Publications by authors named "Mitra K Nadim"

54 Publications

Urinary NGAL as a Diagnostic and Prognostic Marker for Acute Kidney Injury in Cirrhosis: A Prospective Study.

Clin Transl Gastroenterol 2021 May 11;12(5):e00359. Epub 2021 May 11.

Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.

Introduction: Urinary neutrophil gelatinase-associated lipocalin (NGAL) has shown promise in differentiating acute tubular necrosis (ATN) from other types of acute kidney injuries (AKIs) in cirrhosis, particularly hepatorenal syndrome (HRS). However, NGAL is not currently available in clinical practice in North America.

Methods: Urinary NGAL was measured in a prospective cohort of 213 US hospitalized patients with decompensated cirrhosis (161 with AKI and 52 reference patients without AKI). NGAL was assessed for its ability to discriminate ATN from non-ATN AKI and to predict 90-day outcomes.

Results: Among patients with AKI, 57 (35%) had prerenal AKI, 55 (34%) had HRS, and 49 (30%) had ATN, with a median serum creatinine of 2.0 (interquartile range 1.5, 3.0) mg/dL at enrollment. At an optimal cutpoint of 244 μg/g creatinine, NGAL distinguished ATN (344 [132, 1,429] μg/g creatinine) from prerenal AKI (45 [0, 154] μg/g) or HRS (110 [50, 393] μg/g; P < 0.001), with a C statistic of 0.762 (95% confidence interval 0.682, 0.842). By 90 days, 71 of 213 patients (33%) died. Higher median NGAL was associated with death (159 [50, 865] vs 58 [0, 191] μg/g; P < 0.001). In adjusted and unadjusted analysis, NGAL significantly predicted 90-day transplant-free survival (P < 0.05 for all Cox models) and outperformed Model for End-Stage Liver Disease score by C statistic (0.697 vs 0.686; P = 0.04), net reclassification index (37%; P = 0.008), and integrated discrimination increment (2.7%; P = 0.02).

Discussion: NGAL differentiates the type of AKI in cirrhosis and may improve prediction of mortality; therefore, it holds potential to affect management of AKI in cirrhosis.
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http://dx.doi.org/10.14309/ctg.0000000000000359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116001PMC
May 2021

Postoperative acute kidney injury in adult non-cardiac surgery: joint consensus report of the Acute Disease Quality Initiative and PeriOperative Quality Initiative.

Nat Rev Nephrol 2021 May 11. Epub 2021 May 11.

Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA.

Postoperative acute kidney injury (PO-AKI) is a common complication of major surgery that is strongly associated with short-term surgical complications and long-term adverse outcomes, including increased risk of chronic kidney disease, cardiovascular events and death. Risk factors for PO-AKI include older age and comorbid diseases such as chronic kidney disease and diabetes mellitus. PO-AKI is best defined as AKI occurring within 7 days of an operative intervention using the Kidney Disease Improving Global Outcomes (KDIGO) definition of AKI; however, additional prognostic information may be gained from detailed clinical assessment and other diagnostic investigations in the form of a focused kidney health assessment (KHA). Prevention of PO-AKI is largely based on identification of high baseline risk, monitoring and reduction of nephrotoxic insults, whereas treatment involves the application of a bundle of interventions to avoid secondary kidney injury and mitigate the severity of AKI. As PO-AKI is strongly associated with long-term adverse outcomes, some form of follow-up KHA is essential; however, the form and location of this will be dictated by the nature and severity of the AKI. In this Consensus Statement, we provide graded recommendations for AKI after non-cardiac surgery and highlight priorities for future research.
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http://dx.doi.org/10.1038/s41581-021-00418-2DOI Listing
May 2021

Post-Liver Transplant Acute Kidney Injury.

Liver Transpl 2021 May 8. Epub 2021 May 8.

Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, Canada.

