The use of kidneys from deceased donors with acute kidney injury (AKI) to expand the donor pool is an ongoing trend. Prior research on the utilization of AKI donor kidneys, especially from pediatric AKI donors, was limited and has been subject to small sample sizes. In this study, we aimed to evaluate the safety and effectiveness of early post-transplantation outcomes in pediatric deceased donors with AKI.This retrospective study compared the clinical results  of kidney transplantation from deceased donors who were categorized as pediatric donors and adult donors with or without AKI, as defined by the Kidney Disease: Improving Global Outcomes (KIDGO) criteria, at our center between January 2018 and December 2020.Of the 740 patients, 154 received kidneys from pediatric donors , and 586 received kidneys from adult donors . The baseline characteristics were similar in both cohorts. No significant difference was observed in 1-year patient survival, death-censored graft survival, or acute rejection between the AKI and non-AKI groups in both the pediatric and adult cohorts. However, compared with those transplanted with adult AKI kidneys, those transplanted with pediatric AKI kidneys showed a superior recovery of allograft function. In pediatric cohorts, no significant difference was found in serum creatinine/estimated glomerular filtration rate (SCr/eGFR) between the AKI and non-AKI groups, even in the first week post-transplant. In contrast, the post-transplant SCr/eGFR level of the AKI group recipients in adult cohorts did not recover to a level statistically similar to that of non-AKI recipients, even at 6-months post-transplant. Nonetheless, AKI kidney recipients were at an increased risk of DGF in both pediatric (34.1% vs. 16.8%) and adult (38.5% vs. 17.4%) cohorts.Kidney transplantation from deceased donors with AKI has short-term clinical outcomes comparable to those of non-AKI kidney transplantation. Pediatric AKI kidneys have a superior recovery of allograft function. The transplant community should utilize this donor pool to minimize waiting-list-related mortalities. Kidney transplantation is the preferred choice for patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD), owing to improvements in long-term survival and quality of life when compared with maintenance dialysis , 2. HoweAKI is a syndrome characterized by the rapid loss of renal excretory function and can be diagnosed by decreased urine output and/or the accumulation of end products of nitrogen metabolism , 8. AKI This was a retrospective, single-center cohort study of patients who received deceased donor kidney transplants between January 2018 and December 2020. All study data were obtained from the China Scientific Registry of Kidney Transplantation (CSRKT) and the China Organ Transplant Response System (COTRS). The study was performed in accordance with the Declaration of Helsinki, Istanbul declaration standards, and the principles of Good Clinical Practice. All cases of organ donation and transplantation met the Chinese standards for human organ donation . The stuAll recipients were divided into four groups according to donor age  and donor AKI status (with or without AKI). AKI was defined using the Kidney Disease: Improving Global Outcomes (KIDGO) criteria , 21: an All recipients received mycophenolate mofetil  and intravenous methylprednisolone (500 mg) before transplantation. Basiliximab (more in non-AKI group) or antithymocyte globulin was used as induction therapy, and tacrolimus, MMF, and methylprednisolone were administered after kidney transplantation. The minimum concentration of tacrolimus was maintained at 7–10 ng/mL during the first 3 months and at 6–8 ng/mL during the first year post-transplantation. MMF was administered at an oral dose of 0.75 g twice daily, and the MMF area under the curve was maintained at 30–60 mg·h/L. Following intravenous methylprednisolone (1.5 g), oral methylprednisolone was administered at an initial dose of 64 mg/day, which was reduced to 8 mg/day and was eventually maintained at 4–8 mg/day.We collected the baseline data of the donors, including age, sex, body mass index (BMI), history of diabetes, hypertension, cause of death, SCr level, and estimated glomerular filtration rate (eGFR) at admission and before procurement. We also collected the following baseline data of the recipients: age, sex, BMI, history of diabetes and hypertension, cause of ESRD, duration of dialysis, cold ischemia time (CIT), warm ischemia time (WIT), panel-reactive antibody (PRA) ≥ 20%, number of human leukocyte antigen (HLA) mismatches, induction therapy, and clinical outcomes. pre-transplant biopsy is not regularly performed for all AKI donor kidneys in our center. It is only being done as a last resort when the preoperative assessment of the deceased-donor kidney including surgeon appraisal, clinical parameters, and machine perfusion characteristics can not be determinative.The primary endpoints of this study were patient and allograft survival and renal function at different time points . The secondary endpoints included the development of DGF, which was defined as a serum creatinine ≥ 400 µmol/L or required dialysis in the first week after KT , 22. In Continuous variables are presented as median (interquartile range [IQR]) or the mean ± SD and were compared using the Mann–Whitney U test/Kruskal–Wallis H test  or Student’s t-test. Frequencies (percentages) were used for categorical data and were compared using chi-square tests or Fisher's exact test. Graft survival was estimated using the Kaplan–Meier method and compared among groups using the log-rank test. Logistic regression analysis was performed to predicting DGF. Cox proportional hazard regression analysis of risk factors for death-censored graft survival and patient survival. The multivariate analysis included variables that were statistically significant (p < 0.05) in Univariate Analysis and other clinically significant factors. For the inference testing, a two-sided p-value < 0.05 was considered statistically significant. Analyses were conducted using SPSS, version 26.0 .The pediatric study cohort included 154 transplant recipients, including 41 (26.6%) in the AKI group and 113 (73.4%) in the non-AKI group. Pediatric donor kidneys are prioritized for use by children's receptors under our country's existing legislation, while in some situations adult receptors may also be used. However, because there are few pediatric ESRD patients on the waiting list, young and middle-aged adults are the majority recipients of pediatric deceased donor kidney in our center. Deceased donors with AKI were slightly older than those in the non-AKI group  and included fewer male patients ; trauma was the most common cause of death in this study cohort. In this study cohort, 17, 13, and 11 patients had AKI classified as KDIGO stage 1, 2, and 3, respectively (Table There were 586 adult KT during the study period (218 [37.2%] in the AKI group and 368 [62.8%] in the non-AKI group). Cerebrovascular accidents were the most common cause of death in this cohort. Most of the 218 deceased donors with AKI were classified as stage 1 (86 [39.4%]), followed by stage 2 (80 [36.7%]), and stage 3 (52 [23.9%]). A significant statistical difference was observed in the induction immunosuppression regimen in the adult cohort, which may be attributed to the fact that DGF was more likely to occur, and anti-human T lymphocyte rabbit immunoglobulin (ATG) will tend to be selected for preoperative induction immunosuppression therapy. The other donor clinical indicators and recipients’ baseline characteristics were similar  or patient survival  between the two groups . The overall death-censored graft survival rate was 97.7% (AKI group) vs. 97.5% (non-AKI group) at 1 year (p = 0.435). The overall patient survival rate was 98.1% (AKI group) vs. 98.1% (non-AKI group) at 1 year (p = 0.993). No significant differences were observed among the four groups in terms of patient survival (p = 0.682) and death-censored graft survival (p = 0.562). Due to the small cardinal number of pediatric AKI group, the death-censored graft survival rate was appeared to be lower at 1 year when there was one instance of graft loss (because of a severe infection). In the early post-transplantation period, patient and graft survival rates remained acceptable between groups, with a mean follow-up period of 11.44 ± 1.68 months . The history of diabetes in the donors, SCr level at Terminal, warm and cold ischemia time also had a negative effect on DGF , neurohormonal mechanisms, rhabdomyolysis, or the use of nephrotoxic agents in critically ill patients , 11. TheThe literature on AKI recovery patterns, according to the Acute Disease Quality Initiative (ADQI) definition, has found a high rate of early recovery and transient AKI. The cumulative incidence of renal recovery increased progressively from 25% on day 5 to 41% on day 10. However, up to 40% of patients with AKI do not recover by day 7, and 38% of AKI cases persistent beyond 7 days can be defined as acute kidney disease . Some hyPrior research on the utilization of pediatric deceased donors with AKI was limited. Jiang et al.  found thIn the adult cohort, the incidence of DGF was higher in recipients of allografts with AKI than in those without AKI  and tended to increase with the AKI stage, which is consistent with previous studies , 32. LuiDenic et al.  analyzedOur study has several strengths. This was a large-scale clinical cohort study. Previous research , 25 has Kidney transplantation from deceased donors with AKI remains controversial. Prior research on the utilization of donors with pediatric AKI was limited. Compared with non-AKI pediatric donor kidneys, we found that AKI pediatric donor kidneys not only have similar excellent clinical outcomes but also show a comparable recovery speed, which indicates the superior recovery of allograft function of pediatric kidneys. However, in the adult cohort of our study, the downward trend in SCr level was substantially slower in the AKI group than that in the non-AKI group. However, at 1 year post-transplant, there was no statistically significant difference in the graft survival rate, patient survival, and AR between the adult AKI and non-AKI groups. The transplant community should utilize this donor pool, but further long-term prospective studies with larger cohorts are required to strengthen this conclusion. Our data showed that deceased donor AKI status had a negative effect on the DGF rate; it did not affect death-censored graft survival and recipient survival. Therefore, the transplant community should utilize this donor pool to minimize waiting-list-related mortalities. Future prospective studies with long-term kidney allograft outcomes and larger study cohorts are warranted if pediatric deceased donors with AKI are widely adopted.


