The goals of this study are to assess the correlation between 24-hour ambulatory blood pressure (BP) variability and white matter lesions (WML) in patients with cerebral small vascular disease (CSVD) and to provide guidance for the prevention of WML.  A total of 136 patients diagnosed with CSVD and essential hypertension were recruited and divided into two groups. The Fazekas scale was used to quantify the severity of WML. The basic information, BP levels, BP variability, and circadian rhythm changes across these groups were recorded and compared. n = 43, Fazekas score = 1), moderate WML , and severe WML . Age, history of diabetes, and serum uric acid levels were significantly increased between the WML and control groups (P < 0.05). The levels of 24-hour mean diastolic BP  and daytime mean systolic BP  were significantly increased between the control and WML groups. There was no significant difference in the rhythmic classification of BP among all groups (P > 0.05). An ordered multinomial logistic regression analysis revealed that age, triglyceride levels, and nondipper BP were independent risk factors in WML.  The control group consisted of 40 subjects without WML (Fazekas score = 0), and the WML group was composed of 96 patients with WML (Fazekas score ≥ 1). Patients in the WML group were then divided into three subgroups: mild WML ( Age, history of diabetes, serum uric acid levels, 24-hour mean systolic level, and daily mean systolic BP level were significantly increased between the WML and control groups. Age, triglyceride levels, and nondipper BP were independent risk factors in WML in patients with CSVD, while the 24-hour dynamic blood pressure standard deviation and 24-hour dynamic blood pressure coefficient of variation were not associated with the occurrence of WML. Cerebral small vessel disease (CSVD) is a common and potentially destructive subclinical disease characterized by insidious onset, slow progress, and sometimes acute attacks. The manifestations of CSVD detected by magnetic resonance imaging (MRI) include lacunar infarction, lacunes, white matter lesions (WMLs), enlarged perivascular space, and cerebral microbleeds . WML refWMLs are associated with many factors, including age, diabetes, hypertension, smoking, drinking, hyperhomocysteinemia, decreased left ventricular diastolic function, carotid artery intima-media thickness, vitamin D deficiency, renal insufficiency, and metabolic disorders –8. As anIn view of the characteristics of CSVD, high incidence and low diagnosis rate, and the high proportion of WML in CSVD, this study focused on WML in CSVD. Hypertension is the most significant risk factor for CSVD, and ambulatory blood pressure variability is more responsive to blood pressure changes and its impact on disease than office blood pressure. Therefore, we aimed to investigate the correlation between ambulatory BP variability and WML in patients with CSVD and essential hypertension. These results may provide guidance for clinical BP control and the prevention of WML in patients with CSVD and primary hypertension.A total of 136 consecutive patients diagnosed with essential hypertension and hospitalized for CSVD in the Department of Neurology of our hospital between October 2019 and December 2020 were recruited to participate in this study. All subjects were evaluated for study eligibility prior to enrollment.2; (5) with full awareness and willingness to participate. Patients were excluded if they were (1) previously diagnosed with other diseases that may cause hypertension, such as kidney disease, cardiovascular disease, endocrine diseases ; (2) with clear causes of WML, such as carbon monoxide poisoning, immune-mediated white matter demyelination, metabolic diseases, or genetic diseases; (3) with other disorders that might affect BP levels, such as mental problems. All patients provided written informed consent before the study and continued to take their routine medications throughout their participation.The inclusion criteria were as follows: (1) aged between 35 and 80 years; (2) diagnosed with essential hypertension according to the 2018 Chinese Guidelines for Prevention and Treatment of Hypertension-A report of the Revision Committee of Chinese Guidelines for Prevention and Treatment of Hypertension ; (3) metParticipants were all hospitalized patients after outpatient visits. Patients who met the inclusion criteria would write informed consent from each subject before enrollment. Patients and the public will not be involved in the development of the research question or the design of the study. Patients will not be involved in the recruitment of participants or the conduct of the study. The general results would be disseminated to participants through public education activities.The basic information of all recruited patients was collected from medical records, including gender, age, history of smoking, history of drinking, history of diabetes, fasting blood glucose (FBG) levels, blood uric acid (UA) levels, total cholesterol (CHOL) levels, triglyceride (TG) levels, high-density lipoprotein (HDLC) levels, low-density lipoprotein (LDLC) levels, homocysteine (HCY) levels, mean platelet volume (MPV), and platelet count (PLT).All patients underwent 24-hour ABPM after the MRI examination. The ABPM cuff was placed on the nondominant arm of the patient, with the lower edge of the cuff 2 cm above the elbow. Patients were allowed to take routine medications and perform normal daily activities, but were instructed to avoid excessive or strenuous activities. BP was measured every 30 minutes during the day (from 6 a.m. to 6 p.m.) and every one hour during the night (from 6 p.m. to 6 a.m.). The ABPM results with ≥80% valid data were considered eligible for analysis. The following dynamic BP parameters were recorded: 24-hour mean systolic blood pressure (24hSBP), 24-hour mean diastolic blood pressure (24hDBP), daytime mean systolic blood pressure (dSBP), daytime mean diastolic blood pressure (dDBP), nighttime mean systolic blood pressure (nSBP), nighttime mean diastolic blood pressure (nDBP), nighttime diastolic blood pressure coefficient of variation (nDBPCV), 24-hour dynamic blood pressure standard deviation (SD), and 24-hour dynamic blood pressure coefficient of variation (CV). According to the changes in BP levels during the circadian rhythm, there were four ambulatory BP patterns: (1) dipper BP, with a 10%–20% decrease in nSBP; (2) superdipper BP, with a >20% decrease in nSBP; (3) nondipper BP, with a <10% decrease in nSBP; (4) antidipper BP: with an increase in nSBP , 13.n = 40), while those with a score of ≥1 were assigned to the WML group (n = 96). Patients with WMLs were further divided into three subgroups according to the severity of the WMLs: mild WML , moderate WML , and severe WML   and were compared using a Kruskal-Wallis H test. The risk factors were identified by single-factor logistic regression analysis, followed by ordered multinomial logistic regression analysis. A value of P < 0.05 was considered statistically significant.The SPSS 20.0 software was used for statistical analysis. A Levene's test was used to assess the homogeneity of the variances of different variables. Gender, history of smoking, history of drinking, history of diabetes, and ambulatory BP patterns were expressed as a number (frequency) and compared using a chi-square test. Normally distributed data, including the levels of UA, CHOL, TG, HDL, LDL, and MPV, PLT, the ratio of PLT/MPV, and ABPM parameters were presented as mean ± standard deviation (SD) and compared using the one-way ANOVA. Pairwise LSD P > 0.05). Age, history of diabetes, and serum UA levels were significantly increased between the WML and control groups (P < 0.05). The average age of the control group was significantly lower than that of the moderate and severe WML groups . The average age of the mild WML group was significantly lower than that of patients with moderate lesions (P = 0.023) or severe lesions (P = 0.012). The UA levels were significantly different between the mild and severe WML groups (P = 0.042) and between the moderate and severe WML groups (P = 0.04)  were males. The average age of all participants was 61.58 ± 12.93 years. There were 40 cases in the control group , 43 cases in the mild WML group , 24 cases in the moderate WML group , and 29 cases in the severe WML group . There was no significant difference in gender between the control and WML groups ( = 0.04) .F = 3.158, P = 0.026). The 24hSBP of the control group was significantly lower than that of the mild (P = 0.006) and severe (P = 0.015) WML groups. No difference in 24hSBP between other groups was observed. The dSBP was significantly increased among all groups . The dSBP of the control group was significantly lower than that of the mild (P = 0.003) and severe (P = 0.015) WML groups. In addition, the differences in other dynamic BP parameters such as nSBP (SD/CV), nDBP (SD/CV), 24hSBPSD, 24hDBPSD, 24hSBPCV, and 24hDBPCV between groups were not statistically significant (P > 0.05) (The 24hSBP was significantly increased between the control and WML groups ( > 0.05) .χ2 = 6.158, P = 0.724)  .P = 0.004), history of diabetes (P = 0.004), TG levels (P = 0.021), and nDBPCV (P = 0.041) were potential risk factors in WML. The ordered multinomial logistic regression analysis that included potential influential factors (significantly different variables shown in Tables P = 0.018), TG levels (P = 0.049), and nondipper BP (P = 0.042) were independent risk factors in WML  and was called dipper BP. The circadian rhythm of BP played an important role in promoting the normal structure and function of blood vessels without affecting vascular elasticity. Arteriosclerosis is one of the main pathogenic mechanisms of CSVD, which reduces vascular elasticity, increases cerebral arterial pulsatility, and reduces BP buffering. When considering where WML were likely to occur, it was likely that cerebral artery insufficiency led to chronic ischemia and subsequent WML . ABPM isIn summary, age, history of diabetes, blood UA levels, 24hSBP, and dSBP were found to be significantly different between patients with and without WML. Age, TG levels, and nondipper BP were independent risk factors in WML. In BP management for patients with CSVD and essential hypertension, it is important to maintain their BP levels within a normal range and also to monitor BP variations during the circadian rhythm. These results may provide future guidance for the prevention of WML in hypertensive patients with CSVD.


