Acute kidney injury in patients with cirrhosis: Acute Disease Quality Initiative (ADQI) and International Club of Ascites (ICA) joint multidisciplinary consensus meeting.

Patients with cirrhosis are prone to developing acute kidney injury (AKI), a complication associated with a markedly increased in-hospital morbidity and mortality, along with a risk of progression to chronic kidney disease. Whereas patients with cirrhosis are at increased risk of developing any phenotype of AKI, hepatorenal syndrome (HRS), a specific form of AKI (HRS-AKI) in patients with advanced cirrhosis and ascites, carries an especially high mortality risk. Early recognition of HRS-AKI is crucial since administration of splanchnic vasoconstrictors may reverse the AKI and serve as a bridge to liver transplantation, the only curative option. In 2023, a joint meeting of the International Club of Ascites (ICA) and the Acute Disease Quality Initiative (ADQI) was convened to develop new diagnostic criteria for HRS-AKI, to provide graded recommendations for the work-up, management and post-discharge follow-up of patients with cirrhosis and AKI, and to highlight priorities for further research.

Performance of race-neutral eGFR equations in patients with decompensated cirrhosis.

The 2021 Chronic Kidney Disease Epidemiology Collaboration equation [CKD-EPI 2021] is a race-neutral equation recently developed and rapidly implemented as a reference standard to estimate glomerular filtration rate(GFR). However, its role in cirrhosis has not been examined especially in low GFR. We analyzed the performance of CKD-EPI 2021 compared to other equations with protocol measured GFR(mGFR) in cirrhosis. We analyzed 2090 unique adult patients with cirrhosis undergoing protocol GFR measurements using iothalamate clearance from 1985-2015 when listed for liver transplantation at Baylor University in Dallas and Fort Worth, Texas. Using mGFR as a reference standard, the CKD-EPI 2021 was compared to CKD-EPI 2012, MDRD-4, MDRD-6, RFH and GRAIL overall and in certain subgroups(ascites, mGFR≤30 mL/min/1.73 m 2 , diagnosis, MELD and gender). We examined bias(difference between eGFR and mGFR), accuracy(p30: eGFR within ±30% of mGFR) and agreement between eGFR and mGFR categories. CKD-EPI 2021 had the 2 nd lowest bias across the entire range of GFR after GRAIL (6.6 vs. 4.6 mL/min/1.73 m 2 , respectively, p <0.001). Accuracy of CKD-EPI 2021 was similar to CKD-EPI 2012 (p30=67.8% vs. 67.9%, respectively) that was higher than the other equations ( p <0.001). It had a similar performance in patients with ascites, by diagnoses, MELD subgroups, by sex and in non-Black patients. However, it had a relatively higher overestimation in mGFR≤30 mL/min/1.73 m 2 than most equations (18.5 mL/min/1.73m 2 , p <0.001). Specifically, 64% of patients with mGFR≤30 mL/min/1.73m 2 were incorrectly classified to a less severe CKD stage by CKD-EPI 2021. In Blacks, CKD-EPI 2021 underestimated eGFR by 17.9 mL/min/1.73 m 2 that was higher than the alternate equations except RFH ( p <0.001). The novel race-neutral eGFR equation, CKD-EPI 2021, improves the GFR estimation overall but may not accurately capture true kidney function in cirrhosis specifically at low GFR. There is an urgent need for a race-neutral equation in liver disease reflecting the complexity of kidney function physiology unique to cirrhosis given implications for organ allocation and dual organ transplant.

Fluid resuscitation in patients with cirrhosis and sepsis: A multidisciplinary perspective.

