Objective: The non-invasive estimation of central systolic blood pressure (cSBP) is increasingly performed using new devices based on various pulse acquisition techniques and mathematical analyses. These devices are most often calibrated assuming that mean (MBP) and diastolic (DBP) BP are essentially unchanged when pressure wave travels from aorta to peripheral artery, an assumption which is evidence-based. We tested a new empirical formula for the direct central blood pressure estimation of cSBP using MBP and DBP only (DCBP = MBP2/DBP).Methods and Results: First, we performed a post-hoc analysis of our prospective invasive high-fidelity aortic pressure database . The cSBP was 146.0 ± 31.1 mmHg. The error between aortic DCBP and cSBP was −0.9 ± 7.4 mmHg, and there was no bias across the cSBP range (82.5–204.0 mmHg). Second, we analyzed 64 patients from two studies of the literature in whom invasive high-fidelity pressures were simultaneously obtained in the aorta and brachial artery. The weighed mean error between brachial DCBP and cSBP was 1.1 mmHg. Finally, 30 intensive care unit patients equipped with fluid-filled catheter in the radial artery were prospectively studied. The cSBP (115.7 ± 18.2 mmHg) was estimated by carotid tonometry. The error between radial DCBP and cSBP was −0.4 ± 5.8 mmHg, and there was no bias across the range.Conclusion: Our study shows that cSBP could be reliably estimated from MBP and DBP only, provided BP measurement errors are minimized. DCBP may have implications for assessing cardiovascular risk associated with cSBP on large BP databases, a point that deserves further studies. In the recent years, there has been a growing interest toward improving cardiovascular risk estimation using central (aortic root) blood pressure (BP) , 2. It iInvasive recordings at the central level provide the gold-standard measure of true aortic root cSBP, but they are limited to patients requiring catheterization and thus not ethically nor technically feasible in the general population. There has been an ongoing development of new devices to non-invasively estimate cSBP using various waveform acquisition techniques  –27. Some2/DBP  SBP:2/aortic DBPDCBP = aortic MBPThe first aim of our study was to establish the proof-of-concept by studying the accuracy and precision of this DCBP formula at the aortic root level.:The same DCBP formula may well also apply at the peripheral  level, given that MBP and DBP values only slightly differ as pressure travels from aorta to brachial and radial artery2/brachial DBPDCBP = brachial MBP2/radial DBPDCBP = radial MBPThe second aim of our study was to validate these DCBP formulas using MBP and DBP values that were invasively obtained at the brachial and radial artery level.post-hoc analysis of our prospective high-fidelity aortic pressure database (n = 31), subjects with known hypertension (n = 46), grafted hearts (n = 18), idiopathic dilated cardiomyopathy (n = 14), and miscellaneous cardiac diseases, mainly coronary artery disease (n = 30). The invasive BP, namely the time-averaged MBP, cSBP, and DBP were automatically measured.The DCBP formula was tested using a database . All invn = 64). As also previously discussed . All patients or their next of kin were informed and consented to participate. We included 30 consecutive spontaneously breathing patients who were hemodynamically stable and already equipped with a fluid-filled catheter in the radial artery. Only spontaneously breathing patients were included to ensure high-quality pressure signal of carotid tonometry . ExclusiThe theoretical influences of isolated or combined  calibration errors in DBP or MBP on the DCBP-derived estimation of cSBP were studied. The following example illustrates the way calculations were performed: as compared to intra-arterial BP values, a +5% overestimation of MBP together with a +10% overestimation of DBP resulted in a +0.2% overestimation of cSBP by the formula DCBP [(1.05 × 1.05)/1.10 =1.0025]. The DCBP-derived estimates of cSBP were deemed reasonably acceptable from a clinical standpoint if the associated percentage error ranged from −10 to +10%.The normal distribution of data was checked by the Kolmogorov–Smirnov test. Continuous variables were summarized as mean ± standard deviation (SD) or median [interquartile range], and categorical variables as counts (percentages). Correlations between variables were assessed by Pearson's correlation coefficient. Comparison between men and women were performed using Student's unpaired t-test. The error was calculated as the difference between DCBP and cSBP and was expressed in mmHg. The accuracy (mean error) and precision (SD) of DCBP estimate were calculated. As previously recommended , the difPatients were mostly men (78%) and were middle-aged (49 ± 12 years) . The cSB2 = 0.95, p < 0.001  , and it slightly decreased with age .There was a strong linear relationship between DCBP and cSBP [r < 0.001 ]. As com = 0.69) . The % e = 0.69) . The numThe invasive brachial pressures, the cSBP, and the DCBP calculated from brachial pressures are indicated in 2 (Patients were mostly men (77%), with a mean age of 62 ± 14 years and a median body mass index of 22 –26 kg/m22 . Two pat2 = 0.90, p < 0.001 . The % error was −0.2 ± 4.8% of cSBP (range: from −11.1 to 8.2%)  or by age .There was a strong linear relationship between DCBP and cSBP [r < 0.001 ]. As com < 0.001 . The preto 8.2%) . The numResults of the sensitivity analysis are given in 2/DBP. As compared with methods currently used, there is no need for any supplementary device or waveform recording.Our work showed that cSBP may be estimated from peripheral MBP and DBP values only. The cSBP estimation is based on our new formula: DCBP = MBPTo evaluate any new method, it is important to identify the sources of errors which might impact the accuracy of the results , 22. Forpost-hoc analysis of our previously published database  as input factors. In this setting, measurement and calibration errors were more likely to impact accuracy and precision of DCBP. Due to its anatomical proximity and relatively similar characteristics, the carotid pressure is reported to be very similar to the aortic root pressure and often used as a non-invasive surrogate for central pressures , 33. As The high accuracy and reasonably good precision of DCBP may be explained by the fact that our study design minimized additional sources of error. First, when validating DCBP at the aortic level, we used data from high-fidelity pressure catheters as they must be preferred for validation studies –27. Althn value >85 has been recommended for this type of validation study  DCBP formula allows a simple and easy estimate of cSBP without requiring any supplemental device to record waveforms; and hence prevents the unavoidable technical error specifically and potentially associated with each type of device. (2) The proof of concept was established by studying 139 patients, which is a high number of patients for an invasive study, also bearing in mind that a on study ; and (3)on study . The fieThe limitations of our study must be also discussed. DCBP only estimated cSBP value. For this reason, artery tonometry or other waveform transfer function-based methods remain invaluable to estimate the entire pressure wave shape and to document other valuable arterial indices . Studied patients were mostly middle-aged or elderly men. Although the mean error was similar in men and women and only mildly influenced by age, further studies are needed in other populations to cover the overall spectrum of clinical conditions, especially in women and younger patients. The majority of the subjects entering the proof-of-concept study had their cSBP ≥ 140 mmHg at the time of the catheterization, although only one third had known hypertension. This may be explained by the mild sympathetic stimulation know to be often associated with left heart catheterization . It is lThe implications of our study should be discussed. The routine measurement of brachial BP is fundamental to assess the general health and cardiovascular risk of patients, including the diagnosis of hypertension and its subsequent management. The DCBP formula may help to easily estimate cSBP in clinics or help to assess the cardiovascular risk in patients from large clinical databases, both retrospectively and prospectively, provided measurement errors of MBP and DBP are minimized. The evidence supporting a tighter association of cardiovascular end points with central than peripheral BP remains controversial –9. This 2/DBP) in cases where BP measurement errors are minimized. This may have implications for assessing cardiovascular risk associated to cSBP on large BP databases, a point that deserves further studies.In conclusion, our study showed that cSBP could be estimated from peripheral MBP and DBP using DCBP . The patients/participants provided their written informed consent to participate in this study.DC: conception of the study and of the original DCBP formula, data acquisition, calculations, and writing. SM, OH, J-LT, XM, and FM: discussion of the results, analysis, and writing. MJ: data acquisition, calculations, and writing. All authors contributed to the article and approved the submitted version.SM is the owner of Pulse Wave Consulting, a company providing consulting services to the medical devices industry such as Omron and MESI Ltd. This is outside the submitted work. OH had a paid lecture for Cheetah medical and is member of the scientific board of AMOMED. This is outside the submitted work. J-LT reports personal fees from Getinge. This is outside the submitted work. XM reports research grants, personal fees and non-financial support from Pulsion Medical Systems, and research grants and non-financial support from Baxter. This is outside the submitted work. FM is the founder and managing director of MiCo, a Swiss consulting and research company. This is outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Arterial stiffness was measured by carotid‐femoral pulse wave velocity (PWV), and cIMT by carotid ultrasound. 24‐h ABPM was recorded. The middle‐aged stroke patients had higher prevalence of smoking, hypertension, diabetes mellitus, metabolic syndrome and hypercholesterolemia, and had higher PWV and cIMT . In multivariable linear regression analyses adjusted for sex, BMI, smoking, diabetes mellitus, total cholesterol, high‐density lipoprotein cholesterol, triglycerides, eGFR, systolic BP and concomitant antihypertensive treatment, 1SD (4.4 years) higher age was associated with higher PWV  in the younger group, and with higher mean cIMT  in the middle‐aged group. In the middle‐aged group, 24‐h pulse pressure had a significant association with PWV , while the association with cIMT was attenuated . 24‐h diastolic BP was associated with higher cIMT in the middle‐aged group , but not with PWV in either age groups. Among ischemic stroke patients < 60 years, higher age was associated with increased arterial stiffness for patients up to age 44 years, and with cIMT in middle‐aged patients. 