Microvascular angina (MVA) is a frequent condition for which our understanding of the disease pathophysiology and therapeutic perspectives remain unsatisfactory. The current study is designed to test whether an improvement in microvascular resistances could be achieved by elevating backward pressure in the coronary venous system, based on the hypothesis that an increase in hydrostatic pressure could cause a dilatation of the myocardial arterioles, resulting in a reduction of vascular resistances. This approach might have potential clinical implications, as it might suggest that interventions aimed at increasing coronary sinus (CS) pressure might result in a decrease in angina in this subset of patients. The aim of our single-center, sham-controlled, crossover randomized trial is to investigate the effect of an acute increase in CS pressure on a number of parameters of coronary physiology, including parameters of coronary microvascular resistance and conductance.A total of 20 consecutive patients with angina pectoris and coronary microvascular dysfunction (CMD) will be enrolled in the study. Hemodynamic parameters including aortic and distal coronary pressure, CS and right atrial pressure, and the coronary microvascular resistance index will be measured at rest and during hyperemia in a randomized crossover design during incomplete balloon occlusion  and with the deflated balloon in the right atrium (“sham”). The primary end point of the study is the change in index of microvascular resistances (IMR) after acute modulation of CS pressure, while key secondary end points include changes in the other parameters.The aim of the study is to investigate whether occlusion of the CS is associated with a decrease in IMR. The results will provide mechanistic evidence for the development of a treatment for patients with MVA.https://clinicaltrials.gov/, identifier NCT05034224. Microvascular angina pectoris (MVA) is a complex clinical condition in which functional and/or structural changes in the coronary microcirculation result in an increased vascular tone. MVA is diagnosed as symptoms of ischemia with objective evidence of impaired coronary microvascular function  in the absence of obstructive epicardial disease , 2. WhilMicrovascular angina caused by a dysfunctional microvascular bed cannot be treated by standard revascularization therapies and the pharmacological strategies  available also provide limited benefit. As well, while pressure-controlled intermittent coronary sinus occlusion has been shown to improve microvascular resistances in the setting of acute myocardial infarction , there iAs a possible alternative to pharmacological agents, the hypothesis of improving myocardial perfusion by diverting blood from the coronary venous system to an ischemic region (“venous retroperfusion”) has again gained attention during recent years. This therapy is based on the concept that an elevation in backward pressure in the coronary venous system provokes dilatation of the subendocardial arterioles, resulting in a relative reduction of vascular resistance in this area and a redistribution of blood flow to the ischemic subendocardial layers –8. NumerWe investigate whether an increase in coronary sinus pressure leads to a change in coronary microvascular resistances in patients with angina pectoris due to microvascular dysfunction.The study is a sham-controlled, crossover, randomized trial to investigate the effect of changes in coronary venous pressure on microvascular resistances. The hypothesis of the study is that occlusion of the coronary sinus (CS) will be associated with a decrease in the index of microvascular resistances (IMR). The protocol complies with good clinical practice and the ethical principles described in the Declaration of Helsinki and has been approved by the local ethics committee. All patients will provide written informed consent before enrollment.Patients must meet all of the following inclusion criteria: chronic coronary syndrome ; reversible ischemia on non-invasive testing; absence of epicardial stenosis that are compatible with the symptoms and the evidence of ischemia; evidence of microvascular dysfunction as demonstrated by an IMR ≥ 25; willingness to participate and ability to understand, read, and sign the informed consent; age > 18 years.Patients will be excluded from eligibility for study enrollment if any of the following criteria applies: previous coronary artery bypass graft (CABG) with patent graft to the left anterior descending coronary (LAD) such that IMR cannot be measured; epicardial coronary disease  in the LAD territory; second and third degree atrioventricular block; severe valvular heart disease; any cardiomyopathy; pulmonary or renal disease; inability to provide informed consent; any disease reducing life expectancy. Patients unable to understand the scope of the study are classified as not able to give informed consent and are excluded for eligibility for study enrollment. Likewise, patients unable to consent, e.g., for a neurological damage, are treated as not able to give informed consent and are excluded for eligibility for study enrollment .Patients will be enrolled among those treated at the Department of Cardiology, Cardiology I of the University Medical Centre Mainz or, eventually, cooperating centers.Microvascular function measurements will be made (both at rest and during hyperemia) twice in each patient in a sham-controlled, randomized, crossover design. Randomization will be performed after informed consent and if all inclusion criteria and no exclusion criteria are met. Patients will be randomized 1:1 to one of the two study arms  . After tFor the measurements during balloon inflation, incomplete CS occlusion will be achieved with a Swan-Ganz catheter advanced into the CS with access through the femoral or jugular vein. The position of the balloon will be chosen in order to cause a ∼80–90% CS lumen reduction while maintaining stability throughout the measurements. For the sham measurements, the balloon will be kept deflated in the right atrium. Randomization will be done by a computer-generated random sequence .–1⋅min–1) or, in patients with asthma, intracoronary papaverine (10 mg). The distal sensor of the pressure wire will be kept in the same position and the same hyperemic agent will be used for the two sets of measurements . For the assessment of the mean transit time (Tmn) and IMR, 3 boli of 3 ml room-temperature saline will be injected briskly into the guiding catheter as per instructions for use. The presence of drift will be checked at the end of the measurements. All assessments will be performed using the CoroFlow software .Coronary angiography and microvascular function assessments will be performed in the left anterior descending coronary artery using the wire-based thermodilution method. Five to seven thousand international units of intravenous heparin and intracoronary nitrates will be administered before measurements when systolic blood pressure is above 100 mmHg systolic. A guiding catheter will be advanced to the ostium of the left coronary. A pressure wire  equipped with pressure sensor and thermistor will be advanced placed approximately 8 cm into the LAD after ostial equalization. Maximal hyperemia will be induced through intravenous adenosine .Primary endpoint: change in IMR during inflation of the CS balloon as compared to sham.Key secondary endpoints: changes in the following physiological parameters1.Aortic (Pa) and distal coronary pressure (Pd) at rest and during hyperemia (aortic and coronary pressure);2.Pressure in the right atrium (Pra) and in the coronary sinus (Pcs);3.RFR (resting flow ratio);4.FFR calculated as Pd/Pa and as (Pd-Pcs)/(Pa-Pcs);5.Tmn (transit mean time) at rest and during hyperemia, average of the three boli;6.CFR: coronary flow reserve;7.Pd – CS) × Tmn] and using the standard formula (IMRst = Pd × Tmn). CFR is the ratio of baseline Tmn/hyperaemic Tmn.IMR calculated as [(All measurements (including hemodynamic measurements) are applied as clinically indicated and according to CE certificate and the instruction for use. Vascular access is performed using the femoral or jugular vein; the expansion of the balloon is incomplete and performed using low pressure (2–4 ATM). The risk of trauma is thereby minimal. Thus, it is not to be expected that the participation in the study will lead to unneeded or harmful therapeutic interventions.Statistical analysis will be performed with MedCalc .P < 0.0001, median decrease ∼35%) in response to fasudil. Luo  and sham. The primary analysis will be performed as within-subject comparison of the primary parameter. Statistical tests and effect estimates will be calculated using the Wilcoxon test. The effect of randomization and baseline measurements as covariates will be investigated. No treatment by time interaction is expected because the balloon from the experimental intervention will produce a transient increase in CS pressure which will normalize upon deflation. The primary comparison will be performed at a two-sided significance level of α = 0.05. Treatment differences will be displayed by adjusted estimates and 95% confidence intervals. Bias is minimized by randomized sequence allocation. The randomization ratio of the treatment sequences will be 1:1 without any stratification factors. Randomization with permuted blocks will be applied.Patient data will be pseudonymized and collected by the study team. Pseudonymized patient data will be stored digitally on an external hard-drive not connected to the clinical intranet and only accessible to the members of the study team. After 10 years of storage, data will be destroyed. It is not intended to give study participants’ data to a third party. All data will be analyzed after the last patient is discharged from index hospitalization. No interim analysis is intended. However, a Data Safety Monitoring Board consisting of two physicians not affiliated with the study will monitor the safety of the subjects throughout the study. In case a study participant withdraws consent after having his data collected from him, the patient’s data will be anonymized.The protocol has been approved by the local state medical association’s ethics committee. In accordance with the WMA Declaration of Helsinki–Ethical Principles for Medical Research Involving Human Subjects, researchers, authors, sponsors, editors, and publishers all have ethical obligations with regard to the publication and dissemination of the results of research. Researchers have a duty to make publicly available the results of their research on human subjects and are accountable for the completeness and accuracy of their reports. All parties should adhere to accepted guidelines for ethical reporting. Negative and inconclusive as well as positive results must be published or otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of interest must be declared in the publication. Reports of research not in accordance with the principles of this Declaration should not be accepted for publication. The PI of this study, recognizing the seminal importance of this investigation, is committed to the unrestricted and widespread dissemination of all primary and secondary endpoint results and tertiary analyses. At the conclusion of the study, an abstract reporting the primary results will be prepared by the Principal Investigators and presented at an annual scientific meeting. A publication will similarly be prepared for publication in a reputable scientific journal. Following analysis and presentation of the primary endpoint results, active participation of all study group members will be solicited for data analysis and abstract and manuscript preparation and therefore included as co-authors. Submission of all abstracts and publications regarding the primary endpoint and secondary endpoints from the study requires approval by the Principal Investigators after review by all members of the study group.Since all procedures (except for randomization) are clinically indicated and acknowledged in the current literature, a study insurance is not planned.Data collection is ongoing.The study will be financed by own means of the Department of Cardiology of the University Medical Center Mainz (=Sponsor) and means of the W3-Professorship of Translational myocardial and cardiovascular function. Additionally, the research project will be supported by the Clinician Scientist program of Helen Ullrich, which was granted by the German Centre for Cardiovascular Research (DZHK).To assess coronary circulatory function, three different physiological indexes were measured in the present study. FFR is defined as the ratio of maximal coronary blood flow in a diseased artery to maximal coronary blood flow in the same artery without stenosis. FFR is a surrogate marker of inducible myocardial ischemia caused by epicardial coronary stenosis . CFR is Approximately half of patients undergoing diagnostic coronary angiography for typical angina symptoms do not have significant obstructive coronary stenoses . This laInitial evidence from animal studies and a series of patients appears to support the hypothesis that coronary sinus occlusion (CSO) improves microvascular function: Ido et al.  demonstrAlthough this is just preliminary data, they suggest that the redistribution of blood from the subepicardial to the subendocardial space might be associated with a drop in total microvascular resistances and therefore relief of symptoms.Our study has several limitations. First, the present study is a mechanistic study conducted exclusively at one center. In addition, only a relatively small number of patients will be enrolled in each of the two study groups. Furthermore, we only studied the effect of a single occlusion of the CS on microvascular function. Repeated CSO as well as a permanent CSO could alter the effects of a single CSO . Larger HU and TG wrote the first draft. All authors provided critical appraisal and corrections and approved the submitted version.


