Approximately 30% of childhood cancer survivors (CCSs) will develop chronic kidney disease (CKD) or hypertension 15 to 20 years after treatment ends. The incidence of CKD and hypertension in the 5-year window after cancer therapy is unknown. Moreover, extent of monitoring of CCS with CKD and associated complications in current practice is underexplored. To inform the development of new and existing care guidelines for CCS, the epidemiology and monitoring of CKD and hypertension in the early period following cancer therapy warrants further investigation.To describe the design and methods of the KIdney aNd blooD prESsure ouTcomes in Childhood Cancer Survivors study, which aims to evaluate the burden of late kidney and blood pressure outcomes in the first ~10 years after cancer therapy, the extent of appropriate screening and complications monitoring for CKD and hypertension, and whether patient, disease/treatment, or system factors are associated with these outcomes.Two distinct, but related studies; a prospective cohort study and a retrospective cohort study.Five Ontario pediatric oncology centers.The prospective study will involve 500 CCS at high risk for these late effects due to cancer therapy, and the retrospective study involves 5,000 CCS ≤ 18 years old treated for cancer between January 2008 and December 2020.2 or albumin-to-creatinine ratio ≥ 3mg/mmol. Hypertension is defined by 2017 American Academy of Pediatrics guidelines.Chronic kidney disease is defined as Estimated glomerular filtration rate <90 mL/min/1.73 mProspective study: we aim to investigate CKD and hypertension prevalence and the extent to which they persist at 3- and 5-year follow-up in CCS after cancer therapy. We will collect detailed biologic and clinical data, calculate CKD and hypertension prevalence, and progression at 3- and 5-years post-therapy. Retrospective study: we aim to investigate CKD and hypertension monitoring using administrative and health record data. We will also investigate the validity of CKD and hypertension administrative definitions in this population and the incidence of CKD and hypertension in the first ~10 years post-cancer therapy. We will investigate whether patient-, disease/treatment-, or system-specific factors modify these associations in both studies.Results from the prospective study may not be generalizable to non-high-risk CCS. The retrospective study is susceptible to surveillance bias.Our team and knowledge translation plan is engaging patient partners, researchers, knowledge users, and policy group representatives. Our work will address international priorities to improve CCS health, provide the evidence of new disease burden and practice gaps to improve CCS guidelines, implement and test revised guidelines, plan trials to reduce CKD and hypertension, and improve long-term CCS health. The first 5 years post-therapy may be a critical window to mitigate long-term progression and adverse effects of CKD and hypertension in CCS.Research on long-term effects of cancer therapy on kidney function in CCS has been historically limited by small sample size and suboptimal definitions for CKD and hypertension with resulting uncertainty of the onset, severity, and characteristics of these conditions in CCS.18 lack specific or actionable recommendations for detecting, preventing, or treating CKD and hypertension soon after cancer therapy completion. The “Kidney Disease: Improving Global Outcomes (KDIGO)”20 and Pediatric Hypertension21 guidelines do provide actionable recommendations on kidney disease and BP monitoring, although not specific to CCS. To our knowledge, there have been no attempts to harmonize these guidelines to optimize practice. Moreover, the extent of CKD and hypertension monitoring being performed in CCS during the first 5 years after cancer therapy completion is unknown.Current kidney and BP follow-up guidelines ,To investigate CKD and hypertension epidemiology during the first 5 years after cancer therapy and identify evidence-practice gaps in contemporary screening and prevention of CKD and hypertension, and of complications from CKD and hypertension in CCS.Supplementary Table 1). Both studies will be conducted at 5 pediatric oncology sites in Ontario, Canada: Hamilton, Kingston, London, Ottawa, and Toronto.We will perform 2 related multi-center studies in Ontario, Canada. This pair of studies involves a network of clinicians, researchers, biostatisticians, stakeholders, and patient partners  and the SickKids Research Institute will act as a participating site, study and data coordinating center, and the biorepository. ICES  scientists and analysts will be integral members of the study team, receiving secure study data for linkage and analysis with administrative healthcare data.SickKids will provide comprehensive training on the study protocol via video-teleconference covering data collection, biospecimen collection and processing, standardized physical exams and placement of 24-hour ambulatory blood pressure monitoring (ABPM) devices. The study will be submitted to the Ontario Cancer Research Ethics Board (OCREB) for approval, prior to study start . Upon approval, we anticipate recruitment for the prospective study will begin in 2022, with a recruitment target of 500 patients.Evaluate CKD and hypertension prevalence at 3 and 5 years after cancer therapy and prevalence of 24-hour ABPM abnormalities at 5 years after cancer therapy, in CCS at high risk for late kidney and BP outcomes.Investigate changes in estimated glomerular filtration rate , albuminuria, BP, and of CKD and hypertension prevalence from 3 to 5 years post-cancer therapy in CCS at high risk for late kidney and BP outcomes.Investigate whether AKI occurrence during cancer therapy, cardiometabolic risk factors, and/or patient-, condition-, system-, and treatment-specific factors are associated with and/or modify kidney outcomes in CCS at high risk for late kidney and BP outcomes.A secondary but important aim will be to expand our patient representative committee. We will prioritize ongoing engagement with patient partners to ensure their voices are heard and promoted in research planning. An example of this will be to explore ways of communicating information on long-term kidney and BP outcomes to patients and their families, during cancer therapy.This is a prospective cohort study of ~500 CCS followed in pediatric oncology clinics, including “AfterCare” clinics devoted to follow-up of CCS, across 5 Ontario sites over a period of approximately 3.5 years . Study vThe study will enroll CCS who will be ≤18.9 years old at 3 years ± 6 months after cancer therapy completion and received potentially nephrotoxic therapies . Patients with pre-cancer CKD diagnoses will be excluded. Given the challenges differentiating underlying hypertension and hypertension secondary to cancer diagnosis, patients with pre-cancer hypertension diagnoses will be included. The definition for cancer therapy end may vary based on cancer treatment group. For example, cancer treatment end will be at 2 years after transplant for SCT patients. Detailed eligibility criteria are outlined in Site coordinators will screen CCS at approximately 2 years post-cancer therapy . Eligible participants will be approached for informed consent either virtually or in person. To support recruitment, study posters with contact information will be advertised in clinics.Study visits are scheduled 3- and 5-years post-cancer therapy . For Tor21 Sociodemographics, family history of kidney/BP diagnoses, medications, questionnaires,26 QoL measures,28 a 5 mL blood sample, and a 30 mL urine sample will also be collected at this time.Variables of interest collected at 3, 4, and 5 years after cancer treatment are summarized in At the 4-year visit, participants will be contacted  to maintain correspondence and collect minimal data. Then 2 months before the 5-year visit, participants will be mailed 2 urine cups for first-morning samples and a 24-hour urine collection container with instructions; samples will be collected within a week before 5-year follow-up.29 Families will choose whether to have the ABPM device  placed during the study visit or given instructions on how to place the device and perform ABPM within a week of follow-up. Ambulatory blood pressure monitoring will record wake and sleep BP every 20 and 30 minutes, respectively, and participant diaries will be kept throughout the 24-hour period.30The 5-year visit will mirror the 3-year visit with the addition of: urine samples (2 first-morning and one 24-hour sample) and 24-hour ABPM data for patients 5 years + as per guidelines.31Blood will be centrifuged at 4°C (2000 g × 10 minutes) and serum aliquoted into 1 mL cryovials. Urine will be poured into 2 x 15 mL conical tubes for collection and a dipstick urinalysis. Coordinators will scan specimens into REDCap with barcode readers as they collect/store/ship them for real-time monitoring and quality assurance evaluations. Biospecimens will be stored on-site at −80°C until quarterly shipments to SickKids on dry ice. The central biochemistry lab at SickKids will measure several kidney and cardiovascular markers: serum creatinine (SCr) using isotope-dilution mass spectrometry-traceable assay electrolytes, glucose, cholesterol, triglycerides, serum C-reactive protein, urine albumin to creatinine ratio (ACR), and urine protein to creatinine ratio. Yearly, the Ottawa site biochemistry lab will receive serum shipments for Cystatin C measurement (particle-enhanced turbidimetric immunoassay). Leftover biospecimens will be stored at SickKids at −80°C for repeat measurements as needed and future studies.On top of data collected at recruitment and follow-up, clinical data  will be abstracted from patients’ electronic medical records and entered onto paper case report forms (CRFs). Each site will upload de-identified data forms to a secure REDCap database located on the SickKids server. A SickKids data coordinator will enter these data into REDCap and send monthly queries to sites. In previous work, we found central data entry yields fewer errors and reduces study site burden. At the time of participant recruitment, permission will be sought for future data abstraction from patient charts (up to 10 years) to update existing study records.Only at SickKids, 2 sets of laboratory values will be collected retrospectively, as SickKids only recently (2021) started contributing data to Ontario Laboratories Information System (OLIS): SCr values throughout cancer therapy to define AKI, monthly SCr, urine albumin, and protein values between cancer therapy end and 3-year follow-up and between 3-year and 5-year timepoints.3235 The main patient, system, and treatment factors we will utilize from ICES databases include pre-cancer diagnosis and previously diagnosed cardiac/diabetes/liver disease, dialysis procedures/CKD and/or hypertension diagnoses per administrative healthcare data, birthweight, income quintile, rural vs. urban community, and cancer-variables .Following data collection, a database containing all measurements will be sent to ICES for linkage with administrative healthcare data, as done previously.3638 a database of clinical information for pediatric oncology patients in the 5 Ontario tertiary care centers, providing rich cancer data3943; Discharge Abstract Database (DAD), Same Day Surgery (SDS), and MOMBABY, documenting administrative, clinical, and demographic characteristics of patients44; The