Fluid resuscitation is typically needed in patients with cirrhosis, sepsis and hypotension. However, the complex circulatory changes associated with cirrhosis and the hyperdynamic state, characterised by increased splanchnic blood volume and relative central hypovolemia, complicate fluid administration and monitoring of fluid status. Patients with advanced cirrhosis require larger volumes of fluids to expand central blood volume and improve sepsis-induced organ hypoperfusion than patients without cirrhosis, which comes at the cost of a further increase in non-central blood volume. Monitoring tools and volume targets still need to be defined but echocardiography is promising for bedside assessment of fluid status and responsiveness. Large volumes of saline should be avoided in patients with cirrhosis. Experimental data suggest that independent of volume expansion, albumin is superior to crystalloids at controlling systemic inflammation and preventing acute kidney injury. However, while it is generally accepted that albumin plus antibiotics is superior to antibiotics alone in spontaneous bacterial peritonitis, evidence is lacking in patients with infections other than spontaneous bacterial peritonitis. Patients with advanced cirrhosis, sepsis and hypotension are less likely to be fluid responsive than those without cirrhosis and early initiation of vasopressors is recommended. While norepinephrine is the first-line option, the role of terlipressin needs to be clarified in this context.

Incidence and outcomes of acute kidney injury including hepatorenal syndrome in hospitalized patients with cirrhosis in the US.

BACKGROUND & AIMS: Acute kidney injury (AKI) in cirrhosis is common and associated with high morbidity, but the incidence rates of different etiologies of AKI are not well described in the US. We compared incidence rates, practice patterns, and outcomes across etiologies of AKI in cirrhosis. METHODS: We performed a retrospective cohort study of 11 hospital networks, including consecutive adult patients admitted with AKI and cirrhosis in 2019. The etiology of AKI was adjudicated based on pre-specified clinical definitions (prerenal/hypovolemic AKI, hepatorenal syndrome [HRS-AKI], acute tubular necrosis [ATN], other). RESULTS: A total of 2,063 patients were included (median age 62 [IQR 54-69] years, 38.3% female, median MELD-Na score 26 [19-31]). The most common etiology was prerenal AKI (44.3%), followed by ATN (30.4%) and HRS-AKI (12.1%); 6.0% had other AKI, and 7.2% could not be classified. In our cohort, 8.1% of patients received a liver transplant and 36.5% died by 90 days. The lowest rate of death was observed in patients with prerenal AKI (22.2%; p <0.001), while death rates were higher but not significantly different from each other in those with HRS-AKI and ATN (49.0% vs. 52.7%; p = 0.42). Using prerenal AKI as a reference, the adjusted subdistribution hazard ratio (sHR) for 90-day mortality was higher for HRS-AKI (sHR 2.78; 95% CI 2.18-3.54; p <0.001) and ATN (sHR 2.83; 95% CI 2.36-3.41; p <0.001). In adjusted analysis, higher AKI stage and lack of complete response to treatment were associated with an increased risk of 90-day mortality (p <0.001 for all). CONCLUSION: AKI is a severe complication of cirrhosis. HRS-AKI is uncommon and is associated with similar outcomes to ATN. The etiology of AKI, AKI stage/severity, and non-response to treatment were associated with mortality. Further optimization of vasoconstrictors for HRS-AKI and supportive therapies for ATN are needed. IMPACT AND IMPLICATIONS: Acute kidney injury (AKI) in cirrhosis carries high morbidity, and management is determined by the etiology of injury. However, a large and well-adjudicated multicenter database from US centers that uses updated AKI definitions is lacking. Our findings demonstrate that acute tubular necrosis and hepatorenal syndrome have similar outcomes (∼50% mortality at 90 days), though hepatorenal syndrome is uncommon (12% of all AKI cases). These findings represent practice patterns at US transplant/tertiary centers and can be used as a baseline, presenting the situation prior to the adoption of terlipressin in the US.

Management of the kidney transplant recipient in the intensive care unit.