Patients with asthma who have neutrophilic bronchitis may have an underlying cause leading to increased susceptibility to airway infections.Retrospective review of patients with asthma who had a previous history of recurrent exacerbations that had been associated with airway or sinus infections referred to a tertiary asthma center between 2005 and 2020. Demographics, clinical features, and airway inflammation type determined by sputum cytometry were compared between CFTR carriers and non-carriers. Multiple linear regression was used to identify clinical predictors of CFTR carrier status. Response to nebulized hypertonic saline was assessed by comparing the number of infective exacerbations before and after its initiation.CFTR mutation testing. Of these, 13 (17%) were CFTR carriers. The most common mutation was 75 patients underwent CFTR heterozygosity in this cohort with recurrent neutrophilic bronchitis is higher than in the general population. Respiratory disease in CFTR carriers is associated with older age and may cause significant morbidity. Airway neutrophilia is the most common inflammatory subtype, but > 50% had eosinophilic bronchitis requiring treatment. Hypertonic saline appears to be well tolerated and effective in reducing the number of infective exacerbations.The prevalence of The online version contains supplementary material available at 10.1186/s13223-022-00684-0. Asthma is characterized by variable airflow limitation and is usually associated with airway inflammation. The luminal cellular inflammatory component can be characterized based on the proportion of eosinophils and neutrophils found in the sputum . AsthmatCFTR mutation. Individuals who are heterozygous for a disease-causing mutation in CFTR (CF carriers), typically have normal sweat chloride, and have been considered protected from the manifestations of cystic fibrosis [One potential cause of increased susceptibility to airway infections in asthma patients is cystic fibrosis transmembrane conductance regulator (CFTR) hypofunction due to heterozygosity for a damaging fibrosis . Howeverfibrosis , 7, chrofibrosis , and astfibrosis .We previously reported the clinical histories of three asthma patients who were CF carriers and had persistent neutrophilic bronchitis . In the CFTR genetic testing were reviewed. Spirometry, quantitative sputum cell counts, sputum culture, methacholine provocation concentration causing a 20% reduction in forced expiratory volume in 1 s (PC20), chest computed tomography (CT) findings (ascertained from a radiologist report), and serum immunoglobulin concentration data were collected. Genetic analysis was performed by The Hospital for Sick Children molecular diagnostics laboratory, which uses multiplex polymerase chain reaction (PCR) to test for the 39 most common pathogenic CFTR variants in Caucasian populations  airway disease clinic in Hamilton, Ontario between August, 2005 and July, 2020 for recurrent infectious exacerbations (two or more in the previous 12 months). As a part of our diagnostic workup of susceptibility to infections, we examined CFTR mutation analysis in these regardless of previous diagnosis of cystic fibrosis or family history. Ethics approval was obtained from the Hamilton Integrated Research Ethics Board. All charts of patients who underwent Concurrent asthma was determined based on compatible symptoms and at least one confirmatory test (bronchodilator response > 200 mL and > 12% in forced expiratory volume in 1 s (FEV1), PC20 ≤ 8 mg/mL, or ≥ 15% reduction in FEV1 with nebulized saline during sputum induction). Chronic rhinosinusitis was identified based on sinonasal symptoms and confirmation either by nasal endoscopy performed by an otolaryngologist or by CT sinuses.6 cells/g with at least 65% neutrophils, and pleiotropic bronchitis was defined as the presence of both eosinophilic and neutrophilic bronchitis. A patient was considered to have persistent neutrophilia if they had > 2 episodes of neutrophilic bronchitis and was considered to have persistent intense neutrophilia if they had > 2 episodes of neutrophilic bronchitis in which the neutrophil differential exceeded 85%. An exacerbation was defined as a change in symptoms and lung function from a subject’s usual status [Sputum cytometry was performed for every patient at least once, as is the protocol of our clinic. Sputum was induced by inhalation of hypertonic saline, and the expectorate was processed to obtain the total cell count and cell differential using standard methodology . Eosinopl status . In lighl status , 14, an In our clinic, hypertonic saline  is used to attenuate and prevent recurrent infectious exacerbations. The use of nebulized hypertonic saline facilitates airway clearance, reduction of bacterial burden and mitigates stasis. The change in number of infective exacerbations between the year prior to and after starting hypertonic saline in patients was documented and reviewed from the medical chart.Patient demographics, clinical features, and laboratory data were summarized using descriptive statistics. Differences in baseline characteristics between CF carriers and non-carriers were compared using two-sided t-tests for continuous variables and Fisher’s Exact Test for categorical variables. The number of neutrophilic exacerbations before and after hypertonic saline was compared using the Wilcoxon signed-rank test. A significance level of < 0.05 was used for all inferences. The association between different patient characteristics and CF carrier status was assessed using multivariable logistic regression. Backwards stepwise regression was performed using the Akaike information criterion to select the optimal regressors. Analyses were performed using R  and GraphPad Prism 9.0 .CFTR mutation testing. This represents approximately 50% of all patients with asthma and at least one neutrophilic exacerbation, and 20% of all patients in our clinic. Table CFTR mutations were identified in 13/75 patients (17.3%). This is significantly greater than expected assuming a CFTR mutation prevalence of 4% in the general population (p = 0.01). CF carriers were older (67 years (SD 13.2) compared to 56 years (14.7), p < 0.01) on average compared to non-carriers. FEV1% predicted was similar between the two groups . There was a numerical trend to increased prevalence of bronchiectasis (70.0% vs 41.9%) and chronic rhinosinusitis (85.7% vs 33.8%) in CF carriers, but this did not reach statistical significance. Alternate causes of increased susceptibility to airway infections including lymphopenia  and hypogammaglobulinemia were comparable between both groups (p = 0.551 for lymphopenia and p = 1.00 for need for intravenous immunoglobulin therapy).There were 75 patients referred with physician-diagnosed asthma who had 6/g, p = 0.37) and higher prevalence of persistent intense neutrophilia . A similar proportion of both groups also had eosinophilic bronchitis , and approximately one-third in each group required daily oral corticosteroid therapy for optimal control.Neutrophilic bronchitis was the most common sputum finding in both groups. There was a non-significant trend towards increased intensity of neutrophilic bronchitis in CF carriers .The clinical characteristics of each CF carrier are shown in Table Microbiological data is presented in Table The change in number of infective exacerbations between the year prior to and after starting hypertonic saline in patients with physician-diagnosed asthma is shown in Fig. Two independent variables were found to be significant predictors of CFTR heterozygosity—age and number of exacerbations needing hospitalization per year Table . The adjWe conducted a retrospective chart review to characterize clinical features of CF carriers with asthma and recurrent neutrophilic inflammation. Our main findings are: (i) CF carriers are overrepresented in this cohort, supporting the role of CFTR hypofunction in the predisposition of some patients with asthma to recurrent respiratory infections, (ii) the dominant inflammatory type in these patients is neutrophilic bronchitis, but some have eosinophilic inflammation as well, and (iii) hypertonic saline appears to be effective and is well tolerated in this asthmatic population.CFTR mutations in 17% of subjects. The carrier rate of pathogenic CFTR gene mutations is approximately 4% in persons of northern European descent [CFTR heterozygosity in these populations is large. Most recently, the CFTR gene was sequenced in participants from the severe asthma research program (SARP), and potentially pathogenic CFTR variants were found in 9.5% of this severe asthma-enriched cohort [We identified pathogenic  descent , indicat descent . A largeiectasis . Though iectasis , and thed cohort . Our finThree of the 13 CF carriers had the intron 8 splice variant 5 T. This variant is located at a splice acceptor site of intron 8 and causes frequent skipping of exon 9, leading to a dysfunctional CFTR protein. Compound heterozygotes with eference . In our Consistent with our previous study , neutropCFTR mutations even in older patients presenting later in life with exacerbations of asthma associated with recurrent airway infections.In this cohort, asthmatic CF carriers with recurrent infections were older on average compared to non-carriers at the time of diagnosis. The genetic and environmental factors that cause a small subset of CF carriers to develop pulmonary disease have yet to be fully elucidated, and it is possible these factors accumulate over time to produce disease manifestations in certain patients. Evidence supporting this hypothesis includes studies showing that CFTR hypofunction can be acquired from cigarette smoke exposure , bacteri+ channel in the airway may also prove to be helpful in CF carriers in the future [In our cohort, nebulized hypertonic saline was well tolerated in asthma patients despite reduced FEV1 and demonstrable bronchial hyperresponsiveness in some patients. This is an important finding, as there are little data on the safety of hypertonic saline in asthma and these data are limited to mild-to-moderate asthma , 27. Thehibitive . Novel te future .CFTR mutations were detected using a multiplex PCR panel rather than gene sequencing, so rare CFTR variants may have been missed. This could have led to misclassification of CF carriers as non-carriers or true CF patients with compound heterozygosity as CF carriers. However the genetic screen used would detect mutations in over 84% of a pan-ethnic north American population [CFTR mutation analysis was obtained only in patients with recurrent neutrophilic bronchitis, this analysis is limited to those patients with patients referred for asthma who have infective exacerbations. If a broader asthma population were considered, the significance of factors such as bronchiectasis and non-tuberculous mycobacterial disease in predicting CF carrier status may have been more apparent. Finally, given the retrospective nature of the study and the small number of CF carriers studied, our conclusions regarding the safety and efficacy of nebulized hypertonic saline should be considered provisional.This study has several important limitations. First, this is a single center retrospective chart review from a tertiary airway disease clinic, so the morbidity in CF carriers observed is influenced by selection bias and not generalizable to the full CF carrier population. The cohort described represents 20% of our volume, therefore selecting patients for CFTR genotyping could have influenced the results. Second, pulation , so thisIn summary, CF carriers are significantly overrepresented in a cohort of asthma patients with recurrent airway infections referred to a tertiary care centre, and we recommend testing for CFTR mutations in patients with asthma with recurrent airway infections, even in older patients. Neutrophilic bronchitis is the dominant inflammatory type, but some also have concomitant eosinophilic bronchitis that may be severe enough to warrant treatment with an anti-IL5 biological. Hypertonic saline was well tolerated in most patients. Additional research is needed to assess the efficacy of hypertonic saline and other treatment strategies in asthmatics with exacerbations associated with intense neutrophilic bronchitis.Additional file 1: Table S1. The 39 pathogenic variants tested for using multiplex PCR.


