Renal dysfunction occurs frequently in hospitalized patients with advanced chronic liver disease (ACLD)/cirrhosis and has profound prognostic implications. In ACLD patients with ascites, hepatorenal syndrome (HRS) may result from circulatory dysfunction that leads to reduced kidney perfusion and glomerular filtration rate . The traditional subclassification of HRS has recently been replaced by acute kidney injury (AKI) type of HRS (HRS-AKI) and non-AKI type of HRS (HRS-NAKI), replacing the terms “HRS type 1” and “HRS type 2”, respectively. Importantly, the concept of absolute serum creatinine (sCr) cutoffs for diagnosing HRS was partly abandoned and short term sCr dynamics now may suffice for AKI diagnosis, which facilitates early treatment initiation that may prevent the progression to HRS-AKI or increase the chances of AKI/HRS-AKI reversal. Recent randomized controlled trials have established (a) the efficacy of (long-term) albumin in the prevention of complications of ascites (including HRS-AKI), (b) the benefits of transjugular intrahepatic portosystemic shunt placement in patients with recurrent ascites, and (c) the superiority of terlipressin over noradrenaline for the treatment of HRS-AKI in the context of acute-on-chronic liver failure. This review article aims to summarize recent advances in the understanding and management of HRS. The deterioration of kidney function in patients with ACLD has been subdivided into acute kidney injury (AKI), chronic kidney disease (CKD), and hepatorenal syndrome (HRS). Whereas AKI and CKD may occur under similar circumstances as in the general population, HRS is considered a distinct feature of ACLD patients with ascites, is caused by a functional circulatory impairment that is not fully counterbalanced by compensatory mechanisms, and ultimately results in decreased glomerular filtration rate (GFR). In recent years, several definition criteria and (sub)classifications of renal impairment in ACLD have been proposed, mostly aiming to reduce the threshold for diagnosis and treatment. This review aims to provide an overview of the most recent classification of renal dysfunction in ACLD (with a particular focus on HRS), the state-of-the-art therapeutic management, and recent studies providing important implications for an optimized management of HRS.We screened the latest HRS guidelines of relevant societies, such as the International Club of Ascites (ICA) and the European Association for the Study of the Liver (EASL). Furthermore, a literature search on PubMed was performed by using the keywords “hepatorenal syndrome” and “HRS AND cirrhosis”, prioritizing randomized controlled trials (RCTs), meta-analyses, and observational studies relevant for the recent refinement and adaptions in the HRS definition. Importantly, we have put an emphasis on studies published after latest consensus statements and guidelines by the ICA (2015) and EASL (2018). We considered peer-reviewed studies in English and recently published abstracts from RCTs. Finally, we screened ClinicalTrials.gov for ongoing RCTs by using the search term “hepatorenal syndrome”.1. However, owing to its broad availability, sCr is still used to define and quantify kidney dysfunction in ACLD.The definition of renal impairment in ACLD has continually evolved during the past decades, usually reflecting the definitions used for acute or chronic kidney disease (or both) in the general population. These definitions rely mostly on serum creatinine (sCr) for the estimation of GFR considering the limitations of sCr as a biomarker in the setting of ACLD2. Further development of this classification  led to an additional definition criterion of AKI, namely an increase in sCr of 0.3 mg/dL within 48 hours3. This decision was based on multiple studies providing evidence for a significant impact of small short-term sCr increases on prognosis6. Finally, the AKI definition for the general population was refined as an sCr increase of 0.3 mg/dL within 48 hours, an sCr increase of 50% of baseline within 7 days, or urine output of less than 0.5 mL/kg per hour for more than 6 hours 7.First, the Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease (RIFLE) criteria  classified acute kidney dysfunction severity on the basis of sCr, GFR, or urine output (or a combination of these)8. The subsequent AKI definition based on AKIN criteria (see above) displayed improved prognostic accuracy for complications and mortality in multiple studies in patients with ACLD15 and thus was incorporated into ICA consensus recommendations (2015)16. Importantly, the ICA also suggested that baseline sCr values within the last 3 months may be considered if no baseline sCr within 7 days is available.The criteria and terminology for AKI and HRS in patients with ACLD have evolved over time. A first consensus agreement  defined acute renal failure as an sCr increase by 50% from baseline to an sCr of at least 1.5 mg/dL with sCr of less than 1.5 mg/dL and 1b with sCr of at least 1.5 mg/dL), (b) an sCr increase by 2- to 3-fold from baseline defines stage 2, and (c) an sCr increase at least 3-fold from baseline, an sCr value of at least 4 mg/dL in combination with an acute increase by at least 0.3 mg/dL, or initiation of renal replacement therapy (RRT) defines stage 316. Of note, owing to concerns that sodium retention17 and the frequent use of diuretics may interfere with this measure16, the ICA recommendations did not include reduced urine output as a criterion for defining AKI in ACLD. However, a panel of experts (2019) suggested that this criterion be reinstated in a recent position paper18 on the basis of subsequent findings that reduced urine output still has prognostic value19.Finally, three AKI stages with additional substages were defined: (a) an sCr increase of at least 0.3 mg/dL within 48 hours or sCr increase by 1.5- to 2-fold from baseline denotes stage 1 (stage 1a8. An update of the ICA criteria (2007) stated that active bacterial infection—in the absence of shock—is not an exclusion criterion for HRS diagnosis and recommended the use of albumin over saline for plasma expansion20. Both the old and more recent ICA consensus recommendations set common prerequisites for HRS: Cirrhosis with ascites, absence of shock, no current or recent intake of nephrotoxic drugs, and no evidence of structural kidney damage .The ICA (1996) defined HRS as a functional deterioration of kidney function characterized by pronounced circulatory dysfunction in patients with ACLD and portal hypertension. Type 1 was diagnosed in case of a 2-fold increase of sCr to at least 2.5 mg/dL or a decrease of creatinine clearance by 50% to less than 20 mL/min within 2 weeks. Conversely, cases of renal failure with an sCr of at least 1.5 mg/dL not meeting these criteria were named HRS type 216: HRS type 1 was renamed HRS-AKI, and both the time interval for kidney function deterioration (2 weeks) and the sCr cutoff (≥2.5 mg/dL) were abandoned. Kidney dysfunction criteria for HRS-AKI  were aligned with general AKI criteria: sCr increase of at least 0.3 mg/dL within 48 hours or sCr increase by at least 1.5-fold from baseline (sCr levels within 3 months eligible) to reach a final sCr of at least 1.5 mg/dL (corresponding to AKI 1b). Importantly, HRS diagnosis is contingent only upon lack of improvement in kidney function  within 48 hours after cessation of diuretics and volume expansion with albumin (1 g/kg per day up to a maximum of 100 g per day)18 r day)18 . The rev23. First, HRS-NAKI is defined by not meeting HRS-AKI criteria regarding the time course of sCr dynamics delineated above. Second, HRS-NAKI was further determined and subclassified by estimated GFR (eGFR) and the duration of kidney dysfunction on the basis of KDIGO criteria for CKD (2005)24: (a) an sCr increase of more than 50% or an eGFR of less than 60 mL/min per 1.73 m2 for less than 3 months was termed HRS-acute kidney disease (HRS-AKD), and (b) eGFR of less than 60 mL/min per 1.73 m2 for more than 3 months was defined as HRS-chronic kidney disease (HRS-CKD)23. Clinically, HRS-NAKI is typically associated with refractory ascites that is accompanied by gradual decreases in renal function; in contrast, the main clinical feature of HRS-AKI is acute renal failure.Moreover, HRS type 2 was renamed HRS-NAKI , a term endorsed by the EASL (2018) on the basis of the clinical experience that the traditional HRS type 2 comprised very heterogeneous entities or courses of kidney dysfunction23.Criteria for response to AKI treatment were stated within the latest ICA consensus as well as EASL clinical practice guidelines for decompensated cirrhosis and are widely accepted regardless of treatment regimens and presence of HRS: (a) “no response” is defined by the lack of AKI stage regression, (b) “partial response” is achieved by AKI stage regression, although sCr levels remain at least 0.3 mg/dL above baseline value, and (c) “full response” is determined by a return to sCr levels of less than 0.3 mg/dL above the baseline25. Consequently, it was hypothesized that peripheral arterial vasodilation promotes kidney dysfunction that cannot be counterbalanced by activation of the renin–angiotensin–aldosterone system (RAAS) and other compensatory mechanisms26. This assumption was supported by a study assessing systemic and hepatic hemodynamics in patients with ascites before and after HRS development, which found that patients with HRS exhibited increased heart rate but paradoxically decreased cardiac output (possibly indicative of cirrhotic cardiomyopathy27) as well as lower blood pressure while the hepatic venous pressure gradient (HVPG) was higher. Moreover, the RAAS and sympathetic nervous system were highly activated28. Glomerular pressure may be maintained to a certain point ; however, progression of ACLD and aggravation of hyperdynamic circulation or precipitating events such as infections (or both) aggravate systemic vasodilatation and may trigger (HRS-)AKI29.The role of circulatory dysfunction in development of HRS was proposed more than 30 years ago on the basis of the consideration that increased intrahepatic vascular tone promotes the release of vasodilating molecules which lead to splanchnic vasodilation , a patho30 and acutely decompensated31 patients. Similarly, SI-related kidney dysfunction is indicated by the high prevalence of systemic inflammatory response syndrome (SIRS) reported in ACLD patients with AKI33. Bacterial translocation from the gut is believed to promote SI in patients with ACLD on the basis of the pathophysiological concept that  increased exposure to pathogen-/danger-associated molecular patterns stimulates inflammatory responses within the liver and other organs (34.A considerable body of evidence supporting the impact of systemic inflammation (SI) on disease progression and development of extrahepatic organ—in particular, kidney dysfunction—in ACLD has accumulated in recent years. From a clinical perspective, two recent studies demonstrated the negative impact of SI on the course of ACLD in both stabler organs 34.35, whereas ACLD patients with SI-associated kidney injury exhibited increased renal TLR4 and caspase 3 gene expression, as well as urinary TLR4 secretion, as compared with patients without kidney dysfunction36. Recently, cytokine profiles were assessed in patients with acute decompensation (AD) who had no renal dysfunction, hypovolemia-associated  AKI, or HRS-AKI. The last group was characterized by significantly increased levels of different pro-inflammatory cytokines, such as interleukin-6 (IL-6), IL-8, tumor necrosis factor-alpha (TNF-α), vascular cell adhesion protein 1 (VCAM-1), fractalkine, and macrophage inflammatory protein-1 alpha (MIP-1α)37. Thus, an increasing number of studies point to the important direct impact of SI, which is also a central determinant of acute-on-chronic liver failure (ACLF)39, on HRS development.Accordingly, intestinal decontamination with norfloxacin decreased the expression of pro-inflammatory genes  in the kidneys of rats with cirrhosis29. Bile duct–ligated rats  exhibited tubular epithelial injury induced by toxic bile acids, which was ameliorated by treatment with norursodesoxycholic acid (NorUDCA)40. Importantly, further experimental evidence indicates that the efficacy of NorUDCA relates to the relative increase of hydrophilic bile acids, which may have