The outcome measures were angiographic vasospasm, DCI, and the neurologic outcomes at discharge as measured by the modified Rankin scale score . Univariate and logistic regression analyses were performed to evaluate whether blood pressure (BP) and ETCO2 variables were independently associated with outcome measures. Out of 390 patients, 132 (34%) developed moderate-to-severe vasospasm, 114 (29%) developed DCI, and 46% (169) had good neurologic outcomes at discharge. None of the measured intraoperative BP and ETCO2 variables were associated with angiographic vasospasm, DCI, or poor neurologic outcomes. Our study did not identify an independent association between the degree of intraoperative hypotension or hypocapnia in relation to angiographic vasospasm, DCI, or the neurologic outcomes at discharge in SAH patients.Cerebral autoregulation impairment is a critical aspect of subarachnoid hemorrhage (SAH)-induced secondary brain injury and is also shown to be an independent predictor of delayed cerebral ischemia (DCI) and poor neurologic outcomes. Interestingly, intraoperative hemodynamic and ventilatory parameters were shown to influence patient outcomes after SAH. The aim of the current study was to evaluate the association of intraoperative hypotension and hypocapnia with the occurrence of angiographic vasospasm, DCI, and neurologic outcomes at discharge. Intraoperative data were collected for 390 patients with aneurysmal SAH who underwent general anesthesia for aneurysm clipping or coiling between January 2010 and May 2018. We measured the mean intraoperative blood pressure and end-tidal carbon dioxide (ETCO Aneurysmal subarachnoid hemorrhage (SAH) is a severe form of hemorrhagic stroke with high morbidity and mortality ,2. Outco2) parameters play a crucial role in the patient’s outcome after SAH [There are numerous studies demonstrating that blood pressure and end-tidal carbon dioxide ) and calculate the area under the curve (AUC) for the following cutoffs—AUC SBP < 100 and >160 mmHg, AUC MAP < 65 and >100 mmHg, and AUC ETCO2 < 30 and >45 mmHg. The area under the curve was calculated by plotting the time–pressure graph. The plotted area was divided into the smallest possible rectangles or trapezoids. The summation of the area of these rectangles/trapezoids gave the area under the curve. The base of each tiny rectangle/trapezoid was formed by the standardized time axis (X-axis). The height of the trapezoids/rectangles was formed by the blood pressure value (Y-axis). The cumulative area was calculated for the above small quadrilaterals and represented the total area under the curve for the studied blood pressure, taking into account not only the value of the blood pressure but also the time for which it stayed. The majority of patients had arterial monitoring of blood pressure. ETCO2 was measured from induction to end-of-case using capnography. The few initial and final ETCO2 data points  were removed from the analysis for all the patients, as the ETCO2 values before intubation and after extubation may not reflect the actual ETCO2 values. Similarly, blood pressure outlier values were excluded from the analysis , as these likely represented artifacts as a result of leveling, or flushing the arterial line transducer. The intraoperative hemodynamic and ventilatory management of these patients were at the discretion of the attending anesthesiologist, and no specific study intervention was involved.Institutional review board approval was obtained at Washington University in Saint Louis  to conduct this retrospective study. Consecutive patients who presented for clipping/coiling of ruptured aneurysms after SAH from 1 January 2010 to 31 May 2018 were included in this study. A prospective neurocritical care/neurosurgical database and hospital charts were used to review the following details: patient demographics , clinical presentation , treatment modality and the outcome variables. The electronic anesthesia database was used to retrieve the following details: hemodynamic and ventilatory variables (intraoperative—average systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP), and end-tidal carbon dioxide (ETCOAngiographic vasospasm was classified into moderate (25–50% stenosis) to severe (>50% stenosis) narrowing of at least one major intracranial artery on a catheter angiogram . The cat2 values that appeared significantly associated with each outcome in the univariate analysis (p < 0.1) were entered into the multivariate model, adjusting for the known risk factors such as age, Hunt–Hess grade, modified Fisher grade, and type of treatment. A model parameter with p < 0.05 was considered statistically significant. A correlation matrix was constructed using Spearman’s rank correlation coefficient to assess the association between the interested BP/ETCO2 and outcome variables. The correlation values close to 1 indicate a strong association, 0 indicates no association, and −1 indicates a negative association between the assessed variables. Significant correlations are presented with the asterisk symbol (*). The number of asterisks increase with higher significance .Statistical analysis was conducted with SPSS v. 23.0 . The Chi square test or Fisher exact test was used for univariate analysis for categorical variables, and the Mann–Whitney U test for continuous variables. Relevant blood pressure and ETCODuring the study period, we identified a total of 436 patients with the diagnosis of aneurysmal SAH. Out of these, 46 patients were excluded, as 24 patients did not receive a screening catheter angiography to assess for cerebral vasospasm for a variety of reasons, and data for the other 22 patients could not be retrieved. In our current study, a total of 390 patients  with a mean age of 56 ± 15 years were included. Anterior circulation aneurysms accounted for 326 patients (84%), and posterior circulation aneurysms were found in 64 patients (16%). Surgical clipping was performed in 151 patients (39%), and endovascular coiling was performed in 239 patients (61%).2 variables were found to be significant in the univariate analysis. The interrelationships of intraoperative BP and ETCO2 variables with the measured outcomes are demonstrated in the correlation matrix (Angiographic vasospasm occurred in 132 (34%) of the cohort and was associated with younger age, as well as higher Hunt and Hess and modified Fisher grades . None ofn matrix .2 variables were found to be significant in the univariate analysis, a trend in significance was noted for a burden of ETCO2 below <30 mm Hg and a lower average ETCO2. After adjusting for relevant clinical variables, both a burden of ETCO2 < 30 mm Hg  and the intraoperative average ETCO2  were not associated with DCI.DCI occurred in 114 (29%) of the cohort and was associated with higher modified Fisher and Hunt and Hess grades, as well as aneurysm treatment. Of 370 patients with available mRS data at discharge, 169 (46%) had favorable outcomes. This was strongly associated with younger age and lower Hunt and Hess and modified Fisher grades. 