24‐h pulse pressure was associated with arterial stiffness, and 24‐h diastolic BP was associated with cIMT only in middle‐aged patients.The impact of age and 24‐h ambulatory blood pressure (ABPM) on arterial stiffness and carotid intima‐media thickness (cIMT) in ischemic stroke patients younger than 60 years of age is poorly explored. A total of 385 acute ischemic stroke patients  were prospectively included and grouped in younger (15–44 years,  Body mass index (BMI) > 30 kg/m2 was considered as obesity.Venous blood samples were drawn for analysis of fasting serum lipids and glucose. Diabetes mellitus was defined as history of diabetes, use of anti‐diabetic treatment or fasting blood glucose ≥7 mmol/L. Metabolic syndrome was defined according to the modified American Heart Association/National Heart, Lung, and Blood Institute criteria.2.4t test and chi‐square test as appropriate. The association of age with traditional CV risk factors and arterial health parameters (PWV and cIMT) was tested in univariate and multivariate linear regression analyses in both age groups separately, and reported as standardized β‐coefficients and p‐values. Multivariate models were adjusted for sex, BMI, smoking, diabetes mellitus, hypertension, total cholesterol, HDL cholesterol, triglycerides, eGFR, systolic BP and concomitant antihypertensive treatment. A p value < 0.05 was taken as statistical significance in all analyses.Analyses were performed using the IBM SPSS statistical program version 26 . The data is presented as mean ± standard deviation for continuous variables and as percentages for categorical variables. Patients were grouped as young (15–44 years) or middle‐aged (45–60 years), and inter‐group comparison was done by independent student 33.1p < 0.05) . Ninety‐three 24%) patients were younger and 292 (76%) were middle‐aged. The middle‐aged group had higher prevalence of traditional CV risk factors including smoking, hypertension, metabolic syndrome, diabetes mellitus and hypercholesterolemia compared with the younger group  Table . Similar4% patien3.22 = 0.46, p < .001) in the younger group, and with higher mean cIMT  in the middle‐aged group (Table Both mean PWV and cIMT were higher in the middle‐aged group than in the younger group Table . Increas3.33.3.1p < .001) and cIMT  in middle‐aged patients, but not in younger patients . In multivariable linear regression models adjusted for sex, BMI, smoking status, diabetes mellitus, hypertension, total cholesterol, HDL cholesterol, triglycerides, eGFR and concomitant antihypertensive treatment, 24‐h PP had a significant association with PWV in middle‐aged patients, but the association with cIMT was attenuated in this group  and the middle‐aged group , but the association with cIMT was significant only in the middle‐aged group , not in the younger group . In multivariable‐adjusted models, 24‐h diastolic BP was not associated with PWV in either group, but retained a significant association with cIMT in middle‐aged patients . Abbott and coworkers showed that the impact of BP and smoking declined by aging, but diabetes continued to be a risk factor at all ages.Furthermore, age had a closer correlation with PWV, a marker of arteriosclerosis in younger patients, but with cIMT, a marker of atherosclerosis in middle‐aged patients, and this correlation was independent of hypertension and other established CV risk factors. Indeed, in a community dwelling cohort of men and women aged 20–101 years, it was shown that among individuals > 40 years, central arterial stiffening occurred independently of BP levels.The changing pattern of BP with increasing age is widely known. The best predictor of CV disease shifts from diastolic BP to systolic BP and then to PP in parallel with increasing age, probably due to the fact that large artery stiffening and subsequent increase in PP is a phenomenon of higher age, while the resistance of peripheral small arteries (diastolic BP) is a dominant risk factor at younger age.Current study has some limitations. This analysis was based upon cross‐sectional data. Whether increased arterial stiffness is the cause or a consequence of hypertension, and to what extent age modulates this relationship, should be explored in larger prospective longitudinal studies in future. However, Mendelian randomization  analyses in recent genetic studies indicate a bi‐directional causal association between BP and arterial stiffness.5Middle‐aged ischemic stroke patients had significantly higher burden of concomitant comorbidities and markedly increased arterial stiffness indices compared to younger patients. Age was strongly associated with arterial stiffness in younger patients, but its impact on arterial stiffness declined in middle‐aged patients. 24‐h pulse pressure was more closely related to arterial stiffness in middle‐aged patients. These results highlight the importance of hypertension, and the associated arterial damage in middle‐aged ischemic stroke survivors. Hence, every effort should be made to control cardiovascular risk factors, particularly hypertension, as early as possible in order to reduce the risk of premature arterial aging and early vascular events.There are no conflicts of interest for any authors.Sahrai Saeed, Ulrike Waje‐Andreassen and Peter M. Nilsson contributed to study conception and design and drafted the paper. Sahrai Saeed, Ulrike Waje‐Andreassen, Halvor Naess and Annette Fromm contributed to data acquisition. All authors contributed to the data interpretation, critically revised the paper and gave final approval.


A patient with sinus node dysfunction (SND) developed atrial arrhythmias that were abolished after avoidance of nonsteroidal anti-inflammatory medication and by the institution of a deliberate, modest increase in blood pressure, suggesting that there was a vascular component to the rhythm disturbance. Published anatomical evidence for a unique sinus node microcirculation substantiates the premise that SND may be sensitive to arterial flow. Because physicians have been unaware of the presence of a unique sinus node microcirculation, recognition of its presence may alter the approach to treatment of patients with SND and atrial arrhythmias, particularly in the elderly and those with diabetes. Sinus node dysfunction (SND) is likely multifactorial in origin. Two recent reviews of SND and atrial arrhythmias emphasize the role of fibrosis in the structural and functional integrity of the sinus node (SN).3 Not considered in these reviews is the potential contribution of microvascular disease to the pathogenesis of SND.Sinus node dysfunction (SND) or formerly sick sinus syndrome increases with aging, more than doubling for individuals aged 75 to 84 years compared to those a decade younger.The following case report is presented to illustrate the potential reversibility of atrial arrhythmias associated with SND and to raise awareness of the SN microcirculation. Although these consequences of therapy with NSAIDs are recognized in patients with congestive heart failure, hypertension, and coronary artery disease, they have not previously been known to be associated with worsening SND and atrial arrhythmias.An 84-year-old retired physician (nephrology) had a 7-year history of SND with relative bradycardia, premature atrial contractions (PACs), sinus pauses, and short runs of atrial tachycardia that interfered with exercise tolerance. Initial assessment included a stress test and echocardiogram, which were unremarkable. There was no evidence for coronary artery disease nor was there known chronic inflammation. Mild hypertension was controlled with losartan and hydrochlorothiazide. The patient began using nonsteroidal anti-inflammatory medications (naproxen 220 mg) daily for treatment of knee arthritis and she observed an increase in the frequency of arrhythmia thereafter. Cessation of the drug improved the rhythm disturbance and rechallenge caused resumption of the rhythm disturbance. The negative side effects of non-steroidal anti-inflammatory drugs (NSAIDs) in patients with cardiovascular disease are well known to clinicians. Inhibition of cyclo-oxygenase enzymes results in diminished production of prostacyclin, renal afferent arteriolar constriction, and subsequent salt retention. Reduction in prostacyclin causes lowered nitric oxide and endothelial cell dysfunction.The patient also noted that vasodilation from being in hot weather or while bathing was associated with a documented fall in blood pressure (100-105/60-65 mmHg) and the subsequent instigation of PACs, pauses, and runs of atrial tachycardia. An inadvertent increase in the dose of losartan likewise caused lower blood pressure (~110/65 sitting) and a marked increase in the frequency of the rhythm disturbance. Ambulatory ECG recordings during a 2-week period showed thousands of events. Heart rate varied from 44 to 180 beats per minute. The patient then adjusted her blood pressure medications and salt intake to keep the systolic blood pressure at about 130 to 135/75 mmHg. Thereafter she rarely experienced PACs. Resting heart rate rose from about 58 to approximately 68 beats per minute. Both exercise ability and heat tolerance improved considerably and have been sustained. Previous suggestions that she might require catheter ablation of an arrhythmogenic site or need a pacemaker were abandoned. A large glomerular capillary loop with an afferent and efferent arteriole is clearly visible in the photomicrograph  might have a unique microcirculation that is particularly sensitive to changes in arterial perfusion. Her familiarity with the unique renal microcirculation stimulated this consideration. Despite the SN’s primacy as the pacemaker of the heart, surprisingly little is known about the microcirculation of the structure and how it differs from the adjacent atrium. Although it is well known that the sinus node artery arises from both coronary arteries, the arteriolar and capillary supply to the SN has been investigated in only a few studies. India ink injections of post-mortem normal human hearts demonstrated peripheral vascular networks of arterioles and capillary glomeruli that were different from the adjacent atrial myocardium.crograph . This is In the case of this patient, improvement in resting heart rate as well as in the response to adrenergic stimulation with exercise likely diminished the emergence of ectopic beats.The association of SND with atrial tachycardia, atrial ectopy, and atrial fibrillation is well recognized. The chronotropic incompetence of SND may permit firing of alternative impulses arising from the pulmonary vein or coronary sinus.The case study reported herein illustrates several important points. Relative hypotension, particularly in the setting of vasodilatation, was associated with chaotic atrial rhythm disturbances. Use of NSAIDs exaggerated the susceptibility to arrhythmia. Adrenergic stimulation during exercise and from a reduction in blood pressure itself did not result in an appropriate increase in sinus node driven impulses but did trigger output from other sites.These clinical findings as well as previous anatomical evidence for a SN microcirculation with capillary glomeruli, support a potential critical role for the microcirculation of the SN. That the presence of a unique SN microcirculation has not been recognized by physicians previously supports a need to consider its implications and the potential impact of circulatory factors in caring for individuals with SND. Patients with diabetes and known microvascular disease may be particularly sensitive to reduced flow. Elderly patients, and especially those taking antihypertensive medications may likewise be at higher risk for SN hypoperfusion. Thus, the recognition of potentially reversible circulatory factor that may influence SN function may obvert interventional considerations.


