Diabetic kidney disease is the leading cause of end-stage renal disease and is associated with increased morbidity and mortality. This review is an authorized literal translation of part of the Brazilian Diabetes Society (SBD) Guidelines 2021–2022. This evidence-based guideline provides guidance on the correct management of Diabetic Kidney Disease (DKD) in clinical practice.The methodology was published elsewhere in previous SBD guidelines and was approved by the internal institutional Steering Committee for publication. Briefly, the Brazilian Diabetes Society indicated 14 experts to constitute the Central Committee, designed to regulate methodology, review the manuscripts, and make judgments on degrees of recommendations and levels of evidence. SBD Renal Disease Department drafted the manuscript selecting key clinical questions to make a narrative review using MEDLINE via PubMed, with the best evidence available including high-quality clinical trials, metanalysis, and large observational studies related to DKD diagnosis and treatment, by using the MeSH terms [diabetes], [type 2 diabetes], [type 1 diabetes] and [chronic kidney disease].2 < 40%). B. Data from metanalysis, including large observational studies, a single randomized clinical trial, or a pre-specified subgroup analysis. C: Data from small or non-randomized studies, exploratory analyses, or consensus of expert opinion. The degree of recommendation was obtained based on a poll sent to the panelists, using the following criteria: Grade I: when more than 90% of agreement; Grade IIa 75–89% of agreement; IIb 50–74% of agreement, and III, when most of the panelist recommends against a defined treatment.The extensive review of the literature made by the 14 members of the Central Committee defined 24 recommendations. Three levels of evidence were considered: A. Data from more than 1 randomized clinical trial or 1 metanalysis of randomized clinical trials with low heterogeneity (ITo prevent or at least postpone the advanced stages of DKD with the associated cardiovascular complications, intensive glycemic and blood pressure control are required, as well as the use of renin–angiotensin–aldosterone system blocker agents such as ARB, ACEI, and MRA. Recently, SGLT2 inhibitors and GLP1 receptor agonists have been added to the therapeutic arsenal, with well-proven benefits regarding kidney protection and patients’ survival. Diabetic kidney disease is the leading cause of entry into renal replacement therapy and is associated with increased morbidity and mortality , 2.In 2007, the Kidney Disease Outcomes Quality Initiative (KDOQI) proposed the expression of diabetic kidney disease (DKD) in place of diabetic nephropathy (DN) to broaden the spectrum of forms of kidney disease in diabetes mellitus (DM), adding the non-albuminuric phenotype to the already described albuminuric phenotype , 4. The Traditionally, DKD was defined as a sequential evolution of stages where the onset would be characterized by glomerular hyperfiltration and renal hypertrophy, followed by a progressive increase in urinary albumin excretion (UAE) between 30 mg/day and 300 mg/day  and subsequently by UAE greater than 300 mg/day or macroalbuminuria. We decided to keep this nomenclature of micro- and macroalbuminuria throughout the text to be faithful to the existing literature, since the vast majority still use these terms. In the more advanced phases, a progressive loss of glomerular filtration rate (GFR) starts, culminating in end-stage renal disease (ESRD) , 6. HoweThe present review is a literal authorized translation of part of the 2021–2022 Brazilian Diabetes Society (Sociedade Brasileira de Diabetes—SBD) Guidelines. The methodology was published elsewhere in previous guidelines of SBD  and was In brief, the Brazilian Diabetes Society indicated 14 experts to constitute the Central Committee, designed to regulate methodology, review the manuscripts, and make judgments on degrees of recommendations and levels of evidence. SBD Renal Disease Department drafted the manuscript selecting key clinical questions to make a narrative review using MEDLINE via PubMed, using the best evidence available including high-quality clinical trials, metanalysis, and large observational studies related to Diabetic Kidney Disease diagnosis and treatment, by using the MeSH terms [diabetes], [type 2 diabetes], [type 1 diabetes] and [chronic kidney disease].2 < 40%). B. Data from metanalysis, including large observational studies, a single randomized clinical trial, or a pre-specified subgroup analysis. C: Data from small or non-randomized studies,  exploratory analyses, or consensus of expert opinion.Three levels of evidence were considered: A. Data from more than 1 randomized clinical trial or 1 metanalysis of randomized clinical trials with low heterogeneity  for DKD, which combines stages of renal function loss based on glomerular filtration rate (GFR) and urinary albumin excretion (UAE), using the two parameters in a complementary way Fig.  10].Fig.Fig10].FAny abnormally elevated albuminuria test must be confirmed in two out of three samples collected in 3 to 6 months, due to the large daily variability , 13. Facwww.sbn.org.br and www.kidney.org or in apps, such as the official eGFR from the National Kidney Foundation.There are several formulas to estimate GFR. The one recommended by KDIGO is the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration), which, however, may underestimate the GFR in people with diabetes , 17–19. The first screen for DKD IS RECOMMENDED to be at the diagnosis in T2DM, and after 5 years from diagnosis in people with T1DM, starting at 11 years of age.UAE was determined  in 957 pRegarding type 2 diabetes mellitus (T2DM), DKD screening should be performed at the time of DM diagnosis, as 7% of patients already have microalbuminuria at that time [Important note 1: Screening in children and adolescents.In children and adolescents with T1DM, screening can also be done at 2 to 5 years of disease duration and 11 to 17 years of age, considering the observed prevalence of 3% in a cohort study.IT IS RECOMMENDED to perform an annual screening of DKD with the measurement of albumin or albumin/creatinine ratio in a urine sample, together with the estimation of GFR with the serum creatinine-based CKD-EPI equation.Screening should be annual, measuring UAE and estimating GFR (eGFR) from serum creatinine , 21.Urinary albumin should be measured in a random urine sample, for ease of collection . There iAlbumin/creatinine ratio (mg/g) and the albumin concentration (mg/L) in the random urine sample show excellent correlation with the 24-h urinary measurement and can both be used , 23. In GFR and UAE are independent predictors of the course of kidney disease and risk of mortality, and therefore both should be evaluated in screening for DKD .The recent characterization of non-albuminuric forms of DKD also reinforces the importance of adding the estimated GFR to the measurement of albuminuria , 28.IT IS RECOMMENDED that any abnormal test of the albumin/creatinine ratio (above 30 mg/g) or albumin concentration (above 30 mg/L) be confirmed in at least two out of three samples collected with an interval of three to six months because of the high daily variability.Cutoff points for albumin in urine specimens (> 30 mg/g or > 30 mg/L) are derived from comparison with 24-h urine specimens, demonstrating adequate performance as a screening and diagnostic test , 29.In a prospective evaluation, the albumin concentration ≥ 14 mg/L in a urine sample increased approximately threefold the risk of CV events  four times the risk of DKD  and five times the risk of death , which indicates that even values below the mentioned cutoff can predict cardiorenal outcomes .An altered albuminuria test result should be confirmed in two out of three samples, collected in three to six months because of the large daily variability , 13. If Important note 2: Special situations.In special situations, such as puberty, decompensated diabetes, and pregnancy, screening should be individualized and performed at shorter intervals.Important note 3: Albuminuria.Albuminuria above 14 mg/L suggests an increased cardiovascular and renal risk. However, there is no evidence from intervention studies for the prevention of cardiovascular and renal outcomes in this stage. It is suggested that follow-up should be more frequent when there are values between 14 mg/L and 30 mg/L.Some conditions suggest the need to rule out other nephropathies Table .Table 1WTreatment of DKD aims to prevent progression to end-stage renal disease, intervene in cardiovascular events and prevent death. For this, risk factors for progression, such as hyperglycemia, hypertension, albuminuria, dyslipidemia, smoking, obesity, inadequate diet, and sedentary lifestyle, must be addressed.2) enhances ESRD risk sevenfold [2 was found to increase ESRD risk [Several studies have indicated that severe obesity , intensive care in T2DM patients reduced HbA1c from 7.9% to 7.0%, with a 25% risk reduction in microvascular outcomes, although with no reduction in the risk of kidney outcomes specifically .Other randomized clinical trials, whose main objective was to reduce macro and microvascular outcomes, were conducted, such as the ACCORD study (Action to Control Cardiovascular Risk in Diabetes) , ADVANCEIn the ACCORD study , the incIn the ADVANCE study , the intIn the VADT study , the intIn the DCCT study  , 1,441 iThe Epidemiology of Diabetes Interventions and Complications (EDIC) study  was an oIntensive control of hyperglycemia IS RECOMMENDED in individuals with DM to reduce albuminuria.The effect of intensive glycemic control on the decline in GFR and progression to macroalbuminuria in patients with microalbuminuria is not clearly defined. Evidence is derived from subgroup analyses. In this population, maintaining HbA1c below 7% appears to have only a mild long-term effect in delaying progression to end-stage renal failure , 43, 44.The ADVANCE study  randomizThe ADVANCE ON  trial waIn turn, the ACCORD study , in a suIn the VADT study , intensiTaken together, the results of these studies suggest that achieving HbA1c values below 7% has little effect in delaying the progression of kidney disease in patients with T2DM and established DKD. Furthermore, the protective action against progression to renal failure would only be observed after long periods of improvement in glycemic control.The STENO 2  Study waIn patients with T1DM, the DCCT study  did not Regarding mortality, a meta-analysis of randomized controlled trials (RCTs) has shown that intensive glycemic control in patients with T1DM does not reduce overall mortality or microvascular complications, including DKD .A prospective observational study followed 349 T1DM patients from the Joslin Clinic, USA, with proteinuria (DKD stages 1 to 3) for up to 15 years. The group with better glycemic control during the observation period had a smaller drop in eGFR and a lower prevalence of end-stage renal disease (29%), compared to patients who maintained worse glycemic control (42%). A decrease in HbA1c by one point was associated with a 24% protection for the evolution of end-stage renal disease .Important note 4: Target of HbA1c in advanced DKD.It should be considered that very low or very high values of HbA1c are associated with negative outcomes in patients with DKD. In an observational study that evaluated 23,296 patients with DM and eGFR <60 mL/min, HbA1c values >8% and <6.5% were related to higher mortality . This U-Figure 2 or albuminuria >200 mg/g, the use of SGLT2 inhibitors is RECOMMENDED to reduce progression to end-stage renal disease and death.In the treatment of T2DM and DKD with a GFR of 30-60 mL/min/1.73 m2 and albuminuria 200-5000 mg/g (DAPA CKD) and GFR 30-90 mL/min/1.73m2 with albuminuria 300-5000 mg/g (CREDENCE).Randomized clinical trials such as CREDENCE — , 56, usiThe CANVAS study (Canagliflozin Cardiovascular Assessment Study)  used canIn the DECLARE-TIMI 58 [Important Note 5: SGLT2 Inhibitors.SGLT2 inhibitors are associated with a markedly increased risk of a genital infection  and a mildly increased risk of urinary tract infection .  