PURPOSE OF REVIEW: Kidney transplantation is the ideal treatment for patients with chronic kidney disease and end stage renal disease. While centers are performing more transplants every year, the need for organ transplantation outpaces the supply of organ donors. Due to a growing population of patients with advanced kidney disease and a scarcity of kidneys from deceased donors, patients face extended wait times. By the time patients approach transplantation they have multiple comorbidities, in particular cardiovascular complications. Their risk of complications is further compounded by exposure to immunosuppression post kidney transplantation. Kidney transplant recipients (KTRs) are medically complex and may require acute management in the intensive care unit (ICU), as a result of cardiovascular complications, infections, and/or respiratory compromise from lung infections and/or acute pulmonary edema. Acute complication of immunosuppression, such as thrombotic microangiopathy and posterior reversible encephalopathy syndrome may also warrant ICU admission. This review will cover assessment of high-risk complications and management strategies following kidney transplantation. RECENT FINDINGS: For intensivists caring for KTRs, it is imperative to understand anatomical considerations of the transplanted kidney, unique infectious risks faced by this population, and appropriate modulation of immunosuppression. SUMMARY: Recognizing potential complications and implementing appropriate management strategies for KTRs admitted to the ICU will improve kidney allograft and patient survival outcomes.

North American Practice-Based Recommendations for Transjugular Intrahepatic Portosystemic Shunts in Portal Hypertension.

Complications of portal hypertension, including ascites, gastrointestinal bleeding, hepatic hydrothorax, and hepatic encephalopathy, are associated with significant morbidity and mortality. Despite few high-quality randomized controlled trials to guide therapeutic decisions, transjugular intrahepatic portosystemic shunt (TIPS) creation has emerged as a crucial therapeutic option to treat complications of portal hypertension. In North America, the decision to perform TIPS involves gastroenterologists, hepatologists, and interventional radiologists, but TIPS creation is performed by interventional radiologists. This is in contrast to other parts of the world where TIPS creation is performed primarily by hepatologists. Thus, the successful use of TIPS in North America is dependent on a multidisciplinary approach and technical expertise, so as to optimize outcomes. Recently, new procedural techniques, TIPS stent technology, and indications for TIPS have emerged. As a result, practices and outcomes vary greatly across institutions and significant knowledge gaps exist. In this consensus statement, the Advancing Liver Therapeutic Approaches group critically reviews the application of TIPS in the management of portal hypertension. Advancing Liver Therapeutic Approaches convened a multidisciplinary group of North American experts from hepatology, interventional radiology, transplant surgery, nephrology, cardiology, pulmonology, and hematology to critically review existing literature and develop practice-based recommendations for the use of TIPS in patients with any cause of portal hypertension in terms of candidate selection, procedural best practices and, post-TIPS management; and to develop areas of consensus for TIPS indications and the prevention of complications. Finally, future research directions are identified related to TIPS for the management of portal hypertension.

Role of Novel Kidney Biomarkers in Patients With Cirrhosis and After Liver Transplantation.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are important drivers of morbidity and mortality in patients with cirrhosis before and after liver transplantation (LT). In this review, we examine the role of novel kidney biomarkers for early recognition of kidney injury. Studies are limited by lack of reference standards, heterogeneous definitions of outcomes and biomarker cutoffs, and inconsistent diagnostic performance. Overall, a change in biomarker is more relevant than an absolute cutoff. Cystatin C and urinary neutrophil gelatinase-associated lipocalin (uNGAL) are the most studied candidate biomarkers and identify AKI or progression of AKI earlier than serum creatinine (sCr). Kidney injury molecule 1 and liver-type fatty acid-binding protein (L-FABP) also show potential. NGAL and interleukin 18 may play a role in differentiating acute tubular necrosis from other forms of AKI. Combining novel biomarkers with the Model for End-Stage Liver Disease score may assist prognosis. Persistent elevations in select markers (eg, NGAL) can portend irreversible injury. Several pretransplantation markers (including sCr) predict posttransplantation kidney dysfunction. Pretransplantation assessment of clinical factors (eg, age, diabetes) and novel markers (osteopontin and tissue inhibitor of metalloproteinases 1 [TIMP-1]) may predict renal kidney recovery after LT. Intraoperative changes in biomarkers predict early post-LT AKI. Prediction of CKD remains difficult, although a combination of biomarkers (eg, beta-2 microglobulin, CD40) is promising. Novel biomarkers have yet to replace sCr in guideline-based evaluation and management of kidney dysfunction in patients with cirrhosis. We propose a theoretical framework for practical incorporation of these biomarkers that considers patient characteristics (risk for irreversible injury), markers of functional and structural change, and assessment of the AKI-CKD continuum to identify patients at the highest risk for progressive kidney disease before and after LT.

