The concomitant assessment of arterial and venous Doppler patterns predicts postoperative complications after major laparoscopic urologic surgery and may be considered a useful ultrasonographic biomarker to stratify vulnerable patients at risk for development of postoperative complications.Point-of-care ultrasonography (POCUS) with concomitant venous and arterial Doppler assessment enables clinicians to assess organ-specific blood supply. To date, no studies have investigated the usefulness of including a comprehensive perioperative POCUS assessment of patients undergoing major laparoscopic surgery. The primary aim of the present study was to evaluate whether the combined venous and arterial renal flow evaluation, measured at different time points of perioperative period, may represent a clinically useful non-invasive method to predict postoperative acute kidney injury (AKI) after major laparoscopic urologic surgery. The secondary outcome was represented by the development of any postoperative complication at day 7. We included 173 patients, subsequently divided for analysis depending on whether they did (n = 55) or did not (n = 118) develop postoperative AKI or any complications within the first 7 days. The main results of the present study were that: (1) the combination of arterial hypoperfusion and moderate-to-severe venous congestion inferred by POCUS were associated with worst outcomes (respectively, HR: 2.993, 95% CI: 1.522–5.884 and HR: 8.124, 95% CI: 3.542–18,  Perioperative AKI is a serious complication associated with high morbidity and mortality , occurriWhile close attention is generally paid to pre- and postoperative management, the role of surgical techniques and perioperative management in the development of AKI and other complications remains underappreciated.Postoperative AKI may be due to either sudden arterial hypoperfusion causing acute tubular necrosis, or renal venous congestion determined by intraluminal hypertension. These two mechanisms can lead to a dramatic fall in glomerular filtration rate; in fact, the net ultrafiltration pressure is derived from the opposing forces of the blood hydrostatic pressure in the glomerulus versus the combination of capsular hydrostatic pressure and blood colloid osmotic pressure .Point-of-care ultrasonography (POCUS) with arterial Doppler assessment enables clinicians to assess organ-specific blood supply in both arteries and veins ,10. ReceOur hypothesis is that not only arterial perfusion but even venous drainage may influence organ perfusion, determining AKI and other postoperative complications. The primary aim of the present study is to evaluate whether, in patients undergoing major laparoscopic urologic surgery, the combination of IRVF and renal Doppler resistive index (RDRI) measured at different time points of perioperative period represents a clinically useful non-invasive method to predict postoperative AKI (within the first seven days) . The secThis is an observational, monocentric, prospective study. The study was approved by the local ethics committee (CER Liguria: 7/2019-id: 4378) and all the enrolled patients gave written informed consent to the use of their data.Between December 2019 and April 2022, all the adult patients admitted for major laparoscopic surgery to the urology section of the Galliera Hospital, Genova, Italy, were evaluated for enrollment.Inclusion criteria were: age > 18 aa, the ability to provide informed consent, and availability of the operators to perform a POCUS assessment before surgery.2 or dialysis), renal transplantation (planned or received), critical preoperative state , emergency surgery, obstructive uropathy, urinary infection, or sepsis , the Karnofsky scale, and the preoperative American Society of Anesthesiologists Classification (ASA score). Creatinine measurements were obtained before surgery and daily after surgery until discharge. The estimated glomerular filtration rate was calculated using the Modified Diet in Renal Disease formula . AKI wasAll ultrasonographic examinations were performed by two expert operators using a Mindray TE7 ultrasound device  with a 2.5–5.0 MHz convex array transducer for kidney’s examination with the patient in a supine position ,16. AfteThe ultrasound examination was considered technically acceptable if the following criteria were met: (a) the possibility to obtain a clear two-dimensional longitudinal scan with definition of renal parenchyma, (b) a good color Doppler image with visualization of IRVF was feasible, and (c) at least three consecutive Doppler time-velocity spectra were obtained. Pulsed-wave Doppler spectrum was increased by using the lowest frequency-shift range that did not cause aliasing, and the wall filter was set at a low frequency (100 MHz). RDRI was calculated according to Planiol and Pourcelot’s protocol as (VMax–VMin)/VMax . The valAll Doppler examinations were recorded on the day before surgery, at postoperative day 1, and at hospital discharge. The attending physician was unaware of the results of the ultrasound examinations. The investigators were blinded to the clinical parameters while performing the ultrasound assessments.All the variables are expressed as median and interquartile range (IQR) for continuous variables, or as percentage (%) for categorical variables. The Shapiro–Wilk test was used to evaluate the normal distribution of continuous variables. The Mann–Whitney U-test or Fisher’s exact test were used to evaluate differences between groups for continuous or categorical variables, respectively. Cumulative probability for lack of postoperative AKI or any complications in patients with different Doppler profiles were calculated with the Kaplan–Meier product-limit estimator. The censored/uncensored patients corresponded to hospital discharge/occurrence of complications. The log-rank (Mantel–Cox) test was applied to evaluate the difference between Kaplan–Meier curves in Doppler profiles .p < 0.10 without violating the assumption of proportional risk were entered into a multivariate Cox proportional hazard model. In each Cox model both the regression coefficient and hazard ratio (HR) with 95% confidence interval (CI) were calculated. Logistic regression was used to identify independent variables potentially associated with IRVF patterns identified as predictors of complications, by providing odds ratio (OR) with the corresponding 95% CI for each model. The receiver operating characteristic (ROC) curves were used to determine the best cut-off values. The area under the ROC curve (AUC) and the related 95% CI were calculated. Linear forward regression models with the Bayesian information criterion were also performed to evaluate the relationship between independent variables and monophasic IRVF assumed as the dependent variable. Inter-observer variability was tested by intraclass correlation coefficient (ICC) in two-way models for agreement .The main Doppler and clinical variables were entered into a Cox proportional hazard analysis. The variables associated in univariate models with occurrence of postoperative AKI or any complications with a p < 0.05 with a two-tailed null hypothesis. The statistical analyses were carried out by using SPSS  and R environment .Statistical significance was assumed at A total of 200 patients met the inclusion criteria. After exclusion criteria, 173 patients were included in the analysis  and diviThe distribution of the morphology of the IRVF pattern is illustrated in On postoperative day 1, the IRVF pattern was continuous in 22 patients (12.7%), biphasic in 80 (46.2), and monophasic in 71 (41%). The median RDRI was 0.69 (IQR 0.63–0.74). As compared with preoperative measurements, the IRVF pattern worsened in 54 patients (31%), changing from continuous to biphasic in 10, from continuous to monophasic in 8, and from biphasic to monophasic in 36, suggestive of a trend toward stages of more severe congestion.p < 0.001).At hospital discharge, the IRVF pattern was continuous in 32 patients (18.5%), biphasic in 116 (67.1%), and monophasic in 25 (14.5%). The median RDRI was 0.66 (IQR 0.59–0.70). Overall, the IRVF pattern improved from the pre- to postoperative period in 29 patients and remained unchanged in 90, while RDRI significantly increased (0.65 (IQR 0.58–0.70) vs. 0.69 (0.63–0.74) Patients who developed postoperative AKI had more cardiovascular comorbidities treated by oral β-blockers with slightly higher baseline RDRI, higher intra-abdominal pressure due to surgical pneumoperitoneum, lower renal filtration gradient, and lower hemoglobin levels in the postoperative period .p < 0.001) (p < 0.001) with the best cut-off of 0.72 . Inferior vena cava maximum diameter and collapsibility index were not significantly different between the two groups   and higho groups .In multivariate analysis, IRVF pattern and RDRI were the only factors independently associated with postoperative AKI . Kaplan–Of the 55 patients with various types of complications , no one Patients who developed any complications within day 7, compared with patients who did not , had a hp < 0.001) (p < 0.001) with the best cut-off of 0.72 . Inferior vena cava maximum diameter and collapsibility index were not significantly different between the two groups   with a h< 0.001)  and higho groups . In multo groups . Kaplan–o groups .At univariate analysis, the development of monophasic IRVF was associated with high pneumoperitoneum pressure and a large amount of fluid given during the intraoperative period , but notFrom the present cohort, combining arterial and venous Doppler spectra, we can identify six different perfusion profiles: (1) “normal”, with preserved arterial perfusion without congestion characterized by an RDRI < 0.72 and continuous IRVF; (2) ”pure hypo-perfused” with RDRI > 0.72 and continuous IRVF; (3) “compensated congestive profile” with biphasic IRVF but RDRI < 0.72; (4) “mixed mild hypo-perfused and decompensated congestive profile” with biphasic IRVF and RDRI > 0.72; (5) “pure severe congestive profile” with monophasic IRVF but normal RDRI < 0.72; and (6) “mixed severe hypo-perfused-congestive profile” with monophasic IRVF and increased RDRI > 0.72. .The frequency distribution of these profiles was associated with the occurrence of postoperative AKI or any complications .The most frequent profile (number 3) was present in 36% of patients and associated with a low rate of complications (5%). Profiles with arterial hypoperfusion but no congestion (numbers 2 and 4) were associated with a 28–33% complication rate. Profiles with severe venous congestion were associated with complication rates from 46% in the case of isolated venous congestion to 76% in the case of concomitant arterial hypoperfusion. Kaplan–Meier estimates of the time to first postoperative AKI or complication for the six flow profiles are represented, respectively, in The IRVF patterns were identifiable in all cases with complete inter-observer agreement.RDRI could not be determined in one or in both kidneys of 10 subjects (5%) due to poor acoustic windows caused by intestinal gas, presence of surgical drainage or obesity. The inter-rater agreement for RDRI was strong (ICC 0.844 (95% CI from 0.792 to 0.844)).In this study, the prediction of AKI and other postoperative complications after major urologic laparoscopic surgery was researched using a renal point-of-care ultrasound. The main findings were that (1) a postoperative monophasic IRVF pattern predicts AKI or any complications by day 7, (2) high intraoperative abdominal pressure represents the only independent determinant of postoperative monophasic IRVF pattern, and (3) the overall number of postoperative AKI or any complication relies on the balance between arterial inflow and venous outflow in order to ensure the adequacy of peripheral perfusion.Postoperative IRVF patterns have not been extensively studied in the perioperative period of laparoscopic surgery. This study shows that IRVF assessment is feasible with a widely available conventional ultrasonographic system and can provide information on the risk of postoperative AKI as well as any complications within the postoperative day 7. Patients who developed postoperative monophasic IRVF patterns were those who received larger amounts of intraoperative fluids and had higher intra-abdominal pressure, independently of mean arterial pressure. Although a low mean arterial pressure may represent a condition affecting intrarenal circulation, the lack of significant association with changes in IRVF patterns in the present study suggests that mechanisms other than the sole blood supply could be involved in the development of renal dysfunction. Some of these might be the increase in venous resistance to flow induced by high intra-abdominal pressure and reduction of parenchymal compliance due to increased renal interstitial pressure caused by fluid overload; both mechanisms ultimately lead to a “splanchnic tamponade” .This is an important issue to be considered because introduces the concept that splanchnic tamponade due to venous