properties that are less nephrotoxic41. Interestingly, clinical studies have linked increased serum bilirubin with non-response to albumin/terlipressin43. Accordingly, it has been speculated that hyperbilirubinemia might be indicative of an increased renal exposure to bile acids, thereby limiting the efficacy of conventional HRS therapies43. The clinical relevance of CN was further supported by a clinicopathological study in patients with extensive liver dysfunction and jaundice, reporting bile casts in 11 of 13 patients with a diagnosis of HRS44. That study also found a correlation between the presence of bile casts and higher serum bilirubin levels in the overall cohort44. However, that study neither provided reliable information on whether HRS was appropriately diagnosed in all patients (probably due to the retrospective study design) nor on HRS subtype44. Another study assessed kidney biopsies in patients with liver disease and either AKI or CKD and revealed that CN was exclusively found in patients with AKI, again being associated with serum and urinary bilirubin levels. Furthermore, the study suggested that loss of aquaporin 2 in collecting ducts was related to CN  and high bilirubin levels45. Nevertheless, as studies in humans were observational and performed in relatively small, heterogeneous, and highly selected patient populations because of considerable safety concerns related to kidney biopsy45, many open questions remain. For example, it is not clear whether CN is causally linked to either incidence or reversibility of HRS (or both).The concept of cholemic nephropathy (CN) is based primarily on experimental studies indicating that bile acids exert toxic effects on renal tubular cells and the observation that renal tubuli are obstructed by bile casts48. It has been hypothesized that this state is driven by constant bacterial translocation and SI, finally resulting in an inadequate synthesis of glucocorticoids29. Furthermore, Acevedo et al. demonstrated that patients with RAI exhibited lower mean arterial pressure (MAP), a trend of higher blood urea nitrogen at baseline, and increased risk of HRS type 1 46. In contrast, a recent study reported a similar MAP48. Both studies showed no significant differences in inflammatory cytokines between patients with RAI and those without RAI48. Of note, sCr levels at the time of the adrenocorticotropic hormone stimulation test were not significantly different in any of the studies mentioned above48. Thus, the available evidence is not sufficient to draw firm conclusions on whether RAI promotes or aggravates HRS and whether glucocorticoid therapy may exert positive effects in this setting.Relative adrenal insufficiency (RAI) was reported in up to 49% of patients with AD and ascites and seems to be linked to the incidence of infections (or sepsis), AKI-HRS, and mortality51; this was possibly due to a reduction of RAAS activation51. It has been suggested that bedside echocardiography may be useful for assessing volume status and the presence of IAH by measurement of inferior vena cava diameter (IVCD) and inferior vena cava collapsibility index (IVCCI): Those with an IVCD of less than 1.3 cm and IVCCI of more than 40% were reclassified as fluid-depleted, those with an IVCD of more than 2 cm and IVCCI of less than 40% were considered fluid-overloaded, while those with an IVCD of less than 1.3 cm and IVCCI of less than 40% were classified as having IAH. Accordingly, this assessment could guide therapeutic decisions on fluid therapy and the need for an additional LVP52.Furthermore, intra-abdominal hypertension (IAH) is believed to impact on HRS or AKI (or both) in patients with ascites. Previous studies in patients with tense ascites and HRS demonstrated that large-volume paracentesis (LVP) ameliorated IAH, which was paralleled by increases of creatinine clearance and cardiac output as well as decreases of systemic vascular resistance and renal resistive index53. Similarly, a publication from 1970 showed that impaired renal perfusion in cirrhotic patients with kidney dysfunction was caused by vasoconstriction, which disappeared post-mortem54. Of note, these studies were conducted before current diagnostic criteria of HRS were established. Nevertheless, more recent studies revealed that most patients with HRS exhibit sustainable improvement of renal function after liver transplantation (LT), which supports the concept of functional kidney impairment in HRS56.Current diagnostic criteria for HRS include the absence of structural kidney injury, meaning that risk factors for  or evidence of kidney damage  preclude the diagnosis of HRS-AKI. Of note, the paradigm of the absence of structural damage in patients with HRS has never been proven by biopsy-controlled studies. However, early studies indicated that HRS is caused primarily by functional renal failure: A study published in 1969 reported that kidneys from patients dying from “HRS” were successfully transplanted  in 6 of 7 organ recipients and achieved stable improvement (≥6 months) of renal function in 4 of 7 patients18. Various types of AKI—pre-renal AKI, post-renal AKI, HRS-AKI, and acute tubular necrosis (ATN-)AKI—should be considered in patients with ACLD , IL-18, liver-type fatty acid binding protein (L-FABP), albumin, and neutrophil gelatinase-associated lipocalin (NGAL) in patients with ATN-AKI59. NGAL performed particularly well for differentiating between ATN and other types of AKI (area-under-the-receiver operating characteristics [AUROCs] of at least 0.80)61. Interestingly, in a subsequent study by Huelin et al., NGAL displayed an even better diagnostic performance when assessed on day 3 (AUROC 0.87 vs. 0.80 on day 1)61. Nevertheless, about 10% of patients with prerenal AKI and HRS-AKI displayed NGAL levels above the proposed cutoff for identification of ATN, which may indicate that tubular damage occurs in these clinical entities as well61. Unfortunately, these and other studies were based only on clinical and laboratory discrimination for differential diagnosis of AKI (particularly relevant for ATN vs. HRS) while renal biopsies as the diagnostic gold standard were not performed. In this regard, the limited diagnostic performance of these markers could also be explained by the inherent limitations of the imperfect reference standards applied in these studies.Given the complex pathophysiology of HRS-AKI, nailing it down to one main pathogenetic factor is often challenging in clinical practice, where things are usually not just black or white but rather shades of grey; this unveils the difficulty of finding the most accurate diagnosis or treatment strategyith ACLD . Prerena22. The initial measures after diagnosis of AKI include removal of risk factors for kidney dysfunction, namely withdrawal of nephrotoxic drugs  and diuretics, treatment of infections, and fluid therapy depending on volume status (see above) and AKI grade  cessation of non-selective beta blocker (NSBB) treatment, as previous studies have reported an increased risk of AKI or HRS during circulatory stress in patients receiving NSBB therapy62, which is most likely related to its impact on cardiac output63. However, if the benefits still outweigh the potential risks in the individual patient, it seems that NSBB treatment can be safely reinitiated when AKI is resolved65.Because the latest definition criteria of HRS abandoned the mandatory requirement of an absolute sCr cutoff at 2.5 mg/dL, early diagnosis of and treatment uptake for (HRS-)AKI are now facilitated; this may lead to improved (HRS-)AKI reversal given that HRS reversal by vasoconstrictor treatment was contingent on sCr values at treatment initiation in previous studiesKI grade 29. Impor23. The differentiation between AKI 1a and 1b is supported by the observation that AKI 1a is caused by prerenal AKI in about half of patients (vs. 25–30% in AKI 1b), resolves in about 90% of patients (vs. about 50% in AKI 1b), and only rarely progresses to HRS-AKI (14% vs. 34% in AKI 1b)66.Besides removal of risk factors, AKI grade will determine the necessity and time point of plasma volume expansion with albumin. Current EASL clinical practice guidelines recommend that patients presenting with AKI 1b or higher receive albumin for two consecutive days (1 g/kg body weight up to a maximum of 100 g per day) . Convers23. The treatment rationale of albumin use was initially based on its beneficial hemodynamic effect on circulatory dysfunction because of its properties as a plasma expander; however, more recent studies also indicate that albumin modulates SI by binding and thus scavenging or inactivating pro-inflammatory molecules70. Furthermore, albumin improves the autoregulation of renal perfusion which may be attributed to a reduction of SI, oxidative stress, and endothelial activation71.In recent decades, evidence of the beneficial effects of albumin has accumulated in certain settings of ACLD. Albumin is currently indicated for the prevention of circulatory dysfunction after LVP, HRS prevention in patients with spontaneous bacterial peritonitis (SBP), and HRS diagnosis as well as therapy in combination with vasoconstrictors74. Of note, compared with other plasma expanders, albumin exhibited superior efficiency, indicating that additional biological properties of albumin may contribute to its therapeutic effects75. Similarly, an RCT showed that patients with SBP were less likely to develop renal impairment when receiving albumin on top of antibiotic therapy76, which was further supported by the randomized comparison between albumin and hydroxyethyl starch in patients with SBP, which also found that albumin improved markers of endothelial dysfunction and SI77. Importantly, prior studies in patients with HRS also displayed improved renal function upon albumin treatment51 and found that the use of albumin on top of vasoconstrictors improves the chances of HRS reversal78.The beneficial effect of albumin in the prevention of post-LVP circulatory dysfunction was established more than two decades ago, as studies demonstrated that renal function and RAAS activation were ameliorated (or at least stabilized) by albumin infusion79. A subsequent observational study in patients with refractory ascites found reduced mortality and hospitalization and a trend of a reduced HRS incidence80. Moreover, recently published data from two RCTs on short-term  and long-term (pilot PRECIOSA study of patients without infection) albumin treatment exhibited reductions of SI and circulatory dysfunction in patients with decompensated ACLD. Of note, in the pilot PRECIOSA study on long-term albumin therapy, this effect was restricted to the high-dose (1.5 g/kg body weight per week) group. Nevertheless, whereas these trials provided evidence for the long-term use of albumin in patients with ascites , another RCT comprising a placebo group reported a lack of efficacy of long-term low-dose (40 g/15 days) albumin therapy in more advanced patients: Albumin in combination with midodrine  failed to prevent complications  in patients awaiting LT81. The PRECIOSA study  will provide further insights into the efficacy of different pre-emptive albumin administration regimens.Recently, several RCTs have evaluated the effects of pre-emptive long-term albumin administration. The ANSWER study (not placebo-controlled) has investigated the effects of weekly albumin infusion (40 g twice weekly for 2 weeks followed by 40 g per week) for 18 months in patients with uncomplicated ascites and revealed that patients receiving albumin exhibited better ascites control , a decreased risk of renal dysfunction (HR of 0.50), and particularly HRS-AKI incidence (HR of 0.39). Finally, these effects translated into reduced mortality (HR of 0.62)82. Furthermore, the INFECIR-1/-2 an ALB-CIRINF trials  found no significant impact on kidney dysfunction85. Moreover, the ALB-CIRINF study and the ATTIRE trial reported increased occurrence of pulmonary edema (putatively associated with volume overload) in the albumin groups, indicating that the indiscriminate short-term use of albumin not only may lack therapeutic benefit but also may lead to adverse events83.In contrast, the results from the ATTIRE RCT  were recently published and indicated no beneficial effect of albumin on the primary endpoint Because these studies are (or were) conducted in distinct