Coagulopathy and hemostasis management in patients undergoing liver transplantation: Defining a dynamic spectrum across phases of care.

Patients with acute and chronic liver disease present with a wide range of disease states and severity that may require liver transplantation (LT). Physiologic alterations occur that are dynamic throughout all phases of perioperative care, creating complex management scenarios that necessitate multidisciplinary clinical care. Specifically, alterations in hemostasis in liver disease can be pronounced and evolve with disease progression over time. Recent studies and society guidance address this emerging paradigm and offer recommendations to assist with hemostatic management in patients with liver disease. However, patients undergoing LT are unique and diverse, often with unstable disease that requires specialized approaches. Our aim is to provide a focused review of hemostatic management of the LT patient, distinguish unique aspects of the three main phases of care (before LT, perioperative, and after LT), and identify knowledge gaps and critical areas of future research.

Terlipressin and the Treatment of Hepatorenal Syndrome: How the CONFIRM Trial Moves the Story Forward.

Hepatorenal syndrome (HRS) is a form of acute kidney injury (AKI) occurring in patients with advanced cirrhosis and is associated with significant morbidity and mortality. The pathophysiology underlying HRS begins with increasing portal pressures leading to the release of vasodilatory substances that result in pooling blood in the splanchnic system and a corresponding reduction in effective circulating volume. Compensatory activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system and release of arginine vasopressin serve to defend mean arterial pressure but at the cost of severe constriction of the renal vasculature, leading to a progressive, often fulminant form of AKI. There are no approved treatments for HRS in the United States, but multiple countries, including much of Europe, use terlipressin, a synthetic vasopressin analogue, as a first-line therapy. CONFIRM (A Multi-Center, Randomized, Placebo Controlled, Double-Blind Study to Confirm Efficacy and Safety of Terlipressin in Subjects With Hepatorenal Syndrome Type 1), the third randomized trial based in North America evaluating terlipressin, met its primary end point of showing greater rates of HRS reversal in the terlipressin arm. However, due to concerns about the apparent increased rates of respiratory adverse events and a lack of evidence for mortality benefit, terlipressin was not approved by the Food and Drug Administration (FDA). We explore the history of regulatory approval for terlipressin in the United States, examine the results from CONFIRM and the concerns they raised, and consider the future role of terlipressin in this critical clinical area of continued unmet need.

Impact of medical eligibility criteria and OPTN policy on simultaneous liver kidney allocation and utilization.

BACKGROUND: Organ Procurement and Transplantation Network (OPTN) implemented medical eligibility and safety-net policy on 8/10/17 to optimize simultaneous liver-kidney (SLK) utilization. We examined impact of this policy on SLK listings and number of kidneys used within 1-yr. of receiving liver transplantation (LT) alone. METHODS AND RESULTS: OPTN database (08/10/14-06/12/20) on adults (N = 66 709) without previous transplant stratified candidates to listings for SLK or LT alone with pre-LT renal dysfunction at listing (eGFR < 30 mL/min or on dialysis). Outcomes were compared for pre (08/10/14-08/09/17) vs. post (08/10/17-06/12/20) policy era. SLK listings decreased in post vs. pre policy era (8.7% vs. 9.6%; P < .001), with 22% reduced odds of SLK listing in the postpolicy era, with a decrease in all OPTN regions except regions 6 and 8, which showed an increase. Among LT-alone recipients with pre-LT renal dysfunction (N = 3272), cumulative 1-year probability was higher in post vs. prepolicy period for dialysis (5.6% vs. 2.3%; P < .0001), KT listing (11.4% vs. 2.0%; P < .0001), and KT (3.7% vs. .25%; P < .0001). Sixty-seven (2.4%) kidneys were saved in post policy era, with 18.1%, 16.6%, 4.3%, and 2.9% saving from regions 7, 2, 11, and 1, respectively. CONCLUSION: Medical eligibility and safety-net OPTN policy resulted in decreased SLK use and improved access to LT alone among those with pre-LT renal dysfunction. Although decreased in postpolicy era, regional variation of SLK listings remains. In spite of increased use of KT within 1-year of receiving LT alone under safety net, less number of kidneys were used without impact on patient survival in postpolicy era.