2 values were not associated with DCI occurrence or poor neurologic outcomes at discharge and 3 months as measured by the GOS [The key finding in our study is that all the measures of intraoperative hypotension and hypocapnia were not independently associated with the risk of angiographic vasospasm, DCI, or neurologic outcomes in SAH patients undergoing aneurysm repair by clipping or coiling. Despite earlier work suggesting such physiologic measures could influence delayed ischemia and outcomes, our findings are in accordance with two previously published retrospective studies showing that intraoperative blood pressure and ETCO the GOS ,17.Our current study differs from the aforementioned studies in several ways: (1) We defined hypotension and hypertension with both SBP and MBP, whereas the other studies reported MBP only. Investigating the effects of SBP on SAH patients is important, as it is shown to be a critical variable representing the transluminal pressure across the aneurysm wall, and so it is a relevant target to prevent rebleeding . In addiBlood pressure management after SAH is critical, and tight control is desired, as hypertension could result in rebleeding, and hypotension could result in DCI, leading to poor outcomes. Though previous guidelines by the American Heart Association and the neurocritical care society recommended an SBP management of less than 160–180 mmhg until the aneurysm is secured ,23, currIntriguingly, a retrospective study with a larger SAH cohort of 1099 patients evaluated the mean and time-weighted average area under the curve (AUC) for various absolute  and relative thresholds  and did not find an association between hypotension and neurologic outcomes at discharge and 3 months as measured by the GOS . To note2) is one of the major determinants of cerebral blood flow, and CO2 reactivity is generally preserved after SAH [2 or ETCO2 in SAH patients. A retrospective clinical study (with 102 patients) on mechanically ventilated SAH patients showed that the duration of hypocapnia (PaCO2 < 35 mmHg) was associated with symptomatic vasospasm and poor functional outcomes at 3 months as measured by the GOS [2 < 30 mmHg) was associated with poor GOS outcomes at 3 months in SAH patients who were not critically ill and without concurrent intracerebral or intraventricular hemorrhage [2 on SAH outcomes [2 values  and showed that intraoperative hypocapnia was not associated with poor neurologic outcomes in SAH patients undergoing aneurysm repair [2 < 30 and >45 mmHg) validates these findings, showing that intraoperative hypocapnia does not have a significant impact on vasospasm, DCI, or the neurologic outcomes in SAH patients undergoing aneurysm repair. In addition, our study provides evidence that intraoperative hypercapnia does not have an impact on any of the measured SAH outcomes.Carbon dioxide  the impact of blood pressure and ETCO2 variables on long-term neurologic outcomes were not examined in the current study.Our study has several limitations: (1) It is a retrospective study design, which makes it impossible to disentangle causation from associations noted in observations with multiple potential confounders. (2) We reported ETCO2 values  and the 2 values . So, we 2 targets for the perioperative management of SAH patients.Overall, our study found that intraoperative hypotension and hypocapnia may not have a significant impact on angiographic vasospasm, DCI, or the neurologic outcomes in SAH patients. The observational nature of our study, showing an association but not causation, does not recommend a change in the current clinical management, until a more carefully designed prospective randomized trial sheds light on defining the optimal blood pressure and CO


SD was shown to be the most reliable marker for CHF reacutization in both sexes. Conclusion: TeSD could be considered a risk factor for CHF worsening and complications for female and male patients, but different cut offs should be taken into account. Aging and chronic heart failure (CHF) are responsible for the temporal inhomogeneity of the electrocardiogram (ECG) repolarization phase. Recently, some short period repolarization–dispersion parameters have been proposed as markers of acute decompensation and of mortality risk in CHF patients. Some important differences in repolarization between sexes are known, but their impact on ECG markers remains unstudied. The aim of this study was to evaluate possible differences between men and women in ECG repolarization markers for the telemonitoring of CHF patients. Method: 5 min ECG recordings were collected to assess the mean and standard deviation (SD) of the following variables: QT end (QTe), QT peak (QTp), and T peak to T end (Te) in 215 decompensated CHF (age range: from 49 to 103 years). Thirty-day mortality and high levels of NT-pro BNP (<75 percentile) were considered markers of decompensated CHF. Results: A total of 34 patients (16%) died during the 30-day follow-up, without differences between sexes. Women showed a more preserved ejection fraction and higher LDL and total cholesterol levels. Among female patients, implantable cardioverter devices, statins, and antiplatelet agents were less used. Data for Te mean showed increased values among deceased men and women compared to survival, but Te Acutely decompensated chronic heart failure (CHF) is among the most frequent causes of hospitalization in Western countries , presentAside from blood tests and echocardiography, electrocardiogram (ECG) is one of the essential tools in the investigation, management, and follow-up of heart failure among both in-patients and out-patients ,4,5,6. IAs evidenced by many recent studies ,12,13,14Specific diagnostic and therapeutic interventions, together with an education program to enhance clinicians’ and women’s awareness, are desirable .All in all, these patients, especially the oldest ones, frequently show an increased incidence of arrhythmias and electrical conduction disturbances , so they are often excluded from trials , despiteTherefore, we studied the repolarization variables  in order to better understand sex differences in heart failure repolarization markers and to better estimate arrhythmic risk, and those variables were specifically customed for telemonitoring devices.A total of 215 consecutive symptomatic outpatients with acutely decompensated chronic heart failure (adCHF) were enrolled at admission to the Geriatric, Internal Medicine and Cardiovascular divisions of Policlinico Umberto I in Rome from January 2019 to October 2022, with an enrollment interruption of 14 months from March 2020 due to the SARS-CoV2 pandemic. Decompensated CHF were defined as patients with at least one symptom or sign compatible with a reacutization and a previous documented history of CHF, following European Society of Cardiology guidelines (2016 and 2021) ,25. At tA custom-designed card  was used to acquire and digitalize the ECG signals; the sampling frequency was 500 Hz. A single physician (G.P.) rechecked the ECG recordings in a single-blind manner. The same software was used to calculate the study ECG intervals, as described in detail in previous papers—LabView program . In particular, the following intervals from the respective time series in ECG recordings were analyzed: R-R mean (RR), Q-R mean (QR), Q-R-S mean (QRS), Q-T mean (QT), S-T mean (ST), and T peak to T end mean (Te) intervals .SD, QTpSD, TeSD) values for each of these repolarization phase intervals. Software for data analysis was designed and produced by our research group with the LabView program .To identify the repolarization intervals, we used a software originally proposed by Berger  and vali2 test. Uni- and multivariable forward  stepwise logistic regression analysis were used to determine the association between mortality or worsening of CHF and other selected clinical and repolarization variables included in the study. In particular, it was considered dependent on variable 30-day mortality and, as covariates, on the following parameters: QTend (QTe) mean, QTpeak (QTp) mean, Tend standard deviation (Te)SD mean, QTend standard deviation (QTeSD), QTpeak standard deviation (QTpSD), Tend standard deviation (TeSD). The same method was applied to NT-pro BNP Januzzi cut off with the same ECG variables as covariates. Stepwise multiple regression analysis was used to determine possible relationships between the studied variables. Receiver operating characteristic (ROC) curves were used to determine the sensitivity and specificity of the studied parameters predicting mortality and adCHF as well as areas under curves (AUCs), and 95% confidence intervals (CI) were calculated to compare the diagnostic accuracy in all patients but separately with males and females. All data were evaluated by use of database SPSS-PC+ .All variables with normal