these lesions reflect the coexistence of hypertension, observed in 70% of our donors, and of high body weight or obesity, present in all of them. At follow-up, these lesions showed stability or mild histological progression, which could reflect the persistence of risk factors for vasculature damage over time: as mentioned, all our recipients were hypertense, with a high body weight and, in one case, severely obese. Truong’s diabetic recipients had a percentage of IF/TA analogue to ours, but the vascular damage was more severe and already evident in the post-reperfusion biopsies; the entity of the damages kept worsening, while arterial intimal fibrosis and arteriolar hyalinosis encompassed all the histological grades till the most severe, maybe because of a longstanding diabetes , 15.In the context of kidney transplantation, chronic lesions of the tubulo-interstitium are the result of a number of processes that are still matter of debate; the ones identified in our patients were, for example, hypertension, high body weight/obesity, accelerated atherosclerosis, calcineurin inhibitors toxicity, evolution of ischemia reperfusion injury, ageing, polymorphisms in cytokine genes etc., 21, 22.2) than the remaining ones (23.5 kg/m2) and were treated with a greater number of blood pressure lowering drugs (3 as mean). Moreover, it has been well demonstrated that obesity and hypertension interact each other in triggering the worsening of kidney damage [The donors in our cohort had the highest number of years 54–77 y–o) and KDPI 80–100%) compared to the other published records. Singh et al. have recently reported 10-year graft and patient survival data analyzing the mis- matches in donor and recipient diabetes status; they reported a mean donor age of 36–51 years in the different groups, while the donors in the group DD- ND recipient had a mean age of 47 and a mean KPDI of 71% [–77 y–o a0% compary damage . However


A relationship between the 2017 American College of Cardiology and American Heart Association blood pressure thresholds and adverse pregnancy outcomes has been reported, but few studies have explored the diagnostic test properties of these cutoffs.We systematically searched electronic databases (from 2017 to 2021) for reports of blood pressure measurements in pregnancy, classified according to 2017 American College of Cardiology and American Heart Association criteria, and their relationship with pregnancy outcomes.Studies recording blood pressure at <20 weeks gestation were included.Meta-analyses were used to investigate the strength of the association between blood pressure cutoffs and adverse outcomes, and the diagnostic test properties were calculated.Of 23 studies included, there was a stepwise relationship between the American College of Cardiology and American Heart Association blood pressure category  and the strength of the association with preeclampsia. The category of elevated blood pressure had a risk ratio of 2.0 , the stage 1 hypertension category had a risk ratio of 3.0 , and the stage 2 hypertension category had a risk ratio of 7.9 . Between-study variability was related to the magnitude of the association with stronger relationships in larger studies at low risk of bias and with unselected populations with multiple routine blood pressure measurements. None of the systolic blood pressure measurements of <120 mmHg, <130/80 mmHg, or <140/90 mmHg were useful to rule out the development of preeclampsia . Only a blood pressure measurement of ≥140/90 mmHg was a good predictor for the development of preeclampsia . The findings were similar for other outcomes.Although a blood pressure of 120 to 140 over 80 to 90 mmHg at <20 weeks gestation is associated with a heightened risk for preeclampsia and adverse pregnancy outcomes and may assist in risk prediction in multivariable modelling, lowering the diagnostic threshold for chronic hypertension would not assist clinicians in identifying women at heightened risk. A relationship between the 2017 American College of Cardiology and the American Heart Association blood pressure (BP) thresholds and adverse pregnancy outcomes has been reported, but few studies have explored the diagnostic test properties of these cutoffs.Although higher BP values <20 weeks gestation is associated with adverse outcomes, lowering the threshold for chronic hypertension would not improve the identification of women and babies at risk. No abnormal BP threshold <20 weeks gestation, including the current 140/90 mmHg threshold, provides reassurance about the development of preeclampsia or adverse pregnancy outcomes.Our findings do not support lowering the BP level component of the definition for chronic hypertension in pregnancy to below the current 140/90 mmHg threshold.Higher blood pressure (BP) measurements are associated with more adverse outcomes outside of and during pregnancy.In 2017, the American College of Cardiology (ACC) and the American Heart Association (AHA) recommended lowering the BP thresholds for diagnosis of hypertension outside of pregnancy based on the association of these lower BP values with elevated cardiovascular risk. BP was considered to be normal if <120/80 mmHg, and the traditional definition of hypertension (sBP ≥140 mmHg and diastolic BP ≥90 mmHg) has been termed stage 2 hypertension. Two new BP categories were created, namely elevated BP  and stage 1 hypertension .Since 2017, the diagnostic criteria for hypertension from a sBP ≥140 mmHg and a diastolic BP ≥90 mmHg have not been changed in any of the pregnancy hypertension guidelines.14We aimed to evaluate whether the definition of chronic hypertension in pregnancy should be revised according to the ACC-AHA criteria. Here, we present a systematic review of published studies on the association of BP values measured before 20 weeks gestation, classified according to ACC-AHA BP criteria, with preeclampsia and other adverse pregnancy outcomes.This systematic review was prospectively registered with the International Prospective Register of Systematic Reviews under identifier CRD42021229131.We searched Ovid MEDLINE, PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, Latin American and Caribbean Health Sciences Literature, and International Clinical Trials Registry Platform from January 1, 2017 to January 15, 2021, for all original research reports in peer-reviewed journals addressing BP in pregnancy according to the 2017 ACC/AHA guideline criteria.Included were reports of BP measurements in pregnancy before 20 weeks gestation as defined by study authors, classified according to the 2017 ACC/AHA criteria, and their relationship with maternal or fetal and newborn outcomes in pregnancy.BP was categorized as normal (sBP <120 mmHg and dBP <80 mmHg), elevated BP (sBP 120–129 mmHg and dBP <80 mmHg), stage 1 hypertension (sBP 130–139 mmHg and/or dBP 80–89 mmHg), or stage 2 hypertension (sBP ≥140 mmHg and/or dBP ≥90 mmHg), which was also subdivided into nonsevere (sBP 140–159 mmHg and/or dBP 90–109 mmHg) and severe (sBP ≥160 mmHg and/or dBP ≥110 mmHg).Excluded were case reports, duplicate publications (including the more complete or recent data set), and studies that presented BP as a continuous variable without categorization.The main outcomes were preeclampsia , serious maternal complications , preterm birth, fetal and newborn death, small-for-gestational age (SGA) infants, and admission to a neonatal intensive care unit (NICU).The secondary maternal outcomes were miscarriage; maternal death; eclampsia; hemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome; admission to intensive care; intubation or ventilation (other than for childbirth); placental abruption; cesarean delivery; and postpartum hemorrhage.The secondary neonatal outcomes were respiratory support and neonatal seizures.All outcome definitions specified by the study authors were accepted and catalogued. We did not evaluate severe preeclampsia separately from preeclampsia because of the international move away from use of an outcome that is variably definedSevere maternal morbidities  were not included individually; although they are core maternal outcomes in pregnancy hypertension, these are reported infrequently and also occur infrequently.Search results were reviewed by 3 reviewers  and the full text of all relevant studies were retrieved and reviewed for inclusion. Any disagreement about the eligibility of studies was resolved through consensus with the remainder of the review team. Authors were contacted for clarification when required.Data were abstracted by 2 reviewers for each included study using a review-specific form to collect characteristics of the study, patients enrolled (including type of hypertension), BP measurement details , and outcome definitions. Data abstraction was undertaken by all the authors with each study having data extracted by 2 authors. Any disagreement was addressed by consulting the remainder of the group to reach a consensus.Study authors were contacted for information that was unclear or to enquire about accessing data for individual outcomes if only composite outcomes were reported.Methodologic quality was assessed by 2 reviewers, independently, using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool for primary diagnostic accuracy studies.Our primary aim was to assess the usefulness of the ACC-AHA BP criteria for abnormal BP <20 weeks gestation by estimating the strength of the association with adverse outcomes and the associated diagnostic test properties. To undertake meaningful comparisons, we pooled outcome data when evaluated in more than 3 studies.I2 statistic and classified as may not be important (I2 <40%), may represent moderate heterogeneity (30%–60%), may represent substantial heterogeneity (50%–90%), and considerable (≥75%).To evaluate the association between each BP category and adverse outcomes, we conducted a meta-analysis using the Mantel-Haenszel method for combing risk ratios.To evaluate the diagnostic test properties of the lower limit of each BP category as a cutoff (in the way that we currently treat a BP of 140/90 mmHg), we estimated each study’s sensitivity, specificity, and positive (+LR) and negative (−LR) likelihood ratios. Pooled estimates of the likelihood ratios were calculated from the estimated sensitivity and specificity from the bivariate random effects models. Confidence intervals were computed using 100,000 Markov Chain Monte Carlo resamples from the joint bivariate normal distribution of the sensitivity and specificity.Publication bias for each main outcome was assessed when there were at least 10 relevant studies that reported on the outcome. Funnel plots were used to assess asymmetry visually, and if asymmetry were suggested, we performed exploratory analyses to investigate it using Egger’s test and, if necessary, the trim and fill method.Moderation was evaluated descriptively in subgroup analyses that accounted for potential differences in the study characteristics , baseline characteristics of the participants (such as body mass index [BMI] or comorbidities), potential co-interventions (such as aspirin), or outcome definitions.,All analyses were conducted using the meta,,,45A total of 529 publications were identified in the literature search from January 1, 2017 to September 9, 2021, of which 57 duplicates were removed and 420 were excluded following abstract screening, because they were case reports or review articles n=107), did not report the relevant outcomes (n=221), or had no appropriate comparison group (n=92). Of 52 articles selected for full-text review, further exclusions  studies  at a median event rate of 4.0% . Of