BackgroundAn acute coronary syndrome (ACS) event can be linked to several risk factors, including kidney disease. Currently, it is unknown if kidney disease is associated with the in-hospital mortality of patients admitted with ACS, regardless of the main confounders. In this study, we aimed to determine if kidney disease predicts in-hospital mortality among ACS patients.MethodologyThis is a retrospective cohort study that included patients who were admitted to the cardiology center with ACS. The patients were analyzed for their clinical characteristics, previous diseases, risk factors, and blood samples for laboratory analysis. Continuous variables were analyzed using Student’s t-test, and categorical variables using the chi-square test. A p-value of <0.05 was considered statistically significant.ResultsOf the 340 patients who were included in the study, 59 had ST-elevation myocardial infarction. The mean age of the patients was 62.17 years, 59.41% were male, 67.9% were Caucasian, 26% had diabetes, and 20% had a history of coronary artery disease. Age, systolic blood pressure, and a history of myocardial infarction and chronic kidney disease were linked with a higher mortality rate. In the multivariate analysis, only kidney disease was shown to be an independent marker of mortality.ConclusionsAmong individuals admitted with ACS, kidney disease at hospital admission is associated with increased chances of in-hospital mortality, regardless of other major and minor cardiovascular comorbidities and inflammation at baseline. Cardiovascular diseases are the main cause of mortality worldwide. While their incidence has been increasing in developing countries, it has been decreasing in developed countries in the last decades . Almost Despite the rise in the incidence of cardiovascular diseases, the lethality of ACS has been decreasing due to several factors such as the intensification of statin therapy, the more frequent use of antiplatelet medication, improvement in health services and modern interventional therapies, and better intensive care and supportive therapies ,4. HowevThe factors that are linked to higher cardiovascular risk and higher mortality rate in acute events are also related to systemic inflammatory changes, oxidative stress, vascular calcification, and prothrombotic states .Kidney disease causes a systemic and chronic proinflammatory state that contributes to the vascular and cardiac remodeling process, resulting in atherosclerotic lesions, vascular calcification, and senescence, as well as myocardial fibrosis and calcification of the heart valves. Thus, even though factors such as diabetes, systolic hypertension, smoking, little to no physical activities, alcohol abuse, and left ventricular hypertrophy are cardiovascular mortality predictors in patients with kidney disease, chronic kidney disease (CKD) is by itself an important marker of cardiovascular risk .Several related mechanisms have been described for the association between CKD and cardiovascular risk, including oxidative stress, inflammation, vascular calcification, and iron metabolism ,7. HowevTherefore, we propose that kidney disease can not only be a cardiovascular risk factor for outpatients with coronary artery disease but also a marker of cardiovascular in-hospital mortality among individuals who develop ACS. With this study, we aim to evaluate if kidney disease diagnosed at hospital admission is associated with a higher mortality rate in patients with ACS who are admitted to the cardiology department, regardless of potential confounders.This is a retrospective cohort study that evaluates patients admitted to a Brazilian hospital with a confirmed diagnosis of ACS, with or without ST-segment elevation, from 2012 to 2019. The institutional review committee on human research approved the study (protocol number 31349420.0.0000.0020).The inclusion criteria were patients with a confirmed diagnosis of ACS and available records of admission examinations in the first 12 hours, including blood count, troponin, creatinine, C-reactive protein, sodium, and potassium, as well as clinical data such as comorbidities and risk factors.2. Patients with incomplete medical records or those diagnosed with ACS during hospitalization were excluded.Diagnosis of ACS was defined by the physician at admission. Glomerular filtration rate (GFR) was estimated from creatinine values using the CKD-EPI equation, and kidney disease was defined by GFR of <60 mL/minute/1.73 mUpon admission, patients’ gender, age, heart rate, and blood pressure data were collected. The risk factors captured by medical intervention at the time of admission included hypertension, dyslipidemia, diabetes, smoking, obesity and alcoholism, history of a previous cardiovascular event, presence of known coronary artery disease, and peripheral vascular disease. All comorbidities were captured using the electronic health record of the participants. Additionally, blood samples were also collected for laboratory analysis.Statistical analysisData were analyzed using SPSS, version 25 . Descriptive characteristics were calculated for continuous variables  and categorical variables (frequency/percentage). Continuous variables were analyzed using Student’s t-test, whereas categorical variables were analyzed using the chi-square test. To evaluate the association between kidney disease and in-hospital mortality, a multivariate model was developed. Covariates for the multivariate analysis were selected based both on clinical relevance according to a priori assumptions and if they remained statistically significant in the univariate analysis. A p-value of <0.05 was considered statistically significant.Between 2012 and 2019, a total of 756 patients were admitted to the hospital with chest pain or suspected ACS. Of these patients, 449 were excluded for not meeting the inclusion criteria. Finally, 340 patients were included in this study, of which 202 were males (59.4%) and 138 were females (40.6%), with an average age of 62.2 years.Table In the multiple logistic regression analysis, kidney failure, C-reactive protein, previous myocardial infarction, and systolic blood pressure were included, with p-values of 0.028, 0.145, 0.089, and 0.193; odds ratios of 4.82, 2.12, 2.90, and 1.69; and 95% confidence intervals of 1.23-43.51, 0.99-1.02, 0.80-22.67, and 0.95-1.00, respectively. According to the analysis, age, systolic blood pressure, previous myocardial infarction, and history of kidney disease were associated with a higher mortality rate  and cardiovascular events is not well described. Particularly, among individuals with ACS, the impact of kidney disease has not been addressed, regardless of the main confounders. According to the study by Dohi et al., kidney disease is a powerful determinant of long-term all-cause and cardiovascular mortality after ACS . SeveralSeveral factors can explain our findings such as the overlap of risk factors between kidney disease and coronary artery disease, worse inflammation and oxidative stress in kidney disease patients, as well as accelerated vascular calcification . Other fThis study has several limitations. First, because this is a retrospective cohort, confounding cannot be ruled out in our model. Second, the external validity of our findings may be limited because this is a single-center study, which can introduce selection bias in the sample; therefore, the results may not be generalizable to other populations. Finally, information bias is a potential limitation, given that serum creatinine was measured at hospital admission, and the exposure could not be clearly defined as chronic or acute kidney disease.Despite these limitations, this observational study has several strengths. Enrolled individuals were investigated for important confounders of kidney disease, such as previous cardiovascular events, and inflammatory surrogates, such as C-reactive protein levels. Additionally, ACS was defined by the clinical diagnosis according to clear and validated criteria.Among individuals admitted with ACS, kidney disease at hospital admission is associated with increased chances of in-hospital mortality, regardless of cardiovascular comorbidities and inflammation at baseline. These findings may help the development of prognostic scores for ACS risk stratification, as well as to guide further interventions targeting risk reduction for kidney disease in this population.


The effects of pharmacological blood-pressure-lowering on cardiovascular outcomes in individuals aged 70 years and older, particularly when blood pressure is not substantially increased, is uncertain. We compared the effects of blood-pressure-lowering treatment on the risk of major cardiovascular events in groups of patients stratified by age and blood pressure at baseline.We did a meta-analysis using individual participant-level data from randomised controlled trials of pharmacological blood-pressure-lowering versus placebo or other classes of blood-pressure-lowering medications, or between more versus less intensive treatment strategies, which had at least 1000 persons-years of follow-up in each treatment group. Participants with previous history of heart failure were excluded. Data were obtained from the Blood Pressure Lowering Treatment Triallists' Collaboration. We pooled the data and categorised participants into baseline age groups  and blood pressure categories (in 10 mm Hg increments from <120 mm Hg to ≥170 mm Hg systolic blood pressure and from <70 mm Hg to ≥110 mm Hg diastolic). We used a fixed effects one-stage approach and applied Cox proportional hazard models, stratified by trial, to analyse the data. The primary outcome was defined as either a composite of fatal or non-fatal stroke, fatal or non-fatal myocardial infarction or ischaemic heart disease, or heart failure causing death or requiring hospital admission.interaction=0·050). Similar patterns of proportional risk reductions were observed for a 3 mm Hg reduction in diastolic blood pressure. Absolute risk reductions for major cardiovascular events varied by age and were larger in older groups (adjusted pinteraction=0·024). We did not find evidence for any clinically meaningful heterogeneity of relative treatment effects across different baseline blood pressure categories in any age group.We included data from 358 707 participants from 51 randomised clinical trials. The age of participants at randomisation ranged from 21 years to 105 years (median 65 years [IQR 59–75]), with 42 960 (12·0%) participants younger than 55 years, 128 437 (35·8%) aged 55–64 years, 128 506 (35·8%) 65–74 years, 54 016 (15·1%) 75–84 years, and 4788 (1·3%) 85 years and older. The hazard ratios for the risk of major cardiovascular events per 5 mm Hg reduction in systolic blood pressure for each age group were 0·82 (95% CI 0·76–0·88) in individuals younger than 55 years, 0·91 (0·88–0·95) in those aged 55–64 years, 0·91 (0·88–0·95) in those aged 65–74 years, 0·91 (0·87–0·96) in those aged 75–84 years, and 0·99 (0·87–1·12) in those aged 85 years and older (adjusted pPharmacological blood pressure reduction is effective into old age, with no evidence that relative risk reductions for prevention of major cardiovascular events vary by systolic or diastolic blood pressure levels at randomisation, down to less than 120/70 mm Hg. Pharmacological blood pressure reduction should, therefore, be considered an important treatment option regardless of age, with the removal of age-related blood-pressure thresholds from international guidelines.British Heart Foundation, National Institute of Health Research Oxford Biomedical Research Centre, Oxford Martin School. Increased blood pressure is a well known, modifiable risk factor for cardiovascular morbidity and mortality, and antihypertensive medications play an essential cardioprotective role.Evidence before this studyClinicalTrials.gov covering the period between Jan 1, 1966, and Sept 1, 2019, with no language restrictions, for randomised controlled trials investigating blood-pressure-lowering drug treatment. We searched MEDLINE using and expanding on the MeSH terms for “hypertension”, “blood pressure”, and “antihypertensive agents”, including possible variations thereof as well as relevant antihypertensive drug classes. We identified several individual randomised controlled trials and meta-analyses with age-stratified effects of blood-pressure-lowering treatment but no reports with concurrent age and blood pressure stratification at the individual level. Additionally, evidence on treatment effects in individuals older than 85 years and with normal or mildly increased blood pressure was scarce.We searched MEDLINE, the Cochrane Central Register of Controlled Trials, and Added value of this studyWe gathered individual participant-level data from eligible large-scale trials of blood-pressure-lowering treatment. With access to individual participant-level data from 358 707 randomised participants from 51 