distribution were expressed as means ± standard deviation, whereas non-normally distributed variables were expressed as median and inter-quartile range (i.r.) and categorical variables as frequencies and percentages (%). Subjects were grouped in 30-day deceased/survivors and positive to Januzzi NT-proBNP cut off/negative. Moreover, mortality, adCHF were analysed in male and female patients separately. One-way ANOVA and Bonferroni tests were used to compare data for the normally distributed variables; Kruskal–Wallis tests were used to compare non-normally distributed variables ; and categorical variables were analyzed with the χConsidering the initial 239 eligible patients with symptoms of decompensated CHF, 24 patients were excluded because of poor-quality ECGs. Consequently, 215 CHF patients (M/F: 107/108) were finally studied .A total of thirty-four patients died , fifteen  died of bronchopneumonia and respiratory failure, fourteen of terminal heart failure , two of fatal myocardial infarction , and three of sudden cardiac death  . Difference were found regarding causes of death among the two sexes .p < 0.05), HDL-cholesterol (p < 0.05), and LDL-cholesterol than the male group (p < 0.001), end-diastolic diameter (p < 0.001), and creatinine clearance (p < 0.05). Women had a more preserved ejection fraction (p < 0.05), while men showed a more frequent history of myocardial ischemia (p < 0.001), more premature ventricular complexes (p < 0.05), and left (p < 0.05) or right (p < 0.05) bundle branch blocks. Moreover, men have been implanted with a pacemaker or ICD (p < 0.05) more frequently than women (p < 0.005) and antiplatelet drugs (p < 0.05) significantly less often , QRS , QT , and ST  intervals than female patients. The other examined ECG parameters did not show significant sex differences. Considering all study subjects without sex division, the deceased patients reported a significant increase in Te  and TeSD  in comparison to survival subjects  (p < 0.05)  did not reach the statistical significance  with higher levels of NT-proBNP . Male CHF patients with higher NT-proBNP (Jannuzzi cut-off) showed a significant increase in QRSD , QRSSD , QT , QTSD , ST , and STSD . On the other hand, the female CHF patients confirmed a significant increase only for QTSD  and STSD .Regarding the Te and Te < 0.05) A,C. On t < 0.05) A, but Teificance C. FinallT-proBNP B,D. On tAll studied variables obtained from the last part of the repolarization reported a significant specificity-sensitivity curve for mortality A,C,E andSD (The NT-proBNP levels were significantly related to TeSD A–C in boThe main results of our study demonstrated that male and female patients with CHF have different conditions and parameters to be considered in clinical practice ,12,13. AMoreover, from the data collected in our study, women presented higher values of total cholesterol, LDL, and blood pressure. Women frequently reach a late diagnosis  with a mIn order to ensure correct monitoring, even remotely, of patients suffering from heart failure, numerous studies have been produced for the creation of devices and models for risk stratification of exacerbations and acute heart failure ,32,33,34The Tend mean and the T end standard deviation have been shown to be effective in predicting the mortality of patients hospitalized for acute heart failure in various associated pathological conditions ,4,5,7,35These data will therefore be carefully considered in the creation of risk models as specific sex markers for specific cardiovascular preventions . The useAn actual limitation of the study is the absence of patients treated with SGLT2 inhibitors. The sample was, in fact, largely studied before the recent indications provided by the European Society of Cardiology guidelines  on the u


In a different retrospective DKD cohort study , multiple and logistic regression analyses revealed that the baseline urinary GDF15-creatinine ratios predicted a decline in estimated glomerular filtration rate (eGFR) over 2 years. Compared to the plasma GDF15 level, the urinary GDF15-creatinine ratio is less dependent on renal function and sensitively fluctuates with diabetes and statin treatment. It may serve as a good prognostic marker for renal function decline in patients with DKD similar to the urine albumin-creatinine ratio.Sensitive biomarkers can enhance the diagnosis, prognosis, and surveillance of chronic kidney disease (CKD), such as diabetic kidney disease (DKD). Plasma growth differentiation factor 15 (GDF15) levels are a novel biomarker for mitochondria-associated diseases; however, it may not be a useful indicator for CKD as its levels increase with declining renal function. This study explores urinary GDF15’s potential as a marker for CKD. The plasma and urinary GDF15 as well as 15 uremic toxins were measured in 103 patients with CKD. The relationship between the urinary GDF15-creatinine ratio and the uremic toxins and other clinical characteristics was investigated. Urinary GDF15-creatinine ratios were less related to renal function and uremic toxin levels compared to plasma GDF15. Additionally, the ratios were significantly higher in patients with CKD patients with diabetes ( Because several reports showed that the UACR is not sensitive enough as a marker in the early stages of DKD, other biomarkers have been investigated3. Although some protein biomarkers such as ANGPTL4 and MCP-1 have been identified, none of the other biomarkers have shown a prognostic value greater than UACR4.Diabetic kidney disease (DKD) is one of the main causes of CKD and results in end-stage kidney disease if not treated properly. For a long time, the estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR) were used as the main indicators for the progression and outcomes of DKD5. In other disorders caused by mitochondrial dysfunction such as diabetes6, senescence7, cardiovascular disease, neurodegenerative disease8, and COVID-199, the plasma GDF15 levels are increased. However, as for CKD, plasma GDF15 might not serve as a useful prognostic or diagnostic marker as recent reports have shown that plasma GDF15 levels are inversely correlated with eGFR11. On the other hand, only a few studies have investigated the relationship between urinary GDF15 and other parameters in kidney diseases12, although it could be a potential diagnostic tool for kidney diseases.We recently showed that plasma growth differentiation factor 15 (GDF15), a member of the transforming growth factor-β (TGF-β) superfamily, is a diagnostic marker for mitochondrial diseasesThis study investigated the relationship between the urinary GDF15-creatinine ratio and other uremic toxins and clinical characteristics, which highlighted the difference between urinary GDF15 and plasma GDF15. We also explored the association between the urinary GDF15-creatinine ratio and DKD. A further retrospective cohort study suggested that the urinary GDF15 -creatinine ratio could be a good prognostic factor for the decline of kidney function in DKD, similar to UACR.We recruited 103 patients with CKD who were treated at the outpatient clinic in Tohoku University Hospital. In the cohort treated with a statin, 39 patients with CKD at Tohoku University Hospital were recruited. The study protocols were approved by the ethics committee of Tohoku University  and complied with the guidelines of the Declaration of Helsinki. All patients signed written informed consent.13. The urinary GDF15 was normalized by the urinary creatinine (urinary GDF15 -creatinine ratio). The levels of microbiota-derived uremic toxins, including triethylamine-N-oxide (TMAO), phenol sulfate (PS), p-cresol sulfate (pCS), and indoxyl sulfate (InS) were measured by LC/MS/MS14. 