Acute kidney injury spectrum in patients with chronic liver disease:Where do we stand?

Acute kidney injury (AKI) is a common complication of liver cirrhosis and is of the utmost clinical and prognostic relevance. Patients with cirrhosis, especially decompensated cirrhosis, are more prone to develop AKI than those without cirrhosis. The hepatorenal syndrome type of AKI (HRS–AKI), a spectrum of disorders in prerenal chronic liver disease, and acute tubular necrosis (ATN) are the two most common causes of AKI in patients with chronic liver disease and cirrhosis. Differentiating these conditions is essential due to the differences in treatment. Prerenal AKI, a more benign disorder, responds well to plasma volume expansion, while ATN requires more specific renal support and is associated with substantial mortality. HRS–AKI is a facet of these two conditions, which are characterized by a dysregulation of the immune response. Recently, there has been progress in better defining this clinical entity, and studies have begun to address optimal care. The present review synopsizes the current diagnostic criteria, pathophysiology, and treatment modalities of HRS–AKI and as well as AKI in other chronic liver diseases (non-HRS–AKI) so that early recognition of HRS–AKI and the appropriate management can be established.

Acute kidney injury and post-reperfusion syndrome in liver transplantation

In the past decades liver transplantation(LT) has become the treatment of choice for patients with end stage liver disease(ESLD). The chronic shortage of cadaveric organs for transplantation led to the utilization of a greater number of marginal donors such as older donors or donors after circulatory death(DCD). The improved survival of transplanted patients has increased the frequency of long-term complications, in particular chronic kidney disease(CKD). Acute kidney injury(AKI) post-LT has been recently recognized as an important risk factor for the occurrence of denovo CKD in the long-term outcome. The onset of AKI post-LT is multifactorial, with pre-LT risk factors involved, including higher Model for End-stage Liver Disease score, more sever ESLD and pre-existing renal dysfunction, either with intra-operative conditions, in particular ischaemia reperfusion injury responsible for post-reperfusion syndrome(PRS) that can influence recipient's morbidity and mortality. Post-reperfusion syndrome-induced AKI is an important complication post-LT that characterizes kidney involvement caused by PRS with mechanisms not clearly understood and implication on graft and patient survival. Since preLT risk factors may influence intra-operative events responsible for PRS-induced AKI, we aim to consider all the relevant aspects involved in PRS-induced AKI in the setting of LT and to identify all studies that better clarified the specific mechanisms linking PRS and AKI. A Pub Med search was conducted using the terms liver transplantation AND acute kidney injury; liver transplantation AND post-reperfusion syndrome; acute kidney injury AND post-reperfusion syndrome; acute kidney injury AND DCD AND liver transplantation. Five hundred seventy four articles were retrieved on Pub Med search. Results were limited to title/abstract of English-language articles published between 2000 and 2015. Twenty-three studies were identified that specifically evaluated incidence, risk factors and outcome for patients developing PRS-induced AKI in liver transplantation. In order to identify intra-operative risk factors/mechanisms specifically involved in PRSinduced AKI, avoiding confounding factors, we have limited our study to "acute kidney injury AND DCD AND liver transplantation". Accordingly, three out of five studies were selected for our purpose.

The Hippo pathway and its correlation with acute kidney injury

Acute kidney injury(AKI) is a significant clinical complication with a substantial impact on morbidity and mortality, for which therapeutic options remain limited. The Hippo signaling pathway is an evolutionarily conserved pathway implicated in cell proliferation, dedifferentiation, and apoptosis via phosphorylation and inactivation of its downstream effectorsYes-associatedprotein(YAP)/transcriptional co-activator with PDZ-binding motif(TAZ). Recent studies have revealed that the Hippo pathway plays a pivotal role in the pathogenesis and repair of AKI. The Hippo pathway can mediate renal dysfunction through modulation of mitochondrial apoptosis under AKI conditions. Transient activation of YAP/TAZ in the acute phase of AKI may benefit renal recovery and regeneration, whereas persistent activation of YAP/TAZ in severe AKI may lead to maladaptive repair and transition to chronic kidney disease. This review aims to summarize recent findings on the associations between the Hippo pathway and AKI and to identify new therapeutic targets and strategies for AKI.

