Continuous veno-venous hemofiltration (CVVH) can be used to reduce fluid overload and tissue edema, but excessive fluid removal may impair tissue perfusion. Skin blood flow (SBF) alters rapidly in shock, so its measurement may be useful to help monitor tissue perfusion.In a prospective, observational study in a 35-bed department of intensive care, all patients with shock who required fluid removal with CVVH were considered for inclusion. SBF was measured on the index finger using skin laser Doppler  for 3 min at baseline , and 1, 3 and 6 h after starting fluid removal. The same fluid removal rate was maintained throughout the study period. Patients were grouped according to absence (Group A) or presence (Group B) of altered tissue perfusion, defined as a 10% increase in blood lactate from T0 to T6 with the T6 lactate ≥ 1.5 mmol/l. Receiver operating characteristic curves were constructed and areas under the curve (AUROC) calculated to identify variables predictive of altered tissue perfusion. Data are reported as medians [25th–75th percentiles].2 or ultrafiltration rate between groups A and B. Cardiac index and MAP did not change over time, but SBF decreased in both groups (p < 0.05) throughout the study period. The baseline SBF was lower  and the decrease in SBF from T0 to T1 (ΔSBF%) higher  in group B than in group A. Baseline SBF and ΔSBF% predicted altered tissue perfusion with AUROCs of 0.83 and 0.96, respectively, with cut-offs for SBF of ≤ 57 PU  and ∆SBF% of ≥ 45% .We studied 42 patients ; median SOFA score at inclusion was 9 [8–12]. At T0, there were no significant differences in hemodynamic variables, norepinephrine dose, lactate concentration, ScvOBaseline SBF and its early reduction after initiation of fluid removal using CVVH can predict worsened tissue perfusion, reflected by an increase in blood lactate levels.The online version contains supplementary material available at 10.1186/s13613-021-00847-z. Optimal fluid balance is an essential part of patient management. In patients with circulatory shock, fluid administration is widely used to increase cardiac output and restore tissue perfusion, but a high fluid balance can result in tissue edema and is associated with increased mortality –4. When At the bedside, decreased tissue perfusion can be assessed by an abnormally elevated blood lactate concentration, although several medications, such as metformin, propofol or β2 agonists, can also influence lactate levels , 13. TheSkin hypoperfusion occurs before systemic hemodynamic variables worsen , 21–23 aSkin laser Doppler (SLD) is a simple noninvasive tool that has been widely used in clinical studies to evaluate cutaneous microcirculatory perfusion , 26, 30.In the present study, we evaluated changes in SBF during fluid removal with CVVH in patients with circulatory shock and determined whether changes were associated with altered tissue perfusion as reflected by an increase in blood lactate concentration.This prospective, observational study was conducted from 1 November 2017 to 30 October 2018 in the 35-bed Department of Intensive Care of Erasme University Hospital . The study protocol was approved by the local ethical Committee (Protocol number P2017/013/B406201730812), and informed consent was signed by all patients or their next of kin.All consecutive ICU patients with circulatory shock , and 1 (T1), 3 (T3), and 6 (T6) hours later. The researchers who performed the SLD measurements were different from the team managing the CVVHDF. The peripheral perfusion index (PPI) was obtained from the pulse oximeter positioned on the contralateral side to that used for SBF measurements and recorded from the bedside monitor  at the same timepoints.2) and arterial lactate concentration, were obtained at shock diagnosis and at T0, T1, T3 and T6. The use of mechanical ventilation at the time of shock diagnosis, and the duration of CVVHDF and the cumulative fluid balance from the onset of circulatory shock until study inclusion were recorded. The use of sedative agents during the 24 h after ICU admission and at T0 was noted. If the norepinephrine dose was increased during the study period, the time from T0 to the first increase in norepinephrine dose was noted; the MAP just before the first increase in norepinephrine dose was also recorded.Hemodynamic variables, norepinephrine dose and blood gas data, including central venous oxygen saturation  with a small thermostatic SLD probe . This probe enables one to simultaneously measure and alter the temperature at the place where it is positioned. The probe is attached to the skin with a double-sided tape provided with the monitor. The laser beam emitted by the SLD machine has a wavelength of 780 nm, which allows an evaluation depth between 0.5 and 1.0 mm below the skin surface. The back-scattered light is collected by the probe and the change in light wavelength is proportional to the red blood cell (RBC) velocity in the studied area, thus providing a noninvasive measurement of SBF expressed as perfusion units (PU). Data were continuously recorded for future off-line analyses using PeriSoft software 2.5.5 (Perimed). To reduce the short-term intra-individual variation in SLD that has been reported in previous studies –42, the ®, Baxter, Chicago, USA) with a ST100-AN69 membrane had a 14F double-lumen catheter inserted in the femoral or jugular vein. According to our local protocol, blood flow and dialysate flow were set at 2 ml/min/kg and 20 ml/h/kg, respectively. Pre-dilution and post-dilution replacement fluids were prescribed at 20 ml/h/kg and 10 ml/h/kg, respectively. Regional anticoagulation was achieved using trisodium citrate. Arterial blood gases and ionized calcium concentration were evaluated and corrected according to local protocols. The time to initiate fluid removal by CVVHDF and the rate of fluid removal were determined by the care team; the rate was kept stable during the study period.All patients who underwent fluid removal by CVVHDF  curve, and the area under the curve (AUROC) was calculated for the different variables as a measure of their ability to predict altered tissue perfusion. AUROCs are presented as mean ± SD with 95% confidence interval and were compared using the Hanley and McNeil method. To assess possible variables correlated with the different SBF-derived variables, we plotted individual data on graphs and calculated the Pearson or Spearman correlation coefficient (r2) as appropriate. A two-sided p-value < 0.05 was considered as statistically significant. All analyses were performed using STATA15.0 .The normality of the distribution in all variables was tested using a Kolmogorov–Smirnov test and data are presented as median (25th–75th percentiles) or mean (with standard deviation) as appropriate. Patients were separated into two groups according to the absence (group A) or presence (group B) of altered tissue perfusion, defined as an increase in blood lactate of  ≥ 10% over 6 h (with a 6-h lactate ≥ 1.5 mmol/l). Additionally, the patients were grouped by the type of shock (septic shock vs cardiogenic shock) and the start of fluid removal by CVVHDF . Differences between groups were assessed using a Chi-square, Fisher’s exact test, Mann–Whitney n = 1), receipt of blood transfusion (n = 3), and change in ultrafiltration rate during the study period (n = 7) so that 42 were included in the study . Fluid removal was initiated at the same time as CVVHDF in 19 patients, and a median of 3.5 (2.4–5.7) hours after CVVHDF had been started in 23 patients. Tissue perfusion was altered  in 22 patients (Group B) and unaltered in 20 (Group A).Eighty-two patients with circulatory shock were screened; 53 underwent fluid removal by CVVHDF and were considered for inclusion. Eleven were excluded, because of severe agitation , norepinephrine dose, lactate concentration, presence of oliguria, or CRT between groups A and B at the time of diagnosis of shock  at T6, and lactate concentration (p = 0.03) increased during the study period only in group B  . Changes in SBF from T0 to T1 were similar in patients with fluid removal starting at initiation of CVVHDF and those with fluid removal starting later    were correlated with the increase in blood lactate concentration during the first 6 h of fluid removal , with cut-off points of ≤ 57 PU  and ≥ 45% , respectively  and the ∆SBF% from T0 to T1 (0.93 ± 0.05 [0.82–1.0]) were higher than the AUROCs for other variables (–1.0) and2 did not change during the study period.In this prospective observational study, SBF at the start of fluid removal using CVVHDF and a decrease in SBF during the first hour of fluid removal were both related to a worsening of tissue perfusion as measured by an increase in lactate concentration at 6 h compared to baseline. Additionally, despite a reduction in SBF during fluid removal by CVVHDF, MAP, CI, PPI and ScvOIn patients with circulatory shock, increased blood lactate concentration is an indicator of altered tissue perfusion , 43, 44 2, despite the decrease in SBF, suggest that finger SBF was more sensitive than systemic hemodynamic variables and ScvO2 for detecting impaired tissue perfusion. ScvO2 did not decrease during fluid removal by CVVHDF as was reported by Zhang et al. [The stable CI, MAP and ScvOg et al. . This obg et al.  comparedg et al. . This mig et al.  it was dg et al.  observedSBF was lower throughout the study period in patients with altered tissue perfusion. One may argue that the lower SBF in these patients was caused by the higher norepinephrine dose. However, several studies using muscle tissue oxygenation  and sublThe monocenter nature of this study is both an advantage and a limitation. An advantage is the relative homogeneity in procedures. A limitation is that our data may not apply to other units with other protocols in place. Additionally, because of the criteria used to define altered tissue perfusion, we excluded patients who had received propofol because of the potential effect of propofol infusion on lactate concentration , 60. OurA lower SBF at the start of fluid removal using CVVHDF and reduction in SBF over the first hour of treatment are related to the development of new tissue hypoperfusion.Additional file 1: Table S1. Main characteristics in patients without (group A) and with (group B) altered tissue perfusion at the time of diagnosis of shock. Table S2. Hemodynamic variables and skin blood flow (SBF) during the study period in patients with septic shock and cardiogenic shock. Table S3. Hemodynamic variables and skin blood flow (SBF) during the study period in patients in whom fluid removal was started at the same time as continuous veno-venous hemodiafiltration (CVVHDF) or later