congestion is not necessarily caused by fluid overload but may be due to other conditions affecting vascular compliance such as abdominal hypertension or abdominal compartment syndrome, leading to the development of the new concept of “dry” splanchnic tamponade.Most of the ultrasonographic studies on congestion came from the application of VEXUS protocols in cardiologic patients with varying degrees of right and/or left cardiac dysfunction and concomitant fluid overload . HoweverFurthermore, in our study, a considerable number of patients in the postoperative period presented with venous patterns suggestive of mild-to-moderate congestion, without actually developing postoperative AKI or any complications. These findings support the hypothesis that venous congestion may be effectively counterbalanced by a proper cardiac output and arterial in-flow .Moreover, the monophasic IRVF pattern was associated with worst outcomes compared with the continuous or biphasic patterns; these findings are supported by the influence of splanchnic congestion on postoperative complications ,24,25,26RDRI was previously demonstrated to be as a useful tool to assess splanchnic regional perfusion in critically ill patients ,15,16. TOur study is different from all those previously published on the topic as for the first time it simultaneously evaluates arterial perfusion, venous congestion, and their mutual interrelationship. The combination of overt arterial hypoperfusion (RDRI > 0.72) and moderate-to-severe venous congestion (biphasic or monophasic venous patterns) was associated with the worst outcomes, suggesting that only the concomitant assessment of the arterial and venous side of the circulation may provide the entire picture of the adequacy of end-organ perfusion requirements.Hopefully, this concept will pave the way for designing a large randomized clinical trial to investigate if and how addressing the adequacy of splanchnic perfusion more precisely by US can improve the postoperative outcomes of these patients.We acknowledge some study limitations. This is a single-center study from a referral center. It has inherent flaws related to selection and referral bias. Our work was not aimed to evaluate the different effects on splanchnic circulation by different types of urological surgery that may be important factors affecting perfusion. Cardiac output, the major determinant of splanchnic perfusion, was not measured because it does not comply with our ERAS protocol in this type of surgery. The results of the present study refer to elective laparoscopic urological surgery and therefore cannot be transposed to other types of surgery.The concomitant assessment of the arterial (RDRI) and venous (IRVF) side of the circulation predicts postoperative complications after major laparoscopic urologic surgery and may be considered a useful ultrasonographic biomarker to stratify vulnerable patients at risk for the development of postoperative complications. Whether prediction of AKI and other complications can anticipate or ameliorate the treatment of perfusion disorders, improving outcomes requires further investigation.


Optimal target blood pressure to reduce adverse cardiac remodelling in children with chronic kidney disease is uncertain. We hypothesised that lower blood pressure would reduce adverse cardiac remodelling.2—and who could be followed up for 2 years. Children on antihypertensive medication were eligible as long as it could be changed to angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) if they were not already receiving these therapies. Participants were randomly assigned (1:1) to standard treatment (auscultatory office systolic blood pressure target between the 50th and 75th percentiles) or intensive treatment (systolic target <40th percentile) by the chief investigator using a rapid, secure, web-based randomisation system. ACE inhibitors or ARBs were used as first-line agents, with the dose titrated every 2–4 weeks to achieve the target blood pressure levels. The primary outcome was mean annual difference in left ventricular mass index (LVMI) by echocardiography measured by a masked observer and was assessed in the intention-to-treat population, defined as all the children who underwent randomisation irrespective of the blood pressure reached. Secondary and safety outcomes were the differences between groups in mean left ventricular relative wall thickness, renal function, and adverse effects and were also assessed in the intention-to-treat population. This trial is registered with ISRCTN, ISRCTN25006406.HOT-KID, a parallel-group, open-label, multicentre, randomised, controlled trial, was done in 14 clinical centres across England and Scotland. We included children aged 2–15 years with stage 1–4 chronic kidney disease—ie, an estimated glomerular filtration rate (eGFR) higher than 15 mL/min per 1·73 m2·7 [95% CI –2·4 to –1·3] vs –1·2 g/m2·7 [–1·5 to 0·8], with a treatment effect of –0·7 g/m2·7 [95% CI –1·9 to 2·6] per year; p=0·76) and mean value in both groups at the end of follow-up within the normal range. At baseline, elevated relative wall thickness was more marked than increased LVMI and a reduction in relative wall thickness was greater for the intensive treatment group than for the standard treatment group . Six (5%) participants reached end-stage kidney disease  during the course of the study. The risk difference between treatment groups was 0·02  for overall adverse events and 0·07  for serious adverse events. Intensive treatment was not associated with worse renal outcomes or greater adverse effects than standard treatment.Between Oct 30, 2012, and Jan 5, 2017, 64 participants were randomly assigned to the intensive treatment group and 60 to the standard treatment group . Median follow-up was 38·7 months (IQR 28·1–52·2). Blood pressure was lower in the intensive treatment group compared with standard treatment group  but in both groups was close to the 50th percentile. The mean annual reduction in LVMI was similar for intensive and standard treatments (–1·9 g/mThese results suggest that cardiac remodelling in children with chronic kidney disease is related to blood pressure control and that a target office systolic blood pressure at the 50th percentile is close to the optimal target for preventing increased left ventricular mass.British Heart Foundation. Blood pressure is thought to be a key determinant of major clinical outcomes in children with chronic kidney disease, including progression of kidney disease and development of cardiovascular disease. The Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of Chronic Kidney Disease in Pediatric Patients (ESCAPE) trial showed that lowering ambulatory blood pressure targets slows kidney disease progression and remains the basis for current clinical recommendations.Evidence before this studyCurrent recommendations regarding the management of blood pressure in children with chronic kidney disease are heavily based on data from a single trial, the Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of Chronic Kidney Disease in Pediatric Patients (ESCAPE) trial, with slower kidney disease progression in those with lower blood pressure targets . However, recommended targets when using office-based blood pressure measurement are not based on as robust evidence and are higher (auscultatory systolic blood pressure target <90th percentile). Children with chronic kidney disease are predisposed to the development of left ventricular hypertrophy, which is associated with adverse clinical outcomes in early adulthood, but the optimal blood pressure to prevent adverse ventricular remodelling leading to left ventricular hypertrophy is uncertain. Effects of lower compared with higher blood pressure control were studied in a subset of children in the ESCAPE trial with no effect seen on left ventricular mass index (LVMI), but not all participants who underwent randomisation were studied.Added value of this studyTo our knowledge, HOT-KID is the first randomised controlled trial to examine the effect of different levels of blood pressure control on left ventricular remodelling in children with chronic kidney disease. On an intention-to-treat basis, the trial showed no significant effect of intensive office blood pressure reduction (target <40th percentile) compared with standard reduction (target 50th–75th percentile) on the primary outcome: LVMI. However, probably because of better-than-expected blood pressure control on entry to the study, left ventricular hypertrophy was present in only a small proportion of the participants, and LVMI was within the normal range. In contrast to LVMI, relative wall thickening, a measure of remodelling that might precede left ventricular hypertrophy and is itself related to adverse outcomes, was elevated at baseline and was significantly reduced by intensive compared with standard blood pressure reduction. This was despite the blood pressure in the standard treatment group being close to the 50th percentile.Implications of all the available evidenceAlthough the HOT-KID trial has limitations, as it is a small, open-label trial, it supports the concept that a blood pressure target lower than the 50th percentile is close to the optimal for preventing progression of adverse ventricular remodelling. In combination with results of the ESCAPE study, a blood pressure threshold of lower than 50th percentile can be recommended as likely to prevent both progression of kidney disease and adverse ventricular remodelling. A remaining challenge is to clarify the best method of monitoring blood pressure in children and the equivalence of blood pressure thresholds.Definitive evidence to determine the optimal blood pressure target in children to reduce adverse events requires follow-up in sufficiently large numbers over many years to obtain data on clinical events. Such an undertaking is not regarded as feasible currently. In children with chronic kidney disease, the strong association of cardiac remodelling—left ventricular hypertrophy in particular—with adverse cardiac events later in adulthood has led to a focus on cardiac remodelling as a surrogate outcome in this population.12Our previous work using auscultatory office blood pressure highlighted that left ventricular hypertrophy was closely associated with blood pressure and was less likely to occur in patients with blood pressure lower than the 50th percentile.22, with the eGFR calculated using the Schwartz formulaThe HOT-KID study was a parallel-group, open-label, multicentre, randomised, controlled trial. We also completed an observational study as part of HOT-KID, but the results of this study will be reported at a later date. The randomised controlled trial was done at 14 clinical centres across England and Scotland. Children aged 2–15 years were included if they had stage 1–4 chronic kidney diseaseThe trial design complies with the principles of the Declaration of Helsinki and was approved by the Clinical Studies Group of the British Association for Paediatric Nephrology, with recruitment and follow-up supported by all paediatric nephrology centres in the UK. Parents or legal guardians of children gave written informed consent, and participants gave assent as appropriate. Trial participants were enrolled by the study site principal investigator with any queries regarding eligibility discussed with chief investigator (MDS). The study protocol  had no additional amendments to that included in the Participants were randomly assigned (1:1) to receive standard treatment or intensive treatment by the chief investigator (MDS) using a rapid, secure, web-based randomisation system developed in house by the King's Clinical Trials Unit (King's College London). Randomisation was stratified according to clinical centre. Participants and recruiting clinicians were informed of the participant's allocation and trial-related systolic blood pressure targets electronically. Therefore, no unblinding or code breaking was required. Clinicians performing investigations were masked to participants' systolic blood pressure percentile and target, and the trial team and recruiters were masked to results.On the day of baseline assessments (day 0), eligible participants, following consent, underwent standardised measurement of blood pressure, echocardiography, and other study-related investigations, including measurement of plasma creatinine. Assessments were performed in dedicated clinical research facilities where possible, with participants aware of planned trial-related assessments.