At any point during the clinical course of a patient with single or multiple organ failure undergoing ECOS, renal function may improve or deteriorate, as a result of the interaction of multiple factors, including multiorgan crosstalk and physiological consequences of ECOS. Common physiopathological ways in which ECOS may influence renal function includes: 1) multiorgan crosstalk (preexisting or de-novo 2)Hemodynamic changes and 3) ECOS-associated coagulation abnormalities and 3) Also, cytokine profile switch, neurohumoral changes and toxins clearance may contribute to the expected physiological changes related to ECOS. The main objective of this review is to summarize the described mechanisms influencing the renal function during the course of ECOS, including renal replacement therapy, extracorporeal membrane oxygenation/carbon dioxide removal and albumin dialysis.The concept of extracorporeal organ support (ECOS) encompasses kidney, respiratory, cardiac and hepatic support. In an era of increasing incidence and survival of patients with single or multiple organ failure, knowledge on both multiorgan crosstalk and the physiopathological consequences of extracorporeal organ support have become increasingly important. Immerse within the cross-talk of multiple organ failure (MOF), Acute kidney injury (AKI) may be a part of the clinical presentation in patients undergoing ECOS, either as a concurrent clinical issue since the very start of ECOS or as a  Extracorporeal organ support (ECOS) was developed in order to support a failing organ and to prevent and/or reverse secondary multiorgan failure. ECOS provide extensive physiological benefits. However, both multiorganic crosstalk and patient interaction with the extracorporeal support may have renal repurcussions. Kidney vulnerability is the result of both kidney frailty (i.e. preexisting kidney/organic damage) and the summatory of adverse renal events during the clinical course (i.e hipoxia+nephrotoxicity+Hypervolemia). The present manuscript emphasizes on both the shared physiopathological pathways and individual differences to be taken into account for different to be taken into account for different kind of ECOS  as well as kidney vulnerabilty points to be taken into account in order to reach favorable clinical outcomes during ECOS. No, nitro oxide; ROS, reactive oxygen species; ECMO, Extracorporeal Membrane Oxigenation; RRT, Renal Replacement Theraphy; BNP, Brain Natriuretic peptide. Extracorporeal organ support (ECOS) was developed in order to support a failing organ maintaining homeostasis as a bridge to recovery or transplantation .However, both multiorgan crosstalk and the physiological consequences of ECOS  may lead to adverse renal repercussions, In the following paragraphs, a review on the mechanisms that may give place to adverse renal repercussions during ECOS will be made (via the unfolded protein response pathway. Many pathologies (i.e. hypoxia), induce a maladaptive unfolded protein response pathway called ER stress on kidneys, giving place to both AKI and CKD. Tubular inflammatory pathways may be triggered specifically by the interaction of mitochondrial DNA with the endoplasmic reticulum membrane, initiating the continuance of tubular inflammation in AKI. Also, mitochondrial injury gives place to abnormal tubular inflammation, a major fibrotic contributor  and AKI are closely interconnected; CKD increases the kidney vulnerability to AKI, and AKI may worsen preexisting CKD, increasing the odds of end-stage kidney disease  3).At a.At a3).Atributor , 5.via arterio-venous fistulae, developing pulmonary hypertension  is linked to: 1)Correction of volume overload and pulmonary edema, 2) Correction of electrolyte and acid-base disorders and 3) Removal of cardio depressant molecules, including tumor necrosis factor-α, proinflamatory interleukins, pathogen-associated molecular patterns and damage-associated molecular patterns –13.Hemodynamic instability during renal replacement therapy (HIRRT) occurs in 19–43% of CRRT treatments, may be associated to any RRT modality, impair renal recovery and is linked to increased mortality –16HIRRT may be the result of any possible interactions between cardiac output alterations, impaired systemic vascular resistances and endothelial derangements , 13:− Diminished cardiac preload caused by of ineffective mobilization of unstressed blood volume (due to ineffective venoconstriction and/or fluid leak into the interstitium) and can be further increased by Bezold–Jarisch reflex, resulting in loss of peripheral sympathetic vasoconstriction , 13.Other factors related to altered cardiac output include reduced preload due to absolute hypovolemia, increased preload and cardiac dysfunction because of absolute volume overload, and dysregulation of cardiac contraction and electric stability because of acidosis and/or electrolyte disturbances , 13:− During regional citrate anticoagulation, infused citrate is metabolized in the liver and muscle to be fed into the Krebs cycle, producing 3 mmol of bicarbonate for each mmol of trisodium citrate produced; Dyalisate fluid with low concentration of bicarbonate is used. If a very small amount of citrate load is infused, it may give place to a negative bicarbonate balance, and thus metabolic acidosis. Ineffective citrate metabolism does not produce bicarbonate, leading to a negative buffer balance , 13.− When regional citrate anticoagulation is used, calcium is removed as the citrate-calcium complex is replaced to keep homeostasis, inadequate supplementation is related to hypocalcemia , 13. IonHypothermia, a myocardial depressor may develop, being continuous veno-venous modalities, dialysate temperature, dialysate flow and blood flow contributors. Mild hypothermia prevent hypotension by inducing vasoconstriction but is also associated with myocardial stunning. Body temperature <30°C augments cytoplasmatic calcium and cyclic adenosine monophosphate, diminishing calcium sensitivity of contractile proteins, impairing the sensitivity of adrenergic receptors to agonists , 19.Myocardial stunning during RRT, is related to reduced regional myocardial perfusion, (even without coronary artery disease), independently from hypovolemia inflammatory mediators released during bioincompatibility responses and activated complement components modify leukocyte responses and deranges blood vessel homeostasis , 19.per se damage the capillary barrier and microcirculation  contribute to AKI , 33.Mechanical ventilation itself give place to hemodynamics derangement and release of pro-inflammatory cytokines, being plasmatic cytokine levels predictive of AKI and non-recovery of kidney function . AdditioPositive end-expiratory pressure may increase intrathoracic pressure, reducing venous return and cardiac output, augmenting right ventricular afterload, systemic venous pressure, venous congestion, and ultimately diminishing renal perfusion. Also, permissive hypoxia and hypercapnia might ensue and decrease renal blood flow –35Not surprisingly, risk factors for AKI during ECMO include post cardiotomy shock, late ECMO initiation, reduced left ventricle ejection fraction, intraoperative transfusion, high lactate, elevated neutrophil to lymphocyte ratio, and elevated inotropic equivalents –34 and THypoxemia-related pulmonary hypertension pulmonary edema, systemic inflammation and cardiac failure seems to be the main contributing factor to ECMO-associated kidney disfunction, while ECMO-induced hemodynamic changes contribute to perpetuate kidney damage , 62, 63:1. Renal dysfunction is related to left ventricular geometry alterations, diminished midwall fractional shortening, and elevated NT‐proBNP .2. GFR is diminished and renal vascular resistance at the preglomerular afferent site is augmented in heart failure with conserved and reduced ejection fraction .3. Elevated central venous pressure increase intratubular pressure, counteracting glomerular filtration rate (GFR) ECMO itself may contribute to hemodynamic derangements affecting kidney function :1. Pulsatile blood flow is important to maintain renal cortical blood flow; Nonpulsatile perfusion diminishes hemodynamic energy resulting in capillary collapse, microvascular shunting, and release of inflammatory mediators , 42.2. In neonates submitted to venoarterial ECMO  Plasma a3. Amelioration in microcirculatory oxygenation in previously hypoxic and hypoperfused kidney may be associated with ischemia–reperfusion injury , 67.4. About 2% of patients on venoarterial ECMO, presents aortic retrograde dissection that may include renal arteries .5. Systemic thrombotic or air microembolism may cause AKI in patients on venoarterial ECMO.6. Negative pressure generated by the roller or centrifugal pumps may produce hemolysis and hemoglobinuria . Higher Bleeding and thrombotic complications remain the main causes of morbidity and mortality in ECMO and may coexist in the same patient. Among adult ECMO patients 12.9% develop clots in the oxygenator, and 1.6% develops clots in the bridge, while 15.1% present cannula site bleeding, 14.6% surgical site bleeding, 6% present hemolysis, 3.3% disseminated intravascular coagulation, 2.3% cardiac tamponade and 7.4% pulmonary hemorrhage . ECMO ciECMO implies blood contact with nonendothelial surfaces that leads to coagulation and fibrinolytic activation and a complement-mediated inflammatory response. Along with blood stasis, physiopathological mechanisms leading to thrombosis in patients on ECMO include , 44:1. Thrombus Deposition in the Circuit and Oxygenator.2. Pump Thrombosis is rare but clinically relevant;, and may give place to hemolysis.3. Heparin-induced thrombocytopenia (HIT)in vitro Von Willebrand Factor-mediated platelet adhesion, increasing microthrombi generation on fibrinogen, fibrin, extracellular matrix, and collagen at high shear stress. Hemolysis also dysregulates NO, increasing thrombogenesis.4. Hemolysis; Elevated free hemoglobin in plasma induces The Mechanisms giving place to bleeding in ECMO patients include , 44:1. Thrombocytopenia.2. Disseminated Intravascular Coagulation, an acquired disorder characterized by activation of coagulation resulting in fibrin deposition and microthrombi in small and midsized vessels. Associated platelet and coagulation factor consumption may lead to both bleeding or thrombosis.3. Hyperfibrinolysis. Activation of fibrinolysis may be a primary plasmin-mediated process or a secondary process occurring in the setting of thrombin-mediated activation. Both are commonly seen in extracorporeal life support. Clot deposition on the circuit can lead to excessive fibrinolysis characterized by steep increases in D-dimer and hemorrhage .4. Acquired von Willebrand syndrome (AVWS) is characterized by structural or functional defects in von Willebrand factor