these, 13 studies reported on all BP category comparisons . Most studies used the 2013 or 2019 ACOG definitions of preeclampsia, which did not require the presence of proteinuria for the diagnosis.I2=87%) for elevated BP to an RR of 3.1  for stage 1 hypertension and an RR of 8.0 for stage 2 hypertension . Although there was substantial between-study variation in the effects, it was not the presence of an association that differed between studies but rather the magnitude of the association that differed by more than could be expected by chance alone. A stronger relationship with preeclampsia was seen among studies at low risk of bias, those that were larger, and those with unselected populations for whom multiple routine  BP measurements were evaluated , maternal death (n=3/23), HELLP syndrome (n=3/23), pulmonary edema (n=1/23 studies), acute kidney injury (n=1/23 studies), miscarriage (n=2/23 studies), newborn respiratory support (n=1/23), and neonatal seizures (n=2/23). The following maternal morbidities were not reported at all: intubation or ventilation, cortical blindness, retinal detachment, or liver capsule hematoma.This systematic review demonstrated that higher BPs before 20 weeks gestation is associated with a greater risk for subsequent preeclampsia and most adverse pregnancy outcomes. In general, and in comparison with normal BP according to the ACC/AHA criteria, the risk for preeclampsia (and some other adverse outcomes) was greatest among participants with stage 2 hypertension, followed by those with stage 1 hypertension, and then by those with elevated BP. However, when the relevant cutoffs were examined, only the 140/90 mmHg cutoff for stage 2 hypertension when measured before 20 weeks gestation could accurately identify women at increased risk; our findings were similar for other adverse pregnancy outcomes. Neither the lower ACC/AHA BP cutoffs of 120/80 mmHg and 130/80 mmHg nor the currently used 140/90 mmHg cutoff demonstrated any ability to rule out preeclampsia or other adverse pregnancy outcomes. Taken together, these findings suggest that the definition of chronic hypertension in pregnancy, consistent with stage 2 hypertension, should not be revised.Our findings are consistent with literature reporting that chronic hypertension  is a major risk factor for superimposed preeclampsia and other adverse pregnancy outcomes.Our findings are consistent with the published association between higher BP levels (below 140/90 mmHg) and subsequent preeclampsia, a BP ≥140/90 mmHg being 1 of the criteria along with proteinuria or another manifestations of maternal end-organ dysfunction according to ACOG.Strengths of our analysis include inclusion of more than 700,000 women in diverse locations, from countries in Australasia, South America, South Asia, Africa, and East Asia, although most publications reported on women in America. The included studies reported on multiple populations at different risks for preeclampsia–1 at high risk, 3 using only nulliparous participants, and 7 using other low-risk women.,,,Although multiple pregnancy was not specifically addressed in this review, only 4 studies included women with multifetal gestations,,,,,,,,,,,38,,,,Limitations included variable definitions of preeclampsia and variable preeclampsia incidence. We had different subsets of studies for evaluation of each ACC-AHA BP level, because only 7 studies reported on all 4 BP categories.We analyzed aggregate data sets, which precluded full exploration of interactions between BP level and other maternal or pregnancy characteristics, as well as use of BP as a continuous variable. Although BP is not used this way in clinical practice, multivariable models suggest that it has independent predictive power for preeclampsia when used in this fashion.The influence of demographic factors, particularly overweight and obesity, that compound the risk for adverse pregnancy outcomes is unclear from this analysis. Because this was not an individual participant data meta-analysis, we could not adjust for baseline risk factors; however, given that adjustment factors  are confounders in the relationship between BP and adverse outcome, the unadjusted analyses would likely have overestimated the relationship between BP and adverse outcome.9/L and elevated liver enzymes with symptoms).Previous studies have not yet addressed whether treatment of hypertension at thresholds <140/90 mmHg in pregnancy is of benefit. However, the Control of Hypertension In Pregnancy Study (CHIPS) trial showed that control of BP (to a diastolic of 85 mmHg) reduced the incidence of severe maternal hypertension and severe features of preeclampsia  before 20 weeks gestation is not useful in ruling out the development of preeclampsia or related adverse pregnancy outcomes after 20 weeks.Progress in the prediction of preeclampsia or other adverse outcomes from BP measurements is most likely to come from efforts focused on BP levels as a continuous variable or on other BP features (such as variability), specifically as part of multivariable models that include other aspects of maternal history, ultrasonographic assessment, and angiogenic markers.This systematic review of publications examining the relationship between the 2017 ACC-AHA BP criteria and pregnancy outcomes has found no evidence that lowering the diagnostic threshold for chronic hypertension in pregnancy to below 140/90 mmHg would assist clinicians in identifying women more likely to develop preeclampsia or other adverse pregnancy outcomes.


Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), is superior to enalapril for chronic heart failure (CHF) with reduced ejection fraction (EF). However, its efficacy and safety in older Japanese patients in clinical practice are poorly understood. We aimed to investigate the efficacy and safety of ARNI compared with angiotensin receptor blocker (ARB) in older patients with CHF in real-world clinical practice. In addition, nutritional status and body composition were investigated as essential indicators of efficacy.This retrospective single-center observational study enrolled 55 consecutive older patients (aged ≥75 years) with CHF who received ARNI (n = 27) or ARB (n = 28) therapy between October 2020 and March 2021. Blood samples were collected before (baseline) and 4, 12, and 24 weeks after ARNI or ARB therapy initiation. Furthermore, echocardiography was performed before (baseline) and 24 weeks after ARNI or ARB therapy initiation. The efficacy endpoints were changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, left ventricular EF, nutritional status, and body composition changes. The controlling nutritional status (CONUT) score and geriatric nutritional risk index were investigated as nutritional status indices. The safety endpoints were symptomatic hypotension, renal function exacerbation, and hyperkalemia in patients who continued ARNI or ARB therapy for >24 weeks without additional nonpharmacological treatment.p = 0.04). The initial ARNI dose could not be uptitrated in five patients (19%) due to hypotension.There were no significant changes in NT-proBNP levels and estimated glomerular filtration rates; however, there was a significant CONUT score improvement in the ARNI group (least-squares mean difference, −1.0; 95% confidence interval, −1.4 to −0.3; ARNI exhibited significant improvement in the nutritional status in older patients with CHF compared with ARB. However, the ARNI dose should be adjusted according to the patient’s blood pressure. Similar to the PARADIGM-HF trial, a prospective comparative study of ARNI and enalapril in Japanese patients with HFrEF  demonstrated that ARNI was safe and well tolerated in Japanese patients with CHF (3).In Japan, the number of patients aged ≥75 years with chronic heart failure (CHF) is rapidly increasing. Various clinical investigations demonstrated the effectiveness of various pharmacological agents and mechanical supports; however, therapeutic strategies for patients aged ≥75 years are yet to be established. Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), has become a standard treatment for heart failure (HF). The prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure (PARADIGM-HF) trial showed that ARNI reduced the risk of cardiovascular death, all-cause mortality, and HF recurrence more than enalapril in patients with HF and reduced ejection fraction (HFrEF) (5).The prospective comparison of ARNI with ARB global outcomes in HF with preserved ejection fraction (PARAGON-HF) trial showed therapeutic benefits in patients with ejection fraction (EF) below the normal range; however, the therapeutic benefits of ARNI among patients with HF and preserved ejection fraction was not demonstrated (7); the nutritional status of older patients with CHF can easily deteriorate, and the nutritional deficiencies in adults aged ≥70 years increase the risk of hospitalization for HF, contribute to skeletal muscle loss, and are associated with decreased quality of life (6). A subanalysis of the PARADIGM-HF trial revealed that ARNI may be involved in glucose metabolism (8). Furthermore, it has been reported that ARNI improved nutritional status (9); therefore, we hypothesized that ARNI therapy could improve nutritional status in older patients compared with angiotensin receptor blocker (ARB) and also conducted a comparative study on the safety and efficacy of ARNI and ARB in patients aged >75 years who received ARNI or ARB therapy for CHF. Nutritional status and body composition, which are vital efficacy indicators, particularly in older patients, were investigated.The mean ages of the patients were 63.8, 72.7, and 67.9 years in the PARADIGM-HF, PARAGON-HF, and PARALLEL-HF trials, respectively. Therefore, the usefulness of ARNI in patients aged ≥75 years with HF is insignificant. In recent years, ARNI has been extensively used to treat older patients with CHF; however, its safety and efficacy still need to be investigated using real-world data. The nutritional status of older patients with CHF affects their body composition, physical function, and prognosis (10). Patients with CHF with residual left ventricular dysfunction or HF symptoms, despite guideline-based medical therapy in the outpatient clinic or during hospitalization, were selected for ARNI or ARB therapy at the discretion of the cardiologist in charge. ARNI therapy was changed from ARB, and ARB therapy was either initiated as new or changed from ACEI. In the ARB group, ACEI was converted to ARB because ARNI treatment was being considered for future therapy. Direct conversion of ACEI to ARNI would require a 36-h washout period to lower the risk of angioedema. ACEI was converted to ARB as ARB can be converted to ARNI without a washout period. However, during the study period, ARNI was only approved for up to a 2-week prescription, and patients who had difficulty using ARNI due to hospital visits or financial circumstances were consequently assigned to the ARB group. The new ARB therapy was initiated to treat HF. In principle, the starting dose of ARNI therapy was 100 mg/day, and the titrated dose depended on the patient’s systolic blood pressure . The initiation dose of ARB depended on the patient’s SBP at the start. If a patient had SBP of <90 mmHg, the ARNI or ARB dose was adjusted according to the SBP. This study was approved by the institutional review board of Nagano Municipal Hospital , and informed consent was obtained from the patients using an opt-out approach. Furthermore, the study was conducted in accordance with the Declaration of Helsinki. Blood samples were collected at 4, 12, and 24 weeks after ARNI