Chronic kidney disease prediction is an inexact science: The concept of “progressors” and “nonprogressors”

In 2002,the National Kidney Foundation Kidney Disease Outcomes Quality Initiative(NKF KDOQI)instituted new guidelines that established a novel chronic kidney disease(CKD)staging paradigm.This set of guidelines,since updated,is now very widely accepted around the world.Nevertheless,the authoritative United States Preventative Task Force had in August 2012acknowledged that we know surprisingly little about whether screening adults with no signs or symptoms of CKD improve health outcomes and that we deserve better information on CKD.More recently,the American Society of Nephrology and the American College of Physicians,two very well respected United States professional physician organizations were strongly at odds coming out with exactly opposite recommendations regarding the need or otherwise for"CKD screening"among the asymptomatic population.In this review,we revisit the various angles and perspectives of these conflicting arguments,raise unanswered questionsregarding the validity and veracity of the NKF KDOQI CKD staging model,and raise even more questions about the soundness of its evidence-base.We show clinical evidence,from a Mayo Clinic Health System Renal Unit in Northwestern Wisconsin,United States,of the pitfalls of the current CKD staging model,show the inexactitude and unpredictable vagaries of current CKD prediction models and call for a more cautious and guarded application of CKD staging paradigms in clinical practice.The impacts of acute kidney injury on CKD initiation and CKD propagation and progression,the effects of such phenomenon as the syndrome of late onset renal failure from angiotensin blockade and the syndrome of rapid onset end stage renal disease on CKD initiation,CKD propagation and CKD progression to end stage renal disease all demand further study and analysis.Yet more research on CKD staging,CKD prognostication and CKD predictions are warranted.Finally and most importantly,cognizant of the very serious limitations and drawbacks of the NKF K/DOQI CKD staging model,the need to individualize CKD care,both in terms of patient care and prognostication,cannot be overemphasized.

Approach to Acute Kidney Injury: Diagnosis and Management

Acute kidney injury is a critical but commonly occurring medical condition that presents with a sudden decline in kidney function. This comprehensive review article provides an in-depth examination of the risk elements, etiology, diagnosis, management, and preventive approach of AKI. The causes that contribute to the development of AKI include prerenal, intrinsic renal, and postrenal. The diagnostic approach to AKI includes clinical, laboratory, and imaging studies to evaluate the root cause analysis and to find out the severity of kidney injury. Timely and accurate diagnosis is crucial for initiating appropriate management strategies. The treatment strategies may include fluid and electrolyte management, medication adjustments, nutritional support, and renal replacement therapy. The prospect of recovery diverges as it relies on the individual factors, reasons, and gravity of the condition. This review highlights the importance of raising awareness among healthcare professionals and the public about AKI, early recognition of risk factors, and prompt management. Further research is needed to explore novel therapeutic approaches and refine existing management guidelines for this critical condition.

Driving role of macrophages in transition from acute kidney injury to chronic kidney disease

Acute kidney injury(AKI),characterized by acute renal dysfunction,is an increasingly common clinical problem and an important risk factor in the subsequent development of chronic kidney disease(CKD).Regardless of the initial insults,the progression of CKD after AKI involves multiple types of cells,including renal resident cells and immune cells such as macrophages.Recently,the involvements of macrophages in AKI-to-CKD transition have garnered significant attention.Furthermore,substantial progress has also been made in elucidating the pathophysiological functions of macrophages from the acute kidney to repair or fibrosis.In this review,we highlight current knowledge regarding the roles and mechanisms of macrophage activation and phenotypic polarization,and transdifferentiation in the development of AKI-to-CKD transition.In addition,the potential of macrophage-based therapy for preventing AKI-to-CKD transition is also discussed.