α-channel blockers. The use of long-acting drugs with once daily dosing was recommended. Following achievement of the target blood pressure, all children were monitored at least every 4 months at the time of routine hospital appointments, and their office blood pressure was maintained in the assigned target range over the duration of the study. Up-titration, down-titration, or withdrawal of antihypertensive drugs during the trial was determined using the flowcharts shown in the After randomisation, antihypertensive treatment in children whose blood pressure was not at the target level was commenced or modified to achieve the allocated target. For the intensive treatment group, the systolic office blood pressure target was lower than the 40th percentile (Z score –0·26), and for the standard treatment group it was between the 50th and 75th percentile (Z score 0·00–0·67). ACE inhibitors or ARBs were used as first-line agents, with the dose titrated every 2–4 weeks to achieve the target blood pressure levels. In cases in which children were on drugs other than ACE inhibitors or ARBs, an ACE inhibitor or ARB was substituted for another class of drug (with no washout period). Following ACE inhibitors or ARBs, the following drugs were used based on physicians' preferences to achieve target blood pressure: calcium channel blockers, β-receptor blockers, diuretics, or Data were collected by means of a standardised data collection form, with subsequent data entry into a dedicated web-based database (MedSciNet). At each follow-up visit, height, weight, blood pressure, antihypertensive medication, antihypertensive drug adherence, concomitant medications, and adverse outcomes were recorded. Laboratory data  were obtained at baseline and every year thereafter, with additional renal function assessments after an increase in dose of ACE inhibitors or ARBs, or as deemed necessary by the clinician.Office blood pressure was measured by a trained staff member (physician or nurse) and was measured by the same person on each child where possible. Patients were required to rest for at least 5 min in a seated position, systolic blood pressure was initially confirmed by palpation, and then the blood pressure was measured three times in quick succession using auscultation and aneroid sphygmomanometer with an appropriately sized cuff by inflating the cuff higher than systolic blood pressure. Cuff size was selected by ensuring cuff bladder length and width according to standard guidelines.2·7]) as a measure that accounts for body size.Transthoracic echocardiograms were acquired at baseline and at annual intervals by a core team of experienced echocardiographers according to a standardised research protocol. To reduce inter-observer error, investigators travelled to all external centres from the lead centre  and performed all study-related cardiovascular assessments. Each echocardiogram was transferred in DICOM format and stored on a database in the Clinical Research Facilities, St Thomas' Hospital, London, UK, where a single masked investigator (HG) performed the overall image analysis for the primary outcome without knowledge of allocation to treatment group. The intra-observer coefficient of variation for this investigator was 8·5% for left ventricular mass and 7·1% for relative wall thickness. Left ventricular mass varies widely across the paediatric age range 0−16 years). Therefore, to allow standardisation, it is expressed as left ventricular mass index  between the intensive versus standard treatment groups. To take into account the variable follow-up period, the mean annual change in LVMI was calculated. We also report changes in mean left ventricular mass for height Z score. As secondary outcomes, to assess the effect on left ventricular reverse remodelling, we analysed the difference in mean relative wall thickness between the trial groups. We report systolic and diastolic blood pressure in both groups and the proportion of participants requiring antihypertensive medications (together with number of antihypertensive medications). Safety and renal (eGFR) outcomes were additional reported secondary outcomes. Adverse events were monitored by study investigators and logged as appropriate. Potential adverse effects of the drugs were well known to the investigators and were managed according to standard care and according to the protocol. Serious side-effects were reported by investigators on adverse event forms  between participants previously studied in our cohort of children with chronic kidney disease who had blood pressure in the 50th–75th percentile or lower than the 40th percentile. We estimated that 144 participants were required over the 2-year duration to detect this difference with 90% power (significance p<0·05), assuming a dropout rate of up to 20%. A planned blinded interim analysis of the variation in LVMI, after 1 year of follow-up in all participants in the study (not by randomisation) confirmed that this was similar (6·7 vs 6·0 g/m2·7) to that used in the original sample size calculation. Recruitment was slower than expected, and trial recruitment was terminated due to funding constraints at 124 participants. However, at an interim review, it was apparent that the reduced sample size would be mitigated by a longer follow-up period, with the median follow-up being approximately 50% greater than originally anticipated. A formal sample size recalculation was not performed. The primary analysis was then changed to the change in mean LVMI over the duration of the trial, including all available data.On the basis of existing information on LVMI and change in LVMI at annual intervals at proposed blood pressure levels in children with chronic kidney disease, the original sample size was set to detect a difference in change in mean LVMI of more than 3·1 g/mThe primary analysis was the comparison of the outcome measures, assessed according to allocation on an intention-to-treat basis, defined as all the children who underwent randomisation irrespective of the blood pressure reached. No allowance was made for multiple testing of outcomes other than the primary outcome. We analysed the mean annual rate of change in LVMI (95% CI), and the difference (95% CI) in these rates using a restricted maximum likelihood-based repeated measures approach in combination with the Newton-Raphson algorithm. The analysis included the fixed, categorical effects of treatment, clinical centre, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline value of the outcome measure and baseline value-by-visit interaction. We used a common unstructured covariance structure to model the within-patient errors. The Kenward-Roger approximation was used to estimate denominator degrees of freedom. Significance tests were based on least-squares means using a two-sided α value of 0·05 (two-sided 95% CIs).This model accounts for the baseline and all subsequent follow-up measurements, and enables the inclusion of participants with missing measurements. It assumes that the outcome measure changes linearly over time. Patients were followed up for between 1 year and 5 years from baseline and, like all linear mixed models, the model assumes that when data were missing, they were missing at random. We also did a post-hoc sensitivity analysis that relaxes the assumption of a linear change of outcome variable over time was as follows: we estimated mean LVMI (or other outcome measures), with 95% CIs, in each treatment group at each timepoint (from 1 year to 5 years), along with the absolute difference in these means (95% CIs), using a linear mixed-effects model for repeated measures. Subgroup analysis for the primary outcome by age (dichotomised according to the median) and sex was additionally performed post hoc.We did a further post-hoc sensitivity analysis to evaluate the possible influence of missing values for the primary and secondary outcomes. Multiple imputation was done using Markov chain Monte Carlo with the following variables used to impute the missing values: clinical centre, group, time, and baseline measurements . 20 datasets were imputed to generate the average adjusted mean difference reported previously. Adverse events and serious adverse events are summarised by treatment group in the intention-to-treat population. A Wilson test was used to assess difference in risk for overall adverse events and serious adverse events in the intention-to-treat population. The statistical analysis plan is in the This trial is registered with ISRCTN, ISRCTN25006406.The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report other than through providing comments by external reviewers.2. The primary cause of chronic kidney disease in 39 (61%) participants in the intensive treatment group and 42 (70%) participants in the standard treatment group was congenital anomalies of the kidney and urinary tract, and chronic kidney disease was thus lifelong in these participants. Anaemia was treated with oral iron supplementation, and no trial participants received erythropoietin or immunosuppresants for glomerulopathies or other indications during the course of the trial. At baseline, mean clinic blood pressure was 107/63 mm Hg (SD 11/12), with a mean clinic blood pressure Z score of 0·55/0·06 (0·91/1·25); 38 (63%) participants' systolic blood pressure was lower than the 75th percentile in the standard treatment group, and in 12 (19%) participants in the intensive treatment group it was lower than the 40th percentile of the reference population. 80 (65%) participants were on antihypertensive medications at baseline, 52 (65%) of whom were on ACE inhibitors or ARBs alone, nine (11%) on a calcium channel blocker, three (4%) on other antihypertensives , and 16 (20%) on two or more antihypertensive medications including ACE inhibitors or ARBs. Blood pressure and echocardiographic measures at baseline between those on antihypertensives and those without antihypertensive medication were similar .Throughout follow-up, the mean office systolic blood pressure was 103 mm Hg (SD 10) in the intensive treatment group versus 107 mm Hg (10) in the standard treatment group (p=0·0012), mean office diastolic blood pressure was 60 mm Hg (10) versus 64 mm Hg , and mean arterial pressure was 75 mm Hg (9) versus 78 mm Hg , with a mean systolic blood pressure Z score of 0·06 (0·88) versus 0·19 (0·80) and a mean diastolic blood pressure Z score of –0·27 (1·09) versus 0·01 (1·16). Over the course of the study, the number of antihypertensive medications prescribed per patient was higher in the intensive treatment group than in the standard treatment group, with a mean difference between groups of 0·50 , with relatively few children reaching the definition of left ventricular hypertrophy  for the intensive treatment group versus –1·2 g/m2·7 (–1·5 to 0·8) for the standard treatment group . Mean left ventricular mass for height Z score showed an annual change of –0·3 (–0·4 to –0·2) for the intensive treatment group versus –0·2 (–0·3 to –0·1) for the standard treatment group .There was a sustained reduction in LVMI over the course of the trial, but the difference between groups did not reach statistical significance ; table 2vs –0·004 [–0·008 to 0·001]; difference in means –0·020 [95% CI –0·039 to –0·009] per year, p=0·0019). The left ventricular remodelling resulted in more children with normal geometry in the intensive treatment group than in the standard treatment group at all timepoints  during the course of the study . In participants with an eGFR of less than 60 mL/min per 1·73 m2 at baseline, two (11%) of 19 in the intensive treatment group and three (20%) of 15 participants in the standard treatment group had a greater than 30% reduction in eGFR over the course of the study  of 58 participants in the intensive treatment group and two (4%) of 52 participants in the standard treatment group (Over the course of the study, the mean difference in eGFR between the intensive treatment group and the standard treatment group was –3·9 mL/min per 1·73 mhe study . In partnt group .2·7 over a 2-year follow-up period. The two treatment strategies resulted in a reduction in relative wall thickness over time. This contrasts with the increase that is seen in children in the general population.To our knowledge, the HOT-KID study provides the first evidence from a randomised controlled trial on the effects of differing blood pressure targets on cardiac remodelling. The main findings of the HOT-KID study are that, in an intention-to-treat analysis, allocation to an office systolic blood pressure target lower than the 40th percentile versus a target higher than the 50th percentile did not result in a significant reduction in LVMI over the course of several years and that the 95% CIs for change in mean LVMI excluded the effect size we specified as clinically significant: a change of greater than 3·1 g/mIn the context of a near-normal left ventricular mass in the majority of participants and a low prevalence of left ventricular hypertrophy, a change in LVMI is unlikely. In contrast to LVMI, relative wall thickness was elevated in the majority of children, reflecting a tendency to concentric remodelling. Concentric remodelling is a recognised feature of hypertension-mediated organ damage in clinical practice guidelinesSome children in the intensive treatment group did not reach a blood pressure lower than the 40th percentile, and the majority of children in the standard treatment group had blood pressure that was close to the 50th percentile. As a result, the blood