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 (CKD) and reducing graft and patient survival. Multiple definitions of AKI have been proposed and utilized throughout the years with the International Club of Ascites (ICA) definition being the most widely used now for cirrhosis patients. Multiple factors are associated with 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 need for immunosuppression as certain immunosuppressive medications can be nephrotoxic. The calcineurin inhibitor (CNI) tacrolimus is the mainstay of immunosuppression but can result in AKI. Several strategies including use of the monoclonoal antibody basilixamab to allow for delayed tacrolimus start and minimization or elimination of tacrolimus through combination with mycophenolate mofetil (MMF) or mammalian target of rapamycin (mTOR) 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 post-LT. Overall by improving renal function in post-LT patients with AKI, outcomes can be improved.
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http://dx.doi.org/10.1002/lt.26094DOI Listing
May 2021

Diagnosis, evaluation, and management of ascites and hepatorenal syndrome.

Hepatology 2021 May 3. Epub 2021 May 3.

Stanford University, Division of Gastroenterology and Hepatology, Palo Alto, California, USA.

This is a comprehensive guidance on the diagnosis, evaluation, and management of ascites and hepatorenal syndrome in patients with chronic liver disease from the American Association for the Study of Liver Diseases (AASLD). It replaces the prior AASLD guideline on the same topic published in 2012 (1).
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http://dx.doi.org/10.1002/hep.31884DOI Listing
May 2021

Chronic Kidney Disease after Simultaneous Liver Kidney Transplantation: Refining Patient Selection.

Liver Transpl 2021 Apr 20. Epub 2021 Apr 20.

Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

The number of simultaneous liver kidney transplantations (SLKT) performed in the United States have steadily increased over the last 15 years: approximately 1 out of 10 liver transplantations is a dual organ transplant.(1) Given the disparity between availability of donor organs and recipients awaiting transplant and the increasing numbers of patients on the waitlist with MELD ≥ 40 with the majority having acute kidney injury (AKI), the number of patients who will qualify for SLKT will most likely continue to increase.(2) Over the years, the transplant community has refined SLKT listing criteria in order to ensure appropriate utilization of kidney organs given the increasing numbers of SLKT.(2, 3) In 2017, new criteria were formalized to set up a "sustained AKI" and "chronic kidney disease" (CKD) criteria for listing for SLKT.
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http://dx.doi.org/10.1002/lt.26075DOI Listing
April 2021

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

Dig Dis Sci 2021 Mar 24. Epub 2021 Mar 24.

Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine, 3400 Civic Center Boulevard, 4th Floor, South Pavilion, Philadelphia, PA, 19104, USA.

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 m 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.
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http://dx.doi.org/10.1007/s10620-021-06943-1DOI Listing
March 2021

Hepatorenal Syndrome.

Crit Care Clin 2021 Apr 15;37(2):321-334. Epub 2020 Dec 15.

Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, 1520 San Pablo Street, Suite 4300, Los Angeles, CA 90033, USA. Electronic address:

Development of acute kidney injury in patients with chronic liver disease is common and portends a poor prognosis. Diagnosis remains challenging, as traditional markers, such as serum creatinine, are not reliable. Recent development of novel biomarkers may assist with this. Pathophysiology of this condition is multifactorial, relating to physiologic changes associated with portal hypertension, kidney factors, and systemic inflammatory response. Mainstay of treatment remains use of vasoconstrictors along with albumin. Recent guidelines streamline the selection of patients that will require simultaneous liver and kidney transplantation. Posttransplant kidney injury is common relating to multiple factors.
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http://dx.doi.org/10.1016/j.ccc.2020.11.011DOI Listing
April 2021

Simultaneous heart-kidney transplant: Working together to define when one organ is not enough.

Am J Transplant 2021 Mar 15. Epub 2021 Mar 15.

Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

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http://dx.doi.org/10.1111/ajt.16564DOI Listing
March 2021

Acute kidney disease and cirrhosis.

J Hepatol 2021 Mar 24;74(3):500-501. Epub 2020 Nov 24.

Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

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http://dx.doi.org/10.1016/j.jhep.2020.11.006DOI Listing
March 2021

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

J Med Virol 2021 05 1;93(5):2645-2653. Epub 2020 Dec 1.