Kidneys in chronic liver diseases

Acute kidney injury(AKI),defined as an abrupt increase in the serum creatinine level by at least 0.3 mg/dL,occurs in about 20% of patients hospitalized for decompensating liver cirrhosis.Patients with cirrhosis are susceptible to developing AKI because of the progressive vasodilatory state,reduced effective blood volume and stimulation of vasoconstrictor hormones.The most common causes of AKI in cirrhosis are pre-renal azotemia,hepatorenal syndrome and acute tubular necrosis.Differential diagnosis is based on analysis of circumstances of AKI development,natriuresis,urine osmolality,response to withdrawal of diuretics and volume repletion,and rarely on renal biopsy.Chronic glomerulonephritis and obstructive uropathy are rare causes of azotemia in cirrhotic patients.AKI is one of the last events in the natural history of chronic liver disease,therefore,such patients should have an expedited referral for liver transplantation.Hepatorenal syndrome(HRS) is initiated by progressive portal hypertension,and may be prematurely triggered by bacterial infections,nonbacterial systemic inflammatory reactions,excessive diuresis,gastrointestinal hemorrhage,diarrhea or nephrotoxic agents.Each type of renal disease has a specific treatment approach ranging from repletion of the vascular system to renal replacement therapy.The treatment of choice in type 1 hepatorenal syndrome is a combination of vasoconstrictor with albumin infusion,which is effective in about 50% of patients.The second-line treatment of HRS involves a transjugular intrahepatic portosystemic shunt,renal vasoprotection or systems of artificial liver support.

Hydroxyethylstarch revisited for acute brain injury treatment

Infusion of the colloid hydroxyethylstarch has been used for volume substitution to maintain hemodynamics and microcirculation after e.g., severe blood loss.In the last decade it was revealed that hydroxyethylstarch can aggravate acute kidney injury, especially in septic patients.Because of the serious risk for critically ill patients, the administration of hydroxyethylstarch was restricted for clinical use.Animal studies and recently published in vitro experiments showed that hydroxyethylstarch might exert protective effects on the blood-brain barrier.Since the prevention of blood-brain barrier disruption was shown to go along with the reduction of brain damage after several kinds of insults, we revisit the topic hydroxyethylstarch and discuss a possible niche for the application of hydroxyethylstarch in acute brain injury treatment.

Folic acid-induced animal model of kidney disease

The kidneys are a vital organ that is vulnerable to both acute kidney injury(AKI)and chronic kidney disease(CKD)which can be caused by numerous risk factors such as ischemia,sepsis,drug toxicity and drug overdose,exposure to heavy metals,and diabetes.In spite of the advances in our understanding of the pathogenesis of AKI and CKD as well AKI transition to CKD,there is still no available therapeutics that can be used to combat kidney disease effectively,highlighting an urgent need to further study the pathological mechanisms underlying AKI,CKD,and AKI progression to CKD.In this regard,animal models of kidney disease are indispensable.This article reviews a widely used animal model of kidney disease,which is induced by folic acid(FA).While a low dose of FA is nutritionally beneficial,a high dose of FA is very toxic to the kidneys.Following a brief description of the procedure for disease induction by FA,major mechanisms of FA-induced kidney injury are then reviewed,including oxidative stress,mitochondrial abnormalities such as impaired bioenergetics and mitophagy,ferroptosis,pyroptosis,and increased expression of fibroblast growth factor 23(FGF23).Finally,application of this FA-induced kidney disease model as a platform for testing the efficacy of a variety of therapeutic approaches is also discussed.Given that this animal model is simple to create and is reproducible,it should remain useful for both studying the pathological mechanisms of kidney disease and identifying therapeutic targets to fight kidney disease.

Clinical Outcome of Low Dose Contrast during Percutaneous Coronary Intervention in Patients with Moderate to Severe Kidney Impairment

Background: Chronic kidney disease patients are at a greater risk for nephropathy requiring dialysis after percutaneous coronary intervention. Such patients are usually deferred due to fear of “Renalism”.?Objectives This study assesses the outcome of Low dose contrast protocol during PCI in CKD patients whose e-GFR 60 ml/min/1.72 m and investigates a safety margin for contrast use in these high-risk categories.?Methods: Patients were into three groups according to CV/e-GFR ratio: Group (A) low-dose: CV/e-GFR ratio 2.0 Group (B) medium-dose: CV/e-GFR ratio > 2.0 and × bodyweight\s.creatinine). Group (C) high-dose: CV/e-GFR ratio > MACD. Results: A total of 73 patients were enrolled. Average age was 54 ± 8 years,81.4% were male and 18.6% were females and 52% were diabetic. Mean baseline e-GFR was 40 ± 8.0 ml/min/1.73m2. Contrast Volume used in group A was (58.26 ± 15.05) (n = 24), in group B (109.42 ± 17.11) (n = 26) and in group C (304.5 ± 60.30) (n = 23), respectively. The incidences of CI-AKI in the 3 groups were 0%, 11.5% and 35%, respectively (p = 0.02). All-cause death 0%, 17% and introduction of maintenance hemo dialysis was 0%, 11.5% and 26%, respectively (p Conclusion: Low dose contrast protocol is safe, effective and easily applicable technique without CI-AKI or death.