pressure difference between the two groups was modest. This finding might be explained by the tendency of physicians, patients, and their families to be conservative when considering up-titrating or down-titrating therapy, leading to convergence of achieved blood pressure in the two groups. This convergence of achieved blood pressure is in keeping with trials of similar design. In the ESCAPE study, for example, target blood pressure in the two groups of the trial was 24 h mean arterial pressure between the 50th and 95th percentile and lower than the 50th percentile, and the blood pressure difference between the groups ranged between 2·7 mm Hg and 3·9 mm Hg in different study years.The degree to which cardiac remodelling in children with chronic kidney disease is driven by blood pressure or by other chronic kidney disease-specific factors, including anaemia and increased concentrations of phosphate and parathyroid hormone, has been debated.In the children with left ventricular hypertrophy or abnormal geometry, this regressed in both groups. This finding suggests that there is no benefit in targeting a systolic blood pressure to lower than the 40th percentile. However, several factors point to a blood pressure close to the 50th percentile rather than the 75th percentile as being beneficial. Blood pressure in the standard treatment group was much closer to the lower rather than higher end of the 50th–75th percentile target. This combined with the finding of a blood pressure dependence of cardiac remodelling even with a narrow range suggests that the reverse remodelling seen in the standard treatment group would have been attenuated had the majority of children had blood pressure in the upper range of the 50th–75th percentile. Thus, a target of the 50th percentile would seem close to the optimal for preventing cardiac remodelling. In practical terms, any definition of a target requires an upper limit above which treatment is up-titrated. In our study, there was no adverse effect on safety or renal outcomes of targeting to lower than the 40th percentile. Therefore, until data from larger-scale randomised controlled trials of office blood pressure are available, we suggest targeting to an office systolic blood pressure lower than the 50th percentile with up-titration of treatment at the 50th percentile.Our trial focused on the use of office auscultatory blood pressure measurement rather than ambulatory blood pressure measurement. Auscultatory blood pressure was chosen because we have previously found it to be a sensitive predictor of left ventricular hypertrophy.In conclusion, within the constraints of a small open-label trial, the HOT-KID trial suggests that cardiac remodelling in children with chronic kidney disease is related to blood pressure control and that a target office systolic blood pressure at the 50th percentile is close to the optimal target for preventing increased left ventricular mass.Trial-related data are available on reasonable request to the principal investigators.We declare no competing interests.


To explore the correlation between Blood urea nitrogen to creatinine ratio (BUN/Scr ratio) and prognosis of patients with chronic heart failure complicated with renal injury.P < 0.05 were put into Cox regression model, and subgroup analysis was performed on the variables that might affect the patient’s prognosis.A retrospective analysis of 504 patients hospitalized in Guang 'anmen Hospital, Chinese Academy of Traditional Chinese Medicine from March 2006 to June 2014 was conducted. The baseline data were analyzed, and the cutoff value was obtained by receiver operator characteristic curve (ROC) analysis, according to the cutoff value, all the participants were divided into two groups, BUN/Scr < 19.37 group (280 cases) and BUN/Scr ≥ 19.37 group (224 cases). The main end point was defined as all-cause death. The long-term mortality of the two groups was evaluated, and Kaplan–Meier survival curve was drawn. Univariate analysis was performed on all the variables affecting the patient's prognosis, and the variables with P = 0.001]. Subgroup analysis showed that the relationship between BUN/Scr and the prognosis of CHF was influenced by NYHA and eGRF (P < 0.05).The baseline data of 504 patients were analyzed and found that the median follow up was 683. Through ROC analysis of 504 subjects, the cutoff value of BUN/Scr was 19.37. The results of Kaplan–Meier survival curve showed that the mortality rate of patients with ratio ≥ 19.37 was higher than that of patients with ratio < 19.37. After multivariate analysis, COX regression model showed that the mortality of patients with BUN/Scr ≥ 19.37 was 1.885 times that of patients with BUN/Scr < 19.37 [HR = 1.885 (1.298–2.737), BUN/Scr ratio is related to the poor prognosis of patients with CHF, and is an independent predictor of all-cause death. Chronic heart failure (CHF) is a clinical syndrome of cardiac output and/or elevated intracardiac pressures at rest or during stress due to structural and/or functional cardiac abnormality . The preCHF patients often have complications , the mosThe insufficient renal perfusion, due to the dysfunction of ventricular systolic and/ or diastolic function in patients with CHF, leads to pre-renal acute kidney injury. Activation of the sympathetic nervous system and the renin–angiotensin–aldosterone system (RAAS) decreased urea excretions, and activation of neurohormones increased urea absorption, while creatinine could pass freely through the glomerulus without absorption, increasing BUN/Scr. On the contrary, intrinsic renal disease is the irreversible nephron loss, urea clearance rate, and glomerular filtration rate were decreased simultaneously, resulting in normal BUN/Scr . BUN/ScrIn consequence, we conducted the retrospective study to explore the relationship between the BUN/Scr ratio and the prognosis of patients with HF complicated with renal injury.Consecutive admissions from March 2006 to June 2014 to the cardiology department at the Guang’anmen Hospital affiliated to China Academy of Chinese Medical Sciences with an admitting diagnosis of CHF were reviewed. The diagnosis of CHF was based on the 2005 ACC/AHA guideline update for the diagnosis and management of CHF in the adult . All patDemographic characteristics, medical history, the course of CHF, biochemical, and other laboratory indicators, NYHA category, electrocardiograph and transthoracic echocardiography parameters were collected from electronic medical records at admission. Estimated glomerular filtration rate (eGFR) was calculated by the chronic kidney disease (CKD) Epidemiology Collaboration (CKD-EPI) equation . BUN wasAfter discharge, patients were followed up by outpatient electronic medical records system or follow-up telephone calls, all patients were followed up until August 2015. Treatment measures were not interfered during the hospitalization and follow up. The primary endpoint was defined as all-cause mortality during follow-up.t test was used for comparison between groups. Measurement data not conforming to normal distribution were expressed as median  [M]. Kruskal–Wallis H test was used for comparison between groups. Enumerative data were expressed by the number of cases (percentage), and the chi-square test was used for comparison. Kaplan–Meier survival curve was used to analyze the survival rate after grouping according to the tangent point values, compare the differences between groups by the log-rank test. Univariate and multivariate Cox proportional risk regression model were used to analyze the correlation between different ratios and the long-term prognosis of CHF. P < 0.05 indicates that the difference is statistically significant.A receiver-operating characteristic (ROC) curve was used to determine the predictive power of BUN/Scr ratio on CHF all-cause mortality, and select the cutoff value to group. According to the cutoff value, patients were divided into two groups. SPSS 25.0 software and MedCalc 19.5.2 Statistical software were used for statistical processing. Measurement data conforming to normal distribution were expressed as mean standard deviation (mean ± sd), and the independent sample 2 and the median ratio of BUN/Scr was 18.5 (IQR 15.0–23.5).A total of 504 patients were enrolled in this study, the median age of participants was 76 IQR 70–81) years old with the majority being male (51.5%). The median follow up was 683 (IQR 440.5–730) days. The vast majority of participants had NYHA class 3 or 4 at study enrollment with the most common comorbidities being coronary heart disease (83.3%), . There was no statistical significance in age, gender, other complications, and other aspects between the two groups (P > 0.05).According to the cutoff value, patients were divided into BUN/Scr < 19.37 group and BUN/Scr ≥ 19.37 group, baseline data of the two groups were analyzed (see Table P = 0.0002).There were 54 deaths in the group < 19.37 and 75 deaths in the group ≥ 19.37. Then Kaplan–Meier survival curve analysis was conducted. The results show that the survival curve of BUN/Scr ≥ 19.37 was significantly reduced Fig. . The difP < 0.005), NYHA  and BUN/Scr  were the risk factors of all death in CHF patients. After adjusting with the age, gender, LVEF, NYHA, multivariate Cox regression model showed that BUN/Scr was still an independent risk factor for all-cause death in CHF patients .All-cause death was used as the dependent variable and BUN/Scr as the independent variable to conduct univariate Cox regression analysis , P < 0.05]. The interaction between them was statistically significant (P < 0.05). Similarly, the interaction between the ratio and eGFR is statistically significant. The relationship between BUN/Scr and CHF prognosis was not affected by LVEF (P > 0.05).Figure The retrospective analysis of this study concluded that: the results of this study reveals that BUN/Scr ratio is associated with all-cause mortality, and BNU/Scr ≥ 19.37 as the best cutoff points for all-cause mortality, and also associated with higher mortality even after adjustment for other prognostic factors, could be a convenient marker for clinical work.Scr and BUN are two important indicators for clinical evaluation of renal function. Scr is the product of creatine metabolism with a small molecular weight, most of which passes through glomerular filtration, and almost all of the Scr formed in the body can be excreted by urine. Reduced cardiac output and decreased blood volume due to diuretic use, resulting in renal insufficiency, decreased glomerular filtration rate, increased Scr. BUN is absorbed by renal tubular filtration, in patients with heart failure, decreased cardiac output and insufficient arterial filling lead to the release of sympathetic nervous system (SNS) and RAAS, and increased sodium reabsorption in proximal renal tubules, resulting in increased urea concentration. Activation of SNS is a major cause of cardiac dysfunction and vascular injury and can significantly worsen the prognosis , 15. In Considering these mechanisms, elevated BUN/Scr level on admission reveals activation of neurohormones and deterioration of renal function, elevated BUN/Scr ratio is associated with poor prognosis in patients with CHF and is an independent predictor of all-cause mortality. This may be because this ratio represents decreased cardiac output, reduced circulating blood volume, insufficient renal perfusion, unstable hemodynamics, and poor prognosis. There are some similarities between our results and those of others.P = 0.006) [P < 0.0001) [According to the median ratio, 557 acute decompensated heart failure patients were divided into high BUN/Scr ratio group and low BUN/Scr ratio group, and the relationship between ratio and long-term mortality was evaluated. During the median follow-up period of 1.9 years, patients with high ratio had higher mortality (= 0.006) . Matsue = 0.006) . Kaplan– 0.0001) . In our Multiple studies showed that the BUN/Cr value was still statistically significant after adjusting for multiple factors by COX analysis –22. EvenP < 0.05).NYHA is a valuable clinical tool, which is related to the potential severity of heart disease and the medium and long-term mortality . In thisP = 0.022).Many studies have shown that eGFR is a powerful prognostic indicator of CHF , 26. TheThis study has some limitations. First, it was a retrospective observational study conducted at a single center, with a selection bias due to the data availability, and does not represent all patients with HF. Second, since this study was observational in nature, other confounding factors affecting the results cannot be excluded even after adjusting the analysis. Despite these limitations, our study emphasizes that CHF patients with BUN/Scr ≥ 19.37 at admission have poorer long-term outcomes, and has predictive value for the prognosis of patients with CHF.In conclusion, this retrospective analysis indicates that BUN/Cr ratio ≥ 19.37 in HF patients at admission can be used as a simple and effective predictor of all-cause mortality.