Department of Medicine, University of Southern California, Los Angeles, California, USA.

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.
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http://dx.doi.org/10.1002/jmv.26595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675751PMC
May 2021

COVID-19-associated acute kidney injury: consensus report of the 25th Acute Disease Quality Initiative (ADQI) Workgroup.

Nat Rev Nephrol 2020 12 15;16(12):747-764. Epub 2020 Oct 15.

Division of Nephrology, Department of Medicine, University of Alabama, Birmingham, AL, USA.

Kidney involvement in patients with coronavirus disease 2019 (COVID-19) is common, and can range from the presence of proteinuria and haematuria to acute kidney injury (AKI) requiring renal replacement therapy (RRT; also known as kidney replacement therapy). COVID-19-associated AKI (COVID-19 AKI) is associated with high mortality and serves as an independent risk factor for all-cause in-hospital death in patients with COVID-19. The pathophysiology and mechanisms of AKI in patients with COVID-19 have not been fully elucidated and seem to be multifactorial, in keeping with the pathophysiology of AKI in other patients who are critically ill. Little is known about the prevention and management of COVID-19 AKI. The emergence of regional 'surges' in COVID-19 cases can limit hospital resources, including dialysis availability and supplies; thus, careful daily assessment of available resources is needed. In this Consensus Statement, the Acute Disease Quality Initiative provides recommendations for the diagnosis, prevention and management of COVID-19 AKI based on current literature. We also make recommendations for areas of future research, which are aimed at improving understanding of the underlying processes and improving outcomes for patients with COVID-19 AKI.
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http://dx.doi.org/10.1038/s41581-020-00356-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561246PMC
December 2020

Sepsis-associated acute kidney injury: is COVID-19 different?

Kidney Int 2020 12 10;98(6):1370-1372. Epub 2020 Sep 10.

Intensive Care Unit, Royal Surrey Hospital NHS Foundation Trust, Guildford, United Kingdom & Department of Clinical & Experimental Medicine, University of Surrey, Guildford, UK.

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http://dx.doi.org/10.1016/j.kint.2020.08.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481835PMC
December 2020

Community Health Care Quality Standards to Prevent Acute Kidney Injury and Its Consequences.

Am J Med 2020 05 10;133(5):552-560.e3. Epub 2019 Dec 10.

Renal Department, St. James's University Hospital, Leeds, UK; NIHR Diagnostic Evidence Co-operative, Leeds, UK.

As the incidence of acute kidney injury (AKI) increases, prevention strategies are needed across the health care continuum, which begins in the community. Recognizing this knowledge gap, the 22nd Acute Disease Quality Initiative (ADQI) was tasked to discuss the evidence for quality-of-care measurement and care processes to prevent AKI and its consequences in the community. Using a modified Delphi process, an international and interdisciplinary group provided a framework to identify and monitor patients with AKI in the community. The recommendations propose that risk stratification involve both susceptibilities (eg, chronic kidney disease) and exposures (eg, coronary angiography), with the latter triggering a Kidney Health Assessment. This assessment should include blood pressure, serum creatinine, and urine dipstick, followed by a Kidney Health Response to prevent AKI that encompasses cessation of unnecessary medications, minimization of nephrotoxins, patient education, and ongoing monitoring until the exposure resolves. These recommendations give community health care providers and health systems a starting point for quality improvement initiatives to prevent AKI and its consequences in the community.
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http://dx.doi.org/10.1016/j.amjmed.2019.10.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724764PMC
May 2020

Reply to: "Lack of evidence for a continuum between hepatorenal syndrome and acute tubular necrosis".

J Hepatol 2020 03 4;72(3):582-583. Epub 2019 Dec 4.

Division of Nephrology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.

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http://dx.doi.org/10.1016/j.jhep.2019.11.005DOI Listing
March 2020

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

Hepatology 2020 05 29;71(5):1766-1774. Epub 2020 Jan 29.

Baylor University Medical Center, Dallas, TX.