Ontario Health Insurance Plan (OHIP), ICES-derived Physicians Database (IPDB), and Canadian Organ Replacement Register (CORR), databases used to track physician billing, procedures, and specialist referrals46; The Registered Persons Database (RPDB), providing demographic information on all Ontarians with health cards47 and when they leave the Ontario healthcare system,48 providing a method to account for some loss to follow-up; and the OLIS, used to collect laboratory data. A detailed list of data collected from each administrative health data source are provided ,provided . These d2; Grade 2 CKD or worse] or albuminuria [ACR >3 mg/mmol] per KDIGO guidelines19  using height-, sex-, and age-adjusted BP percentile tables29 (Supplementary Table 2).The primary outcomes in this study are post-cancer therapy CKD and hypertension. Chronic kidney disease will be defined as low eGFR [eGFR<90 mL/min/1.73 melines19 . Grade 3tables29 . At the Changes in eGFR, albuminuria, and BP percentile from the 3-year to the 5-year visits, persistent CKD, and persistent hypertension at 3- and 5-year visits, and new CKD or hypertension at the 5-year visit will be recorded. Aim 3 outcomes will be the same as those described above.52 Cardiometabolic risk factors will be ascertained at the study visits and will include glucose, body mass index (BMI) z-score , non-fasting lipid profile , and C-reactive protein.Study exposures of interest pertain mainly to aim 3: AKI during cancer therapy and presence of cardiometabolic risk factors. Acute kidney injury will be defined based on KDIGO guidelines for AKI definition, as a ≥50% SCr rise throughout cancer therapy, from baseline, as previously described.53 age at diagnosis, birthweight, sex (gender), income quintile, rural vs. urban, and baseline cardiac, diabetes or liver disease, unless stated otherwise. Sex-stratified analyses will also be conducted. Effect estimates will be described with 95% confidence intervals.Multivariable analyses described below will include variables of cancer diagnosis classified by a previously described classification system,vs. 5- year CKD and hypertension prevalence using the McNemar test, calculate 3- to 5-year eGFR, ACR, and BP percentile change and proportions of participants with persistent CKD, hypertension and status change. We will use mixed effect models (for repeat measures) to evaluate adjusted associations of AKI and cardiometabolic measures with 3- and 5-year outcomes to evaluate if they modify trajectories by including interaction terms for these measures with time in models. We will also evaluate univariable and multivariable associations of AKI and cardiometabolic measures  with individual 3- and 5-year binary outcomes  using log-binomial regression and continuous outcomes using linear regression . In exploratory analyses, we will determine if analyses above differ by treatment groups , treatment combinations , and diagnosis classification53 in univariable analyses, and if event rates allow, in multivariable analyses. Sample size justification is provided in Supplementary Information.Three- and 5-year prevalence of CKD, hypertension, all categorical 5-year ABPM outcomes, and continuous outcome measures  will be calculated. We will compare 3- In a retrospective cohort of Ontario CCS treated for cancer between 2008 and 2020, we will evaluate:1a. Chronic kidney disease screening, complications monitoring  and nephrology referral;1b. Hypertension screening, complications monitoring  and nephrology referral.2. The validity of several pediatric specific CKD and hypertension administrative algorithms3. Chronic kidney disease and hypertension incidence in the ~10 years after cancer therapy.4. Whether patient, disease/treatment or system factors are associated with each of the above outcomes.54 In sensitivity analyses, we will consider including second cancer and relapse as binary variables in the multivariable analyses described below, rather than as censoring events (not described further).The retrospective multi-center cohort study consists of approximately 5,000 CCS treated for cancer across 5 Ontario sites between January 2008 and December 2020. Hypertension outcome analyses will include SickKids patients only (approximately 2500 CCS) due to data collection feasibility. The inclusion and exclusion criteria are shown in Much of the data used will be obtained from ICES databases . Ideal hypertension monitoring will be defined as performance of a 24-hour ABPM and echocardiogram within 6 months of hypertension appearance, as defined in 21Aim 1 primary outcomes include ideal CKD and hypertension monitoring and appropriate nephrology referral. As shown in 5557 eGFR will be calculated with only SCr if cystatin C is unavailable; a sensitivity analysis for patients with both analytes available will be conducted. Should height be unavailable (for pediatric GFR estimation), validated height-independent eGFR equations will be used.50,5860 Hypertension will be defined as 2 or more consecutive hypertensive values, defined in The primary exposures for aim 1 are CKD and hypertension. CKD will be defined in 2 ways, detailed in 62Aim 2  outcomes will be CKD and hypertension, defined using laboratory data and BP measures, respectively. These outcomes will be defined using the strict criteria described above  and considered the “gold standard.” The diagnostic test will be algorithms based on diagnosis and procedure codes available from ICES databases (described in previous work). These CKD and hypertension algorithms in the ICES databases will be evaluated for their ability to identify or detect CKD and hypertension defined by reference standard-methods.vs. without CKD and hypertension to investigate factors related to variation in clinical practice. Using log-binomial regression , we will estimate the yearly change in ideal monitoring. We will use multivariable log-binomial regression with generalized estimating equations to yield adjusted rate ratios of patient, disease, treatment, and system covariates for ideal monitoring. Analyses will be repeated, adjusting for time as well as provider-level and center-level clustering in monitoring practices.We will calculate yearly proportions of patients with CKD and hypertension who undergo ideal monitoring, and appropriate nephrology referral, separately. We will also evaluate individual CKD and hypertension monitoring components . Yearly measurement rates of eGFR and urine protein measures from the end of therapy will also be calculated. We will compare characteristics and monitoring in CCS with Various diagnosis and procedure code-based algorithms for CKD and hypertension will be evaluated for detecting reference-standard-based CKD and hypertension (Aim 2). Algorithms will be evaluated for validity and level of agreement with the following measures: sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), kappa (κ) statistic, and area under the receiver operating characteristic (ROC) curve.63 to estimate cumulative incidence  and generate cumulative incidence function curves to understand burden and time of CKD and hypertension onset (aim 3). Censoring will occur at system leave date , relapse, second malignancy, or follow-up end.64 Sample size calculation is provided in supplementary information.We will use a sub-distribution hazards model accounting for competing risk of death (Fine and Gray method)At years 3 and 5, we will host videoconference meetings with investigators, patients, stakeholders, and policy representatives to discuss progress, surveys, and update/unify priorities. We also plan to hold working groups to discuss action plans in response to actual and potential findings , discuss steps to impact CCS guidelines based on burden findings from the prospective study and practice gaps from the retrospective study. We will know normative practice patterns, gaps, and associated factors of CKD and CKD-related complications. Our cohort, data and biobank will open countless avenues of novel cross-disciplinary research endeavors and training. Our team will be ideally placed to inform and apply CCS kidney and BP guidelines within the greater context of CCS health and maximize patient and system beneficial impact from the knowledge we generate.While it is known that CCS are at increased risk of adverse kidney effects, limitations in our understanding of long-term effects of cancer therapy may track as late complications. CKD and hypertension burden in the first 5 years after cancer therapy is unclear, as are current recommendations on follow-up for CCS.65The involvement of all major cancer centers in Ontario, facilitating diverse patient recruitment including a spectrum of therapies is a certain strength of this study. Our use of robust definitions for CKD, hypertension, and AKI than currently available will increase the validity of results and applicability to current clinical practice. To our knowledge, this will be the first study to implement 24-hour ABPM, gold-standard for detection of hypertension in a large cohort of CCS, permitting comprehensive diagnosis of types of hypertension.19 or COG.18 KDIGO provides management objectives for patients with or at risk of CKD, but is not adapted to the CCS health context, whereas COG kidney guidelines are used internationally to identify and manage cancer therapy effects in CCS, but does not provide actionable recommendations on managing kidney complications.19 We believe that data generated from this study may enable improvements in both pediatric oncology and of overall CKD and hypertension guidelines, especially with a targeted KT strategy.A major goal is to describe current management of CKD and hypertension complications in CCS and establish practice gaps in this patient population. When consulting best practices in managing CCS at higher risk for CKD, clinicians may turn to KDIGO6668 Mothers experiencing high stress and/or with residences far from neonatal clinics were less likely to attend follow-up appointments.68 If specific barriers are identified, an informed, targeted approach may lead to improved quality of care and health outcomes. Our aim to validate administrative CKD and hypertension definitions in this population would dramatically enhance understanding of disease burdens in this population, using administrative data.Another strength is our assessment of whether cancer-, patient-, therapy-, and system-specific factors influence kidney and BP outcomes or screening and follow-up practices when treating CCS.vs. non-survivors’ characteristics, conduct sensitivity analyses to assess the impact of differential loss to follow-up, and if needed, propensity scores  can be used in multivariable analyses to mitigate these biases. There may be small sample sizes for subgroup analyses of specific treatments; however, our patient partners stressed these subgroup analyses are priorities.Both studies have limitations. In the prospective study, a proportion of CCS will have a cancer relapse, which may prove difficult to discern between worsening disease- and treatment-associated kidney dysfunction. Survivor bias will be an issue when analyzing risk factors for treatment-associated CKD and hypertension. We can compare survivors’ 15 By design, conclusions in the prospective study only apply to high-risk CCS; however, this is a priority population for evidence-based guideline development and will benefit the most from early CKD and hypertension diagnosis and intervention. Moreover, our