1-methyladenosine (m1A) was also measured as a marker for kidney damage15. In the measurement, deuterated internal standards were added for all analytics. The measurements were performed using a TSQ Quantum Ultra triple quadrupole mass spectrometer  equipped with a heated electrospray ionization source system. Samples were scrutinized in a single reaction monitoring mode by monitoring the ion transitions. Data were acquired and analyzed using Xcalibur™ software, version 2.1 .The concentrations of GDF15 in the plasma and urine samples were measured using a Quantikine Human GDF15 ELISA Kit , as previously described16. We recruited 342 patients for this study as reported previously14 and analyzed the levels of GDF15 in the plasma and urine samples. The analyses were approved by the ethics committees of both Tohoku University and Okayama University . All patients provided written informed consent.The urinary biomarker for the continuous and rapid progression of diabetic nephropathy (U- CARE) study was a multicentre, observatory clinical study that aimed to interrogate the urinary biomarkers in diabetic nephropathy (UMIN 00011525)14. Briefly, we built three models as an independent variable examined by a variance inflation factor (VIF) < 10, the urinary GDF15 level normalized by urinary creatinine, and the decrease in eGFR over 2 years, which were used as objective variables to perform the multiple regression analysis. Model 1 was the crude model. Model 2 was adjusted for known factors: age, sex, body mass index (BMI), systolic blood pressure (SBP), HbA1c, and log (eGFR), all of which were baseline values. Model 3 was the full model, adjusted for the Model 2 factors plus other clinical factors, such as diastolic blood pressure (DBP), alanine aminotransferase (ALT), total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), and uric acid (UA).To identify the urinary GDF15 levels that are independently associated with the decline in 2-year eGFR, three multiple regression models were used, as previously described17 in which at least a 15% reduction in eGFR would be associated with a subsequent risk of end-stage renal failure. Using this definition, 32 patients in the U-CARE study had a 15% reduction in eGFR; thus, we enrolled enough patients for statistical analyses. To identify the factors independently associated with the decline in eGFR during the 2 years, the same three multiple logistic regression models were used, as previously reported14: Model 1, only log (urinary GDF15) and UACR, which is a known predictive factor for DKD18 (crude model); Model 2 and Model 1 with known factors )19; and Model 3 and Model 2 with other factors . The results are shown as odds ratios (ORs) with 95% confidence intervals (CIs). ORs for all continuous variables were computed for each standard deviation (SD) change. The stepwise method was performed according to Akaike's information criterion. Other statistical analyses were performed using Graph Pad Prism version 9 . Statistical significance was set at p < 0.05.A logistic regression analysis was used to identify factors independently associated with the decline in eGFR during the 2 years. In this study, we defined a 15% reduction in eGFR during the 2 years as the decline in eGFR. This criterion was based on previous research21. It has been reported that the microbiota-derived uremic toxin plays a role in the pathogenesis of CKD14; however, the extent of the correlation between the GDF15 levels and the concentration of microbiota-derived uremic toxins has not been well investigated. To investigate the differences between plasma and urinary GDF15 in CKD, we enrolled 103 CKD patients , whereas the urinary GDF15 to creatinine ratio was not correlated with eGFR    compared to plasma GDF15 . However, plasma GDF15 was not significantly associated with diabetes  . These data suggested that urinary GDF15 might reflect renal mitochondrial dysfunction more sensitively than plasma GDF15. Since some medications, including statins, have been known to protect the kidneys against diabetes22, we further investigated the effect of statins on the plasma and urinary GDF15 levels in diabetic patients. As a result, the urinary GDF15 to creatinine ratio was significantly lower in the statin-treated group compared to the non-statin group , while plasma GDF15 was not significantly different 5. CKD progression would be associated with the mitochondrial dysfunction as well23. Although the precise mechanism remains unclear, mitochondrial dysfunction showing morphological change, bioenergetic impairment, and the production of reactive oxygen species (ROS) exists in DKD24. GDF15 could then be a good diagnostic marker for kidney diseases. However, plasma GDF15 might not be a useful marker because its level is affected by the deterioration of renal function25. Few studies have reported on urinary GDF15; Perez-Gomez et al. recently showed that the urinary GDF15 levels were associated with the kidney histology patterns, mortality, and the need for renal replacement therapy12. While their study focused on patients suffering from modest renal failure , our study showed that urinary GDF15 is a useful prognostic marker for renal function in early-stage DKD .This study showed that the urinary GDF15 to creatinine ratio was less affected by eGFR and likely to be a good prognostic marker for DKD. We recently showed that plasma GDF15 can serve as a diagnostic marker for mitochondrial diseases by reflecting the mitochondrial function in the tissue26. Based on our data, while both the urinary GDF15 to creatinine ratio and UACR could significantly predict the decline in eGFR, the urinary GDF15 to creatinine ratio built up the c-statistic value of the ROC curve stronger than UACR (urinary GDF15 to creatinine ratio: 0.780 versus UACR: 0.758) despite a statistically non-significant difference. The urinary GDF15 might predict the decline of kidney function in DKD earlier than UACR, although further investigations are needed. Moreover, because the urinary GDF15 is produced mainly by renal tubular cells12, while albumin leakage is from the glomerulus and tubular cells, each marker might have its own advantages. Further research can be expected to show further the usefulness of urinary GDF15 as a marker for kidney diseases.In this study, the urinary GDF15 to creatinine ratio and UACR could both predict the decline in eGFR in DKD patients. However, some studies showed that the mitochondrial dysfunction, such as an alteration of the mitochondrial mortality, bioenergetics, and ROS production, all appear prior to the presence of albuminuria22. Our findings indicated that statin therapy may alleviate intra-renal damage, thereby resulting in decreased urinary GDF15 levels, especially in DKD patients. On the other hand, metformin, an anti-diabetic drug, has been reported to increase plasma GDF15 levels, thereby causing food intake reduction and body weight loss27. Although plasma GDF15 is a biomarker for various diseases, such as cardiovascular diseases28, its function has also been highlighted recently. Further studies are needed to clarify whether urinary GDF15 is associated with other pathological conditions such as senescence, cardiovascular disease, diabetes, and neurodegenerative diseases, all of which are known to cause mitochondrial dysfunction. The function of GDF15 in the kidney should be also investigated further.In this study, the association of urinary GDF15 and plasma GDF15 with renal function, uremic toxins, and aging varied. The differences and similarities in dynamics between plasma and urinary GDF15 may suggest various meanings in medications and pathophysiology. Statins alleviate kidney injury in non-end-stage CKDIn conclusion, this study revealed that the urinary GDF15 to creatinine ratio was significantly increased in patients with diabetes and turned out to be a sensitive prognostic marker for renal function in patients with DKD. The urinary GDF15 levels were less associated with renal function and the concentration of uremic toxins compared to the plasma GDF15 levels, which highlights the usefulness of urinary GDF15.Supplementary Figures.Supplementary Table S1.