The mean eGFR decline was 2.9 ± 5.7 mL/min/1.73 m2/year. eGFR decline correlated (p < 0.05) with age (r = 0.30), initial proteinuria (r = 0.31), nighttime systolic and mean blood pressure , and systolic and diastolic blood pressure dipping . There was no relation between mean arterial pressure during 24 h (MAP 24 h Z-score) and eGFR decline and no difference in eGFR decline between those with MAP 24 h < and ≥50 th percentile. In multivariate analysis, systolic blood pressure dipping (beta = −0.43), presence of proteinuria (beta = −0.35), and age (beta = 0.25) were predictors of eGFR decline. Conclusions: Systolic blood pressure dipping may be a valuable indicator of CKD progression in children.Background: Elevated blood pressure and proteinuria are well-established risk factors for chronic kidney disease (CKD) progression in children. This study aimed to analyze risk factors for CKD progress, emphasizing detailed ambulatory blood pressure (ABPM) data. Methods: In 55 children with CKD II–V, observed for ≥1 year or until initiation of kidney replacement therapy, we analyzed ABPM, clinical, and biochemical parameters. Results: At the beginning, the glomerular filtration rate (eGFR) was 66 (interquartile range—IQR: 42.8–75.3) mL/min/1.73 m Chronic kidney disease (CKD) is an irreversible, progressive condition associated with impaired kidney structure or function. The initial, first stage of CKD is characterized by normal values of estimated glomerular filtration rate (eGFR), which gradually decrease with the progression of the disease, finally reaching the fifth, end stage of kidney disease (ESKD), associated with the necessity to initiate kidney replacement therapy (KRT) . CKD in Major efforts are put into slowing down the deterioration of kidney function, which is the primary goal of conservative treatment. Therefore, identifying potential risk factors for CKD progression is crucial in establishing the most accurate preventive methods for managing the disease. To date, numerous factors predicting CKD progression in children have been identified, including non-modifiable initial CKD stage, primary kidney disease, and age . HyperteThe results of the multicenter ESCAPE (Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of CRF in Pediatric Patients) study showed that strict blood pressure control, defined as mean ambulatory blood pressure during 24 h (MAP 24 h) below the 50th percentile in ambulatory blood pressure monitoring (ABPM), significantly decreases risk for CKD progression and initiation of KRT . SimilarABPM has been an established tool in assessing blood pressure in various pediatric populations for years. Routine ABPM blood pressure assessment in children with CKD is recommended by the European Society of Hypertension  and the Adult studies analyzed the influence of these ABPM parameters, e.g., abnormal circadian BP profile and nighttime hypertension, were risk factors for faster CKD progression ,17, and 2, and ABPM examination performed at the beginning of the observation period. The exclusion criteria were: kidney replacement therapy (KRT) at the beginning of the study, age below 5 and above 17 years, and lack of follow-up data. Fifty-five patients meeting the criteria were enrolled in the study and were observed for at least one year or until the initiation of KRT. The flowchart of patients is presented in The study was a retrospective, single-center, observational analysis. Patients hospitalized in a tertiary care pediatric nephrology department between 2012 and 2020 were evaluated. The inclusion criteria were: diagnosed chronic kidney disease according to KDIGO guidelines [2), expressed as Z-scores according to Polish normative values. Underweight was defined as BMI < 5th percentile, overweight as BMI between 85th and below 95th percentile, and obesity as BMI ≥ 95th percentile [2) was calculated using the Schwartz formula [All initial examinations were performed simultaneously on the same day using a unified protocol. At the beginning of the study, we analyzed, based on available medical records clinical parameters: age (years), sex, and etiology of CKD according to the ESPN/ERA-EDTA  registry , presencrcentile . eGFR . All monitors were programmed to measure blood pressure every 15 min from 6 a.m. to 10 p.m. and every 30 min from 10 p.m. to 6 a.m. Periods of nighttime rest and daytime activity were determined by providing data in individual patient diaries. We measured systolic, diastolic, and mean blood pressures , heart rate (HR), blood pressure loads (BPL), and pulse pressure (PP) during 24 h as well as during activity (a) and rest (r) periods. Nocturnal systolic and diastolic blood pressure dipping  (%) were also evaluated. SBP, DBP, MAP, and HR were also expressed as Z-scores  and were2) [2/year) was then calculated based on the total eGFR change and time of observation. Moreover, the time to deterioration of CKD by at least one stage following KDIGO [After the observation period of at least one year or until initiation of KRT, we analyzed clinical parameters: duration of follow-up period (months), eGFR mL/min/1.73 m2) , and CKD.73 m2 , The primary endpoint was the annualized eGFR slope.2/year.Secondary endpoints were progression to end-stage kidney disease (ESKD) requiring KRT, deterioration of CKD by at least one stage following KDIGO , and fasCollected data were anonymized and stored as a database with double coding  and then statistically analyzed using Dell Statistica 13.3 PL software .p < 0.050, and p > 0.150 excluded the variable from the model. The results of multivariate analyses were expressed as beta, confidence interval (CI), p-value, and hazard ratio for Cox models. We also used receiver operating characteristics (ROC) analysis to calculate the area under the curves (AUC) and Youden’s index to identify the appropriate cut-off values of prognostic factors. The results were considered statistically significant, with p values < 0.050.We assessed the normality of data using the Shapiro–Wilk test. Depending on the distribution, data are expressed as mean ± standard deviation (SD) for variables with normal distribution or median (interquartile range—IQR) for variables with distribution other than normal. The analysis required applying the following statistical tests: Mann–Whitney U test or Student’s t-test for independent groups, Spearman’s rank correlation or the Pearson correlation , Student’s t-test or Wilcoxon test for dependent observations, Kruskal–Wallis ANOVA test, and chi-squared test. We also applied Kaplan–Meier survival analysis in regards to reaching secondary endpoints. Survival curves were compared using the F Cox test. Multivariate analysis was performed using the general regression and Cox proportional-hazard step-wise regression models. The variables were introduced into the model, excluding the ones that correlated with each other with r > 0.60 to avoid collinearity. The criterion for inclusion in the final model was The researchers obtained approval from the local bioethics committee to conduct the study . All procedures involving human participants were in accordance with the highest ethical standards of the institutional research committee and were performed in accordance with the Declaration of Helsinki on the treatment of human subjects and its later amendments. According to Polish Act on Professions of Doctor and Dentist , formal informed consent was not required due to the retrospective nature of the study.The initial clinical and anthropometric parameters of the examined group are shown in 2/year. The mean annualized eGFR slope was 2.9 ± 5.7 mL/min/1.73 m2/year. In the course of the study, nine (16.4%) patients required initiation of KRT after the median of 25 (13–37) months. Kidney function deteriorated by at least one stage in 16 (29.1%) children. Twenty-four (43.6%) children were classified into a fast-progressing group based on annualized eGFR slope (≥3 mL/min/1.73 m2/year). The median time to deterioration of kidney function by ≥1 stage was 21 (6–31) months.The median duration of observation was 27 (16–36) months. The minimal observation period was 6 months (initiation of KRT), and the maximal observation period was 95 months. Median eGFR at the end of observation was 60.1 (24.5–69.0) mL/min/1.73 mABPM parameters and their correlations with annualized eGFR slope are displayed in A disturbed circadian profile of systolic blood pressure was found in 15 (27.3%) patients, 4 (7.3%) of whom also had a disturbed circadian profile of diastolic blood pressure. The remaining patients had a normal circadian blood pressure profile.p = 0.026) as well as the initial proteinuria . There was no significant difference in eGFR slope regarding BMI Z-score  and the primary kidney disease .We also found significant positive correlations between eGFR slope and age (years) , presence of proteinuria  and age (years)  were the only predictors of eGFR decline.In multivariate analysis, SBP dipping (%) , despite the treatment (p = 0.051)  b. There p = 0.024, hazard ratio 0.84, 95% CI 0.72–0.98) was a statistically significant risk factor for CKD progression by one stage.The Cox proportional-hazard step-wise regression model showed that only SBP dipping (%)  . We divided the analyzed population into two groups: children with MAP 24 h ≥50th percentile (n = 41) and MAP 24 h < 50th percentile (n = 14). We found no significant difference in annualized eGFR slope between those groups (3.1 ± 5.9 vs. 2.5 ± 5.2 mL/min/1.73 m= 0.638) .Numerous studies, mainly in adult patient populations, have identified risk factors for the fast progression of chronic kidney disease. Traditionally they are divided into non-modifiable and modifiable ones. The former include age, gender (in adults), race, cause of CKD, stage of CKD at the beginning of follow-up (CKD progression is logarithmic rather than linear) ,6,7, or Along with proteinuria, elevated blood pressure is the most significant factor in CKD progression. The prevalence of arterial hypertension in children with CKD is estimated to be approximately 50–60%, with the prevalence depending on the cause of CKD (more common in glomerular diseases and hemolytic uremic syndrome) and the stage of CKD  ,24,25. HThe most important consequence of arterial hypertension in the pediatric CKD population is its harmful impact on the progression of the disease, finally resulting in ESKD. The