Some studies found that family doctor contract services (FDCSs) had positive impact on the self-measurement behaviors of hypertension patients. However, evidence concerning the association between FDCSs and blood pressure measurement awareness among hypertension patients is not clear.This study aims to explore the relationship between FDCSs and blood pressure measurement awareness among the hypertension patients, and examine whether there is a difference in this relationship among middle-aged and aged adults in rural Shandong, China.A multi-stage stratified random sampling was adopted in 2018 in Shandong Province to conduct a questionnaire survey among the sample residents, in which 982 hypertension patients were included in the study. Pearson chi-square test and logistic regression model were employed using SPSS 24.0 to explore the association between FDCSs and blood pressure measurement awareness.P < 0.001, OR = 2.075, 95% CI 1.391–3.095). The interaction of age and contracting status were significantly correlated with blood pressure measurement awareness . Factors including gender , household income , smoking status , sports habits , self-reported health , distance to the village clinic  and medications  were also found to be associated with the blood pressure measurement awareness of hypertension patients.76.8% of hypertension patients would measure blood pressure regularly. The blood pressure measurement awareness of the signing group was significantly higher than that of the non-signing group when controlling other variables (The government should take efforts to strengthen publicity and education of family doctors and pay more attention to uncontracted, middle-aged, female patients and patients with unhealthy life behaviors to improve the blood pressure measurement awareness. The prevalence of hypertension increases with age , causes In the management of hypertension in China, family doctor contract services (FDCSs) plays an important role. China proposed the establishment of a general practitioner (GP) system to carry out contract services in 2011, which has strengthened the importance of primary care centers in the national health strategy . FDCSs aIn addition to the measurement of hypertension by family doctors, self-measurement is more important. Family doctors can develop good self-measurement behaviors by cultivating awareness of blood pressure measurement to help patients master health status. The Chinese Guidelines for the Prevention and Treatment of Hypertension emphasizes the effect of health awareness on hypertension management . PatientStudies on measurement awareness of hypertension differ across different regions globally. A cross-sectional analysis using data from the CONSTANCES population-based cohort in France suggested that patients' hypertension awareness was low and effective action was required to improve hypertension awareness . AnotherHowever, to date, there are very few studies to explore the association between FDCSs and residents' hypertension self-measurement awareness in China. To remedy this gap, the current study aims to explore whether being contracted with a family doctor is associated with blood pressure measurement awareness in rural Shandong, China. The specific objectives of this study are: (1) to describe the rate of blood pressure measurement awareness among the hypertension patients; (2) to explore the relationship between FDCSs and blood pressure measurement awareness among middle-aged and aged hypertension patients, and other related factors.This study was conducted in 2018 in Shandong Province, the second largest province in China. The sample size calculation was performed by the following formula:uα/2= 1.96, δ= 0.1 π= 0.047, α = 0.05. We found that required sample size was 443. Taking into account the loss and refusal of interviews, the final sample size of the survey was determined to be 500.The prevalence of hypertension awareness among Chinese residents was 46.9% according to previous studies , for refA multistage stratified random sampling method was used to select the participants. First, three cities—Binzhou, Zibo, and Liaocheng located in the northeast, central, and west of Shandong Province, which represented the medium, high, and low levels of economic status according to the GDP per capita (2018), respectively. Second, two counties in each city were firstly chosen at random. Within each county, five townships and five villages in each township were randomly chosen. Eighteen households were randomly selected from each village. To ensure the randomness of the sample, the research team provided the names of all the towns in the sample counties, and commissioned experts from the School of Public Health at the University of North Carolina at Chapel Hill, who had maintained a long-term cooperative relationship, to select the sample towns using a random number table. The investigators were recruited from Shandong University. They were strictly trained before the investigation, including understanding the principles and methods of the survey, and standardizing the definition and interview skills of each study indicator, with the purpose of ensuring the quality of the survey. All the participants were interviewed face-to-face using a structured questionnaire by trained investigators. Completed questionnaires were carefully checked by the supervisors after the interview each day. In total, 2,979 individuals were recruited and completed the whole survey.The diagnosis of hypertension was confirmed by the Chinese Guidelines for the Prevention and Treatment of Hypertension in which hypertension was SBP ≥140 mmHg and/or DBP ≥90 mmHg in the absence of antihypertensive drugs . HyperteThe blood pressure measurement awareness in this study was measured by the following question: “Do you think you need to measure your blood pressure regularly [test yourself at least 1 day a week ]?” and tThe family doctor contracting status of the respondents was measured by the following question: “Did you contract with the family doctors this year?,” they could respond with “yes” (coded as 1) or “no” (coded as 0).We identified the potential confounders on the basis of the existing studies , 26, incThis study was approved by the Ethical Committee of Shandong University School of Public Health. All participants provided informed consent before the face-to-face interview. The data used in this study were anonymized before use.p-value of <0.05 was considered statistically significant.The data were double-entered and coded using EpiData version 3.1, and were analyzed using IBM SPSS 24.0 . All study variables were performed with a descriptive analysis. Pearson chi-square tests were performed to assess whether socio-demographic variables, family doctor contracting status, and other factors were related to awareness of blood pressure measurement. Binary logistic regression model was employed to explore association between family doctor contracting status and blood pressure management awareness, adjusting for gender, educational level, household income per year, smoking status, drinking status, self-reported health, distance to the village clinic, multiple chronic diseases and medications. We also estimated the 95% confidence interval of OR. All tests were two-tailed and a For patients, awareness of blood pressure measurement was associated with household income per year, smoking status, sports activities and medications.P < 0.001).Among 702 participants who had not signed a contract with family doctor , 515 , so the independent variables in the univariate analysis were included in the logistic regression model for adjusting.P < 0.001, OR = 2.075, 95% CI 1.391–3.095) after adjusting for the gender, education level, smoking status, drinking status, self-reported health, distance to the village clinic, multiple chronic diseases and medications. After the interaction items (age and contracting status) were included, model 2 showed that the interaction items were statistically significant . Meanwhile, sensitivity analysis was performed, as shown in the In model 1 , the assP = 0.011, OR = 0.499, 95% CI 0.291–0.855) and smokers  were significantly worse than men and never smokers. The higher the household income, the better the awareness of blood pressure measurement . The awareness in patients with physical habits was significantly higher than that in patients without the habits . Patients who considered themselves unhealthy had higher awareness of blood pressure measurement . The farther the distance from the village clinic , the better the awareness of blood pressure measurement. Awareness of blood pressure measurement was higher in patients taking hypertension medication . As shown in In addition, the result showed that blood pressure measurement awareness was significantly associated with gender, household income, smoking status, sports activities, self-reported health, distance to the village clinic and medications for patients. Specifically, hypertension measurement awareness of women  and blood pressure control status were also unavailable, which were crucial to further understanding hypertension patient's management. Finally, this study was only conducted in Shandong province and the generalizability of the main findings needs to be verified in China.The study demonstrated a significant association between FDCSs and blood pressure management awareness among hypertensive patients in China. Compared with non-contracted patients, patients with FDCSs reported higher hypertension management awareness. And contracted patients with different age groups had different awareness of blood pressure measurement. Some other factors were also found to be associated with blood pressure management awareness among hypertension patients in rural Shandong, including gender, smoking status, sports activities, household income, self-reported health, distance to the village clinic and medications. In order to improve the blood pressure management awareness of hypertensive patients, village clinics and township hospitals should take efforts to strengthen publicity and education based on FDCSs, especially for non-contracted, middle-aged, female patients and patients with unhealthy life behaviors.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.CY and CZ designed the study, CY selected and processed the data and wrote the manuscript. YY, DZ, and JL (4th author) revised the manuscript. All authors contributed to the subsequent drafts, reviewed, and endorsed the final submission.This study was supported by the National Science Foundation of China , the China Medical Board (16–257), Cheeloo Youth Scholar Grant, Shandong University , and NHC Key Laboratory of Health Economics and Policy Research . The funding bodies had no role in the design, data collection, analysis, interpretation of the data, and writing of this article.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The regional oxygen saturation (rSO₂) values of brain and muscle tissues can be measured simultaneously even if blood pressure cannot be measured due to circulatory failure associated with shock and may continuously reflect the oxygen supply‐demand balance. The regional oxygen saturation (rSO₂) values of brain and muscle tissues can be measured simultaneously even if blood pressure cannot be measured due to circulatory failure associated with shock and may continuously reflect the oxygen supply‐demand balance. Patients with shock showed that in the shock state, the value of crSO₂ was higher than that of mrSO₂, and c‐mDrSO₂ increased with the decrease of blood pressure. After resuscitation, the c‐mDrSO₂ decreased with the increase of blood pressure.2) or blood pressure due to circulatory failure associated with shock. Regional oxygen saturation (rSO₂) is known as an indicator of changes in the local oxygen supply‐demand balance.In the field of emergency medical care, we often experience a situation in which we cannot measure pulse oximetric saturation .Here, we show the rSO₂ values of the brain and muscle tissues of healthy volunteers and of three patients in shock in whom we preliminarily evaluated the rSO₂ values of the brain and muscle tissues during their resuscitation. We discuss the potential effectiveness of simultaneously assessing brain and muscle rSO₂ in shock management.22.1We attached the sensors of the rSO₂ monitor to the forehead and dorsal lower leg of 10 healthy volunteers lying in the supine position and measured rSO₂ values at these locations for 3 min  continued to be low, but after 1 h, we could measure a blood pressure by a noninvasive method. Meanwhile, the value of her crSO₂ remained higher than that of her mrSO₂. Although this patient's shock state was prolonged by septic shock caused by bacterial pneumonia, the value of her crSO₂ was always higher than that of mrSO₂, and the c‐mDrSO₂ was large Figure . She die2.3An 82‐year‐old man was transferred to our hospital with a diagnosis of septic shock caused by intestinal perforation. On admission, his blood pressure was 136/52 mmHg (MAP 73 mmHg), and his heart rate was 136 beats per minute under administration of noradrenaline and lactated ringers solution. We urgently performed partial resection of the intestine on the day of transfer. Just after the operation, his MAP was over 65 mmHg with the administration of noradrenaline, and his crSO₂ value was about the same as his mrSO₂ value. However, his MAP gradually decreased to below 60 mmHg at 1.6 h after the operation. Meanwhile, his crSO₂ value remained higher than that of his mrSO₂ value, and c‐mDrSO₂ increased with the decrease of the MAP. His MAP did not decrease any further by 1.8 h after the operation, and the c‐mDrSO₂ stabilized. This patient showed a decrease in his MAP with the development of septic shock caused by intestinal perforation. His crSO₂ value remained higher than