typically presenting with mucocutaneous bleeding as well as excessive bleeding after surgery or trauma.Among the principal causes of kidney derangements in patients with chronic liver disease, Hepatorenal Syndrome (HS) may present in hepatic failure from any cause. HS patients usually have portal hypertension that triggers arterial vasodilatation in the splanchnic circulation increasing production or activity of vasodilators, being NO of outmost importance. Cardiac output progressively rises with concomitant fall in systemic vascular resistance despite local increases in renal vascular resistances in response to activation of the renin-angiotensin and sympathetic activity , 50.HS is a clinical and laboratory-based construct, being its diagnostic criteria :1. Chronic or acute hepatic disease with hepatic failure and portal hypertension.2. AKI development with no other cause for AKI.3. Spontaneous bacterial peritonitis does not exclude the diagnosis of HS.4. Coexistence of another kidney diagnosis does not exclude hepatorenal syndrome.5. In conjunction with excluding other apparent causes of kidney disease, the following criteria also apply; Urine red cell excretion <50 cells per high power field, proteinuria <500 mg/day, and lack of improvement in kidney function after volume expansion with intravenous albumin.HS may be classified as Type 1 (at least a twofold increase in serum creatinine to a level >2.5 mg/dL within less than two weeks) or type 2, less severe, in which the major clinical feature is diuretic-resistant ascites , 50.per se do not cause hepatorenal syndrome. As cirrhotic patients commonly have poor muscle mass and may present with ascites or anasarca, kidney damage may be worse than suggested by creatinine levels , splanchnic vasodilatation, and portosystemic collateral vessels characterize portal hypertension. While vasodilation is present in the mesenteric arterial circulation, intrarenal arteries presents vasoconstriction . IIR is Vasoregulatory pathways responsible for IIR in portal hypertension include Nitric oxide-c-GMP system, aracrine endothelin-1 (ET-1) system, sympathetic alpha adrenergic pathway and angiotensin II (ATII) system. MARS is described to remove this vasoactive substances .In fulminant and acute-on-chronic liver failure, hemodynamic profile includes hyperkinetic circulation including diminished systemic vascular resistance index (SVRI) caused by vasodilation, high cardiac index (CI), and diminished mean arterial pressure (MAP).Hemodynamic changes in patients with acute-on-chronic liver failure (AOCLF) during the MARS include:1. Increased heart rate and increased MAP, whereas CI and stroke volume remain without significant changes. Renin levels decrease. (as Renin is not removable by MARS its reduction reflects a decreased release) .2. Decrease in hepatic venous pressure gradient, and decrease in plasma renin activity and norepinephrine .MARS diminishes hyperdynamic circulation , with no significant changes in pulmonary arterial pressure and capillary pulmonary pressures, suggesting no significant change in circulating volume .Compared to Prometheus, MARS is more effective in both decreasing serum bilirubin levels, and improving circulatory variables such as MAP and systemic vascular resistive index, paralleled with diminished plasma renin activity, aldosterone, norepinephrine, vasopressin and nitrate/nitrite levels . When coMARS may activate the coagulation system following blood contact with artificial materials, resulting in consumption of coagulation factors and platelets. Bleeding and thrombotic complications are described in g both patients undergoing MARS, and patients with liver failure.Bleeding complications are specially associated with mortality and can impose a major constraint on liver transplant surgery. Described hemorrhagic complications include severe thrombocytopenia, hypofibrinogenemia, and DIC , 56.1. In a retrospective report, including 83 MARS sessions among 21 patients, 38% of patients presented clinical or laboratory evidence of severe coagulopathy during 12% of the MARS sessions, leading to premature ending of the liver support session in 33% of patients. All coagulation parameters worsened significantly during MARS; median INR augmented significantly, fibrin D-dimer, platelet counts and fibrinogen median decreased .Reported bleeding complications included bleeding from catheter insertion sites, subdural hematoma, severe consumptive coagulopathy with intracranial hematomas and infarctions, and severe esophageal variceal bleed. Reported mortality due to bleeding complications corresponded to 19% of patients treated with MARS, 5% of MARS sessions, and 44% of episodes of severe coagulopathy .2. In a retrospective report on MARS sessions 53.3% of patients presented clinically significant bleeding; with 89% of them presenting muscle or subcutaneous bleeding or hematoma on the catheter insertion site. Coagulation profiles after MARS were concordant with a negative coagulation effect; PT-INR, aPTT, FDP, and D-dimer significantly increased, while platelet and fibrinogen diminished. MARS also reduced coagulation factors, especially factor V .Two of the mayor advantages of ECOS is the capacity to remove toxins and proinflammatory cytokines; this is important given that inseptic shock, dysregulated immune response to infection gives place to cytokine storm, including uncontrolled release of proinflammatory mediators that evoke cellular toxicity .®-AN69 membrane, CytoSorb® and HA380 cytokine hemoadsorption, polymyxin B endotoxin adsorption, and plasmapheresis have been reported to improve clinical outcomes in septic shock, included increased MAP, decreased norepinephrine inotropic score and vasopressor dependency index , both devices had similar performance regarding removal of water-soluble toxins. Ammonia removal was increased using CytoSorb, and CytoSorb lead to a significant reduction of albumin- bound toxins, total bilirubin and subfractions. Bile acid removal was similar while MARS demonstrated no removal of cytokines interleukin-6 and TNF-alpha (In an NF-alpha .Being the kidney a part of a complex multiorgan homeostatic arrangement, any kidney derangement, must be considered according to the whole clinical scenario. Even if multiple clinical characteristics may be shared among groups, every patients represent a unique physiopathological intersectionality to be analyzed.Multiorgan failure is commonly accompanied by AKI, thus any patient undergoing ECOS should be considered as a patient with high risk of AKI. Being MOF a proinflammatory disease, most physiopathological mechanisms involving kidney damage will include proinflammatory pathways.Patient interaction with the extracorporeal circuit may affect the kidney function by:1. Multiorgan crosstalk pathways.2. Hemodynamic derangements.3. Coagulation derangements.4. Cytokine profile and neurohumoral changes.Expanding the knowledge of ECOS interactions will help to achieve an optimal approach to expected kidney vulnerability or damage scenarios in the course of a successful ECOS (The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Blood pressure (BP) variations depend on various internal, environmental, and behavioral factors. BP fluctuations occur both in normotensive and hypertensive people. Although it fluctuates over the 24-hr day and night, the morning BP increases after waking up and declines throughout sleep. It is typical for BP to decrease by 10% to 20%, while sleeping, known as dipping BP. However, if there is no decrease in nighttime mean systolic BP or a drop of less than 10 mmHg, it is called nondipping BP. Conversely, reverse dipping BP means an increase in mean systolic BP instead of a drop during the night. Reverse dipping is observed in hypertension (HTN), diabetes mellitus (DM), chronic kidney disease (CKD), and obstructive sleep apnea (OSA) syndrome. The introduction of ambulatory BP monitoring (ABPM) led to the emergence of identifying normal and elevated BP patterns. Non-dipping BP increases the risk of cardiovascular system (CVS) complications such as left ventricular hypertrophy, proteinuria, glomerular filtration rate (GFR) reduction, and CKD progression. A loss or blunting of the normal BP profile is recognized as a deleterious variant, and restoring abnormal BP patterns has been reported to significantly impact end-organ damage, morbidity, and mortality.In this non-systematic clinically-oriented, comprehensive review, we aim to update the BP variables and the pathophysiology of nondipping BP and point out the areas which need more investigation from a nephrology perspective because the nondipping BP increases the risk of proteinuria, GFR reduction, and CKD progression. A literature search of PubMed, Google, EMBASE, and Google Scholar was conducted. Checks of selected papers and relevant reviews complemented the electronic search.With improved BP measurement methods, the physiology of BP profile variations is readily detectable during the day and night. A nondipping BP profile is a distinct BP pattern that may have significant end-organ damage effects and therapeutic importance for nephrologists.The pathophysiology of the nondipping BP variant must be clarified to prevent complications, and further investigations are required. Furthermore, there is debate about the best BP index to utilize: systolic BP, diastolic BP, mean arterial pressure, or a mixture of all. All these areas are important and need new research projects. Chronic kidney disease (CKD) is a widespread and significant illness with a global public health impact. Diabetes mellitus (DM) and hypertension (HTN) significantly affect CKD prevalence . The incThe previously reported studies showed that BP records taken outside of clinic settings through ambulatory BP monitoring (ABPM) or at home had a more significant correlation with the frequency of CV events and the consequent deterioration in kidney function . Not onlNormally, there is a 10%-20% reduction in BP at night, which is a physiological variation . IndividThis is a comprehensive non-systematic review article. The institute’s ethical committee has deemed obtaining ethical approval for this type of work unnecessary. A literature search was performed in PubMed, Google, EMBASE, and Google Scholar. Checks of selected papers and relevant reviews complemented the electronic search. Studies were recognized by crossing the following keywords and terms: ambulatory BP, nocturnal BP, reverse dipping, inverted dipping, altered circadian BP rhythm, HTN, target organ damage, kidney and HTN, kidney, and dipping BP, abnormal BP pattern-related mortality, and other phrases.Blood pressure physiologyThe autonomic nervous system (ANS), particularly sympathetic nervous system (SNS) activity, is the primary determinant of circadian changes