negative influence of elevated blood pressure was revealed in two multicenter studies—the European trial ESCAPE  and the Interestingly, our retrospective analysis did not demonstrate the significance of baseline blood pressure values in ABPM on the rate of CKD progression, beyond nocturnal systolic and mean blood pressure. The difference in results may have been derived firstly from a smaller group than in the cited ESCAPE and CKiD studies. In addition, unlike the ESCAPE study, we analyzed only initial ABPM—in the cited European study, ABPM was performed every six months. Moreover, initial eGFR was significantly higher in our group than in the ESCAPE study 68 vs. 46). The populations also differed in age (14.0 vs. 11.5) and etiology of CKD (CAKUT: 40% vs. 69%) [ vs. 46. Nighttime hypertension, including isolated nighttime hypertension, is common in adult and pediatric patients with impaired renal function. Mitsnefes et al. found nighttime hypertension was detected in 41% of pediatric CKD patients, attenuated systolic dipping in 59%, and diastolic dipping in 31% . SympathAdult data suggest that nighttime hypertension is also associated with a faster rate of CKD progression. Retrospective analysis of Chinese adult patients with non-dialysis CKD and arterial hypertension showed that masked uncontrolled hypertension is an independent risk factor for the composite kidney outcome, defined as ESKD or a 50% reduction in eGFR . SimilarThe results of our retrospective study add a voice to the debate about the treatment of arterial hypertension in children with CKD. As mentioned in the introduction, current KDIGO guidelines recommend following 24 h MAP values from ABPM and lowering BP below the 50th percentile in all pediatric CKD patients. Notably, the authors base their recommendations only on the ESCAPE study . It remaProteinuria is a well-established risk factor for CKD progression or eGFR decline. Both CKiD  and the Age was another significant factor for CKD progression in our cohort. Similar findings were found in a retrospective analysis of North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) patients  and the The particular strength of our study is a unique, detailed analysis of ABPM parameters that, to the best of our knowledge, has not been performed in a pediatric cohort before. This analysis contributes new data and indicates potential new risk factors for the progression of CKD in children.However, we are also aware of the limitations of the study. Firstly, the retrospective nature of the study prevented us from an analysis of other biochemical parameters  due to incomplete data. The Oscar 2 SunTech ABPM device, although validated in adults, does not have a pediatric validation yet. However, it was found to be valuable and reliable in our numerous previous studies. Significantly, in our study, we correlated the rate of eGFR loss only with blood pressure values from the initial ABPM recording—the impact of blood pressure during the follow-up period was not analyzed. In our cohort, as already mentioned, the patients presented with relatively high initial eGFR. Proteinuria was assessed only using a single morning sample, not a well-established urinary protein/creatinine ratio or a 24 h collection. A single-center character of the study was associated with a relatively small number of patients, not diversified in terms of, e.g., race. Therefore, our further efforts will be focused on broadening the research into a multicenter study.In our retrospective single-center study, we analyzed the effect of various ABPM blood pressure parameters on the rate of CKD progression in children. In our cohort, in addition to proteinuria and age, the progression of CKD was dependent on systolic and mean resting blood pressure and systolic and diastolic blood pressure dipping. Unlike in the ESCAPE study, there was no association between the rate of CKD progression and 24 h mean arterial pressure (ABPM MAP 24 h). Despite the differences with the latter trial  and the limitations of our study, we believe that when assessing blood pressure in children with CKD, close attention should be paid to the nocturnal blood pressure and circadian blood pressure profile. Large multicenter studies are needed to demonstrate the benefit of normalizing the nocturnal blood pressure and circadian profile, e.g., by giving antihypertensive drugs in the evening.


Mechanical ventilation started with negative-pressure ventilation (NPV) during the 1950s to assist patients with respiratory failure, secondary to poliomyelitis. Over the years, technological evolution has allowed for the development of more comfortable devices, leading to an increased interest in NPV. The patients affected by neuromuscular diseases (NMD) with chronic and acute respiratory failure (ARF) may benefit from NPV. The knowledge of the available respiratory-support techniques, indications, contraindications, and adverse effects is necessary to offer the patient a personalized treatment that considers the pathology’s complexity. Patients with neuromuscular diseases (NMD) can present acute and chronic respiratory insufficiency throughout their life and require respiratory support. Although most NMD share common clinical and functional characteristics, they need to be differentiated because some show peculiarities that determine evolution and potential complications. NMD are rare; however, the large number of pathologies determines a great number of individuals who need respiratory assistance. In particular, Duchenne muscular dystrophy, myotonic dystrophy, spinal muscular atrophy, Pompe disease, and amyotrophic lateral sclerosis lead to respiratory muscle weakness. Typically, this results in an ineffective cough, clearance impairment, airway obstruction, restrictive lung disease, swallowing disorders with dysphagia and aspiration, recurrent respiratory infections, sleep-disordered breathing, alveolar hypoventilation, and respiratory failure. Pulmonary complications are the most frequent cause of death. Sialorrhea is also a common and problematic symptom of patients affected by neuromuscular diseases associated with bulbar and/or facial-muscle dysfunction. Thicker and tenacious oral and pharyngeal secretions may result from the drying management of sialorrhea. Ineffective cough and gastroesophageal reflux can lead to aspiration pneumonia. In the beginning, such patients may be asymptomatic but require a regular and careful clinical follow-up because they may develop severe respiratory failure and pneumonia. Sometimes, patients need resuscitation maneuvers due to swallowing disorders.NMD patients show a restrictive ventilatory syndrome. In addition, the unfavorable conformation of the rib cage can determine areas of atelectasis that—in the context of acute lung injury—can worsen the ventilation/perfusion imbalance, leading to hypoxemia that often requires noninvasive respiratory support.Negative-pressure ventilation (NPV) was used on a large scale in the 1950s to treat patients with respiratory failure postpoliomyelitis. The first devices were very bulky, not transportable, and interfered with patient care and hygiene. Over the years, positive-pressure ventilation has become the treatment of choice for acute and chronic respiratory failure in neuromuscular diseases; however, technological innovations have allowed a new use of NPV in acute and chronic situations that offer an additional option of treatment in patients sometimes dependent even 24 h a day 24 h/day on respiratory support.The interfaces for NPV are as follows: The name “iron lung” comes from the first ventilator designed by Philip Drinker and Louis Agassiz Shaw, a metallic machine. It consisted in a cylindrical ventilation chamber in which the patient lied inside except for his/her head ,2. More The iron lung creates a negative pressure inside the chamber during the inspiration phase, which guarantees the uplift of chest and abdomen, and therefore a downward movement of the diaphragm of the patient lying in a supine position. The uplift of the chest and the downward movement of the diaphragm result in a volumetric increase in the chest and in a consequent inlet of air. Exhalation is allowed from the elastic return of the thoracic-pulmonary system, or eventually by the application of a modifiable positive pressure. The pressure delivery is provided by a high-power pump/blower governed by a digital electronic control unit. The machine can operate in both assisted and controlled mode (sometimes only in controlled mode). Through some portholes located on the chamber, it is possible to access and manipulate the patient’s body, position different probes and catheters, or take blood samples. Since the patient’s head is positioned outside the chamber, the patient can talk, eat, drink, sneeze, cough, and expectorate; in addition, it is possible to perform oral-pharyngeal aspirations as well as fibrobronchoscopy and apply devices for oxygen therapy. The iron lung is equipped by alarms and also by a heating system to improve the patient’s comfort and compliance. The poncho, also called “wrap” or “pneumo-wrap”, is a ventilatory interface that works synergically with the NPV ventilator to generate an effective negative extrathoracic pressure. The pressure is delivered inside a poncho-shaped suit, which the patient has to wear, closed at the neck, wrists, and ankles with straps that ensure airtightness. The empty space between the suit and the patient’s body is guaranteed by a metal/plastic net connected to a supporting plane placed at the back. The poncho is often made with GORE-TEX, and is available in different sizes. The ventilator connected to the poncho can operate both in controlled and assisted mode with sensors positioned at the level of the upper airways.The cuirass  is a venSimilarly to the “poncho”, the cuirass connected to the ventilator can operate in both controlled and assisted modes. The cuirass applies the negative pressure on a lower surface, but compared to the poncho, it can assist the patient during the exhalation phase by providing a modifiable positive pressure. At present, there are four different ways to provide NPV: (1) cyclical negative pressure; (2) negative and positive pressure; (3) continuous negative extrathoracic pressure (CNEP); 4) negative pressure/CNEP [ negative(1) Cyclical negative pressure: the negative pressure is delivered during inspiration, while expiration is passive.