that of his mrSO₂, and the c‐mDrSO₂ increased in tandem with the decrease of his MAP Figure . He was 2.4A 38‐year‐old woman was transferred to our hospital with a diagnosis of hemorrhagic shock following postpartum hemorrhage. On admission, her blood pressure was 74/40 mmHg (MAP 38 mmHg), and her heart rate was 86 beats per minute. We attached the rSO₂ sensor to her forehead and dorsal upper arm on admission and measured the values of crSO₂ and mrSO₂. The crSO₂ value was higher than that of her mrSO₂ value, and there was a c‐mDrSO₂. The bleeding from her uterus persisted, and her hemoglobin on admission was 6.5 g/dl. We began the administration of red blood cells at admission, and her MAP gradually increased. When her MAP rose above 85 mmHg, her crSO₂ value became about the same as that of her mrSO₂. In this patient with a low MAP due to hemorrhagic shock following postpartum hemorrhage, the value of her crSO₂ was higher than that of her mrSO₂ and a c‐mDrSO₂ was present. After her blood pressure began to increase, the c‐mDrSO₂ became much smaller Figure . After t3We revealed the following three points by simultaneously measuring the values of crSO₂ and mrSO₂. First, the value of crSO₂ is almost the same as that of mrSO₂ in healthy volunteers. Second, even if SpO₂ or blood pressure cannot be measured due to circulatory failure associated with shock, it is possible to measure crSO₂ and mrSO₂. Third, in the shock state, there is a difference in rSO₂ values between brain and muscle, and the value of crSO₂ is higher than that of mrSO₂. The present study is the first report, to our knowledge, to suggest that measurement of crSO₂ and mrSO₂ in shock patients may continuously and clearly reflect the oxygen supply‐demand balance.There are three stages of shock: stage I (compensatory shock), stage II (decompensatory shock), and stage III (irreversible shock). Particularly, in the early phase of stage I, blood flow to the organs decreases, but blood flow in the major organs manages to be maintained by the physiological response generated to recover blood circulation.Among the studies of patients in shock, there are reports that the value of crSO₂ is low when the MAP is low but that it increases with the increase in MAP.In this first report of the simultaneous measurement and assessment of the values of crSO₂ and mrSO₂ in shock patients, we illustrate in Figure Case 1 shows that in patients with septic shock, MAP, crSO₂, and mrSO₂ change from (A) to (B) with the administration of fluid resuscitation and vasopressors. Case 2 shows that MAP, crSO₂, and mrSO₂ of the patients with septic shock change from (C) to (B). Case 3 shows that in patients with hypovolemic shock, MAP, crSO₂, and mrSO₂ change from (B) to (C) with the administration of red blood cells. The candidates for appropriately targeting MAP are those showing a change from (C) to (B) or from (A) to (B) to preserve major organ blood flow. We consider that stage I of the three stages of shock matches with (C), stage II matches with (B), and stage III matches with (A).Our study showed that even if SpO₂ or blood pressure cannot be measured due to circulatory failure associated with shock, it is still possible to measure the values of crSO₂ and mrSO₂. Besides, because the values change in real time with fluctuation of the blood pressure, unlike with previous monitoring devices, the rSO₂ monitor may continuously and clearly reflect the changes in the local oxygen supply‐demand balance. Further, simultaneous measurement of crSO₂ and mrSO₂ rather than either crSO₂ or mrSO₂ alone may be helpful as a real‐time method for evaluating therapeutic effect.A limitation of this study is the presence of selection bias associated with the choice of healthy volunteers and case reports used. We are continuing to accumulate additional cases and examining whether the simultaneous measurement of crSO₂ and mrSO₂ might be a useful method to evaluate adequate blood pressure in shock management. We will also consider the effects of therapeutic interventions such as the administration of noradrenalin or red blood cells.4We evaluated the usefulness of the simultaneous measurement of crSO₂ and mrSO₂ and found that it might be an objective and noninvasive method of evaluating blood pressure management in shock patients.None declared.A.M., R.T., and M.O. conceived the study and participated in its design. A.M., S.N., and J.T. collected and generated the data. A.M. wrote the first draft. T.H. and T. Shio. helped to draft the manuscript. A.M., T.H., R.T., M.O., S.N., J.T., T. Shio., T. Shima., and T. Sa. read and approved the final manuscript.The study protocol was approved by the Institutional Review Board of Osaka University , which waived the need to obtain patient written informed consent because of the observational nature of the study.


Allogeneic stem cell transplantation is a curative treatment option for several hematological diseases. Data about health status and late complications of long-term survivors of this therapy are limited, so we conducted a prospective study. This analysis focusses on kidney function and urological complications. Interestingly, the BK polyomavirus plays an important role in this patient population and can lead to severe impairment of kidney function. This was only previously described in the acute situation following transplantation. Further studies should address causal therapy development for this severe viral infection.p = 0.019), creatine > 100 µmol/L (p < 0.001), and cystatin c > 1.11 mg/L (p = 0.021), respectively. We were not able to identify a single risk factor for BKPyV viruria in univariate or multivariate Cox regression. Conclusions: BKPyV-associated nephropathy might be one reason for impaired kidney function in long-term survivors of aSCT.Background: Allogeneic stem cell transplantation (aSCT) is a common treatment for a variety of hematological diseases. Advances in transplantation practices have led to an increasing number of long-term aSCT survivors, but data about health status and late complications are sparse. This analysis focusses on kidney function and urological complications in this population. Methods: This study is a prospective unicentric non-interventional trial. Before starting the study, we obtained the approval of the local ethics review board. Furthermore, the study was registered at WHO Clinical Trial Registry. The study protocol is available via UTN. Results: We were able to include 33 patients with a mean age of 60.5 years (SD 11.1). The median survival time following allogeneic stem cell transplantation was 9.0 years (IQR 8.5–13.0). Five patients (15.2%) had BKPyV viruria with mean 218.3 (SD 674.2) copies/mL. BKPyV viruria was significantly linked to pre-existing chronic kidney failure ( Allogeneic stem cell transplantation (aSCT) is a common treatment for a variety of hematological diseases. Advances in transplantation practices and supportive care have led to improved outcomes and an increasing number of long-term aSCT survivors. Most deaths after aSCT occur within the first 2 years as a result of relapse, acute or chronic Graft-versus-host disease (GvHD), infections, or other acute or subacute toxicities . HoweverOne specific acute complication of aSCT is the BK polyomavirus (BKPyV)-associated hemorrhagic cystitis, which can occur in 5–60% of cases. Likewise, BKPyV-associated nephropathy (BKVAN) is a major challenge in the management of aSCT patients and can lead to severe morbidity and even mortality ,12,13,14Consequently, we conducted a prospective clinical study to assess the health status and quality of life in long-term survivors of adult aSCT (>5 years following transplantation) at our institution. Regarding the primary end point, this descriptive analysis focuses on urological complications, kidney function, and viral infections. Secondary endpoints included association of urological complications, kidney function. and BKPyV, with the main clinical parameters and identification of risk factors for BKPyV-associated diseases.The study was designed according to the guidelines in the synthesis of qualitative research (ENTREQ) found on the equatornetwork.org . Before 5 bacterial colony forming units (CFU). Additionally, we defined cytomegalovirus (CMV) reactivation as a reactivation requiring treatment according to international standards. Chronic kidney failure was defined according to the KDIGO clinical practice guidelines , and acute renal failure was defined according to the definition of the Acute Kidney Injury Network (AKIN).The term “viruria” was defined as positive quantitative polymerase chain reaction (PCR) for the viruses BKPyV, JCPyV , and adenovirus  in the urine. Bacterial urinary tract infection (UTI) was defined as urogenital symptoms with positive urine culture and more than 10p-values were based on a two-sided hypothesis; p < 0.05 was considered to be significant. All statistical calculations were performed using a statistical package for the Social Sciences 26.0 software .For each numeric variable, the numeric distribution was preliminarily assessed by the Kolmogorov–Smirnov test. Descriptive statistics were performed with mean and standard deviation for normal distribution or with median and IQR for non-parametric data. For parametric continuous variables, the Student t-test was used, and for parametric categorical variables, the chi-square test or the Fisher exact test was used. For risk factor assessment univariate and multivariate, the Cox regression method was used, and the significance was tested with the Wald statistic. Kaplan–Meier plots were used to estimate the median overall survival. All reported We included 33 patients with a mean age of 60.5 years (SD 11.1). Another three patients who met the inclusion criteria declined to participate in this study . Acute myeloid leukemia (AML) was the most frequent underlying hematological disease (36.4%). The median survival time following allogemic stem cell transplantation was 9.0 years (IQR 8.5–13.0). Pre-existing chronic kidney failure was seen in two patients (6.1%), while preexisting urological disease was quite frequent, e.g., 21.2% urolithiasis in the patient history. p = 0.019), creatine > 100 µmol/L (p < 0.001), and cystatin c > 1.11 mg/L (p = 0.021), respectively. At the time of presentation for our study, 6 patients (18.2%) had abnormal high creatine and 10 patients had abnormal high cystatin C (30.3%). Postrenal genesis of kidney failure was ruled out by ultrasound in these patients. Furthermore, 3 patients (9.1%) had significant asymptomatic bacteriuria all with E. coli and 5 patients (15.2%) had BKPyV viruria with mean 218.3 (SD 674.2) copies/mL. These findings were difficult to predict since there was no significant association with microhematuria or leucocyturia and no patient reported urinary tract symptoms. Interestingly, BKPyV viruria was significantly linked to preexisting chronic kidney failure  survivors of adult aSCT. This was a subgroup-analysis focusing on urological complications, kidney function, and urological infections. Regarding the study population, we reported on an older patient cohort with a mean age of 60.5 years. As expected, the most frequent underlying disease was AML. Otherwise, the study population appeared heterogenous, which is also expected in studies analyzing patients undergoing adult aSCT for various diseases . Of noteOur results regarding CKD and renal failure are comparable to the study from Jo et al. . At the Consequently, this raises the question for BKVAN therapy. So far, no causal treatment has been established . SeveralDespite the prospective nature and novelty regarding BKPyV in long-term survivors of aSCT, we must assume that our study also has several limitations, for example, exposure to nephrotoxic substances and plasma viral loads of BKPyV have not been assessed.CKD is a clinical challenge in long-term survivors of aSCT. BKVAN may contribute to CKD in this population. Here, we present the first study investigating this phenomenon. BKVAN is difficult to predict, and no therapy is established. Further studies in long-term survivors of aSCT should focus on careful monitoring of kidney function, BKPyV viruria, plasma viral load, and therapy development by targeting the immune response.