In the C2 , the combination of SGLT2 inhibitors with another antidiabetic drug, preferably metformin, SHOULD BE CONSIDERED to optimize glycemic control and potential reduction of cardiovascular risk, considering the limitations determined by glomerular filtration.In patients with T2DM and DKD with GFR >30 mL/min/1.73 mIn a sub-analysis evaluating patients using metformin from the TREAT study  , cardiovA recent Asian retrospective cohort study, involving 10,426 T2DM patients with DKD, confirms that the use of metformin was associated with lower overall mortality, with HR 0.65  and further demonstrating reduced progression to end-stage renal disease, with HR 0.67 . Metformin did not increase the risk of lactic acidosis  .Important note 6: Metformin adjustment for GFR.2, it is recommended to reduce the dose of metformin, which should be limited to a dose of 1 g per day to minimize the risk of lactic acidosis. Metformin should not be use for GFR < 30 mL/min/1.73 m2. In individuals with DKD and GFR between 30 and 45 mL/min/1.73 mIn T2DM patients with DKD and GFR > 30 mL/min/1.73 m 2 , the use of GLP-1 receptor agonists (GLP-1 RA) SHOULD BE CONSIDERED to reduce albuminuria.Cardiovascular safety studies show that the use of GLP-1 RA, both daily  and weekA meta-analysis  suggestsA real-life study with more than 38,000 patients using GLP-1 RA, compared to DPP4 inhibitors, suggests a benefit in hard outcomes, with a 24% decrease in renal death, hospitalization for renal events, or the initiation of renal replacement therapy.2.Figure 2 , with HbA1c above the target, insulin treatment SHOULD BE CONSIDERED as a priority to improve glycemic control.In individuals with T2DM and DKD with eGFR <30 mL/min/1.73 mGlucose and insulin metabolism are greatly altered in patients with advanced kidney disease. There is a great risk of hypoglycemia because of reduced renal gluconeogenesis, reduced renal clearance and degradation of insulin, increased glucose uptake in dialysis, impaired hormonal counter-regulation, and nutritional deprivation. Therefore, the use of insulin with careful titration should always be thought of as the main choice for blood glucose control .2) with poorly controlled or that had frequent hypoglycemia with oral agents or NPH insulin, received insulin Glargine at bedtime, starting with 0.1 U/kg and later being titrated. In four months, HbA1c decreased from 8.4% ± 1.6 to 7.7% ± 1.2 (p < 0.001), without affecting the BMI and with no adverse event records [Regarding long-acting analogs, insulin Glargine is safe and effective in T2DM patients with advanced CKD, with a stable half-life and a longer duration of action. In a small, non-randomized study, 89 patients with T2DM and CKD , but there was no benefit with NPH . In addition, the incidence of nocturnal hypoglycemia was three times lower with Glargine (p = 0.047) .2. With the switch from Detemir or Glargine (U100 or U300) to Degludec, the prevalence of mild hypoglycemia decreased from 78 to 34.2%, and that of severe hypoglycemia, from 8 to 1.3% [Regarding the long-acting analog Degludec, a small observational, retrospective, open-label study lasting 36 weeks evaluated its use in 36 patients with T2DM and eGFR < 45 mL/min/1.73 m to 1.3% .The DEVOTE study  , involvi2 with no difference in the incidence of hypoglycemia. The BRIGHT study was one 24-week, open-label, multicenter study with T2DM patients, who randomized to nocturnal Glargine-U300 (n = 466) or Degludec-U100 (n = 463) with 24 week follow-up, with the main outcome being reduced HbA1c.A sub-analysis of the BRIGHT study  showed a2 , and HbA1c above target, DPP-4 inhibitors, some sulfonylureas (glipizide and gliclazide) and GLP-1 RA MAY BE CONSIDERED to improve glycemic control.In patients with T2DM and DKD with a GFR of 15-30 mL/min/1.73 m2 [Concerning sulfonylureas, glipizide and gliclazide are completely metabolized in the liver, generating inactive metabolites. The renal function does not affect their clearance or half-life, yet they should be used with caution, and dose titration is recommended when estimated GFR (eGFR) is less than 30 mL/min/1.73 m2 .A 54-week randomized clinical trial, with 129 T2DM patients over 30 years of age, with end-stage kidney disease on dialysis and 7–9% HbA1c, compared glipizide and sitagliptin. The group of 64 patients using sitagliptin 25 mg/day reduced baseline HbA1c by 0.72% vs 0.87% in the 65 patients who received glipizide 2.5 mg/day. The number of symptomatic hypoglycemia was not significantly different between the two groups . There was no severe hypoglycemia in the sitagliptin vs 5 episodes in the glipizide group, as these values were similar  [In a non-randomized six-month trial, monotherapy with linagliptin (5 mg/day) in 21 patients with T2DM on hemodialysis reduced the glycated albumin (GA) from 21.3% ± 0.6% to 18.0% ± 0.6% throughout the treatment period, with no change in body weight. None of the patients had hypoglycemia .2) were randomized to receive saxagliptin or placebo. After a mean duration of two years, saxagliptin did not change the relative risk of hospitalization for heart failure when compared to placebo, regardless of renal function (p = 0.19 for interactions). The median HbA1c at one year was lower when compared to placebo in saxagliptin-treated patients with severe renal impairment . At least one adverse event occurred in 152 patients (88%) treated with saxagliptin.In a sub-analysis of the SAVOR-TIMI trial 53 , 336 patEstimated GFR must be considered regarding the use of medications for glycemic control in DKD. Table Important note 8: Options beyond insulin in severe DKD.DPP-4 inhibitors should be dose-adjusted according to GFR  can be used in severe DKD, but with caution and with dose reduction.In individuals with T2DM on dialysis and HbA1c above the target, IT IS RECOMMENDED the use of insulin as a priority.Therapeutic individualization is very important in patients with DKD, especially in those with stages 4 and 5, because of the increased risk of hypoglycemia. Overall, insulin analogs appear to have a lower risk of hypoglycemia and better postprandial control compared to human insulin , 77.Regarding basal insulins, glargine (U100 and U300), degludec, and detemir are stable and effective, but there are few studies in this population (patients with DKD), indicating that they are associated with a reduction in hypoglycemia, especially degludec when compared to detemir and glargine U100 , 78.Concerning ultra-fast insulins, glulisine and aspart do not show pharmacokinetic differences in patients with severe CKD , 80. As Important note 9: Insulin in peritoneal dialysis.The use of insulin in the dialysis solution in patients undergoing peritoneal dialysis is uncommon, and the reasons are the greater chance of peritoneal bacterial infection, use of higher doses, and higher occurrence of hepatic steatosis. Therefore, further studies are needed to evaluate the beneficial effect of this route, so that the subcutaneous route is preferably indicated , 82.In DM patients on dialysis, the use of insulin regimens based on hemodialysis time and pre-and post-dialysis blood glucose levels is RECOMMENDED, requiring a reduction of at least 25% of the dose of fast or ultra-fast insulin given just before the meal before dialysis.In general, dialysis patients use two insulin regimens, one for the procedure day and one for the non-procedural days. The insulin regimen should be individualized, when in use, based on the time of hemodialysis and blood glucose values Fig. .Fig. 4ReA reduction of at least 25% of the dose of rapid or ultra-rapid insulin given in the meal before dialysis is required Fig. .Important Note 10: Insulin analogs in dialysis.Insulin analogs should be applied after dialysis due to the possibility of insulin adsorption by the dialysis membrane.Important Note 11: DPP-4 inhibitors in dialysis.DPP-4 inhibitors can be considered for use in T2DM patients on dialysis with caution and dose reduction, as they are effective and likely to be safe. Since they have been tested in small studies, however, their long-term safety, especially regarding hypoglycemia, must be confirmed in larger studies.Intensive treatment of hypertension is RECOMMENDED due to the cardiovascular benefits and the evolution of DKD.Breakthrough studies, such as that by Parving , showed A meta-analysis of 40 studies with 100,354 participants (70% with T2DM subgroups and 30% with T2DM exclusively) demonstrated that a 10 mmHg reduction in systolic blood pressure was associated with a lower risk of mortality , of cardiovascular events , of coronary heart disease ; of stroke ; and of retinopathy (RR 0.87 95% CI 0.76–0.999). However, no reduction in the progression of DKD to ESRD was observed. The greatest benefit was among patients with baseline blood pressure > or = 140 mmHg. An additional reduction below 130 mmHg reduced the risks of stroke, retinopathy, and albuminuria .A blood pressure goal < 130/80 mmHg IS RECOMMENDED for patients with DKD who can reach this goal without side effects.In proteinuric T2DM patients, the RENAAL study (Reduction of Endpoints in NIDDM with Angiotensin II Antagonist Losartan) demonstrated that achieving systolic pressure < 130 mmHg slowed the progression of DKD and postponed the need for dialysis .Regarding the lower blood pressure limit to be reached in DKD patients, some studies, including the IDNT , show that blood pressure ≤ 120/80 mmHg were associated with an increase in cardiovascular events .Therefore, for patients with DKD, a blood pressure target of around 130/80 mmHg is suggested, which is in line with other guidelines.In a meta-analysis of 19 studies including 44,989 participants , 2,496 cardiovascular events were observed after 3.8 years (1.0 to 8.4 years). In the intensive treatment group, the mean pressure was 133/76 mmHg vs. 140/81 mmHg in the less intensive group. In the intensive group, it was observed a 14% reduction in the RRs of cardiovascular events (95% CI 4—22%), 13% in acute myocardial infarction (95% CI 0—24%), 22% in stroke (95% CI 10—32%), 10% in albuminuria (95% CI 3–16%) and 19% reduction in retinopathy progression (95% CI 0—34%). The benefits were evident even in patients with a baseline blood pressure < 140 mmHg, more evident in the groups with vascular disease, kidney disease, and diabetes. However, there was no benefit for heart failure, cardiovascular/total death, or end-stage renal disease .A blood pressure goal < 130/80 mmHg IS RECOMMENDED for adult patients with DM and increased risks of stroke and atherosclerotic cardiovascular disease.The