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.
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http://dx.doi.org/10.1002/hep.30932DOI Listing
May 2020

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

J Hepatol 2019 10 11;71(4):811-822. Epub 2019 Jul 11.

Division of Nephrology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.

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. In 2007, the International Club of Ascites (ICA) classified HRS into types 1 and 2 (HRS-1 and HRS-2). 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. 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. 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.
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http://dx.doi.org/10.1016/j.jhep.2019.07.002DOI Listing
October 2019

Quality Improvement Goals for Acute Kidney Injury.

Clin J Am Soc Nephrol 2019 06 17;14(6):941-953. Epub 2019 May 17.

Division of Nephrology, Department of Medicine, University of Michigan, Ann Arbor, Michigan; and.

AKI is a global concern with a high incidence among patients across acute care settings. AKI is associated with significant clinical consequences and increased health care costs. Preventive measures, as well as rapid identification of AKI, have been shown to improve outcomes in small studies. Providing high-quality care for patients with AKI or those at risk of AKI occurs across a continuum that starts at the community level and continues in the emergency department, hospital setting, and after discharge from inpatient care. Improving the quality of care provided to these patients, plausibly mitigating the cost of care and improving short- and long-term outcomes, are goals that have not been universally achieved. Therefore, understanding how the management of AKI may be amenable to quality improvement programs is needed. Recognizing this gap in knowledge, the 22nd Acute Disease Quality Initiative meeting was convened to discuss the evidence, provide recommendations, and highlight future directions for AKI-related quality measures and care processes. Using a modified Delphi process, an international group of experts including physicians, a nurse practitioner, and pharmacists provided a framework for current and future quality improvement projects in the area of AKI. Where possible, best practices in the prevention, identification, and care of the patient with AKI were identified and highlighted. This article provides a summary of the key messages and recommendations of the group, with an aim to equip and encourage health care providers to establish quality care delivery for patients with AKI and to measure key quality indicators.
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http://dx.doi.org/10.2215/CJN.01250119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556737PMC
June 2019

Hepatorenal Syndrome.

Clin J Am Soc Nephrol 2019 05 17;14(5):774-781. Epub 2019 Apr 17.

Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California

Hepatorenal syndrome is a severe complication of end-stage cirrhosis characterized by increased splanchnic blood flow, hyperdynamic state, a state of decreased central volume, activation of vasoconstrictor systems, and extreme kidney vasoconstriction leading to decreased GFR. The contribution of systemic inflammation, a key feature of cirrhosis, in the development of hepatorenal syndrome has been highlighted in recent years. The mechanisms by which systemic inflammation precipitates kidney circulatory changes during hepatorenal syndrome need to be clarified. Early diagnosis is central in the management and recent changes in the definition of hepatorenal syndrome help identify patients at an earlier stage. Vasoconstrictive agents (terlipressin in particular) and albumin are the first-line treatment option. Several controlled studies proved that terlipressin is effective at reversing hepatorenal syndrome and may improve short-term survival. Not all patients are responders, and even in responders, early mortality rates are very high in the absence of liver transplantation. Liver transplantation is the only curative treatment of hepatorenal syndrome. In the long term, patients transplanted with hepatorenal syndrome tend to have lower GFR compared with patients without hepatorenal syndrome. Differentiating hepatorenal syndrome from acute tubular necrosis (ATN) is often a challenging yet important step because vasoconstrictors are not justified for the treatment of ATN. Hepatorenal syndrome and ATN may be considered as a continuum rather than distinct entities. Emerging biomarkers may help differentiate these two conditions and provide prognostic information on kidney recovery after liver transplantation, and potentially affect the decision for simultaneous liver-kidney transplantation.
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http://dx.doi.org/10.2215/CJN.12451018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500947PMC
May 2019

Acute kidney injury in cirrhosis: implications for liver transplantation.

Curr Opin Crit Care 2019 04;25(2):171-178

Department of Critical Care Medicine.