Experimental models for preclinical research in kidney disease

Acute kidney injury(AKI)and chronic kidney disease(CKD)are significant public health issues associated with a long-term increase in mortality risk,resulting from various etiologies including renal ischemia,sepsis,drug toxicity,and diabetes mellitus.Numerous preclinical models have been developed to deepen our understanding of the pathophysiological mechanisms and therapeutic approaches for kidney diseases.Among these,rodent models have proven to be powerful tools in the discovery of novel therapeutics,while the development of kidney organoids has emerged as a promising advancement in the field.This review provides a comprehensive analysis of the construction methodologies,underlying biological mechanisms,and recent therapeutic developments across different AKI and CKD models.Additionally,this review summarizes the advantages,limitations,and challenges inherent in these preclinical models,thereby contributing robust evidence to support the development of effective therapeutic strategies.

Kidney disease models:tools to identify mechanisms and potential therapeutic targets

Acute kidney injury （AKI） and chronic kidney disease （CKD） are worldwide public health problems affecting millions of people and have rapidly increased in prevalence in recent years. Due to the multiple causes of renal failure, many animal models have been developed to advance our understanding of human nephropathy. Among these experimental models, rodents have been extensively used to enable mechanistic understanding of kidney disease induction and progression, as well as to identify potential targets for therapy. In this review, we discuss AKI models induced by surgical operation and drugs or toxins, as well as a variety of CKD models （mainly genetically modified mouse models）. Results from recent and ongoing clinical trials and conceptual advances derived from animal models are also explored.

Chronic renal dysfunction in cirrhosis:A new frontier in hepatology

Chronic kidney disease(CKD)in patients with liver cirrhosis has become a new frontier in hepatology.In recent years,a sharp increase in the diagnosis of CKD has been observed among patients with cirrhosis.The rising prevalence of risk factors,such as diabetes,hypertension and nonalcoholic fatty liver disease,appears to have contributed significantly to the high prevalence of CKD.Moreover,the diagnosis of CKD in cirrhosis is now based on a reduction in the estimated glomerular filtration rate of<60 mL/min over more than 3 mo.This definition has resulted in a better differentiation of CKD from acute kidney injury(AKI),leading to its greater recognition.It has also been noted that a significant proportion of AKI transforms into CKD in patients with decompensated cirrhosis.CKD in cirrhosis can be structural CKD due to kidney injury or functional CKD secondary to circulatory and neurohormonal imbalances.The available literature on combined cirrhosis-CKD is extremely limited,as most attempts to assess renal dysfunction in cirrhosis have so far concentrated on AKI.Due to problems related to glomerular filtration rate estimation in cirrhosis,the absence of reliable biomarkers of CKD and technical difficulties in performing renal biopsy in advanced cirrhosis,CKD in cirrhosis can present many challenges for clinicians.With combined hepatorenal dysfunctions,fluid mobilization becomes problematic,and there may be difficulties with drug tolerance,hemodialysis and decision-making regarding the need for liver vs simultaneous liver and kidney transplantation.This paper offers a thorough overview of the increasingly known CKD in patients with cirrhosis,with clinical consequences and difficulties occurring in the diagnosis and treatment of such patients.

Short-term Rosuvastatin Treatment for the Prevention of Contrast-induced Acute Kidney Injury in Patients Receiving Moderate or High Volumes of Contrast Media： A Sub-analysis of the TRACK-D Study