ADA recommends a blood pressure target < 130/80 mmHg for individuals at high cardiovascular risk (with atherosclerotic cardiovascular disease (ASCVD), or with ASCVD risk ≥ 15% in ten years), based on the risk analysis of previous studies , 89.In a recent meta-analysis of individual participants data including 344,716 subjects from 48 RCTs (approximately 30% with DM), it was shown that a 5 mmHg reduction in systolic blood pressure reduced the risk of major CV events by 10% . This reduction was independent of previous CVD diagnosis and blood pressure levels, with a benefit even for normal blood pressure .It is RECOMMENDED to use angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) for patients with albuminuria, to reduce kidney disease progression, regardless of blood pressure levels.Renin–angiotensin–aldosterone system (RAAS) blockers (ACEI and ARBs) reduce ACR and the progression of DKD to more advanced stages, regardless of the blood pressure effect , 91, 92.In a meta-analysis of 1,028 studies of the effect of RAAS blockers on renal outcomes, 24 studies met the inclusion criteria (20 with ACEI and 4 with ARB). ACE inhibitors were associated with a trend towards a reduction in end-stage renal failure , and the use of ARB reduced the risk . Both reduced the risk of doubling creatinine , but neither reduced the mortality .Another meta-analysis on RAAS blocker, both ACEI, and ARBs, showed a reduction in albuminuria in T1DM and T2DM patients with microalbuminuria, and a reduction in the progression to macroalbuminuria, but not for end-stage renal failure or mortality .The DETAIL study   showed aAnother meta-analysis of 100 studies with data from 22,365 patients with DKD, mainly T2DM, showed no difference between ACEI and ARBs in preventing end-stage renal disease and doubling creatinine, as well as in reducing albuminuria .The use of an ACEI or ARB is recommended for all patients with increased UAE, regardless of BP values , 97.Important Note 11: RAAS Blockers.After starting RAAS blockers, serum creatinine may increase by up to 30%. In this situation, the drug should not be discontinued, as this response is associated with the preservation of renal function, even in patients with baseline serum creatinine above 1.4 mg/dL. Creatinine elevations greater than 30%, in turn, should raise suspicion of renal artery stenosis  .Combination therapy with ACEI and ARB IS NOT RECOMMENDED, due to the increased risk of hyperkalemia, worsening of renal function, orthostatic hypotension, and syncope.2, with randomization to add lisinopril (10–40 mg/day) or placebo. The study was stopped early owing to safety concerns. From 1,448 patients with a 2.2-year follow-up, there were 152 events in the monotherapy group and 132 in the combination . There was no reduction in mortality or cardiovascular events. However, there was an increased risk of hyperkalemia  and of acute kidney injury  [The VA-NEPHRON D study evaluated the use of losartan (100 mg/day) in T2DM patients with at least 300 mg/g albuminuria and eGFR 30–89.9 mL/min/1.73 m< 0.001) .2 and serum potassium levels <5.0 mEq/L.The use of mineralocorticoid receptor antagonists SHOULD BE CONSIDERED for blood pressure control and renal protection, in association with ACEIs or ARBs in patients with GFR ≥ 25 mL/min/1.73 mA recent meta-analysis evaluating the nephroprotective effect of mineralocorticoid receptor antagonists (MRAs) assessed 22 studies in patients with DKD and 12 studies in non-diabetic kidney disease. Alone or in combination with RAAS blockers, MRAs reduced the ACR by 24.55% and proteinuria by 53.93% compared to placebo .Spironolactone is associated with a significant reduction in albuminuria. However, side effects, especially in men, such as gynecomastia and sexual dysfunction should not be forgotten .2 , with serum potassium levels <5.0 mEq/L.The use of non-steroidal mineralocorticoid receptor antagonists MAY BE CONSIDERED for renal protection, in association with ACEIs or BRAs, in patients with GFR ≥ 25 mL/min/1.73 mFinerenone is a non-steroidal selective MRA that has been shown to block many of the deleterious effects of overactivation of mineralocorticoid receptors that play an important role in the progression of cardiorenal disease. The complementary studies FIDELIO-DKD and FIGARO-DKD evaluated, in patients with T2DM and CKD, the effect of finerenone on cardiovascular and renal outcomes at different stages of kidney disease.2) using ACE inhibitors or ARBs and demonstrated that finerenone was associated with a lower incidence of the composite renal outcome , with HR 0.82 95% CI of 0.73–0.93, p = 0.001 and number needed to treat (NNT) of 29 patients, in addition to lower incidence of secondary cardiovascular outcome , HR 0.86 95% CI 0.75–0.99, p = 0.03 and NNT of 42. In the study, the patient's enrollment potassium level should be ≤ 4.8 mmol/L and checked regularly. In case of increase (> 5.5 mmol/L), the drug was withheld for 72 h, and potassium levels were reassessed. Finerenone was well tolerated, but a slight increase in hyperkalemia was observed (2.3% vs. 0.9%) [The FIDELIO-DKD trial randomized 5,734 T2DM patients with DKD (GFR 25–75 mL/min/1.73 ms. 0.9%) .2—CKD stages 2–4; or ACR 300–5000 mg /g and eGFR of 60 mL/min/1.73 m2 -DRC stages 1–2). Patients on finerenone had a significant decrease in the primary composite CV endpoint  , with the benefit driven primarily by a lower incidence of hospitalization for heart failure  compared to placebo. The composite renal endpoint occurred in 350 patients (9.5%) in the finerenone group and in 395 (10.8%) in the placebo group . Hyperkalemia was four times more frequent in the finerenone group (1.2% vs. 0.4%) [In the FIGARO trial, this observation was expanded to 7,437 patients with T2DM and CKD (ACR 30–300 mg/g and eGFR between 25 and 90 mL/min/1.73 ms. 0.4%) .The FIDELITY study was a pre-specified analysis compiling the two studies, FIDELIO and FIGARO. In this analysis, 13,026 participants with a mean follow-up of 3 years were included. Composite cardiovascular outcome occurred in 825 patients (12.7%) in the finerenone group and 939 patients (14.4%) in the placebo group . The composite renal endpoint occurred in 360 (5.5%) patients in the finerenone group and 465 (7.1%) in the placebo group  with NNT of 60 patients. Hyperkalemia leading to permanent treatment withdrawal was more frequent in the finerenone group (1.7%) than in the placebo group (0.6%). The FIDELITY analysis suggests that finerenone was associated with a significant 20% reduction in ESRD, as well as a reduction in all nonfatal composite renal outcomes .2 and post-transplanted patients, the use of high-potency statins IS RECOMMENDED to reduce cardiovascular events.In patients with DKD and eGFR < 60 mL/min/1.73 m2, and 21.5% had albuminuria. Atorvastatin was associated with a modest improvement in albuminuria. Atorvastatin was also associated with an attenuation of eGFR decline ; p = 0.01 but did not change the incidence of new cases of albuminuria or regression to normoalbuminuria [In the renal outcomes sub-analysis of the CARDS trial, which randomized 2,838 T2DM individuals without the previous cardiovascular disease to receive either 10 mg atorvastatin or placebo once daily, 34% of patients had eGFR between 30 and 60 mL/min/1.73 muminuria .The use of statins decreases the number of cardiovascular events (combined outcome), without decreasing overall or cardiovascular mortality in patients with advanced DKD, regardless of the doses used , 106.2, there was a 42% reduction in major cardiovascular events in the group using 10 mg atorvastatin and a 61% reduction in ischemic stroke, like that observed in the analysis all study patients (37% reduction in cardiovascular events (p = 0.4 interaction) [In the CARDS study, in 970 patients with eGFR between 30 and 60 mL/min/1.73 mraction) .Statins have a modest effect on albuminuria and the rate of fall in GFR , 105 andNational Kidney Foundation recommends the use of statins to reduce cardiovascular events in patients with pre-dialysis DM [The lysis DM .Study of Heart and Renal Protection) [In the SHARP study (tection) , the comtection) . On the tection) .In the case of post-renal transplant patients, in the ALERT study, the use of statins was associated with a lower risk of cardiac death, infarction, and cardiac interventional procedures . Based oThe use of fibrates may be associated with a slight decrease in eGFR (a transitory effect that is reversed with the discontinuation of the drug), which is not secondary to kidney damage . Regardi2.The risk of developing myopathy increases with loss of kidney function and in combination with statins, especially gemfibrozil. The use of fenofibrate should be avoided if GFR <30 mL/min/1.73 mImportant note 12: LDLc in DKD.In patients with CKD, KDIGO recommends that LDL-c values be used to calculate cardiovascular risk, but no longer to decide on the use of lipid-lowering drugs. This recommendation is reinforced, as in patients with CKD, the relationship between LDL-c levels and cardiovascular events seems to be different from the general population .In patients with DKD on dialysis, without clinical arterial disease, IT IS NOT RECOMMENDED to start using statins. However, in patients who were already using a statin before starting dialysis, it should be continued.Deutsch Diabetes Dialyze) [In the 4D study  , patientand cardiovascular events in patients with regular hemodialysis) [The AURORA study   includedPravastatin Pooling Project database performed a pooled analysis of the results of three randomized trials with pravastatin 40 mg vs. placebo, including 19,700 patients with chronic renal failure (eGFR 60–30 mL/min/1.73 m2) [For patients with CKD, but not on hemodialysis, the 1.73 m2) . There w1.73 m2) .post hoc analysis of 731 patients with T2DM, a reduction in the risk of fatal and non-fatal cardiac events was observed with the use of rosuvastatin [Neither atorvastatin nor rosuvastatin reduced cardiovascular mortality, infarction, and/or stroke in hemodialysis patients , 118. Hovastatin .effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease) [vs. placebo of the two medications. The group allocated to the simvastatin and ezetimibe had a mean LDL-c reduction of 33 mg/dL during a mean follow-up of 4.9 years. There was a 17% proportional reduction for major atherosclerotic events for simvastatin plus ezetimibe compared to placebo .The SHARP study (The disease)  aimed toModification of Diet in Renal Disease) equation was compared at the beginning and end of follow-up in 9,656 participants. No decline in kidney function was observed over five years. In contrast, estimated GFR improved in both treatment groups and was significantly higher at the 80 mg dose, suggesting that such benefit may be related to medication dosage [A sub-analysis of the TNT study assessed how intensive lipid lowering with 80 mg of atorvastatin would affect renal function, compared with 10 mg, in patients with coronary heart disease. A total of 10,001 patients with coronary heart disease and LDL-c levels < 130 mg/dL were randomized in a double-blind fashion to 10 mg/day or 80 mg/day atorvastatin therapy. The GFR estimated using the MDRD  is recommended .Protein intake above 20% of daily calories or above 1.3 g/kg ideal weight/day is associated with increased albuminuria, more rapid loss of renal function, and CV