Race Adjustment in eGFR Equations Does Not Improve Estimation of Acute Kidney Injury Events in Patients with Cirrhosis.

BACKGROUND: Accuracy of glomerular filtration rate estimating (eGFR) equations has significant implications in cirrhosis, potentially guiding simultaneous liver kidney allocation and drug dosing. Most equations adjust for Black race, partially accounted for by reported differences in muscle mass by race. Patients with cirrhosis, however, are prone to sarcopenia which may mitigate such differences. We evaluated the association between baseline eGFR and incident acute kidney injury (AKI) in patients with cirrhosis with and without race adjustment. METHODS: We conducted a retrospective national cohort study of veterans with cirrhosis. Baseline eGFR was calculated using multiple eGFR equations including Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), both with and without race adjustment. Poisson regression was used to investigate the association between baseline eGFR and incident AKI events per International Club of Ascites criteria. RESULTS: We identified 72,267 patients with cirrhosis, who were 97.3% male, 57.8% white, and 19.7% Black. Over median follow-up 2.78 years (interquartile range 1.22-5.16), lower baseline eGFR by CKD-EPI was significantly associated with higher rates of AKI in adjusted models. For all equations this association was minimally impacted when race adjustment was removed. For example, removal of race adjustment from CKD-EPI resulted in a 0.1% increase in the association between lower eGFR and higher rate of AKI events per 15 mL/min/1.73 m2 change (p < 0.001). CONCLUSIONS: Race adjustment in eGFR equations did not enhance AKI risk estimation in patients with cirrhosis. Further study is warranted to assess the impacts of removing race from eGFR equations on clinical outcomes and policy.

Post-Liver Transplant Acute Kidney Injury.

Acute kidney injury (AKI) is a common condition following liver transplantation (LT). It negatively impacts patient outcomes by increasing the chances of developing chronic kidney disease and reducing graft and patient survival rates. Multiple definitions of AKI have been proposed and used throughout the years, with the International Club of Ascites definition being the most widely now used for patients with cirrhosis. Multiple factors are associated with the development of post-LT AKI and can be categorized into pre-LT comorbidities, donor and recipient characteristics, operative factors, and post-LT factors. Many of these factors can be optimized in an attempt to minimize the risk of AKI occurring and to improve renal function if AKI is already present. A special consideration during the post-LT phase is needed for immunosuppression as certain immunosuppressive medications can be nephrotoxic. The calcineurin inhibitor tacrolimus (TAC) is the mainstay of immunosuppression but can result in AKI. Several strategies including use of the monoclonoal antibody basilixamab to allow for delayed initiation of tacrolimus therapy and minimization through combination and minimization or elimination of TAC through combination with mycophenolate mofetil or mammalian target of rapamycin inhibitors have been implemented to reverse and avoid AKI in the post-LT setting. Renal replacement therapy may ultimately be required to support patients until recovery of AKI after LT. Overall, by improving renal function in post-LT patients with AKI, outcomes can be improved.

Estimating Glomerular Filtration Rate in Cirrhosis Using Creatinine-Based and Cystatin C-Based Equations: Systematic Review and Meta-Analysis.