or ARB therapy initiation. Baseline blood samples were collected when ARNI was changed from ARB and when ARB was newly started or changed from ACEI. Patients’ demographic data, including age, sex, body mass index (BMI), heart rate, SBP, medical history, and information on baseline treatments, were collected. The collected clinical laboratory data included plasma B-type natriuretic peptide (BNP) concentrations, hemoglobin, N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations, albumin, total lymphocyte count, creatinine (Cre), estimated glomerular filtration rate (eGFR), potassium, total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C). Echocardiographic data were measured for efficacy analysis before and 24 weeks after ARNI therapy initiation. Using the modified Simpson method in the apical four- and two-chamber views, left ventricular EF (LVEF) was calculated.This retrospective observational study enrolled 55 consecutive older patients (aged ≥75 years) with CHF from Nagano Municipal Hospital who received ARNI (n = 27) or ARB (n = 28) therapy between October 2020 and March 2021. CHF was diagnosed based on the Framingham Heart Study criteria (11). We defined CONUT score of ≥5 as a low nutritional status. Thus, immune defenses, caloric depletion, and protein reserves can be assessed using the CONUT score. The GNRI is a useful tool for predicting the risk of morbidity and mortality in hospitalized older patients (13). We defined GNRI of <92 as low nutritional status. The GNRI was calculated from serum albumin and BMI as follows (14):In this study, the controlling nutritional status (CONUT) score and geriatric nutritional risk index (GNRI) were used to evaluate nutritional status. The CONUT score was developed for hospitalized patients as a screening tool for nutritional status. The following parameters were used to calculate the score: total lymphocyte count (count/mL), TC level (mg/dL), and serum albumin level (g/dL) 2) × 22];GNRI = 14.89 × serum albumin (g/dL) + 41.7 × present body weight/[(height)2 + 41.7 × BMI/22Body fat mass, present body fat, intracellular and extracellular water, extracellular water/total body water, skeletal muscle mass, and basal metabolism were measured using a bioelectrical impedance analyzer ; however, this device cannot be used in patients with a pacemaker or implantable cardioverter defibrillator implanted because it applies weak electric current. Thus, measurement could not be performed on one patient with an implanted pacemaker in the ARNI group.The efficacy endpoints were changes in NT-proBNP levels, LVEF, nutritional status, and changes in body composition. The CONUT score and GNRI were used to evaluate nutritional status.The safety endpoints were symptomatic hypotension, renal function exacerbation, and hyperkalemia in patients who continued ARNI or ARB therapy for >24 weeks.th revision (ICD-10). The definition of ischemic heart disease is a past percutaneous coronary intervention procedure and/or ischemia evaluation is performed and positive. Peripheral artery disease was defined as claudication by limb artery stenosis and an ankle-brachial index of 0.90. Hypertension was defined as a home blood pressure of 135/85 mmHg, clinical room blood pressure of 140/90 mmHg, or the use of oral antihypertensive drugs. Dyslipidemia was defined as fasting serum triglyceride ≥ 150 mg/dL, HDL-C < 40 mg/dL, or the use of oral antihypertensive drugs. Anemia was defined as hemoglobin of ≤12 g/dL (woman) or ≤13 g/dL (man). Diabetes mellitus (DM) was defined as hemoglobin A1c level of ≥6.5%  or receiving medical treatment for DM. Malignancy and stroke were defined as receiving medical treatments for malignancy/stroke or a history of stroke/malignancy before admission. Chronic kidney disease was defined as eGFR of <60 mL/min/1.73 m2. The eGFR was calculated from the serum Cre level, age, weight, and sex using the following formula: eGFR = 194 × Cr1.094 × age − 0.287 (man) or eGFR = 194 × Cr1.094 × age − 0.287 × 0.739 (woman).We checked the patients’ medical records and extracted their diagnoses. Disease was classified according to the International Statistical Classification of Diseases and Related Health Problems, 10t-test or Mann-Whitney U test.Continuous variables were expressed as median with interquartile range (IQR) and categorical variables as frequency and percentage. Clinical data were compared between the two groups using unpaired Student’s The primary comparison was the least-squares mean difference (LSMD) between the ARNI and ARB groups at 24 weeks posttreatment. The p value of <0.05 was considered to indicate statistical significance. All analyses were conducted using the SPSS software version 24.0 .p = 0.84). The clinical characteristics of the patients are summarized in p = 0.40). The groups had no significant differences in the baseline median SBP, CONUT score, and GNRI. CONUT score of ≥5 was observed in 13 (48.1%) and 10 (35.7%) patients in the ARNI and ARB groups, respectively (p = 0.41). GNRI of <92 was observed in 12 (44.4%) and 9 (32.1%) patients in the ARNI and ARB groups, respectively (p = 0.48). There were no significant differences in medical history. p = 0.04). All patients had been treated with olmesartan prior to ARNI therapy  with CHF who received ARNI (n = 27) or ARB (n = 28) therapy were enrolled in the study. The median follow-up periods of the ARNI and ARB groups were 197 (IQR 180-250) days and 191 (IQR 178-244) days, respectively ( therapy . Furtherp = 0.16) (p = 0.04). The numbers of patients with HFrEF in the ARNI and ARB groups were 11 (40.7%) and 6 (21.4%), respectively. There was a significant reduction in patients with LVEF of <40% in the ARNI group compared with baseline at 24 weeks post-ARNI therapy (p = 0.04).There were no significant changes in NT-proBNP concentrations between the ARNI and ARB groups  . Echocar = 0.16) . The basp = 0.04); however, there was no significant increase in the total lymphocyte count  and TC  . In the ARNI group, the CONUT score showed a significant decrease , but there was no significant change in GNRI   . There w = 0.07) . Body co = 0.07) . In the This cohort had no mortality from any cause or hospitalization for CHF. Among 27 patients who received ARNI therapy, 7 (26%) had SBP <110 mmHg at initiation, which was an exclusion criterion in the PARAGON-HF trial. Furthermore, two patients (7%) had SBP <100 mmHg at initiation, which was an exclusion criterion in the PARADIGM-HF and PARALLEL-HF trials. Furthermore, five patients (19%) were not titrated from 100 mg, however, none discontinued ARNI therapy within 24 weeks. Among 28 patients who received ARB therapy, 8 (29%) had SBP <110 mmHg, and at the time of initiation, no patient had SBP <100 mmHg. There were no patients with deteriorating renal function or hyperkalemia in the ARNI or ARB group .In this study, we investigated the efficacy and safety of ARNI therapy by comparing it with ARB in older Japanese patients in real-world clinical practice; there was a significant improvement in the CONUT score in the ARNI group. However, the NT-proBNP did not decrease in the ARNI group compared with the ARB group. SGLT2 inhibitors were recently approved for the treatment of HF during the study period, and prescriptions for older patients were less frequent.(3).There was no significant improvement in NT-proBNP levels in the ARNI group compared with the ARB group during the study period; however, due to the trend toward improvement, a similar result is expected if the observation period is prolonged. Another factor could be the insufficient number of patients to detect significant changes. This cohort exhibited no significant changes in conventional echocardiographic parameters, including left ventricular systolic and diastolic functions. LVEF of <40% may have contributed to the insignificant difference in LVEF improvement in the ARNI group compared with the ARB group. However, there were significant improvements among patients with LVEF of <40% in the ARNI group, suggesting the possibility of LVEF improvement in older patients as in previous reports (15).This study evaluated the representative nutritional status indices, CONUT score, and GNRI as efficacy parameters. It is established that the CONUT score and GNRI are predictors of hospitalization in older patients. The CONUT score significantly improved in the ARNI group compared with the ARB group. The ARNI group showed a 1.0-point improvement in the CONUT score compared with the ARB group in LSMD. A 1.0-point improvement in the CONUT score may contribute to an improvement in all-cause mortality and cardiovascular death. It was hypothesized that nutritional status improvement may play a role in the prognostic effect of ARNI; however, GNRI exhibited no improvement. The CONUT score appears to be influenced by increased albumin levels. The formula for determining the GNRI is significantly dependent on the BMI. We assumed that the lack of change in the GNRI was due to the lack of change in the BMI. Patients with acute HF are often overhydrated, and the BMI often decreases with dehydration. However, the obesity paradox has been proposed, and attention should be given to lowering the BMI of older patients with CHF (16). The European Society for Clinical Nutrition and Metabolism guidelines also indicate the importance of nutritional status, including serum albumin, in patients with CHF (17). ARNI therapy was previously reported to improve the pre-albumin levels and nutritional status in patients with CHF. It has not been clearly explained that ARNI improves nutritional status, but it has been suggested that enhanced congestion in the gastrointestinal tract improves digestion and absorption. It has also been suggested that the effects of the renin-angiotensin-aldosterone system improve inflammation and reduce albumin consumption (18). The multifaceted effect of ARNI improves albumin levels, which may be effective for improved prognosis.It is well known that a decrease in serum albumin level is correlated with mortality and length of hospital stay due to HF (8). Such multifaceted effects of ARNI could result in the improvement of nutritional status as reported in previous studies (9).A subanalysis of PARADIGM-HF revealed the possibility that ARNI is involved in glucose metabolism, which is presumed to be due to the effect of neprilysin on elevated active GLP-1 concentrations (21). In this study, no significant changes in body composition were observed during the study period, and sarcopenia did not improve. However, measurement with BIA alone is not an accurate assessment, as it should be combined with the measurement of grip strength and dual-energy X-ray absorptiometry.It has been suggested that body composition, measured by bioelectrical impedance analysis (BIA), is correlated with sarcopenia (1). In the PARALEL-HF study, the most common adverse effect in ARNI was hypotension (2). The mean SBP in the PARADIGM-HF and PARALLEL-HF studies were 124 and 122 mmHg, respectively. In this study, the ARNI group had a median baseline SBP of 121 mmHg. The ARNI dose could only be increased to 400 mg/day in a few patients, indicating the significance of prescription reviews to prevent lowering blood pressure in older adults. The initiation of ARNI therapy is associated with diuretic dose reduction (22). No significant deterioration in renal function was observed in this study; this may be due to the ability of several patients to reduce the dose or discontinue the use of diuretics.In the PARADIGM-HF trial, drug dose reductions and discontinuations as well as symptomatic hypotension were common in patients