in BP. However, other neurohormonal systems that control BP also affect circadian rhythm, suggesting their involvement in diurnal fluctuations in BP . AccordiUrine sodium concentration decreases due to V2-antidiuretic hormone (ADH) receptor increased activity in the collecting duct of the neuron by ADH. Inhibition of this action leads to increased sodium excretion. During the day, the plasma ADH level is higher than at nighttime, leading to more sodium reabsorption by nephron tubules and collecting ducts, leading to a higher body content of sodium during the daytime. ADH and other vasopressor hormone plasma levels decrease during nighttime, leading to more loss of sodium and the consequent dipping of BP. This theory was supported by a clinical study by Bankir et al. . AnotherAnother suggested theory for the dipping of BP at sleeping is position. While sleeping, humans lie flat, which logically causes BP to drop. Furthermore, during sleeping, autonomic nerve activity alters by decreasing sympathetic and increasing parasympathetic, affecting BP. Moreover, blood flow redistribution and decreased blood pooling in lower limbs compared with an upright position increase kidney blood flow, eGFR, sodium filtration, and excretion in lying down. Although these are suggestive BP dipping mechanisms at night, further investigatory studies are required to prove or disprove them.Blood pressure measurement and blood pressure typesHistorically, BP measurement was usually done by physicians. As time evolved, the nurses and even the patients started to measure it, using oscillometric automatic BP machines. The ABPM allows BP measurement while the subject is awake or asleep. ABPM is usually taken every 20-30 minutes throughout the daytime and every hour during sleeping . The meaABPM seems to be a more reliable predictive method and the best for the prediction of death as compared to the clinic BP measurement . The ABPBP phenotypes are detected from the discrepancy between ABPM and office BP readings. ABPM is acknowledged as a gold standard for assessing a "real" hypertensive state. Additionally, ABPM is the sole method for evaluating aberrant circadian BP patterns, such as the nonexistence of a physiological nocturnal BP decline ,28. It iCombining office and out-of-office BP values, such as self-measured home BP or 24-hour ABPM, provided an accurate assessment of the BP status over the past four decades. Its use has become more frequent in clinical and research settings . The comABPM also allows one to assess day-night BP fluctuation since it provides a considerably greater number of BP readings over 24 hours than office and home BP readings. Most people with normal and high BP readings have a BP circadian rhythm. Nocturnal BP levels are 10% to 20% lower than daytime due to the drop in sympathetic tone and the concurrent rise in vagal activity during sleep. In the past, people with aberrant circadian rhythms (nondippers) have often been defined as having nocturnal BP drops lower than 10% ,38. PhysSeveral combinations of approaches are available to define the ‘sleeping time’. Using diary card entries is an uncomplicated strategy. Some people prefer a limited timeframe to describe the evening, such as midnight to 6 AM, eliminating overlapping times when patients may be awake or asleep . This maA nondipping BP pattern's clinical use hinges on consistency from one instance to the next. Manning et al. revealed that only 54% of 79 untreated HTN and normotensive subjects could be reliably categorized as dippers . In othePhysiology of dipping blood pressureAt the start of sleep, recognizable changes occur in autonomic and endocrine activities, including a decrease in sympathetic outflow to the heart and muscle, vascular bed, and a decrease in renin-angiotensin system activity ,51. ParaPhenylephrine is an α-adrenoceptor agonist which does not cross the blood-brain barrier to counteract the natural decline in sympathetic activity due to external stimuli . The BP The peripheral baroreflex arch is controlled by a central nervous system-determined set point . BecauseAn experiment focused on how sleep affects the efferent part of the sympathetic system activity in the vascular muscle bed, causing vasoconstriction. One potentially implicated route in the circadian BP profile is primarily addressed by maintaining nocturnal BP increased to non-physiological ranges using intravenous vasoconstrictors . HoweverThe relevance of the rennin-angiotensin system in BP control and permanently resetting the baroreflex has previously been acknowledged ,62. HearPerspectives of blood pressure physiologyNocturnal non-dipping control significance indicates that BP dipping during overnight sleep is a process of active downregulation. Any violation of this process, such as extrinsic nondipping, is vigorously retaliated against by the body, even causing BP levels to drop the next day without a significant autonomic and sympathetic response imbalance. The research emphasizes the significance of coordinated central neurological systems, which, via baroreflex mechanisms, actively reduce BP during sleep. This presents a fresh viewpoint on the function of sleep-in controlling BP under physiological and pathological circumstances. To clarify the mechanism(s), new studies are required on the mechanism(s) of the physiology of BP changes during daytime and sleeping time.Blood pressure variancesDisruptions in the BP rhythms increase the risk of diseases associated with hypertension independently of the actual BP readings. However, this technique needs to consider the daily regularity of BP change. Clinical guidelines are being improved to include using ABPM to acquire data over extended periods of activity and rest while doing daily activities ,64. ThisIn healthy people, the daily rhythm of the BP is defined by a morning rise after waking up, which peaks throughout the daytime, followed by a nighttime dip. In 1988, the term "nondipper" was developed to refer to HTN patients with a diminished nocturnal decline who also had an elevated risk of stroke . NondippABPM usage in a primary care setting revealed nocturnal HTN in 30% of individuals with normal office BP readings , suggestDipping blood pressureMost normal individuals possess a dipping BP pattern in which their nocturnal BP is 10-20% less than their daytime BP. Over the last three decades, dipping patterns in hypertensive patients have been intensively examined. Comparing the overall mortality in hypertensive dippers and nondippers verified that the dippers had a decreased risk of overall mortality, which was reinforced by the lack of heterogeneity across trials. Moreover, comparing the risk of stroke among the two groups demonstrated no significant differences; the same was true for subgroup analysis of ischemic strokes . AdditioDecreased dipping and nondipping patterns indicate increased CV risk and HTN-associated organ damage ,81,82. TMechanism of blood pressure dipping during sleepThe natural drop in BP during sleep is due to inactivity and sleep. This reduction may be countered by arguing that sedentary lifestyles and low sleep quality are to blame. It has been hypothesized, for instance, that those with a higher CV event risk are also more likely to be identified as non-dippers because they are less active throughout the day . It was The alteration in systemic activity of the autonomic nervous system during sleep is primarily due to a decrease in parameters such as sympathetic and increased parasympathetic activities, HR and cardiac output. When autonomic dysfunction occurs, BP does not drop as it should during sleep and may even rise throughout the night  : concomiNondipping blood pressureAlthough it is debatable, there is mounting evidence that individuals with essential HTN and nondipping BP probably have more risk of target organ damage . A nondiThe nondipping BP profile links with a higher rate of CV events and target organ damage. However, there are also concerns about how well ABPM measures the dipping status. Furthermore, nondipping has yet to be given a precise definition. A nondipping profile may have anomalies in extracellular volume and vascular resistance modulation as its pathophysiological mechanism(s). Additionally, variations in day and nighttime activities, sleep quality, and body positioning when sleeping are also involved. The ABPM may define the physiological status, assess the efficacy of the antihypertensive medication, and detect white-coat HTN, masked HTN, and uncontrolled masked HTN. ABPM seems more reliable in predicting prognosis and death than clinical measures .Most people have significantly lower BP at night. A decrease in the typical nocturnal drop should be considered abnormal . Of thisMechanism of nondipping blood pressureThe loss of the kidney’s ability to eliminate sodium during the daytime contributes to a diminished nocturnal BP reduction . NocturnRelevance of nondipping blood pressure to end-organ damageResearch shows that non-dippers have more pronounced cardiac and extracardiac organ damage than individuals who maintain their nightly BP .As compared to the dippers, the non-dippers have significantly higher rates of left ventricular hypertrophy, increased thickness of carotid intima and media, microalbuminuria, and cerebrovascular disorders . SignifiReverse dipping blood pressureCompared with the daytime readings, reverse or inverted dipping is defined by unaltered or even higher nocturnal BP. Reverse or inverted dipping is a severe, not uncommon, disruption in the circadian BP rhythm. It is often seen as a particularly dangerous BP phenotype . It is fThe left ventricular mass index in CKD was considerably higher in reverse dippers than in non-dippers and dippers . In CKD,A study has established a substantial link between reversed BP dipping profile and increased urine protein excretion . ProteinThe risk of ESRD and CV events related to reverse dipping BP was assessed in 1024 patients. Patients with reversed BP exhibited higher renal and CV events rates than patients with maintained circadian BP rhythm, regardless of 24-hour systolic BP values ,113. TheThe research evaluated the advantages of improving overnight BP regulation . ResearcReporters showed that reversed dipping BP profiles were more prevalent in the elderly, smokers, males, and a history of CVD . PressioThe Chronic Kidney Disease Japan Cohort research revealed that 15.5% of CKD patients had elevated nighttime BP . A greatWhite coat hypertensionUsually, the measurement of BP in a healthcare facility leads to higher readings for people who are generally not used to the place and/or medical professionals. Around 10-30% of patients with high BP values are inappropriately diagnosed with HTN. Although they do not have HTN, they have what is known as white coat HTN (WCHTN). The overall prevalence of WCHTN is about 10-15% in the general population and reported in about 30% in high BP readings at the clinic ,126. TheThomas Pickering has introduced the term “white-coat hypertension”, describing people who did not take medicine for their high BP. These people have high office BP readings, but their BP readings are normal when monitored by the ABPM method. These people would have a low risk of CV events . The recGuidelines advise using ABPM or HBPM for out-of-office BP monitoring to diagnose doubtful HTNs, including identifying white-coat HTNs. Those with suspected WCHTN should have the diagnosis verified within 3-6 months after their initial high BP reading, advisably by the ABPM method. Also, they should have ABPM or HBPM every year to see if persistent high BP is developing . On the Automated self-office BP recording may reduce the late diagnosis of WCHTN and the number of people who require long hours of BP measurements . One wayAlthough the ABPM or HBPM recording may increase the service cost, it can effectively reduce the long-term treatment costs when the office BP reading is doubtful . A modelPathogenesis of albuminuria in white coat hypertensionIn recent years, the clinical pathogenicity of WCHTN itself has been demonstrated ; howeverMasked hypertensionSince Thomas Pickering in 2002 announced the term ‘masked HTN’, it gained widespread attention . The freApproximately 20% of those missed individuals who go untreated may develop masked HTN. Masked HTN increases carotid atherosclerosis risk and the LV muscle mass index compared with normotensive persons . A JapanSustained (persistent) hypertensionA subject with high BP readings both during home monitoring and at health facilities is labeled as having sustained HTN, which is highly linked to an increased risk of renal and cardiac damage, necessitating early anti-HTN therapy initiation.Kidney and blood pressure variationAlthough some researchers have indicated that nocturnal BP predicts CVD and death , others The currently available data revealed no discernible difference in urine protein content between nondippers and dippers with low BP. Previous research on progressive reduction in the estimated glomerular filtration rate (eGFR) showed that nighttime BP was the best indicator of renal disease development . In a reDue to a need for more robust reported data, it is still being determined whether reversing non-dipper to dipper BP patterns by BP-lowering agents to potentiate renoprotective effects is significantly effective. Many clinical studies have shown that the normalization of BP’s diurnal rhythm by anti-hypertensives improves proteinuria in early diabetic nephropathy  and loweThe likelihood of developing kidney disease is more in nondipper than the dipper-hypertensive-CKD patients. Kado et al. reported that normotensive nondipping CKD patients have a lesser risk of rapid eGFR drop . AdditioBorrelli et al. concluded that high systolic BP measured by ABPM or nocturnal BP dipping loss is linked to higher CVD and CKD progression rates, especially in CKD patients . A non-dFew studies focused on the urine albumin excretion while examining the association between renal outcomes and BP rhythm in normotensive patients. Previous research in normotensive population revealed a weak correlation between dipping BP profiles and left ventricular mass index  but not The current data revealed no discernible difference in protein urine content between non-dippers and dippers with low BP. Previous research on progressive eGFR reduction showed that nighttime BP was the best indicator of development of renal disease . In a reThe normalization of the diurnal rhythm of the BP by administering anti-hypertensives has been shown in many clinical studies to improve proteinuria in early diabetic nephropathy  and loweBecause ABPM interrupts the sleeping state and lowers daytime activity, which results in greater nocturnal BP and lowers daytime BP than typical, the repeatability of ABPM may sometimes be limited. Even at intervals of many weeks, previous research revealed that some people had a distinct circadian BP profile in serial ABPM . The 48-The low incidence of individuals who exhibit dipping BP patterns is another drawback, possibly due to the small sample size that impacted the significance of BP variations in the reported data. Furthermore, even though the nondipping profile was not a factor for the development of kidney disease in normotensive individuals, there is a precise value of the BP risk threshold. Prospective interventional research with several ABPM tests is required to set a target BP. Uncertainty persists on the best time to take BP readings that accurately represent the declining BP trend and the average readings day and night. Previous research showed that self-home BP recording is an alternate tool for forecasting end-organ damage and reasonably correlating with ABPM, and both are superior to office BP monitoring .Kado et al. reported that a nondipping BP profile in normotensive CKD patients does not indicate a risk for a quick fall in eGFR . The nonAmbulatory blood pressure monitoring has impacted blood pressure classification and encouraged research on hypertension patterns, effects, and types. Physical activity, subjective sleep quality, and consecutive day recordings improve the reproducibility of blood pressure measurement. Volume-related variables may play a role in abnormal blood pressure patterns. Nondipping hypertension is linked to salt sensitivity, renal function impairment, sodium retention, and mineralocorticoid-induced hypertension; however, further studies are required to certain the relationship.Reversing the BP dipping pattern may have poor CV prognostic effects, although there is conflicting evidence; hence, more research is needed on treatment approaches that restore circadian BP rhythms and the long-term effect of circadian rhythms' restoration.


High visit-to-visit blood pressure variability (BPV) and hypertension are risk factors for mild cognitive impairment (MCI) and probable dementia (PD). Few articles assessed the effect of BPV on the MCI and PD in intensive blood pressure treatment and the different functions of three types of visit-to-visit BPV: systolic blood pressure variability (SBPV), diastolic blood pressure variability (DBPV) and pulse pressure variability (PPV).post hoc analysis of the SPRINT MIND trial. The primary outcomes were MCI and PD. BPV was measured by average real variability (ARV). The Kaplan-Meier curves were used to clarify the difference in tertiles of BPV. We fit Cox proportional hazards models to our outcome. We also did an interaction analysis between the intensive and standard groups.We performed a p < 0.05). Meanwhile, higher SBPV and PPV in the intensive group were associated with an increased risk of PD (SBPV: HR(95%) = 2.1 (1.1–3.9), p = 0.026; PPV: HR(95%) = 2.0 (1.1–3.8), p = 0.025 in model 3) and higher SBPV in the intensive group was associated with an increased risk of MCI(HR(95%) = 1.4 (1.2–1.8), p < 0.001 in model 3). The difference between intensive and standard blood pressure treatment was not statistically significant when we considered the effect of the higher BPV on the risk of MCI and PD .We enrolled 8,346 patients in the SPRINT MIND trial. The incidence of MCI and PD in the intensive group was lower than that in the standard group. 353 patients had MCI and 101 patients had PD in the standard group while 285 patients had MCI and 75 patients had PD in the intensive group. Tertiles with higher SBPV, DBPV and PPV in the standard group had a higher risk of MCI and PD (all post hoc analysis of the SPRINT MIND trial, we found that higher SBPV and PPV were associated with an increased risk of PD in the intensive group, and higher SBPV was associated with an increased risk of MCI in the intensive group. The effect of higher BPV on the risk of MCI and PD was not significantly different in intensive and standard blood pressure treatment. These findings emphasized the need for clinical work to monitor BPV in intensive blood pressure treatment.In this  This number could grow to 13.8 million by 2060, barring the development of medical breakthroughs to prevent, slow or cure AD (Visit-to-visit blood pressure variability (BPV) represents a dynamic and characteristic physiologic feature of the cardiovascular system function  and is aThe SPRINT-MIND trial has demonstrated that compared with standard blood pressure treatment (SBP target <140 mm Hg), intensive blood pressure (SBP target <120 mm Hg) can significantly reduce the occurrence of MCI as well as the combined occurrence of MCI or PD . The eff2.2.1.post hoc analysis of the SPRINT  MIND (Memory and Cognition in Decreased Hypertension) trial. Data were obtained from the National Institutes of Health Biologic Specimen and Data Repository Information Coordinating Center (https://biolincc.nhlbi.nih.gov/studies/sprint/).We performed a post hoc analyses of the SPRINT MIND trial  and diastolic blood pressure (DBP) were measured at baseline, monthly for the first 3 months and every 3 months thereafter. The mean counts of blood pressure measurement was 10.8 ± 2.5. Pulse pressure (PP) was calculated as follows: PP = SBP − DBP. Mena et al.  conclude2.3.The outcomes of this study were probable dementia (PD) and mild cognitive impairment (MCI). All participants were classified into 3 categories: no cognitive impairment, mild cognitive impairment, or probable dementia. MCI represents the transitional stage from the cognitive changes of normal aging to very early dementia . The dia2.4.via the two-tailed t-test  or the Mann–Whitney U test (skewed distribution). The Kolmogorov–Smirnov test assessed the normal distribution of data.We used frequencies and percentages to reflect the categorical variables and means ± standard deviations or medians (intertertile ranges) to express the continuous variables based on the data distribution. Chi-square analysis was used to evaluate the differences in categorical variables. We can identify any significant differences between groups http://www.R-project.org). Statistical significance was set at p < 0.05.The Kaplan-Meier curves were used to indicate the difference in the risk of MCI and PD among different BPV tertiles separately and the logrank test was used for comparison between different Kaplan-Meier curves. Cox proportional hazards models were used to describe the effect of SBPV, DBPV or PPV on the rate of MCI and PD. We used a variety of models: Model 1 adjusted age, BMI, sex and race. Model 2 adjusted age, BMI, sex, race, smoke, estimated glomerular filtration rate, Framingham 10-year cardiovascular disease risk score, subclinical cardiovascular disease and total cholesterol. Model 3 further adjusted the mean blood pressure  based on the