Accurate estimation of kidney function in cirrhosis is crucial for prognosis and decisions regarding dual-organ transplantation. We performed a systematic review/meta-analysis to assess the performance of creatinine-based and cystatin C (CysC)-based eGFR equations compared with measured GFR (mGFR) in patients with cirrhosis. A total of 25 studies (n = 4565, 52.0 years, 37.0% women) comprising 18 equations met the inclusion criteria. In all GFR equations, the creatinine-based equations overestimated GFR (standardized mean difference, SMD, 0.51; 95% confidence interval [CI], 0.31-0.71) and CysC-based equations underestimated GFR (SMD, -0.3; 95% CI, -0.60 to -0.02). Equations based on both creatinine and CysC were the least biased (SMD, -0.14; 95% CI, -0.46 to 0.18). Chronic kidney disease-Epi-serum creatinine-CysC (CESC) was the least biased but had low precision and underestimated GFR by -3.6 mL/minute/1.73 m2 (95% CI, -17.4 to 10.3). All equations significantly overestimated GFR (+21.7 mL/minute/1.73 m2 ; 95% CI, 17.7-25.7) at GFR <60 mL/minute/1.73 m2 ; of these, chronic kidney disease-Epi-CysC (10.3 mL/minute/1.73 m2 ; 95% CI, 2.1-18.4) and GFR Assessment in Liver Disease (12.6 mL/minute/1.73 m2 ; 95% CI, 7.2-18.0) were the least biased followed by Royal Free Hospital (15 mL/minute/1.73 m2 ; 95% CI, 5.5-24.6) and Modification of Diet in Renal Disease 6 (15.7 mL/minute/1.73 m2 ; 95% CI, 10.6-20.8); however, there was an overlap in the precision of estimates, and the studies were limited. In ascites, overestimation of GFR was common (+8.3 mL/minute/1.73 m2 ; 95% CI, -3.1 to 19.7). However, overestimation of GFR by 10 to 20 mL/minute/1.73m2 is common in patients with cirrhosis with most equations in ascites and/or kidney dysfunction. A tailored approach is required especially for decisions regarding dual-organ transplantation.

Management of acute kidney injury associated with Covid-19: what have we learned?

PURPOSE OF REVIEW: Although initially kidney involvement in COVID-19 infection was felt to occur relatively infrequently, this has proved not to be the case. In critically ill patients with COVID-19, multiorgan failure including acute kidney injury (AKI) is common and is associated with an increased risk of mortality and morbidity. This review focuses briefly on the epidemiology and pathophysiology of COVID-19 associated AKI as well as options for management. RECENT FINDINGS: The risk factors for AKI are common to both noncovid-related AKI and COVID-19 associated AKI. Kidney injury in COVID-19 associated AKI may arise through several mechanisms, including not only direct effects on the kidney leading to tubular injury but also through the effects of treatment of multiorgan failure complicating infection. During surge conditions, the use of kidney replacement therapy has embraced all modalities including the use of peritoneal dialysis. The use of blood purification techniques has been proposed, but to date, the results are variable. SUMMARY: COVID-19 associated AKI is common, affecting approximately a quarter of patients hospitalized with COVID-19. Glomerular injury can occur, but in the main tubular injury seems most likely leading to AKI, which should be managed following clinical pathways informed by accepted guidelines.

Advances in management of hepatorenal syndrome.

PURPOSE OF REVIEW: Hepatorenal syndrome (HRS) is encountered frequently in patients with end-stage liver disease and remains an important cause of morbidity and mortality in this patient population. This review will focus and provide updates on pathophysiology, assessment of kidney function, new definitions, and treatment and prevention of HRS. RECENT FINDINGS: Pathophysiology of HRS has been elucidated more recently and in addition to hemodynamic changes, the role of systemic inflammatory response contributes significantly to this process. Assessment of kidney function in patients with liver cirrhosis remains challenging. Novel glomerular filtration rate equations have been developed in patients with liver disease to better estimate kidney function and changes made in the definition of acute kidney injury (AKI), which are more aligned with KDIGO criteria for AKI. Vasoconstrictors, especially terlipressin, along with albumin remain the mainstay of pharmacological treatment of HRS-AKI. Biomarkers have been useful in differentiating ATN from HRS at an early stage. SUMMARY: HRS remains a significant cause of morbidity and mortality for patients with end-stage liver disease. Newer understanding of mechanisms in development and pathophysiology of HRS have helped with elucidation of the disease process.