Femoral vein Doppler (FVD) is simpler than the VExUS score which is a multimodal scoring system based on combination of IVC diameter, hepatic venous Doppler, portal vein pulsatility and renal vein Doppler, may be useful in assessing right ventricular overload and signs of venous congestion. There is limited data on the relationship between FVD and VExUS score.P < 0.001) while the agreement between FVD and CVP was weak .Adult post-cardiac surgery patients were assessed for venous congestion using the VExUS score and FVD. Agreement between VExUS and FVD was studied using Kappa test, sensitivity, specificity, PPV and NPV for VExUS and FVD was calculated keeping CVP as gold standard. In total, 107 patients were enrolled, with a mean age of 55.67 ± 12.76. The accuracy of VExUS and FVD for detecting venous congestion was 80.37 (95% CI of 71.5 to 87.4) and 74.7 (95% CI of 65.4 to 82.6), respectively. The level of agreement between FVD and VExUS was moderate (Kappa value of 0.62, FVD has good accuracy for detecting venous congestion and shows moderate agreement with VExUS grading. With potentially easier physical accessibility and a shorter learning curve for novices, it may be a simple and valuable tool for assessing venous congestion.The online version contains supplementary material available at 10.1186/s13089-023-00321-w. In recent years, several groups have begun to shift focus onto the deleterious effects of venous congestion. Traditional assessment of right heart congestion such as peripheral edema, input and output charting and weight have limited accuracy and may not reflect intravascular venous hypertension. While jugular venous distension may be more applicable, it can be difficult to reliably assess, and while central venous pressures (CVP) has been well correlated to poorer outcomes , it requThis is a prospective observational study conducted in the adult post-cardiac surgical unit of a tertiary care center. The center is one of the largest cardiac centers in India which specializes in minimally invasive coronary bypass, complex valve surgeries, pulmonary thromboendarterectomy and cardiac transplantation. All adult consecutive post-cardiac surgery patients were included for the study. Patients with inadequate window for USG, in respiratory distress , liver cirrhosis, deep vein thrombosis of lower limb, pregnant women were excluded from the study. The study was approved by the ethics committee (NH/AEC-CL-2022-833) and waiver of consent was obtained. Baseline demographic details were obtained from medical records. USG examination for VExUS score, femoral vein pulsatility were done by an trained and intensivist with more than 5 years’ experience in bedside ultrasound. All images were reviewed and scores were confirmed by another intensivist with extensive bedside ultrasound experience. Any discrepancy in score were discussed and resolved.Ultrasound assessment was performed bedside using a Sonosite M Turbo machine using a cardiac probe (1–5 MHz) Patients were positioned in the dorsal decubitus position with the head of bed elevated at 30°. In the same position, CVP was recorded using a central venous catheter with the transducer positioned at mid thoracic level. Hepatic venous Doppler was done, visualizing either the middle hepatic vein in the subxiphoid area or the right hepatic vein from a lateral angle. Similarly, the portal vein Doppler was interrogated from a lateral approach. All Doppler examinations were recorded and measured at end-expiration during respiratory pause.The VExUS score was obtained using the published guidelines detailed in Additional file All the patients had CVP line inserted through right internal jugular vein, none were in the femoral vein. All patients were monitored with CVP in which the transducer was zeroed at the mid-axillary point. Mean CVP value read on display was recorded. The mean CVP values were noted simultaneously to the femoral venous Doppler examination.The FVD was obtained with the patient in supine position with a linear array probe. Common femoral vein was identified just 2–3 cm below the inguinal ligament and it was examined in both short and long axis with angle correction within 60°. Normal FVD was defined as antegrade mildly pulsatile uninterrupted pattern with respiratory variation and retrograde flow of less than 1/3rd of antegrade flow  Figs. , 3.FVD was considered significant or suggestive of venous congestion if either of the criteria was fulfilled:P = 4(TRmax)2] was used to calculate this pressure difference using peak TR velocity. This method was used to calculate systolic pulmonary artery pressures. Mean PAP were approximated from the systolic PAP (SPAP) using the following formula: mPAP = 0.61 × SPAP + 2 mmHg [Pulmonary artery pressure was estimated using continuous wave (CW) Doppler of the tricuspid regurgitation (TR) tracing. This method allows measurement of the peak regurgitant velocity which represent the pressure difference between the right ventricle and right atrium. The simplified Bernoulli equation [The primary outcome was the correlation between FVD and the VExUS score. Based on the pulsatility and congestion in the hepatic vein, portal vein and inferior vena cava, VExUS grading is done from 0 to 3, where grade 0 means no congestion and grade 1–3 means increasing degree of congestion. The FVD was described as normal, pulsatile, or pulsatile with flow reversal. Pulsatile and pulsatile with flow reversal FVD patterns were considered suggestive of venous congestion. A CVP of 12 mmHg or more was considered indicative of venous congestion, a threshold used in much of the literature.Secondary outcomes were the correlation between FVD or VExUS score with CVP; correlation with other markers of volume overload such as edema and pulmonary artery pressure; effect of mechanical ventilation on correlation between FVD and VEXUS score.Grade 1: Absence of any edema.Grade 2: Mild bilateral ankle edema.Grade 3: Moderate ankle and lower leg edema.Grade 4: Generalized edema (anasarca) with or without pulmonary edema.Edema was graded according to the criteria:Grade 2–4 was considered edematous condition.Pulmonary artery pressures were measured by echocardiography.P value < 0.05 was considered statistically significant.A sample size of 112 patients was required for an expected agreement in diagnosis  between FVD and VEXUS of 0.7 with an estimated prevalence of an elevated CVP of 30%. Data were analyzed using SPSS Statistics for Windows, Version 21.0. Baseline patient characteristics were expressed using mean and standard deviation or median with interquartile range for continuous variables, frequency with percentage for categorical variables. The association between categorical variables  was analyzed using Chi-square test or Fisher exact test. Agreement in diagnosis was analyzed using Cohen’s Kappa test. Sensitivity, specificity, positive predictive value, negative value and accuracy was calculated along with 95% confidence interval, keeping CVP as a gold standard. A A total of 107 patients were enrolled for the study. Mean age of the patients was 55.67 ± 12.76 with 78 males (72.9%). The median EURO score was 2  and 56 (52.3%) were mechanically ventilated (Table P < 0.001) and 78% had VExUS grade 1 to grade 3 congestion (P < 0.001). Similarly, 86.4% of patients having VExUS grade 1 to grade 3 congestion had abnormal pulsation in FVD (P < 0.001). Among patients with a VExUS grade between1 and 3, 86.4% had abnormal FVD Doppler patterns . However, 50% of patients with raised PA pressure had abnormal FVD showing no significant correlation between FVD and PA pressure .When analyzed for correlation between peripheral edema and FVD Table , 32.7% oOur results show a strong correlation between femoral venous Doppler and splanchnic solid organ venous Doppler (VExUS). This comes as no surprise as the femoral veins are in a direct axis to the IVC and the right atrium, hence significant flow perturbations should be noted in parallel. As right atrial pressures elevate causing venous congestion, the dampening of central pulsatility attenuates, converting normal continuous venous flow to interrupted pulsatile venous flow, essentially the CVP tracing becomes reflected in the peripheral venous system Fig. . This phWhen there is no significant venous congestion, peripheral veins tend to be smaller, non-plethoric, owing to low intraluminal pressure. The Doppler profile demonstrates an indistinct pattern with respiratory variation. As the intraluminal pressure rises due to venous congestion, the vein rounds out and the Doppler profile exhibits a pulsatile pattern with less respiratory variation and becomes a representation of the CVP waveform. With severe congestion and impaired right ventricular systolic function and tricuspid regurgitation, the CVP waveform shows prominent V and Y waves, giving it a bidirectional pulsatile pattern on FVD Fig. . This leOurs is not the first group to investigate the association between venous congestion and femoral Doppler. Abu-Yousef et al. found a strong correlation between elevated right atrial pressure with good specificity, but lacked sensitivity . While CThis study adds one more entry to the study of venous congestion markers as we do not have a single gold standard entity. The potential advantage of CFV is that it might not be subjected to the controversy surrounding IVC visualization (short Axis vs long Axis) , 14, aloFVD measurement is advocated in supine position hence might not be feasible in orthopneic patientFVD mirrors IVC hence the fallacies of IVC as a marker of venous congestion specifically in higher intraabdominal pressure, cirrhosis and respiratory distress make it unreliableDeep venous thrombosisVaricose veins with saphenofemoral junction incompetence might give confounding resultsFemoral venous pulsations can be seen in healthy individuals but typically without systolic reversal. We have used CVP as the gold standard which has its own limitations in the clinical settings.There are several pitfalls and limitations of femoral venous Doppler. Those include:In our study, we have taken CVP as gold standard marker for venous congestion which has it’s set of limitations.Additional file 1. VExUS methodology