trials (with 22 000 participants aged ≥80 years), this study enabled detailed investigation of age-stratified and blood-pressure-stratified effects on major cardiovascular events and death. We found pharmacological blood pressure reduction to be effective across a wide range of ages with no evidence that relative risk reductions for prevention of major cardiovascular events varied by baseline systolic or diastolic blood pressure levels, down to less than 120/70 mm Hg. Although we found evidence for diminishing relative risk reductions with increasing age and limited statistical power for detection of an effect in the oldest age group in isolation (90 years at the end of the study), absolute risk reductions did not follow the same pattern and appeared to be even larger in the older age groups. Stratified effects on all-cause death followed a similar pattern, with no evidence to suggest treatment increases mortality in any age group.Implications of all the available evidenceThis detailed study of age-stratified and blood-pressure-stratified effect of antihypertensive medication provides compelling evidence for the effectiveness of pharmacological blood pressure reduction into old age irrespective of baseline systolic or diastolic blood pressure. These findings challenge the common approach of withholding antihypertensive treatment for older adults, in particular when their blood pressure is not highly abnormal. Treatment should, therefore, be considered an important option regardless of age with removal of age-related blood-pressure thresholds from international guidelines.Epidemiological studies have suggested that increased blood pressure is a major risk factor for cardiovascular events across different age categories and over a wide range of blood pressure.vs ≥65 years) and could not investigate effects based on narrower age groups and by other important characteristics such as baseline blood pressure.19Thus far, robust evidence from randomised controlled trials (RCTs) has been lacking, in part because of the under-representation of older individuals in clinical trials. To date, the Hypertension in the Very Elderly Trial (HYVET) is the only large-scale trial that has exclusively recruited patients aged 80 years and older.The third cycle of the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC) had access to individual participant-level data of over 350 000 randomly assigned patients with 22 000 patients aged 80 years and older.BPLTTC is a collaboration of the principal investigators of major clinical trials of pharmacological blood-pressure-lowering treatment. The collaboration is coordinated by the University of Oxford  and, based on the last update, includes information from 52 randomised trials.In this meta-analysis of individual participant-level data, we used the resources provided by the BPLTTC. The Ethics approval for this phase was obtained from the Oxford Tropical Research Ethics Committee (OxTREC reference 545–14), and the analysis plan was approved by the BPLTTC steering committee and collaborators before releasing the data for analysis.The primary outcome was defined as either a composite of fatal or non-fatal stroke, fatal or non-fatal myocardial infarction or ischaemic heart disease, or heart failure causing death or requiring hospital admission. The secondary outcomes were all-cause death and each component of the primary outcome. For each trial, randomised groups were classified into the two groups of “intervention” and “comparator”. For placebo-controlled trials, the placebo group was considered as the comparator and the active group as the intervention. For trials comparing different drug classes, the group in which the blood pressure reduction was greater was considered as intervention and the other treatment groups as comparator. Trials that compared more intense versus less intense strategies were classified as the intervention versus comparator groups. Detailed information about the comparison groups, trial design, patient characteristics, and level of blood pressure reduction for each trial have been reported elsewhere.21To identify age-specific effects, we categorised participants into five groups that were based on their age at baseline . To examine the risk reduction across blood pressure categories, we stratified the participants into seven categories of baseline systolic blood pressure  and six categories of baseline diastolic blood pressure .vs comparator). Patients entered the analysis at the date of the randomisation and were followed up until the earliest occurrence of the outcome of interest, death, or end of the trial. Mean systolic blood pressure reduction between randomised groups, excluding the first 12 months, among all trials that aimed at achieving a difference in blood pressure, was 6·3 mm Hg (95% CI 6·1–6·4) and the average diastolic blood pressure reduction was 3 mm Hg (2·9–3·0).We did a one-stage, individual participant-level data, meta-analysis using stratified Cox proportional hazard models, with fixed treatment effects, and participants as the units of analysis.interaction was adjusted for multiple testing using Hommel's method to avoid chance finding.We plotted cumulative incidence curves by treatment allocation and age categories. Hazard ratios (HRs) and their 95% CIs were presented using forest plots with standardisation by 5 mm Hg reductions in systolic blood pressure and 3 mm Hg reductions in diastolic blood pressure. To test whether treatment effects varied across prespecified subgroups of age categories and systolic and diastolic blood pressure at baseline, we used likelihood-ratio tests for interactions. Likelihood-ratio tests compared models with and without interactions between treatment effect and age or blood pressure categories. The calculated pThe funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.Of the 52 randomised trials included in the BPLTTC, we excluded one trial because it did not report the outcome of interest. Therefore, 51 trials comprising 358 707 participants were included in the analysis . We founinteraction=0·050). A pharmacological reduction of 5 mm Hg in systolic blood pressure lowered the risk of major cardiovascular events in participants aged 55 years or younger (HR 0·82 [95% CI 0·76–0·88]), those aged 55–64 years (0·91 [0·88–0·95]), those aged 65–74 years (0·91 [0·88–0·95]), and those aged 75–84 years , the total serious adverse event rates were similar in the two study groups.Our study represents the most detailed analysis of blood-pressure-lowering treatment effect by age and blood pressure to date. However, our study has several limitations, which should be taken into account when interpreting our results. Our effect estimates for people aged 85 years and older at randomisation  were uncertain because of the comparatively smaller number of participants developing the main outcome compared with other age groups in the study. Relatedly, because of the typically restricted eligibility criteria of RCTs, other groups such as those with a high multimorbidity and polypharmacy burden, frail individuals, and individuals living in institutions have been under-represented.In conclusion, we found no evidence to substantiate the common approach of withholding antihypertensive treatment for older adults, in particular when their blood pressure is not highly elevated. Although the findings for people aged 85 years or more at study entry were less compelling, the overall patterns were consistent and suggestive of worthwhile reductions in cardiovascular outcomes across all age groups. Although clinical decision making for initiation and continuation of pharmacological blood-pressure-lowering will continue to be based on harm-benefit trade-offs for any individual, our study does not support the common belief that such trade-offs justify the overemphasis of several clinical practice guidelines on an individual's age or starting blood pressure. Therefore, pharmacological blood pressure reduction should be considered as an important treatment option for the prevention of cardiovascular events even in those aged 80 years or older and guidelines should be simplified to remove any differing blood pressure thresholds by age.https://www.bplltc.org.The governance of the BPLTTC have been reported previously. The BPLTTC is governed by the University of Oxford's policies on research integrity and codes of practice and follows the university's policy on the management of research data and records. Scientific activities based on BPLTT dataset are overseen by the BPLTT Steering Committee. All data shared with the BPLTTC are considered confidential and will not be provided to any third party. Requests for data should be made directly to the data custodians of individual trials. Information about individual projects is posted at Heart, outside the submitted work; and research support and consulting fees to the University by Medtronic. JC reports grants from the National Health and Medical Research Council of Australia, outside the submitted work. CJP has recived grants from the US National Institutes of Health/National Heart, Lung and Blood Institute, BioCardia, GE Health Care, Caladrius Biosciences, Merck, Sanofi, CSL Behring, XyloCor Therapeutics, Mesoblast, Ventrix, and Athersys. All other authors declare no competing interests.MN reports grants from the British Heart Foundation, outside the submitted work. DC reports grants from the British Heart Foundation, during the conduct of the study. KR reports grants from the British Heart Foundation, the UK Research and Innovation Global Challenges Research Fund, Oxford Martin School, University of Oxford, and NIHR Oxford Biomedical Research Centre, University of Oxford, during the conduct of the study; personal fees from


An adverse effect of colloids on kidney function is related to the incidence of postoperative kidney failure. The study aimed to assess the effect of a 3% gelatin solution on kidney function based on the urinary kidney injury molecule-1 (uKIM-1) level. This study used a parallel design and enrolled 64 adult patients with a mean age of 52.5 ± 13.1 years, all of whom underwent a thyroidectomy procedure under general anesthesia. Patients were randomly assigned to three comparison groups, each receiving a different dose of 3% gelatin solution during the thyroidectomy procedure. The patients from study groups A (n = 21) and B (n = 21) received a 3% gelatin solution at a dose of 30 ml/kg and 15 ml/kg body weight, respectively, during the first hour of the procedure. The patients from the control group C (n = 22) received an isotonic multi-electrolyte solution. Serum creatinine levels were determined, and urine samples were collected to determine levels of uKIM-1 before, 2 h, and 24 h after surgery. The patients’ demographic data, type and volume of fluid and hemodynamic status during the surgery were collected from relevant anesthesia protocols and were included in the study data. There were no statistically significant changes between groups in hemodynamic parameters such as systolic and diastolic blood pressure, heart rate, and oxygen saturation values. A statistically significant increase in uKIM-1 level was noted in patients receiving the 3% gelatin solution regardless of the dose. A statistically significant difference in uKIM-1 level was observed between groups A, B, and C measured 24 h after surgery, with the highest uKIM-1 level in group A. Measurement of uKIM-1 level could be an early and sensitive biomarker of kidney injury. Kidney toxicity of a 3% gelatin solution, evaluated based on the level of uKIM-1 in urine, correlates with transfused fluid volume. This study was retrospectively registered in the ISRCTN clinical trials registry (ISRCTN73266049, 08/04/2021:  Some colloids have been found to be associated with impaired kidney function, renal replacement therapy, and coagulation disorders and to lead to increased mortality4. However, only a few researchers have addressed the adverse effects of gelatin administered in the operating room5. Optimal fluid therapy in the perioperative setting is intended to maintain a euvolemic state and replenish the possible fluid losses associated with surgery. Optimal fluid therapy ensures the proper function of the circulatory system, optimal tissue perfusion, and kidney function. Maintaining a balanced fluid therapy is extremely difficult—the fluid type, volume, and rate of administration have to be adjusted for the type of surgery and its duration, preoperative fluid deficits, potential fluid losses, and co-morbidities of the patient. Numerous studies have established the adverse effects of colloids on kidney function and their relationship to the incidence of postoperative acute kidney injury (AKI)8. The development of kidney dysfunction in the perioperative setting leads to increased mortality, prolonged hospital stay, and higher costs of treatment10.In recent years, much research has focused on the