(2) Negative/positive pressure: a subatmospheric pressure is delivered during inspiration and a positive pressure during expiration. This biphasic mode can be applied by cuirass and has shown to enhance tidal volume in patients with chest-wall deformities in comparison to the only NPV . (3) Continuous negative extrathoracic pressure (CNEP): the ventilator generates a constant negative pressure during the whole respiratory cycle while the patient spontaneously breathes. In animal models, CNEP and positive end-expiratory pressure (PEEP) have shown similar physiological effects .(4) Negative pressure/CNEP: the ventilator has a CNEP mode but there are some inspiratory cycles in which the negative pressure is increased. The first use of NPV dates back to the polio epidemic. These patients, in which the neuromuscular impairment was secondary to the neurological damage induced by the poliovirus, required both an acute and chronic respiratory support . PatientThe candidates to NPV are usually patients who cannot adapt to noninvasive ventilation (NIV) because they do not tolerate a facial mask due to facial deformity, are claustrophobic, or produce excessive airway secretions. Considering the potential effects on cardiopulmonary circulation, NPV is also beneficial in young patients and children who have undergone complex cardiac reconstructive surgery.There are different indications and contraindications for the use of NPV that also depend on the disease. In neuromuscular patients with respiratory failure, they are listed in Over the years, the technological evolution has allowed lighter and more comfortable devices starting from the iron lung to the cuirass, up to the soft cuirass available today. Despite this technological progress, to date, no guidelines have been set on the indication and modality of NPV.NPV was used for the first time to treat the acute respiratory failure (ARF) of neuromuscular patients during the poliomyelitis epidemic . In thatThere are few data in the literature regarding the use of NPV in the pediatric intensive setting. The treatment of ARF in a pediatric ICU is a challenge due to the risk of invasive positive-pressure ventilation in terms of barotrauma, volutrauma, and atelectrauma. Noninvasive ventilation techniques can avoid these problems and NPV can represent an alternative strategy to noninvasive positive-pressure ventilation in pediatric patients with abnormal facial morphologies, anxiety, excessive oropharyngeal secretions and emesis ,21. In lThe major advantage of NPV is the preservation of physiological functions, such as speech, cough, swallowing, and feeding. These aspects are very relevant for patients who are continuously ventilated, who may be dependent on respiratory support before or after the acute event. Moreover, NPV, unlike positive-pressure ventilation , allows fibrobronchoscopy to be performed for various procedures without interruption from the respiratory support.Limits of NPV have to be considered: firstly, the lack of protection of the upper airways, and secondly, upper-airway obstruction due to both the downfall of the tongue on the posterior pharyngeal wall and the lack of preinspiratory upper-airway muscle activation. These problems are particularly relevant in comatose patients, in those with neurological disorders associated with bulbar dysfunction , and in patients affected by apnea during sleep. In unconscious patients with normal bulbar function, the placement of a nasogastric tube and the positioning of an oropharyngeal airway can reduce the problem of aspiration pneumonia and upper-airway closure due to the collapse of the tongue.The intermittent upper-airway collapse leading to obstructive apnea is a potential risk associated to NPV in patients affected by neuromuscular diseases. This complication was firstly recognized several decades ago: the glottic closure was observed in normal subjects hyperventilated in iron lungs and was thought to represent a protective reflex against hyperventilation. The lack of pre-inspiratory activation of upper-airway muscles predisposes these structures to collapse when exposed to negative pressure. Hill et al. observed some clustering of disordered breathing events during REM sleep in Duchenne muscular dystrophy patients during NPV, when the breathing pattern was irregular and the upper-airway tone was reduced . For thiThe most common side effects reported with NPV are poor patient compliance, upper-airway obstruction, and musculoskeletal pain  Table 3Table 3. In case of prolonged use, as happens with all interfaces, the appearance of decubitus is possible. All noninvasive ventilatory techniques, reducing the need for endotracheal intubation and its related complications and difficulty in weaning, should be considered potentially advantageous in certain subgroups of patients. Although the literature suggests the effectiveness of NPV in the treatment of ARF in patients with neuromuscular diseases, many important aspects still need to be clarified. The lack of expertise in many centers probably limits its use. Prospective controlled studies have to be performed in order to evaluate the effect of NPV on both mortality and length of hospital stay in patients affected by neuromuscular disorders who develop ARF.NPV should also be considered as an option for the treatment of neuromuscular patients with ARF at home. In addition, NPV can be utilized by patients with chronic respiratory failure, who, for a variety of reasons, are unable to tolerate noninvasive positive-pressure ventilation or are dependent on mechanical ventilation 24 h a day; in this case the possibility of alternating different devices can prevent the onset of complications and decubitus. Although some side effects of NPV can occur in neuromuscular patients, the overall benefits in this group of patients outweigh its side effects.


The mean follow-up was 5.6 2 statistic: 22.4). Adding serum albumin and bilirubin levels to the model further improved it, and a model using 5 variables showed the best performance in the predictive ability . The accuracy of this model was validated in an external cohort (n = 5153). This novel simplified prediction model may be clinically useful for predicting ESKD in patients with diabetes.This study aimed to develop a simplified model for predicting end-stage kidney disease (ESKD) in patients with diabetes. The cohort included 2549 individuals who were followed up at Kyushu University Hospital (Japan) between January 1, 2008 and December 31, 2018. The outcome was a composite of ESKD, defined as an eGFR < 15 mL min Early and accurate prediction of progression to ESKD is of practical benefit in patients with diabetes.Diabetic kidney disease (DKD) continues to be the leading cause of end-stage kidney disease (ESKD) and accounts for 4. However, these two variables may not be sufficient for clinical decision-making, especially in DKD. In fact, other clinical variables, such as glycemic control, affect the progression of DKD6. Various prediction models for the progression of CKD to ESKD have been reported10, and some ESKD prediction equations are widely used through electronic applications10. However, CKD is heterogenous in the variability of progression rates and its pathogeneses. Therefore, developing a prediction model specific for DKD is important. None of the CKD models include variables related to glycemic control such as hemoglobin A1c (HbA1c) levels. Therefore, several prediction models have also been reported for predicting ESKD in people with diabetes15. These models showed a moderate to good performance for predicting ESKD, but they used many predictive variables in addition to the eGFR (or creatinine) and albuminuria. For clinical use, the ideal prediction models should not only be accurate, but also easy to implement. In this study, we aimed to develop a simplified, but accurate model for predicting ESKD in patients with diabetes using a few commonly available variables that are easy to measure in the primary care setting.In current clinical practice, the estimated glomerular filtration rate (eGFR) and the presence of proteinuria  are used as the main predictors for progression of chronic kidney disease (CKD) including DKD21. Since bilirubin and albumin are potent endogenous antioxidants in serum24, these variables may play an important role in the progression of DKD28. Therefore, in this study, we first evaluated the relative importance of various possibly predictive variables including serum bilirubin and albumin levels for ESKD using a machine learning random forest model. The benefit of the machine learning approach is that it can use a data-driven approach to analyze a large number of variables. We then developed a final simplified prediction model using the minimum number of selected important variables and Cox proportional hazard model, which may be useful for predicting ESKD in primary care. We also validated the performance of this model in an independent external cohort.In recent years, oxidative stress has been considered to be an important pathogenic factor in the development of DKDA total of 2,549 patients  were eligible for inclusion in the analysis. Table The random forest model using 20 variables showed an excellent predictive ability for ESKD , and selected eGFR, proteinuria, HbA1c, serum albumin, and serum bilirubin as the most important predictors in descending order . Despite the difference in baseline characteristics, the predictive performance of Model 5 was excellent in discrimination (C-statistic: 0.951) in the external cohort. In calibration, its performance was moderate without recalibration (2 statistic: 36.1 at a 5-year risk)  , its performance was good in discrimination (C-statistic: 0.862) and adequate in calibration without recalibration (2 statistic: 23.1 at a 5-year risk) 12. A similar prediction model using 11 variables was reported in Chinese patients with diabetes 14. However, these models lacked external validation and thereby may not be generalized well to other populations. The model reported by Elley et al. showed a good performance in the predictive ability in the development cohort and the external validation cohort (C-statistic: 0.89–0.92), but this model used 10 variables including sex, ethnicity, age, diabetes duration, albuminuria, serum creatinine, systolic blood