Hyperlactatemia is associated with a poor prognosis in cardiac surgery patients. This study explored the impact of target blood pressure management during cardiopulmonary bypass (CPB) on blood lactate levels after cardiac surgery.n = 20 for each. Norepinephrine was titrated only during CPB to maintain MAP at the target level. Blood lactate levels in the two groups were detected before the operation (T0), at the end of CPB (T1), at the end of the operation (T2), 1 h after the operation (T3), 6 h after the operation (T4) and 24 h after the operation (T5). The primary outcome was the blood lactate level at the end of the operation (T2). The secondary outcomes included the blood lactate level at T1, T3, T4, and T5 and the dose of epinephrine and dopamine within 24 h after the operation, time to extubation, length of stay in the ICU, incidence of readmission within 30 days, and mortality within 1 year.Adult patients undergoing cardiac valve surgery between 20/1/2020 and 30/6/2020 at Shanghai Chest Hospital were enrolled. The patients were randomized into a low mean arterial pressure (L-MAP) group (target MAP between 50 and 60 mmHg) or a high mean arterial pressure (H-MAP) group (target MAP between 70 and 80 mmHg), P = 0.008) and at the end of CPB and 1 hour after surgery. The dose of epinephrine within 24 h after the operation, time to extubation and length of stay in the ICU in the L-MAP group were significantly higher than those in the H-MAP group.Forty patents were enrolled and analyzed in the study. The lactate level in the H-MAP group was significantly lower than that in the L-MAP group at the end of the operation (3.1  vs. 2.1 , Maintaining a relatively higher MAP during CPB deceased the blood lactate level at the end of surgery, reduced epinephrine consumption, and shortened the time to extubation and length of stay in the ICU after surgery.ChiCTR2000028941. It was conducted from 20/1/2020 to 30/6/2020 as a single, blinded trial in Shanghai Chest Hospital.This single-center, prospective, RCT has completed the registration of the Chinese Clinical Trial Center at 8/1/2020 with the registration number  Hyperlactatemia usually occurs after cardiac surgery, which is related to poor prognosis , 2 and iBlood flow has a pulsatile characteristic in normal heart activities. However, nonphysiological advection perfusion is adopted during cardiopulmonary bypass (CPB) in many heart centers. Unlike advection perfusion, which provides kinetic energy to normalize blood flow, pulsatile perfusion reduces the potential energy under the same mean arterial pressure (MAP), resulting in decreased blood flow in capillaries and microcirculation perfusion. Thus, we supposed that a relatively high MAP during CPB may benefit microcirculation perfusion in reducing blood lactate levels, which is a sensitive indicator of poor microcirculation perfusion. Based on the Guidelines for CPB in 2019 European Adult Cardiac Surgery , it is s− 1, alanine aminotransferase (ALT) < 50 U•L− 1, creatinine (Cr) < 111 ųM•L− 1, blood urea nitrogen (BUN) < 9.5 mM•L− 1, and brain natriuretic peptide (BNP) < 100 pg•ml− 1 who required observation in the intense care unit (ICU) after surgery. The ICU researchers were blinded to the group assignments. The exclusion criteria were patients who underwent reoperation within 24 h after the initial operation due to surgical factors.This single-center, prospective, RCT study was conducted in accordance with the Declaration of Helsinki tenets and the Basel, and approved by the Shanghai Chest Hospital of Shanghai Jiaotong University research ethics board (KS1960) at 31/10/2019 and registered at the Chinese Clinical Trial Center on 8/1/2020 with registration number ChiCTR2000028941. This study was performed by adhering to the Consolidated Standards of Reporting Trials (CONSORT) statement. Forty patients who were scheduled for cardiac valve surgery in the Cardiovascular Surgery Department of Shanghai Chest Hospital  from 20/1/2020 to 30/6/2020 were enrolled in the study. All enrolled patients signed their informed consent without knowing their groups. The inclusion criteria were patients older than 18 years with a New York Heart Association Class (NYHAC) level II-III, blood lactate level < 1.6 mM•L− 1] during CPB. MAP was continuously measured every 15 min and used for analysis in both study groups. The area under or upper the curve (AUC) out of the target blood pressure range was calculated as previously described  or N . Kolmogorov–Smirnov tests were used to assess the distribution of continuous variables. Normally distributed variables were analyzed using Student’s t test; otherwise, nonnormally distributed variables were analyzed using Mann–Whitney U-tests. Classified variables, including sex, ASA classification, hypertension, diabetes prevalence, NYHAC and surgical type, were recorded as numbers or percentages. Categorical variables were compared using a chi-square test or Fisher’s exact test as appropriate.P < 0.05 (2-sided) was considered statistically significant. We estimated the effect of continuous monitoring on the area under or upper the curve (AUC) out of target blood pressure using the 2-sample Wilcoxon rank-sum test and Hodges Lehmann estimation of location shift with the corresponding asymptotic 95% CI. The balance of baseline and surgical characteristics was compared using absolute standardized difference scores (ASDs) as previously described [The blood lactate level and MAP at multiple time points were analyzed with ANOVA for repeated measures and least significant difference post hoc testing. escribed . Imbalan− 1 vs. 3.68 ± 1.16 mM•L− 1 in the L-MAP group at the end of the operation. It was calculated that 20 cases for each group were needed based on α = 0.05 and β = 0.1 using a two-sided two-sample unequal-variance t test.The sample size was calculated based on our pre-experimental results. The lactate level in the H-MAP group was 2.46 ± 1.13 mM•LThe basic characteristics of the enrolled patients are summarized in Table The MAPs during CPB are shown in Fig. As shown in Fig. As shown in Table The cause of hyperlactacidemia falls into two types: insufficient perfusion or hypoxia of the tissue, such as shock or ischemia , and actIn this study, we observed the impact of targeted blood pressure management during CPB on lactate levels after cardiac surgery and found that the blood lactate level in the H-MAP group was significantly lower than that in the L-MAP group at the end of surgery and 1 h after surgery, suggesting that maintaining a relatively higher perfusion pressure (MAP 70–80 mmHg) during CPB was more conducive to improving the perfusion and oxygen supply to reduce lactate levels after surgery. This conclusion was further confirmed by the shortened time of extubation, reduced length of ICU stay, and use of less epinephrine for circulation support 24 h after the operation in the H-MAP group.- 1[− 1 by insulin infusion during the perioperative period. Considering these factors, we further compared HR, MAP, HCT, blood glucose, Cr, BUN, surgery time, aortic occlusion time, CPB time and post-CPB time, finding no significant differences between the two groups.In addition, MAP before anesthesia induction showed no significant difference between the two groups. Although studies have shown that blood pressure before anesthesia induction does not reflect the actual blood pressure of patients , maintai- 1. In both- 1, but the- 1. However- 1, but the- 1, our stuMost current studies on how to maintain a safer MAP during CPB focus on the relationship between MAP and postoperative acute kidney injury (AKI) or cognitive dysfunction. Although there was no significant difference in postoperative cognitive dysfunction between the H-MAP group (70–80 mmHg) and the L-MAP group (40–50 mmHg) , maintaiWe found that certain individual differences mattered much in target blood pressure management. Preoperative basic blood pressure and the antihypertensive drugs used by the patients should all be taken into consideration when performing blood pressure management precisely. On the other hand, many vasoconstrictors, such as epinephrine, could potentially bias the lactate value perioperatively. It has been reported that the median dose of epinephrine increased plasma lactate by 0.25 μg/kg/min, while dopamine had the opposite effect . Norepin− 1 during that time. Therefore, multicenter, larger-sample studies are required in the future. Based on the finding that a relatively high MAP improved tissue perfusion during CPB, our future study will monitor the peripheral circulation during CPB by ultrasound and calculate oxygen supply and consumption for more convincing evidence [There are also some limitations in this study. For instance, this is a single center with a limited number of cases. Due to the small sample size, we compared the baseline of patients by absolute standardized difference scores (ASDs) . We founevidence , 22.Targeted MAP management between 70 and 80 mmHg during CPB could better ameliorate the lactate level after cardiac surgery compared with MAPs between 50 and 60 mmHg. A relatively high blood pressure may be more conducive to improving tissue perfusion and oxygen supply, reducing the lactate level, and shortening the time of extubation and length of ICU stay, all of which are beneficial to cardiac surgery patients.