harmful effects of colloids used in patients hospitalized in the intensive care unit (ICU)11.An early diagnosis of AKI is essential for effective treatment. Traditional blood and urine markers used to diagnose kidney injuries, such as urea and creatinine levels, are neither sensitive nor specific. In kidney injury, when the glomerular filtration rate (GFR) decreases, the half-life of creatinine increases in the period between 4 and 24–72 h after the GFR decreases. Therefore, a change in the creatinine level is delayed by up to 24 to 36 h. New biomarkers, such as neutrophil-gelatinase associated lipocalin (NGAL), cystatin C (CC), kidney injury molecule-1 (KIM-1), interleukin-18 (IL18), liver-type fatty acid-binding protein (L-FABP), N-acetyl-β-D-glucosaminidase (NAG), α-glutathione transferase , metalloproteinase tissue inhibitor type 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP-7), might be more beneficial for early detection of acute kidney injuries12. KIM-1 has proven to be a specific marker of histopathological changes in the proximal tubule in response to ischemia, hypoperfusion, or toxicants. It is expressed to a lesser extent in the case of an infection or chronic kidney disease14. After the injury, the extracellular domains of KIM-1 separate from the cell surface and enter the urine15. Previous studies have shown that tissue expression and urinary excretion of KIM-1 are sensitive and specific markers of AKI17.KIM-1 expression is low in healthy persons, and it is usually undetectable in urine, but its expression increases on the apical membrane of the nephron proximal tubule in the case of injury or ischemia. The level of KIM-1 is therefore markedly increased within hours following kidney injury20. Gelatin preparations can be extremely useful in these situations, but establishing their adverse effects on kidney function is essential22. Therefore, this study aimed to determine the effect of the gelatin solution used intraoperatively during a thyroidectomy on kidney function by assessing the urinary KIM-1 (uKIM-1) level. In addition, we hypothesized that the nephrotoxicity of gelatin solutions depends on the dose and total volume of transfused fluid and that gelatin solutions might have a nephrotoxic effect in patients with coexisting renal disease regardless of dose.Colloids are fluids used primarily for a hemorrhagic shock when the rapid securing of blood products is not possibleIn the analyzed period, 126 patients, including 97 females and 29 males, qualified for a thyroidectomy procedure. Of these, 21 patients  did not consent to participate in the study. Thus, a group of 105 patients  were enrolled in the study. Forty-one patients  were excluded due to an American Society of Anaesthesiologists (ASA) score > II. Ultimately, 64 patients  with an ASA score of I–II were enrolled in the study. Another nine patients  were excluded during further observation due to study protocol violation (no urine sample 2 h after the procedure). The Consolidated Standards of Reporting Trials (CONSORT) 2010 flow diagram for the study process is presented in Fig. Ultimately, the analysis involved 55 patients, all of whom were female Table . In the p = 0.023), we did not find any significant difference between the groups regarding age, height, or BMI. Furthermore, the mean surgery time was 81.0 ± 25.0 min for the whole population, with no statistically significant difference between the analyzed groups .Apart from the statistically significant difference in mean body weight between groups B and C . In the second hour of the surgery, the patients received 11.9 (2.7 ÷ 14.5), 14.0 (12.4 ÷ 15.4), and 3.0 (0.0 ÷ 11.9) mL/kg in groups A, B, and C, respectively. In this second hour of the surgery, patients in group B received a statistically higher dose of fluid than patients in groups A and C (p < 0.001).In the first hour of the surgery, patients in group A received 23.3 (19.7 ÷ 25.0) mL/kg of the 3% gelatin solution, group B received 15.0 (12.8 ÷ 16.7) mL/kg of the 3% gelatin solution, and group C received 27.1 (24.2 ÷ 2.5) mL/kg of the Multi-Electrolyte Fluid  and 24 h after surgery . See Fig. The serum creatinine levels in the preoperative and postoperative periods were within the normal range in all patients 0.8–1.3 mg/dL). There was no statistically significant difference between the groups in creatinine levels in the baseline (Table .3 mg/dL.p < 0.001) and 24 h after surgery . There was no statistically significant difference between baseline serum creatinine and serum creatinine levels 24 h after surgery (p = 0.672). Among the analyzed groups, a statistically significant decrease in serum creatinine levels 2 h after surgery, as compared to the baseline, was observed in group A (p = 0.001) and group C (p = 0.014). In comparison, a statistically significant decrease in serum creatinine 2 h after surgery, as compared to 24 h after surgery, was observed in groups A (p = 0.014) and B (p = 0.007).In the whole analyzed population, serum creatinine level 2 h after surgery was statistically significantly lower than it was both before surgery . A statistically significant increase in uKIM-1 levels 24 h after surgery, as compared to the baseline, was observed in groups A  and B . A statistically significant change in uKIM-1 level was observed between groups A and C  24 h after surgery.A statistically significant increase in uKIM-1 level 2 h after surgery, as compared to the baseline, was observed only in group B  is < 55 mm/Hg and lasts more than 10 min27. According to the KDIGO  guidelines28, major surgery is among the risk factors for the development of AKI. In order to eliminate additional factors affecting renal function in this study, procedures of low invasiveness were selected, and arterial blood pressure was strictly controlled during surgery, without hypotension observed. Additionally, all patients underwent a uniform anesthetic regimen with propofol, fentanyl, and rocuronium, in doses adjusted to body weight—this enabled assessment of the effects of the fluids used on renal function by evaluating uKIM-1 concentration.The patients who qualified for our study were those undergoing surgery with a potentially low risk of intraoperative bleeding. AKI develops in 7.5% of patients in the postoperative period after non-cardiac surgery and is associated with an eight-fold increase in mortality within 30 days of surgeryThe hemodynamic status of our patients was stable, and proper tissue perfusion was obtained; this allowed for an assumption that the fluid balance was adequately maintained and allowed hypoperfusion periods to be ruled out as a potential cause of kidney function impairment. Also, decreased serum creatinine levels and increased GFR values in the second hour after surgery confirmed that an optimal fluid balance was most likely maintained.29. There was no increase in serum creatinine levels within 24 h after surgery in our study population. Therefore, diuresis volume was not determined, but none of the patients reported any diuresis issues following surgery. As we could not show any adverse effects of the fluids administered on kidney function using the AKIN definition, we decided to analyze kidney function using an alternative biomarker: uKIM-1.Both an increase in serum creatinine level and impairment of diuresis are symptoms of already developed kidney dysfunction and provide AKI definition elements according to Acute Kidney Injury Network (AKIN) criteria30.An increase in uKIM-1 level precedes increased creatinine levels and a decrease in diuresis, allowing for the faster implementation of prophylactic measures to prevent overt AKI development. In addition, the uKIM-1 level is described as an early and sensitive biomarker of kidney tubule injury31 on the canine shock model showed the harmful effect of gelatin on kidney function, as it increases uKIM-1 levels. The same hypothesis was also confirmed in our study. Both groups (group A and group B) receiving the gelatin solution infusion increased the uKIM-1 levels significantly. Moreover, the administered fluid volume (3% gelatin solution) also affected kidney function. The highest uKIM-1 level 24 h after surgery was observed in group A, where the highest volume of the 3% gelatin solution had been administered (23.3 [19.7 ÷ 25.0] mL/kg). The results are consistent with the available literature reports32.An experimental study by Boy et al.33. Even though uKIM-1 is not present in healthy volunteers’ urine34, our results show that only levels ≥ 0.32 ng/mL can predict kidney injury.Our analysis of uKIM-1 as a biomarker showed that, in comparison to creatinine, it could be a sensitive and specific kidney function marker. The results are consistent with the Food and Drug Administration (FDA) data that includes uKIM-1 as a useful marker of drug-induced kidney injuryThis study has some potential methodological limitations to be mentioned. First, this was a single-center study; thus, the generalizability of the results to the whole country is insufficient. Well-designed multi-center studies are needed. However, it should be pointed out that this study has been designed as a preliminary randomized controlled trial (RCT). In addition, despite adequate sample size calculation, the number of patients included in the study was relatively small, and the study sample should be larger in the future to avoid undermining the statistical power of the test and minimize the formation of artifacts. Notably, only female patients were included in the analysis period, so the results only refer to the female gender and should not be related to male patients. Future studies should include examinations performed on patients of both sexes and consider any inter-gender differences in uKIM-1 levels. In addition, none of the patients included in the study developed overt AKI; therefore, it would be worthwhile to design studies that also include patients with developed AKI in the context of evaluating the therapeutic effect of a 3% gelatin solution on renal function based on the uKIM-1 level as a specific marker of kidney tissue injury.An early diagnosis of kidney damage allows for rapid implementation of treatment or elimination of the damaging factor. For this purpose, it is necessary to use biomarkers with high specificity and sensitivity. The search for such a marker should be a priority in view of the increasing number of drugs and therapeutic substances with nephrotoxic effects.The uKIM-1 level could be an early and sensitive biomarker of kidney injury. Determination of uKIM-1 levels in patients undergoing thyroidectomy has shown that intraoperatively administered gelatin solutions can have detrimental dose-dependent effects on the kidneys. A 3% gelatin solution at a dose over 15 ml/kg body weight has been shown to have nephrotoxic effects.The study was designed as a prospective parallel randomized clinical trial. The study was conducted between April 2014 and December 2014 at the Department of Anaesthesiology and Intensive Care and the Department of Surgery at the University Hospital in Wroclaw, Poland. The study initially recruited 126 patients, of which 76 were assessed for eligibility. A group of 12 patients did not fulfill the below eligibility criteria (n = 3) or declined to participate (n = 9) and were excluded from further stages of the study. Ultimately, the study sample included 64 patients with a mean age of 52.5 ± 13.1 years. No patients were lost to follow-up or did not receive the allocated intervention. It should be noted that 9 patients  were excluded from analysis due to a lack of urine samples in the second hour after surgery , no blood coagulation disorders and no allergy to anesthetic agents. Informed and written consent to participate in the study was obtained. The exclusion criteria comprised an ASA score > II, impaired kidney function before the surgery (serum creatinine > 1.3 mg/dL), current immunosuppressive therapy, confirmed gelatin allergy or anesthetics allergy, blood coagulation disorders, or refusal to participate in the study. The patients’ enrolment was performed by researcher Patrycja Leśnik.https://www.random.org). Before the study, a list of patients with their respective numbers and group assignments was generated. The randomization list was given to the anesthesiologist by the coordinating nurse on the day of surgery in the operating theatre. A triple blinding procedure was used that involved participants, as well as the assessor and data analyst.On the day of surgery, all patients were randomly assigned into one of three comparative groups: A, B, and C. Allocation concealment was provided by the researcher Patrycja Leśnik using central randomization in a 1:1:1 ratio generated by computer software . The study was carried out in accordance with the guidelines of the Declaration of Helsinki and Good Clinical Practice. Informed and written consent was obtained from all the patients. During the premedication visit on the