Extrapulmonary manifestations of severe acute respiratory syndrome coronavirus-2 infection.

Coronavirus disease 2019, the infectious disease caused by severe acute respiratory syndrome coronavirus-2, has resulted in a global pandemic with unprecedented health, societal, and economic impact. The disease often manifests with flu-like symptoms and is dominated by pulmonary complications, but widely diverse clinical manifestations involving multiple organ systems can result. We posit that viral tropism and the aberrant host immune response mediate the protean findings and severity in this disease. In general, extrapulmonary manifestations are a harbinger of or contemporaneously associate with disease progression, but in the case of some extrapulmonary findings (gastrointestinal and dermatologic), may track with milder disease. The precise underlying pathophysiological mechanisms remain incompletely elucidated, and additional immune phenotyping studies are warranted to reveal early correlates of disease outcomes and novel therapeutic targets.

MELD-GRAIL-Na: Glomerular Filtration Rate and Mortality on Liver-Transplant Waiting List.

BACKGROUND AND AIMS: Among patients with cirrhosis awaiting liver transplantation, prediction of wait-list (WL) mortality is adjudicated by the Model for End Stage Liver Disease-Sodium (MELD-Na) score. Replacing serum creatinine (SCr) with estimated glomerular filtration rate (eGFR) in the MELD-Na score may improve prediction of WL mortality, especially for women and highest disease severity. APPROACH AND RESULTS: We developed (2014) and validated (2015) a model incorporating eGFR using national data (n = 17,095) to predict WL mortality. Glomerular filtration rate (GFR) was estimated using the GFR assessment in liver disease (GRAIL) developed among patients with cirrhosis. Multivariate Cox proportional hazard analysis models were used to compare the predicted 90-day WL mortality between MELD-GRAIL-Na (re-estimated bilirubin, international normalized ratio [INR], sodium, and GRAIL) versus MELD-Na. Within 3 months, 27.8% were transplanted, 4.3% died on the WL, and 4.7% were delisted for other reasons. GFR as estimated by GRAIL (hazard ratio [HR] 0.382, 95% confidence interval [CI] 0.344-0.424) and the re-estimated model MELD-GRAIL-Na (HR 1.212, 95% CI 1.199-1.224) were significant predictors of mortality or being delisted on the WL within 3 months. MELD-GRAIL-Na was a better predictor of observed mortality at highest deciles of disease severity (≥ 27-40). For a score of 32 or higher (observed mortality 0.68), predicted mortality was 0.67 (MELD-GRAIL-Na) and 0.51 (MELD-Na). For women, a score of 32 or higher (observed mortality 0.67), the predicted mortality was 0.69 (MELD-GRAIL-Na) and 0.55 (MELD-Na). In 2015, use of MELD-GRAIL-Na as compared with MELD-Na resulted in reclassification of 16.7% (n = 672) of patients on the WL. CONCLUSION: Incorporation of eGFR likely captures true GFR better than SCr, especially among women. Incorporation of MELD-GRAIL-Na instead of MELD-Na may affect outcomes for 12%-17% awaiting transplant and affect organ allocation.

A Model for Glomerular Filtration Rate Assessment in Liver Disease (GRAIL) in the Presence of Renal Dysfunction.