high-risk groups definitions are aligned with risk groups delineated by the COG long-term follow-up guidelines, which will enhance future KT. One potential issue is 3 and 5-year prospective study event rates may be lower than expected; however, previous work69 demonstrates high event rates and including only high-risk CCS makes this problem unlikely. If low event rates are found, this will direct future research on the timing of CKD and hypertension onset in CCS. We may not see much change between the 3- and 5-year outcomes, but this first-of-its-kind evaluation of sustained kidney or BP abnormalities will establish rate-of-change data for future research. ABPM will only be done at the 5-year visit to reduce attrition bias. Similar to most albuminuria studies, ACR is susceptible to postural proteinuria and overestimation. This is a challenge in all pediatric studies evaluating proteinuria. We attempt to mitigate this by providing participants with instructions to effectively perform first-morning urine prior to the 5-year visit. We acknowledge that the study aim is descriptive in measuring changes in the outcomes.We acknowledge including study visits before 3 years would provide insight on early post-therapy development of CKD and hypertension. We chose 3-year follow-up for cohort entry to improve feasibility/cost and allow time for resolution of immediate therapy-related effects, while capturing patients early enough to identify early detection and intervention opportunities.70 We will evaluate pre vs. post 2013 eras and will include this variable in analyses if differences are found. The retrospective study is susceptible to surveillance bias; sicker patients are tested more often for CKD, thus included in analyses. We will use this large database to calculate CKD incidence using routinely collected data, but because of ascertainment bias concerns, this was not the primary goal of this study. A possible challenge for the retrospective study relates to using tests  to determine if complication monitoring occurs; it will not be possible to know if a test is specifically done to monitor for CKD. For atypical tests , this is likely not an issue. We also may be unable to infer the specific intentions of clinicians when ordering the test, nor if treatments were given in response to abnormal test results; we can only know whether or not tests were done. In future work, we may determine if treatments were given in response to test abnormalities by incorporating healthcare provider surveys with prospective data collection.In the retrospective study, practice drift may be evident. However, we do not expect this as COG guidelines have not changed significantly in recent editions in 2013.19 and hypertension21 exist but are not adapted to the natural history of CKD and hypertension specifically in CCS. We aim to prospectively study 3-year and 5-year CKD and hypertension outcomes and retrospectively determine whether appropriate screening practices are used for kidney outcomes in CCS. With this information we will be able to identify practice gaps within the current CCS healthcare context in Ontario and inform modifications to current guidelines for monitoring late kidney complications in CCS.72Guidelines to monitor CKDClick here for additional data file.Supplemental material, sj-docx-1-cjk-10.1177_20543581221130156 for KIdney aNd blooD prESsure ouTcomes in Childhood Cancer Survivors: Description of Clinical Research Protocol of the KINDEST-CCS Study by Adree Khondker, Michael Groff, Sophia Nunes, Carolyn Sun, Natasha Jawa, Jasmine Lee, Vedran Cockovski, Yasmine Hejri-Rad, Rahul Chanchlani, Adam Fleming, Amit Garg, Nivethika Jeyakumar, Abhijat Kitchlu, Asaf Lebel, Eric McArthur, Luc Mertens, Paul Nathan, Rulan Parekh, Serina Patel, Jason Pole, Raveena Ramphal, Tal Schechter, Mariana Silva, Samuel Silver, Lillian Sung, Ron Wald, Paul Gibson, Rachel Pearl, Laura Wheaton, Peter Wong, Kirby Kim and Michael Zappitelli in Canadian Journal of Kidney Health and Disease


Background and Objectives: Cardiac rehabilitation (CR) plays an essential role in peripheral artery disease (PAD), leading to improved functional status, increased quality of life, and reduced arterial stiffness. We aimed to assess factors associated with clinical improvement 6 months after enrolment in a rehabilitation program at an academic medical center in north-eastern Europe. Materials and Methods: We conducted a prospective cohort study on 97 patients with PAD admitted to a single tertiary referral center. At the 6-months follow-up, 75 patients (77.3%) showed improved clinical status. We analyzed demographics and clinical and paraclinical parameters in order to explore factors associated with a favorable outcome. Results: Hypertension (p = 0.002), diabetes mellitus (p = 0.002), dyslipidemia (p = 0.045), and obesity (p = 0.564) were associated with no clinical improvement. Smoking cessation (p < 0.001), changing sedentary lifestyle (p = 0.032), and improvement of lipid and carbohydrate profile as well as functional status parameters and ambulatory arterial stiffness index (p = 0.008) were factors associated with clinical improvement at the 6-months follow-up. Conclusions: PAD patients require an integrative, multidisciplinary management to maintain functional status and increase quality of life. Improving carbohydrate and lipid profile, adopting a healthy lifestyle, quitting smoking and increasing exercise capacity are predictors for clinical improvement 6 months after enrolment in a CR program. Peripheral artery disease (PAD) has a high prevalence among cardiovascular diseases, but is often underdiagnosed or undertreated, which occurs secondary to atherosclerotic damage to peripheral arteries . DespiteCardiovascular diseases (CVD) remain the main cause of mortality and morbidity in industrialized countries despite notable technological advances . The manArterial stiffness is a predictor of cardiovascular mortality and morbidity. It is widely used nowadays used to assess target organ damage in hypertensive patients ,7. Both Lifestyle changes, proper diet, and drug administration as well as awareness regarding the natural evolution of the disease are essential components of any CR program. The aim of this study was to assess the clinical and paraclinical factors associated with improvement in functional status 6 months after the start of the CR program.We conducted a prospective cohort study on 120 patients admitted to a single tertiary referral center in North-East Romania, with a diagnosis of PAD. The diagnosis was based on the presence of intermittent claudication (IC) and an ankle-brachial index (ABI) less than 0.9 or in the presence of symptoms suggestive of PAD and previous history of peripheral revascularization. The exclusion criteria were: age less than 18 years old, patients with contraindications for cardiopulmonary exercise testing, or those with incomplete data regarding treatment or assessed investigations. Of the 120 patients initially enrolled, 16 were excluded due to follow-up drop-out, and for seven patients, due to technical reasons, it was not possible to perform 24 h ambulatory blood pressure monitoring at the 6-month follow-up. The final study group comprised 97 patients .2). AASI was defined as 1 minus the regression slope of diastolic on systolic blood pressure (BP) values derived from a 24-h ambulatory blood pressure monitoring (ABPM) recording [Patients underwent an extensive evaluation prior to enrolment in the study, which included laboratory tests, cardiopulmonary exercise testing, and ambulatory blood pressure monitoring for 24 h. For the 97 PAD patients enrolled, demographics, personal medical history, tobacco and alcohol consumption habits, and chronic medication were obtained from the observation charts. We used the current guidelines to evaluate and define comorbidities such as arterial hypertension , heart fecording . All patAt the 6-month follow-up biological samples, cardiopulmonary exercise testing and blood pressure monitoring were repeated. The 97 patients were divided into two groups on the 6-months follow-up, based on the presence or absence of clinical improvement assessed as staging in a class lower than at enrolment using the Fontaine classification system . During t-test . Categorical variables were compared using the Fisher Exact test. A p-value of ≤0.05 was considered statistically significant. To explore factors associated with clinical improvement at 6-month follow-up, a regression analysis was performed. Receiver-operator characteristic analyses were performed to calculate area under the curve for clinical parameters. The descriptive analysis was performed using SPSS statistics software .Data were reported as the mean ± standard deviation (SD) and as a number (frequency or percentages). Continuous variables were compared using the The study was approved by the Ethics Committee of the University of Medicine and Pharmacy “Grigore T. Popa” Iași and of the Clinical Rehabilitation Hospital Iași, and was conducted according to the Helsinki Declaration. All patients signed an informed consent statement which mentioned that the results would be used for research purposes.2 with a decreasing value at the 6-month follow-up of 24.14 ± 3.17 kg/m2 (p = 0.037). Percentage of sedentary patients , smokers , and alcohol consumers  decreased after enrolment in the study. The 6-month assessment showed a decrease in systolic blood pressure values by 4.3%  and diastolic by 3.6% , but without statistical significance for the analyzed group.We analyzed 97 patients with PAD on admission and at the 6-month follow-up after the start of the CR program. According to the presence or absence of clinical improvement, we divided the 97 patients into two groups: those with a favorable evolution of the clinical status  and those without clinical improvement after the CR program (22 patients). The demographics and resting hemodynamics are presented in p = 0.002), diabetes mellitus , dyslipidemia  and obesity  were more frequent in the group of patients without clinical improvement at the 6-month follow-up (p = 0.310), chronic obstructive pulmonary disease  or venous insufficiency . Regarding clinical parameters, the improvement or disappearance of paresthesia (p = 0.005) and the feeling of cold feet (p = 0.001) and cold skin (p = 0.028) were parameters associated with favorable clinical outcomes after a 6-month CR program. Quitting smoking  and embracing a healthy lifestyle  improves the functional status of PAD patients.Comorbidities, symptoms, biological parameters and those associated with cardiopulmonary exercise testing were analyzed in association to clinical improvement. Hypertension . Statistically significant results were obtained for low-density lipoprotein (LDL) cholesterol  and triglycerides , as well as fasting glucose  and HbA1C  (e of 4%) .2peak) , peak systolic BP , and perception of effort on the Borg scale  are statistically significant parameters associated with clinical improvement. At enrolment, patients were classified on the basis of cardiopulmonary exercise test results predominantly in Weber class C , with predominantly moderate  or moderately-severe  functional limitation. At the 6-month follow-up, after regular physical training, the degree of functional limitation decreased, remaining predominantly moderate , specific to Weber B class . ABI values , echocardiographic parameters, especially left ventricular