patient populations and provided divergent results, the identification of those who benefit most from pre-emptive albumin treatment is crucial for treatment individualization and optimization of resource allocation. Because the therapeutic effect of albumin seemed to differ between the ANSWER and the ATTIRE studies, which addressed different patient groups, pre-emptive albumin treatment may be effective only within a certain therapeutic window and in distinct clinical settings. Furthermore, high doses of albumin seemed to be required to obtain a clinical benefit.87. Terlipressin (which has yet to be approved in the US) is the first-line treatment recommended by EASL; however, noradrenaline, as well as midodrine in combination with octreotide, has also shown some efficacy for HRS therapy29.Vasoactive drugs are the other cornerstone of HRS therapy, as these pharmacological agents reduce splanchnic pooling and increase the effectively circulating blood volume and thus may improve renal perfusion . Multiple studies, including RCTs, have confirmed the efficacy of vasoconstrictors for HRS-AKI therapy89. Accordingly, terlipressin decreases HVPG while raising MAP. Noradrenaline and midodrine increase the vascular tone and thus MAP (and possibly HVPG) by activating α1-adrenergic receptors. However, whereas noradrenalin and terlipressin are potent vasopressors, midodrine achieves only modest increases in MAP. Octreotide is a somatostatin analogue and thus promotes splanchnic vasoconstriction29, thereby decreasing HVPG.Although all these drugs are vasoconstrictors, they have distinct properties that might relate to differences in efficacy: Terlipressin is a vasopressin analogue and exerts systemic and splanchnic vasoconstriction via vasopressin 1A receptor activation, while agonism at vasopressin 1B receptors activates the adrenocorticotropic hormone–cortisol axis which may be relevant for HRS because of the amelioration of RAI90 as well as the lower required dose and a favorable side effect profile91, continuous infusion  should be preferred92. Of note, the recommended initial dosing regimen of continuous terlipressin infusion23 is based mostly on the study design of the trial by Cavallin et al.91 and may need further refinement in the future. Noradrenaline is administered by continuous infusion and requires a central venous catheter. Octreotide is usually administered subcutaneously every 8 hours or as a continuous infusion, whereas midodrine is given orally.Of note, terlipressin may be given by intravenous boluses, but owing to its stability at room temperature94. Therefore, this review will focus on relevant advances regarding studies on terlipressin and noradrenaline.Several studies have indicated that the efficacy of midodrine in combination with octreotide for HRS therapy is inferior to that of other vasoconstrictors98. For HRS-AKI, noradrenaline has exhibited an efficacy similar to that of terlipressin in several (non)randomized and (non)controlled trials; however, available trials were likely underpowered to confidently establish the non-inferiority (or possibly even superiority) of noradrenaline101. Efforts to combine available trials in meta-analyses were unable to provide clear evidence in the comparison between terlipressin and noradrenalin  and this was due primarily to trial design differences that limited the interpretability of comparisons102. Importantly, predictors of non-response to HRS therapy include sCr levels22, high model for end-stage liver disease (MELD) score, sepsis98, and ACLF severity103. Thus, differences in patient selection directly impact on the efficacy of HRS therapy, which further limits between-study comparisons. Therefore, the harmonization of study design and proper sample size seems crucial for future trials.Multiple (non)randomized and (non)controlled trials have demonstrated the efficacy of terlipressin on HRS during the last two decades97. Of note, sCr significantly decreased in the terlipressin group; in general, achieving an sCr decrease was associated with improved outcomes. HRS-AKI was defined by the old ICA criteria  in that study97. However, one post-hoc analysis and one meta-analysis considering patients from this trial reported that patients receiving terlipressin had higher chances of HRS reversal105. More specifically, the post-hoc analysis by Wong et al. reported that patients with SIRS were significantly more likely to achieve HRS reversal when they received terlipressin (32% vs. 3% receiving placebo)104. The results of the CONFIRM trial (RCT comparing terlipressin vs. placebo) comprising a considerably higher number of patients, as compared to previous studies, were recently published and clearly established the efficacy of terlipressin on reversal of HRS type 1 (32% vs. 17% in placebo group). Of note, the old ICA criteria20 (sCr cut-off of 2.25 instead of of 2.5 mg/dL) were applied in that study, probably delaying treatment initiation106. However, that study found no difference in overall and transplant-free survival (about 50% in both groups) after 90 days, underlining the paramount importance of liver transplantation to improve outcomes beyond kidney function. Respiratory failure tended to be more common in the terlipressin arm, as did death due to respiratory failure, which may be explained by the development of pulmonary edema due to increases in afterload. Importantly, the risk of this potentially lethal complication may be reduced by continuous infusion91.Recent RCTs have confirmed the dilemma that different patient populations and HRS definitions may complicate interpretability of study results: The REVERSE trial did not detect a significant benefit by terlipressin on HRS reversal et al. directly compared terlipressin with noradrenaline in patients with HRS-AKI and ACLF107. Terlipressin exhibited superior efficacy over noradrenaline in HRS reversal , reduced the need for RRT (57% vs. 80%), and ameliorated prognosis . Importantly, that study used most recent AKI staging and treatment response criteria of the ICA and EASL107 and may represent one of the first RCTs with an adequate sample size to support the rationale for abandoning absolute sCr values and 2 weeks latency for HRS diagnosis . Moreover, it seems that terlipressin is particularly effective in the context of SIRS/ACLF and should be preferred over noradrenaline in this setting.Finally, a recent RCT by Arora 108, antibiotic prophylaxis may display beneficial effects on HRS. Consequently, an RCT by Fernández et al. showed that in selected patients with ascites at high risk for SBP, primary prophylaxis with norfloxacin reduced the risk of HRS (28% vs. 41% in the placebo group)109. The protective effect on HRS development was not confirmed by the NORFLOCIR study (RCT norfloxacin vs. placebo in patients with Child–Pugh stage C)110. However, the results of that study should be interpreted with caution, as it was not powered to evaluate this endpoint and included a high proportion of patients with severe alcoholic hepatitis. Moreover, a broadening of the prophylactic use of antibiotics is controversial because of the potential emergence of antibiotic resistance, although the global study initiated by the ICA did not observe an association between prophylactic quinolone use and infections with multidrug-resistant bacteria111. Finally, results of the LIVERHOPE efficacy trial  are awaited, as they may provide further insights into the efficacy of poorly adsorbable antibiotics for preventing HRS development in patients with decompensated ACLD.Given the pathophysiological concept of the impact of SI on kidney dysfunction in ACLD and the close association between AKI and SBP112. Given that minor reductions of portal pressure by medical therapies translate into reduced risks of developing refractory ascites and HRS114, transjugular intrahepatic portosystemic shunt (TIPS) implantation may prevent the development of HRS-(N)AKI112. TIPS placement exerted beneficial effects on RAAS and sympathetic activity115 and significantly reduced HRS incidence in patients with refractory ascites 116 and thus is an interesting treatment option to prevent and treat HRS-NAKI , which typically is associated with recurrent or refractory ascites117. In this regard, a comparison of the results of the most recent RCT118 with earlier studies indicates that TIPS may be particularly effective  if placed in patients with recurrent  rather than refractory ascites as defined by ICA criteria112. Moreover, a small observational study reported that patients with HRS-AKI  receiving TIPS displayed increased GFR and urinary sodium excretion119. Nevertheless, further and larger trials are warranted to consolidate the efficacy of covered TIPS grafts for prevention and treatment of renal dysfunction and to weigh these potential beneficial effects against adverse events such as hepatic encephalopathy. The use of small-diameter or underdilated covered controlled expansion stents may prove useful in this regard121, as recent non-randomized studies showed a reduced incidence of hepatic encephalopathy and similar efficacy for ascites control and prevention of variceal bleeding123.Patients with ascites are at risk of developing SBP or HRS-(N)AKI or both; thus, interventions targeting incidence of ascites or ascites control will likely ameliorate these downstream complications124 on the basis of the observation that RRT for HRS-AKI does not improve the prognosis125, and patients with renal failure and/or RRT who were either not listed or not transplanted exhibited exceedingly high (85–95%) short- and mid-term mortality rates128. A large study comprising more than 2,000 patients found that only 9% of patients on RRT before LT developed a need for chronic dialysis within 6 months55. Importantly, Piano et al. recently reported that LT waitlist patients with HRS-AKI responding to terlipressin and albumin exhibited a lower risk of requiring RRT and developing CKD after LT129. In contrast, patients with HRS-NAKI responding to terlipressin (61%) displayed high relapse rates after cessation of treatment  and no significantly improved kidney outcomes post-LT130. Again, these data underline the clinical diversity between HRS-AKI und HRS-NAKI and point to early and consequent identification of HRS subtype and the importance of individualized treatment strategies.RRT is considered merely a bridging treatment to LT23. Previous studies have identified risk factors for persistent renal dysfunction after LT, including the need for and duration of RRT and time period of AKI before LT as well as age and diabetes131. According to current recommendations, SLKT should be considered if patients (a) have AKI stage 3, (b) exhibit an eGFR of not more than 35 mL/min or GFR of not more than 25 mL/min , or (c) require RRT or a combination of these factors. More specifically, these three scenarios  should last for more than 4 weeks, counted from the onset of any of these criteria132. Sequential transplantation of liver and kidney  in patients with HRS was discussed as a potential strategy to avoid futile kidney transplantations in patients who would recover from LT alone and thus optimize organ utilization133. However, this proposal is based primarily on retrospective studies that did not systematically address (or even exclude134) patients with HRS; this underlines that more reliable studies on patient selection are warranted.Since both HRS-AKI and HRS-NAKI mostly resolve after LT, simultaneous liver and kidney transplantation (SLKT) remains disputed in the context of HRSRecent changes in the definition and diagnosis of HRS have facilitated early recognition and treatment initiation, which may result in better chances of reversal and survival of HRS-AKI. Albumin in combination with vasoconstrictor therapy remains the medical cornerstone therapy of HRS-AKI. Recent data suggest that terlipressin should be preferred over noradrenaline for treatment of HRS-AKI in the context of ACLF. Nevertheless, mortality of patients with HRS remains high, indicating that prevention of HRS and associated pathomechanisms—such as bacterial translocation and SI—should be the focus of further research. To this end, development of pathophysiology-related biomarkers and disease-modifying HRS treatments targeting SI or hyperdynamic circulation (or both) are urgently needed.ACLD, advanced chronic liver disease; ACLF, acute-on-chronic liver failure; AD, acute decompensation; AKI, acute kidney injury; AKIN, Acute Kidney Injury Network; ATN, acute tubular necrosis; AUROC, area-under-the-receiver operating characteristic; CKD, chronic kidney disease; CN, cholemic nephropathy; EASL, European Association for the Study of the Liver; eGFR, estimated glomerular filtration rate; FeNa, fractional urinary sodium excretion; GFR, glomerular filtration rate; HR, hazard ratio; HRS, hepatorenal syndrome; HVPG, hepatic venous pressure gradient; IAH, intra-abdominal hypertension; ICA, International Club of Ascites; IL, interleukin; IVCCI, inferior vena cava collapsibility index; IVCD, inferior vena cava diameter; KDIGO, Kidney Disease: Improving Global Outcomes; LT, liver transplantation; LVP, large-volume paracentesis; MAP, mean arterial pressure; NAKI, non-acute kidney injury; NGAL, neutrophil gelatinase-associated lipocalin; NorUDCA, norursodesoxycholic acid; NSBB, non-selective beta blocker; RAAS, renin–angiotensin–aldosterone system; RAI, relative adrenal insufficiency; RCT, randomized controlled trial; RRT, renal replacement therapy; SBP, spontaneous bacterial peritonitis; sCr, serum creatinine; SI, systemic inflammation; SIRS, systemic inflammatory response syndrome; SLKT, simultaneous liver and kidney transplantation; TIPS, transjugular intrahepatic portosystemic shunt; TLR4, Toll-like receptor 4