Ankle-brachial index (ABI) and toe-brachial index (TBI) are the recommended tests for the diagnosis of lower extremity peripheral artery disease (PAD) and the assessment of its severity, whereas Doppler ultrasound (DUS) is usually used to localize vascular lesions. However, the performance of DUS as an alternative to TBI and ABI measurement is unknown.The goals were (i) to evaluate the correlation between DUS parameters of distal arteries of the lower extremities with TBI in patients with PAD; (ii) to evaluate the correlation between DUS parameters of distal arteries with ABI; and (iii) to assess the diagnostic accuracy of maximal acceleration time of pedal arteries to detect toe pressure ≤30 mmHg.An observational retrospective study was conducted for 1 year on patients with the diagnosis of PAD on DUS. Demographic data, ABI, TBI, and DUS parameters of the dorsal pedis and lateral plantar arteries (DPA and LPA) were recorded.max) was the most correlated to TBI on both univariate  and multivariate analysis (p < 0.0001). DUS parameters had a weaker correlation with ABI. ATmax > 215 ms showed high diagnosis accuracy to a toe pressure of 30 mmHg or less [sensitivity of 86% [0.57–0.98] and negative predictive value of 97% [0.89–1.00]].Seventy-seven patients with 88 limbs were included, aged 69 [interquartile range: 11 years] with 28.6% of diabetic patients. The highest acceleration time of either DPA or LPA (ATmax demonstrates a high correlation with TBI in patients with PAD, and high diagnostic accuracy for detection of critical limb ischemia. Based on these results, ATmax can represent the next step in evaluating PAD severity with DUS, in patients with advanced lower extremity PAD.AT Lower extremity peripheral artery disease (PAD) is a major burden worldwide, with a steady and significant increase in prevalence over the last decades , 2. PAD Ankle-brachial index (ABI) and toe-brachial index (TBI) are both accepted methods for diagnosing and assessing PAD severity, as a reflection of lower extremity perfusion . ABI is Arterial duplex ultrasound (DUS) has shown a good correlation with angiography on iliac and femoral arteries, but remained weak on distal arteries . Hence, Therefore, this study (i) evaluates the correlation between Doppler ultrasound of distal arteries of the lower extremities  with TBI, in patients with occlusive PAD; (ii) evaluates the correlation between DW parameters of distal arteries of the lower extremities with ABI; and (iii) assesses the diagnostic accuracy of the highest acceleration time of pedal arteries to detect toe pressure ≤30 mmHg.A retrospective study was conducted between January 1 and December 31, 2020 in a single university hospital, from consecutive patients, addressed to our vascular medicine unit for diagnosis or follow-up of PAD.Diagnosis of occlusive PAD was the only inclusion criterion. Diagnosis of PAD was based on the Doppler ultrasound criteria and is given below. For patients with occlusive PAD on both lower limbs, each limb was included separately.Proximal occlusive PAD was defined as occlusion of at least one of the following arteries: aorta or common iliac artery, external iliac artery or common femoral artery, femoral superficial artery, or popliteal artery, diagnosed or confirmed by DUS. Patients with occluded iliac or femoral artery bypass were also included in the study. Patients with distal PAD (stenosis and/or occlusion of at least one of below-the-knee arteries) and/or proximal non-occlusive PAD  were not included.Exclusion criteria were: age under 18 years old, toe or more proximal amputation, protected adults, history of arterial revascularization procedures on the included lower limb causing permeability of arterial axis for the aorta to the popliteal artery.2). For this study, patients were considered as a non-smoker if they had never smoked or declared at least 1-year tobacco cessation. Otherwise, they were considered active smokers.The following demographics data were obtained from the patient electronic medical record: age, gender, declared walking distance before pain, tobacco habits, arterial blood pressure, history of hypercholesterolemia, diabetes, and or severe to terminal chronic kidney failure .All measures were performed by vascular physicians .Patients were scanned in decubitus position. Duplex Doppler ultrasound imaging was performed using a GE Vivid E95  or a Siemens Sequoia . A 4–9 MHz linear array transducer was used for popliteal, fibular, anterior, and posterior tibial arteries, and a 5–14 MHz one for the dorsalis pedis artery (DPA) and LPA. Each ultrasound probe was covered with transmitting gel. Pulsed Doppler waveforms were obtained from a longitudinal slice of the studied artery, with a Doppler color box size adjusted to the size of the vessel. The emission sound beam was placed to be parallel to the flow direction of the vessel. The Doppler sample was obtained at 60° or less, with a volume applied to the center of each artery with a spectral Doppler scrolling of 66 mm/s. Peak-systolic velocity (PSV) and end-diastolic velocity (EDV) were measured manually and expressed in cm/s. Resistivity index (RI), without unit, was calculated as lic peak , 10  with the patient in a supine position after at least 10-min of rest. Blood pressure cuffs were adapted to the weight and height of the patient (10-cm or 12-cm cuff).Bilateral systolic blood pressure (SBP) on the dorsalis pedis artery and the posterior tibial artery was measured with an 8-MHz continuous Doppler probe  and a sphygmomanometer . If blood flow was still detected with a pressure cuff inflation of 250 mmHg or more, arteries were considered as “incompressible.” The value of 250 mmHg was considered as relevant as previously described in international recommendations , with hiAnkle-brachial index (ABI) was then calculated by dividing the highest value of the two SBPs of the leg by the highest value of the right and left arm SBPs .Toe blood pressures were measured by a Laser Doppler flowmetry, using an automatic measure device , and TBI was calculated by dividing the toe pressure by the highest value of right and left arm SBPs. Pressure measurement was conducted according to the instructions of the manufacturer and as described in the literature . A pressThe performer of TBI was not blind to the DW measurements but due to automatic measuring of TBI, we consider the ranking bias to be minimal.max, ATmean, and ATmin, respectively).The following DW parameters were studied: PSV, EDV, RI, and AT on both DPA and LPA, the sum of PSV (from DPA and LPA), highest, lowest, and mean value of AT between DPA and LPA  with TBI in patients with occlusive PAD, on both univariate and multivariate analyses. Age and ABI (as known marker/risk factor of PAD) were also compared to TBI.Our second objective was to evaluate the diagnostic accuracy of the most TBI-correlated variable to detect toe pressure ≤30 mmHg.www.R-project.org), using the R studio interface. Because this cohort was not derived from random selection, all statistics are deemed to be descriptive. No imputation was made for missing data. Continuous variables are expressed as means and interquartile range (IQR), defined as the first and third quartiles. Categorical variables are expressed as counts and percentages. To evaluate the concordance of the Doppler measures, the correlation of DW parameters between contiguous arteries  was tested by Pearson's correlation. Pearson's correlation test was used to correlate Doppler waveform measures with TBI for univariate analysis. All quantitative variables had a normal distribution with no outliers, validating Pearson's correlation test. A Pearson's correlation >0.68 is considered a strong/excellent correlation   known risk factors of PAD in literature  (tobaccoctor ≥5) .p < 0.05. No indeterminate results were recorded.Receiver operating characteristics (ROC) curve represented sensitivity vs. 1—specificity  of the highest acceleration time of pedal arteries according to the presence or absence of toe pressure ≤30 mmHg; and was used to optimal cut-off value to detect toe pressure ≤30 mmHg. The area under the ROC curve (AUC) was used to measure the accuracy of the highest acceleration time of pedal arteries to detect toe pressure ≤30 mmHg. Significance was accepted for value of A total of 92 patients were screened. Six were excluded for the absence of toe pressure measurements, and nine were excluded for the absence of recording of either dorsal pedis artery or LPA. Seventy-seven patients were finally included with a total of 88 limbs.Patient characteristics are summarized in r = −0.75 and −0.75, respectively).r = −0.78). The highest correlation to TBI comes about with the highest value of AT between DPA and LPA  (AT 0.0001) .Regarding our second objective, every DW parameter significantly correlated to TBI was also to ABI but correlation coefficients were systematically lower.max) statistically differs according to the presence or absence of toe pressure ≤30 mmHg: 171.4 vs. 259.7 ms, respectively, p < 0.0001). Diagnosis accuracy of ATmax is high with an area under curve of 0.89 [95% CI [0.81–0.98]]   and imaging, such as CT angiogram, magnetic resonance angiogram, and DUS , 15–17. ia (CLI) . ATmax wAcceleration time seems to be more and more described in the literature as associated with PAD. For example, in 2020, Yagyu et al. published that the acceleration time ratio between the popliteal  and the common femoral artery was highly predictive of femoropopliteal artery lesions with an AUC of 0.93 . RecentlIn our study with patients with occlusive PAD, no DW variable showed a high correlation with ABI. This result is understandable considering the low sensibility of ABI in this population , 6, 25. r = −0.75 and −0.75, respectively). This led us to the conclusion that the highest value of acceleration time of either pedal artery (ATmax) allowed us to moderately increase the correlation (r = −0.78) but also to have a satisfying measure for every included patient. Considering PAT or DAT, missing values were recorded in 22.7 and 21.6% of our population, respectively, due to arterial occlusion. These results could perhaps be explained by the fact that our included patients had more severe PAD. When we considered the highest acceleration time, ATmax could be measured in all our patients as none presented concomitant dorsal and plantar arterial occlusion. On multivariable analysis , ATmax remained highly associated with TBI (p < 0.001).Our results are not consistent with those of Sommerset et al.  as, in oTo help categorize PAD severity through DW, recent studies have studied the benefit and reproducibility of a 13-category arterial Doppler waveform classification, called the “Saint Bonnet classification” , 27.mean) and lowest (ATmin) acceleration time on pedal arteries show strong correlations with TBI. These results need to be replicated on the wider population to confirm the superiority of ATmax compared to ATmean and ATmin.Even if the highest value of acceleration time on pedal arteries showed the best correlation to TBI, mean . However, this study was a proof of concept study and this preliminary result should be validated by a prospective study including a larger number of patients. Second, the prognosis value of ATmax was not evaluated in this work since no patient follow-up was performed. This was not the aim of the study but further studies are required. Third, all ABI and TBI measures were performed by three vascular physicians and intraindividual variability was not evaluated. However, these measures were performed by highly trained and experienced vascular physicians. Moreover, TBI reproducibility could be considered satisfactory due to automatic measuring.Several limitations in this study should be addressed. First, the study was retrospective which cannot provide exhaustive bias control. The number of included patients is modest  is highly correlated to TBI in patients with occlusive PAD. ATmax with a cut-off value of 215 ms could represent a step forward for the diagnosis of toe pressure ≤30 mmHg, one of the criteria of critical limb ischemia. This measure might be of great interest to clinicians who do not have access to TBI.This study suggests that the highest acceleration time of either DPA or LPA (ATMore studies are needed to confirm if the highest acceleration time of pedal arteries is more predictive of PAD severity than plantar acceleration time alone; and confirm the optimal cut-off value for detecting critical limb ischemia.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.J-ET, GM, MC, CT, VC, JG, and DL: conception and design, revising, approval for publication, and agree to be accountable for all aspects of the work. J-ET, GM, JG, DL, and CT: data analysis. J-ET, GM, DL, and MC: drafting. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