Background:Current randomized trials have demonstrated the effects of short-term rosuvastatin therapy in preventing contrast-induced acute kidney injury (CIAKI).However,the consistency of these effects on patients administered different volumes of contrast media is unknown.Methods:In the TRACK-D trial,2998 patients with type 2 diabetes and concomitant chronic kidney disease (CKD) who underwent coronary/peripheral arterial angiography with or without percutaneous intervention were randomized to short-term (2 days before and 3 days after procedure) rosuvastatin therapy or standard-of-care.This prespecified analysis compared the effects of rosuvastatin versus standard therapy in patients exposed to (moderate contrast volume [MCV],200-300 ml,n =712) or (high contrast volume [HCV],≥300 ml,n =220).The primary outcome was the incidence of CIAKI.The secondary outcome was a composite of death,dialysis/hemofiltration or worsened heart failure at 30 days.Results:Rosuvastatin treatment was associated with a significant reduction in CIAKI compared with the controls (2.1％ vs.4.4％,P =0.050) in the overall cohort and in patients with MCV (1.7％ vs.4.5％,P =0.029),whereas no benefit was observed in patients with HCV (3.4％ vs.3.9％,P =0.834).The incidence of secondary outcomes was significantly lower in the rosuvastatin group compared with control group (2.7％ vs.5.3％,P =0.049) in the overall cohort,but it was similar between the patients with MCV (2.0％ vs.4.2％,P =0.081) or HCV (5.1％ vs.8.8％,P =0.273).Conclusions:Periprocedural short-term rosuvastatin treatment is effective in reducing CIAKI and adverse clinical events for patients with diabetes and CKD after their exposure to a moderate volume of contrast medium.

Current aspects of renal dysfunction after liver transplantation

The development of chronic kidney disease(CKD)after liver transplantation(LT)exerts a severe effect on the survival of patients.The widespread adoption of the model for end-stage liver disease score strongly impacted CKD incidence after the procedure,as several patients are transplanted with previously deteriorated renal function.Due to its multifactorial nature,encompassing pre-transplantation conditions,perioperative events,and nephrotoxic immunosuppressor therapies,the accurate identification of patients under risk of renal disease,and the implementation of preventive approaches,are extremely important.Methods for the evaluation of renal function in this setting range from formulas that estimate the glomerular filtration rate,to non-invasive markers,although no option has yet proved efficient in early detection of kidney injury.Considering the nephrotoxicity of calcineurin inhibitors(CNI)as a factor of utmost importance after LT,early nephroprotective strategies are highly recommended.They are based mainly on delaying the application of CNI during the immediate postoperativeperiod,reducing their dosage,and associating them with other less nephrotoxic drugs,such as mycophenolate mofetil and everolimus.This review provides a critical assessment of the causes of renal dysfunction after LT,the methods of its evaluation,and the interventions aimed at preserving renal function early and belatedly after LT.

How tubular epithelial cells dictate the rate of renal fibrogenesis?

The main threat to a kidney injury, whatever its cause and regardless of whether it is acute or chronic, is the initiation of a process of renal fibrogenesis, since fbrosis can auto-perpetuate and is of high prognostic significance in individual patients. In the clinic, a decrease in glomerular fltration rate correlates better with tubulointerstitial damage than with glomerular injury. Accumulation of the extracellular matrix should not be isolated from other significant cellular changes occurring in the kidney, such as infiltration by infammatory cells, proliferation of myofbroblasts, obliteration of peritubular capillaries and atrophy of tubules. The aim of this review is to focus on tubular epithelial cells （TEC）, which, necessarily involved in the repair process, eventually contribute to accelerating fibrogenesis. In the context of injury, TEC rapidly exhibit phenotypic and functional changes that recall their mesenchymal origin, and produce several growth factors known to activate myofbroblasts. Because they are high-demanding energy cells, TEC will subsequently suffer from the local hypoxia that progressively arises in a microenvironment where the matrix increases and capillaries become rarifed. The combination of hypoxia and metabolic acidosis may induce a vicious cycle of sustained inflammation, at the center of which TEC dictate the rate of renal fbrogenesis.

Age, estimated glomerular filtration rate and ejection fraction score predicts contrast-induced acute kidney injury in patients with diabetes and chronic kidney disease： insight from the TRACK-D study