Glomerular hyperfiltration, initiating development of obesity-related glomerulopathy, results in an enlargement of the glomeruli and unsealing of the filtration barrier. It can be followed by adaptive focal segmental glomerulosclerosis and chronic kidney disease (CKD). The aim of the study was to determine the expression pattern of lipid metabolism and selected kidney damage markers in obese adolescents and to identify potential factors which can predict CKD.z-score > 2. Sixty-two healthy and normal-weight individuals served as controls. The factors associated with the rate of glomerular filtration in obese adolescents were assessed by linear regression methods using univariate and multivariate analyses. The risk of developing CKD was estimated using the Fisher’s exact test.The study group consisted of 142 adolescents with a BMI The study group was divided into “elevated,” “normal,” and “decreased” glomerular filtration rate (GFR) patients. Increased urine galectin-3  concentration was diagnosed in all patients. “Decreased GFR” subjects expressed increased urine concentration of neutrophil gelatinase-associated lipocalin (NGAL) and daily megalin excretion. Thirty-nine study participants developed CKD. Increased uric acid (UA) concentration was associated with CKD development both in “normal” and “decreased GFR” patients. Additionally, in “normal” GFR patients, increased concentrations of cholesterol (Ch), triglycerides (TG), and NGAL were associated with CKD.Increased serum concentrations of Ch, TG, and UA and increased urine concentration of NGAL might predict CKD development in obese adolescents with normal and decreased GFR.A higher resolution version of the Graphical abstract is available as Supplementary informationThe online version contains supplementary material available at 10.1007/s00467-021-05403-2. Recent decades have revealed a significant change in the eating behavior and lifestyle of adolescents. These changes are mainly observed in the increasing consumption of high-calorie foods and sweet drinks, as well as in a more sedentary lifestyle and a significant lack of exercise . The lasAs a consequence, the steadily increasing global prevalence of overweight and obesity has reached epidemic proportions . It is fObesity is a well-established low-grade inflammatory state reflected by the presence of circulating endocrine bioactive proinflammatory compounds and accompanied by reduced levels of anti-inflammatory adipokines . The incIn animal models of ORG (Fisher rats ad libitum feeding), glomerulomegaly is followed by increasing cellular volume of podocytes, although at a lower rate than the increase in the volume of glomerular tuft . As the The process of kidney damage in obese people is, however, more complex. The visceral adipose tissue may release into the circulation nonesterified fatty acids which can be accumulated in the liver, heart and kidneys . In the The actual incidence of ORG is unknown. This is due to the fact that the undisputed diagnosis of ORG can only be made on the basis of a kidney biopsy (and these are performed less and less frequently) . MoreoveMany attempts have been made to indicate the marker(s) of ORG progression. These include microalbuminuria , researcGalectin-3 —a β-galactoside-binding lectin—has been shown to be involved in a number of biological processes including cell adhesion and activation , chemoatThere are very few reports of Gal-3 in urine. Primarily its presence and clinical significance are described in blood serum. It is regarded as a sensitive diagnostic or prognostic biomarker for various pathological conditions including heart failure and cardiovascular diseases, oxidative stress, inflammation, and autoimmunity , 25–27. Determine the expression pattern of lipid metabolism as well as kidney function markers  in obese adolescents with normal, increased, and decreased glomerular filtration rate (GFR).Identify markers that may indicate an increased risk of developing CKD in obese adolescents.In line with the above, the aim of the current report was to:The protocol of the present study was approved by the Poznan University of Medical Sciences Local Bioethics Committee (resolution No 679/17). All investigations have been carried out in accordance with the Helsinki Declaration. The study participants and/or their legal guardians have given their written consent to participate in the study. Finally, the study has followed the standards of Good Clinical Practice.The study was conducted between 1 January 2018 and 30 June 2021 and involved 458 patients (recruited between 1 January 2018 and 31 December 2020), admitted to the Department of Pediatric Nephrology and Hypertension, Poznan University of Medical Sciences because of suspicion of arterial hypertension (single rise in blood pressure recorded by the school nurse). All subjects were hospitalized to perform 24 h arterial blood pressure monitoring (ABPM), echocardiography (ECHO), electrocardiography, and to perform laboratory tests: peripheral blood morphology , serum creatinine, cystatin C, uric acid, urea, Na, K, Ca, Mg, total cholesterol, triglycerides, HDL, fasting glucose, TSH, fT3, fT4, liver enzymes , total protein, C-reactive protein (CRP), adiponectin as well as 24 h urine for albumin, Gal-3, megalin, NGAL, MMPs and TIMPs.As many as 224 subjects were not admitted to the study, as at least one of the following criteria was present: (1) age < 10 years or ≥ 16 years; (2) arterial hypertension; (3) genetic obesity or familial hyperlipidemia; (4) any aberrations in ECHO and electrocardiography; (5) hepatic dysfunction ; (6) autoimmune disease; (7) diabetes; (8) coexistence of neoplastic and/or any infectious disease; (9) morphological abnormalities in the urinary tract system; (10) renal hypotrophy (or a single kidney); (11) CKD; (12) kidney failure; (13) any complications of the perinatal period (including intrauterine growth restriction); (14) birth before the age of 36 weeks; (15) history of chronic disease; (16) history of oral contraceptive, antihypertensive, antidiabetic or lipid-lowering drugs as well as corticosteroids use; or (17) unsigned informed consent.Arterial hypertension, according to the guidelines of the European Society of Hypertension , for teez-score ≤ 2; (3) no arterial hypertension; (4) normal concentration of serum cortisol, glucose, thyroid hormones, and electrolytes; (5) no morphological abnormalities in the urinary tract system ; (6) GFR range between 90 and 130 ml/min/1.73m2; (7) absence of any chronic comorbidities; and (8) signed informed consent.One hundred and forty-two adolescents were allocated for the study group. Sixty-two served as control subjects who met the following inclusion criteria: (1) age 10–16 years; (2) BMI z-score > 2; (3) no arterial hypertension; and (4) signed informed consent.Patients enrolled in the study group had to meet the following inclusion criteria: (1) age 10–16 years; (2) BMI p < 0.05 level. The clinical and biochemical data in study subjects are summarized in Table With our available sample size, this study had 85% power for comparison of means in independent samples at the z-scores using WHO reference values for pediatric BMI [Weight and height were measured using a certified columnar scale  with BMI function. BMI values were transformed into BMI tric BMI .2/3 × H (m)1/2]  . It was pulation .A 5 ml whole blood was taken from all fasting adolescents in the morning between 7:00 and 8:00, after all-night rest on the first day of hospitalization. Half of the total blood was used for routine laboratory tests in all patients, and the rest of the blood sample was centrifuged. Serum with added BHT (10 ul 0.5 M BHT/1 ml sample) was frozen at – 80 °C and preserved for further analyses.Laboratory tests in all patients also included first morning urinalysis and 24-h urine collection . The 24-h urine amount was measured after thorough mixing. 10 ml of each urine sample was then centrifuged within 2 h after collection at 1,000 rpm for 10 min to remove cellular debris. The cleaned urine samples were stored at − 72 °C until next measurement.2. In contrast, a reduced GFR (hypofiltration) was defined as GFR < 90 ml/min/1.73 m2 [GFR was assessed by Filler formula involving serum cystatin C concentration, instead of plasma creatinine , 33. Hyp/1.73 m2 .2 for a period of at least 3 months [CKD was defined as kidney damage or GFR lower than 60 ml/min/1.73 m3 months .Daily megalin excretion was estimated using Human LRP2/Megalin ELISA assay . The concentrations of NGAL, Gal-3, MMP12, and TIMP2 were estimated using Human Lipocalin-2/NGAL Quantikine ELISA Kit , Human LGALS3/Galectin-3 ELISA Kit , Human MMP-12 ELISA Kit , and TIM2 Human ELISA Kit , respectively.Finally, serum adiponectin concentration was assessed with the use of Human Adiponectin ELISA kit .All samples from patients and controls were run in duplicate. The assays were performed according to the manufacturer’s instructions. The optical density (OD) value was determined twice, using a microplate reader, set to 450 nm and 540 nm as a wavelength correction. The readings at 540 nm were subtracted from the readings at 450 nm to correct for optical imperfections in the plate. The concentrations of NGAL, Gal-3, MMP12, TIMP2, and adiponectin were calculated based on the standard curve. These standards were also assayed in duplicate.2 test was employed to analyze nominal data.All continuous variables are expressed as the mean ± SD. Statistical analysis was performed through the following steps: (1) Shapiro–Wilk test was used to determine the normal distribution of data; (2) one-way analysis of variance was employed to compare “elevated GFR,” “normal GFR,” and “decreased GFR” study subjects and controls; (3) Bonferroni correction was used as a general alpha adjustment for all of the multiple comparisons performed in the study; (4) non-parametric continuous variables were compared using the Kruskal–Wallis test; and (5) Pearson χr greater than 0.7 was considered a strong correlation. Anything between 0.4 and 0.7 was a moderate correlation, and anything less than 0.4 was considered a weak or no correlation.The independent factors for CKD development were determined using Fisher’s exact test. Generally, in Pearson correlation, a value of The factors potentially affecting the rate of glomerular filtration in obese adolescents  were assessed using linear regression methods utilizing univariate and multivariate analyses. Regression coefficients (β) and 95% confidence interval (CI) for β were estimated for all linear models. The regression models were adjusted for age and sex.All of the statistical analyses were performed using the Statistica 13.3 PL software package . A value of p < 0.05 was considered statistically significant.z-score > 2), at the moment of entry into the analysis, were divided into “elevated GFR” (n = 42), “normal GFR” (n = 85), and “decreased GFR” (n = 15) according to GFR values estimated