with low SBP This study had several limitations. First, the sample consisted of patients recruited from a single hospital; furthermore, as it is a retrospective study, it may not be representative of the population. Second, in the evaluation of chronic disease, the treatment period was relatively short. Therefore, a longer study period is needed to investigate the risk and benefits. Third, the type of ARB used for ARB therapy was not standardized. Fourth, baseline EF was significantly different between the ARNI and ARB groups. Fifth, ARNI and ARB were not randomized; thus, confounding factors were not eliminated. Sixth, the CONUT score is a nutritional status index, and whether its improvement indicates actual improvement in nutritional status is unclear. Seventh, no extensively detailed investigation of blood pressure trends was conducted after the initiation of ARNI or ARB therapy. Eighth, changing the therapy from ACEI to ARB is not recommended for the treatment of heart failure, except when intolerance is evident. Finally, these data cannot exclude the effects of concomitantly-administered medications.ARNI therapy improved the CONUT score, a nutritional status index, in the treatment of older patients with CHF compared with ARB therapy. In addition, there is a risk of hypotension due to ARNI therapy; thus, the dose of ARNI should be adjusted according to the blood pressure of each patient.NoneWe thank all the staff of Nagano Municipal Hospital for their cooperation with our research.All authors (1) made substantial contributions to the study concept or the data analysis or interpretation; (2) drafted the manuscript or revised it critically for important intellectual content; (3) approved the final version of the manuscript to be published; and (4) agreed to be accountable for all aspects of the work.The IRB approval code is No. 0021 from Nagano Municipal Hospital.


Systemic inflammatory rheumatic diseases predispose to premature birth, accelerated atherosclerosis, and increased cardiovascular disease (CVD). While glucocorticoids (GCs) are used in various rheumatic diseases, and the associations between GC excess and increased prevalence of CVD complications are well established, the mechanisms underlying GCs’ role in atheroma development are unclear. We conducted an observational study to address GC therapy’s effect on arterial stiffness using the cardio-ankle vascular index (CAVI) in patients with rheumatic diseases. Twenty-eight patients with rheumatic disease received initial GC therapy with prednisolone at doses ranging from 20 to 60 mg/d. CAVI was examined at baseline and 3 and 6 months after GC therapy. Changes in CAVI and inflammatory parameters were evaluated. GC therapy increased the mean CAVI after 3 months but decreased it to pretreatment levels after 6 months. The mean CAVI substantially decreased with GC treatment in patients <65 years but increased in patients ≥65 years. Alterations in CAVI during the 6-month GC treatment negatively correlated with the lymphocyte-to-monocyte ratio (LMR) at baseline. Conversely, no correlation was observed between alterations in CAVI values and conventional inflammatory markers (C-reactive protein and erythrocyte sedimentation rate). Multivariate analysis of factors related to changes in CAVI highlighted young age, high prednisolone dosage, and LMR at baseline. GC temporarily exacerbates but eventually improves arterial stiffness in rheumatic diseases. Particularly in young patients, GC may improve arterial stiffness by reducing inflammation. Therefore, the LMR before GC therapy in rheumatic diseases may be a potential predictor of arterial stiffness. Systemic inflammatory rheumatic diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) result in increased cardiovascular morbidity and mortality owing to accelerated atherosclerosis and premature coronary artery disease (CAD) ,2. TradiRecently, the lymphocyte-to-monocyte ratio (LMR) was identified as a novel systemic inflammatory marker  and has The cardio-ankle vascular index (CAVI) has been established as a marker of arterial stiffening and is associated with atherosclerosis-related diseases, including diabetes, hypertension, and aging . Data reIn this study, we investigated the association between changes in CAVI and inflammation over a 6-month follow-up in patients who received GC therapy for rheumatic diseases. The effects of GC therapy on the progression of arterial stiffness were also investigated.n = 5), polymyalgia rheumatica (n = 5), SLE (n = 3), ImmunoglobulinG4-related disease (n = 3), dermatomyositis/polymyositis (n = 3), adult-onset Still’s disease (n = 3), remitting seronegative symmetrical synovitis with pitting edema syndrome (n = 2), systemic sclerosis (n = 2), RA (n = 1) and relapsing polychondritis (n = 1). We included patients with high disease activity who were newly starting treatment with prednisolone at doses of 20–60 mg daily (mean daily dose: 45.2 ± 1.9 mg (SD)). Patients were excluded if they had previously received GCs or other immunosuppressive drugs. Fasting morning blood samples were collected before the patients started treatment and after 3 and 6 months of GC therapy.This retrospective observational study was conducted using the opt-out method, and approved by the Ethics Committee of the Toho University Sakura Medical Center . From the patients with rheumatic diseases who were newly received GC from April 2022 to April 2023 at Toho University Sakura Medical Center, we selected 28 patients who underwent CAVI measurements to monitor cardiovascular complications . The undClinical information and laboratory data were obtained from a structured interview, self-reported questionnaires, physical examinations, and blood tests. Body mass index (BMI) was calculated based on measured height and weight. The baseline blood pressure was calculated by taking the average of two readings. The morning blood samples were collected to measure the baseline levels of serum C-reactive protein (CRP) using latex nephelometry , total cholesterol, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) using the homogeneous method , and triglycerides using enzymatic assay . Complete blood counts, including lymphocyte, neutrophil, and monocyte counts, were performed for each participant using an automatic blood counting system . The LMR is the ratio calculated by dividing the absolute lymphocyte counts by the absolute monocyte counts from the blood test.We assessed the presence or absence of hypertension (defined as hypertension if they had systolic blood pressure (SBP) ≥140 mmHg and/or diastolic blood pressure (DBP) ≥90 mmHg  or were CAVI measurements were taken using a VaseraVS-3000 vascular screening system  before starting GC therapy and at 3 and 6 months post-treatment, as described by Shirai et al. . The sysp < 0.05. Statistical analyses were performed using Prism ver. 8.0  and EZR on R Commander statistical software ver. 1.61 . Numerical data were expressed as mean ± SD and the median with the interquartile range. Changes during GC treatment were assessed using Friedman’s test, followed by Dunnett’s multiple comparison test. To compare the two groups, the Mann–Whitney U test was applied for numerical data, and Fisher’s exact test was used for categorical data. Spearman’s rank correlation coefficient was used to verify the correlation between changes in the CAVI and inflammatory markers. Simple linear regression models were used to assess the relationship between changes in CAVI and patient characteristics, inflammatory markers, lipid variables, or HbA1c and screen for independent variables to be included in the multiple linear regression model. A backward stepwise multiple linear regression was conducted to build a candidate model. The final multiple regression model was presented and interpreted after performing model diagnostics. The level of significance was set at p < 0.05), while mean CAVI increased in patients aged ≥65 years .p = 0.006) (p = 0.7444) and erythrocyte sedimentation rate   A. In con 0.2255) A,B.We examined the independent influence of the CAVI changes in the patients with rheumatic diseases using multiple regression analyses adjusted for patient characteristics , prednisolone dose at baseline, inflammatory markers , lipid variables , and HbA1c . FactorsThis is the first study to demonstrate changes in arterial stiffness assessed using CAVI during GC therapy in patients with rheumatic diseases. We demonstrated that CAVI increased after 3 months of GC therapy and then decreased to pretreatment levels after 6 months in patients with rheumatic diseases. CAVI increased after 3 months in patients >65 years and tended to decrease after 6 months of GC therapy, whereas CAVI decreased significantly in younger patients. Our results also imply that GC may normalize pressure wave reflections in patients with rheumatic diseases. Changes in CAVI levels were negatively correlated with LMR at baseline, and LMR was an independent factor associated with the progression of arterial stiffness. These results suggest that LMR may be an important predictor of the progression of arterial stiffness associated with rheumatic disease during GC treatment.CAVI is a recently developed index of arterial stiffness calculated from the heart-ankle pulse wave velocity (PWV) adjusted for blood pressure by β, a stiffness parameter. Therefore, CAVI represents the stiffness of the arterial tree from the origin of the aorta to the ankle and is not influenced by blood pressure changes during measurement . As bodySixty-four patients with low disease activity SLE  had significantly increased CAVI compared with healthy controls  . Sato etWe previously investigated the effects of nitroglycerin on arterial stiffness in patients with and without CAD using CAVI ,24. AfteLMR was first defined as a biomarker for infectious diseases and reflects the balance between the effector and the host . LymphocInflammation plays an important role in the initiation and progression of atherosclerotic processes . LymphocThis study has some limitations. As the study was performed at a single hospital with a retrospective observational design, patient selection bias may have affected the results. The study population was relatively small, and a larger number of patients is needed. Our study included patients with various rheumatic diseases. Although we analyzed the differences in CAVI between inflammatory diseases  and non-inflammatory diseases , no difference was found in the variation in CAVI values between the two groups. Further research on individual diseases will be needed in the future. Additionally, we evaluated the effect of GC therapy for > 6 months on arterial stiffness in patients with rheumatic disease. However, the long-term influence of GC therapy on the progression of arterial stiffness in patients with rheumatic diseases remains unclear. Further multicenter, large-scale prospective studies are needed to strengthen our conclusions.GC temporarily exacerbates arterial stiffness and then improves it in rheumatic diseases. Particularly in young patients, GC may improve arterial stiffness by reducing inflammation. CAVI is a useful clinical marker for evaluating arterial stiffness in patients with rheumatic diseases undergoing GC therapy. LMR may be a potentially available, easily calculable, and cost-effective parameter for arterial stiffness prognosis before GC therapy in rheumatic diseases. In conclusion, our findings suggest that patients with rheumatic diseases, especially those aged <65 years, may reduce vascular damage by receiving appropriate GC therapy to relieve arterial constriction.