Purpose Of Review: Acute kidney injury (AKI) in cirrhosis consists of varying phenotypes, with hepatorenal syndrome (HRS) representing a single entity. Prompt recognition and diagnosis of AKI cause identifies appropriate therapeutic measures. This review provides an overview of AKI definitions, highlights challenges in quantifying renal impairment in cirrhosis, lists novel diagnostic AKI biomarkers, and summarizes transplantation implications.

Recent Findings: Biomarkers (neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, interleukin-18, and liver-type fatty acid-binding protein) may assist in the identification of underlying acute tubular necrosis. Of these, neutrophil gelatinase-associated lipocalin is the most promising; however, significant overlap occurs among AKI phenotypes, with diagnostic values yet to be defined. Mainstay treatment of HRS consists of albumin and vasopressors. Acute-on-chronic liver failure grade independently predicts response to terlipressin treatment. Many end-stage liver disease patients with AKI have underlying chronic kidney disease with important implications on pre and postliver transplantation mortality. Simultaneous liver-kidney transplant candidacy is based on low likelihood of renal recovery.

Summary: Novel biomarkers may assist in identification of acute tubular necrosis and persistent/severe AKI. Norepinephrine has been suggested to be inferior to terlipressin, with additional research required. Increasing acute-on-chronic liver failure grade correlates with lower likelihood of vasopressor response in HRS. Severe preliver transplantation AKI confers significantly worse postliver transplantation renal outcomes.
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http://dx.doi.org/10.1097/MCC.0000000000000590DOI Listing
April 2019

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

Hepatology 2019 03 20;69(3):1219-1230. Epub 2019 Feb 20.

Baylor University Medical Center, Dallas, TX.

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 m . Prediction of development of chronic kidney disease (mGFR < 20 mL/min/1.73 m , 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 m , the median difference (eGFR-mGFR) was GRAIL: 5.24 (9.65) mL/min/1.73 m as compared with CKD-EPI: 8.70 (18.24) mL/min/1.73 m , MDRD-4: 8.82 (17.38) mL/min/1.73 m , and MDRD-6: 6.53 (14.42) mL/min/1.73 m . Before LT, GRAIL correctly classified 75% as having mGFR < 30 mL/min/1.73 m versus 36.1% (CKD-EPI), 36.1% (MDRD-4), and 52.8% (MDRD-6) (P < 0.01). An eGFR < 30 mL/min/1.73 m 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.
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http://dx.doi.org/10.1002/hep.30321DOI Listing
March 2019

Author Correction: Hepatorenal syndrome.

Nat Rev Dis Primers 2018 Oct 15;4(1):33. Epub 2018 Oct 15.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.

The original version of this article omitted an initial from the name of contributing author Patrick S. Kamath, who was listed as Patrick Kamath. The article has now been corrected.
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http://dx.doi.org/10.1038/s41572-018-0035-2DOI Listing
October 2018

Hepatorenal syndrome.

Nat Rev Dis Primers 2018 09 13;4(1):23. Epub 2018 Sep 13.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.

Hepatorenal syndrome (HRS) is a form of kidney function impairment that characteristically occurs in cirrhosis. Recent changes in terminology have led to acute HRS being referred to as acute kidney injury (AKI)-HRS and chronic HRS as chronic kidney disease (CKD)-HRS. AKI-HRS is characterized by a severe impairment of kidney function owing to vasoconstriction of the renal arteries in the absence of substantial abnormalities in kidney histology. Pathogenetic mechanisms involve disturbances in circulatory function due to a marked splanchnic arterial vasodilation, which triggers the activation of vasoconstrictor factors. An intense systemic inflammatory reaction that is characteristic of advanced cirrhosis may also be involved. The main triggering factors of AKI-HRS are bacterial infections, particularly spontaneous bacterial peritonitis. The diagnosis of AKI-HRS is a challenge because of a lack of specific diagnostic tools and mainly involves the differential diagnosis from other forms of AKI, particularly acute tubular necrosis. The prognosis of patients with AKI-HRS is poor, with a median survival of ≤3 months. The ideal treatment for AKI-HRS is liver transplantation in patients without contraindications. Medical therapy consists of vasoconstrictor drugs to counteract splanchnic arterial vasodilation together with volume expansion with albumin. Effective measures to prevent AKI-HRS include early identification and treatment of bacterial infections and the administration of albumin in patients with spontaneous bacterial peritonitis.
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http://dx.doi.org/10.1038/s41572-018-0022-7DOI Listing
September 2018

Acute Kidney Injury After Liver Transplantation.