ejection fraction  , and associated ABPM parameters improved, especially those correlated with arterial stiffness: pulse pressure  and AASI .Cardiopulmonary exercise testing results after 6 months of aerobic physical training showed additional improvement among patients with clinical benefit. Thus, peak oxygen uptake (VOp = 0.001), HbA1C by at least 4% (p = 0.001), and lipid profile parameters such as LDL-cholesterol (p = 0.013) and triglycerides (p = 0.026) are associated with improved functional status. Physical training led to improvement in clinical signs such as paresthesia (p = 0.008) and feeling of cold feet (p = 0.003) or cold skin (p = 0.037). The receiver operating characteristic curve of the clinical signs and ABI values associated with clinical improvement identified positive predictive values of paresthesia (area under the curve <AUC> = 0.669), feeling of cold feet (AUC = 0.693) and cold skin (AUC = 0.625), or ABI value (AUC = 0.652) in the assessment of clinical status after 6 months of physical training in PAD patients . These aspects are consistent with existing data in the literature, as it is known that PAD predominantly affects patients over 50 years of age. In terms of sex predominance, recent studies have shown an equal prevalence between males and females ,20. In op = 0.002), diabetes mellitus (p = 0.002), dyslipidemia (p = 0.045), and obesity (p = 0.564) were more frequent in the group of patients without clinical improvement at the 6-month follow-up.The majority of patients enrolled in the study had a high number of cardiovascular risk factors, which negatively impacts prognosis and increases the risk of an acute cardiovascular event, therefore emphasizing the need to enroll them in special CR programs. Hypertension (p < 0.001) and cardiovascular-mortality (p < 0.001) in patients with type 2 diabetes mellitus [p <0.05) or canagliflozin (p < 0.05). Empagliflozin decreased both pulse pressure (compared with baseline) (p < 0.001) and AASI (p = 0.059) [Of the patients, 57.7% had diabetes mellitus, most with inadequate glycemic control (HbA1C 7.96 ± 2.23 g%). Diabetes mellitus is associated with a 2-fold increased risk of developing PAD, coronary artery disease, or ischemic stroke and is associated with an increased risk of arterial stiffness or microcirculation abnormalities ,22. Patimellitus . Clinica= 0.059) .p = 0.001) and fasting glucose by at least 7% (p = 0.001) from baseline is statistically significant for stagnation of functional decline and improving arterial stiffness as a result of improved endothelial dysfunction and decreased pro-inflammatory or pro-oxidative processes.Umpierre et al. conducted a meta-analysis of randomized controlled clinical trials based on structured exercise training regiments (such as aerobic or resistance) and dietary advice and evaluated the effect of CR programs on serum HbA1C levels in patients with type 2 diabetes mellitus . They deArterial stiffness is independently associated with PAD and could be included in the diagnostic and risk stratification strategy in these patients given the increased risk of a major cardiac event . Age, thThe analysis of the determinants of arterial stiffness helps risk stratification, therapeutic management, and secondary prevention in PAD, its role as a predictor of mortality and morbidity being recognized in several studies until now . Arteriap = 0.024) and AASI . Moreover, with the help of logistic regression, we concluded that the improvement of these two determinants following physical training and multidisciplinary management are associated with clinical improvement and lessening of the arterial stiffening process in PAD patients. The improvement of these parameters is linked to the increased pulsatile flow and enhanced bioavailability of nitric oxide secondary to regular physical training. Vascular compliance decreases with age, leading to increased systolic BP and reduced diastolic BP, making pulse pressure an easily quantifiable clinical marker which reflects decreased vascular compliance [Pulse pressure and AASI are markers of arterial stiffness. In our study, we monitored the blood pressure profile both before the start of the cardiovascular rehabilitation program and at 6 months and found improvement in both pulse pressure , regular physical training, and proper nutrition, leading to an improved functional status and increased quality of life. The benefits of physical training translate into reduced BMI and body fat, improved blood pressure profile , increased exercise capacity (VO2 peak: p = 0.034), and improved lipid and carbohydrate parameters . Between these parameters there is a reciprocal potentiation effect, also evident in our study, which is explainable by the multiple implications of endothelial dysfunction, the implication of the of the renin-angiotensin-aldosterone system as well as inflammatory processes, which determine both intrinsic changes in the quality of the arterial wall and its thickness. Strasser et al. demonstrated that abdominal obesity and visceral fat are positively associated with large artery stiffness [Obesity and dyslipidemia are also associated with a negative prognostic and functional decline leading to a decrease in quality of life and self-independence in PAD . Both adtiffness . The acctiffness ,43. Freetiffness .2), enrolling a total of 235 patients from eight trials. Arterial stiffness parameters were assessed 8 weeks after the start of physical training, concluding that aerobic training does not induce a statistically significant reduction in them (p = 0.14). The reduction of the arterial stiffening process was observed in association with the decrease of SBP in a subgroup of obese patients who underwent a low-intensity aerobic training (p < 0.01), but further research is needed in the area [p = 0.047) and BMI (p = 0.037) in PAD patients with clinical improvement at the 6-month follow-up, which supports the data from the literature.Montero et al. conducted a meta-analysis on the effect of CR programs on arterial stiffness in obese patients . Smoking cessation leads to improvement of pulse pressure and AASI by relieving endothelial dysfunction and antagonizing pro-inflammatory status and increased tissue absorption of smoke particles [p < 0.05%) [Smoking is the main risk factor associated with PAD and through systemic and vascular inflammation, endothelial function, and damage to the extracellular matrix affect arterial elastic properties, which influence the arterial stiffness ,49. In o< 0.05%) . In anot< 0.05%) . In a sy< 0.05%)  conclude< 0.05%) , but to < 0.05%) .p = 0.026) results in improvement of clinical parameters and of parameters associated with arterial stiffness (AASI and pulse pressure).In our study, the biological assessment carried out at enrolment revealed elevated serum levels of lipid profile , fasting blood glucose, and inflammatory markers (CRP). The improvement in mean serum values of these parameters secondary to the CR program suggests the beneficial role of physical training associated with multidisciplinary management. Lipid-lowering medication and drug treatment of diabetes mellitus improve the prognosis of patients with PAD, leading to decreased mortality rate or cardiac hospitalizations ,56. A sip = 0.013) and triglycerides by at least 13% (p = 0.026) are favorable predictors for clinical improvement at the 6-month follow-up. Studies have demonstrated that inflammatory markers such as C-reactive protein, tumor necrosis factor, or interleukin 6 have a statistically significant correlation with arterial stiffness [p = 0.047), the statistical analysis did not reveal this parameter as an independent predictor (p = 0.086).In our cohort, we demonstrated that decreasing serum levels of LDL-cholesterol by at least 10% (tiffness . In our p = 0.046) and ABI values (p = 0.031) at the 6-month follow-up.The referral of PAD patients to specialized cardiovascular rehabilitation centers is low, increasing adherence to treatment, awareness of the importance of enrollment in such programs, and the beneficial results both physical and psychological being the goals of the work presented. The benefits of physical training translated into increased walking distance (p = 0.031) and lower AASI values (p = 0.008), results similar to those presented in the literature. Brewer et al. demonstrated that increased brachial pulse pressure and higher aortic augmentation index are associated with functional decline and implicitly with decreased quality of life by limiting daily activities [In PAD, arterial stiffness is associated with walking distance in treadmill test . In our tivities . Arteriativities . Vasculativities . Severaltivities ,63. Tanativities .2 peak). Cardiopulmonary testing performed 6 months after the start of the CR program showed a significant increase in VO2 peak in patients of the first group . The increasing of VO2 peak occurs secondary to increased cardiac output  and O2 extraction . Regular exercise decreases sympathetic activity, enhances the parasympathetic nervous system, and modulates arterial baroreflex function, leading to lower blood pressure at exercise and rest and decreased heart rate variability. In our study, at the 6-month assessment we observed a reduction in peak systolic blood pressure at cardiopulmonary testing , this being an independent predictor associated with clinical improvement 6 months after the start of a recovery program . At the peripheral vascular level, regular exercise improves NO-mediated vasodilation and stimulates endothelial progenitor cell formation, with increased arteriolar diameter and improved O2 extraction. These changes are clinically translated into improved Borg Scale score as we demonstrated in our study using logistic regression (p = 0.004). In addition to increasing exercise capacity, physical training is associated with a decrease in arterial stiffening due to improvements in nitric oxide bioavailability, which causes an increased vasodilatory effect. These issues underpin the improvement of both AASI and the VO2 peak, thus contributing to the concept of arterial “de-stiffening” and improving endothelial function [The benefits of physical training are noticeable on a morphological level, a hemodynamic one, as well as on a metabolic level. The main objective of our study was to assess exercise capacity (expressed as VOfunction .Our study has several limitations due to the relatively small number of cases analyzed and variability in the assessment of improvement of clinical signs. We excluded those records where critical information was unavailable. This was done to minimize the risk of misclassification, introducing a limited risk of selection bias. Further on, the clinical improvement may be attributable to other various factors besides those that were mentioned in our study. As well, the 6-month limited time monitorization data may be modified on a longer follow-up.In our study we demonstrated that improving carbohydrate and lipid profile, adopting a healthy lifestyle, quitting smoking, and improving clinical signs as well as increasing exercise capacity were central elements associated with preserving functional status, decreasing the arterial stiffening process, and increasing quality of life in patients with PAD that underwent CR programs. Based on the data presented, the design of an integrative algorithm to evaluate the effectiveness of CR programs may represent a future research direction.