The highly variable rate of decline in kidney function in patients with immunoglobulin A nephropathy (IgAN) provides a major clinical challenge. Predicting which patients will progress to kidney failure, and how quickly, is difficult. Multiple novel therapies are likely to be approved in the short-term, but clinicians lack the tools to identify patients most likely to benefit from specific treatments at the right time. Noninvasive and validated markers for selecting at-risk patients and longitudinal monitoring are urgently needed.This review summarizes what is known about demographic, clinical, and histopathologic prognostic markers in the clinician’s toolkit, including the International IgAN Prediction Tool. We also briefly review what is known on these topics in children and adolescents with IgAN. Although helpful, currently used markers leave clinicians heavily reliant on histologic features from the diagnostic kidney biopsy and standard clinical data to guide treatment choice, and very few noninvasive markers reflect treatment efficacy over time. Novel prognostic and predictive markers are under clinical investigation, with considerable progress being made in markers of complement activation. Other areas of research are the interplay between gut microbiota and galactose-deficient IgA1 expression; microRNAs; imaging; artificial intelligence; and markers of fibrosis.Given the rate of therapeutic advancement, the remaining gaps in biomarker research need to be addressed. We finish by describing our route to clinical utility of predictive and prognostic markers in IgAN. This route will provide us with the chance to improve IgAN prognosis by using robust, clinically practical markers to inform patient care. Of these, 19% of patients had a ≥50% decline in eGFR, 4 of whom had kidney failure; in contrast, 29% of patients had clinical remission . The study found no baseline marker that could identify those at risk for progression.n = 1130), which enrolled patients from 13 European countries with median proteinuria of 1.2 g/day and mean eGFR of 74 ml/min per 1.73 m2, one-quarter of patients had reached the composite end point of kidney failure or a 50% decline in eGFR.IgAN is a leading cause of chronic kidney disease (CKD). However, predicting which patients will progress to kidney failure, and how quickly, remains a major challenge for clinicians. The rate of decline in kidney function is highly variable, even in patients diagnosed in the relatively early stages of the disease. Three examples illustrate this challenge. First, the Norwegian kidney biopsy registry followed-up with 145 patients with proteinuria <1 g/d and estimated glomerular filtration rate (eGFR) >60 ml/min per 1.73 mRecent advances in our understanding of IgAN pathophysiology have led to several novel agents being evaluated in patients with IgAN.As we will discuss, certain clinical and histological data at the time of biopsy have been widely validated for risk stratification, but their role in treatment selection has not. Further, no validated prognostic serum or urine biomarkers for IgAN other than eGFR and proteinuria exist. We are, therefore, at a crossroads, with a clear chance to improve the prognosis of this disease, but only if we have robust, clinically practical prognostic and predictive markers to inform patient care. We need to know which biomarkers and genes to assess in IgAN, in which combination, in which patients, and how often. This review examines the status quo and identifies gaps that need to be addressed to allow clinical practice to keep pace with translational research.,,What do we already use to inform clinical decisions in IgAN? Uncontrolled hypertension,2 or proteinuria ≥0.5 g/24h.,n = 121) than in those with sustained proteinuria <1 g/d (n = 171). Importantly, regardless of their proteinuria level at biopsy, patients who achieved even a partial remission (<1 g/d proteinuria), whether spontaneously or with intervention, progressed to kidney failure at a much slower mean rate (−0.030 ± 0.46 ml/min per 1.73 m2 per month) than patients who did not achieve remission .,Proteinuria is a marker of kidney damage, contributing to progressive CKD by promoting persistent inflammatory and fibrogenic responses.n = 5660) showed that initial microscopic hematuria, including mild hematuria , was associated with a significant 87% increase in the risk of kidney failure in the long-term. Conversely, macroscopic hematuria was associated with a significant 32% decrease in riskn =1333), time-averaged hematuria during follow-up was a significant, independent predictor for kidney failure or a 50% decline in eGFR.,Other measures obtained from urinalysis have the potential to be informative about IgAN progression, though the relationship has yet to be defined. In particular, the role of hematuria in IgAN prognosis is not clear-cut, partly because there is no internationally validated, straightforward, or standardized measure; and partly because the requirement for fresh urine samples makes it difficult to measure centrally in global clinical trials. Automated laboratory methods may eventually allow us to standardize the quantification of microscopic hematuria, although there are a number of analytical challenges to overcome.,,Because IgAN requires a biopsy for diagnosis, histopathology of the kidney provides crucial prognostic information to guide IgAN management, typically via the widely used Oxford MEST  score. Analysis of 3 large observational data sets showed that the lesions included in the original Oxford MEST score have a predictive value that is independent of clinical factors.MEST-C may also have some value in treatment selection. In a retrospective, propensity score matching study in 858 patients from Japan (one-third of whom received renin-angiotensin system blockers), patients with M1, E1, S1, C1 + 2, and T0 scores were likely to benefit from corticosteroids. In contrast, patients with substantial tubulointerstitial scarring (T1 + 2) scores were less likely to respond.In summary, until recently, clinicians relied on broad categorizations based on a small number of markers to estimate the extremely heterogeneous rate of kidney function decline in patients with IgAN. Could the integration of these clinical and histopathologic markers improve prognostic accuracy?,,,The International IgAN Prediction Tool combines clinical, histopathologic, and demographic variables, as well as the use of renin-angiotensin system blockers and immunosuppression at biopsy. Based on the model, patients are assigned to risk categories, which show each patient’s mean predicted risk of experiencing either a 50% decline in eGFR or progression to kidney failure within up to 80 months from biopsy.The International IgAN Prediction Tool has been validated in a large external cohort of Chinese and Argentinian patients, 73% of whom were on renin-angiotensin system blockers treatment before biopsy, to ensure that it can be retained as clinical practice evolves; this may be more representative of current clinical practice than the original validation cohort, in which that proportion was 30%.2,,Despite its contribution to improving clinical care in IgAN, the International IgAN Prediction Tool only has prognostic value–current Kidney Disease: Improving Global Outcomes guidelines state that the tool should not be used to assess the likelihood of treatment response in an individual patient.Therefore, the status quo is that clinicians treating patients with IgAN rely heavily on data obtained at biopsy, with very few biomarkers to guide the choice of therapy or reflect the efficacy of therapy without doing another biopsy. It is difficult to ascertain the extent of fibrosis and measure structural changes in the kidney over time. Further, because novel therapies are introduced into the treatment algorithm, predictive markers to aid patient selection will be increasingly important. In the next sections, we consider potential novel biomarkers in IgAN  and some,,,Owing to the role of complement in IgAN pathogenesis,Biopsy analyses have linked complement activation, identified by glomerular C3 deposition, with glomerular injury, inflammation, and a high risk of disease progression.,Complement activation has also been associated with crescent formation in IgAN by measuring the urinary concentration of mannose-binding lectin, Bb, C4d, C3a, C5a, and soluble C5b-9 in a study of 100 patients.,Specific markers of the AP, Factor H, and FHRs are likely markers of disease progression in IgAN, but their roles are less clear-cut. Multiple studies have shown that elevated levels of urinary Factor H  are associated with features of IgAN progression, including interstitial fibrosis, glomerular sclerosis, tubulointerstitial damage, and an overall decline in kidney function.,Turning to markers of lectin pathway activation, these have been linked to disease activity and progression in about one-quarter of patients with IgAN.Staining of biopsy samples using assays for different components of the complement pathways should ideally be standardized and widely used; it represents a key area where clinically valuable insights can already be obtained. Although it is true that alternative methods may be more practical, it may be more difficult to remove confounding factors. For example, urinary excretion of C4d or the C4d-to-creatinine ratio was an independent predictor of progression to kidney failure in one cohort study of 168 patients with IgAN and crescent lesions.n = 127, with 86 matched healthy controls) linked changes in specific gut microbe populations, notably expansion of Escherichia-Shigella, with IgAN; this change was reversed in patients who responded to immunosuppression.Neisseria in their tonsils and increased serum production of anti-Neisseria IgA. However, no