by Filler formula. As compared to controls, they presented albuminuria and had a significantly lower serum adiponectin concentration (p = 0.005) and higher urine Gal-3 concentration (p = 0.004). “Decreased GFR” obese adolescents (as compared to controls) have been additionally reported with significantly higher serum concentrations of uric acid (p = 0.004), triglycerides (p = 0.037), and cholesterol (p = 0.043) as well as significantly higher NGAL urine concentration and daily urine megalin excretion (p = 0.005).Obese study participants (BMI Obese and control adolescents did not differ in blood pressure (both office and during 24-h monitoring), peripheral blood morphology, and serum biochemical parameters .None of the examined adolescents had MMP12 in urine, and the concentrations of TIMP2 were comparable in all study participants. The clinical characteristics of all adolescents are summarized in Table As mentioned above, the group of obese adolescents was not homogeneous. It was composed of “elevated GFR,” “normal GFR,” and “decreased GFR” patients. Therefore, separate analyses were performed for each of the above-mentioned 3 subgroups.r = 0.528) and one moderate negative correlation between “urine galectin-3 concentration” and “serum adiponectin concentration.”In the “elevated GFR” obese study participants, we have noticed one moderate positive correlation between “urine galectin-3 concentration” and “albuminuria” (r = 0.706).The group of “normal GFR” obese patients had a strong correlation between “urine galectin-3 concentration” and “urine NGAL concentration” (r = 0.474), the next one between “urine NGAL concentration” and “urine megalin excretion” (r = 0.524), and the last one between “serum uric acid concentration and urine megalin excretion” (r = 0.511). These results are presented in Table In the “decreased GFR” obese adolescents, three positive moderate correlations were reported. The first one between “serum uric acid concentration” and “urine NGAL concentration” . Eleven of them were initially designated as “increased GFR” individuals (26.2%), 16 as “normal GFR” study participants (18.9%), and 12 initially recognized with decreased GFR (80%)."Elevated GFR" obese study participants, who developed CKD during the follow-up period, did not differ in peripheral blood morphology, serum creatinine, cystatin C, uric acid, urea, Na, K, Ca, Mg, total cholesterol, triglycerides, HDL, fasting glucose, TSH, fT3, fT4, liver enzymes, total protein, CRP, adiponectin as well as 24 h urine for albumin, Gal-3, megalin, NGAL, or TIMP2 values from their peers who did not develop CKD.n = 14; 87.5%), cholesterol , and triglycerides  as well as urine NGAL concentration , as compared to “normal GFR” obese adolescents who did not develop CKD.The majority of “normal GFR” obese study participants who developed CKD, were initially found with increased concentrations of serum uric acid  were found initially to have normal serum uric acid concentration (4.1 ± 0.3 mg/dL) as compared to their peers who developed CKD.Finally, “decreased GFR” obese adolescents who did not develop CKD within the observation period (p < 0.0001), serum triglycerides concentration (p = 0.0006), serum cholesterol concentration (p < 0.0001), and urine NGAL concentration (p = 0.0003), developed CKD over a follow-up period of 6 to 30 months. “Decreased GFR” obese study participants who continue to have normal values of serum uric acid concentration are at lower risk of CKD development (p = 0.0088).Using Fisher’s exact test, it was determined that “normal GFR” obese adolescents, who initially had elevated serum uric acid concentration , and, according to GFR value estimated by Filler formula, they were divided into “elevated GFR,” “normal GFR,” and “decreased GFR” subjects. As expected, all of the study participants had albuminuria and decreased serum concentrations of adiponectin. However, the indicators of dyslipidemia , as well as increased serum uric acid concentration, increased urine NGAL concentration, and increased megalin daily excretion, appeared only in “decreased GFR” adolescents. On the other hand, all of the study group participants  had increased urine Gal-3 concentrations.Our study group did not include adolescents diagnosed with hypertension. All of them were obese  correlations have also been shown between urine Gal-3 concentration and serum adiponectin and albuminuria (“elevated GFR” participants), as well as daily megalin excretion and NGAL urine concentration and serum uric acid concentration (“decreased GFR” subjects). These results suggest not only the key role of adiponectin in obesity-related kidney damage but also indicate megalin and NGAL as markers illustrating the progress of kidney injury in obese adolescents who have no arterial hypertension.z-score > 2 in children and adolescents corresponds to 97.7 percentile and indicates the risk of multiple organ damage, including kidney injury [z-score between 1 and 2); therefore, the weight loss and appropriate treatment should be initiated promptly. In numerous studies, introduction of angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers in obese patients with proteinuria or biopsy-proven ORG resulted in significant decrease of proteinuria [BMI y injury . These steinuria –16. Whatteinuria . For thiIn line with the above, the implementation of dietary treatment and the introduction of ACE inhibitors in obese adolescents should be adapted to appropriate stage of disease defined not only by GFR and albuminuria, but also by the increased concentrations of urine Gal-3 and NGAL, daily megalin excretion, as well as increased serum uric acid concentration.Several limitations must be mentioned when discussing the results of the present study. First, it is a single-center study, so our cohort of 142 obese adolescents is not representative of the overall national population. Moreover, the participants were not randomly selected. Simply, all study subjects who met inclusion criteria were involved in the study protocol. Third, our study uses data that were collected two years ago and thus might not precisely reflect the current epidemiological situation.None of the study participants had a kidney biopsy. For this reason, we were unable to recognize ORG despite the presence of subnephrotic albuminuria in any of them. This means that potential kidney remodeling in obese adolescents (which we described as obesity-related kidney damage) could only be identified indirectly.We also present a relatively short observation period. Thus, we do not know how many patients would eventually develop CKD and kidney failure. The size of the “decreased GFR” obese adolescents group is relatively small, so it is difficult to draw an unambiguous conclusion that the normal concentration of uric acid may have a protective effect on the development of CKD.Supplementary file1 (DOCX 31 KB)Supplementary file2 (DOCX 31 KB)Supplementary file3(PPTX 76.3 KB)Below is the link to the electronic supplementary material.


The arboviruses that cause disease in humans are members of five viral families: Bunyaviridae, Togaviridae, Flaviviridae, Reoviridae, and Rhabdoviridae.Dengue virus is an arbovirus of the Flavivirus genus, belonging to the Flaviviridae family. Flaviviruses are single-stranded RNA-encapsulated viruses that use different membrane mediators to penetrate the cell, where in the cytoplasm they use the JAK-Stat complex for viral replication. This group of pathogens is characterized by having immature, mature and not very mature virions in coexistence, facilitating infectivity. In the immunocompetent host, the response to viral infection depends on the release of alpha, beta and gamma interferons, corresponding to the initial phase of the innate immune response. This response is manifested by fever, inflammatory response and infection control within about seven days. In transplant recipients, immunosuppressants, especially calcineurin inhibitors, can limit this interleukin-mediated response, causing a lower frequency of fever. On the other hand, antiproliferative drugs may justify the higher frequency of bone marrow toxicity, especially leukopenia and thrombocytopenia, resulting in a longer hospital stay. Other signs of dengue, such as myalgia, arthralgia and erythema, may have their presentation distorted by the chronic use of steroids published in this issue of the BJN, attention is drawn to the clinical-laboratorial presentation of longer bone marrow toxicity, with more prolonged thrombocytopenia than in the general population, and a low frequency of fever. The frequency of acute kidney injury (AKI) was 58%, and although most dengue cases were moderate/severe cases , there was no mortality or kidney graft loss, with return to baseline renal function in most, but not all patients, during the study period. Nassin et al., in a Pakistani study with the largest number of kidney transplant recipients (Rx) with dengue ever published (102 patients), reported that in 14.3% of those with graft dysfunction, it persisted after six weeks of follow-up.In this case series by Ribeiro et al..AKI, which is frequent in cases of dengue in renal transplant patients, should be carefully evaluated, since the reduction in glomerular filtration may be a consequence of systemic hemodynamic imbalance, tissue damage by the virus, or acute rejection episodes, due to the immunomodulation induced by the viral infection or reduced immunosuppression in more severe viral conditions. In this series, there was no case of acute graft rejection. In another series of dengue in kidney transplant patients, the reported incidence of acute rejection was very low, and a recent systematic review on the subject pointed out that graft loss occurs infrequently, and it is usually not associated with renal rejection, but to other concurrent factors); in all RTx, the presence of fever and/or viral-like condition associated with cytopenia (leuko- or thrombocytopenia) should motivate the inclusion of dengue in the differential diagnosis; due to cytopenia, it may be necessary to reduce immunosuppression in a good number of cases; the treatment usually given to those affected in the general population  seems to prevent mortality and enable the recovery of renal function in transplant patients affected by dengue similar to those in this study.The paper by Ribeiro et al. adds considerable knowledge about the behavior and management of dengue infection in kidney transplanted patients who require hospitalization in our environment. The clinical and laboratorial workup, although with some peculiarities, is quite similar to that of the general population .A word of caution regarding the return of renal function to baseline in most transplant patients studied is the need for an individualized approach. RTx should be considered as patients with Chronic Kidney Disease (CKD) at different stages and who are at high risk of progression to dialysis and higher mortalityIn a series with more than 100,000 patients who had in-hospital AKI, , whom Heung et al., followed for one year after the acute episode, demonstrated that the risk of progression to stage 3 CKD increases with the severity of the episode, but the risk is already significantly increased even in patients who had mild elevations in serum creatinine levels which, returned to normal within two days: RR of 1.43 ., which is why for these - and for all patients, transplanted or not, who presented an episode of AKI - long-term follow-up is carried out so that, if necessary, there is prompt establishment of kidney and cardioprotective measures.The fact that a number of transplant recipients in this study already had elevated baseline serum creatinine may characterize some AKI episodes as acute-on-chronic kidney disease, where the trend towards progression to renal chronicity is even higher.The possibility of dengue transmission through kidney transplantation is well documented, but there is no specific guidance for screening for this virus in kidney donors, leaving the suggestion that, in kidney donors from very high prevalence regions, screening for the virus should be consideredSince Brazil is an endemic country for dengue infection and because the national series of dengue fever in patients undergoing transplants are relatively small, national multicenter studies on this topic would be highly desirable.