Transplantation 2018 10;102(10):1636-1649

Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA.

Since the implementation of the Model of End-stage Liver Disease score-based allocation system, the number of transplant candidates with impaired renal function has increased. The aims of this review are to present new insights in the definitions and predisposing factors that result in acute kidney injury (AKI), and to propose guidelines for the prevention and treatment of postliver transplantation (LT) AKI. This review is based on both systematic review of relevant literature and expert opinion. Pretransplant AKI is associated with posttransplant morbidity, including prolonged post-LT AKI which then predisposes to posttransplant chronic kidney disease. Prevention of posttransplant AKI is essential in the improvement of long-term outcomes. Accurate assessment of baseline kidney function at evaluation is necessary, taking into account that serum creatinine overestimates glomerular filtration rate. New diagnostic criteria for AKI have been integrated with traditional approaches in patients with cirrhosis to potentially identify AKI earlier and improve outcomes. Delayed introduction or complete elimination of calcineurin inhibitors during the first weeks post-LT in patients with early posttransplant AKI may improve glomerular filtration rate in high risk patients but with higher rates of rejection and more adverse events. Biomarkers may in the future provide diagnostic information such as etiology of AKI, and prognostic information on renal recovery post-LT, and potentially impact the decision for simultaneous liver-kidney transplantation. Overall, more attention should be paid to pretransplant and early posttransplant AKI to reduce the burden of late chronic kidney disease.
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http://dx.doi.org/10.1097/TP.0000000000002305DOI Listing
October 2018

Proenkephalin (PENK) as a Novel Biomarker for Kidney Function.

J Appl Lab Med 2017 Nov;2(3):400-412

Department of Intensive Care, Radboud University Medical Centre, Nijmegen, the Netherlands.

Background: The assessment of kidney function and detection of acute kidney injury (AKI) remain cumbersome. On the one hand, because of limited accuracy of established tests: The most widely used methods are creatinine based, which lack in sensitivity, as creatinine is not purely filtrated by the kidney and rises relatively late after onset of AKI. On the other hand, because of labor-intensiveness: Gold standard inulin clearance and comparable methods involve intravenous compound infusion, blood sampling at several time points, and have error-sensitive determination methods. In recent years, several biomarkers have been put forward (e.g., NGAL, KIM-1, TIMP-2*IGFBP-7), but clinical implementation is limited up to now.

Content: Proenkephalin (PENK) represents a new candidate to determine kidney function. This peptide is cleaved from the precursor peptide preproenkephalin A alongside enkephalins (endogenous opioids) and is filtrated in the glomerulus. PENK plasma concentration appears to accurately represent glomerular filtration rate in patients diagnosed with sepsis or cardiac diseases. Moreover, increased PENK concentration is found to be associated with longer-term outcome concerning AKI and cardiac diseases. Lastly, the predominant receptor of enkephalins, the δ-opioid receptor, is expressed with the highest density in the kidney, suggesting that enkephalins could also exert a direct effect on kidney function.

Summary: In this review, we present an overview of enkephalins and the assessment of kidney function using this possible new functional biomarker PENK and compare it with established and novel biomarkers.
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http://dx.doi.org/10.1373/jalm.2017.023598DOI Listing
November 2017

Renal dysfunction and cirrhosis.

Curr Opin Crit Care 2017 Dec;23(6):457-462

aHepatology & Liver Intensive Care, Hospital Beaujon, Clichy, University Paris Diderot, Paris, France bDivisions of Critical Care Medicine and Hepatology, University of Kansas Medical Center, Kansas City, Kansas cDivision of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, California, USA.