adjustment of Model 2. All models met the proportional hazard assumption. We also performed interaction analyses between different blood pressure treatment arms (standard blood pressure treatment vs. intensive blood pressure treatment). All analyses were performed using the statistical software package R . Notably, SBPV, DBPV and PPV in the intensive group were also significantly lower than that in the standard group . There was no significant difference in other variables between the two groups, including demographic and laboratory data .8,346 patients were eventually enrolled in the analysis, including 4,170 in the intensive blood pressure treatment group (the intensive group) and 4,176 in the standard blood pressure treatment group (the standard group). The average age of the participants was 67.7 ± 9.2 years and there were 2,926 (35.1%) women in the study. p = 0.005; PD: 1.8% vs. 2.4%, p = 0.049).In terms of outcome, the incidence of MCI and PD in the intensive group was lower than that in the standard group  medications, in the whole population, the average of the types of AH medications in the standard group was 1.9 ± 1.0 and patients in the intensive group took an average of 2.6 ± 1.0 types of AH medications. The types of AH medications for the different BPV tertiles were demonstrated in 3.2.p < 0.0001; DBPV: p = 0.0257; PPV: p <0.0001) and PD  respectively. As was shown in p = 0.0037; PPV: p = 0.0018) and PD . However, there was no significant difference in the risk of MCI or PD among different DBPV tertiles  in the intensive blood pressure treatment group.As was shown in 3.3.p < 0.001; DBPV: HR(95%) = 1.3 (1.0–1.7), p = 0.048; PPV: HR(95%) = 1.6 (1.2–2.2), p = 0.001).We used three COX regression models to analyze the association between BPV and MCI. As was shown in p < 0.001 in Model 2; DBPV: HR(95%) = 1.2 (0.9–1.6), p = 0.312 in Model 2; PPV: HR(95%) = 0.9 (0.7–1.2), p = 0.596 in Model 2). The adjustment of visit-to-visit mean blood pressure in model 3 did not change the association between higher SBPV and the growing risk of MCI (HR(95%) = 1.4 (1.2–1.8), p < 0.001).In the intensive group, only the highest tertile of SBPV remained a significant difference in the risk of MCI compared with the lowest in Model 1 and Model 2 (SBPV: HR(95%) = 1.5 (1.2–1.8), In the standard group, elevated BPV was significantly associated with an increased risk of MCI in Model 3. In the intensive group, only higher SBPV was statistically significant with the increased risk of MCI.3.4.p = 0.002; DBPV: HR(95%) = 2.0 (1.2–3.3), p = 0.008). In Model 2 with multiple covariates adjusted, the risks of MCI in T3 of SBPV and PPV were significantly higher than that in T1 (SBPV: HR(95%) = 2.4 (1.4–4.3), p = 0.003; PPV: HR(95%) = 1.8 (1.0–3.4), p = 0.049). In Model 3, which considered visit-to-visit mean blood pressure, the risks of PD in T3 of all these three types were significantly higher than in T1.(SBPV: HR(95%) = 2.4 (1.4–4.4), p = 0.003; DBPV: HR(95%) = 1.8 (1.1–3.0), p = 0.030; PPV: HR(95%) = 2.0 (1.1–3.7), p = 0.026).We adjusted the same models for the association between different BPV and PD. As was shown in p = 0.029; DBPV: HR(95%) = 1.2 (0.7–2.1); p = 0.564; PPV: HR(95%) = 2.0 (1.1–3.6), p = 0.030). The adjustment of visit-to-visit mean blood pressure in model 3 did not change the association between higher SBPV or PPV and the growing risk of MCI (SBPV: HR(95%) = 2.1 (1.1–3.9), p = 0.026; PPV: HR(95%) =2.0 (1.1–3.8), p = 0.025).In the intensive group, the highest tertiles of SBPV and PPV, compared with the lowest, increased the risk of PD in Model 1. After adjusting the covariates in Model 2, the highest tertiles of SBPV and PPV remained a significant difference with the risk of MCI compared with the lowest (SBPV: HR(95%) = 2.0 (1.1–3.8), In the standard group, elevated BPV was significantly associated with an increased risk of PD in Model 3. In the intensive group, higher SBPV and PPV were statistically significant with the increased risk of PD.3.5.p for interaction >0.05). It demonstrated that compared with standard blood pressure treatment, intensive blood pressure treatment made no difference in the effect of the higher tertile of BPV on the risk of MCI and PD.As was shown in 4.post hoc analysis of the SPRINT MIND trial, we investigated the association of three types of BPV with MCI and PD in intensive and standard blood pressure treatment. In the standard group, we found that the increase of SBPV, DBPV and PPV showed a positive relationship with the higher risk of MCI and PD. In the intensive group, we found higher SBPV and PPV were associated with an increased risk of PD and that higher SBPV was associated with an increased risk of MCI. Moreover, the difference between intensive and standard blood pressure treatment was not statistically significant when we considered the effect of the higher BPV on the risk of MCI and PD. These findings emphasized the need for clinical work to monitor BPV in intensive blood pressure treatment.In this In the standard group, previous studies assessed the different effects of three types of BPV on different domains of cognition. Tan Lai Zhou  evaluateMoreover, this study further explored the relationship between various BPV and MCI or PD in intensive blood pressure treatment. Previous research has found that SBPV was associated with the development of probable dementia in intensive blood pressure treatment . Our stuCompared with standard blood pressure treatment, we found that the strong relationship between higher BPV and increased risk of MCI and PD did not change after implementing intensive blood pressure treatment. Our findings were consistent with the previous study where Adam de Havenon  showed tThe strengths of our study included the use of three types of BPV and the well-characterized, large study population, which made it possible to adjust for a large variety of covariates. The adjustment of visit-to-visit mean blood pressure in model 3 increased the credibility of the article.post hoc analysis of a trial that conformed to neither the population nor the randomization model of statistical inference. Secondly, the trial excluded persons with type 2 diabetes, previous stroke, advanced kidney disease, or symptomatic heart failure which limited our results to patients without corresponding basic diseases. Thirdly, the assessment of cognitive function was based on the endpoint events (MCI or PD), which were unable to evaluate either different cognitive dimensions or subtypes of MCI and PD.We acknowledged that there were some limitations of our study. First of all, it was a 5.post hoc analysis of the SPRINT MIND trial, we found that, in standard blood pressure treatment, elevated BPV, regardless of using any of the three BPV types, was significantly associated with an increased risk of MCI. In intensive blood pressure treatment, higher SBPV and PPV were associated with an increased risk of PD, and higher SBPV was associated with an increased risk of MCI. The effect of higher BPV on the risk of MCI and PD was not significantly different in intensive and standard blood pressure treatment. These findings indicated visit-to-visit BPV as a risk factor for MCI and PD, independent of mean blood pressure. Moreover, it was of great value for clinical work to monitor BPV, especially SBPV or PPV, in both standard and intensive blood pressure treatment.In this


The existence of eosinophils was documented histopathologically in the first half of the 19th century. However, the term “eosinophils” was first used by Paul Ehrlich in 1878. Since their discovery and description, their existence has been associated with asthma, allergies, and antihelminthic immunity. Eosinophils may also be responsible for various possible tissue pathologies in many eosinophil-associated diseases. Since the beginning of the 21st century, the understanding of the nature of this cell population has undergone a fundamental reassessment, and in 2010, J. J. Lee proposed the concept of “LIAR” , underlining the extensive immunoregulatory functions of eosinophils in the context of health and disease. It soon became apparent that mature eosinophils  are not structurally, functionally, or immunologically homogeneous cell populations. On the contrary, these cells form subtypes characterized by their further development, immunophenotype, sensitivity to growth factors, localization, role and fate in tissues, and contribution to the pathogenesis of various diseases, including asthma. The eosinophil subsets were recently characterized as resident (rEos) and inflammatory (iEos) eosinophils. During the last 20 years, the biological therapy of eosinophil diseases, including asthma, has been significantly revolutionized. Treatment management has been improved through the enhancement of treatment effectiveness and a decrease in the adverse events associated with the formerly ultimately used systemic corticosteroids. However, as we observed from real-life data, the global treatment efficacy is still far from optimal. A fundamental condition, “sine qua non”, for correct treatment management is a thorough evaluation of the inflammatory phenotype of the disease. We believe that a better understanding of eosinophils would lead to more precise diagnostics and classification of asthma subtypes, which could further improve treatment outcomes. The currently validated asthma biomarkers  are insufficient to unveil super-responders among all severe asthma patients and thus give only a blurred picture of the adepts for treatment. We propose an emerging approach consisting of a more precise characterization of pathogenic eosinophils in terms of the definition of their functional status or subset affiliation by flow cytometry. We believe that the effort to find new eosinophil-associated biomarkers and their rational use in treatment algorithms may ameliorate the response rate to biological therapy in patients with severe asthma. The existence of eosinophils was documented histopathologically in the first half of the 19th century in Gottlieb Gluge’s textbook of pathology from 1843. However, the term “eosinophils” was first used by Paul Ehrlich at the end of the 19th century (1878). At that time, their existence was associated with the pathogenesis of asthma. During the 20th century, the notion of the role of eosinophils in the human body was subject to considerable turbulence. While eosinophils were perceived as regulatory elements that dampen the proinflammatory activity of mediators released by mast cells during the 1970s and 1980s, in the later 1980s and 1990s, eosinophils began to be considered as terminal effector cells of immunopathological inflammation, causing tissue damage. The presence of eosinophils has traditionally been associated with defence against helminthic infections and with the