mortality; therefore, it should be avoided. A meta-analysis with 779 patients from 13 RCTs demonstrated a benefit from a low-protein diet with improved eGFR and reduced proteinuria , 125.The effect of dietary protein restriction becomes more evident the greater the adherence to dietary modification and, when RAAS inhibitors are used, it is less frequent and the BP control less strict .A high protein intake is associated with an increase in glomerular filtration rate, serum urea, acid uric acid, and urinary calcium excretion when compared to a normal/low protein intake in normal subjects, as reported in a meta-analysis including 30 randomized controlled trials .Therefore, the rationale for protein restriction in the CKD setting is based on the decrease in kidney overload, which leads to an improvement in renal hemodynamics by decreasing the intraglomerular pressure and glomerular hyperfiltration. It is also a key strategy to control uremia and uremic toxins, as well as oxidative stress, metabolic acidosis, phosphorous, hyperparathyroidism, insulin resistance, and blood pressure .According to KDOQI guidelines, for CKD 3–5 patients not on dialysis and without DM, it is recommended a low-protein diet providing 0.55–0.60 g dietary protein/kg body weight/day, or a very low-protein diet providing 0.28–0.43 g dietary protein/kg body weight/day with additional keto acid/amino acid analogs to meet protein requirements (0.55–0.60 g /kg body weight/day), as these approaches halt the progression of CKD (1A) and improve the quality of life (2C) .Likewise, for CKD 3–5 patients not on dialysis but with DM, it is suggested a dietary protein intake of 0.6–0.8 g/kg body weight per day to maintain a stable nutritional status and optimize glycemic control to avoid CKD progression (opinion) . Thus, tFor CKD patients under chronic hemodialysis (1C) and peritoneal dialysis (opinion) without DM, it is recommended to prescribe a dietary protein intake of 1.0–1.2 g/kg body weight per day to maintain a stable nutritional status . For thoTo note, protein restriction should be prescribed under close clinical supervision to avoid inadequate caloric intake, protein loss and hypercatabolism, inflammation, and altered glucose homeostasis .Importantly, the impact of a very low-protein diet on kidney disease progression is a subject of debate in the literature. The Modification of Diet in Renal Disease (MDRD) study evaluated the effect of two schedules of protein restriction in patients with nondiabetic CKD 4. When the intervention of a low-protein diet (0.58 g/kg/d) was compared to a very low-protein diet (0.28 g/kg/d) supplemented with a mixture of essential keto acids and amino acids (0.28 g/kg/d), the latter group presented higher rates of mortality and no beneficial effect on CKD progression was observed .Important note 13: Meat consumption and Diabetic Kidney Disease.An alternative is to replace red meat with other protein sources. A diet where red meat was replaced by chicken, rich in polyunsaturated fatty acids, was able to decrease the UAE in T2DM patients with micro and macroalbuminuria , 132.The limit for a sodium intake of up to 1.5 g/day, or of salt, up to 3.75 g/day, SHOULD BE CONSIDERED when there is arterial hypertension.When making dietary recommendations for patients with DKD, it should be considered that, in most cases, there is associated hypertension. Thus, limiting dietary salt intake should be a goal to be achieved.Decreasing dietary salt enhances the antihypertensive effect of drugs . FurtherSalt restriction should be included in a DASH (Dietary Approaches to Stop Hypertension) diet pattern, that is, high consumption of fruits, vegetables, and low-fat dairy products. In T2DM patients, this dietary pattern is associated with lower blood pressure values. This diet, however, is not recommended for dialysis patients .Diabetic kidney disease (DKD) is the leading cause of entry into renal replacement therapy and is associated with increased morbidity and mortality. Traditionally, DKD is defined as a sequential evolution of stages characterized by a progressive increase in urinary albumin excretion (UAE) between 30 mg/day and 300 mg/day  and followed by UAE levels greater than 300 mg/day or macroalbuminuria. In this phase, a progressive loss of glomerular filtration rate (GFR) starts, culminating in end-stage renal failure. In recent years it has been recognized that this evolution does not always happen, as there are patients who lose glomerular filtration without developing albuminuria, a fact associated with multiple factors such as hypertension, dyslipidemia, obesity, and age. To prevent or at least postpone the advanced stages of DKD with the associated cardiovascular complications, intensive glycemic and blood pressure control are required, as well as the use of renin–angiotensin–aldosterone system blocker agents such as ARB, ACEI, and MRA. Recently, SGLT2 inhibitors and GLP1 receptor agonists have been added to the therapeutic arsenal, with well-proven benefits regarding kidney protection and patients’ survival.


One hour plasma glucose concentration (1hPG) during an oral glucose tolerance test (OGTT) may be an alternative to 2-h plasma glucose concentration (2hPG) in the identification of individuals at increased risk of hyperglycaemia, although its role is not fully understood.mellitus diagnosis, in a sample of patients with morbid obesity.We aim to investigate the relationship of these measures with other glucose parameters, as well as their relationship with cardiometabolic risk markers and the level of agreement for prediabetes mellitus diagnosis.We retrospectively evaluated 656 patients with morbid obesity without diagnosed diabetes. To define prediabetes with 2hPG, 2022 American Diabetes Association guidelines criteria were used, while for 1hPG, glucose ≥ 155 mg/dL was considered. Cohen’s Kappa coefficient was used to assess the agreement between both measures of prediabetes ρ = 0.281, p < 0.001), fasting plasma glucose (FPG) , glycated haemoglobin (Hb1AC)  and were negatively correlated with homeostatic model assessment for cell-β function (HOMA-β) . 2hPG were also correlated with the same parameters, except for HOMA-β.A Cohen’s Kappa coefficient of 0.405 (p < 0.001) was obtained. The 1hPG were positively correlated with homeostatic model assessment for insulin resistance (HOMA-IR) (A fair agreement between 1 and 2hPG was verified. 1hPG criteria may be a useful indicator of β-cell dysfunction and insulin resistance in patients with morbid obesity without diabetes diagnosis. Systolic (SBP) and diastolic blood pressure (DBP) were also retrieved, being measured using a mercury sphygmomanometer. The 2022 American Diabetes Association guidelines criteria and glucose ≥ 155 mg/dL were used to define pre-T2DM, for 2hPG and 1hPG, respectively. Data on smoking habits was also retrieved.In addition to clinical parameters, data on HbA1c, serum insulin, creatinine, transaminases, as well on lipid profile , were also taken from the hospital clinical files. Values of HOMA-IR [ × /405] were used as a measure of insulin resistance (IR)  and valur) correlation coefficient or the Spearman (ρ) correlation coefficient, as appropriate. Statistical analysis was performed using SPSS Statistics 25.0 . A significance level of 5% was considered.Continuous variables were described as mean and standard deviation (SD), or as median and interquartile range (IQR), and were compared using Student’s T-test or the Mann–Whitney test, as appropriate. Categorical variables were summarised as counts and proportions. The Cohen’s Kappa coefficient was computed to evaluate the agreement between the two measures of pre-T2DM diagnosis—1hPG and 2hPG (primary endpoint). For the secondary objective, correlations between continuous variables (the relationship of 1hPG and 2hPG with parameters of glucose metabolism and cardio-metabolic risk) were carried out using the Pearson  and had a mean ± SD age of 40.3 ± 10.1 years (Table p < 0.001), corresponding to a fair agreement between 1 and 2hPG , fasting glucose  and HbA1c , and negatively correlated with HOMA-β . Values of 2hPG were also correlated with the same variables, except HOMA-β . The insulinogenic index showed to be negatively correlated with both 1hPG  and 2hPG  , HbA1c , HOMA-IR  and of C-Peptide , and lower HOMA-β  (Table p = 0.402) . No significant differences were observed regarding HDL, LDL, total cholesterol, high sensitivity C-reactive protein (hsCRP), creatinine, HOMA-IR or HOMA-β  identifying individuals at lower risk than the other criteria, which are currently in use . 1hPG se.[Regarding our secondary objectives, we observed that 1hPG values were negatively correlated with β-cell function and insulinogenic index and were positively correlated with IR, fasting glucose and HbA1c. Similar results were obtained for 2hPG, except for HOMA-β. Looking for the correlation coefficients, overall, the correlations seemed to be stronger for 1hPG than 2hPG. Bergman et al. showed t.. Other s., 28 haveThe insulinogenic index on the OGTT can be used as an index of early phase insulin secretion , 30. It According to our findings, 1hPG were significantly and positively correlated with triglycerides, and negatively correlated with HDL-C. This is in accordance with the observation that dyslipidaemia in T2DM patients is characterised by high triglyceride levels and decreased HDL-C, which can be observed many years before the onset of clinically-relevant hyperglycaemia , 33. TheAlthough it has been previously demonstrated that 1hPG is associated with inflammatory markers (e.g.: hsCRP)  this wasThis study has limitations that should be mentioned. The included patients came from a tertiary hospital, and they were referenced for BS, which can skew the results as it is a very specific population, moreover, these results may not be generalizable to populations of different traits. Therefore, further studies including a more diversified sample of patients should be taken to corroborate our findings. Furthermore, the impact of the found changes in each method on the progression to T2DM after BS has not been evaluated, which limit the conclusions concerning the accuracy of the methods in predicting T2DM progression. Moreover, data on carotid echocardiography, ABI, vascular endothelial function that would help on identifying potential cardiometabolic risk factors, were not available for this study population, and should also be considered a potential study limitation. Additionally, although most of the recuited patients were female (86.9%) this percentage is in agreement with the the sex distribution of patients who attended bariatric appointments.This study showed that 1hPG could be an alternative for the diagnosis of prediabetes in morbidly obese patients. Considering the paucity of research regarding the agreement between 1 and 2hPG in people with morbid obesity, this study provided relevant insights on this regard. Also, this study was strengthened by the large number of subjects included.A fair agreement between 1 and 2hPG was found. 1hPG may be useful for evaluating β-cell dysfunction and IR in morbidly obese patients without diagnosed diabetes. Abnormalities in 1hPG could represent a more severe metabolic perturbation, which is characterised by higher glycaemic, lower insulin sensitivity, and a markedly reduced β-cell function.