Cardiovascular events such as myocardial infarction and stroke are life-threatening complications associated with Neurofibromatosis type 1 (NF1). As previous studies observed an association between cardiovascular events and the loss of circadian variations of blood pressure, we investigated the 24 h circadian rhythm of blood pressure (BP) in 24 NF1 patients  by using ambulatory blood pressure monitoring (ABPM).Only one-third of the patient were dippers, 50% were non-dippers, and 17% were risers. Reduced variability of systolic and diastolic nocturnal blood pressure was observed in NF1 patients compared with several studies of normotensive individuals (p = 0.024). In NF1 patients, the blunted systolic nocturnal decline was significantly associated with the number of neurofibromas (p = 0.049) and the presence of a plexiform neurofibroma (p = 0.020).Most NF1 patients in this study showed a “non-dipper” pattern with a blunted nocturnal BP decline, which is considered an independent risk factor for cardiovascular events in normotensive and hypertensive individuals. Periodic monitoring of BP should be included in NF1 follow-up guidelines to diagnose masked hypertension or a non-dipper/riser pattern which would significantly increase the morbidity and mortality of NF1 patients to implement therapeutic strategies.The online version contains supplementary material available at 10.1186/s13023-023-02766-7. Neurofibromatosis type 1 (NF1) is the most frequent genodermatosis with an incidence of 1:3,000 individuals. NF1 patients are prone to develop peripheral nerve sheath tumors such as cutaneous and plexiform neurofibromas. Other manifestations are café-au-lait spots, axillar and inguinal freckling, optic glioma, and skeletal dysplasia. Life expectancy in NF1 is limited by the increase risk of malignancy and cardiovascular events [Cardiovascular disease is a frequent cause of premature death in individuals with NF1  such as In NF1, most studies on blood pressure have been performed in children rather than in adults . Data onWe studied 24 NF1 patients  with a median age of 39 years (IQR 27–54 years). Table The median (IQR) 24 h BP was 110.5 (104.5–116.0)/ 69.5 (66.5–73.5) mmHg, and the median (IR) pulse rate was 73.9 (67.0–83.0) bpm. The median (IQR) nocturnal decline of systolic/diastolic and pulse rate was 9.53 (5.0-11.1)/ 13.5 (9.6–17.9) % and 11.7 (6.8–14.3) %. The 24 h ABPM identified 33% of NF1 patients as “dippers”, 50% as “non-dippers”, and 17% as “risers”. There were no differences in gender or body mass index among the three groups . As expected, systolic (p < 0.003) and diastolic nocturnal decline (p < 0.03) were higher in “dippers” than in “non-dippers” or “risers”.NF1 patients showed an increased proportion of “non-dippers” (67%) compared with previous cohorts of normotensive healthy individuals Table . Thus, NIn NF1 patients, the blunted systolic nocturnal decline was significantly associated with the number of cutaneous neurofibromas p = 0.049) and the presence of a plexiform neurofibroma (p = 0.020)  and the presence of different comorbidities  in 29% of individuals, which are known to reduce the nocturnal decline in BP [Interestingly, a high proportion of non-dippers was also observed in the cohort of normotensive individuals described by Yalim et al.; half of them had even a riser pattern. This could be due to a higher mean body mass index of the cohort . The diagnosis of NF1 in all patients was made according to the guidelines of the 1987 NIH Neurofibromatosis Conference Statement . Each NFFor ABPM we used a Microlife WatchBP O3 AMBULATORY Professional 24-hour BP Monitor  weighing 260 g (including batteries). This device employs an oscillometric method with a pressure static accuracy of ± 3 mmHg and 5% pulse accuracy. Ambulatory blood pressure monitoring was performed on regular workdays. No patients played sports or took medication during the study. The reading frequency was programmed for every 30 min from 8:00 a.m. to 10:00 p.m. (daytime) and every 60 min from 10:00 p.m. to 8:00 a.m. (night-time). Recordings were considered satisfactory for analysis if more than 75% of data were obtained.Hypertension was diagnosed when the ABPM average systolic 24-h mean BP was at least 130/80 mmHg, the daytime systolic average is at least 135/85 mmHg and the nighttime systolic average is at least 120/70 mmHg. Circadian patterns were classified by nocturnal systolic BP fall as “extreme dipper” (≥ 20%), “dipper” (10-19.9%), “non-dipper” (0-9.9%), and “riser/reverse dipper (< 0%). We then divided the patients into three subgroups: “dippers”, “non-dippers”, and “risers”. The systolic nocturnal decline of BP was calculated as follows: *100 / mean daily systolic blood pressure. The diastolic and pulse rate nocturnal decline was calculated using the same formula.Data analysis was performed using SPSS for Windows v.25.0 software . Due to the limited number of patients, non-parametric tests were used. The data were expressed as median and IQR. For continuous variables, we applied Wilcoxon rank-sum tests and Kruskal-Wallis tests depending on the number of groups to be compared (2 or more than 2). For count variables, we used Fisher’s exact test (graphpad.com). The chi-square test with Yates’ correction was used for big samples. P values of < 0.05 were considered as statistically significant.Below is the link to the electronic supplementary material.Supplementary Material 1


In clinical practice, kidney (dys)function is monitored through creatinine-based estimations of glomerular filtration rate . Creatinine is recognized as a late and insensitive biomarker of glomerular filtration rate (GFR). The novel biomarker proenkephalin (PENK) may overcome these limitations, but no PENK-based equation for eGFR is currently available. Therefore, we developed and validated a PENK-based equation to assess GFR.In this international multicenter study in 1354 stable and critically ill patients, GFR was measured (mGFR) through iohexol or iothalamate clearance. A generalized linear model with sigmoidal nonlinear transfer function was used for equation development in the block-randomized development set. Covariates were selected in a data-driven fashion. The novel equation was assessed for bias, precision (mean ± SD), and accuracy  in the validation set and compared with MDRD and CKD-EPI.2. In order of importance, PENK, creatinine, and age were included, and sex or race did not improve performance. The PENK-based equation mean ± SD bias of the mGFR was 0.5 ± 15 ml/min per 1.73 m2, significantly less compared with MDRD  and 2009 CKD-EPI , not reaching statistical significance compared with 2021 CKD-EPI . The P30 accuracy of the PENK-based equation was 83%, significantly higher compared with MDRD  and 2009 CKD-EPI , similar to 2021 CKD-EPI .Median mGFR was 61 [44–81] ml/min per 1.73 mOverall, the PENK-based equation to assess eGFR performed better than most creatinine-based equations without using sex or race.  Abnormal kidney function presages adverse clinical outcomes and is an important adjunct to the dosing of renally excreted drugs. Creatinine-based equations, such as MDRD,PENK, fully: proenkephalin A 119–159 is an endogenous protein (molecular weight ∼4.5 kDa), with no protein binding or cleaving known, that is purely filtered by the glomerulus and not secreted or absorbed in the tubules.,Data were collected according to the ethical principles of the Declaration of Helsinki and approved by local medical ethical committees.,,,,,,,Cr,CrGFR was measured using iohexol plasma clearance or iothalamate renal clearance using the gold standard method of each compound and obtained as part of clinical practice or research purposes.During the GFR assessments, plasma samples were collected for PENK and creatinine concentration measurement using the sphingotest penKid sandwich immunoassay , as described previously.Apart from plasma PENK and creatinine, additional covariates included sex, age, race , and patient diagnostic category: potential kidney donor, post-kidney donor, post-kidney transplant recipient, post other than kidney organ recipient, CKD, post-cardiac surgery, and septic (shock) patients. A generalized linear model with a sigmoidal nonlinear transfer function was used for continuous output regression and equation building. The cohort was block randomized into a development and validation set (ratio 1.5:1), ensuring equal distribution of measured eGFR and type of patient over the sets. The validation set was blinded until the equations were determined. SaddlePoint-Signature  was used for these analyses. SPSS  and GraphPad Prism  were used for statistical tests. Data are presented in medians with interquartile ranges [IQRs], mean ± SD, or frequencies with a 95% CI as appropriate.t test. Furthermore, the Lin’s concordance correlation coefficient was used.Cr equation was published while this analysis was ongoingP values of <0.05.The newly developed equation was evaluated using a validation data set. The performance was tested in the total validation cohort and in subgroups of stable patients and critically ill patients with sepsis and those with post-cardiac surgery. The equation was assessed for bias, accuracy, and precision, through Bland-Altman analyses. For bias, the mean and predicted-kidney function differences were analyzed, depicted as mGFR minus eGFR (negative bias reflects overestimation), and tested using a paired n = 671, stable), post-other organ transplant , post-cardiac surgery , potential kidney donors , known to have CKD , post-kidney donation , and diagnosed with having septic shock . Patients had a median [IQR] age of 60 [48–68] years, and 41% were female. Median [IQR] creatinine was 115 [88–142] μmol/l, and median [IQR] mGFR was 61 [44–81] ml/min per 1.73 m2. In stable patients, the median [IQR] mGFR was 55 [41–74] ml/min per 1.73 m2, whereas in critically ill patients, it was 95 [74–113], illustrating that also patients with a hyperdynamic circulation and increased renal blood flow were included in the critically ill cohorts.The GFR was measured by gold standard methods (mGFR) in 1354 patients . PatientP < 0.001) with the mGFR, compared with −0.75 (−78 to −72) (P < 0.001) for log(10) creatinine (P < 0.001) for MDRD, 0.84 (P < 0.001) for 2009 CKD-EPI, and 0.85 (P < 0.001) for 2021 CKD-EPI. Apart from PENK, available variables were tested through bootstrap iterations, using absolute and logarithmic (10) representation of continuous variables. The correlation coefficient of proenkephalin with the mGFR was 0.76, followed by creatinine at 0.75 and age at 0.17 (Log(10) PENK had a Pearson’s correlation coefficient of −0.76 (95% CI −79 to −73) . The equation was tested for performance in the total validation set (n = 543) and separately in validation subgroups of stable patients (n = 456) and critically ill patients (n = 87). Contour plots illustrate the impact of each parameter in the PENK-Crea equation on the calculated eGFR, compared with 2021 CKD-EPI  was developed using a combined group of all stable and critically ill patients  and 2009 CKD-EPI , not reaching statistical significance compared with 2021 CKD-EPI   and 2009 CKD-EPI (76% (72–79), P < 0.001) but not significantly higher compared with 2021 CKD-EPI (80% (77–83), P = 0.13)  . The med CKD-EPI . The P30 = 0.13) . The P20t was 14 .Figure 22” , “G2, 60 to 89 ml/min per 1.73 m2” , and “G3a to b, 30 to 59 ml/min per 1.73 m2” . There was no statistically significant difference between PENK-Crea and the creatinine-based equations in category “G4 to 5, ≤29 ml/min per 1.73 m2”   . For bia2 compared with the mGFR, significantly less compared with those of the MDRD  and 2009 CKD-EPI , and while statistically significant, not clinically relevant different compared with 2021 CKD-EPI  , 2009 CKD-EPI (77 (73–81)%, P < 0.001) and higher than the 2021 CKD-EPI (80% (76–83), P = 0.01), whereas the 95% CI is partly overlapping  . The med8 ± 0.03 . The accrlapping . For bia2 with the mGFR, significantly less than the 2009 CKD-EPI , similar compared with the MDRD  . The median [IQR] bias was 12 [−3 to 21] for PENK-Crea, 10 [−2 to 24] for MDRD, 11 [1–24] for 2009 CKD-EPI, and 6 [−4 to 18] for 2021 CKD-EPI. The accuracy, calculated as the percentage of eGFRs between a range of ±30% of the mGFR, was not statistically significant between the equations: 72% (63%–81%) for PENK-Crea, compared with 69% (59%–79%) for MDRD, P = 0.63, 69% (59%–79%) for 2009 CKD-EPI, P = 0.61, and 82% (73%–90%) for 2021 CKD-EPI, P = 0.10   and highP = 0.10 . In the  CKD-EPI . For biaIn this study, a novel equation to assess eGFR using proenkephalin was developed and validated in a broad cohort including healthy organ donors, stable outclinic patients, patients with CKD, and critically ill patients. The new PENK-Crea equation to calculate the eGFR performed better than widely used creatinine-based equations, both in bias and accuracy. Overall performance was similar to or better than the newly developed 2021 CKD-EPI equation. Finally, the addition of sex and race did not further improve the performance of the equation.,,,,,Multiple large observational studies have revealed that increases in PENK concentration predict and are associated with the occurrence of acute kidney injury.,2. Especially in this range, dose adjusting of renally cleared drugs becomes relevant, especially in critically ill patients or hospitalized patients with CKD prone to develop acute-on-chronic kidney injury.The analyses for covariate selection for the equation revealed that PENK concentration was most strongly correlated to mGFR and resulted for the larger part in the narrowing of the root mean square error of the equation, which underlines the more accurate reflection of PENK of the GFR. The addition of creatinine and age resulted in further relevant improvements. The MDRD and 2009 CKD-EPI equations also include sex and race. The use of the latter is controversial,In critically ill patients, it is notoriously unreliable to accurately assess kidney function based on creatinine, as active tubular secretion of creatinine may conceal acute decreases in GFR. Furthermore, critically ill patients lose muscle mass within days, leading to reduced creatinine production and overestimating the eGFR. Proenkephalin avoids these issuesA limitation of our study is that the PENK-Crea equation has yet to be validated in larger cohorts of critically ill patients, as the number of critically ill patients in our validation cohort was relatively small. Nevertheless, a strength of this study is that the cohort used for equation development and validation included a broad range of patients, including healthy potential kidney donors, patients with established CKD, and critically ill patients. Consequently, the equation can be applied to a wide range of patients. Second, gold standard methods to determine the true mGFR were used in all patients of the cohort. Furthermore, the data-driven approach applied to develop the equation ensures an unbiased selection of covariates. However, even though this cohort consisted of multiple patient types and was block randomized in a blinded fashion to create a representative internal validation cohort, the performance of the PENK-Crea equation is still to be validated in external cohorts.,,,,Although both exogenous compounds iohexol and iothalamate are considered the most accurate methods to measure GFR,In conclusion, we developed an equation to calculate eGFR using the novel biomarker for kidney function PENK, with creatinine and age. Overall, this PENK-Crea equation performs better to calculate GFR compared with most conventional or more novel creatinine-based equations. Furthermore, the frequently used covariates sex and race, of which the latter is under scrutiny, did not further improve the performance of the equation and are therefore not included in the PENK-Crea equation. These results warrant validation in external patient cohorts that will facilitate future studies into possible clinical benefits of more accurate GFR measurement.RB has received a travel reimbursement from SphingoTec. PP has received travel and consultancy reimbursement from SphingoTec. JCL has received grants from Allena, Arkray, Siemens, and Retrophin; others from Federation Bio, Novobiome, and Orfan-Bridgebio; and grants and others from Alnylam Pharmaceuticals, Dicerna Pharmaceuticals, OxThera, and Synlogic. ASJ presently or has in the past consulted for most of the major diagnostic companies and SphingoTec. CCW, JS, and BA are employed by SphingoTec GmbH. The proenkephalin measurements were conducted by SphingoTec, GmbH. The remaining authors declare no competing interests.


In contrast, 24 h diastolic BP was higher in men than in women . As compared with women, men were being treated with a higher average number of antihypertensive medications daily  and were more commonly receiving calcium-channel-blockers  and β-blockers . In conclusion, the present study shows that among PD patients, the levels of ambulatory BP and intensity of antihypertensive treatment are higher in men than in women. Longitudinal studies are needed to explore whether these gender-related differences in the severity of hypertension are associated with worse cardiovascular outcomes for male patients undergoing PD.Prior studies have shown that among patients with chronic kidney disease not yet on dialysis, the faster progression of kidney injury in men than in women is, at least partly, explained by sex differences in ambulatory blood pressure (BP) control. The present study aimed to investigate potential differences in the levels of ambulatory BP and intensity of antihypertensive treatment between men and women with end-stage kidney disease undergoing long-term peritoneal dialysis (PD). In a case-control design, 48 male PD patients were matched for age and heart failure status with 48 female patients in a 1:1 ratio. Ambulatory BP monitoring was performed with an oscillometric device, the Mobil-O-Graph . The BP-lowering medications actually taken by the patients were prospectively recorded. No gender-related differences were observed in 24 h systolic BP (129.0 ± 17.9 vs. 128.5 ± 17.6 mmHg,  Hypertension is an important cause of cardiovascular morbidity and mortality in both the general population and in patients with end-stage kidney disease (ESKD) undergoing long-term peritoneal dialysis (PD) ,2. In thPrior studies have shown that there are gender-related differences in the severity of hypertension in patients with chronic kidney disease who are not yet on dialysis ,7. For e2; (v) the presence of nonfunctioning arteriovenous fistula in both arms that limited the possibility of accurate assessment of BP; and (vi) recent hospitalization for acute coronary syndrome or stroke. All clinical procedures were carried out in accordance with the Declaration of Helsinki and its latest amendments. The study protocol was approved by the Ethics Committee of the School of Medicine, Aristotle University of Thessaloniki , and it was registered in http://www.clinicaltrials.gov (accessed on 18 July 2018) (unique identifier: NCT03607747).This was a secondary analysis incorporating data from a cross-sectional study that was conducted in 4 PD centers in Northern Greece aiming to investigate the epidemiology of hypertension in the PD population . PatientFor the aims of the present analysis, a member of the investigative team (I.K.), who did not participate in the enrollment process and was unaware of the BP readings, matched at a 1:1 rate 48 male PD patients with 48 female PD patients for age and history of heart failure. All participants visited their PD unit to complete the prespecified protocol procedures. Data on demographic characteristics, medical history, laboratory parameters, antihypertensive treatment, and the prescribed PD regimen were prospectively collected.Office BP measurements were taken by a nurse trained in this technique, according to the 2018 European Society of Hypertension/European Society of Cardiology (ESC/ESH) guidelines . In all Ambulatory BP monitoring was performed for 24 h with an oscillometric device, the Mobil-O-Graph . Office and ambulatory BP readings were taken from the same arm to avoid inter-arm differences between these 2 techniques. The device was programmed to record ambulatory BP at 20 min intervals in the daytime period (07:00–23:00) and at 30 min intervals in the nighttime period (23:00–07:00). The ambulatory BP monitoring was judged as accurate if >80% of the readings were valid with no more than 2 non-consecutive daytime hours with <2 valid recordings and no more than 1 nighttime hour without a valid BP recording .Hypertension was diagnosed based on at least one of the three following criteria: (i) standardized office BP of ≥140/90 mmHg; (ii) average 24-h ambulatory BP of ≥130/80 mmHg; and (iii) the use of at least 1 antihypertensive agent of any category.t-test or a Mann–Whitney U test, as appropriate. Between-group comparisons of the categorical variables were performed with a Chi-squared test or a Fisher’s exact test. All tests were two-tailed, and a p-value of <0.05 was considered statistically significant. The analysis was conducted using the Statistical Package for Social Sciences (SPSS) version 27.0 .The continuous variables are presented as means ± standard deviations (SDs) or medians and interquartile ranges (IQRs). The categorical variables are reported as frequencies (n) and percentages (%). The Kolmogorov–Smirnov test was used to examine if each variable was normally distributed. Comparisons of the continuous data between males and females were performed with an independent p = 0.012) and lower levels of serum creatinine (5.9 (4.8–7.6) vs. 8.0 (5.5–13.9), p = 0.008). With respect to the mode of PD, the proportion of patients receiving continuous ambulatory PD was higher in the group of women than in the group of men . There were no statistically significant differences between the two genders in the prevalence of cardiovascular comorbidities, in the smoking status, or in other basic hematological or biochemical parameters (The study enrollment procedure is depicted in rameters .p = 0.890). In contrast, the average 24 h ambulatory diastolic BP was significantly higher in men than in women . These gender-related differences were consistent during both the daytime and nighttime periods. In detail, the daytime ambulatory diastolic BP  and nighttime ambulatory diastolic BP (78.8 ± 14.0 vs. 73.8 ± 11.1 vs. p = 0.056) were higher in men than in women. The office and ambulatory heart rates were similar for the two groups. In addition, volume status, as assessed with the method of