day preceding the surgery, the patients gave their written informed consent to participate in the study. The standards from CONSORT were followed, and the CONSORT checklist was used for enrolment and allocation of patientsPatients received one peripheral intravenous access in the operating theatre, 5-lead electrocardiogram (ECG), non-invasive blood pressure (NIBP), and pulse oximeter. Following the Clinic of General, Gastroenterological, and Endocrine Surgery standard procedure, patients had their last meal in the afternoon of the day before surgery and received fluids until midnight. The same standard general anesthesia procedures were used in all anesthetized patients. Anesthesia was induced with propofol 2 mg/kg body weight, fentanyl 0.1 mg, and rocuronium 0.6 mg/kg body weight, followed by maintenance of anesthesia with inhaled sevoflurane and intravenous fentanyl. During surgery, arterial blood NIBP was monitored at 5-min intervals, and continuous ECG, SaO2, and train-of-four (TOF) monitoring was used.The primary study outcome was to observe changes in uKIM-1 levels determined from urine samples using an enzyme-linked immunoassay (ELISA) method. The secondary study outcome was to detect serum creatinine level changes determined from venous blood samples using laboratory methods. The same measurement timepoints were set for both outcomes at baseline, postoperative 2 h, and postoperative 24 h. Demographic data  were included in the study data.2, measured continuously), systolic (SBP), and diastolic blood pressure , as well as data concerning the type and volume of fluids administered during the first and second hour of the procedure, were collected from relevant anesthesia protocols and included in the study data.Heart rate , arterial blood oxygen saturation , and black on the right leg. These basic leads yield enough information for rhythm monitoring.Pulse oximeter measurements were performed by the sensor device, which was placed on a fingertip. The device passes two wavelengths of light through the body part to a photodetector. It measures the changing absorbance at each wavelength, allowing it to determine the absorbances due to pulsing arterial blood.Serum creatinine level was determined in blood samples collected via venous cannula before surgery and 2 h and 24 h after surgery. The determination of creatinine in serum samples was performed with an enzymatic method through the Alinity c Creatinine Reagent Kit  and the analyzer Alinity . The limit of detection for serum creatinine was 0.05 mg/dl (4.5 μmol/l).Urine samples of 15 mL were collected from patients by spontaneous micturition on the day preceding the surgery and then 2 h and 24 h after surgery to determine KIM-1 level. The 15 mL urine samples were collected in urinary cups and centrifuged at 2000–3000 rpm for 20 min; the supernatant obtained was stored at − 72 °C. The quantitative determination of uKIM-1 was performed using an enzyme-linked immunoassay (ELISA) kit according to the manufacturer’s protocol: Human Urinary TIM-1/KIM-1/HAVCR Quantikine ELISA Kit . The test was performed on a 96-well plate coated with an anti-human KIM-1 antibody. At first, 100 µl of assay diluent was added to each well. Then, 50 µl of the standard at concentrations of 0, 0.156, 0.312, 0.625, 1.25, 2.5, 5 and 10 ng/ml was added in duplicate. The remaining wells were filled with 50 µl of patient and control urine, added in duplicate. After 2 h of incubation at room temperature, the liquid from each well was removed. The wells were washed four times with 400 µl of a wash buffer. Then, 200 µl of human TIM-1 conjugate was added to each well and left for 2 h at room temperature. After 2 h of incubation, the wells were washed four times with 400 µl of a wash buffer. Subsequently, 200 µl of substrate solution was added to each well, and it was left for 30 min at room temperature in the dark. After 30 min of incubation at room temperature, the reaction was stopped with a stop solution. Absorbance was read using a microplate reader, the Tecan Infinite 200 , at 450 nm and 540 nm (wavelength correction). The minimum detectable level of human KIM-1 ranged between 0.003 ÷ 0.046 ng/ml.The person performing the below-mentioned experimental procedures was the same anaesthesiologist for all groups, who had at least 5 years of professional expertise. The primary general purpose of the study was prevention in terms of assuring proper kidney function and preventing kidney damage. Therefore, all patients were carefully monitored for possible adverse events such as allergic reactions to local anesthetics, technical difficulties of the blockade, or hematoma.The patients from the first group  received an anaesthesiologic intervention in the form of a 3% gelatin solution  at a dose of 30 ml/kg body weight during the first hour of the procedure and then the isotonic multi-electrolyte solution  at a dose of 15 ml/kg body weight/hour.The patients from the second group  received an anesthesiologic intervention in the form of a 3% gelatin solution  at a dose of 15 ml/kg body weight during the first hour of the procedure and then the isotonic multi-electrolyte solution  at a dose of 15 ml/kg body weight/hour.The patients from the third group  received an active-controlled intervention in the form of an isotonic multi-electrolyte solution  at a dose of 30 ml/kg body weight during the first hour of the procedure and then the isotonic multi-electrolyte solution  at a dose of 15 ml/kg body weight/hour.f = 0.5) with the statistical power of 80% and α = 0.05. For one-way ANOVA with three groups, the sample size of at least N = 42 was needed for detecting a large enough effect size (Cohen’s f = 0.5) with a statistical power of 80% and α = 0.05. Statistical power analysis was conducted with the software G*Power version 3.1.9 .For the analysis of variance (ANOVA) with three groups and three repeated measures, the sample size of at least N = 30 was needed for detecting a large effect size  for normal distribution parameters and homogeneous variances was checked with the Student’s t-test for the related variables. The significance of differences in average values (medians) between two groups for parameters with a distribution considerably deviating from the theoretical normal distribution or heterogeneous variances was verified with the Wilcoxon test. For variables that were not significantly different from the normal distribution, ANOVA was used. The Tukey’s honest significant difference (HSD) test was used as a post-hoc test; thus, the observed significance level included performing multiple comparisons. For variables that were significantly different from the normal distribution, the Kruskal–Wallis test was used, and for dependent variables, the Friedman test was used. The Dunn’s test was used as a post-hoc test, corrected for multiple testing (the Bonferroni correction was used here). The results were considered statistically significant when the p-values were lower than 0.05.Statistical analysis was performed using Statistica software version 13.3 . The distribution of all the quantitative parameters  was checked for consistency with the normal distribution. The conformity assessment was carried out using the Shapiro–Wilk and Kolmogorov–Smirnov tests. The critical significance level was assumed at


Background: The 24-hour (24-h) creatinine clearance (CrCl) is the most common method for measuring GFR in clinical laboratories. However, the limitations of CrCl have resulted in the widespread acceptance of mathematically derived estimated glomerular filtration rate (eGFR) using Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD) and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations in predicting eGFR. The aim of the study was to compare 24-h CrCl with eGFR derived from these formulae and to identify which could be the best alternative. Method: A prospective study was conducted involving 140 CKD patients. Creatinine and cystatin C concentrations were determined using the cobas 6000 analyzer. The eGFR was calculated using the CG formula, 4-variable MDRD and CKD-EPI equations, and Bland-Alman plots bias was determined. Results: The CG and MDRD formulas had mean eGFR values similar to CrCl and correlation coefficients (r) were highest for CG (0.906) and lowest for MDRD (0.799). The CG equation was in agreement with 24-h CrCl in all but stage V CKD while the MDRD equation compared well in all except Stage IV CKD. The CG equation was positively biased (0.9857) while the MDRD had a negative bias (−0.05). Conclusion: The Cockcroft-Gault formula provides a more accurate assessment of GFR than 24-h CrCl and would be recommended as a substitute to provide the best estimate of GFR in our population. Worldwide, chronic kidney disease (CKD) has been acknowledged as a public health challenge and over the last decade there has being significant increase in both incidence and prevalence in various populations . In 20172 due to kidney injury or lessened function that persist for three months or more [The glomerular filtration rate (GFR) provides a precise measure of renal function and according to Kidney Disease Quality Outcome Initiative, CKD is defined by GFR < 60 mL/min/1.73 m or more .125I-iothalamate, technetium-99m diethylenetriamine-pentaacetic acid (99mTc-DTPA) or chromium-51 (51Cr)EDTA in the determination of mGFR, have been found to be reliable and precise in patients with ESRD [Kidney function can be assessed by the determination of measured GFR (mGFR) via the clearance from the plasma of administered exogenous filtration substances such as inulin, the gold standard as well as iohexol . Renal iith ESRD , but theCreatinine clearance (CrCl) is a mGFR methodology that provides an assessment of renal function based on the clearance of creatinine from a given volume of blood plasma per unit time. CrCl involves the determination of creatinine in plasma and an accurately timed 24-h urine sample, and the biomarker satisfy most of the criteria as an ideal marker for mGFR assessment including being present in fairly stable concentration in the blood and freely filtered at the glomerulus . HoweverEstimated GFR (eGFR) equations such as the Cockcroft-Gault (CG) and the Modification of Diet in Renal Disease (MDRD) formulas were recommended by The National Kidney Foundation Dialysis Outcome Quality Initiative (K/DOQI) in the assessment of kidney function particularly in individuals with acute or chronic renal disease . The CG 125I-iothalamate [The original MDRD equation reported in 1999 was developed to predict GFR using serum creatinine levels and other factors such as age, gender and ethnicity. The equation was assessed in a cross-sectional study comprising 1628 persons with variable degrees on kidney impairment using a stepwise regression procedure, with standard GFR determined from renal clearance of halamate . Simplifhalamate . There ahalamate ,23. Howecrea, CKD-EPIcys and CKD-EPIcrea/cys, and a recent meta-analysis comprising 35 studies with 23,667 participants found that estimates of CKD-EPIcys and CKD-EPIcrea/cys were closer to mGFR and were more accurate and less bias compared with CKD-EPIcrea [The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula was established in 2009 and validation data showed that it performed better than the MDRD formula particularly at higher GFR with greater accuracy, less bias and better precision . There a-EPIcrea .In this study, the eGFR formulas are considered as alternatives to 24-h CrCl and in the latter the collection of urine is cumbersome with the possibly introduction of errors. Therefore, the eGFR formulas are proposed as tools to circumvent the urine collection with possibly improved overall eGFR results.Nevertheless, the most common routine and practical method for measuring GFR is accomplished with a 24-h urine collection for CrCl evaluation. The aim of the study was to compare 24-h CrCl with eGFR using the formulas  and to identify which amongst the eGFR formulas closely correlates with 24-h CrCl. The study also sought to (i) evaluate how well eGFR values stratifies patients with CKD, (ii) determine the correlation of eGFR to 24-h CrCl and (iii) examine the mean values of the different formulas to stage of CKD.A description of the study was previously published . In summThe study received approval from The University of the West Indies/University Hospital of the West Indies Faculty of Medical Sciences Ethics Committee and the protocol for the conduct of research outlined were adhered to.The inclusion criteria for persons recruited to the study were as follows: aged 18 to 98 years; CKD with reduced renal function (stage 1 to 4); aetiologies of chronic disease such as diabetes mellitus (type 1 and 2), hypertension, systemic lupus erythematosus, obstructive uropathy, chronic glomerular nephritis and autosomal dominant polycystic kidney disease, and compliance with instructions concerning urine sample collection.The exclusion