We collected one-time blood and urine from healthy subjects (n = 5) without renal disease. We applied immunoenzymatic ELISA and xMap Luminex flow fluorimetry to determine TFF3 in serum and urine. There was a significant difference in TFF3 levels in the serum of patients collected on the first one or two days after kidney transplantation compared to the control group (determined by ELISA and Luminex) and six months and one year after kidney transplantation (ELISA). We observed a correlation between creatinine concentration and urinary TFF3 concentration (ELISA and Luminex) and a negative association between eGFR and urinary (ELISA) and serum (Luminex) TFF3 concentration in patients on the first and second days after kidney transplantation. We noted significant correlations between eGFR and TFF3 levels in the serum and urine of patients determined by the two methods six months and one year after transplantation. In women, we observed that urinary TFF3 concentration increased significantly with increasing creatinine and that with increasing eGFR, urinary TFF3 concentration determined by two methods decreased significantly. In the present study, the choice of diagnostic method for the determination of TFF3 in serum and urine significantly affected the concentration of this biomarker. The values of this parameter determined by ELISA were higher than those assessed using the Luminex assay. Based on the presented results, we can conclude that TFF3 has great potential to monitor renal transplant patients. Determination of this protein in parallel with creatinine and eGFR levels in serum and urine may provide helpful diagnostic information.Intestinal trefoil factor 3 (TFF3) is a protein secreted by many cell types, and its serum and urine levels vary in patients with kidney disease. Therefore, the present study aimed to determine the diagnostic value of TFF3 in allogeneic kidney transplant patients included in the one-year follow-up. To analyze the influence of the diagnostic method used, we studied the type of biological material and the time elapsed since renal transplantation on the parameter’s value. The study also aimed to investigate the relationship between TFF3 levels and creatinine and estimated glomerular filtration rate (eGFR) values in the serum and urine of the patients studied. The study used blood and urine samples from adult patients ( Indirect assessment of renal damage in patients after allogeneic kidney transplantation is mainly based on evaluating values of classical laboratory parameters, including serum electrolytes, urea, and creatinine, with an estimation of estimated glomerular filtration rate (eGFR) and a general urinalysis, which is insufficient. Therefore, the panel of these tests should be expanded to include new parameters, including protein biomarkers . A biomaIntestinal trefoil factor 3 (TFF3) is a member of the human trefoil factor family, along with the peptides TFF1 and TFF2 . It alloThe intestinal trefoil factor can be used as a biomarker in patients with kidney damage . The resp = 0.001) and Luminex (p = 0.004). Additionally, TFF3 levels in patient serum were determined using ELISA six months (p = 0.009) and one year (p = 0.013) after kidney transplantation.We used the nonparametric Mann-Whitney U test  to compap = 0.022) and Luminex (p = 0.006) (p = 0.013) and Luminex (p = 0.030) increased significantly with increasing creatinine  . In womeeatinine . Signifip = 0.004) and serum TFF3 concentration determined by Luminex (p = 0.004). In the female renal transplant patients studied, the urinary TFF3 concentration determined by the two methods decreased significantly with increasing eGFR. In all study patients six months and one year after transplantation, significant correlations were observed between eGFR and TFF3 concentrations in both serum and urine, determined by two methods.The correlation analysis between eGFR and TFF3 concentration was in line with the relationships discussed above . On the p < 0.0001) in the serum of renal transplant patients tested at three time points combined using ELISA (Me = 20.35 ng/mL) relative to the TFF3 value determined by Luminex (Me = 6.02 ng/mL). It was confirmed in a detailed analysis one to two days, six months, and one year after kidney transplantation. Serum TFF3 levels in renal transplant patients assessed using ELISA were significantly higher one to two days (p < 0.0001), six months (p < 0.0001), and one year after renal transplantation (p < 0.0001) relative to values obtained using the Luminex method. When TFF3 levels were averaged in the urine of renal transplant patients collected at the three time points together, we found significantly higher levels of this biomarker (p < 0.0001) determined by ELISA (Me = 122.33 ng/mL) relative to values determined by Luminex (Me = 35.39 ng/mL). Detailed analyses separately for each of the three intakes also confirmed it.There was a significantly higher concentration of TFF3 (p < 0.0001), six months (p = 0.006), and one year (p = 0.010) after kidney transplantation compared to the values of this biomarker determined by Luminex .The relationship between glucose and TFF3 was also checked by Spearman’s rank method six months and a year after kidney transplantation by ELISA and Luminex methods, but no significant correlations were found  after transplantation and a subsequent decrease, irrespective of the presence of DGF. The present study confirmed this relationship and showed that serum TFF3 levels determined by ELISA decrease significantly after renal transplant surgery. In contrast, no such relationship was shown in serum as determined by the Luminex method or in urine by both methods. In contrast, Pianta et al. [n = 81), concluded that urinary TFF3 concentration testing is not a promising biomarker for the early diagnosis of delayed graft function.TFF3 is synthesized in the urinary tract epithelia, mainly the proximal and distal tubules and collecting ducts . Elevatea et al. , based oThe study presented here extends the knowledge of this biomarker in renal function after transplantation, as seen by the significant correlations between TFF3 and creatinine and eGFR at different times. We found the choice of diagnostic method for the determination of TFF3 in serum and urine to have a significant effect on the concentration of this biomarker. The values of this parameter determined with ELISA are higher than those assessed using the Luminex assay.There are several limitations worth noting in this analysis. A small sample size and the single center approach suggest the need for validation in larger, multi-center populations. It would be judicious to plan a biopsy prior performed at time points corresponding to blood and urine collections. Furthermore, our findings need to be validated through other studies to ensure consistency of observed associations and their subsequent impact on clinical trial design. Monitoring patients for only 24 h, 6 and 12 months after kidney transplantation may not have captured all variables which contribute to ongoing renal injury in this group. However, a notable strength of the study is the prospective design which enabled access to urine output and serum creatinine values for 24 h, 6 and 12 months after kidney transplantation in all patients. Thus, it is likely that this marker will show clinically relevant performance. Further research efforts are certainly needed for the pursuit of data on each patients clinical course, such that it is understood whether or not the TFF3 levels that are being obtained might possibly also reflect other recent events in the patients clinical course. Based on the results of our and other authors’ studies, TFF3 is a promising marker for monitoring the status of renal transplant patients; however, these data should be approached with caution, and further studies are needed.We conducted the study between 2018 and 2022. The study included adult kidney transplant patients from deceased donors in the region of northwestern Poland. They were patients of the Transplant Clinic of the Independent Public Clinical Hospital No. 2 PUM in Szczecin. The exclusion criterion for the study was the recipient’s age below 18 years, and the inclusion criterion was preserved graft function one year after surgery. The study group comprised 19 patients, including nine women and 10 men, aged 26 to 71 years (mean age 51.9 ± 12.1 years) and weighing 61 to 114 kg (mean 78.32 ± 13.33 kg). Their mean time on dialysis was 2.79 ± 3.60 years (0 to 16 years). Demographic data of the study group are presented in The Bioethics Committee of the Pomeranian Medical University in Szczecin (resolution no. KB-0012/114/12) approved the study. The study was conducted following the Declaration of Helsinki.® Performance Assay. We performed the assays according to the protocols provided by the manufacturer. Serum creatinine was determined using a colorimetric assay based on the Jaffé method on a Cobas C 501 instrument from Roche Diagnostics , while eGFR was calculated according to the CKD-EPI formula.We used two methods to determine TFF3 concentrations: enzyme-linked immunosorbent assay immunoenzymatic (ELISA) and xMap Luminex flow fluorimetry. Both assays were from R&D Systems : the Human TFF3 Quantikine ELISA Kit and the Human Kidney Biomarker Premixed Magnetic LuminexStatistical results were analyzed using Statistica 13.3 . We examined the distribution of the data using the Shapiro-Wilk test, taking into account the division into test and control groups and separately for the values of the variables obtained on the first day, six months, and one year after renal transplantation. A nonnormal distribution characterized the variables assessed, so data were presented in tables and graphs in the form of the median, minimum, and maximum values and lower and upper quartiles, and the tests used in the analyses were nonparametric.In conclusion, TFF3 in serum and urine may be a promising biomarker for diagnosing renal function and prognosis, mainly on the first and second days after kidney transplantation. Simultaneous determination of this biomarker and creatinine and eGFR levels in the patient’s serum and urine may provide helpful diagnostic information. Furthermore, large-scale studies are warranted to investigate the diagnostic and prognostic value of serum and urine TFF3 levels in renal transplant patients.