Increased intracranial pressure (ICP) and hypotension have long been shown to lead to worse outcomes in the severe traumatic brain injury (TBI) population. Adequate sedation is a fundamental principle in TBI care, and ketamine is an attractive option for sedation since it does not commonly cause systemic hypotension, whereas most other sedative medications do. We evaluated the effects of ketamine boluses on both ICP and cerebral perfusion pressure (CPP) in patients with severe TBI and refractory ICP. 2 was maintained between 35 and 40 mmHg. The primary outcome was a reduction in ICP with a subsequent increase in CPP.  We conducted a retrospective review of all patients admitted to the neurointensive care unit at a single tertiary referral center who had a severe traumatic brain injury with indwelling intracranial pressure monitors. We identified those patients with refractory intracranial pressure who received boluses of ketamine. We defined refractory as any sustained ICP greater than 20 mmHg after the patient was adequately sedated, serum Na was at goal, and COp < 0.001). Ketamine boluses led to an increase in CPP by 2 mmHg (IQR −5 to +12), which was also significantly different from baseline (p < 0.001).  The patient cohort consisted of 44 patients with a median age of 30 years and a median presenting Glasgow Coma Scale (GCS) of 5. The median reduction in ICP after administration of a ketamine bolus was −3.5 mmHg (IQR −9 to +1), and the postketamine ICP was significantly different from baseline ( In this single-institution study of patients with severe traumatic brain injury, ketamine boluses were associated with a reduction in ICP and an increase in CPP. This was a retrospective review of 43 patients and is therefore limited in nature, but further randomized controlled trials should be performed to confirm the findings. Severe traumatic brain injury (TBI) continues to plague the worldwide medical community with over 5.48 million cases each year, which accounts for over half of all trauma-related deaths . The iniMost recent TBI studies along with expert opinion divide treatment algorithms for increased ICP into three tiers of therapy. The first tier involves using short-acting analgesic and sedative agents such as fentanyl, propofol, and midazolam to increase sedation –10. ThesKetamine is a dissociative anesthetic that binds to the N-methyl-d-aspartate (NMDA) receptor, leading to a blockade of excitatory synaptic activity. The use of ketamine in brain injury has previously been reported to be a contraindication due to early studies showing an increase in ICP following its administration , 14. TheThe objective of this study was to determine the effects of bolus doses of ketamine on both ICP and cerebral perfusion pressure (CPP) in a patient population with severe TBI.This is a retrospective observational study in which patients admitted to a tertiary university-affiliated adult neurocritical care unit in San Antonio, Texas, USA, were identified between 1 January 2014 and 31 December 2017. Patients were identified by searching the pharmacy charge database and determining which patients received intravenous (IV) ketamine. The list of patients who had received ketamine was then evaluated, and only patients who had sustained a severe TBI, had an ICP monitor in place, and were on mechanical ventilation were selected for inclusion. This list was further refined by including only patients with refractory ICP who were already receiving osmotherapy, adequately sedated, and being administered analgesia infusions. Patients were cared for at the discretion of the attending neurosurgeon and neurointensivist. Institutional review board approval was obtained, waiving the requirement for written informed consent as this was a retrospective chart review.All data were collected prospectively in the medical record up to hospital discharge, interinstitutional transfer, or death, whichever occurred first, and then evaluated retrospectively. Data collected on admission included age, weight, gender, presenting Glasgow Coma Scale (GCS), intracranial lesions, epidural hematoma (EDH), subarachnoid hemorrhage (SAH), subdural hemorrhage (SDH), contusions and axonal injury, and acute ischemic stroke (AIS). Data collected during the ICU course included the type of ICP monitor  and/or Codman monitor . Additional data collected included bolus and/or continuous infusion doses of ketamine, fentanyl, propofol, dexmedetomidine, benzodiazepines, pentobarbital, and paralytics, along with hypertonic saline and mannitol boluses. The ICP was recorded at the beginning of each hour, and the ketamine boluses were administered during that hour.The intervention of interest was all IV boluses of ketamine administered by the treating team. Ketamine infusions for sedation/analgesia and bolus dosing of ketamine were given at the discretion of the attending neurointensivist. Although no official protocol was in place at the time of the study, it was agreed upon practice of the neurointensivists at the time that ketamine was given when ICP was sustained greater than 20 mmHg and documented during that hour, serum sodium was between 150 and 155, if an EVD was in place it was open and draining, and other sedative boluses had failed to improve the ICP; therefore, ketamine boluses were only given if all other therapies failed to improve the ICP. In addition, ketamine boluses were considered if there was concern that boluses of other common sedatives  would cause significantly more hypotension.2) between 35 and 40 mmHg. Transition to more aggressive therapy including sedation boluses, mannitol, decompressive hemicraniectomy, pentobarbital coma, and paralysis was all at the discretion of the attending neurosurgeon and neurointensivist. A frontotemporal-parietal craniectomy was performed for all patients who had a decompression, and extra-axial mass lesions were removed, but parenchymal lesions were not. ICP was treated if there was a sustained elevation in ICP greater than 20 mmHg for more than 5 minutes that was not attributed to coughing or routine nursing care and documented in the last hour by the nursing staff. Boluses of ketamine were only given after ensuring all other parameters including head of bed elevation, PaCO2, serum sodium, and adequate sedation were ensured and never if the ICP was lower than 20 mmHg. Ketamine boluses were dosed at 2 mg/kg. Adequate sedation was defined as an RASS of −3 to −4.Patients admitted with severe TBI were managed according to the 3rd edition of the Brain Trauma Foundation guidelines which were the published guidelines during the duration of the study. ICP was maintained <20 mmHg, and SBP was maintained >90 mmHg , 18. AllThe primary outcome measure was the proportion of ketamine boluses that resulted in both an improved ICP and CPP, measured on an hourly basis . This outcome was computed a posteriori based on the presence of a decrease in ICP and a concomitant increase in CPP.The secondary outcomes were change in ICP and CPP from the preketamine bolus baseline (in mmHg).U test was used for continuous variables. Correlations between two continuous variables were analyzed using Spearman's correlation test.Results are expressed as the median and interquartile range (IQR) or frequencies and proportions. Fisher's exact probability test was used to undertake unadjusted univariate tests in order to establish an association between the primary outcome and categorical variables. The Mann–Whitney R2), adding other variables whose inclusion gives the most improvement of the fit, and repeating this process until no further improvement is achieved.Logistic regression was used to compare odds ratios of improving both ICP and CPP, whereas forward stepwise linear regressions were used to identify factors independently associated with change in ICP and CPP, which means starting with no variables in the model, testing the addition of each individual variable and measuring the model's goodness of fit .Quadratic regressions with 95% confidence intervals were used to identify the correlation between baseline ICP and change in ICP and baseline CPP and change in CPP. The models were adjusted for multiple measures. We defined the efficacy zone of ketamine boluses as the zone of a decrease in ICP above a certain baseline ICP value (identified by the regression line) and an increase in CPP below a certain baseline CPP value (identified by the regression line). The groups were further classified by graphic representations according to significant variables identified in the regression model . We performed a subgroup analysis in which we included only the ketamine boluses that were administered as the sole intervention documented during that hour and when the ICP was greater than 20 mmHg. A There were 69 patients initially identified, and after review of those charts, 43 patients were deemed able to be included in the analysis. The remaining 26 patients did not have ketamine bolus data and were only placed on continuous ketamine infusions. Of those 43 patients, there were 216 individual boluses of ketamine administered. Of the 216 ketamine boluses, 98 (45%) still had elevated ICP greater than 20 mmHg after the bolus. Of those patients, 68 (68%) still had an overall decrease in their ICP, but the decrease was not enough to bring the ICP less than 20 mmHg. The patient cohort consisted of 32 males and 11 females with a median age of 27 years (IQR 20–40), presenting the GCS of 5 (IQR 3 to 7) and the median ketamine bolus dose of 150 mg (IQR 100 to 200) . The majp < 0.001). The median change in CPP after ketamine bolus was an increase in 2 mmHg (IQR −5 to +12), which was a significant increase from baseline (p < 0.001). Univariate analysis is available in the online supplemental appendix (The proportion of ketamine boluses that resulted in both an improved ICP and CPP was 46% (99/216). The median change in ICP after ketamine bolus was −3.5 mmHg (IQR −9 to +1), which was a significant decrease from baseline  and the presence of a SDH  were independently associated with improvement in both parameters. CPP had a favorable response to ketamine administration in the presence of a paralytic infusion, concomitant benzodiazepine infusion, or hemicraniectomy. The presence of paralytics or benzodiazepines during the ketamine bolus raised the CPP by 8.7 and 7.0 mmHg, respectively . When evp < 0.001). The median change in CPP after ketamine bolus was an increase of 3 mmHg . The greatest effect on CPP was on those patients whose CPP was less than 80 mmHg. The median number of boluses per patient was 4 (IQR 2 to 6).In the subgroup of patients who received only a bolus of ketamine for ICP >20 mmHg, the proportion of ketamine boluses that resulted in both an improved ICP and CPP was 49% (63/128). The median change in ICP after ketamine bolus was −5 mmHg  [The explanation for the ICP decrease after ketamine administration is still unknown, but likely related to the overall sedative effects of ketamine . In addiased ICP , 22, 28.ased ICP . Up to 8ased ICP . The fac ICP [2) .Another interesting finding of our review is that patients with decompressive hemicraniectomy actually had a slight increase in ICP after administration of a ketamine bolus. This finding is likely explained by alteration in the pressure reactivity index caused by the cranial defect. The pressure reactivity index is defined as the ability of the cerebral vessels to respond to changes in arterial blood pressure with a reactivity index defined as a moving correlation between the mean ICP and the mean arterial pressure. A negative pressure reactivity index signifies normal working cerebral autoregulation in that an increase in the mean arterial pressure leads to a decrease in ICP due to vasoconstriction. A positive reactivity index, therefore, signifies altered cerebrovascular reactivity since an increase in mean arterial pressure will lead to an increase in ICP . MultiplIn the future, further prospective studies could evaluate ketamine's influence on ICP in various patient populations. Since this is one of the only medications that have shown some efficacy at both decreasing ICP and increasing CPP, it might be worthwhile in specific subgroups of patients with severe traumatic brain injury, such as those who responded appropriately to the initial bolus. Further studies comparing ketamine's overall ability to control ICP compared to ability of other commonly used sedatives in the ICU would be important. Other studies evaluating the effect of ketamine on cerebral oxygenation along with its impact on cerebral autoregulation would likely be beneficial too.2 values, and Na values at the time of the bolus were not recorded. We were also not able to assess a potential interaction between the timing of the hemicraniectomy and the effect of the ketamine boluses. We did not either collect data on potential adverse events associated with ketamine boluses. Finally, we did not have data in the medical record to determine why some patients only received 1-2 boluses before stopping, but it was likely because there was no change in the ICP.A few significant limitations exist in this study. The first is that it is a retrospective review of patients from a single institution. Second, the ICP values were measured hourly and not necessarily immediately after the ketamine bolus, so a larger response to ketamine that occurred immediately after the bolus was unable to be observed; however, it could be also possible we were not able to capture worsening ICP, the exact magnitude or the intervention being unknown. In addition, some of the ICPs appear to be in the normal range prior to the ketamine bolus. As those values were recorded hourly by the bedside nurse, it is likely there was a higher ICP spike during the hour that was not recorded by the nurse but for which ketamine was administered. Outcomes were difficult to assess as there was no control group, and confounding variables such as bolus doses of other medications could have partly contributed to the reduction in ICP, although this was controlled for in the statistical analysis. In addition, the lack of a formal protocol in the ICU for the administration of ketamine limits the generalizability of the data along with the fact that the specific RASS values, PaCOIn this retrospective review of patients with severe TBI and refractory ICP, we showed a significant association between a ketamine bolus and a reduction in ICP and an increase in CPP. This is one of the only studies to evaluate the effect of ketamine boluses on both ICP and CPP and should lead to future hypotheses in patients with severe TBI. Randomized controlled trials are needed to better evaluate the effect of ketamine boluses and determine if there is an outcome benefit to its use as a sedative and/or rescue therapy in severe TBI patients.