criteria for persons recruited to the study were as follows: aged less than 18 years; normal renal function; multiple myeloma and cancers such as prostate, breast and colorectal; current use of immunosuppression, previous kidney transplantation; and severe comorbid disorders such as chronic active hepatic, cirrhosis and congestive cardiac failure.Demographic data, including age, gender, date of birth, height and weight were collected. Height and weight were measured in the renal clinic. The date of CKD diagnosis, age, stage and cause of renal impairment at diagnosis as well as any comorbid conditions were ascertained from the patients themselves and/or confirmed by docket search .2).The footwear of the patients were removed and their height measured to the nearest 0.5 cm by means of a wooden platform with height rule. The weight of the patients was measured to the nearest 0.5 kg with manual Seca 761 scales  after removed of footwear. Having determined the weight and height the body mass index (BMI) was calculated as weight in kilograms divided by height in metres squared (kg/mSeven (7) mL of venous blood was obtained from each participant by venipuncture from the antecubital fossa or another convenient site. The samples were collected in Vacutainer tubes and allowed to clot for 30 min. Separation was carried out by centrifugation at 3500 rpm for 5 min at room temperature and then the serum was aliquoted.Blood samples were processed within three hours of receipt in the Chemical Pathology Laboratory at the Department of Pathology, The University of the West Indies. Specimens were stored at −70 °C for assays not completed within 24-h.At the time of consent, the participants were given directives on the proper collection of a 24-h urine sample. They were asked to repeat the instructions to ensure comprehension . ParticiThe 24-h urine specimen was submitted on the morning of completion of collection. To determine completeness patients were asked to describe the process followed and volume was also deemed adequate based on normal excretion rate .Each participants provided two consecutive 24-h urine collections (in a 4.5 litre plastic bottle containing thymol as the preservative). The volume of urine in each bottle was determined and 55-mL aliquots of urine were pipetted into test tubes and frozen at −20°C until analyzed for creatinine.Serum and urine biochemistry tests were performed on the cobas 6000  analyser . Serum aFor urine creatinine a 1:10 dilution was automatically performed by the c501 module of the cobas 6000 analyzer before the assay is initiated. On reaction with picric acid at alkaline pH a yellow-orange complex is produced. The development of color being equivalent to the concentration of creatinine in the urine as well as serum samples .Cystatin C was measured by the Tina-quant Cystatin C Gen. 2, a particle enhanced immuno-turbidimetric assay that is standardized against ERM-DA471/IFCC  reference material. Cystatin C in the specimen binds to anti-cystatin C-coated latex particles and the degree of turbidity from the reaction is measured at 546 nm, and is equivalent to cystatin C concentration .2) from the 24-h urine collection was calculated in the laboratory information management system (LIMS), Chemical Pathology Laboratory, Department of Pathology, The University of the West Indies. The eGFR was calculated using the CG formula, 4-variable isotope dilution mass spectrometry (IDMS) traceable MDRD, CKD-EPIcrea, CKD-EPIcrea/cys and CKD-EPIcys equations and reported in mL/min [The CrCl  and 3b (eGFR of 30–44.9 mL/min/1.73 m2) [CKD is defined as eGFR < 60 mL/min/1.73 m1.73 m2) .crea (iii) CKD-EPIcys and (iv) CKD-EPIcrea/cys formulas. A p-value < 0.05 (two- tailed) indicated statistical significance.The data analysis was conducted using the IBM Statistical Programme of the Social Science (SPSS) version 22 and Microsoft Excel. Demographic characteristics are presented as mean ± standard deviation (SD). The frequency of different causes of CKD were determined. The Pearson coefficient (r) was used to assess the correlation of results by conventional 24-h urine CrCl and (1) CG formula and (2) eGFR by the (i) four-variable IDMS traceable MDRD (ii) CKD- EPIp < 0.05 (two-tailed).Results were also analyzed by linear regression and scatter plots. The Kolmogorov-Smirnov test was used to determine normality and Bland-Alman plots bias. Comparisons of the mean eGFRs at different stages of kidney disease were assessed by the paired t-test at significance level The etiologies of CKD in this group of patients was previously published . The majp < 0.05, two-tailed). Correlation coefficients (r) was highest for CG 0.906 (r2 = 0.820), followed by CKD-EPIcrea/cys 0.901 (r2 = 0.812), CKD-EPIcys 0.895 (r2 = 0.801) CKD-EPIcrea 0.863 (r2 = 0.744) and MDRD 0.799 (r2 = 0.638)  .cr had a value of 54.79 mL/min which borderline significant and the other equations had significant differences compared with CrCl  and >124 μmol/L (n = 87). In the former group results compared well with 24-h CrCl and were statistically insignificant for CG, MDRD and the CKD-EPIcrea equations while for the latter the CG and MDRD equations compared well   .In the sub-group of patients with CrCl < 60 mL/min, the CG formula proved to be similar compared with 24-h CrCl while the MDRD and CG formulas were comparable when CrCl ≥ 60 mL/min . All metcrea there was significant bias  equation. Precision was greater for the CG formula compared to 24-h CrCl. Bland-Altman analyses were not performed for the CKD-EPIcys, and CKD-EPIcrea/cys as the independent t-tests showed significant bias between the differences of the means.The MDRD had a negative bias (−0.05) with LOA of −72.4318 to 72.38184. The results for the CG and MDRD formulas were satisfactory, but unacceptable for the CKD-EPIcrea, CKD-EPIcys and CKD-EPIcrea/cys equations and its comparison with 24-h CrCl in a Caribbean population mainly of African descent. In this study, results from Pearson correlation analysis indicated strong positive correlations for cystatin- and creatinine-based equations with 24-h CrCl, and these values were also highly correlated with each other. However, the correlations between serum creatinine and cystatin-based eGFR values were lower and moderately negative.To our knowledge this is the first published report of the determination of eGFR using the CG, MDRD, CKD-EPIp < 0.05) while the MDRD formula displayed weakest correlation . Results reported for CG and MDRD formulas in a study by Hahn et al. of patients before autologous and allogeneic bone marrow transplant showed similar order though weaker values as the correlation for the CG formula (r = 0.63) was slightly higher than the MDRD formula (r = 0.54) [p < 0.001) and MDRD  respectively [In our study, the CG formula showed the highest correlation  . Moreove = 0.54) . Also, rectively .crea, CKD-EPIcrea/cys and CKD-EPIcys equations in decreasing order of values were lower than 24-h CrCl, while that produced by MDRD was slightly higher. Lower mean eGFR values for CG of 32.18 mL/min/1.73 m2, MDRD 26.56 mL/min/1.73 m2 and 24-h CrCl of 21.75 mL/min/1.73 m2 were found in 64 CKD patients in Nigeria with stable disease [crea/cys gave lower GFR estimates; findings that are similar to that obtained by Hu et al. [When the overall means were compared in this study, the eGFRs determined by CG, CKD-EPI disease . The difu et al. .2, which were higher than ours. The disparity between the findings of Verhave and ours could be differences in weight, body mass index (BMI) and stage of CKD [2, which was closer to ours [In this study our findings of the MDRD formula producing a mean value that was greater than that obtained by 24-h CrCl and CG formula is in contrast to evidence of other researchers such as Verhave et al. who reported lower values. Also, Verhave et al. examined data of 8592 participants in the Prevention of Renal and Vascular End-stage Disease study and found that the mean GFRs for 24-h CrCl, MDRD and CG were in the range of 77.5–94.6 mL/min/1.73 me of CKD . However to ours .crea equations overestimates in stage 2–5 and underestimates in stage 1. CG formula had the strongest association in stage 1–3 CKD, sub-population with CrCl < 60 mL/min and with both serum creatinine results ≤124 μmol/L and >124 μmol/L. Results of comparison of the MDRD formula with 24-h CrCl indicated superior performance in males, 24-h CrCl levels ≥ 60 mL/min/1.73 m2 and the sub-population < 60 years old. The CKD-EPIcrea equation had the strongest relationship with 24-h CrCl in stage 5 CKD, in the age-group > 60 years old and in females. CG tended to overestimates 24-h CrCl in the <60 age group and underestimates in the age group ≥60 years compared to the MDRD and CKD-EPIcrea formulas.The majority of the patients in our study according to 24-h CrCl was in stage III. The finding is similar to that of Krzanowski et al. who reported that the highest proportion of CKD patients were designated to stage 3 . A compacys was the most accurate compared with CKD-EPIcrea/cys, and CKD-EPIcrea and performed best in the analyses of sub-group such as those persons with mGFR < 60 mL/min/1.73 m2, aged less than 70 years and those participants who were of the Asia ethnic group [Kumar and colleagues who performed a retrospective study involving 91 CKD patients reported that the CG formula showed good approximation to 24-h CrCl only in stage 2–4 CKD while it was stage 2–5 for the MDRD (2006) formula . Similaric group .crea [Studies have highlighted the significance of careful calibration of serum creatinine measurements in order to accurately and reliably determine the 24-h CrCl or eGFR in patients with normal or slightly decreased kidney function ,45. The crea .51Cr-EDTA) by 0.99 mL/min/1.73 m2 and 1.94 mL/min/1.73 m2 respectively [125-I-iothalamate GFR by 2.7 mL/min/1.73 m2 [The evaluation of bias, a measure of systematic error in this observational study of validated CKD patients by Bland-Altman analysis showed satisfactory negligible negative bias (−0.05) for the MDRD formula (LOA of −72.4318 to −72.3318) and a very small positive bias (0.9857) for CG (LOA of −47.3044 to −49.27579). This indicate that when the entire study population was considered, the MDRD equation underestimates 24-h CrCl by 0.05 mL/min and the CG formula overestimates the same by 0.99 mL/min. This shows good global agreement between 24-h CrCl and MDRD as well as CG. Notably, in our study the measure of precision was reported as the 95% limits of agreement and the CG formula was more precise than the MDRD equation. Fairly similar findings were reported by Froissart et al. in a large adult European population where the MDRD and CG formulas overestimated measured GFR  ,52. HoweThe authors also noted that the overall performance of the formulas used in this study could be affected by different parameters such as all are influenced by age, CG by BMI and body weight, and CKD-EPI and MDRD do not consider the lean body mass and weight of patient. These factors could introduce overall bias in the study . HoweverFurthermore, another limitations is that most of the CKD patients recruited in the study were deemed to be in stage 3 by the 24-h CrCl. We are aware that this could introduce bias and we attempted to mitigate this possibility by one of the authors, a nephrologist ensuring that the clinical characteristics, creatinine levels and clearance were associated with stage 3 disease.Our population was totally Afro-Caribbean and extensive studies have not been done in this population. Populations in most studies have proportionately less black subjects and differences have even been shown in South African vs. and blacks in United States of America and European .The differences in eGFR estimates between the cystatin and creatinine-based equations warrants the need for population-based studies in Jamaica with satisfactory sample sizes to validate these eGFR formulas. This will afford the necessary data required to determine the most suitable eGFR equation to utilize in assessing CPD patients in the local setting.The CG formula compared most favorably and is the best alternative to 24-h CrCl given the limitations of the latter. The performance of 24-h CrCl was enhanced as the creatinine assay used in this study is traceable to IDMS and stringent measures were employed regarding urine collection. It could be recommended as a substitute to provide the best estimate of GFR in our population. The MDRD formula should be used with caution as there is a tendency to overestimate GFR. More studies are warranted to verify the role of cystatin C in predicting development of CKD as well as other adverse outcomes associated with the disease. Studies comparing estimated GFR to measured GFR using exogenous markers such as inulin or iohexol would be best to determine the method most appropriate for our population as 24-h CrCl has a number of limitations including its overestimation of the true GFR.