pressure, HbA1c, smoking status, and previous cardiovascular disease status13. A recent study developed a machine learning based prediction model called the feed-forward neural network model15. In that model, 18 variables were used in patients with diabetes and nephropathy participating in past clinical trials, including RENAAL, IDNT and ALTITUDE studies . The machine learning approach appears to be superior to the traditional hypothesis-driven statistical methods in terms of its data-driven approach to analyze a large number of possibly predictive variables. Our random forest model using 20 variables also showed an excellent predictive ability for ESKD (C-statistic 0.935). However, the main obstacle is that many predictive variables are not readily obtainable in primary care, thus limiting their usefulness to clinicians’ managing patients with diabetes. In contrast, Keane et al. reported a simple prediction model using four variables  in a cohort from the RENNAL study11. They selected those four variables from 23 baseline variables using the Cox proportional hazard model with backward selection process, with P < 0.01 required for inclusion in a final model. However, our analysis using both the machine learning approach and the Cox proportional hazard model showed that HbA1c levels and bilirubin levels were more important predictors than hemoglobin levels for predicting ESKD. The mean follow-up period was much shorter in the RENNAL study than in our study (3.4 years vs. 5.6 years), and decreasing hemoglobin level is a generally late sign of renal impairment. Their model may be effective for risk prediction at a time shorter than 3 years. Thus, our simplified 5-year prediction model may be more useful than previous prediction models in clinical practice. Our model could guide clinicians in making clinical decision earlier regarding intensification of monitoring and preventive therapies or referral to specialists. Risk information helps patients to become aware of their current risk, promote motivation on improving their lifestyle. In our study, the nomogram based on our model was built to predict the absolute ESKD probability for each individual. The 5-year risk equation we showed can be also used as electronic applications. These tools may provide practical risk predictive tools for future clinical application.Previously, several prediction models for ESKD in patients with diabetes have also been reported22. We previously showed a lower prevalence of nephropathy and other vascular complications, as well as reduced oxidative stress, in patients with diabetes and Gilbert syndrome, which is a hereditary hyperbilirubinemia25. Accumulating evidence has also shown that serum bilirubin levels are negatively associated with the progression of DKD28. Taken together, it is most likely that serum bilirubin may prevent the progression of nephropathy via its anti-oxidative activities. This possibility is supported by an animal study, which showed that bilirubin prevented renal oxidative stress and dysfunction in type-1 diabetic rats and type 2 diabetic mice29. In addition, serum bilirubin levels have been reported to be affected by oxidative stress-related factors such as smoking, obesity, hypertension, metabolic syndrome, and cardiovascular diseases in addition to genetic factors34, all of which are possible risk facors for DKD. Therefore, serum bilirubin levels might represent a total susceptibility determined by such factors to the progression to ESKD. In line with these concepts, the effect of anti-oxidative properties of albumin on the progression to ESKD may be plausible, although the effect of serum albumin levels may be mainly explained by their association with the levels of albuminuria. Albumin is thought to be an important serum antioxidant in addition to serum bilirubin25. In serum, free thiol groups are one of the most important scavengers of hydroxy radicals and other oxidants and are largely located on albumin35. Serum albumin levels have been reported to be inversely associated with the cardiovascular disease risk and aging, supporting its possible causal relationships with the oxidative stress-related status and diseases38. The mechanisms underlying the close associations of serum bilirubin and albumin levels with the progression to ESKD should be clarified in future studies.The reason why serum bilirubin levels were so important among various predictive variables for predicting ESKD remained to be elucidated. Bilirubin is a product of heme catabolism by heme oxygenase, which is a major antioxidant enzyme. Bilirubin is thought to have a protective effect on oxidative stress-induced organ damage through its strong antioxidant activity40.There are several limitations to this study. First, we might not have obtained ideal information regarding clinical data and timely assessment of endpoint, compared with controlled clinical trials. Second, the sample size may not have been sufficient to develop prediction models. Third, we used proteinuria by a conventional urine test rather than measurements of albuminuria because the rate of albuminuria measurements was low in the electronic medical record data, although proteinuria data are much more easily obtainable than those of albuminuria measurement in primary care. Forth, a competitive risk analysis of death was not performed because only 16 death cases occurred and the relationship between each death and kidney dysfunction was unknown in this study using electronic medical records. Despite these limitations, our prediction models showed a good performance in the independent external validation as well as the development cohorts. Lastly, although the excellent performance in discrimination of our prediction model was confirmed in an external cohort, the performance in calibration should be evaluated in more various populations including different ethnicities, and cohorts outside Japan for widespread adoption of this model, because patient characteristics, healthcare system, and treatment strategies vary between health centers, regions and countries, and such heterogeneity can affect risk estimates and their calibrationIn conclusion, we developed a simplified and accurate 5-year prediction model using the commonly available clinical variables of eGFR, proteinuria, HbA1c, serum albumin and bilirubin levels, which are easy to measure. Prospective studies should be done to establish its clinical usefulness in reducing ESKD in patients with diabetes.−1 [1.73 m]−2, received dialysis or renal transplantation at baseline. Other exclusion criteria were co-occurrence of acute kidney injury or cancer during follow-up, or co-occurrence of liver cirrhosis, other hepatobiliary diseases with abnormal liver enzyme levels  between January 1, 2008 and December 31, 2018. Eligible patients with diabetes were aged 20–69 years and had laboratory data, including the eGFR, and serum bilirubin and albumin levels at baseline. In this study, diabetes was defined as casual blood glucose levels For the independent external validation cohort, we obtained data from the medical record data for patients (n = 5153) who were followed up at 5 hospitals or one disease management institute from January 1, 2008 to December 31, 2020 and had laboratory data, including the eGFR, HbA1c levels, proteinuria, serum albumin levels, and bilirubin levels, at baseline. The same exclusion criteria as those in the development cohort were used.All procedures were performed in accordance with the relevant guidelines and regulations. Informed consent was obtained from all participants and/or their legal guardians. The study was approved by the ethics committees of Kyushu University Hospital and other related institutes.41. HbA1c levels were presented as the National Glycohemoglobin Standardization Program value and the International Federation of Clinical Chemistry and Laboratory Medicine mmol/mol units converted using the National Glycohemoglobin Standardization Program converter for HbA1c, available at http://www.ngsp.org/convert1.asp. The presence of hypertension was based on the ICD code. Dyslipidemia was defined as serum low-density lipoprotein cholesterol levels Twenty variables were used to select important variables for the prediction model for ESKD, including age, sex, body mass index (BMI), smoking status, presence of hypertension, presence of dyslipidemia, eGFR, HbA1c, serum albumin, serum bilirubin, serum uric acid, red blood cell count, white blood cell count, platelet count, presence of proteinuria, and medication use  . In this study, we also evaluated the predictive value of these variables for ESRD using the Cox proportional hazard model to confirm the results of the random forest model. In the Cox proportional hazard model, variables were standardized by subtracting the mean and dividing by the standard deviation, and they were then applied to the Cox proportional hazard model to compare the relative importance. Thus, we selected the important variables from both models, and then developed a sequential series of models using Cox proportional hazard analysis. We used Harrell’s concordance statistic (C-statistic) as a measure of discrimination for ESKD to evaluate the performance of the model42. Calibration was assessed using the Nam and D’Agostino 2 statistic to examine how closely each model’s predicted probabilities agreed with the observed ESKD outcomes43. The prediction risk calculated from a Cox proportional hazard model at time 44. The value of To select important variables for predicting ESKD, we evaluated the relative importance of 20 variables using a random forest model 45. To confirm that our missForest prediction models were robust and not sensitive to missing data, we also used another imputation method, where we imputed the missing data by multiple imputation method  in this analysis. The results in this method were similar to those in the missForest models . The significance of differences was determined by the chi-square test for categorical variables and the unpaired t test or the Mann–Whitney U test for continuous variables. We performed statistical analyses using R .There were missing data for the smoking status, dyslipidemia, and proteinuria in this study. For our data imputation approach, we used the random forest imputation algorithm, called missForest (missForest package version 1.2, Supplementary Information.