Deceased donor kidney transplantation (DDKT) is a major therapeutic option for patients with end-stage renal diseases. Although medical techniques improved in recent years, acute or chronic rejection after DDKT is not uncommon and often results in poor graft survival. Therefore, the determination of risk factors is very important to stratify patients and to improve outcomes. This study aims to evaluate the risk factors for treated rejection (TR) of patients after DDKT.Clinical data of deceased donors and corresponding recipients were retrospectively collected. The primary outcome was TR defined as the treatment for rejection within 24 months after DDKT. Univariate comparisons of baseline characteristics were performed with Chi-square test, t-test, and Mann–Whitney U test. Logistic regression was constructed to analyze potential risk factors. Receiver operating characteristic (ROC) curve and Jordan index were generated to determine the optimal cutoff value. The association between continuous variables and TR was examined and visualized by using restricted cubic spline (RCS) models.P = 0.040), platelet , absolute neutrophil count , and HLA-DQ mismatch  showed statistical significance. RCS models showed that patients with higher levels of uric acid had increased risk of TR.Data of 123 deceased donors and 246 recipients were obtained and analyzed. The median age was 41 (4–62) years for recipients and 39 (1–65) years for donors. The recipients who died or suffered graft loss during the follow-up period were 8 (3.3%) and 12 (4.9%), respectively. After univariate analysis and subsequent multivariate analysis, the preoperative serum uric acid (OR, 2.242; 95% CI, 1.037–4.844; Serum uric acid and other three indicators were found to be the independent risk factors for TR, which may contribute to stratify patients and develop personalized regimen in perioperative period. Worldwide, kidney transplantation from deceased donors is a major therapeutic option for patients with end-stage kidney diseases . With thOn the other hand, it is reported that kidneys from deceased donors may suffer from various injurious factors during the donation . Among tIndeed, the association of rejection in DBD with inferior graft outcomes has been established previously . MeanwhiWe retrospectively collected the data of both donors and recipients performed DDKT between 2015 and 2018 in West China Hospital. The end of follow-up period in this study is December 2020. After the exclusion of eight donors and 16 paired recipients due to lack of major preoperative information, insufficient follow-up data, dual organ transplantation, and donor age older than 65, we included 123 donors and 246 recipients and analyzed their data 3. RecipThe primary clinical outcome was TR defined as the treatment for rejection within 24 months after the DDKT. DGF was defined as receiving dialysis within 1 week after the transplantation. Overall graft loss means regaining permanent dialysis after the transplantation or death with functional graft by any cause. Cold ischemic time (CIT) was established by the time from cold storage to reperfusion following implantation. Serum creatinine of recipients at implantation and within 24 months after transplantation was available for evaluating renal function and graft performance. Human leukocyte antigen (HLA) mismatch according to the UK allocation policy was defined as the incongruity of HLA-A, HLA-B, HLA-DR, HLA-DQ, HLA-Type I, and HLA-Type II between donor and recipient. Baseline characteristics of the included 123 pairs and transplantation were assessed as covariant for exploring potential risk factors.P-values less than 0.10 in the correlation analyses, which might be conducive to seek potential correlation and risk factors. Logistic regression model was constructed to analyze potential risk factors. Significant variables in correlation analyses were incorporated into the regression model. In addition, estimated glomerular filtration rate (eGFR) was included in multivariate analysis for adjusting the effect of renal function on outcomes.Statistical analyses in this study were performed using SPSS 23.0 . Mean value and standard deviation or median with ranges were calculated for continuous variables. Rates or proportions were calculated for categorical variables. The Kolmogorov–Smirnov test was used to indicate the distribution of variables. Univariate comparisons between transplants with rejection versus without rejection were made with Chi-square tests, t-test, and Mann–Whitney U test when appropriate. Meanwhile, variables were deemed to be statistically significant at P-values were two-sided, and the statistical significance was defined as P < 0.05.In multivariate analysis, the stepwise regression method was chosen to prevent multicollinearity among variables. Receiver operating characteristic (ROC) curve and corresponding Jordan index (subtract 1 from the sum of sensitivity and specificity) were generated to determine the optimal cutoff value for continuous variables in the regression model. The area under the curve (AUC) in ROC analysis is considered as a predictor to distinguish patients with or without TR. The AUC between 0.8 and 0.9 represents a high-rank results test, and the AUC between 0.5 and 0.6 represents a poor test. The peak point locating at where the sensitivity and specificity were maximized simultaneously was highest cutoff point. The association of variables on continuous scales with primary outcome was examined through the use of restricted cubic spline (RCS) regression models with multifactorial adjustment. RCSs with equally spaced percentiles  were used to capture the association, to visualize the relationship, and to test the potential non-linearity. In regression analysis, Of 246 DDKT recipients, 128 (52.0%) were from donors suffered severe craniocerebral injury, 84 (34.2%) from intracranial hemorrhage, and 34 (13.8%) from other diseases such as intracranial tumors. The median (range) age was 41 (4–62) years for recipients and 39 (1–65) years for donors. The recipients who died or suffered graft loss during the follow-up period were 8 (3.3%) and 12 (4.9%), respectively. Maintenance immunosuppressive therapy of recipients was the combination of tacrolimus, mycophenolate mofetil (MMF), and prednisone (97%) or the combination of cyclosporin, MMF, and prednisone (3%). Recipients who suffered from cardiovascular events, hyperparathyroidism, diabetes, anemia, and psychiatric disorders following transplantation were 6 (2.4%), 5 (2.0%), 5 (2.0%), 2 (0.8%), and 3 (1.2%), respectively. Of 246 recipients, 48 (19.5%) were diagnosed as TR. Overall, 26 (10.6%) were antibody-mediated rejection, 18 (7.3%) were T-cell–mediated rejection, and 4 (1.6%) were mixed form. Their levels of serum creatinine and cystatin C seem to be higher compaed with non-TR at same time within 24 months, indicating the adverse effect of TR on renal function . Of transplantation-related variables, HLA-B mismatch, HLA-DQ mismatch, and HLA-Type II showed significant correlation with TR . Unexpectedly, several parameters of preoperative laboratory workup showed robust association with TR. The uric acid (UA) (P = 0.004), platelet (PLT) (P = 0.034), white blood cell (WBC) (P = 0.003), and absolute neutrophil count (ANC) (P = 0.003) showed statistical significance of association with TR. All characteristics of transplants and their relevance to TR are shown in The median (range) body mass index (BMI) of recipients was 21.5 (13.7–38.2) kg/mvia ROC curve and corresponding Jordan index (P = 0.002), preoperative UA , PLT , WBC , and absolute lymphocyte count (ALC)  of recipients demonstrated the potential risk for TR. Meanwhile, HLA-B mismatch  and HLA-DQ mismatch  might be risk factors for TR. Previous kidney transplantation did not acquire statistical assignment, perhaps due to the small sample (n = 11).Optimal cutoff values of meaningful continuous variables in preliminary correlations analyses were confirmed an index Figure 1P = 0.040), platelet > 185 × 109 , ANC > 5.0 × 109 , and HLA-DQ mismatch  still showed statistical relevance and could be considered as the independent predictors for TR (P < 0.001) (P < 0.001) , we also noted that several unexpected indicators from hemato-biochemical work-up of recipients showed statistical significance in the regression model. Precisely, UA with cutoff value of 400 μmoI/L, PLT with 185 × 109, and ANC with 5.0 × 109 exhibited robust association with TR and maybe considered as the risk factors for it.Re-transplantation, grafts from deceased donors, and high level of panel-reactive antibody (PRA) have been reportedly associated with increased risk of graft loss and rejection after transplantation , 13. In P = 0.037; and OR, 2.164; 95% CI, 1.018–4.599; P = 0.045, respectively) . To test potential non-linearity, RCS regression models were used, which showed that the risk of rejection was relatively flat until UA was around 450 μmoI/L and then began to increase rapidly afterward, supporting the association between UA and TR. However, the comprehensive effect of UA on graft outcomes still remains controversial in published studies  for the publication of any potentially identifiable images or data included in this article. This study was approved by the Institutional Ethical Committee of the West China Hospital.FXZ: project development, data collection, data analysis, and manuscript writing. JL: project development, data analysis, and data collection. YX: data analysis. FZ: data analysis. KW: data collection. WW: data collection. JY: project development and data analysis. TL and XW: project development, data analysis, manuscript correction, and manuscript editing. All named authors meet the ICMJE criteria for authorship in this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.