Estimation of glomerular filtration rate (eGFR) in patients with liver disease is suboptimal in the presence of renal dysfunction. We developed a model for GFR assessment in liver disease (GRAIL) before and after liver transplantation (LT). GRAIL was derived using objective variables (creatinine, blood urea nitrogen, age, gender, race, and albumin) to estimate GFR based on timing of measurement relative to LT and degree of renal dysfunction (www.bswh.md/grail). The measured GFR (mGFR) by iothalamate clearance (n = 12,122, 1985-2015) at protocol time points before/after LT was used as reference. GRAIL was compared with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD-4, MDRD-6) equations for mGFR < 30 mL/min/1.73 m2 . Prediction of development of chronic kidney disease (mGFR < 20 mL/min/1.73 m2 , initiation of chronic dialysis) and listing or receipt of kidney transplantation within 5 years was examined in internal cohort (n = 785) and external validation (n = 68,217, 2001-2015). GRAIL had less bias and was more accurate and precise as compared with CKD-EPI, MDRD-4, and MDRD-6 at time points before/after LT for low GFR. For mGFR < 30 mL/min/1.73 m2 , the median difference (eGFR-mGFR) was GRAIL: 5.24 (9.65) mL/min/1.73 m2 as compared with CKD-EPI: 8.70 (18.24) mL/min/1.73 m2 , MDRD-4: 8.82 (17.38) mL/min/1.73 m2 , and MDRD-6: 6.53 (14.42) mL/min/1.73 m2 . Before LT, GRAIL correctly classified 75% as having mGFR < 30 mL/min/1.73 m2 versus 36.1% (CKD-EPI), 36.1% (MDRD-4), and 52.8% (MDRD-6) (P < 0.01). An eGFR < 30 mL/min/1.73 m2 by GRAIL predicted development of CKD (26.9% versus 4.6% CKD-EPI, 5.9% MDRD-4, and 10.5% MDRD-6) in center data and needing kidney after LT (48.3% versus 22.0% CKD-EPI versus 23.1% MDRD-4 versus 48.3% MDRD-6, P < 0.01) in national data within 5 years after LT. Conclusion: GRAIL may serve as an alternative model to estimate GFR among patients with liver disease before and after LT at low GFR.

News in pathophysiology, definition and classification of hepatorenal syndrome: A step beyond the International Club of Ascites (ICA) consensus document.

Renal dysfunction is a common, life-threatening complication occurring in patients with liver disease. Hepatorenal syndrome (HRS) has been defined as a purely "functional" type of renal failure that often occurs in patients with cirrhosis in the setting of marked abnormalities in arterial circulation, as well as overactivity of the endogenous vasoactive systems.4,5 In 2007, the International Club of Ascites (ICA) classified HRS into types 1 and 2 (HRS-1 and HRS-2).5 HRS-1 is characterised by a rapid deterioration of renal function that often occurs because of a precipitating event, while HRS-2 is a moderate and stable or slowly progressive renal dysfunction that often occurs without an obvious precipitant. Clinically, HRS-1 is characterised by acute renal failure while HRS-2 is mainly characterised by refractory ascites. Nevertheless, after these two entities were first described, new concepts, definitions, and diagnostic criteria have been developed by nephrologists for renal dysfunction in the general population and hospitalised patients. In particular, the definitions and characterisation of acute kidney injury (AKI), acute kidney disease and chronic kidney disease have been introduced/refined.6 Accordingly, a debate among hepatologists of the ICA led to a complete revision of the nomenclature and diagnosistic criteria for HRS-1, which was renamed HRS-AKI.7 Additionally, over recent years, greater granularity has been gained regarding the pathogenesis of HRS; it is now increasingly recognised that it is not a purely "functional" entity with haemodynamic derangements, but that systemic inflammation, oxidative stress and bile salt-related tubular damage may contribute significantly to its development. That is, HRS has an additional structural component that would not only make traditional diagnostic criteria less reliable, but would explain the lack of response to pharmacological treatment with vasoconstrictors plus albumin that correlates with a progressive increase in inflammation. Because classification, nomenclature, diagnostic criteria and pathogenic theories have evolved over the years since the traditional classification of HRS-1 and HRS-2 was first described, it was considered that all these novel aspects be reviewed and summarised in a position paper. The aim of this position paper authored by two hepatologists (members of ICA) and two nephrologists involved in the study of renal dysfunction in cirrhosis, is to complete the re-classification of HRS initiated by the ICA in 2012 and to provide an update on the definition, classification, diagnosis, pathophysiology and treatment of HRS.