This study aimed to evaluate the effect of low- and high-pressure pneumoperitoneum pressures applied during robotic-assisted laparoscopic prostatectomy (RALP) using near-infrared spectroscopy (NIRS) on regional cerebral oxygenation saturation  physical status I-II, who would undergo elective RALP. The patients were divided into two groups . Patients’ demographic data, durations of anesthesia, surgery, pneumoperitoneum, and Trendelenburg position, intraoperative estimated blood loss, fluid therapy, urine output, hemodynamic and respiratory data, and rSO2 values increased significantly during the pneumoperitoneum combined with steep Trendelenburg position (fromt3tot6) and at the end of the surgery (t7) in both groups, compared to the values 5 min after the onset of pneumoperitoneum in the supine position (t2) (P < 0.05), but no statistical significance was observed between the two groups. No cerebral desaturation was observed in any of our patients. Hemodynamic and respiratory parameters were preserved in both groups. The blood lactate levels were significantly higher in patients operated at high-pressure pneumoperitoneum, compared to those with low-pressure pneumoperitoneum (P < 0.05).  The rSO We believe that low-pressure pneumoperitoneum, especially in robotic surgeries, such as robotic-assisted laparoscopic prostatectomy (RALP), can be applied safely. The steep Trendelenburg position is defined as the body tilted at an angle of 30 to 40°. It has been reported that the long-term pneumoperitoneum combined with steep Trendelenburg impairs cerebrovascular autoregulation, increases the risk of intracranial pressure (ICP) and cerebral edema, and may cause neurological deterioration secondary to hemodynamic changes such as increased mean arterial blood pressure and increased systemic vascular resistance [1]. There is, thus, an increasing interest in determining optimal pressure with minimal adverse effects of pneumoperitoneum since it provides adequate surgical workspace during laparoscopy [2]. In studies conducted to determine the optimal pneumoperitoneum pressure during RALP, it has been shown that, compared to the standard pneumoperitoneum pressure of 15 mmHg, 12 mmHg of pneumoperitoneum pressure does not cause postoperative complications [3] and reduces hospital stay and postoperative ileus rate [2]. It has been stated that during RALP, secondary to the pneumoperitoneum combined with steep Trendelenburg, cerebral blood volume and ICP increases, and consequently, cerebral edema, hypoperfusion, and ischemia may occur . Therefore, additional methods are needed to enable early diagnosis and treatment of cerebral dysfunction during robotic surgery [5]. Jugular venous oxygen saturation (SjvO2) well illustrates the ratio of cerebral blood flow to cerebral metabolic rate, which is used as an indirect marker of cerebral metabolic oxygen rate. Yet, SjvO2 is invasive and difficult to use [6]. 2) by using different absorption characteristics of oxygenated and deoxygenated hemoglobin  in cerebral oximeter . Studies have shown that rSO2 values below 50% or less than 75% of the baseline values are associated with cerebral ischemia, postoperative cognitive dysfunction, and even longer hospital stay [8–10]. The NIRS has been utilized to observe whether or not the cerebral oxygen delivery is adequate in patients who undergo surgical procedures with a high risk of adverse neurological outcomes [10–12]. The NIRS has started to be applied for noninvasive evaluation of cerebral damage in many recent operations, where cerebral oxygenation is thought to be affected directly or indirectly, as in the case of surgical position [12–14]. It has been reported in the literature that although a decrease in rSO2 is associated with postoperative cognitive dysfunction [15], a reduction in rSO2 can improve with blood transfusion or 100% oxygen therapy [16]. However, steep Trendelenburg position and pneumoperitoneum administration must be avoided in patients with a history of cerebrovascular disorders or cerebral ischemia as the pneumoperitoneum pressure administered in the steep Trendelenburg position has also been reported to increase ICP exaggeratedly, and result in a disaster in such patients [17]. Near-infrared spectroscopy (NIRS) is a device that reflects the balance between cerebral oxygen consumption and demand and allows continuous and noninvasive monitoring of regional cerebral oxygenation saturation . All patients were informed, and those patients whose written consents were obtained between January and July 2018 were included in the study. This study followed the Strengthening of the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines [18].Patients between the ages of 18 and 80, with a body mass index (BMI) of ≤40 kg/m2, with the American Society of Anesthesiology (ASA) score I-II, and those scheduled for elective RALP were included in the study. The patients were informed about the possible risks, benefits, and complications. The patients with the following conditions were excluded from the study: declined to give written informed consent, were under 18 or over 80 years of age, with an ASA score of III and above, with neurological disease and history of cerebrovascular disease, being treated for congestive heart failure, anemia, hematological disorder, and any metabolical disease, had acute intracranial vascular lesions , requiring emergency surgery. The patients were divided into two groups: low-pressure pneumoperitoneum  and high-pressure pneumoperitoneum . 2 values (right and left), vasopressor support therapy and blood gas  values were recorded. Data collection was conducted by a blinded anesthesia nurse. The patient was carefully monitored during the operation, and the data including hemodynamic parameters, rSO2 values, blood gas values, fluid therapy, and urine output were recorded at regular intervals. While the data related to the study were recorded by a blinded anesthesia nurse in the anesthesia form, they were also recorded in a separate data collection form.As a routine, a preoperative evaluation was performed for RALP. The patients’ demographic data , durations of anesthesia, surgery, pneumoperitoneum, and Trendelenburg position, estimated amounts of intraoperative blood loss, intraoperative fluid therapy, and urine output, hemodynamic data , rSO2 values were recorded by placing a NIRS probe  in the frontotemporal region of all patients. Following the premedication with 0.04 mg/kg IV midazolam, anesthesia was induced with 2 mcg/kg IV fentanyl, 2-3 mg/kg IV propofol, and 0.6 mg/kg IV rocuronium. Intraoperative ASA basic monitoring protocol was applied, including electrocardiogram (ECG), HR, noninvasive blood pressure (NIBP), SpO2, and end-tidal carbon dioxide (etCO2). The patients were intubated with the appropriate size of the endotracheal tube. Following the tracheal intubation, invasive arterial pressure  , urine output, and esophageal body temperature were monitored. The patients were ventilated in the volume-controlled mode. In order to reduce the negative effect of the pneumoperitoneum combined with the 30° steep Trendelenburg position on the lungs, ventilator settings were set with the tidal volume of 6–8 mL/kg and with the inspiratory/expiratory ratio of 1:2 and 4–7 cm H2O positive end-expiratory pressure (PEEP). To maintain an etCO2 within 30-35 mmHg, the tidal volume or the respiratory rate adjusted, appropriately . Anesthesia was maintained with 40% dry air-oxygen mixture and 0.8–1.5 age-adjusted minimum alveolar concentration (MAC) of desflurane. MAP was maintained within 20% of the pre-induction value in both groups by adjusting remifentanil infusion at 0.1–0.2 µg /kg/min IV. Muscle relaxation was achieved with 10 mg IV rocuronium at the discretion of the participating anesthesiologist and according to the surgeon’s needs. During anastomosis, fluid therapy was restricted (1 mL/kg/h) until ureterovesical anastomosis was completed in order to prevent blurring in the surgical site, and reduce the development of fascial, pharyngeal, and laryngeal edema in the steep Trendelenburg position [19]. After the ureterovesical anastomosis was completed and the patient was placed back in the supine position, a 1 L Ringer’s lactate bolus was administered, taking into account the patient’s volume. Twenty minutes before the surgery ended, all patients were administered 1000 mg IV paracetamol and 100 mg IV tramadol for postoperative analgesia in addition to ondansetron 4 mg IV infusion for antiemetic prophylaxis. At the end of the surgery, 0.05 mg/kg IV neostigmine and 0.02 mg/kg IV atropine were administered to antagonize the neuromuscular block. All patients were awakened in the operating room and then transferred to the recovery room. Postoperative analgesia was maintained with paracetamol for the first 72 h . The recovery time was defined as the time from the discontinuation of the inhalation agent and remifentanil at the end of the surgery to the removal of the tracheal tube [17].An 18 G vascular catheter was inserted in all patients taken to the operating room to start the IV fluid treatment. Right and left basal rSOThe da-Vinci surgical robot , designed to transform, filter, and transmit the surgeon’s hand motion, was used for RALP. All patients were placed in a modified lithotomy position during surgery after anesthesia induction. The arms were placed adjacent to the body. Shoulder pads were placed on the patients’ acromioclavicular joints. The pressure points were supported with soft pads. Pneumoperitoneum was obtained using an automatic insufflator . During robotic and auxiliary port placement, the initial pneumoperitoneum was set to 15 mmHg. After the port was placed in the supine position, the patient was placed in the 30º Trendelenburg position. Pneumoperitoneum pressure was set to the desired level (15 mmHg or 12 mmHg) during the surgical procedure, at the surgeon’s own discretion [2].t1), 5 min after the onset of pneumoperitoneum in the supine position (t2), during the combination of Trendelenburg position and pneumoperitoneum , and at the end of surgery (t6). Blood gas parameters were also recorded baseline (t1), 5 min after pneumoperitoneum in the supine position (t2), 30 min (t3), 60 min (t4), and 120 min (t5) after pneumoperitoneum in the Trendelenburg position, and at the end of the surgery (t6). Hypotension was defined as more than 20% decrease in basal MAP [20]. Hypotension was planned to be treated first with liquid boluses, followed by 5–10 mg IV ephedrine boluses. Vasopressor treatment was planned in patients when the treatment was insufficient. Perioperative Hb concentration was kept above 7 g/dL. Red blood cell transfusion was planned for patients with Hb concentration below 7 g/L. Hemodynamic parameters were recorded at baseline (5 min after induction) (t1), 5 min after the onset of pneumoperitoneum in the supine position (t2), during the combination of Trendelenburg position and pneumoperitoneum , and at the end of surgery (t7). Cerebral desaturation was defined as a rSO2 value below 75% of the baseline value  for 15 s [17]. NIRS is a noninvasive imaging method that reflects the balance between supply and demand in cerebral oxygenation using different absorption characteristics of HbO2 and Hb [7]. NIRS is routinely performed in all robotic cases in our hospital to evaluate cerebral oxygenation. All patients were informed about the benefits and possible complications of NIRS in the preoperative period. NIRS sensors were placed in the frontotemporal area of all patients after the skin surface was cleaned with alcohol and before preoxygenation. The head was held in a neutral position with a silicone pillow to optimize the arterial and venous mixture. NIRS values were recorded before the anesthesia induction  and percentage (%), while continuous data are presented as mean (standard deviation) or median (interquartile range). Normality analysis was performed using the Shapiro–Wilk test. Student t-test and Mann–Whitney U test were used for