BackgroundAsthma exacerbations, defined as acute or subacute progressive worsening of airway spasm, are a significant cause of disease morbidity. Risk factors for exacerbation include sex, age, race, socioeconomic status, baseline lung function, smoking history, and exposure to respiratory viruses. It is believed that white cells play an essential role in the pathogenesis of such attacks; however, the current understanding of the relationship between cell lines during an asthma attack is minimal.MethodsThis report represents a retrospective study for patients admitted to ICU for asthma exacerbations. The Medical Information Mart for Intensive Care iii (MIMIC iii) version 1.4 database was used to identify patients admitted for asthma exacerbations. The demographics, laboratory data gathered in addition, to clinical variables and outcomes were determined.ResultsThe length of stay increased with the increase in WBC (p = 0.001). Intubated patients had an increased white blood cell (WBC) count when compared with non-intubated patients . In addition, patients with normal basophil counts on presentation were less likely to need intubation than those presenting with low basophils  and those presenting with basophilia . Furthermore, prolonged intubation (for three days or more) was positively correlated with eosinophil counts. On the other hand, there was no statistically significant association between the length of ICU and the patient's age, smoking status, or gender .ConclusionAsthma exacerbation is a disease of heterogeneous pathophysiology. The leukocyte count is associated with the length of stay and the need for mechanical ventilation.  Asthma is a chronic inflammatory disease of the airways. It is characterized by episodic airflow restriction and airway narrowing, representing an excessive airway response to various stimuli. Its pathophysiology involves genetic, epigenetic, and environmental factors leading to persistent inflammatory, functional, and structural airway changes. Exacerbations, defined as acute or subacute progressive worsening of asthma, are a significant cause of disease morbidity and are associated with a decline in pulmonary function . Risk faIt has been found that besides Th2 cells, other inflammatory cells play a role in the pathogenesis of asthma . StudiesThis study aims to compare the concentration of white blood cells in peripheral blood among patients admitted to the intensive care unit due to asthma exacerbations, as well as their respective inflammatory cell ratios, and describe their association with clinical outcomes.Study designThis report represents a retrospective study for patients admitted to the ICU for asthma exacerbations. The Medical Information Mart for Intensive Care iii (MIMIC iii) version 1.4 database was used to identify patients admitted for asthma exacerbations using the International Classification of Diseases, 9th Revision: 493.xx . The demStudy populationPatients were identified using the following inclusion criteria: asthma exacerbation medical code  and age 18 years or older . PatientStatistical analysisData analysis was performed using SPSS version 24.0 . Continuous and categorical variables were presented as mean ± standard deviation and frequency/percentages, respectively. Lab values were evaluated as continuous, ranges, and ratios. Normality plots were used to evaluate the distribution of continuous variables. Fischer's exact test, independent sample T-test, and ANOVA test were used to evaluate bivariate relationships. Linear and binary logistic regression models were fitted to evaluate the factors of ICU stay and intubation, respectively. To achieve normality of error terms, the ICU stay was square-rooted. Tests were interpreted at a significance level alpha = 0.05.PatientsIn total, data from 120 patients were included in the study. They were between 19 and 89 years old. The mean age at the time of admission was 45.5 ± 16.3 years. Overall, 88 (73.3%) of the participants were females, whereas 32 (26.7%) were males. In terms of race, 50 patients (41.7%) were Black, 46 (38.3%) were White, 11 (9.2%) were Hispanic, 3 (2.5%) were Asian, and the remaining patients were not categorized. Of the 120 patients, 77 (64.2%) were nonsmokers, and 42 (35%) were smokers. There were 65 (54.2%) who had a food or drug allergy, and 55 (45.8%) who had no history of allergy (Table Oxygen requirementsOxygen requirements during the ICU stay were as follows: 38 (31.7%) required no supplemental oxygen, 38 (31.7%) required oxygen therapy via a nasal cannula, 4 (3.3%) required a face mask, 10 (8.3%) required an NRM, and 11 9.2%) required therapy with NIV/Bipap. IMV was needed for 19 (15.8%) of the patients, and the mean intubation period was 0.6 ± 2 days. The mean ICU stay was 2.6 ± 2.9 days . In addition, prolonged intubation (for three or more days) was positively correlated with eosinophil counts  on presentation were less likely to need intubation than those presenting with low basophils  and those presenting with basophilia   p-value 0.178, lymphocytes (L) p-value 0.504, eosinophils (E) p-value 0.182, basophils (B) p-value 0.079, monocytes (M) p-value 0.686, N/L p-value 0.398, E/N p-value 0.2, and E/B p-value 0.2). No differences among races were noted concerning intubation , stay , and WBC counts .Regression analysis3 , smoking status , or gender . On the contrary, the length of stay increased with the increase in WBC, which was defined as a WBC of more than 11,000 cells/mmAsthma exacerbations are an exaggerated airway response to various environmental stimuli and are the primary cause of hospitalization in asthmatic patients. Those episodes can be severe and require medical intervention. Etiologies that trigger asthma exacerbation include respiratory infection, cigarette smoke, allergens, and pollutants .The pathogenesis of such attacks is complex; however, evidence suggests that the interaction between the innate immune response and the adaptive immunity microenvironment in the lung causes immune dysregulation and triggers an acute asthma attack . The innThe innate immune system interacts with antigens through a group of receptors called toll-like receptors (TLR). When a ligand is bound to the receptor, the latter binds adapter proteins that initiate signaling cascades, causing cytokine release and cell recruitment . Some stAs a part of the innate immune system, bronchial epithelial cells express TLR, CD40, and intercellular cell adhesion molecule-1 (ICAM-1) in addition to major histocompatibility complex (MHC), allowing them to present antigens to T cells and induce an inflammatory response in the presence of interferon-gamma (IFN-γ) . On the Th1 cells are mainly involved in intracellular pathogens elimination and are associated with autoimmunity. The primary role of IFN-γ is to enhance phagocytic abilities by activating phagocytes , while ITh2 cells play a critical role in fighting extracellular parasites and the initiation and persistence of asthma and other allergic diseases. IL4 is a principal cytokine involved in allergic reactions. It causes IgE secretion by B cells that bind to mast cells and basophils, leading to their degranulation and release of several active metabolites, consequently triggering an allergic reaction . IL4 alsTh17 cells are involved in immunity against extracellular microbes and have a role in the pathogenesis of autoimmune diseases . IL17 inAnother cell that presents a crucial regulatory element during an inflammatory response is the T regulatory (Treg) cell. After the clearance of pathogens, those cells negatively regulate the immune response to maintain immunologic tolerance to self and prevent immunopathology . IL10, TFor many years, it was considered that asthma is a Th2-type disease, where the inflammatory reaction driven by Th2 cytokines predominates over the Th1 cytokines. However, growing evidence suggests that both Th1 and Th2 responses have a role in asthma, and the disease represents a heterogenous result of multiple pathways rather than a homogeneous pathology . In addiSuch complex biological interactions between inflammatory pathways are expressed as variable clinical presentations. Eosinophilic asthma (EA) is a phenotype characterized by an elevated peripheral eosinophil count. It is classified as allergic or non-allergic asthma. The allergic subtype is IgE-mediated and has an early onset in life. Patients diagnosed with this subtype often have an atopic background.On the other hand, the non-allergic subtype is characterized by late-onset and non-elevated IgE levels. Patients with no peripheral eosinophilia are considered to have non-eosinophilic asthma (NEA). Such patients usually have severe diseases and are steroid-resistant . In thisThere is mounting evidence that leukocytosis predicts survival in different medical conditions, such as cancers . Jo et aLeukocytes and intubationPatients with severe asthma exacerbations usually respond to first and second-line therapies. However, about 30% of asthmatic patients admitted to the ICU do not respond to such therapies and require mechanical ventilation . The decIn this study, 19 patients (15.8%) were intubated for a mean duration of 0.6 days. Patients with leukocytosis on admission were more likely to require mechanical ventilation .During an allergic reaction, IgE binds to basophils, promoting their degranulation and release of histamines and leukotrienes, which contributes to airway smooth muscle contraction and anaphylaxis. In addition, basophils can be activated by cytokines. IL-3 induces basophils' development and activation and promotes the release of IL-4 and IL-6 from basophils in an IgE-independent manner . StudiesOn the other hand, studies have reported that blood eosinophil count is an important factor in predicting asthma exacerbation . Those cBronchial macrophages are primary sources of critical proinflammatory cytokines in asthmatic patients, including TNF-α, IL-1β, IL-6, and IL-8 ,44. The The MLR has been demonstrated as a marker in several medical field studies. It was reported as an independent prognostic factor for patients with advanced gastric cancer and hepatocellular carcinoma ,47. In tAsthma, gender, and raceAsthma is more severe in young boys; however, there is a gender switch at puberty, where the disease becomes more severe in females . ProgestIn this study, 73.3% of the patients admitted to the ICU were females. However, gender was not associated with the length of stay, oxygen requirements, or the need for intubation Tables , 5.Several studies have demonstrated racial differences in asthma-related morbidity. African Americans have a more significant risk of uncontrolled asthma, a lower likelihood of response to treatment, lower lung function, and a higher risk of asthma exacerbations . SocioecAsthma exacerbation is a heterogeneous pathology rather than a disease of a single entity. A peripheral white cell count has a role in predicting the length of hospital stay and the need for mechanical ventilation, where an increased leukocyte count is associated with invasive mechanical ventilation and an increased intensive care unit stay. In addition, patients with normal basophil counts are less likely to be intubated. Such results might help predict the outcomes of patients admitted to the intensive care unit with acute asthma exacerbation.