Acute kidney injury (AKI) is becoming a public health problem worldwide. AKI is usually considered a complication of lung, heart, liver, gut, and brain disease, but recent findings have supported that injured kidney can also cause dysfunction of other organs, suggesting organ crosstalk existence in AKI. However, the organ crosstalk in AKI and the underlying mechanisms have not been broadly reviewed or fully investigated. In this review, we summarize recent clinical and laboratory findings of organ crosstalk in AKI and highlight the related molecular mechanisms. Moreover, their crosstalk involves inflammatory and immune responses, hemodynamic change, fluid homeostasis, hormone secretion, nerve reflex regulation, uremic toxin, and oxidative stress. Our review provides important clues for the intervention for AKI and investigates important therapeutic potential from a new perspective. Acute kidney injury (AKI) is a severe condition and is associated with a worsened prognosis in critically ill patients. Clinically, AKI is determined based on elevated serum creatinine levels (a marker of the kidney excretory function) and reduced urinary output (a quantitative marker of urine production) within 7 days. According to the KDIGO definition, AKI can be classified into three stages 1–3) relying on a list of functional criteria  1,2]. H–3 relyin. H–3 relAKI can be induced by a broad range of causative factors depending on different clinical settings, such as sepsis, hemorrhage, low output after cardiac surgery, and the application of chemotherapy drugs. These factors contribute to the high incidence of AKI worldwide. According to a recent meta-analysis of 154 studies, the incidence of AKI was 8.3% in ambulatory patients, and as high as 20–31.7% in patients at various levels of in-hospital care . The symAccumulating evidence indicates that the communication between injured kidneys and other organs, including the heart, lung, liver, brain, and gut, is mediated by a range of inflammatory cytokines and immune cells . However2), can directly or indirectly act on the kidney through a variety of signaling pathways to regulate renal blood flow (RBF), glomerular filtration rate (GFR), glomerular and tubular development, renin secretion and other pathophysiological processes [In the context of the global coronavirus disease 2019 (COVID-19) pandemic, the effects and mechanisms of lung–kidney communication are of great interest to the scientific community and commendable progress has been made . As a rerocesses , suggestIn addition, the lung and kidneys work together to ensure the stability of blood pressure through the renin–angiotensin–aldosterone system (RAAS)  and kallp < 0.001), suggesting that ARSD is an independent risk factor for AKI [p < 0.001) [Several clinical epidemiological studies have shown that several types of renal dysfunction, including hematuria, proteinuria and AKI, are the most common complication of acute respiratory distress syndrome (ARDS). An observational study of 8029 critically ill patients (including 1879 patients with ARDS) found that the incidence rate of AKI in patients with ARDS was higher than in those without ARSD  .Conversely, the adverse effects of AKI on the lung are mainly reflected in the increasing frequency and duration of IMV and the susceptibility to respiratory complications and respiratory failure ,32,33,34P. aeruginosa-induced pneumonia model, researchers revealed strong evidence of tubular injuries, such as elevated plasma creatinine, cystatin C, urinary NGAL, and the pathological phenomenon of brush-border collapse and mild tubular cell apoptosis [Besides the clinical research, kidney–lung communication has also been observed in various animal models and it contributes to the development of lung and kidney disease individually or synergistically. In the ischemia-reperfusion (IR)-induced AKI mouse model, Hassoun et al., revealed that 66 apoptosis-related genes and 29 inflammation-related genes were activated in the lung; moreover, the activated apoptotic genes were mainly located in pulmonary endothelial cells, indicating that it may be an important mechanism of ALI . Similarpoptosis . Similarpoptosis , and in poptosis .Under pathological conditions, the mechanisms of kidney–lung crosstalk involve an inflammatory response  and a fluid homeostasis imbalance caused by kidney or lung injury   Figure .+ T cell invasion [Systemic inflammatory response syndrome (SIRS) characterized by increased levels of circulating cytokines and chemokines, including IL-1β, IL-6, IL-8, MCP-1, and TNF-α, was observed in AKI or ALI patients and animal models, which may cause lung and kidney inflammation, cell apoptosis, increases in endothelial barrier permeability, oxidative stress, and aggravation of pulmonary edema ,34,41. Ainvasion ,45,46.There is sufficient evidence to demonstrate that pulmonary edema after AKI is not only associated with fluid overload caused by renal failure, but also with reduced pulmonary fluid clearance capacity due to the down-regulation of pulmonary Na, K-ATPase, epithelial sodium channels (ENaC), and aquaporin-5 expression ,47. Seve2 can trigger systemic vasodilation, which then activates the RAAS in a feedback manner and indirectly reduces renal blood flow to induce AKI [Furthermore, given that the kidneys are extremely vulnerable to hypoxia, even short-term hypoxemia can adversely affect renal function, and lung injury-induced hypoxemia and hypercapnia inevitably influence renal function. Hypoxemia and hypercapnia have been demonstrated to, directly or indirectly, decrease renal blood flow, resulting in renal dysfunction ,51,52. Oduce AKI .Furthermore, increasing numbers of novel mediators have been identified in kidney–lung interactions . RecentlAs the “engine” of human beings, the heart possesses a strong blood pumping capacity and constantly provides sufficient blood to the body’s tissues and organs, relying on rhythmic contraction and relaxation. The normal cardiac output of a healthy adult male at rest is about 5 L/min, and about 20% of this output is received by the kidney, indicating a tight functional connection between the heart and kidney . The relAs early as 1836, Robert Bright first observed structural changes in the hearts of patients with advanced kidney disease . Since tAKI which occurs following acute cardiac events, such as acute decompensated heart failure (ADHF), acute coronary syndrome (ACS), cardiogenic shock, and cardiac surgery, is classified as type 1 CRS . A largeConversely, type 3 CRS is clinically used to define cardiac injury caused by various AKI. As early as 2003, the American Heart Association defined both proteinuria and a decline in glomerular filtration rate (GFR) as independent risk factors for the development of cardiovascular disease ; howeverIn addition, the heart–kidney pathophysiological interaction also has been detected in various animal models. In the rat coronary artery ligation-induced myocardial infarction (MI) model, Lekawanvijit et al. found increased IL-6, TGF-β, Kim-1 expression, and macrophage infiltration in the kidney within 1 week . MoreoveOn the other hand, in a rat model of ischemia-reperfusion injury (IRI), the apoptotic myocardial cells were increased in the heart, indicating that AKI results in the alterations observed in the heart which is important in the morbidity and mortality observed clinically .Kidney–heart communication is most directly reflected in hemodynamic changes . The traThe kidney and heart are linked through neurohumoral mechanisms involving the sympathetic nervous system (SNS), RAAS, and AVP . In the Persistent inflammatory stress is associated with immune imbalance, both of which play a critical role in the pathological communication between the kidney and heart . SystemiThe kidney has a rich vascular network (glomerular capillaries and peritubular capillaries) and abundant blood flow (20% of cardiac output), which provide sufficient oxygen and nutrition for tubules to ensure their physiological function. Clinically, most of the pathogenesis of AKI can be attributed to ischemic injuries, such as kidney transplantation, cardiac surgery, sepsis, and shock-induced AKI ,85. Henc+ in the lumen, it can send a signal, causing the afferent arteriole contraction or relaxation. This phenomenon is called tubuloglomerular feedback. In addition, active substances such as renin, endothelin, and prostaglandin are released from the glomerular complex to the vessels, which also participate in the regulation of renal blood flow [The physiological connection between renal tubules and blood vessels helps to regulate renal blood flow. For example, when the renal distal convoluted tubule macula densa senses a change in the concentration of Naood flow .Epidemiological studies have shown that vascular injury plays a pivotal role in the development of AKI caused by various etiologies. Plasma endothelial injury molecules are strong and independent predictors of AKI incidence and are positively associated with AKI mortality ,88. A stThe communication between the kidney and the vasculature is classically manifested in sepsis-induced AKI, where interstitial inflammation and thrombosis are the more predominant pathological changes . In animPre-renal ischemia is considered to be the major mechanism of AKI . Thanks Although ischemia and low-flow theory can partially explain prerenal AKI, it is still subject to several clinical challenges. Many studies have demonstrated that high central and renal venous pressure may play an important role in AKI ,96. On tEndothelial cells are located in the inner layer of blood vessels and are able to mount rapid and specific responses to various injury stresses in AKI ,98. The Vascular endothelial growth factor (VEGF) and its receptors (VEGFR) are important regulators of angiogenesis and vascular permeability . In sepsThrombosis may occur and aggravate ischemia and hypoxia injury during AKI. Notably, coagulation abnormalities may occur in all capillaries and show unique heterogeneity. For example, the loss of endothelial protein C receptor (EPCR) may occur in arterioles, and