pathogenesis of allergies. Since the beginning of the 21st century, theories about their physiological roles in the human body have been further revised. Furthermore, in 2010, J. J. Lee, the former president of the International Society for Eosinophils, proposed the concept of “LIAR”   on the airway status after a challenge with an inhaled allergen in unselected patients with mild asthma conducted in 2000. However, the result was a significant reduction of eosinophils in the peripheral blood for 16 weeks and the induction of sputum four weeks after infusion, with no effect on clinical outcomes—late allergic reaction or histamine-induced hyper-reactivity . DisappoIn the subsequent phases of clinical biological testing directed against IL-5, based on examination of the absolute number of eosinophils in the peripheral blood, threshold values of the absolute count of peripheral eosinophils have most often been set in the range of 150–400/μL. However, it can generally be assumed that the higher the number of eosinophils in peripheral blood is, the greater the probability their presence in tissues, including induced sputum, is. At the same time, the effect of antieosinophil treatment is greater . It is aRegarding the discussion of the usefulness of examining peripheral eosinophils to estimate airway eosinophilia and thereby identify the inflammatory endotype, the risk of worsening or exacerbating asthma and the evaluation of its responsiveness to therapy  continues to persist. Manali Mukherjee and Parameswaran Nair highlighted many issues: (1) the concentration of eosinophils in the induced sputum can predict the loss of asthma control with higher sensitivity compared to their concentration in the peripheral blood , (2) theThere are, however, even more unsolved questions and associated doubts regarding the reliable implementation of peripheral blood eosinophilia examination into routine clinical practice. These include (6) uncertainty regarding the association of clinical outcomes with the values of peripheral eosinophilia, (7) determination of the genuinely reliable threshold value (if one exists) of blood eosinophilia for predicting the clinical course of the disease and its response to targeted therapies directed against IL-5(R), (8) determination of the number of times it be measured (due to its variability), and finally, (9) whether monitoring of the number of eosinophils in the peripheral blood can be used to monitor the treatment effectiveness, especially in patients with a severe form of the disease, in whom a low degree of correlation with eosinophils in the induced sputum has been proven .In summary, the examination of eosinophils in the peripheral blood is necessary, although still debatable and problematic, when reviewing a patient with asthma. Undoubtedly, it provides information regarding the inflammatory endotype, the estimation of the prognosis, and the probability of the effect of anti-inflammatory treatment . The recommended cut-off values for the absolute number of eosinophils in patients with asthma, their frequency, and interpretation are summarized in Asthma treatment is principally directed against two key pathogenetic pillars—bronchial obstruction and airway inflammation. The treatment of inflammation with inhaled corticosteroids has proven to be crucial and has been the dominant recommendation for all disease severities since the 1970s. Unfortunately, more than 2–3% of asthmatics suffer from disease that is refractory to treatment with a tendency to have severe exacerbations and a necessity for repeated or continuous treatment with systemic corticosteroids, which come with complications and consequences ,89,90. LThe following text focuses on registered drugs that are primarily directed against eosinophils  and drugs that are currently being researched (depemokimab–anti-IL-5 and lirentelimab–anti-Siglec-8).1, κ). The registration studies DREAM  [The monoclonal antibody mepolizumab was used for the first time in an animal model in 1992 . Less thum, ≥3%)  and MENSum, ≥3%)  initiateum, ≥3%) . Finallyum, ≥3%)  focused um, ≥3%) , and theum, ≥3%) , followeum, ≥3%) , eosinopum, ≥3%) ,102, andum, ≥3%) .4, κ) that, similarly to mepolizumab, is directed against human interleukin-5 (IL-5). Its binding prevents its interaction with the relevant receptors on the cell surface. The development of reslizumab followed the academic and clinical mepolizumab programs. Therefore, when reslizumab entered the market, it was already clear that specific biological therapies can only achieve a clinically relevant effect in selected groups of patients.Reslizumab (SCH55700) is a humanized monoclonal antibody  that binds to the alpha subunit of the IL-5 receptor (IL-5Rα) on the surface of eosinophils. The emergence and development of benralizumab were intrinsically linked to the description of the structure and function of IL-5R, which is expressed explicitly on the surfaces of eosinophil precursors and basophils. In addition, the absence of fucose on the Fc fragment of benralizumab enables high-affinity binding to FcγRIII receptors on immune effector cells, such as natural killer (NK) cells, thus facilitating the induction of the apoptotic death of eosinophils and basophils by antibody–dependent cell-mediated cytotoxicity (ADCC) [Benralizumab (MEDI-563) is a humanized, afucosylated, monoclonal antibody (IgGy (ADCC) . Combiniy (ADCC) .Moreover, thanks to its regulated process, the apoptotic death of eosinophils prevents the uncontrolled release of the content of cytotoxic granules. Therefore there is no paradoxical rise in the concentration of IL-5 ,114. Dur1 compared to the baseline level was recorded as early as week 4, which persisted until the end of the treatment, an effect that was generally positively correlated with the baseline eosinophil level [The efficacy of benralizumab was assessed in larger cohorts in three registrational, randomized, double-blind, placebo-controlled phase III clinical trials. The SIROCCO  and CALIil level .Another posthoc analysis demonstrated the more pronounced effect of benralizumab on the reduction of exacerbations in the population of asthmatics whose initial eosinophil concentration did not reach 300/μL in the peripheral blood if they (1) simultaneously used oral corticosteroids, (2) suffered from nasal polyps, or (3) had a reduced forced vital capacity (FVC) <65% . Finallyn = 211). There was an improvement in the prebronchodilation value of FEV1 after 12 weeks of treatment with benralizumab at a dose of 30 mg sc every four weeks [In the following study, ZONDA  asthma pur weeks . In anotur weeks . The regur weeks . This exur weeks ,15,127.1, κ) directed against IL-5 that interacts with the same epitope of IL-5 as mepolizumab but with a higher affinity and longer biological half-life [In addition to the registered preparations that target eosinophils, we address two other drugs. The first is depemokimab , an inhibitory receptor that is selectively expressed on mature eosinophils and mast cells and has a low level of expression on basophils [The last selective antieosinophilic biologic drug is lirentelimab (AK002), a humanized, non-fucosylated IgGasophils ,130. Lirasophils . Recentlasophils . It can asophils ,133,134.Eosinophils are an extraordinarily dynamic and inhomogeneous cell population at both the level of progenitors  and at the stage of fully matured and immunocompetent cells and under both physiological and pathological circumstances, including in asthma patients. Indeed, it has historically been known that there are two different specific gravity cell types of eosinophils: those with a normal density (specific gravity > 1.085 g/L) and those with a lower density (specific gravity < 1.085 g/L), the latter of which represents the activated phenotype ,136. PrimedCD11c− to a Siglec-FhighCD11clow phenotype in lung tissue was associated with eosinophil recruitment to the airways, as all BALF eosinophils were of the latter phenotype. Moreover, specific morphological differences were related to particular immunophenotypes . The authors proposed that the Siglec-FhighCD11clow phenotype switch is associated with the migration of eosinophils into the mucosal compartment [medCD11c−), and (4) type-2 eosinophils . Type-1 eosinophils are interstitial/stromal eosinophils that are found in transient morphogenetic contexts and during Type-1 (Type 2-low) immune activation. This is in contrast to Type-2 eosinophils, which are associated with the epithelium and Type-2 immune environment [Later, Abdala Valencia et al. analyzed the phenotype plasticity of murine eosinophils in digested lung tissue and BALF using flow cytometry 6 h after the ovalbumin challenge. The gradual transition from a Siglec-Fpartment . Similarpartment . This coironment .medCD62L+CD101low, IL-5 independent parenchymal cells with a ring-shaped nucleus), and inflammatory eosinophils, iEos . The study also demonstrated that rEos express genes that have been implicated in the negative regulation of the immune response, surprisingly inhibiting Type 2 inflammation. Additionally, the authors described two phenotypically distinct eosinophil subsets in the human lungs of healthy donors, CD62L+IL-3Rlow, and in the sputum of patients with asthma, CD62LlowIL-3Rhigh [In accordance with this model of eosinophil functional divergence, in 2016, Mesnil et al. discovered phenotypically distinct subtypes of eosinophils in the murine lungs under steady-state conditions and after house-dust-mite (HDM)-induced allergic inflammation. These cells were classified as resident eosinophils, rEos  . In physConcurrently, whether this differentiation is initiated after entering the tissue microenvironment or may be detected even before in circulation has been debated. Alternatively, it is unclear whether these differences could arise through eosinophil “endotyping” as a pattern of adaptations imprinted during their development in the bone marrow in the peripheral circulation or through tissue-induced plasticity and local transformation of eosinophil function through interactions with their lung tissue niches .Early studies in the 1980s reported the presence of hypodense eosinophils in the circulation of asthmatic patients , and theFor over one hundred years, we have recognized that there is a clinically relevant connection between these cells and eosinophilic (Type 2-high) asthma, leading to advanced diagnostic and therapeutic opportunities. However, despite the enormous progress in this field, we are still struggling with central questions regarding the disease phenotyping, selection, timing, monitoring, switching, or quitting of specific antieosinophil biological treatments. Future questions to be answered include (1) how can we improve asthma diagnostics, especially regarding inflammatory endotype establishment ? (2) Which biological treatment will be the best for a particular patient ? (3) How can we monitor the treatment effect ? (4) If we register the clinical effect of the treatment, how can we be sure that the efficacy is the best achievable? How fast and stable can the clinical response be? (5) Is the clinical response sufficient to continue the treatment, or should we consider switching or quitting (or maybe doubling) the treatment due to a lack of efficacy?In everyday clinical practice, we must follow only validated and standardized biomarkers with well-defined cut-off levels for use in the diagnosis, treatment strategy, and monitoring of asthma patients . All of these measurements aim to detect the Type 2-high inflammatory endotype and are not perfectly correlated due to differences in background cytokine regulation. Therefore, respective or mixed positivity indicates another signal in the disease pathology or a slightly different inflammation phenotype, thus supporting the use of a different treatment strategy . It is, Taken together, even though we regularly assess asthma patients using all validated biomarkers, the general clinical nature of the disease  is always a blend of distinct processes (inflammatory endotypes) that are potentially susceptible to more plausible interventions  . This reAll of the abovementioned limitations of successful severe asthma biological therapy necessitate a more detailed understanding of the immunopathology of the disease. We believe that an improvement in treatment outcomes will rely on obtaining a better understanding of disease biology, leading to more precise diagnostics and endo/phenotyping of the disease. The currently validated biomarkers  are insufficient to unveil super-responders fromall severe asthma patients and thus give only a blurred picture of the disease phenotype. On the other hand, there is emerging evidence that an increased number of hypodense/activated eosinophils in the peripheral blood is a pathognomic feature of asthma  that corMoreover, the respective cellular populations may be readily detectable in the peripheral blood. The dysregulation of their rates can reflect allergen challenges in allergic asthma patients  or the psine qua non” in asthma diagnostics and phenotyping, the results simplify complex biological processes under the asthma umbrella. Unfortunately, this isolated information is insufficient to render a clear picture of the disease and ease the decision about which treatment approach has a greater chance of successfully achieving control of a patient’s asthma or even inducing clinical or complete remission. This unsatisfactory situation is a tremendous challenge in the search for more detailed diagnostic approaches based on the complex clinical background associated with a repetitive biomarker analysis. We suggest one possible extension regarding an eosinophil immunophenotype analysis that may provide helpful information for the future.Eosinophils represent a fascinating cell population with a vast field of action in the human body. Our understanding of their roles in specific pathologies has exponentially increased over the last 20 years, which has led to the development of targeted antieosinophil biological therapies based upon interactions with either the major eosinophil growth factor (IL-5) or with eosinophil surface molecules (IL-5Rα or Siglec-8) to induce cell death through apoptosis. Both approaches represent treatment modalities with significant clinical or laboratory ramifications and differences. Although examination of the eosinophil count in peripheral blood has become a condition that is “


Linear and logistic regressions were utilized to analyse the relationship between proteinuria reduction and basal characteristics. Results: A total of 58 patients were enrolled in the study: 32 patients (55.1%) were in the R group and 26 patients (44.9%) in the nR group. R’s patients had a significant higher uProt at baseline . There was a significant correlation between baseline uProt and proteinuria reduction with SGLT2i in both univariate  and multivariate analyses . In the multivariate analysis, there was a significant positive correlation between the estimated glomerular filtration rate (eGFR) and proteinuria reduction  and a significant negative correlation with body mass index (BMI) . The multivariate logistic regressions show a positive correlation of being in the R group with diabetic retinopathy at baseline (Odds Ratio (OR) 3.65, CI 0.97 to 13.58, p = 0.054), while the presence of cardiovascular disease (CVD) at baseline is associated with being in the nR group , even if these statements did not reach statistical significance. Conclusions: In this real-life experience, following the administration of SGLT2i, a reduction of more than 30% in proteinuria was observed in more than half of the patients, and these patients had a significantly higher baseline proteinuria value. Variables such as eGFR and BMI are variables that, considered in conjunction with proteinuria, can help predict treatment response before therapy initiation. Different phenotypes of diabetic kidney disease may have an impact on the antiproteinuric response.Introduction: Proteinuria is a major risk factor for the progression of chronic kidney disease (CKD). Sodium-glucose cotransporter 2 inhibitors (SGLT2i) demonstrated a nephroprotective and antiproteinuric effect in people with type 2 diabetes (T2DM) and proteinuric CKD. We conducted a retrospective study to evaluate clinical and laboratory variables that can help predict proteinuria reduction with SGLT2i therapy. Materials and methods: Patients affected by T2DM and CKD who started any SGLT2i were included in the study. Patients were stratified into two subgroups, Responder (R) and non-Responder (nR), based upon the response to the therapy with SGLT2i, namely the reduction in a 24 h urine proteins test (uProt) of ≥30% from baseline levels. The aim of the study is to analyse differences in baseline characteristics between the two groups and to investigate the relationship between them and the proteinuria reduction. A Kruskal–Wallis test, unpaired t-test and Chi Proteinuria is not only a marker of kidney impairment, but also a major risk factor for cardiovascular disease (CVD), the progression of chronic kidney disease (CKD) ,2 and acProteinuria is a common feature of diabetic kidney disease (DKD), being present despite proper treatment, in a striking proportion (around 70%) of patients referred to nephrologists . It is bReducing proteinuria is associated with improved outcomes for patients , to suchIn recent years, targeting the renin-angiotensin-aldosterone system (RAAS) has been the only pharmacological approach for reducing proteinuria and improving renal outcomes in patients with CKD. In recent decades, novel sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i) became the new pillar of treatment for people with type 2 diabetes mellitus (T2DM) and proteinuric CKD, since more and more studies demonstrated the nephroprotective and antiproteinuric effect of these drugs ,19,20,21While new trials have been conducted to assess the SGLT2i’s protective effects on cardiovascular and renal events in patients without T2DM and with normoalbuminuria, it has already been shown that many patients (up to 50% of patients) do not respond to these drugs in terms of proteinuria reduction . CurrentWe conducted a retrospective study to evaluate clinical and laboratory variables that can help to predict proteinuria reduction with SGLT2i therapy in people with T2DM and CKD.This observational retrospective, single-centre study was conducted at IRCCS Azienda Ospedaliero-Universitaria Policlinico Sant’Orsola  by the Nephrology, Dialysis and Renal Transplantation Unit and the Endocrinology and Diabetes Prevention and Care Unit. All the patients included in this study were referred to our multidisciplinary outpatient service from 1 April 2019 to 9 February 2022.The inclusion criteria were patients aged > 18 years, with a diagnosis of T2DM and CKD, and an expressed informed consent. All patients included in the study cohort completed a cycle of therapy with currently available SGLT2i . A cycle was defined as the period from the start of therapy at the first outpatient visit to the second outpatient visit during follow-up after therapy initiation. The length of follow-up was not predetermined but followed the dictates of clinical practice. Patients who discontinued therapy due to non-compliance or adverse events were not included in the study. Compliance with therapy was assessed via the presence of glucosuria on a urine dipstick.2 and 30 mL/min/1.73 m2 (stage G2 and G3 in the KDIGO classification), was eligible for inclusion in the study. People with CKD stages G4 and G5, those on dialysis and kidney transplant recipients were excluded from the study cohort.The diagnosis and classification of CKD followed the 2012 Kidney Disease Improving Global Outcomes (KDIGO) guidelines . Any patThe cause of chronic kidney disease, although not diagnosed histologically, was likely attributable to diabetic kidney disease, and thus attributable to T2DM or to hypertensive and metabolic complications . Patients with a histological diagnosis of glomerulonephritis or nephropathy secondary to immune, oncological or haematological diseases were excluded from the study. Similarly, patients with suspected glomerular pathology not secondary to diabetic disease or complications were excluded from the study. The study procedures were in accordance with the Helsinki Declaration. The study protocol and consent form were approved by the Ethics Committee of IRCCS Azienda Ospedaliero-Universitaria di Bologna .From the first outpatient visit, data were retrospectively collected regarding medical history, current health status and ongoing therapy. In particular, we collected anamnestic data, including the presence of comorbidities such as cardiovascular disease and diabetic retinopathy, and anthropometric data, such as weight and height for calculating body mass index (BMI), and blood pressure measurements. Blood samples were also taken at the baseline visit to measure fasting blood glucose and glycated haemoglobin (Hba1c) levels, lipid panel , high-density lipoprotein cholesterol (HDL)) and measures of kidney function (serum creatinine and eGFR). Urine collection over 24 h was used to measure urinary excretion of proteins (uProt) expressed as mg/die (or mg/24 h). Finally, information regarding ongoing antidiabetic , GLP1 receptor agonists (GLP1RA), thiazolidinedione, sulfonylureas), antihypertensive and nephroprotective therapy (ACE inhibitors (ACEi) and Angiotensin receptor blockers (ARB)) was collected.From the second outpatient visit onwards, laboratory data were retrospectively collected, with a focus on