Intensivists target different blood pressure component values to manage intensive care unit (ICU) patients with sepsis. We aimed to evaluate the relationship between individual blood pressure components and organ dysfunction in critically ill septic patients.In this retrospective observational study, we evaluated 77,328 septic patients in 364 ICUs in the eICU Research Institute database. Primary exposure was the lowest cumulative value of each component; mean, systolic, diastolic, and pulse pressure, sustained for at least 120 min during ICU stay. Primary outcome was ICU mortality and secondary outcomes were composite outcomes of acute kidney injury or death and myocardial injury or death during ICU stay. Multivariable logistic regression spline and threshold regression adjusting for potential confounders were conducted to evaluate associations between exposures and outcomes. Sensitivity analysis was conducted in 4211 patients with septic shock.Lower values of all blood pressures components were associated with a higher risk of ICU mortality. Estimated change-points for the risk of ICU mortality were 69 mmHg for mean, 100 mmHg for systolic, 60 mmHg for diastolic, and 57 mmHg for pulse pressure. The strength of association between blood pressure components and ICU mortality as determined by slopes of threshold regression were mean (− 0.13), systolic (− 0.11), diastolic (− 0.09), and pulse pressure (− 0.05). Equivalent non-linear associations between blood pressure components and ICU mortality were confirmed in septic shock patients. We observed a similar relationship between blood pressure components and secondary outcomes.Blood pressure component association with ICU mortality is the strongest for mean followed by systolic, diastolic, and weakest for pulse pressure. Critical care teams should continue to follow MAP-based resuscitation, though exploratory analysis focusing on blood pressure components in different sepsis phenotypes in critically ill ICU patients is needed.The online version contains supplementary material available at 10.1186/s13613-023-01101-4. Despite extensive evidence-based management guidelines, sepsis and associated septic shock remain common and deadly , 2. HealMean arterial pressure (MAP) is a widely accepted target as a clinical determinant of organ perfusion –11. The We have previously reported that risks of mortality and AKI become apparent at MAP of 85 mmHg and increase progressively at lower thresholds in septic ICU patients . HoweverWe conducted a retrospective analysis using the eICU Research Institute (eRI) database that consists of 3.3 million unique ICU admissions from 364 ICUs across the US from 2004 to 2016 , laboratWe included adult ICU patients (aged ≥ 18 years) with non-surgical sepsis diagnoses from the eRI database. We first identified patients with valid sex and admission diagnosis from the database. We excluded patients who were discharged from ICU within 24 h as organ dysfunctions of these patients were more likely caused by hypotensive events before ICU admission. Patients who underwent surgery before ICU admission were not included as intraoperative blood pressure records were not available. Sepsis patients were defined as those with infection and overall SOFA score ≥ 2 on the day of admission /3. We set the following plausibility filters to remove artifacts: SBP ≥ 300 or ≤ 20 mmHg, SBP ≤ DBP + 5 mmHg, or DBP ≥ 225 mmHg or ≤ 5 mmHg, or MAP ≥ 250 mmHg or ≤ 10 mmHg consistent with prior published analyses , 15, 19.Potential confounders were defined a priori based on demographics and clinical variables that might affect the incidence of hypotension in ICU and organ dysfunction. Age, gender, ethnicity, BMI, APACHE IVa score, admission type, admission year, hospital bed size, medications before admission , laboratory measurements on ICU admission , past history , and ventilator status on the day of admission were collected and used for the analysis.The primary outcome was ICU mortality assessed from 24 h after admission to ICU discharge. To account for competing risks, we defined secondary outcomes as a composite outcome of AKI and death and a composite outcome of myocardial injury and death . DiagnosWe assessed the univariable relationships between the lowest value maintained for ≥ 120 min and primary and secondary outcomes for each blood pressure component. The entire population was ordered by exposure level from lowest to highest and divided into 100 bins. The proportion of patients having any outcome was calculated for each bin, and a 5-bins central simple moving average was calculated. We conducted multivariable thin plate logistic regression splines adjusting for the previously listed confounders using smooth functions of exposure, age, BMI, and APACHE IVa score. Smoothness parameters were optimized using generalized cross-validation. The probability of developing each outcome across the exposure level was predicted, conditioning on the other variables as either mean or reference values. Multivariable threshold logistic regression with a hinge effect of threshold was conducted to estimate component-specific threshold pressures. We assumed the slope for the log-odds of outcomes to be zero in the higher range, suggesting that the risk of outcomes first decreased as blood pressure increased and then reached a plateau at the threshold. The strength of association between blood pressure component and outcome was evaluated by the absolute value of the slope before the estimated threshold. We visualized estimated probability of outcomes across the standardized blood pressure components.Optimal resuscitation methods could be different in patients with septic shock according to the current Surviving Sepsis Campaign Guidelines suggesting the use of several advanced measurements for septic shock, including passive leg raising combined with cardiac output measurement, fluid responsiveness against stroke volume, systolic pressure, and pulse pressure, and periodical capillary refill time monitoring . TherefoThe change-point determined by the threshold logistic regression was used as a threshold to calculate time-weighted average for each blood pressure component. Association between time-weighted average and ICU mortality was also evaluated using multivariable thin plate logistic regression adjusting for the same variables. Predicted probability of ICU mortality with 95% confidence interval was visualized using estimated regression coefficients.To evaluate the risks of ICU mortality for abnormal pressures quantitatively, the overall population was categorized into several groups by exposure levels and multivariable logistic regression was conducted to estimate the odds ratio (OR) for the primary outcome. A group of patients with physiologically normal values for each blood pressure component was set as a reference: MAP ≥ 75 mmHg, SBP ≥ 110 mmHg, DBP ≥ 60 mmHg, and 40 ≤ PP < 50 mmHg, respectively. The odds of ICU mortality in the reference groups were compared to that of other groups using different cut-off values. As the number of events in subgroups were limited, a subset of confounders including age, BMI, APACHE IVa score, ethnicity, admission type, admission year, hospital bed size, hemoglobin, albumin, WBC, BUN, and lactate were adjusted for.The heterogeneity of effects of hypotension exposure on ICU mortality was evaluated in the following subgroups: age , average vasopressor rate in norepinephrine equivalents , ventilator status (yes or no), past history of cancer (yes or no), and admission type . The cumulative amount of dopamine, dobutamine, norepinephrine, epinephrine, phenylephrine, and vasopressin was collected and converted to norepinephrine equivalent doses . Averagehttps://github.com/philips-labs/Hypotension_Septic_ICU_Patients_Publication.git.Data were analyzed using Python version 3.7.6 and R 4.1.2 software . All code and documentation are available online at We identified 77,328 ICU patients with sepsis who met all inclusion and exclusion criteria for the primary outcome analyses  ± SD (1 and − 1 on the x-axis) for each blood pressure component was as follows: 62 ± 10 mmHg for MAP, 94 ± 14 mmHg for SBP, 48 ± 9 mmHg for DBP, and 35 ± 12 mmHg for PP in overall sepsis cohort and 56 ± 8 mmHg for MAP, 84 ± 10 mmHg for SBP, 44 ± 8 mmHg for DBP, and 28 ± 10 mmHg for PP in septic shock patients. The estimated change-points for the risk of ICU mortality were 69 mmHg for MAP, 100 mmHg for SBP, 60 mmHg for DBP, and 57 mmHg for PP, respectively (see Additional file Figure Associations of time-weighted average under component-specific threshold with ICU mortality are shown in Fig. Relationships between exposure categories and ICU mortality are shown in Table The results of subgroup analysis are shown in Additional file While hypotension avoidance is considered vital, blood pressure management can vary among clinicians and hospitals focused on achieving different blood pressure component targets. We investigated whether individual blood pressure components were differently associated with ICU mortality, AKI, and myocardial injury in septic ICU patients. Across all blood pressure components, we found statistically significant associations between the lowest pressure sustained for 2 h and the risk of worse outcomes. However, the strength of association of blood pressure components was higher for MAP, SBP, DBP and PP in descending order. Detrimental effects of hypotension, as well as the order of strength among components, were also confirmed in time-weighted average analysis accounting for the difference in ICU length of stay across patients. Our findings are consistent with previous studies conducted in the ICU and operating room showing the association between increasing hypotension and the risk of organ dysfunction , 25, 26.Globally, MAP has been used as the main target of sepsis management since it is a key determinant of organ perfusion pressure , 7, 27. Ahuja and colleagues performed blood pressure components analysis for the surgical patients and found a similar increase in risk associated with all components, although the change points identified in that study for important blood pressure thresholds were slightly lower for each of the components . The preThe current Surviving Sepsis Campaign Guidelines recommend titrating vasopressors to a minimum MAP ≥ 65 mmHg . We founWe applied stringent criteria to exclude patients with infrequent BP measurements. A little less than 50% of the blood pressure readings were invasive measurements in the current study. Although there may still exist measurement errors, the risk of information bias is expected to be lower than the previous studies in the ICU, which have not reported the proportion of invasive and non-invasive measurements , 10.The present study has several limitations. First, the retrospective and observational nature of the study design leaves it open to potential confounding bias. Although we adjusted for all measured variables in multivariable thin plate logistic spline and threshold logistic regression, we could not control for unmeasured potential confounders such as ejection fraction, cardiac index, and stroke volume variation, as these variables were not included in the database. Second, the incidence of ICU mortality and secondary outcomes was low in our study. Exclusion criteria to remove patients with less than 24 h of stay and DNR status could lead to low ICU mortality. Organ dysfunction or death of patients with short ICU length of stay is likely caused by various factors preceding ICU admission rather than ICU hypotension. DNR patients usually do not receive hemodynamic management and they may be extremely hypotensive for long periods without any intervention. Thus, we believed these exclusion criteria were needed for valid analysis. The eRI database's mortality was slightly lower than other large databases as it was the only dataset that included patients from community hospitals who might be less severe than those treated in tertiary care hospitals . HoweverIn septic ICU patients, lower level of all blood pressure components including mean, systolic, diastolic and pulse pressure were associated with higher mortality, acute kidney injury and myocardial injury. The strength of this association was the highest for mean pressures followed by systolic and diastolic and least for pulse pressure. We estimated the change-points for the risk of ICU mortality were 69 mmHg for mean, 100 mmHg for systolic, 60 mmHg for diastolic, and 57 mmHg for pulse pressure. Knowing blood pressure components are closely related we recommend intensivists should continue to follow current MAP based guidelines for sepsis resuscitation. Future work should focus on identifying individualized blood pressure component targets for critically ill patients.Additional file 1. Additional Results.