bioimpedance spectroscopy, did not significantly differ between the men and the women (As shown in he women .p = 0.460) or the use of the reference-standard method of ambulatory BP monitoring  for the diagnosis of hypertension. However, the men were being treated with a higher average number of antihypertensive medications daily . Furthermore, as compared with the women, the men were more commonly being treated with calcium channel blockers  and β-blockers . In contrast, the male patients were less frequently receiving treatment with mineralocorticoid receptor antagonists than the women .There were no significant gender-related differences in the prevalence of hypertension either with the use of office recordings  and 48 h ambulatory diastolic BPs  were higher in men than in women [p = 0.029), despite the more intensive use of antihypertensive drug therapy in the men [The present study showed that among patients undergoing long-term PD, the levels of ambulatory BP were higher in men than in women. In addition, the intensity of antihypertensive treatment, such as the average number of prescribed BP-lowering medications as well as the use of calcium channel blockers and β-blockers, was greater in the male PD patients than in the female PD patients. The findings of the present study are accordant with the results of a prior cross-sectional analysis that compared the rates of ambulatory BP control between 129 male and 91 female patients receiving maintenance hemodialysis . In thisThese sex-related differences in BP levels have biological plausibility. Mechanistic studies have provided evidence that the differences between the two genders in the activation of the renin-angiotensin system (RAS) and the sympathetic nervous system, nitric oxide metabolism as well as the release of sex hormones may mediate the greater severity of hypertension in men than in women ,13. AnimThe strength of the present study lies in its careful evaluation of hypertension with the concomitant use of standardized office and ambulatory BP measurements. Unlike the cross-sectional design of prior studies ,10, an iLarger and longer-term observational studies are needed to confirm or refute the results of our analysis. If such gender-related differences in the severity of hypertension truly exist, then the worse ambulatory BP measurements in men might be a plausible mechanistic explanation for the sex differences in cardiovascular outcomes among patients receiving kidney replacement therapy.


Bleeding from the lower gastrointestinal tract (LGITB) is a common clinical presentation. Recent guidelines have recommended for incorporation of clinical risk assessment tools in the management for LGITB. We derived and validated a novel clinical scoring system to predict safe discharge after LGITB admission, and compared it to other published scoring systems in current literature.A retrospective cohort of 798 patients with LGITB from August 2018 to March 2021 was included in the derivation cohort. Multivariate binary logistic regression was performed to identify significant clinical variables predictive of safe discharge. A clinical scoring system was developed based on the results, and validated on a prospective cohort of 312 consecutive patients with LGITB from April 2021 to March 2022. The performance of the novel scoring system was compared to other LGITB clinical risk assessment scores via area under the receiver operating characteristics curve (AUROC) analysis.Variables predictive of safe discharge included the following; absence of previous LGITB admission, absence of ischemic heart disease, absence of blood on digital rectal examination, absence of dizziness or syncope at presentation and the systolic blood pressure and haemoglobin levels at presentation. The novel score had an AUROC of 0.907. A cut-off point of 4 provided a sensitivity of 41.9%, specificity of 97.5%, positive predictive value of 96.4% and negative predictive value of 51.5% for prediction of safe discharge. The score performs comparably to the Oakland score.The novel LGITB clinical risk score has good predictive performance for safe discharge in patients admitted for LGITB. Bleeding from the gastrointestinal tract (GITB) can be divided based the relation of the source with the ligament of Treitz. Upper GITB (UGITB) is defined as haemorrhage proximal to the ligament of Treitz while lower GITB (LGITB) is defined as haemorrhage beyond this anatomical landmark. GITB is a common reason for hospital admissions, with an estimated 1.74 events per 1000 individuals annually , 3 and hThe clinical outcomes of LGITB can be highly variable. While most patients with LGITB have spontaneous clinical improvement and does not require hospitalisation , 6, it hMultiple clinical scores have been published to assess the outcomes in patients who presented with LGITB. However, the outcomes measured are heterogeneous and most of the scores have not been validated in an external population , 9–16. TThe study comprises a derivation cohort and a separate validation cohort. The derivation cohort was derived from patients aged ≥ 21 years who were admitted to the surgical unit in Sengkang General Hospital between August 2018 and March 2021 with a diagnosis of LGITB. Eligible patients were identified from the hospital database by key terms available within the discharge diagnosis, including 'gastrointestinal bleeding', 'lower gastrointestinal bleeding', 'rectal bleeding', 'intestinal bleeding', 'diverticular bleed', 'colorectal cancer', 'colitis', 'haemorrhoids'. Exclusion criteria included patients who had UGITB , elective admissions via the clinic or patients who had opted for palliative care and comfort measures upon admission due to other comorbidities. The validation cohort was a prospective cohort of consecutive patients who were admitted to our unit between April 2021 to March 2022, with similar inclusion and exclusion criteria applied.Our definition of safe discharge was modified from Oakland . This wap-value ≤ 0.1) were then entered into a multivariate binary logistic regression model. Variables found to be significant on the multivariate model (defined as p ≤ 0.05) were included into the clinical score. Each variable was assigned points corresponding to its unstandardized coefficient on the multivariate model to develop the scoring system. The scoring system was validated by applying the score on the validation cohort. The performance of the model was assessed with calculation of the area under the ROC curve (AUROC), and subsequently compared to the AUROCs of other published clinical scores using the method described by DeLong et al. [Data collected from the eligible patients included their demographic information, past medical history, Charlson score, chronic medications, symptoms on admission, vital signs at the Emergency Department triage, laboratory results on admission, endoscopic findings (if performed), interventions performed, high dependency (HD) or intensive care unit (ICU) admission, in-hospital deaths and readmissions or deaths within 28 days related to LGITB. The derivative phase focused on the identification of significant variables predictive of safe discharge. Categorical variables were analysed using the Pearson X2 test, and continuous variables were analysed with the Kruskal–Wallis test. Variables which were identified to be statistically significant in the prediction of safe discharge for LGITB .Statistical analysis was performed using IBM SPSS Statistics for Windows, Version 26.0.  for the derivation and validation of the scoring system. Comparison of the AUROC curves was performed using MedCalc Statistical Software version 19.2.6 , discharged against medical advice before treatment was completed (13), elective admissions for diagnostic or therapeutic purposes (462), absence of LGITB symptoms (590), admission for other concurrent medical issues (68), palliative management opted by patient or family on admission (57), and presence of UGITB (98). The final derivative cohort had 798 patients , lower initial median Hb levels , higher median INR , lower median APTT  and lower median bicarbonate levels  (Table p = 0.008). Otherwise, the cohorts were similar in terms of the distribution of diverticular disease , malignancy  and haemorrhoids  as the aetiology of the LGITB. Both cohorts were also similar in the proportion of patients who were deemed to have met the criteria for safe discharge  (Table p = 0.299). There were 2 mortalities while inpatient (0.18%), and 7 deaths within 28 days of discharge (0.63%).Comparison of the demographic characteristics of the derivation and validation cohorts is illustrated in Table In the derivation cohort, 19 clinical variables were significantly associated with safe discharge on univariate analysis: female gender, prior LGITB admission, absence of diabetes, absence of ischemic heart disease, absence of liver disease, no antiplatelet usage, absence of DRE findings of blood, presence of abdominal tenderness, absence of syncope or dizziness, lower Charlson score, higher SBP and DBP at triage, lower HR at triage, higher initial Hb levels, lower platelet count, lower INR levels, higher APTT levels, lower urea and creatinine levels, and higher bicarbonate levels Table . 139 casIn multivariate binary logistic regression, the significant variables were previous LGITB admission , presence of ischemic heart disease , DRE findings of blood , presence of syncope or dizziness , lower SBP  and lower initial Hb levels  , presence of ischemic heart disease , DRE findings of blood , presence of syncope or dizziness , SBP 120-134 mmHg , 90-119 mmHg , < 90 mmHg ; initial Hb 11–12.9 g/dL , 10–10.9 g/dL  and < 10 g/dL .Development of the clinical score was based on the unstandardised coefficients of the clinical variables, rounded to the nearest 0.5 (Table p = 0.103)  in the prediction of safe discharge was established by calculating the AUROC of the validation cohort. The AUROC was 0.907 (95% CI 0.870–0.937). This was similar to the AUROC of the derivation cohort  of 95% for safe discharge with the highest Youden’s index when applying the score to the derivation cohort Table . When apThis study has developed and validated a clinical scoring system which can predict for safe discharge in patients admitted via the ED for LGITB. The variables included in our scoring system are previous LGITB admission, Ischemic heart disease history, DRE findings, presence of syncope or dizziness, initial SBP at triage and initial Hb levels. In addition, we have also externally validated other scoring systems which were developed for LGITB, some of which have yet to be validated in an Asian population. Lastly, we have compared our scoring system with others, and concluded that it has a comparable performance with the Oakland score. A score of ≤ 4 has a 96.4% predictive value for safe discharge following admission for LGITB. Lastly, our clinical score can be easily applied by the reviewing clinical team as all the variables would be available following consultation at the ED. A brief history of the patient’s past medical history and current symptoms, a targeted physical examination including a DRE and obtainment of the patient’s vital signs and a full blood count would be all that is required for computation of our clinical score.Clinical scores can play an