the values of uProt, eGFR, BMI and HbA1c.Proteinuria changes (both absolute and percentage) were calculated between baseline and post-treatment uProt levels. Patients were stratified into two subgroups based upon the response to the therapy with SGLT2i, namely the reduction in uProt of ≥30% from baseline levels. These two groups were called Responder (R) and non-Responder (nR).The aim of the study was to analyse differences in baseline characteristics between the two groups and to investigate the relationship between them and the proteinuria changes. Additionally, relationships between proteinuria changes and variations in other laboratory variables, both from a renal and diabetological point of view, were explored.p-value of <0.05 was considered statistically significant.The statistical analysis was performed with R Software (version 2022.07.01+554). Descriptive statistics were used to analyse differences between R and nR groups at baseline and at follow-up. Categorical variables were expressed as percentage; continuous variables were expressed as means ± standard deviation (parametric variables) or median and interquartile range (IQR) (nonparametric variables). The Kruskal–Wallis test and unpaired t-test were employed to test the differences between the means of the two groups in both skewed and symmetric variables. The Chi-squared test was used to test the difference of percentage (%) between the two groups. Linear regressions were utilized to analyse the relationship between proteinuria change (absolute change) and baseline characteristics in both univariate and multivariate analyses. Basal characteristics were included in the multivariate analysis by selecting “a priori” the most known variables associated with proteinuria . Linear regressions were also used to test the relationship between changes in proteinuria with eGFR and HbA1c variation, respectively. Finally, univariate and multivariate logistic regressions were conducted to analyse the association between baseline characteristics and changes in proteinuria among baseline and post-treatment visits. The sample size was determined based on the expected dimension, depending on the recruitment rate at the participating centre. A 2) and had a significantly higher uProt . Thus, R patients had a higher prevalence of diabetic retinopathy but a lower prevalence of history of CVD . There were no significant differences between the two groups in terms of BMI, blood pressure control, Hba1c levels or lipid panel. Approximately 90% of patients were in therapy with RAAS inhibitors titrated to the maximum tolerated dose, and there were no differences between the two groups. In terms of antidiabetic therapy, metformin was the most common drug followed by insulin, GLP1-RA and DPP4i. Each of these drugs was equally distributed between R and nR.A total of 58 patients were enrolled in the study: 32 patients (55.1%) were in the R group and 26 patients (44.9%) in the nR group. Baseline characteristics of the cohort population and the two groups are summarized in Dapagliflozin was the most common SGLT2i (60.3%), followed by Empagliflozin (19.0%), Canagliflozin (17.2%) and Ertugliflozin (3.4%), and there were no significant differences in the distribution of these molecules between R and nR.p < 0.001) and in the multivariate model . The graphic correlation between uProt and proteinuria reduction is shown in p = 0.016) and a significant negative correlation with BMI . No correlations with Hba1c levels and age at baseline were observed in either the univariate or the multivariate analyses.The results of univariate and multivariate linear regressions assessing the correlation between baseline characteristics of all patients in the study cohort and the variation in proteinuria after the initiation of SGLT2 inhibitors are summarized in p = 0.09 in univariate; OR 3.65, CI 0.97 to 13.58, p = 0.054 in multivariate). On the other hand, the presence of CVD at baseline is associated with lower odds of being in the R group . Neither of these statements reached statistical significance. The multivariate model is shown graphically in The results of the univariate and multivariate logistic regressions assessing the correlation between baseline comorbidities (CVD and diabetic retinopathy) and the response to treatment in terms of a reduction in proteinuria of more than 30% are summarized in p = 0.928). There were no significant differences in these variables between the two groups. However, we observed a significant difference (p = 0.017) in the ΔeGFR between the R and nR groups, with a decrease (−10.43%) in the R group and an increase (+2.31%) in the nR group. Additionally, we observed a trend toward statistical significance (p = 0.052) in the change of Hba1c values between the R and nR groups, with a decrease in the R group (−5.97%) and an increase in the nR group (+3.70%). Univariate linear regression analyses were used to test the correlation between changes in uProt and Hba1c, as well as between percentage changes in uProt and eGFR at follow-up (p = 0.059). However, there was a significant positive correlation between ΔuProt and ΔHba1c .ollow-up . There wIn recent years, several randomized controlled trials have investigated the nephroprotective effect of SGLT2i therapy, mainly in terms of risk reduction in renal-specific outcomes such as a reduction in eGFR, onset of end-stage kidney disease and death from renal causes ,18,19. Sp < 0.0001) in the CREDENCE trial and −35.1%  in people with T2DM in the DAPA-CKD trial. Our study population is comparable, with a mean value of urinary protein (uProt) of 1170 mg/24 h [In renal-specific RCTs such as DAPA-CKD and CREDENCE, the mean value of albuminuria, calculated as the urinary albumin-to-creatinine ratio (UACR), was 923 mg/g and 1017 mg/g, respectively, in people with T2DM receiving SGLT2i therapy. These studies demonstrated the antiproteinuric effect of these agents, with a mean reduction in albuminuria against a placebo of −31%  .p = 0.011) [p = 0.013), microalbuminuric −25%  and macroalbuminuric −32%  [p < 0.001) [On the other hand, another study included patients with both micro and macroalbuminuria (UACR ranging from 30 to 3500 mg/g), with a mean UACR value of 270 mg/g in the dapagliflozin group, and a mean reduction in albuminuria relative to the placebo of −21.0%  . In a po= 0.011) . Similar< 0.001) . As the 2 calculated by PAI clearance [It is well known that proteinuria is a common feature of diabetic nephropathy and DKD. These conditions are characterized by a phenomenon called glomerular hyperfiltration, which involves a supraphysiologic elevation in eGFR that is mainly induced by alterations in glucidic metabolism, systemic hypertension, obesity and vascular and tubular factors in the kidney ,30,31. Tlearance . The expIn this study, although statistical significance was not reached, a trend in terms of treatment response based on comorbidities was highlighted. In particular, diabetic retinopathy seems to be positively associated with a reduction in proteinuria, while CVD is negatively associated. DKD is characterized by a spectrum of phenotypes in which the most common one, the so-called ‘classical’ phenotype, is characterized by glomerular hyperfiltration, the onset and worsening of albuminuria and a subsequent decline in eGFR. Furthermore, a ‘non-proteinuric’ phenotype has been described as being characterized by the absence of macroalbuminuria but a progressive decline in eGFR . A retroThe results of the current study suggest that higher baseline proteinuria levels and the presence of retinopathy are associated with a greater reduction in proteinuria with SGLT2i treatment. Conversely, lower baseline proteinuria levels, the absence of retinopathy and the presence of CVD may indicate a non-proteinuric phenotype of DKD or other factors beyond DKD only, such as hypertension, atherosclerosis and obesity, where the antiproteinuric effect of SGLT2i may be less pronounced. Therefore, different clinical phenotypes of DKD may have different responses to SGLT2i treatment in terms of proteinuria reduction, with a stronger response in classical DKD. Further research is needed to confirm these findings and to investigate the potential impact of different DKD phenotypes on treatment response.Jongs and colleagues demonstrated a significant correlation between Hba1c levels at baseline and the albuminuria reduction. Nonetheless, people with T2DM had a higher reduction in albuminuria compared to those without T2DM, suggesting a glucose mediated effect in SGLT2i therapy. In the current study, there was no significant correlation between Hba1c levels and the response to treatment. In their post hoc analysis, Jongs and colleagues divided patients into two groups based on Hba1c levels being below or over 8.5% . In the Obesity is a common comorbidity in diabetic patients that can increasingly complicate kidney involvement in DKD. Nowadays, obesity and overweight are commonly acknowledged as risk factors not only for T2DM but also for CKD in people without T2DM . Thus, oOne last point of discussion may be that SGLT2 inhibitors have a greater effect on reducing proteinuria in patients with higher baseline values. Recent studies have demonstrated consistent nephroprotective effects across all levels of albuminuria . FurtherThe limitations of this study were the cohort population size and the retrospective analysis. Further studies are necessary which aim to investigate the relationship between baseline variables and proteinuria reduction with SGLT2i therapy.In conclusion, in the current real-life experience, after the administration of SGLT2i therapy in DKD patients, a reduction of more than 30% in proteinuria was observed in more than half of the patients. However, a significant percentage of patients do not adequately respond to SGLT2i therapy in terms of reducing proteinuria. Baseline proteinuria seems to be a reliable characteristic that can help predict the response to treatment before therapy initiation. eGFR and BMI are variables that, in association with proteinuria, can help predict treatment response. Anamnestic features, such as cardiovascular disease and baseline proteinuria, could be considered in patient assessment before starting SGLT2i therapy.Different phenotypes of DKD may have an impact in terms of antiproteinuric response. Patients with important antiproteinuric effects indeed presented increased levels of albuminuria at baseline and more frequently presented retinopathy. On the other hand, patients with lower baseline proteinuria and CVD presented a reduced antiproteinuric response to the drug. The long-term impact on kidney function of these different perspectives must be explored, but interestingly, a different pathogenetic pathway may present a different response to gliflozin.