the analysis of independent groups. Categorical variables were analyzed using Pearson chi-square or Fisher’s exact test. Repeated measures of variance (ANOVA) was used to test any change in rSO2 among the study time points. Differences within the group were analysed with a paired t-test with Bonferroni correction. The P-value less than 0.05 was considered statistically significant.Statistical analysis was performed using SPSS version 23 . Categorical data are presented as absolute frequency  in the 12-mmHg pneumoperitoneum group, while it was 66.30 (6.01) in that of the 15 mmHg pneumoperitoneum group. The sample size was computed with a confidence interval of 95% and a significance level of 5%, and it was concluded that each group should consist of 19 patients to obtain statistically significant values. Considering the drop-out rate, it was estimated that there should be at least 22 patients in each group.The sample size was calculated using the G*power 3 analysis program  before the study. A pilot study was carried out on 8 patients from each group. Power analysis was based on NIRS changes under 12 and 15 mmHg pressures of pneumoperitoneum. The mean rSOA total of 60 patients were asked to participate in the study. Nine patients did not meet the inclusion criteria, four patients declined to participate in the study, and two surgeries were cancelled. Therefore, data from the remaining 45 patients, 22 in the 12-mmHg pneumoperitoneum group (Group I) and 23 in the 15-mmHg pneumoperitoneum group (Group II), were analyzed for the study .Characteristics of the patients, including age, body mass index (BMI), ASA physical status, smoking, and comorbidities are summarised in Table 1.No statistically significant differences were found between the two groups in terms of the duration of surgery and anesthesia . Moreover, duration of pneumoperitoneum and Trendelenburg were similar . No patient needed vasopressor therapy or a bolus of ephedrine in the intraoperative period in both groups. The intraoperative estimated blood loss was similar (P = 0.255). None of the patients required blood transfusion. No statistically significant difference was found between the two groups in terms of intraoperative fluid therapy (P = 0.126) and urine output (P = 0.729) (Table 2).2. However, when the rSO2values were compared with the values 5 min after the onset of pneumoperitoneum in the supine position (t2); it was observed that the right and the left rSO2 values increased significantly during the pneumoperitoneum combined with steep Trendelenburg position (fromt3tot6) and at the end of the surgery (t7) in both groups (Table 3). No patient had a rSO2 value <75% of the baseline value for ≥15 s.No statistically differences were found between the two groups in terms of changes in rSOHemodynamic changes of patients are shown in Table 4. In terms of HR and MAPs, no statistical significance was observed in all time periods, and both HR and MAP were maintained during RALP in both groups. Although the SPO2 value was higher in Group I, compared to Group II, no statistically significant difference was found between the two groups. t2,t3,t4, andt5; P values were 0.028, 0.032, 0.041, and 0.027, respectively) (Table 5). Although Hb levels of patients were lower in Group I compared to Group II, they were not statistically significant (Table 6). In both groups, PaCO2 values started to increase from the onset of pneumoperitoneum, and peak at the end of the surgery . Although PaO2 values were lower in Group II, they were maintained in both groups during the study . Although the blood lactate levels were at normal levels in both groups, when compared between the groups, it was observed that the blood lactate levels were statistically significantly higher in patients operated at high-pressure pneumoperitoneum , and at the end of the surgery (t7) in both groups. There was no statistical significance between the rSO2 values in both groups. No cerebral desaturation was observed in any of our patients. Throughout the surgery, the blood lactate levels were significantly higher in patients who underwent high-pressure pneumoperitoneum than those who had low-pressure pneumoperitoneum. On the other hand, despite the Hb levels being lower in patients undergoing low-pressure pneumoperitoneum, there was no significant difference observed between the groups. Our study showed that rSO2 levels, the rSO2 values were observed to increase from the onset of pneumoperitoneum in patients with both low- and high-pressure pneumoperitoneum. This increase in rSO2 levels can be explained by an increase in cerebral blood flow and secondary to an increase in PaCO2 levels. Although our study found out that the hemodynamic parameters of the patients were preserved, it was also stated in the literature that the increase in MAP may contribute to the increase in cerebral blood flow during Trendelenburg [17]. In many studies, it has been reported that, when applied alone or in combination, Trendelenburg position and pneumoperitoneum increased ICP, which is related to increased venous pressure, cerebral blood volume, and cerebrospinal fluid volume that obstruct cerebral venous drainage . Besides, it has been shown that pneumoperitoneum pressure applied during laparoscopic surgery prevents venous return from lumbar venous plexuses by increasing catecholamine release, independent of PaCO2, increasing ICP, and cerebral blood flow [17]. Cerebral blood flow can range from 2.7 to 8.0 kPa in line with the change in PaCO2 [23]. Park et al. evaluated the effect of pneumoperitoneum on cerebral oxygenation in the steep Trendelenburg position with NIRS in patients undergoing RALP and showed that rSO2 values increased significantly from the 30th min. of pneumoperitoneum to the end of surgery [17], which is consistent with our results. Another study also reported that rSO2 values increased significantly, from 70% to 73% during RALP [24]. A number of studies conducted with a focus on the correlations between rSO2 and ICP revealed that the rSO2 decreased as cerebral perfusion pressure declined due to increased ICP . In our study, although no significant difference was detected for the effect of different pneumoperitoneum pressures applied during RALP on rSOAlthough hemodynamic changes caused by carbon dioxide insufflation are well tolerated, they are frequently seen in patients undergoing laparoscopic surgery. The cardiovascular complication rate in patients who undergo laparoscopic surgery may increase as a result of creating a pneumoperitoneum. Yet, it has been shown that lower intra-abdominal pressure levels are feasible and safe, besides reducing the cardiovascular consequences of a high-pressure carbon dioxide pneumoperitoneum [26]. A study by Ekici et al., which evaluated the cardiac effects of different intraabdominal pressures in laparoscopic cholecystectomy, showed that MAP and HR increased significantly in patients who were applied both low- and high-pressure pneumoperitoneum, compared to the baseline values, though there was no significant difference between the two groups [26]. As a matter of fact, our study found out that hemodynamic parameters were preserved in patients who were applied both low- and high-pressure pneumoperitoneum.Cerebral oxygen saturation shows the balance between cerebral oxygen consumption and demand and is affected by heat, cerebral blood flow, Hb level, and cerebral metabolic rate [7]. Cerebral oximetry provides information about the blood flow below its location, under the localization of the probe [7]. In our study, the NIRS probe was placed in the frontotemporal region of the patients and thus, information was obtained only about the regional oxygenation of the frontotemporal cortex. Therefore, the increase in cerebral oxygen saturation in this study should not imply an increase in normal global oxygenation [7]. Cerebral desaturation did not occur in any patients in our study, which is an especially important finding for patients who will undergo major surgery at an advanced age. It has been reported in the literature that the incidence of cerebral desaturation is 26% in elderly patients who underwent major abdominal surgery [15].Many factors may affect the surgical site during laparoscopic surgery [27]. It is generally thought that higher pressure pneumoperitoneum can provide a better view of the surgical site . However, high-pressure pneumoperitoneum has not only hemodynamic but also undesirable surgical effects on the patient [30]. It has been reported in the literature that low-pressure pneumoperitoneum can be applied reliably [31], and because of the higher abdominal wall compliance in the low-pressure pneumoperitoneum [32], it can provide a better surgical view compared to high-pressure pneumoperitoneum [27]. In like manner, it was observed in our study that low-pressure pneumoperitoneum not only preserved the hemodynamics of the patients but also provided surgeons with sufficient vision. The European Association for Endoscopic Surgery recommends the use of the lowest intraabdominal pressures to achieve the surgical view for the sake of patient safety, rather than the use of routine intraabdominal pressures in laparoscopic surgeries [33].However, it is also believed that using lower pressure pneumoperitoneum during laparoscopic surgery may decrease surgical visualization and complicate surgical dissection, thereby increasing the risk of the duration of surgery, blood loss, or organ damage . Yet, studies have indicated that there is no significant difference in low- and high-pressure pneumoperitoneum in terms of duration of surgery, hospital stay, and intraoperative blood loss [3]. No significant difference was found in our study between the durations of surgery, anesthesia, pneumoperitoneum, and Trendelenburg position, or estimated blood loss in patients undergoing low- and high-pressure pneumoperitoneum. Although Hb levels were lower in patients with low-pressure pneumoperitoneum, no statistically significant difference was found between the two groups, and no intraoperative blood transfusion was required in any of our patients. Despite the prolonged duration of surgery in patients undergoing low-pressure pneumoperitoneum, it is not statistically significant. High intraabdominal pressures may cause lactic acid accumulation in patients undergoing prolonged laparoscopic procedures. Taura et al. compared the different levels of intraabdominal pressures (15 vs. 10 mmHg) undergoing laparoscopic sigmoidectomy and found that blood lactate levels were higher in patients with high-pressure pneumoperitoneum [34]. Although blood lactate levels were within normal limits in both groups in our study, blood lactate levels were found to be higher in patients who were applied high-pressure pneumoperitoneum. Increase in blood lactate levels may result from increased anaerobic metabolism due to tissue ischemia caused by high-pressure pneumoperitoneum [35].This study has several limitations. First, the study was planned prospectively but observationally. Prospective and randomized controlled studies are needed. Second, our study was planned on male patients, and could not be generalized to the general population or geriatric population. Thirdly, since the study was planned observationally, no tests were performed to evaluate the cognitive dysfunctions of the patients in the postoperative period.2 values increased in patients undergoing RALP, there was no significant difference between the low- and high-pressure pneumoperitoneum. It was found that hemodynamic and respiratory parameters were better maintained in patients undergoing low-pressure pneumoperitoneum. Contrary to what is stated, low-pressure pneumoperitoneum did not significantly increase bleeding rates. Also, despite low- and high-pressure pneumoperitoneum having a similar effect on hemodynamic parameters, it was observed that low-pressure pneumoperitoneum has a more positive effect on blood lactate levels. For these reasons, we believe that low-pressure pneumoperitoneum can be applied reliably, especially in robotic surgeries such as RALP. However, further studies with a larger sample size are required to confirm the results of this study.In conclusion, although it was found that rSOApproval was obtained from the Ethics Committee of the University of Health Sciences, Antalya Training and Research Hospital (No: 16/10). Written informed consents were obtained from the patients.