Postoperative acute kidney injury (AKI) is associated with poor clinical outcomes. Early identification of high-risk patients of developing postoperative AKI can optimize perioperative renal management and facilitate patient survival. The present study aims to develop and validate a nomogram to predict postoperative AKI after liver resection in older patients.n = 599) and validation  datasets. The training cohort was used to construct a predictive nomogram for postoperative AKI with the logistic regression model which was confirmed by a validation cohort. The model was evaluated by receiver operating characteristic (ROC) curve, calibration plot, and decision curve analysis in the validation cohort. A summary risk score was also constructed for identifying postoperative AKI patients.A retrospective observational study was conducted involving data from 843 older patients scheduled for liver resection at a single tertiary high caseload general hospital between 2012 and 2019. The data were randomly divided into training . The six predictors selected and assembled into the nomogram included age, preexisting chronic kidney disease (CKD), non-steroidal anti-inflammatory drugs (NSAIDs) usage, intraoperative hepatic inflow occlusion, blood loss, and transfusion. The predictive nomogram performed well in terms of discrimination with area under ROC curve (AUC) in training : 0.68–0.78) and validation  datasets. The nomogram was well-calibrated with the Hosmer-Lemeshow chi-square value of 9.68 (P = 0.47). Decision curve analysis demonstrated a significant clinical benefit. The summary risk score calculated as the sum of points from the six variables (one point for each variable) performed as well as the nomogram in identifying the risk of AKI .Postoperative AKI occurred in 155 (18.4%) patients and was highly associated with in-hospital mortality (5.2% vs. 0.7%, This nomogram and summary risk score accurately predicted postoperative AKI using six clinically accessible variables, with potential application in facilitating the optimized perioperative renal management in older patients undergoing liver resection.NCT04922866, retrospectively registered on clinicaltrials.gov on June 11, 2021.The online version contains supplementary material available at 10.1186/s12871-022-01566-z. Despite the recent technical advances in surgical procedures, there have been considerably high rates of operative mortality and morbidity resulting from complex surgical procedures, especially in emergency surgery cases . Among tIn the older population, however, the incidence of postoperative AKI is significantly higher as the filtration capacity of the kidney decreases about 1% every year after the age of 40, even in the healthy population , 12. MicGenerally, in-depth knowledge of risk factors and identification of high-risk populations, who are predisposed to develop AKI is urgently warranted as a preventive measure to minimize operative mortality rate and to design efficient therapeutic strategies. Efficient preventive measures to reduce the risk of AKI include precise assessment of renal functions, careful administration of nephrotoxic drugs, minimizing procedural injuries, and an effective intravenous fluid regimen. However, no validated model is currently available to predict the risk of postoperative AKI in older patients following liver resection surgery. Therefore, the present study aimed to establish and validate a predictive nomogram and a simple risk score assessment to identify the risk of developing postoperative AKI in older patients following liver resection. It would be of great clinical significance for clinicians to be able to predict whether a patient would need special attention for optimal renal management after hepatectomy surgery.Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) guidelines [This retrospective observational study was conducted using the dataset of inpatient surgeries in the First Medical Center of Chinese PLA General Hospital. The study design and data analysis were approved by the Institutional Committee for Medical Research Ethics  and registered at clinicaltrials.gov (identifier: NCT04922866). The requirement for written informed consent was waived for this retrospective study. This manuscript adheres to the idelines .− 1·1.73 m− 2, emergency operation, concurrent operation, laparoscopic operation, or liver transplantation surgery were excluded.Older patients (≥ 65 years) admitted to the hospital for elective hepatectomy between January 2012, and July 2019 were included in this cohort. While patients no more than 65 years old, preoperative baseline GFR < 15 ml·minData acquisition from the electronic medical record (EMR) system was performed using SQL Server . To facilitate the clinical use of predictors, we considered the inclusion of both preoperative and intraoperative parameters into the nomogram, which might closely affect renal function. From the patient record integrated management system , we extracted the relevant patient demographics, including age, sex, body mass index (BMI), combined hypertension, diabetes, cardiovascular and pulmonary diseases, CKD, American Society of Anesthesiologists physical score (ASA PS), and length of hospital stay. The prescribed medication regimen included non-steroidal anti-inflammatory drugs (NSAIDs), nephrotoxic antibiotics, glucocorticoids, and preoperative and intraoperative diuretics. Serum biomarkers included serum creatinine, albumin, bilirubin, hemoglobin, and fasting blood glucose. From the anesthesia information management systems , intraoperative data were retrieved, including types and duration of the surgical procedures performed and extent of liver resection, intraoperative hepatic inflow occlusion, blood pressure and infusion of vasoactive drugs, the requirement for intraoperative infusion and transfusion, and volumes of blood loss and urine output.− 1 within 48 h or a 1.5-fold increase from preoperative baseline within seven days after surgery, according to the Kidney Disease: Improving Global Outcomes (KDIGO) criterion [− 1·1.73 m− 2 for adults based on the CKD Epidemiology Collaboration (CKD-EPI) equation [The primary outcome was postoperative AKI, defined as an absolute increase in serum creatinine level of ≥26.5 μmol·lriterion . Baselinequation . Blood tContinuous variables were reported as medians with quartiles and compared using Wilcoxon rank-sum test as they were abnormally distributed checked by Skewness-Kurtosis All test. Categorical data were reported as frequencies and percentages and compared using the chi-squared test or Fisher’s exact test as appropriate.n = 599) and validation (n = 244) cohorts with a split ratio of 70 and 30% using randomization method. The training dataset was used to develop the prediction model in the final logistic regression. Firstly, a univariate analysis was performed using the Wilcoxon rank-sum test for continuous variables and the chi-squared test for categorical variables, with postoperative AKI as the outcome. Secondly, for the independent predictors included in the model, candidate variables that were clinically relevant to AKI and P-value less than 0.1 in univariate analysis were included in the multivariable model. Additionally, the number of outcome events was considered, that is, at least ten outcome events per variable (EPV) generally [The overall 843 patients were divided into training  curve. The model’s calibration was evaluated using the Hosmer-Lemeshow goodness of fit test. Finally, the decision curve analysis (DCA) was performed to reveal the net benefits with each threshold probability . StatistA total of 930 participants were screened for eligibility from January 2012 to July 2019. After the exclusion of 77 patients who undertook combined or multiple surgeries, 853 patients were selected with liver resection. Additionally, ten subjects with missing values were excluded, thus leaving behind 843 individuals who were enrolled in the final analysis   patients developed postoperative AKI. Patients who developed postoperative AKI were at a higher risk of death (5.2%) before discharge than those without AKI    of 0.73 : 0.68–0.78) and 0.71 (95% CI: 0.63–0.80) in the training and validation cohorts, respectively  among older populations, and associated with six-fold increased mortality rates compared with no occurrence of AKI, corroborating results from previous studies by Lim and Slankamenac , 22. TheSeveral prediction models for postoperative AKI have been developed in noncardiac surgeries , 22, 23.In this context, minimization of surgical trauma and bleeding were fundamental protective strategies for renal conservation and also equally crucial to restore liver function and minimize resection extent. Inflammatory responses to surgical stress and trauma lead to tubular injury and subsequent development of AKI, potentially due to microcirculatory dysfunction, oxidative stress, and endothelial cell injury . This grPrevious studies have suggested CKD as the most important patient-related risk factor . It was − 1·h− 1 was the optimal threshold for oliguria, nevertheless a moderate association and poor predictive value for postoperative AKI [Low central venous pressure (CVP) was required during the hepatectomy to reduce bleeding complications and mortality. Hughes has consolidated reduced blood loss and transfusion requirement by maintaining CVP below 5 mmHg, by intravenous fluid restriction, and by applying diuretics . At the tive AKI –36. Numetive AKI . In the There are some limitations in this study. First, the study aimed to evaluate the independent risk factors predicting postoperative AKI in older patients with liver resection. Therefore, the predictors involved were commonly available in clinical settings and did not include complex frailty and comorbidity index, which represent the risk associated with perioperative mortality. Second, although intraoperative factors affecting renal function were incorporated into the model, the target mean arterial pressure (MAP) during surgery and fluid management strategies were not available in this retrospective analysis, the surrogate indicators did not obviously increase the model’s predictive performance. This special attention will require further study and in combination with emerging biomarkers and novel oxygenation monitoring, clinical risk predictive models may aid in future investigations of effective prevention and treatment strategies. Third, data were derived from a retrospective single-center cohort. The reproducibility and generalization of the model in other populations are unknown. Before the model is implemented in clinical applications, it is essential to be externally validated in open, prospective multicenter studies.A nomogram and risk scoring system that accurately predicts postoperative AKI in older patients undergoing liver resection were established in this study. This model considered AKI based on six conveniently available variables in clinical conditions. It could provide guidance for both clinical decision-making and scheduling a tighter perioperative follow-up in AKI high-risk patients.Additional file 1. Patient characteristics and perioperative variables stratified by AKI. Notes: “Vasopressors” in vasoactive agents include ephedrine, epinephrine, dopamine, norepinephrine, and phenylephrine. “Vasodilators” in vasoactive agents include urapidil and nicardipine. Nephrotoxic antibiotics refers to aminoglycoside and sulfonamide antibiotics. Continuous data are shown as medians (quartiles) and compared using Wilcoxon rank-sum test. Categorical variables are shown as frequencies (percentages) and compared using chi-squared test or Fisher’s exact test as appropriate. Abbreviations: AKI, Acute kidney injury; ASA PS: American Society of Anesthesiologists physical score; BMI, Body mass index; CI, Confidential interval; CKD, Chronic kidney disease; eGFR, estimated glomerular filtration rate; LOS, Length of hospital stay; MAP, Mean arterial pressure; NSAIDs, Non-steroidal anti-inflammatory drugs; OR, Odds ratio.Additional file 2. Graphical representation of the regression model with confidence intervals. Abbreviations: NSAIDs, Non-steroidal anti-inflammatory drugs.Additional file 3. The online web-based calculator for predicting acute kidney injury among older patients with liver resection surgery. https://yuyao0505.shinyapps.io/DynNomapp. Abbreviations: CKD, Chronic kidney disease; NSAIDs, Non-steroidal anti-inflammatory drugs.Additional file 4. Predictors for AKI in multivariable logistic regression model including intraoperative diuretics, urine output, vasopressors, and fluid balance. Notes: “Vasopressors” in vasoactive agents include ephedrine, epinephrine, dopamine, norepinephrine, and phenylephrine. Abbreviations: CI, Confidential interval; CKD, Chronic kidney disease; NSAIDs, Non-steroidal anti-inflammatory drugs; OR, Odds ratio.Additional file 5. Summary risk score model and sensitivity/specificity values of the predictors for AKI. Abbreviations: AUC, Area under ROC curve; CKD, Chronic kidney disease; NSAIDs, Non-steroidal anti-inflammatory drugs; ROC, Receiver operating characteristic.Additional file 6. Sensitivity and specificity values of risk score model.