thrombomodulin (TM) is mainly lost in peripheral capillaries, which may partly explain the failure of single anticoagulant agents to significantly improve renal function ,104,105.During AKI, multiple adhesion mediators, such as P-selectin, E-selectin, vascular cell adhesion molecular 1 (VCAM1), and intercellular adhesion molecule 1 (ICAM1), are upregulated in the endothelial cells ,107. ThrThe liver is the largest metabolic organ, whereas the kidney is the major excretory organ. Fatefully, they cooperate to maintain body homeostasis; in other words, they are functionally linked. Hence, the metabolites are the major mediators of kidney–liver communication under physiological conditions. For instance, the energy of the kidney is derived from fatty acids that are mainly produced in the liver, which means that liver dysfunction inevitably affects renal function. Moreover, various toxic or insoluble substances (drugs), and hormones are increased in solubility or inactivated by the liver and then excreted by kidneys . When thHepatorenal syndrome (HRS) describes a kidney function impairment in patients with severe liver disease, particularly advanced cirrhosis, without substantial alterations in kidney histology. In HRS, there is a notable reduction in GFR and an increase in serum creatinine levels. According to the rate of renal function decline, the HRS is subclassified into two clinical types. Type 1 is defined as a rapid reduction in renal function via a 50% reduction in creatinine clearance in less than two weeks, and in the initial 24 h, below 20 mL/min or an increase in initial serum creatinine to a concentration of at least 2.5 mg/dL. This pattern of HRS is now known as acute kidney injury (AKI)-HRS. Type 2 is the chronic impairment of kidney function, and this pattern of HRS is now known as chronic kidney disease (CKD)-HRS ,111. In Unlike the prominent clinical manifestations of HRS, there are limited clinical reports explicitly describing the effects of AKI on the liver. The abnormal liver function that appears in patients with critically AKI is associated with high in-hospital mortality . In addiAlthough the changes in renal injury markers  with time can be observed in a mouse liver cirrhosis model induced by bile-duct ligation (BDL) , human HHowever, several experimental studies have shown that AKI promotes oxidative stress, inflammation, apoptosis, and tissue damage in hepatocytes and increases vascular permeability and leukocyte infiltration into the liver ,119,120.A series of vasodilators and vasoconstrictors play a role in the communication of the liver and kidney in HRS. Under cirrhosis conditions, intrahepatic vascular resistance is elevated and the vasodilators, such as nitric oxide, carbon monoxide, prostaglandins, and endocannabinoids, are increased, resulting in splanchnic arterial vasodilation and effective arterial blood volume (EABV) reduction. Consequently, systemic vasoconstrictor pathways, such as the RAAS, sympathetic nervous system, and arginine vasopressin (AVP), are activated as compensatory mechanisms for increasing the EABV. These mechanisms result in reductions in renal blood flow and the glomerular filtration fraction, eventually, leading to AKI ,115,121.Bile acid and its related metabolites, cytokines and chemokines, are mediators of kidney–liver crosstalk. Histopathologic studies have shown that 18–75% of patients with AKI-HRS present intratubular bile acid casts which can directly poison tubular cells and elicit tubulointerstitial inflammation, lipid peroxidation, and oxidative stress in the kidney ,122,123.Systemic inflammation occurs in almost half of the patients with AKI-HRS, independent of the presence of infection . The incA healthy gut contains the largest absorptive surface in the body, 70–80% of the body’s immune cells, and at least 1000 genera of bacteria, which together form three barriers including the physical, immune, and biological barriers ,130. TheRecent clinical and experimental studies have shown communication between the kidney and gut, which has sparked new research and much debate concerning the pathophysiology and treatments. However, most studies have mainly tackled the development and progression of CKD or ESRD, and limited research is available regarding the relationship between AKI and gut dysbiosis ,134. GutMoreover, Nakade et al. have revealed that the level of serum D-serine significantly correlates with decreased kidney function in AKI patients . A prospEscherichia coli and Enterobacter were increased, but Lactobacillus, Ruminococcaceae, Faecalibacterium, and Lachnospiraceae were decreased in an IRI-AKI model. Moreover, the germ-free mice which received the post-AKI microbiota exhibited more serious kidney injury and inflammation after an ischemia-reperfusion operation compared with the mice which received the microbiota from a sham group [AKI-induced gastrointestinal homeostasis disruption has been confirmed in the laboratory. Recently, Yang et al. found that the gut microbiota am group . On the am group . Zou et am group . These rIncreasingly, it is recognized that the intestinal microbiota plays a crucial role in the gut–kidney axis. In the process of AKI, the microbiota can produce compounds that have protective or harmful effects on the kidneys. SCFAs, including acetate, propionate, and butyrate, are one kind of nephroprotective compound produced from indigestible food in the colon by the gut microbiota . The proOn the other hand, microbiota-derived uremic toxins can cause further kidney damage in AKI. Several uremic toxins have been identified, such as indoxyl sulfate (IS), para-cresyl sulfate (PCS), Trimethylamine-N-oxide (TMAO), indole-3 acetic acid (IAA), etc. ,149. NorDuring AKI, increased inflammatory cytokines and activated immune cells can cause gut barrier function damage and increase permeability. Intestinal hyper-permeability is a common reason for aggravating kidney failure in AKI patients. The intestinal epithelium apical tight junctions and junctional adhesion molecules (JAM) contribute to the integrated gut’s barrier function, which prevents the luminal contents from escaping into the internal environment. In septic AKI, the expression of zonulaoccludens-1 (ZO-1), one of the multiple claudin isoforms in the tight junction complex, is downregulated, leading to intestinal hyper-permeability . In addi2)2 + H2O → CO2 + 2NH3). The ammonia is transformed into caustic ammonium hydroxide (NH3 + H2O → NH4OH), which can destroy the tight junction proteins that keep epithelial cells together [Furthermore, urea accumulation caused by kidney dysfunction is another cause of increased intestinal permeability. Urea diffuses from the blood into the gut lumen, where it is converted to ammonia by gut bacterial urease , glomerular diseases, and diabetic nephropathy . One basDepending on its severity, the long-term outcomes of AKI include GFR decreases, nephron loss, and increased risk of CKD, cardiovascular disease, and kidney cancer ,170,171.The concept of kidney lifespan can be used to indicate the prognosis of AKI. The number of healthy nephrons determines the individual kidney lifespan. Notably, the number of nephrons is set at birth and starts to decline with age around the age of 25 . By age Suitable therapeutic strategy and management probably improve the outcome of AKI. However, no specific drug has been consistently and reproducibly shown to have a protective effect on the kidneys. In the setting of AKI-induced distant dysfunction, anti-oxidants, anti-inflammatory agents, and renal replacement therapy are consequentially helpful based on the mechanisms discussed above.Several groups have revealed that the administration of anti-oxidants, such as prostaglandin E1 (PGE1), glutathione, vitamin E, and thymoquinone, significantly alleviates lung and liver injury after AKI ,178,179.Severe inflammation mediates the damage to organs induced by AKI. Hence, anti-inflammation is one of the main therapeutic approaches to treat organ injury. Delivering IL-10, or blocking IL-6, CXCL1, and TNF-α have been demonstrated to alleviate AKI-induced lung injury ,183,184.Renal replacement therapy  is commonly applied to provide renal support for critically ill patients with AKI, especially those with hemodynamic instability . Renal rOther therapeutic strategies including interventions with RAAS inhibitors, atrial natriuretic peptide (ANP), probiotics, and prebiotics, could be promising approaches targeting the crosstalk between injured kidneys and other organs.Considering AKI is not a disease but rather a loose collection of syndromes, the first step in managing AKI is to determine its cause . HoweverVolume status and hemodynamics should be carefully reviewed in patients with severe AKI. When the renal hypoperfusion  is sustained and the adaptive response is inadequate, renal damage can occur due to inadequate oxygen and nutrient delivery, and epithelial cell injury or death ,192. On In physiological conditions, the kidneys and other organs are adequately perfused at a mean arterial pressure of 65 mmHg . Normal Clinically, the phenomenon that drugs aggravate AKI should not be ignored. All potential nephrotoxic agents that can be stopped should be avoided. Indispensable drugs should only be used at the required dose for the time needed and carefully monitored. If possible, drug concentration monitoring should be established . ContrasBlood electrolyte solution imbalances should be noted, especially in critically ill patients. Non-physiologic ratios of sodium and chloride may worsen AKI . In addiAKI is not only a common complication following other organ failures, but also causes distant organ dysfunction and is an important cause of high mortality in hospitalized patients. In this review, we examined the clinical and laboratory evidence concerning organ crosstalk in AKI, and summarized the underlying mechanisms of AKI-induced distant dysfunction and organ failure-induced AKI based on the current findings. These mechanisms include inflammation, immune responses, hemodynamic change, fluid homeostasis, hormone secretion, nerve reflex regulation, uremic toxins and oxidative stress. Besides these factors, exosomes have been demonstrated to participate in mediating muscle–kidney , adipose