Background and objectives: This study aimed to assess the clinical significance of serum cystatin C in the early diagnosis of renal injury and its association with dyslipidemia in young T1D patients. Materials and Methods: A total of 779 subjects were evaluated for kidney function by estimating glomerular filtration rate (eGFR) based on serum creatinine (eGFRcreat) and cystatin C (eGFRcys). Results: The median age of study subjects was 16.2 years , diabetes duration—5.3 years . The median of HbA1c was 8%  ); 24.2% of participants had HbA1c < 7% (53 mmol/mol). Elevated albumin excretion rate was found in 13.5% of subjects. The median of cystatin C was 0.8 mg/L , the median of creatinine—63 µmol/L . The median of eGFRcys was lower than eGFRcreat . A total of 30.2% of all patients were classified as having worse kidney function when using cystatin C vs. creatinine for eGFR calculation. Linear correlations were found between cystatin C and HbA1c, r = −0.088, p < 0.05, as well as cystatin C and HDL, r = −0.097, p < 0.01. Conclusions: This study showed that cystatin C might be used as an additional biomarker of early kidney injury in young patients with T1D. Recent data suggest the benefits of GFR calculated with serum cystatin C for evaluation of early risk for end-stage renal disease [Diabetic kidney disease is defined as renal dysfunction or structural abnormalities lasting for 3 or more months and highly affecting the patient’s quality of life . StartinCystatin C is a low-molecular-weight protein Mw 13,343 Da), an inhibitor of endogenous cysteine protease 3 Da, an . Recent Increased cystatin C and disorders of lipid metabolism are associated with a higher risk of cardiovascular diseases (CVD), which are the leading cause of mortality in patients with type 1 diabetes (T1D) ,8,9. EarRecent studies showed that cystatin C is a valuable marker for acute kidney injury in the pediatric population and even helps to stratify CVD risk in children with chronic kidney disease ,12. HoweSince there are controversies regarding the role of cystatin C in the assessment of kidney function, we aimed to assess the clinical significance of serum cystatin C in the early diagnosis of renal injury and its association with dyslipidemia in young T1D patients.A cross-sectional population-based study was carried out in Lithuanian University of Health Sciences, Department of Endocrinology, the whole project is described previously . This pa2). BMI values were converted to Z-scores and stratified into 4 weight status groups: underweight, normal weight, overweight, and obesity, using the World Health Organization approach [Detailed clinical assessment and examination of this cohort were described previously , brieflyapproach . Waist capproach .Diabetes control was assessed by glycated hemoglobin (HbA1c). Fasting blood samples were taken for analysis of lipid profile, creatinine, and cystatin C. All patients were screened for diabetic retinopathy and neuropathy, and the level of albuminuria in 24-h urine was assessed.HbA1c, lipids, and serum creatinine were measured using UniCel DxC 800 Synchron system . Normal cut-off values for HbA1c were 4–6% (20 mmol/mol–42 mmol/mol). Optimal metabolic control was defined as HbA1c below 7% (53 mmol/mol) without severe hypoglycemias as recommended by International Society for Pediatric and Adolescent Diabetes (ISPAD) . Normal The estimated glomerular filtration rate (eGFR) values were calculated using serum creatinine (eGFRcreat) and serum cystatin C (eGFRcys) for all participants. Creatinine-based Schwartz formula  for eGFR2; Level 2—GFR 60–89 mL/min/1.73 m2; Level 3—GFR 30–59 mL/min/1.73 m2; Level 4—GFR 15–29 mL/min/1.73 m2 and Level 5—GFR < 15 mL/min/1.73 m2.Kidney function was staged according to American Diabetes Association (ADA) guidelines : Level 1Furthermore, we classified patients according to eGFRcreat and eGFRcys levels: Group 1—if eGFRcreat level was equal to eGFRcys level; Group 2—if eGFRcreat level < eGFRcys level; Group 3—if eGFRcreat level > eGFRcys level.Digital fundus photos were taken and evaluated by a single ophthalmologist specialized in diabetic retinopathy.All patients were screened for the level of albuminuria in 24-h urine as reported earlier [All patients were screened for the presence of symptoms or signs of symmetrical peripheral neuropathy. We applied Michigan Neuropathy Screening Questionnaire and evaluated the sensations of vibration, pressure, and temperature. Diagnosis of peripheral neuropathy was confirmed if two or more of these tests were abnormal ,26.t-test, χ2 statistics, parametric one-way ANOVA , and Mann–Whitney U-test  or Kruskal–Wallis one-way ANOVA  were used. Pearson correlation coefficient , and Spearman’s coefficient  were used while testing associations between continuous variables. p-values < 0.05 were considered statistically significant. All p-values were 2-tailed.IBM SPSS Statistics software was used for statistical analyses. Student’s 2-tailed n = 399) were females. The median of age at inclusion was 16.2 years , age at the onset of T1D—9.4 years , the median of diabetes duration—5.3 years . There were 51.9% (n = 404) of patients with diabetes duration ≥ 5 years.Overall, 779 patients with T1D were included in the study, 51.2% (n = 581) of participants, 20.1% (n = 155) were overweight, 3.6% (n = 28)—obese and 1% (n = 8)—underweight. Optimal WtHR was found in 85.3% (n = 622) of participants.Normal BMI was found in 75.3% (n = 188) of all patients. Higher than normal serum cystatin C concentration was present in 10.8% (n = 84) of all patients.Optimal glycemic control was found in 24.2%  vs. 87  mL/min/1.73 m2, p < 0.001.The median of eGFRcys was lower in the whole cohort compared to eGFRcreat, 92  vs. 101  mL/min/1.73 mp < 0.001.The grouping of all patients by kidney function level using either eGFRcreat or eGFRcys is presented in After grouping patients according to the equivalency of eGFR levels calculated by creatinine and cystatin C, we found that 30.2% of patients had worse eGFR levels calculated using cystatin C (Group 2 when eGFRcreat level < eGFRcys level), 61.1% had the same eGFR level using both biomarkers (Group 1) and 8.7% were classified as Group 3 (when eGFRcreat level > eGFRcys level).End-stage renal disease in diabetes patients is known to be the leading cause of increased risk for premature mortality . Only haThe main finding of our study was that using cystatin C helped to find those young T1D patients who may be suffering from early kidney damage, as one-third of the whole cohort was classified with worse eGFR levels when using cystatin C vs. creatinine. As demonstrated in the Tsai et al. study where the adult population using eGFR based on cystatin C helped to reclassify kidney function from preserved to reduced, especially in patients with diabetes , this meIt is known that the pathogenesis of diabetic kidney damage starts with glomerular hypertrophy, hyperfiltration and hyperperfusion state , therefo2) [2.Leem et al. demonstrated that cystatin C is not only a reliable biomarker but also is associated with the recovery prognosis of acute kidney injury in critically ill adults . Further2) , though Consistent with the Third National Health and Nutrition Examination Survey (NHANES III), our study showed that the levels of serum cystatin C were higher in children compared to adults  and wereA negative correlation between serum cystatin C and HbA1c was found in our investigation, which is in agreement with the SEARCH for Diabetes in Youth Study and the results from Maahs et al.’s study ,35, howeOne of the limitations of our study is that we did not measure GFR as it is considered to be the best assay of kidney function . HoweverThe other challenge that our study faced was the lack of pediatric normative values for serum cystatin C. However, this is a worldwide issue, even for the most frequently used biomarkers, such as neutrophil gelatinase-associated lipocalin, kidney injury molecule-I, and serum cystatin C, there are insufficient reference values in the pediatric population .Serum cystatin C adds significance for diagnosing early kidney damage, as our study showed it could be successfully used in young patients with T1D for estimating GFR. To assess the precise prognostic value of cystatin C, we need further follow-up studies of these young T1D patients to identify those who will develop advanced diabetic kidney disease.