In patients undergoing high-risk surgery, it is recommended to titrate fluid administration using stroke volume or a dynamic variable of fluid responsiveness (FR). However, this strategy usually requires the use of a hemodynamic monitor and/or an arterial catheter. Recently, it has been shown that variations of central venous pressure (ΔCVP) during an alveolar recruitment maneuver (ARM) can predict FR and that there is a correlation between CVP and peripheral venous pressure (PVP). This prospective study tested the hypothesis that variations of PVP (ΔPVP) induced by an ARM could predict FR.2O for 30 s was performed before skin incision. Invasive mean arterial pressure (MAP), pulse pressure, heart rate, CVP, PVP, pulse pressure variation (PPV), and stroke volume index (SVI) were recorded before ARM (T1), at the end of ARM (T2), before volume expansion (T3), and one minute after volume expansion (T4). Receiver-operating curves (ROC) analysis with the corresponding grey zone approach were performed to assess the ability of ∆PVP (index test) to predict FR, defined as an ≥ 10% increase in SVI following the administration of a 4 ml/kg balanced crystalloid solution over 5 min.We studied 60 consecutive patients scheduled for high-risk abdominal surgery, excluding those with preoperative cardiac arrhythmias or right ventricular dysfunction. All patients had a peripheral venous catheter, a central venous catheter and a radial arterial catheter linked to a pulse contour monitoring device. PVP was always measured via an 18-gauge catheter inserted at the antecubital fossa. Then an ARM consisting of a standardized gas insufflation to reach a plateau of 30 cmH∆PVP during ARM predicted FR with an area under the ROC curve of 0.76 . The optimal threshold determined by the Youden Index was a ∆PVP value of 5 mmHg  with a sensitivity of 66%  and a specificity of 82% . The AUC’s for predicting FR were not different between ΔPVP, ΔCVP, and PPV.During high-risk abdominal surgery, ∆PVP induced by an ARM can moderately predict FR. Nevertheless, other hemodynamic variables did not perform better.The online version contains supplementary material available at 10.1186/s12871-023-02194-x. When caring for patients undergoing high-risk surgery, the judicious titration of fluid administration in order to avoid both hypo- and hypervolemia (and the resulting perioperative complications) is considered standard of care . This isThe primary objective of this study was to test the hypothesis that dynamic variations of PVP (∆PVP) during an ARM can predict FR in mechanically ventilated patients undergoing high-risk abdominal surgery. Secondary objectives were (1) to compare FR predictability between ΔPVP and other hemodynamic variables  and (2) to analyze the relationship between CVP and PVP by a linear regression and a Bland-Altman analysis.We applied the 2015 STARD guidelines for performing and reporting the results of this study , which tInclusion criteria were adult patients (≥ 18 years old) scheduled for a high-risk abdominal surgery and equipped with a radial arterial catheter connected to a cardiac output hemodynamic monitoring device (standard practice in our institution). Non-inclusion criteria were the presence of cardiac arrhythmias or known right ventricular dysfunction.20, and a respiratory rate adjusted to achieve an end tidal carbon dioxide between 35 and 40 cm H2O. Baseline fluid administration consisted of a balanced crystalloid infusion (Ringer’s lactate) at a rate of 1 ml/kg/h and fluid challenges of 4 ml/kg to optimize SVI during surgery.Anesthesia management was standardized in all patients during the study period. Upon arrival in the operating room, patients were moved onto a heated mattress. The following noninvasive monitors were attached: 5-lead electrocardiogram, noninvasive blood pressure, rectal temperature probe, frontal lobe electroencephalogram , and depth of neuromuscular block monitoring. A Foley catheter was introduced. Vascular access consisted of two large-diameter peripheral venous catheters . Care was taken to ensure that the patient’s arm with the peripheral intravenous catheter was unobstructed by draping, tucking, or positioning. A radial arterial catheter was also inserted after anesthesia induction and connected via the Flotrac sensor to an uncalibrated pulse contour analysis monitoring device . Then a 16 cm, 8.5 F triple-lumen central venous catheter  was placed under ultrasound guidance into the right jugular vein. All pressure transducers  were placed at the level of the mid-axillary line. General anesthesia was induced with sufentanil and propofol with neuromuscular blockade being initially achieved using succinylcholine  and maintained intraoperatively with atracurium. Maintenance of anesthesia was achieved using a sufentanil infusion and inhaled sevoflurane. All patients received mechanical ventilation using a volume control mode with tidal volumes of 7 to 8 ml/kg of predicted body weight, a positive end expiratory pressure (PEEP) of 5 cm H2O for 30 s . We also recorded the respiratory variations of the arterial pulse pressure induced by mechanical ventilation [pulse pressure variation (PPV)] at T1, T3, and T4.We calculated the absolute values of the variations (∆) of the hemodynamic parameters between the value at the plateau pressure of 30 cmHIn order to verify the reliability of SV throughout the study protocol, the correlation between SV measurements at the two baseline steps (T1 before ARM and T3 before volume expansion) was compared using a random-effects model to ensure that large changes did not occur .Differences between T1 and T2, and between T3 and T4 were assessed by a Wilcoxon test or a paired sample t-test according to the distribution of the differences. Responder and non-responder group data were compared using a Mann-Whitney test. The relationship between PVP and CVP was determined by a linear regression analysis plotting all the paired data using the coefficient of determination R² and by a Bland-Altman analysis with multiple observations per individual. To assess the ability of measured/calculated parameters to identify responders of intravascular fluid administration, receiver-operating characteristic (ROC) curves were generated, varying the discriminating threshold for ∆SVI, ∆CVP, ∆PVP, ∆MAP, ∆PP, and PPV. The optimal threshold value using the Youden index  was also determined. The areas under the ROC curves were calculated for each variable and compared as described previously . We defi® Statistical Software version 19.6.4 .A sample size of 55 patients was calculated to be sufficient to demonstrate that PVP variations could predict fluid responsiveness with an area under curve (AUC) above 0.75 , a ratioSixty patients were included in the statistical analysis. No patients were excluded, and no patient was given any vasopressor medication. No patients experienced hemodynamic instability during the ARM requiring a cessation of the maneuver. Table Supplemental Fig. 1).Hemodynamic variables at the study baseline, during the ARM, before the fluid challenge and after the fluid challenge between responders and non-responders are shown in Table PVP before the ARM in fluid responder patients was significantly lower than in non-responder patients (p = 0.0125). PVP increased significantly whatever the categorization of the patient (responder or not responder). Figure supplemental Fig. 2). The Bland-Altman analysis with the limits of agreement and their 95% CI is presented Fig. The regression equation between PVP and CVP was significant , with a coefficient of determination (R²) of 0.37  with a Bland-Altman analysis showing large limits of agreement (+ 5.7/-9.1 mmHg). A Study observed an improved PVP to CVP correlation with increasing CVP values , anotherThe study has known limitations. First, the sample size calculation could have been further optimized by choosing a higher null hypothesis ROC curve value. We ultimately decided to use 0.5 as the null hypothesis AUC ROC curve value in order to avoid establishing an insurmountably large sample size requirement, at the known cost of a weakened statistical outcome. Secondly, our protocol was conducted prior to surgical incision, where hemodynamics are not affected by significant surgical-induced changes in sympathetic tone. However, the vasoplegia induced by the anesthesia induction may have affected pulse pressure by decreasing the DAP. Further studies are needed to explore if ΔPVP can predict FR during the intraoperative period, wherein fluid expansion is typically more complex. It is important to note that a fluid challenge is recommended before incision to optimize fluid status when stroke volume is measured . AdditioIn patients undergoing high-risk abdominal surgery, ∆PVP induced by an ARM can moderately predict FR with a high grey zone inclusion. Interestingly, other hemodynamic variables did not better predict FR. As the PVP values do not rely on additional expensive devices, the clinician may benefit from this additional hemodynamic variable to better optimize the patient’s fluid status. In the current era of enhanced recovery within the context of reducing health care costs, additional non-invasive and low-cost approaches may be warranted. However, further outcome studies based on these data should be performed to confirm its potential role in perioperative hemodynamic management.Below is the link to the electronic supplementary material.Supplementary Material 1Supplementary Material 2Supplementary Material 3Supplementary Material 4