To evaluate the association between shear wave elastography parameters and arterialresistance in kidney transplant recipients.This was a prospective cross-sectional study involving consecutive adult kidney transplantrecipients. All patients underwent color Doppler to evaluate the resistive index (RI) andultrasound shear wave elastography for the quantification of renal allograft stiffness.p < 0.001), as was the mean shear wave velocity . Multivariate analysis identifiedtwo independent predictors of arterial resistance: age  and shear wave velocity .We evaluated 55 patients, of whom 9 (16.4%) had an RI defined as abnormal (≥ 0.79)and 46 (83.6%) had an RI defined as normal (< 0.79). The mean age was higher in theabnormal RI group than in the normal RI group (68.0 ± 8.6 years vs. 42.6 ± 14.1years; We observed an association between rigidity in the cortex of the transplanted kidney, asevaluated by shear wave elastography, and arterial resistance, as evaluated by color Doppler,in kidney transplant recipients. Worldwide, the incidence of end-stage renal disease in all age groupsincreased by 34.4% between 1990 and 2017(2). InBrazil, there were more than 10 million newly reported cases of chronic kidney disease, as wellas nearly 36,000 deaths related to the disease, in 2017. Due to its high cost, renal replacementtherapy is still of limited availability in many regions of the world. In contrast, kidneytransplantation is cost-effective, regardless of the donor type(3).Kidney transplantation is considered the procedure of choice for patients with end-stage renaldisease, prolonging survival and reducing costs(4). In addition, in an outpatient setting, renal allograft function isassessed by using a multimodal approach, including Doppler ultrasound examination, clinicalevaluation, and analysis of laboratory results. However, none of those tests alone is specificenough to detect incipient dysfunction of a renal allograft(5).Regarding the diagnosis of chronic nephropathy, renal biopsy remains the gold standardprocedure. Nonetheless, there are biopsy-related risks, such as chronic allograft injury, andthere is broad variation in interobserver agreement among pathologists6,7,8). Ultrasound hascertain advantages, including the fact that it is readily available at most imaging centers, aswell as having been proven safe and being a low-cost method. However, the usefulnessof the resistive index (RI) in predicting acute rejection is still under debate because of itslow diagnostic performance, which is due to the influence of extrarenal factors.Doppler ultrasound is currently the noninvasive method of choice for the evaluation ofpathological alterations in the kidneys and has been widely used in the assessment of renalallograft status((10).Ultrasound elastography has emerged as a tool to assist in the assessment of tissue stiffness,is already in use at major centers around the world, and has been the subject of a series ofrecent studies in the radiology literature of Brazil. Shear waveelastography (SWE) is the most effective noninvasive technique for assessing renal fibrosisafter transplantation(16) and assessing tissuevelocity in response to a low-frequency pulse, a low velocity being indicative of tissuestiffness(17). The use of SWE can revealsignificant differences between allograft stability and acute or chronic allograftdysfunction(16).Morphological imaging of the renal allograft is performed mainly by B-mode ultrasound,computed tomography, or magnetic resonance imaging. However, structural evaluation of the renalparenchyma continues to be a challengeTo our knowledge, there have been few studies evaluating the association between ultrasoundelastography and Doppler ultrasound in kidney transplant recipients, especially in Brazil.Therefore, the aim of this study was to evaluate the association between SWE parameters andarterial resistance in kidney transplant recipients in Brazil.(18).This was a prospective cross-sectional study. The study protocol was approved by the ResearchEthics Committee of the Pontifical Catholic University of Rio Grande do Sul (Reference no.93226218.2.0000.5336), in the city of Porto Alegre, RS, Brazil. All of the authors signed aconfidentiality agreement to ensure the anonymity of the data obtained from the electronicmedical records of the hospital, and all participating patients gave written informed consent.The study was conducted in accordance with the guidelines set forth in the Declaration ofHelsinki, and the article was prepared in accordance with The Strengthening the Reporting ofObservational Studies in Epidemiology statementThe study included consecutive adult kidney transplant recipients who were referred to anoutpatient nephrology clinic in southern Brazil for ultrasound imaging evaluation. Patients whohad stage V chronic kidney disease and were on dialysis were excluded, as were those who hadbeen diagnosed with hydronephrosis and those who were in their second or third trimester ofpregnancy.We collected demographic data  and clinical data . Allpatients underwent color Doppler to determine the RI and SWE for the assessment of renalallograft stiffness (quantification of the tissue elasticity). All ultrasound and SWE scans wereperformed by a board-certified radiologist, with eight years of experience, who was blinded tothe clinical and biochemical profiles of the patients.Ultrasound examinations were performed with a portable, stand-alone ultrasound system , a 3–5 MHz convex transducer, and a 5–14 MHzlinear transducer. All patients were examined in the supine position. The length of thetransplanted kidney was measured by B-mode ultrasound. Color Doppler was used in order toevaluate tissue perfusion and to calculate the RI for the transplanted kidney:Intrarenal Doppler of the segmental arteries was performed at three representative locations, and the19,20,21). The SWEmeasurements were obtained in a single region of interest (ROI): an area of renal parenchyma.The distance from the skin to the ROI was recorded as kidney depth. All patients were examinedbetween 8:00 a.m. and 10:00 a.m., on an empty stomach and in the supine position. The study wasconducted under controlled conditions. The ROI was positioned perpendicular to the surfaceclosest to the skin, with minimal compression of the transducer to avoid external compressionof the transplanted kidney, followed by activation of the tissue image quantification mode withthe acquisition of the shear wave velocity in the ROI, which was displayed on a color-codedmap. Thirteen quantification cursors were placed within the ROI in the renal cortex, eachproviding the values for shear wave velocity (in meters per second) and elasticity . The stiffness of the renal cortex of the transplanted kidney was calculated bydetermining the average values for the shear wave velocity and elasticity , a total width of 0.15, a two-sided type I errorof 0.05, and a power of 0.80, we calculated the sample size required to be 55 subjects (G *Power software version 3.1.9.2).Using the effect size estimated in the study conducted by Chiocchini et al.p < 0.05.The statistical analysis was performed with the Predictive Analytics Software package,version 18.0 . Quantitative variables are expressed as mean± standard deviation or as median (interquartile range [IQR]), whereas qualitativevariables are expressed as absolute and relative frequencies. For analysis purposes, patientswere categorized into two groups by renal RI: < 0.79  and ≥ 0.79. A multivariate analysis was performed by using binary logistic regressionwith generalized linear models to identify the independent variables associated with theDoppler RI. The level of significance was set at Between September 2018 and July 2019, 55 patients were enrolled in the study. The mean age was46,0 ± 16.4 years; 38 (69.1%) of the patients were male, and 44 (80%) self-identified asWhite. p < 0.001), as was the mean shear wave velocity . There were no significant differencesbetween the two groups regarding sex, race, estimated glomerular filtration rate, serumcreatinine, graft size, and kidney donor type. Multivariate analysis identified two independentpredictors of arterial resistance: age  and shear wave velocity .We identified a positive association between SWE parameters and arterial resistance in kidneytransplant recipients. In addition, age and shear wave velocity were found to be independentpredictors of arterial resistance. These findings indicate that SWE can not only quantify tissueelasticity in a renal allograft but also predict arterial resistance.23,24,25,26). An RI > 0.8 are usually typical of allograftmalfunction and death with a functioning graft(27). Ba et al.(24) found thatan increase > 1 in the RI could reflect absence of end-diastolic blood flow, resulting in aworse prognosis for renal allograft survival. Recent studies of the extrarenal factorsinfluencing the RI in kidney transplant recipients  have demonstrated that the RI is dependent on the vascularcharacteristics of the recipient.Determination of the RI is a useful tool in assessing the prognosis for graft survival in thechronic period after transplantation, because it reflects the vascular status of theallograft. Renal sampling by SWEhas been shown to have a reliability of 97.6%(22). In a study conducted in Turkey, renal parenchymal stiffness correlatedpositively with the RI(33). In a study of 50kidney transplant recipients under clinical suspicion of allograft fibrosis in Italy, a strongcorrelation was observed between low tissue elasticity and moderate-to-severe interstitialfibrosis(35). In addition, several studieshave indicated that an increase in shear wave velocity is predictive of a worsened estimatedglomerular filtration rate, as well as renal fibrosis, in kidney transplantrecipients.Although color Doppler is an established method to assess renal allografts, ultrasoundelastography seems to show renal impairment earlier. Kidney stiffness has been used as apredictor of renal allograft fibrosis(Our study has some limitations. First, the post-transplant period was not evaluated. Inaddition, no biopsies were performed, so we were unable to compare our results with the biopsyfindings. Furthermore, all of the results were interpreted by the same examiner. Moreover, therewas no control group of healthy patients to rule out the possibility that the advanced age ofthe patients in our sample was the cause of the abnormal stiffness of the renal parenchyma.However, to our knowledge, this is the first study to investigate the association between renalstiffness, as assessed by SWE, and arterial RI, as assessed by ultrasound Doppler, in kidneytransplant recipients in Brazil.In conclusion, the stiffness of the renal cortex of a transplanted kidney appears to correlatewith arterial resistance in kidney transplant recipients. In addition, monitoring renalallografts by SWE may provide an additional early prognostic index to assess chronic renaldysfunction.