Mean change in blood pressure in 2 years did only slightly differ in non-clinically relevant ranges, when compared across tertiles of baseline NLR. NLR as a marker of inflammaging was not associated with unfavorable blood pressure profiles in older individuals with or without hypertension.The neutrophil-to-lymphocyte ratio (NLR) is a marker for systemic inflammation. Since inflammation plays a relevant role in vascular aging, the aim of this study was to investigate whether NLR is associated with blood pressure profiles in older adults. This study was performed within the framework of the SCOPE study including 2461 outpatients aged 75 years and over. Mean blood pressure values, namely systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP) were investigated across tertiles of NLR. Change in blood pressure levels in 2 years of follow-up were compared across categories of baseline NLR. Data of 2397 individuals were used, of which 1854 individuals had hypertension. Mean values of blood pressure did not differ across categories of baseline NLR in individuals without hypertension. Individuals with hypertension with a high-range NLR had lower SBP and PP when compared to those in low-range NLR (mean difference SBP −2.94 mmHg,  Hypertension is very common in older adults and viewed as an accelerated form of vascular aging ,2. VascuImmunosenescence refers to the significant changes of the immune system with aging . It resuThe aim of this study was to explore whether NLR as marker of inflammation is associated with blood pressure profiles in older adults aged 75 years and over with and without hypertension.The present study was performed within the framework of the Screening for Chronic Kidney Disease among Older People across Europe (SCOPE) study. The SCOPE study (European Grant Agreement no. 436849), is a multicenter 2-year prospective cohort study involving patients older than 75 years attending outpatient services in participating institutions in Austria, Germany, Israel, Italy, the Netherlands, Poland and Spain. Methods of the SCOPE study have been extensively described elsewhere . ParticiBlood samples were obtained during baseline visit to assess clinical laboratory tests including the differentiated white blood cell count. The NLR was calculated by dividing the absolute neutrophil count by the absolute lymphocyte count. No specific normal values or cut-off point of NLR in older adults exist and most researchers have explored NLR in categories in their own population. The authors decide to categorize participants in groups of low-range, mid-range and high range values of NLR using tertiles stratified for the presence of hypertension.Blood pressure measurements were conducted during baseline visit and also every following visit after 1 and 2 years of follow-up using an oscillometric device with a brachial cuff in resting position. SBP and DBP were measured and documented in millimetres of mercury (mmHg). PP, also expressed in mmHg, was calculated as the difference between SBP and DBP. PP is a marker of age-related vascular stiffness in which higher values of PP indicate greater stiffness  . Since bDemographic data and socioeconomic status were documented. Information on alcohol use, smoking status, medical history and use of medication was collected, including the use and type of antihypertensive medication. Additionally, the cumulative illness rating scale for geriatrics (CIRS-G) was calculated . During p-value of <0.05 was considered statistically significant.Descriptive statistics were expressed as percentage for categorical variables and mean and standard deviation (SD) or median and interquartile ranges (IQR) for continuous variables, depending on normal or non-normal distribution. First, characteristics were compared between participants with and without hypertension using the Chi square test for categorical variables and T-test or Mann–Whitney U test for continuous variables, depending on normal or non-normal distribution. Second, cross-sectional analyses were conducted in which mean values of SBP, DBP and PP were compared across tertiles of NLR using analysis of variance (ANOVA) stratified for the presence of hypertension. Multivariate analyses were also conducted with adjustment for covariates age, sex, BMI, diabetes mellitus, CIRS-G and the use of antihypertensive medication. Third, mean change of SBP, DBP and PP in two years of follow-up were compared across tertiles of NLR stratified for the presence of hypertension using ANOVA. In multivariate analyses, these tests were adjusted for baseline value of SBP, DBP or PP and previous identified covariates. Individuals who were lost to follow-up, died or with missing data were excluded from related analyses . A p-valIn total, 2461 participants were enrolled in the SCOPE study and 2397 participants were included in the analyses as result of missing data on 64 participants. The complete flowchart on the included and excluded individuals is shown in p < 0.001), had higher BMI , SBP  and PP  than individuals without hypertension. Additionally, the prevalence of comorbidities was higher in individuals with hypertension, than in those without hypertension, such as the prevalence of chronic kidney disease , stroke  and diabetes mellitus , resulting in higher comorbidity score . The amount of neutrophils was higher in individuals with hypertension than in those without hypertension , whereas lymphocytes count did not differ between groups (1.7 vs. 1.6 × 109/L), resulting in higher values of NLR in individuals with hypertension . Individuals with hypertension more often used anti-hypertensive medication than individuals without hypertension . Most frequently, individuals with hypertension used ACE-inhibitors/ARBs (72.5%). They also used beta-blockers (49.4%), diuretics (46.7%) or calcium channel blockers (32.7%).Individuals with hypertension were older . Mean values of DBP were 77.9 ± 10.9 mmHg, 77.4 ± 11.9 mmHg and 77.3 ± 11.0 mmHg, respectively, with no differences across categories. Mean values of PP were 64.3 ± 15.9 mmHg, 64.1 ± 16.5 mmHg and 62.4 ± 16.0 mmHg, respectively. Individuals in the high-range NLR had lower PP when compared to low-range NLR .Mean values of SBP were 142.0 ± 18.8 mmHg, 141.5 ± 18.7 mmHg and 139.7 ± 18.3 mmHg from lowest to highest tertile of NLR, respectively. Individuals in the high-range NLR had slightly lower SBP when compared to low-range NLR .Mean change in blood pressure values in 2 years did only slightly differ in non-clinically relevant ranges.The low-range NLR tertile contained individuals with a value up to 1.77, whereas the high-range NLR started from 2.53. Mean values of blood pressure across tertiles of NLR are presented in Mean change of blood pressure levels in individuals without hypertension are also presented in NLR as a marker of inflammaging, was not associated with unfavorable blood pressure profiles in individuals with and without hypertension aged 75 years and over. Mean changes in blood pressure levels during a follow up of 2 years were close to zero and no differences could be observed in changes of blood pressure levels, when comparing individuals with low-range, mid-range or high-range NLR.The role of oxidative stress and inflammation in vascular aging and development of hypertension is well established . During As far as we are concerned, no studies have investigated the possible association between NLR and blood pressure profiles in old age. We had hypothesized that a higher rate of inflammation would be associated with unfavorable blood pressure levels, however, the findings could not confirm our hypothesis. We took into account also the potential of anti-inflammatory effects of the different type of antihypertensive medication on this association ,29,30, hSome limitations of the present study deserve consideration. First, we decided to analyse blood pressure levels across tertiles of NLR, instead of a continuous number which could have affected the results. This decision was based on the fact that no normal values for older adults exist and since it is not known whether or not every step of higher or lower NLR is as relevant. Second, blood pressure values were documented from one measurement per visit, while 24 h blood pressure measurement could have provided another view on blood pressure profiles. Third, we did not took into account changes in medication during follow-up which could have affected the mean levels of blood pressure of time. Fourth, as stated previously, we cannot exclude that the length of follow-up might be too short to investigate a possible relation between inflammation and blood pressure profiles. Fifth, survival bias could have led to a ceiling effect in which individuals with the most unfavorable profiles were not included or could not be followed up. The present study also has strengths. We have studied a large real-world population of older adults in 7 different countries, with no strict inclusion criteria, therefore our findings may apply for a large population of older adults across Europe. Moreover, all data were obtained systematically in participating centers, which makes these results very reliable. Furthermore, NLR is a novel and interesting marker to investigate, so the present study contributes in this relatively new field of research. Additionally, multiple blood pressure values were included, among which SBP, DBP and PP. Since blood pressure profiles can change with aging those three included measurements were able to reflect different angles of vascular aging.In conclusion, in older adults with higher rates of inflammation, we expected to find unfavorable blood pressure profiles reflecting elevated arterial stiffness and higher rate of vascular aging. However, this association was not found. The search for contributing factors to accelerated vascular aging even at higher age is still highly relevant in order to recognize individuals at risk for cardiovascular outcomes and optimize possible treatment strategies.