A growing number of research strongly suggest that metabolic syndrome and dyslipidemia contribute to the establishment of a pro-inflammatory state in asthma, according to accumulating data. However, the majority of recent research has focused on the association between lipids and asthma in children and adolescents, with contradictory findings. Consequently, we analyzed the relationship between serum lipid and blood eosinophil counts using data from the NHANES in the USA.After screening the individuals from the 2011 to 2018 NHANES survey, a total of 2,544 out of 39156 participants were eligible for our study. The potential association was discussed using the linear regression model, XGBoost algorithm model, generalized additive model, and two-piecewise linear regression model. In addition, we ran stratified analysis to identify specific demographics.After adjusting for covariates, the result indicated that blood eosinophil counts decreased by 45.68 /uL for each additional unit of HDL-C (mmol/L). But serum LDL-C, total cholesterol or triglyceride was not correlated with blood eosinophil counts. Furthermore, we used machine learning of the XGBoost model to determine LDL-C, age, BMI, triglyceride, and HDL-C were the five most critical variables in the blood eosinophil counts. The generalized additive model and two-piecewise linear regression model were used to further identify linear relationship between the serum HDL-C and blood eosinophil counts.Our study elucidated a negative and linear correlation between serum HDL-C and blood eosinophil counts among American asthmatic adults, suggesting that serum HDL-C levels might be associated with the immunological condition of asthmatic adults. There was no correlation between serum LDL-C, total cholesterol, or triglyceride levels and blood eosinophil counts. EosinopLipid metabolism issues are known to be linked to inflammation. In recent years, a growing number of studies have strongly suggested that metabolic syndrome and dyslipidemia contribute to the development of an asthmatic pro-inflammatory state –10. HoweConsequently, the purpose of this study was to examine the relationship between lipid profiles and peripheral blood eosinophil counts in adults with asthma. The National Health and Nutrition Examination Survey (NHANES) was investigated for secondary data analysis. After controlling for a large number of confounding variables, we attempted to clarify the relationship between serum lipid and blood eosinophil counts among asthmatic patients in the United States and to explain the contradictory findings.22.1Every two years, the National Health and Nutrition Examination Survey (NHANES), conducted by the Centers for Disease Control and Prevention (CDC), collected data on the health and nutritional status of the U.S. population. NHANES utilized a complex, stratified sampling design to select samples of non-institutionalized civilians that are representative of the population. The NCHS Institutional Review Board approved the NHANES database in accordance with the revised Helsinki Declaration. Before the data collection procedures and exhaustive health examinations, the informed consent forms were completed.2.2Our study applied data from four NHANES cycles (2011–2018). For the second analysis, these data included demographic data, examination data, laboratory data, diet data, and questionnaire data. When we initially screened the NHANES database, all participants (n=39156) from 2011 to 2018 were included. We included following individuals: (1) age≥18 years old (N=23825) (2) complete blood eosinophil counts data (N=21678) (3) complete serum lipid data (N=21237). Meanwhile, in the process of further screening, the following individuals were excluded: (1) individuals without asthma (n=18009) (2) missing data about covariates at least one of the following (n=684): education level; marital status; poverty to income ratio (PIR); BMI; smoked status; alcohol intake; hypertension history; diabetes history; COPD history. In the end, a total of 2544 asthmatic American adults were attended in our study. 2.3The lipid profile was evaluated using samples from subjects who had fasted for at least 8.5 h but less than 24 h. Using enzymatic assays, total cholesterol (TC), triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), and low density lipoprotein-cholesterol (LDL-C) levels were determined. On the NHANES website, you can find thorough instructions for specimen collection and processing.2.4in vitro diagnostic use in clinical laboratories. On the NHANES website, you can find a detailed description of laboratory procedures.Blood differential counts were performed by using the Beckman Coulter HMX , a quantitative and automated hematologic analyzer and leukocyte differential cell counter for 2.5http://www.cdc.gov/nchs/nhanes/) contains a more comprehensive description of the variables.We chose the following variables as potential covariates in our study due to some confounding factors that may affect the results. Participants’ continuous variables consisted of age (years old), poverty to income ratio , BMI (kg/m2) and alcohol intake (gm). And categorical variables were comprised of race/ethnicity , educational level , marital status , smoking status (whether smoked at least 100 cigarettes in life), lipid-lowering drugs use (whether lipid-lowering drugs use in past 30 days), antiallergic drugs use , hypertension history  and diabetes history , and COPD history . The assessment of asthma was based on the information from the questionnaire section of the US National Health Interview Survey. In order to assess asthma, participants were asked, “Has a doctor or other health professional ever told you that you have asthma?” If the participant responds “yes,” he or she was regarded as asthma patient. The official NHANES website  to confirm the validity of the regression analysis results. Next, we performed stratified analyses to determine the association between HDL-C and blood eosinophil counts in specific subgroups. To determine whether individual characteristics influenced the association between HDL-C and blood eosinophil counts, interaction tests were conducted. Eventually, the XGBoost algorithm model’s machine learning was intended to determine the relative importance of various variables on the effect of blood eosinophil counts. R software (Version 4.2.0) and the R package were used to conduct all statistical analyses. A p-value 0.05 was considered statistically significant in our study.33.13.2Three weighted univariable and multivariable regression models were used to assess whether the relationships between serum lipid and blood eosinophil counts among American asthmatic adults were statistically significant Table 2.3.3To verify the stability of multivariable regression analyses results, we further analyzed stratified associations between the serum HDL-C levels and blood eosinophil counts in a specific subgroup by gender, age, race, education level, marital status, poverty to income ratio, BMI, COPD history, lipid-lowering drugs use and antiallergic drugs use Table 4.3.4During the model development and validation phase, we identified the relative importance of chosen variables correlated with blood eosinophil counts using machine learning. Variables included age, poverty to income ratio (PIR), BMI, HDL-C, LDL-C, total cholesterol and triglyceride. According to the results of XGBoost algorithm model, we observed that LDL-C, age, BMI, triglyceride, and HDL-C were the five most critical variables in the blood eosinophil counts Figure 23.5The generalized additive model (GAM) is highly attuned to recognizing linear or nonlinear relationships. To verify the validity of multivariable regression analysis results, we explored the nonlinear or linear relationship between HDL-C levels and blood eosinophil counts using the GAM. Using GAM, we constructed a smooth fit curve to represent the relationship based on Model III Figure 34According to our knowledge, this study is one of the largest cross-sectional studies to explore the relationship between serum lipid levels and blood eosinophil counts in asthmatic individuals to date. The study population consisted of 2,544 National Health and Nutrition Examination Survey participants (2011–2018). In this investigation, HDL-C levels were adversely linked with blood eosinophil counts both before and after adjustment for sociodemographic, laboratory, personal life history, comorbidities, and medication use data, but serum LDL-C, total cholesterol or triglyceride was not correlated with blood eosinophil counts. LDL-C, age, BMI, triglyceride, and HDL-C were determined to be the five most important factors in blood eosinophil counts by machine learning of the XGBoost model. After controlling for confounders, the blood eosinophil counts fell by 45.68/uL for each increased unit of HDL-C (mmol/L), demonstrating a statistically significant difference. As a relatively essential variable, HDL-C was incorporated into generalized additive model and two-piecewise linear regression model to validate the robustness of the outcome.Previous studies had shown the association between eosinophilia and dyslipidemia in general populations –14. A crACOS is a condition characterized by overlapping clinical features of both diseases. A meta-analysis of 19 studies indicated the prevalence of ACOS across studies to be even higher with an average of 26.5% . PreviouThe findings that HDL-C particles are negatively associated with blood eosinophil counts in asthma, which are similar to the associations of HDL-C with lower cardiovascular risk , HDL notOur study has several advantages over earlier research. First, our research provides a nationally representative, somewhat large sample of asthmatic adults with information on a number of potential confounding variables. Secondly, because confounders may influence the results, we use stratified analysis to identify the potentially protected group with higher HDL-C values. Then, we employ the machine learning of the XGBoost algorithm model to determine the relative importance of selected variables correlated with blood eosinophil counts. Using the generalized additive model, we observed the linear association between serum HDL levels and blood eosinophil counts. Although the precise relationship between HDL-C and eosinophil count remains unknown, the linkage has the potential to inspire the development of innovative asthma treatments. To elucidate the relationship between eosinophil count and serum lipid and to identify the underlying mechanism, additional research is required.via their release from bone marrow adipocytes (Nonetheless, we accept that our study has some limitations. Although the scope of our study is nationwide, the majority of the data is derived from the American population. As a result of unequal national development, dietary models may vary between countries. Due to the limitations of the cross-sectional study design, we cannot establish a causal association between serum lipid levels and blood eosinophil counts. Recent research has revealed, however, that free fatty acids directly impact myelopoiesis in the bone marrow ipocytes , which t5This nationally representative study demonstrated that serum HDL-C was independently and inversely connected with blood eosinophil counts among American asthmatic adults, suggesting that serum HDL-C might be associated with the immunological status of asthmatic adults. However, there was no correlation between serum LDL-C, total cholesterol, or triglyceride levels and blood eosinophil counts. We hope that more individuals will recognize the significance lipids play in asthma, in the future.http://www.cdc.gov/nchs/nhanes/.Publicly available datasets were analyzed in this study. This data can be found here: The studies involving human participants were reviewed and approved by NCHS Research Ethics Review Board. The patients/participants provided their written informed consent to participate in this study.JW carried out the study design, data extraction and statistical analysis, drafted and revised the manuscript. MG conducted data extraction, statistical analysis, and revision of the paper. RZ carried out statistical analysis, drafted and revised the manuscript. CH conducted data extraction, drafted and revised the manuscript. SG participated in the study design, management of study and revision of the paper. All authors contributed to the article and approved the submitted version.