Dasatinib, which is used to treat treating chronic myeloid leukemia, induces increases in blood lymphocytes during the treatment. In addition, neutrophil–lymphocyte count ratio (NLR) is associated with the related to development of chronic kidney disease (CKD). However, it has not been reported whether development of CKD during long-term dasatinib treatment is related to lymphocyte count or NLR. This study aimed to reveal the relationship between CKD and lymphocyte count or NLR during long-term dasatinib treatment.A retrospective study was conducted in patients treated with dasatinib for 6 months or longer. Risk factors for CKD development were explored using multivariate analysis. Changes in maximal lymphocyte count and NLR over time were examined separately.n = 8) and No CKD group (n = 25) who received dasatinib were enrolled. In univariate analysis, significant differences between the groups were observed in maximal lymphocyte count, lymphocytosis, age, and estimated glomerular filtration rate at baseline. As the factor independently associated with the development of CKD, maximal lymphocyte count  was identified. In this analysis, age had borderline significance ]. After 6 months of dasatinib therapy, lymphocyte count was significantly lower in CKD group  than in the No CKD group [3501 (966‒7888)/μL] (p = 0.020). However, no significant difference in lymphocyte count was observed between the groups at the last follow-up. During the study period, the median NLR in the No CKD group fluctuated between 1.11 and 1.42, and median NLR in CKD group was increased from 1.13 to 2.24 between after 6 months of dasatinib therapy and the last follow-up.A total of 33 patients in CKD group (The development of CKD during dasatinib therapy was associated with lower maximal lymphocyte counts. In contrast, the higher levels of lymphocytes induced during dasatinib treatment may prevent CKD progression. Dasatinib, a targeted inhibitor of oncogenic breakpoint cluster region-Abelson leukemia virus (BCR-ABL) tyrosine kinase, has profoundly improved the outcome of chronic myeloid leukemia (CML) and Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph-ALL). In patients with CML, near-normal life expectancy is possible by treatment with dasatinib as first-line therapy or as second-line treatment in patients intolerant or resistant to other tyrosine kinase inhibitors (TKIs) –3. In paSince neutrophil–lymphocyte count ratio (NLR) has been associated with inflammatory status, higher NLR is a potential indicator of deterioration of kidney function in patients with CKD . In addiThe objectives of this study were to reveal whether increases in lymphocytes and/or reduction of NLR is associated with development of CKD in patients on long-term dasatinib treatment.The present study was a secondary analysis based on the data collected in our previous study that examined the risk factors of creatine kinase elevation during dasatinib treatment . A retroThe following data were retrieved from electronic medical records between baseline and the last follow-up as long as the patient remained in the present study: demographics; primary diagnosis; complete blood count; blood chemistry including albumin at baseline; kidney function test of creatinine and estimated glomerular filtration rate (eGFR); presence of CKD at baseline; concomitant use of known nephrotoxic medications ; previous use of other TKIs; development of CKD during the periods in patients received other TKIs prior to dasatinib; lymphocytosis; and onset of adverse events. In addition, the ratio of maximal to baseline lymphocyte count was calculated. In the present study, GFR was estimated using the Modification of Diet in Renal Disease equation that has been shown to provide a more accurate estimation in Japanese . In patiIn the analysis of development of adverse events, lymphocytosis, lymphocyte counts, and NLR, the study period was defined as the duration from after 4 weeks (4-weeks) of dasatinib treatment to the last follow-up for patients who did not develop CKD. For patients who developed CKD, the duration from after 4 weeks of dasatinib therapy to the onset of CKD was included.A complete blood count was performed at least once a week for the first 1 month, and once every 1 to 12 weeks thereafter. In all patients, chest X-ray was performed prior to dasatinib treatment and during treatment. While patients were administered a standard dose of dasatinib, initial and maintenance dosages with modification were considered in special populations, such as elderly individuals. Follow-up interval, time of chest X-ray examination, and interruption or dosage reduction of dasatinib therapy due to adverse events were decided at the discretion of the treating physician.2 persisting for 90 days or longer. In patients treated with other TKIs prior to dasatinib, development of CKD during the periods in which other TKIs were administered was examined separately.Since serum creatinine fluctuates greatly, median serum creatinine level was calculated for 7 days before starting dasatinib therapy, and the median level was defined as baseline serum creatinine. Development of CKD was defined as an estimated eGFR less than 60 mL/min/1.73 mIn the analysis between development of CKD and lymphocyte count or NLR, changes in the maximal lymphocyte count and NLR over time were separately examined at baseline, 4-weeks, after 6 months (6-months), and at the last follow-up of dasatinib treatment. NLR was obtained by dividing the absolute blood neutrophil count by the lymphocyte count for each complete blood count monitoring during follow-up. Median lymphocyte count and NLR were calculated.9/L on 2 or more occasions after 4 weeks of dasatinib therapy, according to previous reports  at baseline and lower maximum lymphocyte count [3279 (1246‒4183) (/µ/L)] during the examined period, compared to the No CKD group. In addition, 17 patients (68%) without CKD developed lymphocytosis, the rate of which was significantly higher than that of patients with CKD (p = 0.012). The two groups did not differ significantly in sex ratio, serum albumin, creatinine, development of adverse events, concomitant nephrotoxic agents, hypertension, diabetes mellitus, previous use of other TKIs, Sokal score, the ratio of maximal-baseline lymphocyte count and NLR. However, a significantly higher frequency of lymphocytosis was observed in No CKD group than in CKD group (p = 0.018)  years], lower eGFR  than in the No CKD group [3501 (966‒7888)/μL) .There was a strong and significant rank correlation between maximal and median lymphocyte counts  in this study than in previous reports  in patients without CKD. Furthermore, 88% of 33 patients in this study had baseline CKD stage 2. Therefore, the difference in baseline kidney function may be associated with the higher rate of CKD development herein. Nevertheless, maximal lymphocyte count was identified rather than eGFR at baseline.Caution should be exercised to generalize our findings. The eGFR at baseline was significantly lower in CKD group than in the No CKD group. Because of the small number of patients with CKD development, 2 covariates, the maximal lymphocyte count and age, were identified in multivariate analysis using the stepwise method. Eventually, eGFR at baseline was not excluded as a risk factor for CKD. Furthermore, median decrease in the eGFR between baseline and the last follow-up was 15% in CKD group. In this analysis, a subtle reduction was included due to the assessment of deterioration of CKD stage from 2 to 3a. In addition, the frequency of CKD occurrence was higher in this analysis 24%) than that in previous reports (5‒7%) [% than thIn general, since kidney structure and function are associated with age-related changes, eGFR decreases with advancing age. However, in our study, lower maximal lymphocyte count was an additional risk factor for CKD. In contrast, a higher lymphocyte count may prevent CKD progression. In this regard, our findings are consistent with those of a previous report .Since NLR has been associated with inflammatory status, NLR increases with CKD stage deterioration . In addiHerein, 2 patients, an 86-year-old woman and a 70-year-old woman, received dasatinib at doses of 20 mg and 50 mg daily, respectively. While the patient who received dasatinib at a dose of 50 mg daily did not develop CKD, the other patient who received dasatinib at a dose of 20 mg daily developed CKD. Recently, Naqvi and colleagues reported that during long-term follow-up, low-dose dasatinib (50 mg daily) remained effective and safe in patients with newly diagnosed chronic-phase CML . In the The molecular mechanisms underlying CKD in patients treated with dasatinib have not yet been sufficiently elucidated. However, since dasatinib is involved with the platelet-derived growth factor and Src family kinases other than BCR-ABL, a possible mechanism of nephrotoxicity during dasatinib treatment is the disruption of the vascular endothelial growth factor signalling pathway through inhibition of the Src family kinases , 20.The present study has several limitations. First, the risk factors for CKD were assessed using maximal lymphocyte count because maximal lymphocyte count was strongly correlated with lymphocytosis during the study period . TherefoIn conclusion, the development of CKD during dasatinib therapy was associated with lower lymphocyte counts. Therefore, the higher levels of lymphocytes induced by dasatinib treatment may prevent CKD progression.