This study assessed the feasibility of five separate machine learning (ML) classifiers for predicting disease progression in patients with pre-dialysis chronic kidney disease (CKD). The study enrolled 858 patients with CKD treated at a veteran’s hospital in Taiwan. After classification into early and advanced stages, patient demographics and laboratory data were processed and used to predict progression to renal failure and important features for optimal prediction were identified. The random forest (RF) classifier with synthetic minority over-sampling technique (SMOTE) had the best predictive performances among patients with early-stage CKD who progressed within 3 and 5 years and among patients with advanced-stage CKD who progressed within 1 and 3 years. Important features identified for predicting progression from early- and advanced-stage CKD were urine creatinine and serum creatinine levels, respectively. The RF classifier demonstrated the optimal performance, with an area under the receiver operating characteristic curve values of 0.96 for predicting progression within 5 years in patients with early-stage CKD and 0.97 for predicting progression within 1 year in patients with advanced-stage CKD. The proposed method resulted in the optimal prediction of CKD progression, especially within 1 year of advanced-stage CKD. These results will be useful for predicting prognosis among patients with CKD. Chronic kidney disease (CKD) is a global health problem associated with a high risk of adverse clinical events and high health care costs . In addiCKD is typically silent and extremely variable. Moreover, the development of several chronic diseases have been associated with CKD progression, making clinical management particularly challenging. Timely interventions for patients with CKD could improve the quality of medical care and reduce morbidity, mortality, and healthcare costs ,9. ThereTo provide a clinical database for medical assessments and improve healthcare quality, the pre-ESRD patient care and education program was initiated by the National Health Insurance (NHI) administration under the Ministry of Health and Welfare in Taiwan. The program includes CKD patients classified as Stages 3B to 5. In addition, the NHI reimbursement program has been shown to improve health care quality for patients with early-stage CKD (Stages 1 to 3A) . The manIn the present study, predictive models for progression from pre-dialysis CKD to ESRD were established for patients with Stages 2 to 5 CKD using various ML algorithms, including LR, RF, extreme gradient boosting (XGBoost), SVM and Gaussian naïve Bayes (GNB). Important classification features were evaluated for their value as high-risk factors to determine the optimal predictive features for use in each of the five models. Optimal model development could promote early CKD diagnosis and improve CKD management, preventing progression to kidney failure. These results could improve access to timely treatments among patients with CKD.2 and as Stage 3 if 45 < eGFR < 59.9 mL/min/1.73 m2. Advanced-stage CKD was defined as Stage 3B if 30 < eGFR < 44.9 mL/min/1.73 m2, as Stage 4 if 15 < eGFR < 29.9 mL/min/1.73 m2 and as Stage 5 if eGFR < 14.9 mL/min/1.73 m2. Based on the NHI program requirements, eGFR was calculated using the simplified Modification of Diet in Renal Disease equation. The outcome of this study was ESRD, defined as the diagnosis of renal failure, the initiation of hemodialysis or peritoneal dialysis. None of our study subjects were treated by kidney transplantation. Transfer to other hospitals, death and loss to follow-up were regarded as observation endpoints without reaching ESRD. De-identified data associated with patients diagnosed with Stages 2–5 CKD and enrolled in the two NHI CKD programs were retrieved from the hospital information database. The study was reviewed and approved by the Institutional Review Board (IRB) of Taipei Veterans General Hospital (No. 2020-01-024BC). Due to the use of de-identified data, the need for informed consent was waived by the IRB.In the retrospective cohort study, a total of 858 patients enrolled in the NHI program and diagnosed with early- (Stages 2 and 3A) or advanced-stage  CKD were treated from November 2006 to December 2019 at a branch of the Taipei Veterans General Hospital, including 516 with early-stage CKD and 342 with advanced-stage CKD. Early-stage CKD was defined as Stage 2 if 60 < eGFR < 89.9 mL/min/1.73 mIn total, 858 patients with CKD were enrolled in this study, comprising 119 patients with Stage 2, 397 with Stage 3A, 111 with Stage 3B, 143 with Stage 4 and 88 with Stage 5. The numbers of early-stage CKD patients who progressed to ESRD within 3 and 5 years were 44 (5 with stage 2 and 39 with stage 3A) and 50 (6 with stage 2 and 44 with stage 3A), respectively. The numbers of advanced CKD patients who progressed to ESRD within 1 and 3 years were 38 (10 with stage 4 and 28 with stage 5) and 59 , respectively. A flow chart of the patient selection and categorization processes is shown in The dataset was divided into patients managed with and without ESRD. In addition to the original dataset, the synthetic minority over-sampling technique (SMOTE) was also applied. Randomized data subsets were used for cross-validation (K = 5). The LR, RF, XGBoost, SVM and GNB classifiers were used to determine whether pre-dialysis CKD data could be used to predict progression to ESRD. The Shapley additive explanations (SHAP) value was used to select important characteristic factors for predicting CKD progression. Model retraining was performed using the most important risk factors for CKD progression to achieve optimal classification outcomes. The progression of CKD to kidney failure among patients diagnosed with early-stage CKD was followed for up to 5 years and the models were used to identify risk factors for CKD progression within 3 and 5 years. The progression of CKD to kidney failure in patients diagnosed with advanced-stage CKD was followed for up to 3 years and the models were used to identify risk factors for CKD progression within 1 and 3 years. The flow chart of model training and performance evaluation is shown in Each subject’s predictor variables and baseline characteristics were obtained initially during the first clinic visit. The clinical characteristics of CKD were classified into four categories. Demographic variables included age, sex, height and weight. Laboratory data included serum and urine assessments, including eGFR, hemoglobin, hematocrit, creatinine, BUN, sodium, potassium, calcium, phosphorus and UPCR. Comorbid conditions included hypertension, diabetes and cardiovascular diseases. Risk-related biophysical and biochemical data included blood pressure, lipid profile and HbA1c levels. Those variables missing greater than 30% of values were excluded from the analysis. The missing values for other variables were replaced with multiple imputation. The study created five datasets using the multivariate imputation via chained equations module in the R package to perform the data imputation. All baseline characteristics and laboratory variables were obtained from the NHI pre-ESRD Patient Care and Education Program and the NHI Reimbursement Plans that Improve Health Care Quality of Early-Stage CKD Program implemented by the NHI.In this study, baseline demographic and laboratory data from the first clinic visit at which CKD was diagnosed were used to train the models. Due to differences in the collection of clinical characteristics, clinical data for Stages 2–3A CKD (early stage) were processed separately from clinical data for Stages 3B–5 CKD (advanced stage). Clinical indicators, including age, eGFR, serum creatinine, urine creatinine, LDL-C, HbA1c and UPCR, were associated with a significant risk of ESRD among patients diagnosed with Stages 2–5 CKD. In addition to these risk factors, the indicators associated with a significant risk for ESRD among Stages 3A–5 CKD include uric acid, albumin, fasting plasma glucose (FPG), triglyceride, cholesterol, hemoglobin, hematocrit, BUN, sodium, potassium, calcium and phosphorus. The detailed demographic characteristics of the cohort are listed in The characteristics of patients with early-stage CKD (Stages 2 to 3A) and advanced-stage CKD (Stages 3B to 5) are shown in The predictive performances of the tested five models were evaluated using the AUROC analysis and other discrimination indicators. Significant performance differences were identified between the five models. The performances of each model to predict the progression of early- and advanced-stage CKD to ESRD are shown in To assess the contributions of various features to the prediction of ESRD progression, the SHAP value method was applied. For the progression of early-stage CKD to ESRD within 3 and 5 years, 13 features were analyzed by SHAP, as shown in According to the SHAP analysis, the top six features were used to retrain the model for predicting the progression of early-stage CKD within 5 years, as shown in In the present study, we evaluated several models for the ability to predict the progression of Stages 2–5 pre-dialysis CKD to ESRD. Based on our results, the SMOTE method can significantly improve the abilities of five models to predict CKD progression. The RF classifier showed the highest AUROC of 0.99 for predicting progression from advanced-stage CKD to ESRD within 1 year while achieving a sensitivity of 0.96, a specificity of 0.91, an accuracy of 0.93 and a precision of 0.90, as shown. Similarly, the XGBoost classifier showed an AUROC of 0.99, a sensitivity of 0.96, a specificity of 0.94, an accuracy of 0.95 and a precision of 0.93 for predicting the progression of advanced-stage CKD to ESRD within 1 year. Compared with the other classifiers, both the RF and XGBoost classifiers are more suitable for the early prediction of progression in patients with advanced-stage CKD.In patients with early-stage CKD, the performance of the RF classifier was better than the performance of the XGBoost classifier, including better sensitivity, specificity, accuracy, precision and F1 scores. The AUROC values for the RF classifiers were 0.97 and 0.98 for predicting progression to ESRD within 3 and 5 years, respectively. Therefore, the RF classifier demonstrated the best performance for predicting progression in patients with both early- and advanced-stage pre-dialysis CKD. In a different study, Ravindra et al. reported an accuracy of 0.94 achieved by an SVM neural network for distinguishing between CKD and non-CKD . In addiIn our study, we ranked the features associated with early- and advanced-stage CKD according to the SHAP value. The primary impact of urine creatinine can be observed for both early- and advanced-stage CKD. The results indicated that low urine creatinine levels are associated with a low risk of progression to ESRD, whereas eGFR and systolic blood pressure are risk factors for progression that can be observed during early-stage CKD. These results demonstrated that a low eGFR level is associated with a high risk of ESRD. High systolic blood pressure is an important risk factor that can be identified in early-stage CKD. Seyedzadeh et al. reported that ESRD was concurrent with several clinical symptoms, among which hypertension (52.3%) was the most commonly identified symptom in 128 patients . In our Anemia or low serum albumin are also common complications of CKD. Our findings indicated that low hematocrit and albumin levels are associated with an increased risk of ESRD among patients with advanced-stage CKD. Anemia is strongly associated with poor kidney function in CKD patients . A previTo assess the optimal predictive model for the progression of pre-dialysis CKD to ESRD, the top six features  identified for early-stage CKD and the top 10 features  identified for advanced-stage CKD were used to retrain all five models. The RF classifier demonstrated the optimal risk prediction performance for the progression of pre-dialysis CKD to ESRD. The AUROC values for the RF classifier with SMOTE were 0.96 for the progression of early-stage CKD within 5 years and 0.97 for the progression of advanced-stage CKD within 1 year. A slight difference (0.98 to 0.96) was observed for the RF classifier when using only six features compared with using all features for the prediction of early-stage CKD progression. Similarly, the AUROC of the RF classifier using only the top 10 features showed a slight decline (0.99 to 0.97) compared with the RF classifier using all features when predicting advanced-stage CKD progression. The results indicated that the RF classifier could be used with specific features to predict ESRD risk in patients with pre-dialysis CKD. This approach can help clinicians understand the risk factors associated with ESRD and the progression of patients with CKD at different stages.An effective predictive model can help medical teams quickly and easily identify the key factors contributing to the deterioration of renal function, track the rate of renal function decline and modify the care goals on a rolling basis. In addition, predicting the time of progressing to ESRD can early remind care providers, patients and relatives with facing to the dangers and complications of ESRD. Certain strategies, such as stricter diet control, treatment of electrolyte imbalances and acidemia, improvement of anemia and uremia, or early decision on dialysis mode can be intervened in time to reduce the impact on the body and on life. Our approach provides a reference to clinical strategy. Nonetheless, there are several limitations to this study. First, this cohort consisted of a relatively small sample, so the model performance may have been affected by the training data. Second, the laboratory data was limited by geography and subject demographics, limiting the generalizability of these findings to the wider population. Third, the individual laboratory records may have changed over time. Because our models were based on baseline data, our study cannot present the trajectory of disease progression. A longitudinal model is likely to better reflect associations between risk factors and disease progression and should be evaluated in future studiesThe present study demonstrated a reliable ML method for predicting the risk of progression to eventual ESRD among patients with Stages 2–5 CKD. The RF classifier with SMOTE showed the best performance for the early diagnosis of CKD prognosis. In addition, the high performance of ML classifiers was achieved when limiting the analysis to predominant features. This approach reveals that the RF classifier is suitable for risk assessments among patients with pre-dialysis CKD and the results could be potentially advantageous for patient screening initiatives.