important role in the management of patients with UGITB. These scores allow the clinician to accurately identify patients who are either at high risk of adverse clinical events or can be safely managed in the outpatient setting. As the incidence of LGITB increases, there is a pressing need for similar risk stratification scores to be developed for this condition. The 2019 BSG guidelines and 2021 European Society of Gastrointestinal Endoscopy (ESGE) Guidelines have both recommended that a risk assessment tool be incorporated into the initial management of patients presenting with LGITB to guide physician decision on disposition . In receOur score had multiple common variables with the Oakland score: previous LGITB admission, DRE findings, SBP and haemoglobin. However, our score also included 2 new variables: the presence of ischemic heart disease and the presence of syncope or dizziness. We hypothesize that the presence of ischemic heart disease emerged as a significant variable due to the lower blood transfusion thresholds that clinicians may have for this specific population. While the recommended blood transfusion threshold is 7 g/dl for asymptomatic patients, this threshold is increased to 8 g/dl for patients with ischemic heart disease . Hence, While the novel score has a similar AUROC for safe discharge as the Oakland, applicability of the scores in our validation cohort has yielded different outcomes. An Oakland score of ≤ 8 yielded a predictive value of 94.3%, 17.3% sensitivity and 98.3% specificity for safe discharge; however, only 11.2% of the cohort had Oakland scores of ≤ 8. A point cut-off of 4 for our novel scoring system provides a predictive value of 96.4%, with a 41.9% sensitivity and 97.5% specificity for safe discharge. In contrast to the Oakland score (11.2%), 26.7% of the validation cohort fell within the score range of ≤ 4. This indicates that utilization of our score may allow a larger proportion of patients to be safely discharged with similar performance metrics as the Oakland score.There are several limitations to our study. This is a single tertiary centre study, and thus generalisability to other centres and populations will require further validation. There may also be selection bias as the patients included were those who were admitted via the ED with LGITB. Patients who presented to the ED with LGITB but were subsequently discharged were not included in this study. Hence, the included patient cohort may be biased towards LGITB cases which were more clinically significant with admission deemed necessary. The retrospective nature of the score derivation also meant that variables which were subjective (e.g. patient’s symptoms) may be limited by accuracy of clinical documentation. Nonetheless, we believe the derived novel score will be useful to guide safe discharge after admission for LGITB. Prospective validation efforts are currently on-going and we hope to share the results with the surgical community in the near future.In conclusion, we derived and validated a novel scoring system to predict for safe discharge after presentation with LGITB. Prospective validation studies should be performed to assess its applicability in clinical practice.


Diabetic retinopathy (DR) is a common complication of DM and may go unnoticed until irreversible damage occurs. Its screening can contribute to the early detection. Although, there are no studies which investigate the ability of digital retinography to detect vascular changes in pre-diabetic patients.Identify the prevalence and severity of RD in patients with pre-diabetes.Cross-sectionalstudy carried out in a sample of patients with pre-diabetes and weight excess characterized from January 2020 to April 2023. Sociodemographic and clinical variables were collected, in addition to lifestyle habits. Retinographic evaluation was also performed using a Digital Retinography. For the analysis of all variables, the adopted significance level was 5%. The software used for the analysis was SPSS version 25.0.Of 108 patients selected 7.1% have alteration in the exam indicating DR. Among the participants with diabetic retinopathy, four had the moderate form (50%), three the moderate form (37%) and only one participant had the severe form (13%).Our findings highlight the importance of preventive measures and adequate control of these conditions in pre-diabetic patients, in order to prevent or delay the progression of diabetic retinopathy and, consequently, reduce the risk of blindness and other ocular complications.The online version contains supplementary material available at 10.1186/s13098-023-01154-2. Prediabetes, a condition in which blood glucose values are above reference values, however, below diagnostic values for diabetes mellitus (DM), is positively associated with the risk of all-cause mortality and the incidence of chronic 'diabetes-related' complications, cardiovascular outcomes, stroke, chronic kidney disease, cancer, and dementia –3. In 20With a global prevalence of 22.3% diabetic retinopathy (DR) remains a common complication of DM and a leading cause of preventable blindness in the adult working population . This isUnderstanding that retinal screening contributes to the early detection of diabetic retinopathy and timely treatment, previous studies have investigated digital retinopathy, as a method with high sensitivity and specificity is essential for an effective screening program of digital retinopathy , 9. Howeidentify the prevalence and severity of RD in patients with pre-diabetes.Given the context presented, the objective of this study was to Instituto Metabólica de Medicina Avançada”, in Belo Horizonte, Minas Gerais, Brazil, in a convenience sample of patients with pre-diabetes and characterized by HbA1c ≥ 5.6% and ≤ 6.4 in the period from January 2020 to April 2023.A cross-sectional study performed at the “The inclusion criteria were: patients aged 18 years or older, with laboratory test HbA1c lower than 5.7% with 2 or more fasting glucose levels above 126 mg/dL. We did not include patients who already had HbA1c values, greater than 6.4% and/or those with active heart disease including: myocardial infarction, congestive heart failure, angina pectoris, or malignant diseases under treatment or with an interval shorter than 6 months after its completion, pregnant women and those who were diagnosed with autoimmune diseases being treated with corticosteroids and/or immunosuppressant. The sample size consisted of 108 participants.The sociodemographic variables  were collected using a clinical standardized registration form, as well as the clinical variables: BMI, systemic arterial hypertension (SAH), obstructive sleep apnea, lower limb osteoarthritis, mental disorders, medications in use and pre-existing retinal damage . Life habits (smoking) were also collected.Education level was defined as Elementary School High School University education. Smoking was categorized into yes and no.SAH was defined as Blood Pressure (BP) ≥ 140/90 mmHg in two outpatient measurements, according to the American Heart Association (AHA) or the use of antihypertensive medications .It was performed a retinographic evaluation using a Digital EYER Retinographer (BAYER) with color photos of the fundus of both eyes, without pupillary dilation, taken by a single technician.The evaluation parameters used were the presence of micro aneurysms, hemorrhages, abnormal arteriovenous crossings, and focal or generalized arteriolar narrowing.The images of the digital retinography were sent for the elaboration of a report by two ophthalmologists from a specialized reference center in Belo Horizonte. A crossing of the fundus images was carried out between the two professionals with a subsequent comparison of the results. The same-trained technician who photographed the retina and sent it to the specialized center evaluated the patients.Faculdade Ciências Médicas de Minas Gerais, according to CONEP regulations, under the number CAAE: 64721722.2.0000.5134. We obtained informed consent from all participants using a procedure approved by the Ethics Committee.We conducted this study in accordance with resolution 466/2012. This research was submitted to the analysis and appreciation of the Research Ethics Committee (CEP) of The freedom and integrity of research participants and the preservation of data that could identify them were protected. Privacy and confidentiality were guaranteed. In order to guarantee the confidentiality of the data, the researcher formally committed to the requirement of a prior signature of the commitment form to participate in the project and use of data in files , and continuous variables as mean and standard deviation (SD), minimum and maximum values. Quantitative variables were tested for normality using the Kolmogorov–Smirnov test. The t-test was used for the age variable and the Mann–Whitney test was used for BMI and glycated hemoglobin. For categorical variables, the Chi-square and Chi-square tests with Monte-Carlo simulation were used. In all tests, the significance level adopted was 5%, therefore, comparisons whose p-value was less than or equal to 5% were considered significant. The software used for the analysis was SPSS version 25.0.Of 108 patients selected, 7.1% have alteration in the exam indicating DR. Among the participants with diabetic retinopathy, four had the moderate form (50%), three the mild form (37%) and only one participant had the severe form (13%).   (p = 0.007), dyslipidemia (p = 0.002) and obesity (p = 0.026), all showing a higher percentage for participants with retinopathy. Furthermore, the median value of glycated hemoglobin was higher in patients who had diabetic retinopathy p = 0.031) (Table 1 (Table The results suggest that the presence of comorbidities, such as SAH, dyslipidemia and obesity, as well as inadequate glycemic control, represent factors associated with the risk of developing diabetic retinopathy in patients with pre-diabetes. The pathophysiology of DR is complex, but studies demonstrate an association between SAH, a sedentary lifestyle, and poor eating habits with the increase in the global prevalence of DR , 12. FurDyslipidemia and obesity variables were impaired in the regression model, as there were no cases for the “no” category in those who had retinopathy, but according to the result of the univariate analysis above, the importance of these variables as an associated factor was perceived. In the final model, only the SAH variable was associated with retinopathy in pre-diabetic patients, but this result cannot be extrapolated to the population.An attempt was made to build a regression model in order to find the factors that together would be associated with diabetic retinopathy in pre-diabetic patients. It is known that the sample is small for this inference, so it is important to increase the sample size to identify any interesting findings in future work.In conclusion, our findings highlight the importance of preventive measures and adequate control of these conditions in pre-diabetic patients, in order to prevent or delay the progression of diabetic retinopathy and, consequently, reduce the risk of blindness and other ocular complications.Additional file 1: Figure 1A: Result of digital retinography.Additional file 2: Figure 1B: Results of diabetic retinopathy severity.