The optimal hemodynamic targets and management of patients with acute brain injury are not completely elucidated, but recent evidence points to important impact on clinical outcomes. We performed an international survey with the aim to investigate the practice in the hemodynamic targets, monitoring, and management of patients with acute ischemic stroke (AIS), intracranial hemorrhage (ICH) and subarachnoid hemorrhage (SAH).This survey was endorsed by the European Society of Intensive Care (ESICM). An electronic questionnaire of 76 questions divided in 4 sections  was available between January 2022 to March 2022 on the ESICM website.One hundred fifty-four healthcare professionals from 36 different countries and at least 98 different institutions answered the survey. Routine echocardiography is routinely performed in 37% of responders in AIS, 34% in ICH and 38% in SAH. Cardiac output monitoring is used in less than 20% of cases by most of the responders. Cardiovascular complications are the main reason for using advanced hemodynamic monitoring, and norepinephrine is the most common drug used to increase arterial blood pressure. Most responders target fluid balance to neutral , and normal saline is the most common fluid used. Large variability was observed regarding the blood pressure targets.Hemodynamic management and treatment in patients with acute brain injury from cerebrovascular diseases vary largely in clinical practice. Further research is required to provide clear guidelines to physicians for the hemodynamic optimization of this group of patients. Heterogeneity exists in the approach of hemodynamic management of cerebrovascular disease.Pharmacologic strategies to achieve targets and monitoring targets are different across centers.Advanced, serial hemodynamic monitoring is not a standard of care in brain injured patients and it is reserved to most severe cases, although benefit might extend to hemodynamically stable patients.The hemodynamic management of cerebrovascular diseases is of fundamental importance in order to minimize secondary brain damage , 2. CereClinical strategies of hemodynamic management of these pathologies are still based on moderate/low quality of evidence retrieved from relatively small studies, and no strong recommendations are reported in the most updated consensuses on these topics –9. Both In the AIS the choice of the optimal pressure target is still debated. A recent multicentric randomized trial did not find difference in long-term clinical outcomes in AIS patients between intensive [target systolic arterial pressure (SAP) 130–140 mm Hg within 1 h] or “standard” (SAP < 180 mm Hg) blood pressure-lowering treatment over 72 h . In ICH This is an international survey, proposed by the Neuro-intensive Care (NIC) and the Cardiovascular Dynamics (CD) sections of the European Society of Intensive Care Medicine (ESICM). No ethical approval was necessary for the development of this survey. The Steering committee, which included representatives of both ESICM sections, performed a non-systematic review of the literature  on hemodynamic management of AIS, ICH and SAH patients and created a questionnaire of 76 questions divided in 4 sections . The survey was reviewed and approved by the Research committee of the ESICM and was tested in a pilot cohort of potential respondents, including the Steering Committee. The survey was available on the ESICM website between January 2022 to March 2022. Three reminders were sent to potential responders. The questionnaire was created considering some issues around this topic, such as low levels of evidence, lack of good-quality studies and controversial results from observational trials. The survey was designed to identify (a) characteristics of the participants demographics, type of hospital/specialty and available neuromonitoring tools; (b) protocols for the hemodynamic management of this population; (c) hemodynamic targets used in this group of patients; (d) clinical management and use of hemodynamic monitoring in this population. Advanced hemodynamic monitoring was defined as the use of any further tool able to estimate cardiac output .The target audience was ESICM members who had agreed to participate in ESICM surveys at the time of their membership registration and who treat patients with cerebrovascular diseases in their clinical practice. The investigators invited NIC or CD sections members, asking them to involve more respondents locally. Participants did not receive compensation for their participation in the survey, which was distributed via the ESICM office, thus protecting data confidentiality and anonymity. The survey was registered within the ESICM Survey portfolio.Data from the questionnaire were exported as a comma-separated value report from the Surveymonkey® software package and subsequently stored as an Excel file . Descriptive statistics were computed for all study variables. The results are presented as numbers and percentage. Continuous variables are reported as mean [standard deviation (SD)] or median [interquartile range (IQR)], whereas categorical variables were reported as frequency and proportion.As shown in Table According to the responders, most of the patients with neurological critical illness are admitted to mixed general-neurocritical care unit (53%), and less commonly to specialist neurocritical care unit (29%) or other ICUs/wards. The majority of neurocritical patients are managed by anesthesiology intensivist (56%), followed by general/respiratory medicine intensivist (23%) and neurology intensivist (11%). Finally, in most of the centers (39%) a qualified specialist is 24/7 present.A standardized protocol for arterial blood pressure management in patients with AIS is used by the 46% of the responders.The use of echocardiography is quite heterogeneous: most of the participants (37%) declared to perform routine echocardiography during the first 24 h to rule out possible acute left ventricular dysfunction, while 9% only in selected cases. Cardiac output monitoring is used in less than 20% of cases by most (62%) of the participants; capillary refill time is used by less than half of the participants (40%)  by electrocardiogram (ECG) and invasive blood pressure (IBP), while less frequently by non-invasive blood pressure, NIBP and ECG (34%). Advanced hemodynamic monitoring is rarely used 10%) (Table 0% (TableThe most common indication for advanced hemodynamic monitoring was developing cardiovascular complications (34%), followed by sepsis/septic shock (25%), difficult blood pressure management (16%) and worsening of neurological symptoms (6%).Initial management of low blood pressure is mostly based on MAP-based protocol (55%), no specific protocol is reported in the 14% of the answers, and norepinephrine is largely the most used first-line agent in the treatment of hypotension in AIS patients with preserved heart function (80%). The preferred first-line agent for lowering blood pressure is urapidil (24% of the answers), followed by beta-blockers (21%), calcium channel blockers (15%) and clonidine (14%).Most of the participants monitor fluid balance every hour (31%) and a neutral fluid balance is the target according to 62% of the participants. A positive (13%) or negative (6%) balance are rarely defined as a hemodynamic target. When fluids administration is required, crystalloids [ringer lactate (35%) or normal saline (32%)] are usually preferred.In ICH patients, a standardized protocol for arterial blood pressure management is used by the 43% of the responders. Echocardiography was reported to be performed by the 34% of the responders and CO monitoring is used in less than 20% of patients by the 53% of the responders. CRT is performed by 37% the participants. The commonest indication for advanced monitoring is the development of cardiovascular complications (35%), followed by the requirevent of vasoactive drugs (26%).The most commonly reported arterial pressure target was < 140/90 mmHg (36%), followed by < 160/90 mmHg (29%). Hemodynamic monitoring is performed by NIBP and ECG in 12%, and IBP and ECG in the 52% of the answers. Advanced hemodynamic monitoring is rarely used (6% of responders).Initial management of low blood pressure is usually performed by a MAP-based protocol 53%) and the first-line agent in the treatment of hypotension is norepinephrine (74%). Drugs used in these patients as first line for lowering arterial blood pressure are usually beta-blockers 21%), calcium channel blockers (15%) and clonidine (10%). Fluid balance is mostly monitored hourly (31%) and the majority (59%) of participants aim at a neutral daily fluid balance, with the preferred fluids being ringer lactate (33%) and normal saline (28%) , followed by the need for blood pressure drugs (28%), neurological complications (22%) and vasospasm (20%).The most frequently reported goals for blood pressure before aneurysm treatment are < 140/90 mmHg (31%) and < 160/90 mmHg (22%). After aneurysm treatment, in patients without vasospasm the most common blood pressure targets are MAP 90 mmHg (24%) and MAP 80 mmHg (21%). Blood pressure in patients with vasospasm is mostly managed by targeting MAP on neurological status (32%) and targeting to a MAP of 100 mmHg (15%). Hemodynamic SAH monitoring is represented by IBP and ECG in the 44% of the answers, and NIBP and ECG in the 12%. Advanced hemodynamic monitoring is rarely used (9% of the answers).Initial management of low blood pressure is usually performed by MAP-based protocol (49%), and the preferred first-line agent in the treatment of hypotension is norepinephrine (69%).Fluid balance is mostly monitored every hour 29%) and a neutral daily fluid balance is targeted by most participants 44%), a positive balance by 38 answerers (25%), and a negative balance by five (3%) survey responders. Fluids most commonly used in these patients include normal saline (30%) and Ringer lactate (28%)  the answers were mostly obtained from European centers with medium-to-high surge capacity, managing a high number of the considered neurological diseases; (2) at least one-third of the participants use echocardiography to investigate cardiac function of the patients during the first 24 h from admission, whereas advanced hemodynamic monitoring is rarely routinely adopted, being dedicated to those patients with neurological complications or cardiovascular impairment. CRT is used by about 40% of the participants; (3) only half of the participants use a standardized protocol for blood pressure management in AIS, ICH and SAH patients; (4) MAP or SAP-based protocols are adopted to titrate systemic pressure targets; however, these targets are not universally accepted and consistent across centers; (5) norepinephrine is widely the most commonly adopted drug as first-line drug for managing hypotensive events.Although hemodynamic management in cerebrovascular diseases is known to be crucial to minimize secondary brain damage, hemodynamic goals that should be achieved are still debated . The cliIn brain injured patients, systemic blood pressure is the most defined hemodynamic target, and an invasive monitoring is applied in selected cases of AIS, ICH and SAH Tables , 3, 4. BIn AIS and ICH patients, standard hemodynamic management is the most oriented towards a strict control of blood pressure. In SAH patients, the findings of the survey are more heterogeneous. Besides invasive BP, echocardiography, CRT and advanced invasive hemodynamic monitoring are frequently used in SAH both in the initial phase of the disease and the vasospasm phase. One possible explanation is that in the early phase, echocardiography and advanced invasive monitoring are used to stabilize patients with cardiac stunning, frequently occurring in SAH patients. In the vasospasm phase, advanced monitoring and sequential echoes are frequently used, with the aim of increase MAP (and obtain MAP variations thresholds over time in SAH), while avoiding systemic complications. Moreover, the participants showed a more liberal attitude towards the fluid balance management in the vasospasm phase.Overall, fluid therapy approach may be considered conservative in these patients, with most centers aiming at a neutral fluid balance. This finding may be explained by the intention of avoiding further swelling of the cerebral area surrounding lesion. A recent large prospective, multicentre, trial enrolling more than 2000 patients in two cohorts of traumatic brain injured patients, showed that a mean positive daily fluid balance was associated with higher ICU mortality per 0.1 L increase . In SAH Advanced invasive and non-invasive hemodynamic monitoring using echocardiography is not frequently used; advanced monitoring is reserved to AIS and ICH patients developing cardiovascular or neurological complications, but not routinely used as standard management. This tool is widely adopted to obtain an initial assessment, but not as a part of the sequential dynamic monitoring system. However, the role of cardiac output in influencing cerebral blood flow is not widely acknowledged, especially regarding systemic blood pressure management . As confThis survey presents several limitations which must be mentioned. The external validation of this survey is intrinsically limited by the bias regarding the selection of respondents and the accuracy of the questions in defining a specific issue. For this reason, it may hardly be considered as a complete snapshot of daily clinical practice, since most of the answers are obtained from very skilled centers, overrepresenting for a particular subgroup of physicians.Respondents from specialized neuro ICUs were included together with those working in general ICUs, yielding more generalizable findings. This survey refers only to physicians’ clinical practice in hemodynamic management of acute brain injuries without including patients’ data and only considering ICU management. Finally, the response rate cannot be calculated considering the design of the study, since participants were encouraged to involve more respondents locally.Highlighting the heterogeneity of hemodynamic monitoring and the lack of specific protocols of treatment on fluid management in neurocritical care patients, this survey may be also considered as a starting point to guide a research agenda in this field Fig. . StartinThis ESICM survey shows important heterogeneity in the approach of hemodynamic monitoring and management of brain injured patients, including pharmacologic and non-pharmacological strategies. This survey may pave the way for the development of a research agenda, in the field of hemodynamic management of this population of patients, where evidence is importantly lacking.