Objectives: Olfactory dysfunction is a clinical sign that is important to detect with coexistent upper airway comorbidities in patients with asthma. This study aimed to investigate the etiology of olfactory dysfunction in patients with asthma and the relationship between fractional exhaled nitric oxide (FeNO) levels. Materials and Methods: This study included 47 asthma patients who were evaluated for olfactory dysfunction at Hiroshima University Hospital between 2012 and 2020. The etiologies of olfactory dysfunction were evaluated, and they were classified according to the FeNO levels of patients with asthma. Results: Olfactory dysfunction was observed in 30 patients with asthma, with chronic rhinosinusitis (77%) being the most prevalent etiology. Eosinophilic chronic rhinosinusitis (ECRS) was the most prevalent etiology of olfactory dysfunction in asthma patients with high FeNO levels (≥25 ppb), while non-eosinophilic chronic rhinosinusitis (NCRS) was the most prevalent etiology in asthma patients with low FeNO levels (<25 ppb). Additionally, the prevalence of ECRS was significantly higher in asthma patients with olfactory dysfunction and high FeNO levels (74%) than in those with either high FeNO levels or olfactory dysfunction and those with low FeNO levels and no olfactory dysfunction . Conclusions: We found that ECRS was the predominant cause of olfactory dysfunction in patients with high FeNO levels, while NCRS was more common in those with low FeNO levels. The present study showed that both ECRS and NCRS are common etiologies of olfactory dysfunction in patients with asthma. Additionally, this study supports the link between upper and lower airway inflammation in patients with asthma complicated with olfactory dysfunction. Olfaction is one of the most important sensations in humans to maintain a high quality of daily life, and it is also essential to avoid danger signals around residual environments. Olfactory dysfunction is a clinical sign that is important to detect with coexistent upper airway comorbidities in patients with asthma. The etiology of olfactory dysfunction is diverse, and over 200 causes of olfactory dysfunction have been reported; frequent causes of olfactory dysfunction in the general population have been reported to be idiopathic, rhinitis, sinus infection, upper respiratory tract infection, and head trauma ,2. BecauChronic rhinosinusitis (CRS) is a heterogeneous disease caused by various inflammatory mechanisms with a considerable social burden . It is dInterestingly, we and others have shown that fractional exhaled nitric oxide (FeNO) levels are elevated in patients with ECRS, irrespective of comorbid asthma ,12,13. NThis study, therefore, aimed to investigate the etiology of olfactory dysfunction in patients with asthma and to assess the relationship between FeNO levels and the etiology of olfactory dysfunction. For this purpose, a group of asthma patients was evaluated for olfactory dysfunction and was classified by FeNO levels. We found that ECRS comorbidity was the most prevalent etiology of olfactory dysfunction in the asthma patients with higher FeNO levels. The results further substantiated the clinical significance of the prevalence of both ECRS and NCRS as common etiologies of olfactory dysfunction in asthma patients and implied intimate links between upper and lower eosinophilic airway inflammation.This study included 47 adult asthma patients who had been evaluated for olfactory dysfunction at Hiroshima University Hospital between 2012 and 2020. All the patients were Japanese. Clinical records and laboratory data were collected from the patients’ medical records. All procedures contributing to this work complied with the ethical standards of the Helsinki Declaration of 1975, revised in 2013. The Medical Ethics Committee of Hiroshima University approved this study (E-2033) and waived the requirement for obtaining signed informed consent as this was a retrospective observational study.Patient backgrounds and characteristics, including age, sex, body mass index (BMI), asthma control test (ACT) score, asthma control questionnaire (ACQ) score, asthma medication use, pulmonary function test results, FeNO levels, and blood eosinophil counts, were collected. Olfactory dysfunction was evaluated using a T&T olfactometer, the SNOT-22, and medical interviews . T&T olfactometry  has been commonly used in Japan for evaluating patients with olfactory dysfunction. The device utilizes 5 distinct odors, i.e., b-phenylethyl alcohol, methyl cyclopentenolone, isovaleric acid, g-undecalactone, and skatole, with 7–8 graduated concentration levels. Odor detection and cognitive thresholds are recorded for each element, with a normal cognitive threshold being less than 1.0. The severity of olfactory dysfunction is classified by the mean T&T cognitive threshold: a value of 1.0 or less indicates no dysfunction, 1.1–2.5 is mild, 2.6–4.0 is moderate, 4.1–5.5 is severe, and 5.6 or more is labeled as anosmia . The jud®  following the recommendations of the European Respiratory Society/American Thoracic Society [During this study period, because the same patient may have had more than one form of olfactory dysfunction  at different stages of the disease, we considered any form of smell disorder to be olfactory dysfunction . Atopic  Society . The nasThe etiology of olfactory dysfunction was determined according to clinical history and the results of blood tests, nasal endoscopy, plain radiography, computed tomography, and magnetic resonance imaging ,16,17,18p < 0.05. Finally, the prevalence of ECRS was compared according to olfactory dysfunction and FeNO levels. Statistical analyses were performed using JMP Pro version 16 software .Between-group comparisons were performed using the chi-square test, Fisher’s exact test, or the Mann–Whitney U test with Bonferroni correction, as applicable. Quantitative data are presented as mean ± standard deviation (SD). The patients were classified into ECRS, NCRS, and no-CRS groups for comparison. Multivariate logistic regression analyses were performed to investigate factors associated with ECRS, independent of age, sex, and lung function. We compared the etiology of olfactory dysfunction according to FeNO levels. Statistical significance was set at n = 17), NCRS (n = 13), and no-CRS (n = 17)  . The ageCRS was identified as the most prevalent etiology of olfactory dysfunction and was present in 77% (23/30) of the patients with asthma a. Other We compared the prevalence of ECRS among the groups classified according to the presence of olfactory dysfunction and FeNO levels. The prevalence of ECRS was significantly higher in asthma patients with olfactory dysfunction and high FeNO levels (74%) compared with those with either high FeNO levels or olfactory dysfunction and those with low FeNO levels (<25 ppb) and no olfactory dysfunction  . The posA total of 80% of olfactory dysfunction cases were evaluated with T&T olfactometry. Olfactory dysfunction is pathologically divided into three categories: i.e., conductive dysfunction, sensorineural dysfunction, and central dysfunction . In the p < 0.025)  . ConversThis study showed that CRS was the most common etiology of olfactory dysfunction in patients with asthma. Moreover, ECRS was the most common etiology in patients with high FeNO levels, whereas NCRS was the most common etiology in patients with low FeNO levels. Additionally, having both high FeNO levels and olfactory dysfunction were associated with a significantly higher prevalence of ECRS compared with either one of them. The present results showed that both ECRS and NCRS are common etiologies of olfactory dysfunction in patients with asthma and support the link between upper and lower airway inflammation in patients with asthma complicated with olfactory dysfunction. The diagnostic value of NO measurements in patients with BA as a comorbidity has been investigated in a series of studies based on the “one airway/one disease” theory. For example, the use of FeNO in determining the likelihood of steroid responsiveness was strongly recommended for individuals with BA .To the best of our knowledge, this was the first study to report on the etiology of olfactory dysfunction in detail in patients with asthma. In this study, CRS accounted for 77% of the etiologies of olfactory dysfunction, ECRS (53%), and NCRS 23%), with other etiologies including allergic rhinitis, post-viral infection, olfactory cleft inflammation, olfactory epithelium inflammation, and idiopathic. A previous study in general practice reported that the main etiologic diagnoses for olfactory dysfunction were post-viral (34.8%), sinonasal (18.0%), traumatic (15.7%), idiopathic (24.7%), and other (6.7%) in 299 patients with olfactory dysfunction . Another3%, with Olfactory dysfunction is etiologically divided into three categories; conductive dysfunction , sensorineural dysfunction , and central dysfunction  . OlfactoThe establishment of classifying CRS endotypes has been attempted, involving histological features such as eosinophilia and specific molecular biomarkers. The integrated analysis of the CRS phenotype and endotype could provide insights into treatment responses and the pathobiology. In particular, classification based on the level of airway NO production and related enzymes has drawn attention with continuing efforts. In this sense, the measurement of FeNO levels and accompanied enzyme activities could provide a foundation for new and specific interventions targeting molecular pathways that underlie endotype-specific inflammation in CRS . Nitric oxide synthase (NOS) is an enzyme responsible for NO production from L-arginine to L-citrulline by the action of the NADPH and tetrahydrobiopterin-dependent oxidation . In humaIt is noteworthy that the presence of ECRS has previously been associated with persistent asthma and pronounced eosinophilic inflammation in the lower airways ,30. Our Prior studies have indicated that increased FeNO levels correlated with elevated eosinophil counts and a decrease in FEV1 among asthma patients ,32. SimiIn this study, the prevalence of olfactory dysfunction was high in both ECRS and NCRS (94.1% and 61.5%), which was in agreement with the findings of previous studies that primarily included populations without asthma . In geneIn this research, allergic rhinitis was identified in 72.3% of the participants. The incidence of allergic rhinitis has surged markedly since the 1990s ,42,43 anThe limitations of this study included its retrospective design and small sample size. The sample size was relatively small because the patients were selected from those who had asthma, had visited an otorhinolaryngologist, and had undergone some imaging studies. Olfactory dysfunction was evaluated using various methodologies; 16% were evaluated with a medical interview. Self-reported olfactory assessment has been reported to be less sensitive and possibly underestimated in previous studies . Though This study showed that both ECRS and NCRS were common etiologies of olfactory dysfunction in patients with asthma. ECRS was the most common etiology of olfactory dysfunction in patients with high FeNO levels, whereas NCRS was the most common etiology in patients with low FeNO levels. The results of this study also suggested that the combined assessment of FeNO levels and olfactory dysfunction could be used to detect patients with asthma who are at high risk for ECRS. These results supported the link between upper and lower airway inflammation in patients with asthma complicated with olfactory dysfunction.