Background The occurrence of contrast induced acute kidney injury （CIAKI） has a pronounced impact on morbidity and mortality.The aim of the present study was to appraise the diagnostic efficacy of age,estimated glomerular filtration rate （eGFR） and ejection fraction （AGEF） score （age/EF（％）＋1 （if eGFR was ＜60 ml·min-1·1.73 m2）） as an predictor of CIAKI in patients with diabetes mellitus （DM） and concomitant chronic kidney disease （CKD）.Methods The AGEF score was calculated for 2 998 patients with type 2 DM and concomitant CKD who had undergone coronary/peripheral arterial angiography.CIAKI was defined as an increase in sCr concentration of 0.5 mg/dl （44.2 mmol/L） or 25％ above baseline at 72 hours after exposure to the contrast medium.Post hoc analysis was performed by stratifying the rate of CIAKI according to AGEF score tertiles.The diagnostic efficacy of the AGEF score for predicting CIAKI was evaluated with receiver operating characteristic （ROC） analysis.Results The AGEF score ranged from 0.49 to 3.09.The AGEF score tertiles were defined as follows：AGEFlow ≤0.92 （n=1 006）; 0.92 ＜AGEFmid ≤1.16 （n=1 000）,and ACEFhigh ＞1.16 （n=992）.The incidence of CIAKI was significantly different in patients with low,middle and high AGEF scores （AGEFlow=1.1％,AGEFmid=2.3％ and AGEFhigh=5.8％,P ＜0.001）.By multivariate analysis,AGEF score was an independent predictor of CIAKI （odds ratio=4.96,95％ CI：2.32-10.58,P ＜0.01）.ROC analysis showed that the area under the curve was 0.70 （95％ CI：0.648-0.753,P ＜0.001）.Conclusion The AGEF score is effective for stratifying risk of CIAKI in patients with DM and CKD undergoing coronary/peripheral arterial angiography.

Clinical and pathophysiological understanding of the hepatorenal syndrome:Still wrong or still not exactly right?

The hepatorenal syndrome(HRS)is one major extrahepatic complication of endstage liver diseases.While circulatory dysregulation is considered as primary etiology for HRS,cirrhosis-related(systemic)inflammation and/or cardial dysfunction may also play a key pathogenic role in HRS development.Exclusion of other causes of acute kidney injury(AKI)is required for diagnosis of HRS-AKI by the definition of the International Club of Ascites.However,the pathophysiology of HRS is not understood completely and there are still limited therapeutic options.Reversibility of renal dysfunction after liver transplantation indicates that HRS-AKI is a functional disorder caused by altered cellular function.The interplay between systemic inflammation and the onset of kidneyrelated hypometabolism may have a key role and needs to be studied in depth.This minireview challenges simplified views of the HRS in the context of diagnostics and therapy stressing the need for further evidence to advance the knowledge on this syndrome.

Epidemiology, pathophysiology, clinical characteristics and management of childhood cardiorenal syndrome

Cardiorenal syndrome(CRS) is a new term recently introduced to describe the acute or chronic comorbid state of the heart and kidney that has been long known and frequently managed in very sick individuals. The tight and delicate coordination of physiological functions among organ systems in the human body makes dysfunction in one to lead to malfunction of one or more other organ systems. CRS is a universal very common morbidity in the critically ill, with a high mortality rate that has received very little research attention in children. Simultaneous management of heart and renal failures in CRS is quite challenging; the therapeutic choice made for one organ must not jeopardize the other. This paper reviews the epidemiology, pathophysiology, clinical characteristics and management of acute and chronic CRS in children.

Kidney disease in non-kidney solid organ transplantation

Kidney disease after non-kidney solid organ transplantation(NKSOT)is a common post-transplant complication associated with deleterious outcomes.Kidney disease,both acute kidney injury and chronic kidney disease(CKD)alike,emanates from multifactorial,summative pre-,peri-and post-transplant events.Several factors leading to kidney disease are shared amongst solid organ transplantation in addition to distinct mechanisms unique to individual transplant types.The aim of this review is to summarize the current literature describing kidney disease in NKSOT.We conducted a narrative review of pertinent studies on the subject,limiting our search to full text studies in the English language.Kidney disease after NKSOT is prevalent,particularly in intestinal and lung transplantation.Management strategies in the peri-operative and post-transplant periods including proteinuria management,calcineurin-inhibitor minimization/sparing approaches,and nephrology referral can counteract CKD progression and/or aid in subsequent kidney after solid organ transplantation.Kidney disease after NKSOT is an important consideration in organ allocation practices,ethics of transplantation.Kidney disease after SOT is an incipient condition demanding further inquiry.While some truths have been revealed about this chronic disease,as we have aimed to describe in this review,continued multidisciplinary efforts are needed more than ever to combat this threat to patient and allograft survival.