differences in stool microbiota were observed between the 2 groups.IgAN pathogenesis is associated with impaired function of the intestinal mucosal barrier and potentially with an imbalance in the associated bacterial populations; in predisposed patients, this may favor an inflammatory response and increase Gd-IgA1 production, as seen in Gd-IgA1 levels in serum and urine samples from patients with IgAN.MicroRNAs may help determine the risk of progression in IgAN; some of these noncoding RNAs have a role in controlling immune response and kidney fibrosis. One small pilot study investigated 4 microRNAs that were differentially expressed in kidney biopsies from IgAN progressors versus non-progressors. Of the 4, all increased the discrimination score of the International IgAN Prediction Tool, although none reached significance; miR-150-5p was the most strongly associated with risk of progression.,Various other potential markers of IgAN progression have been proposed, but none have been validated. Few studies include appropriate comparator groups, for example, controls with non-IgAN glomerular diseases; or adjust for nonspecific effects of CKD stage. Potential markers include interstitial kidney inflammation,n = 948).Finally, the use of artificial intelligence in kidney pathology has shown promising accuracy in identifying patients with IgAN at high risk of disease progression. Automated prediction of kidney failure using a deep learning predictive score based on 496 biopsy images from 442 patients was shown to be noninferior to MEST-C in terms of prognostic accuracy in a randomly selected subgroup of 95 samples. Although the deep learning predictive score correlated significantly with the tubulointerstitial score, there was no correlation with mesangial, endocapillary, segmental sclerosis, and crescent parameters. However, the artificial intelligence approach incorporated interstitial fibrosis and hyaline casts within the deep learning predictive score. These parameters reflect reduced GFR  and proteinuria , calling into question the added clinical value of deep learning predictive score over MEST-C so far.18F-FDG-PET to identify inflammation or other probes to assess fibrosis.Although it is difficult to monitor kidney fibrosis noninvasively, imaging techniques such as diffusion kurtosis imaging may have clinical value in the long term.,,In the meantime, a study including 49 patients with IgAN showed that serum endotrophin, a molecule present in fibrotic kidneys, was associated with interstitial fibrosis in biopsies in a multiple regression analysis.Many of the prognostic markers discussed above are likely to also predict response to certain treatments, although evidence for this from prospective trials is lacking. A handful of additional markers have been solely and specifically evaluated as markers of patient selection and likelihood of response to treatment. For example, a prospective study evaluated whether the intensity of inflammatory cell infiltration in the kidney could predict response to immunotherapy in 621 Chinese patients with IgAN at high risk of progression. Analysis of cellular infiltrates in biopsy specimens showed that patients with samples in the highest tertile of CD206+ macrophage infiltration in the glomeruli were 40 times more likely to respond to immunosuppression compared with those in the lowest tertile.N = 515) supports this, indicating that posttransplant (but not pretransplant) serum Gd-IgA1 level is associated with IgAN recurrence.Another example of a biomarker that may be useful for patient selection is Gd-IgA1, the first “hit” in IgAN pathogenesis. A high concentration of circulating Gd-IgA1 is a feature of IgAN but insufficient to account for the full spectrum of kidney damage associated with the disease. However, it may be informative in patients for whom a transplant is an option: a subset of patients who presented with clinically severe IgAN, with higher serum levels of Gd-IgA1 than others, appeared to be more likely to experience disease recurrence after transplant.The trajectory of eGFR over time differs between children and adults with IgAN. In a multiethnic cohort of 1060 children with IgAN, the trajectory was typically nonlinear, first showing an initial increase in eGFR after kidney biopsy, followed by a plateau, before a linear decline a few years later similar to that seen in adults.Multivariate analysis of the VALIGA data set in patients <18 and <23 years of age showed that eGFR and proteinuria at biopsy did not predict progression. However, similar to adults, time-averaged proteinuria had significant predictive value, as did mean arterial blood pressure at biopsy and over time.Validation of the MEST score has been difficult in children, with studies often underpowered because they rely on the attainment of end points such as a 50% drop in eGFR from the rate at biopsy or kidney failure. These are unusual events detected in only 5% of 1060 cases included in an evaluation of the International IgAN Prediction Tool in children (<18 years of age) from various continents.Early research indicates that some novel markers identified in adult patients with IgAN may also have clinical value in children. In one study in 44 children with IgAN, high serum IgA:C3 ratio together with extensive glomerular C3 staining were associated with persistent kidney inflammation, potentially predicting IgAN progression.1.Given the highly variable incidence and severity of disease across geographies and ethnicities, validation studies should ideally be done in multiethnic populations. Studies performed exclusively in one location or ethnic population should be replicated in others.2.Although potentially complicated, an essential part of validation studies will also be to account for the impact of additional immunologic diseases or other comorbidities on kidney function. Without controlling for this, it will be difficult to robustly imply the causation of a decline in kidney function and identify clinically reliable biomarkers.3.The search for new biomarkers also needs to consider the systematic nonspecific effects of kidney function. Examples of these potential confounding effects include retention of low molecular weight proteins in serum at low GFR; low molecular weight proteinuria, typical of widespread tubular damage; and glomerular spillage of larger serum proteins that may simply reflect proteinuria.4.Development of validated, practical assays that can be used in the clinical setting, not only research-grade assays, is needed. A standardized methodology will be needed to address problems such as discrepancies in the assays used or in urinalysis that may be due to differences in expertise between clinical sites.5.As novel risk factors are validated, they need to be integrated into the International IgAN Prediction Tool  or be included in the creation of a different risk prediction tool. If this is not possible, guidance on which measures take precedence over others will be needed.6.The confounding effect of genetic factors, such as collagen IV mutations associated with IgAN, has to be considered and further investigated.7.Over time, biomarker research will need to turn to questions associated with the long-term treatment of patients with IgAN, for example in patients who have already received immunosuppressive treatment and shown a marked reduction of proteinuria but later show a relapse in proteinuria.Many of the data sets described above are small, single-center, retrospective studies that sometimes provide conflicting evidence. Although these are valuable starting points for large, prospective studies, their interpretation for everyday clinical practice is limited. We propose some points for future biomarker research to help clear the path to clinical implementation  as follo,At present, there is no robust basis for changing the current Kidney Disease: Improving Global Outcomes guidance that there are no accepted serum or urine biomarkers for IgAN progression apart from eGFR and proteinuria. However, the importance of establishing a prognosis and predicting treatment efficacy cannot be overstated for patients with IgAN and their caregivers. Establishing a prognosis can alleviate anxiety if the risk of progression is low or provide a rationale for more intensive management if the risk of progression is high. Noninvasive monitoring of specific risk factors and determining their independent significance can also guide treatment selection and sequence. This is increasingly important now that novel drugs are in the latter stages of clinical development,In addition to considerations of everyday clinical decision-making, incorporating risk stratification into clinical trials will improve the power of studies by ensuring that patients’ risk profiles are matched with an appropriate trial. It is hoped that ongoing registries, such as the Canadian Glomerulonephritis Registry–linked to the Translational Research Initiative – and the National Kidney Foundation Patient Network, will provide further insights into IgAN progression and corresponding markers.DCC has received payment for expert testimony from the Canadian Medical Protection Association; has participated in a Data Safety Monitoring Board or Advisory Board for Alexion, Alnylam, Calliditis, ChemoCentryx, Dimerix, Kyowa Hakko Kirin Co, Novartis, Reistone, Vera Therapeutics, and Zyversa; and has a leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, for NephCure, NephSAP/ASN, SONG-GN, and UpToDate. RC has worked as Scientific Advisor for Alnylam, ARGENX, Calliditas, Chinook, Menarini, Novartis, Ostuka-Visterra, Purespring, Reata, STADApharm, and Travere; serves on the Data Safety Monitoring Board in clinical trials of AMGEN and Bayer; and receives honoraria as Section Editor of UpToDate. JF has received consultancy fees and/or honoraria from AstraZeneca, Calliditas, Chinook, Novartis, Omeros, STADApharm, and Travere; and serves on the Data Safety Monitoring Board in clinical trials of NovoNordisk and Visterra.