After adjustment for duration of diabetes, history of cardiovascular disease and serum albumin, ox-LDL remained a significant effect modifier of the association between proteinuria and eGFR decline over time (p = 0.04). Our study shows that in proteinuric DKD, circulating ox-LDL levels amplified the magnitude of the association between proteinuria and progression of DKD.Proteinuria is characterized by low accuracy for predicting onset and development of diabetic kidney disease (DKD) because it is not directly associated with molecular changes that promote DKD, but is a result of kidney damage. Oxidized low-density lipoprotein (ox-LDL) reflects oxidative stress and endothelial dysfunction, both underlying the development of proteinuria and loss of kidney function in DKD. We aimed to investigate whether ox-LDL modifies the association between proteinuria and progression of DKD in a cohort of 91 patients with proteinuric DKD and diabetic retinopathy, followed for 10 years. The primary endpoint was a combined kidney outcome of eGFR decline ≥30% or progression to end-stage kidney disease. After the end of the study, we considered the percentage change of eGFR over time as our secondary outcome. Proteinuria was associated with both outcomes, and ox-LDL amplified the magnitude of this link ( During the past decade, the prevalence of type 2 diabetes mellitus (T2DM) has increased to epidemic proportions worldwide. One of the most common complications of T2DM, diabetic kidney disease (DKD), occurs in 40% of T2DM patients over their lifetime and is the main cause of end-stage kidney disease (ESKD) in the USA and worldwide . In receWe enrolled 91 patients with documented proteinuric DKD, followed in the Diabetic Nephropathy Clinic of the University General Hospital of Alexandroupolis, Greece. To establish proteinuric DKD, and not T2DM and chronic kidney disease (CKD) from another cause, inclusion criteria included history of documented T2DM for at least 7 years, presence of diabetic retinopathy, eGFR < 90 mL/min and persistent proteinuria, whereas patients with acute illness, tumor, chronic inflammation, urinary tract disease or any evidence of non-diabetic CKD were excluded from the study. At baseline we recorded demographic, somatometric and clinical data, and we obtained blood samples from all participants. eGFR was calculated by the CKD-EPI calculation.Both the PhD Scientific Committee and the Ethics Committee of the Scientific Council of the University General Hospital of Alexandroupolis approved our study protocol in 2007 (1046/1 November 2007) and re-approved it after a minor correction regarding the calculation of eGFR in 2011 (1130/25 November 2011). Our study protocol was in conformity with the Helsinki Declaration of Human Rights. All participants provided written informed consent at enrollment.Laboratory analyses have been extensively described before . In shorAfter initial assessment, all patients were prospectively followed up for 10 years (2008–2018) with the primary outcome being the progression to ESKD requiring dialysis or eGFR decline of at least 30% from baseline. Death was accurately recorded and was considered as a competitive event. To determine the deterioration of kidney function after the follow-up, we re-evaluated eGFR at the end of the study, and we calculated the percentage eGFR change over time (ΔeGFR/baseline eGFR divided by the follow-up time) for each patient (secondary endpoint). We collected follow-up data for all participants via follow-up visits, hospital medical records, death certificates or via integrated telephone interview.We used the Shapiro–Wilk test to test data for normality, and normally distributed variables were presented as mean (SD), whereas non-normally variables were presented as median (range) and binary variables as percent frequency. To identify potential confounders associated with deterioration of kidney function, and possibly acting on the effect modification by ox-LDL on the UPCR-deterioration of kidney function association, we divided our study cohort into tertiles according to eGFR values , p values and 95% confidence intervals (CIs). Statistical analyses were conducted by STATA 13.0 for Windows, College Station, Texas, USA and IBM Statistical package for Social Sciences .For the secondary endpoint, we forced all baseline variables from Baseline anthropometric, clinical and biochemical data of 91 patients with proteinuric DKD in total and according to eGFR tertiles are presented in p = 0.003 and 1.05, 95%CI 1.02–1.08, p < 0.001, respectively). To find possible determinants of deterioration of kidney function, we performed Fine and Gray regression analysis on an exploratory basis for all variables in p = 0.032), SBP , T2DM duration  and serum albumin  were associated with the composite outcome. Fine and Gray analysis showed that ox-LDL cholesterol was a strong modifier of the association between UPCR and the composite outcome of kidney function deterioration in the crude analysis , p = 0.002) and SBP  remained significant, independent predictors of eGFR decline of at least 30% from baseline or progression to ESKD.During the follow-up period , 17 patients presented the combined kidney outcome of eGFR decline of at least 30% from baseline or progression to ESKD, whereas 13 patients died. On univariate Fine and Gray analysis, baseline UPCR and plasma ox-LDL were significantly associated with the composite kidney endpoint  and multivariate models , adjusted for ox-LDL, UPCR, albumin, T2DM duration and history of CV disease . Having this in mind, our inclusion criteria included history of T2DM for at least 7 years, presence of proteinuria, eGFR below 90 mL/min and the presence of diabetic retinopathy. Our inclusion criteria to establish DKD, and not T2DM and CKD due to other causes, have been used in other previous studies ,18,19. ADuring the follow-up period, 18.7% patients presented the primary kidney endpoint. Proteinuria was independently associated with both the primary outcome and with eGFR decline over time at the end of the study. Data from large epidemiological studies suggest that proteinuria is an independent predictor of DKD progression. The Chronic Renal Insufficiency Cohort (CRIC) Study enrolled 1908 participants with T2DM and decreased eGFR, and it found that 28% of them had some degree of proteinuria . ProteinTo our knowledge this is the first research study reporting an effect modification by ox-LDL on the association between UPCR and DKD progression in proteinuric DKD. Traditionally, epidemiologic studies aim to investigate whether a certain risk factor is causally related with the occurrence of a certain disease. However, it has been documented that causal risk factors might not have the same impact under all conditions. Their effect might be modified (either magnified or minimized) by other factors, implicated in their pathophysiologic pathway. This phenomenon is termed as interaction or effect modification in research medicine  and has The finding in our study, that ox-LDL and UPCR are intra-related entities, is in keeping with the hypothesis of a role of these two biomarkers in the development and progression of DKD. Cross-sectional data suggest that among T2DM patients divided into normo-, micro- and macro-albuminuric, there is a graded increase in ox-LDL circulating levels, regardless of glycemic control ,11. MoreOur study has certain limitations that should be addressed, including the low sample size and the observational design, which precludes establishing any causality. As in any observational study, although we adjusted our models for several factors, our results might have been influenced by other unidentified confounders. Moreover, we did not re-assess ox-LDL levels at the end of the study and the number of patients in each group was too small to draw definite conclusions on the examined associations. Despite these limitations, this study supports that there might be an interplay between ox-LDL and UPCR in the pathogenesis of DKD. Future larger, well-designed studies with larger sample size assessing a broader range of parameters in other DKD patterns (both proteinuric and non-proteinuric) are needed in order to draw definite conclusions regarding the possible interaction between ox-LDL and proteinuria as predictors of DKD progression.In conclusion, our study shows that UPCR is independently associated with progression of DKD and deterioration of kidney function in proteinuric DKD, and that circulating ox-LDL levels might modify this association. The pathophysiology of the link between ox-LDL-UPCR and progression of DKD requires further investigation, but this observation suggests a role of UPCR in the deleterious effect of ES and ED on progression of DKD.