Purpose Of Review: Hepatorenal syndrome (HRS) does not represent the predominant phenotype of acute kidney injury (AKI) in cirrhosis. Early recognition of HRS helps initiate appropriate therapy. The aims of this review are to present redefinition of AKI, to list new biomarkers, to report recent data on vasopressors in HRS and to propose criteria for simultaneous liver and kidney transplantation (SLKT).

Recent Findings: Urine output, which was not part of the definition of AKI might be reconsidered as it has an independent prognostic value. Biomarkers (NGAL and IL-18) could help identify ATN. However, cut-off values have to be clarified. Vasopressors with albumin represent first option in HRS. Continuous infusion of terlipressin has a better safety profile than intravenous boluses. SLKT should be considered whenever native kidney recovery is unlikely [i.e. prolonged renal replacement therapy (RRT) and/or GFR less than 25 ml/min for 6 weeks prior to transplantation].

Summary: New definitions and recent biomarkers may help differentiate HRS from ATN at an earlier stage. Urine output should be reconsidered in the definitions. Even in patients who are not candidates for transplantation, a short trial of RRT is justified whenever needed. SLKT should be considered whenever posttransplant renal recovery is unlikely.
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http://dx.doi.org/10.1097/MCC.0000000000000457DOI Listing
December 2017

Inequity in organ allocation for patients awaiting liver transplantation: Rationale for uncapping the model for end-stage liver disease.

J Hepatol 2017 09 5;67(3):517-525. Epub 2017 May 5.

Division of Hepatobiliary, Pancreas, and Abdominal Organ Transplant Surgery, University of Southern California, Los Angeles, CA, United States.

Background & Aim: The goal of organ allocation is to distribute a scarce resource equitably to the sickest patients. In the United States, the Model for End-stage Liver Disease (MELD) is used to allocate livers for transplantation. Patients with greater MELD scores are at greater risk of death on the waitlist and are prioritized for liver transplant (LT). The MELD is capped at 40 however, and patients with calculated MELD scores >40 are not prioritized despite increased mortality. We aimed to evaluate waitlist and post-transplant survival stratified by MELD to determine outcomes in patients with MELD >40.

Methods: Using United Network for Organ Sharing data, we identified patients listed for LT from February 2002 through to December 2012. Waitlist candidates with MELD ⩾40 were followed for 30days or until the earliest occurrence of death or transplant.

Results: Of 65,776 waitlisted patients, 3.3% had MELD ⩾40 at registration, and an additional 7.3% had MELD scores increase to ⩾40 after waitlist registration. A total of 30,369 (46.2%) underwent LT, of which 2,615 (8.6%) had MELD ⩾40 at transplant. Compared to MELD 40, the hazard ratio of death within 30days of registration was 1.4 (95% CI 1.2-1.6) for patients with MELD 41-44, 2.6 (95% CI 2.1-3.1) for MELD 45-49, and 5.0 (95% CI 4.1-6.1) for MELD ⩾50. There was no difference in 1- and 3-year survival for patients transplanted with MELD >40 compared to MELD=40. A survival benefit associated with LT was seen as MELD increased above 40.

Conclusions: Patients with MELD >40 have significantly greater waitlist mortality but comparable post-transplant outcomes to patients with MELD=40 and, therefore, should be given priority for LT. Uncapping the MELD will allow more equitable organ distribution aligned with the principle of prioritizing patients most in need. Lay summary: In the United States (US), organs for liver transplantation are allocated by an objective scoring system called the Model for End-stage Liver Disease (MELD), which aims to prioritize the sickest patients for transplant. The greater the MELD score, the greater the mortality without liver transplant. The MELD score, however, is artificially capped at 40 and thus actually disadvantages the sickest patients with end-stage liver disease. Analysis of the data advocates uncapping the MELD score to appropriately prioritize the patients most in need of a liver transplant.
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http://dx.doi.org/10.1016/j.jhep.2017.04.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735955PMC
September 2017

Intensive care unit management: Renal replacement therapy, ventilator management, volume assessment, and optimal management of hypotension.

Clin Liver Dis (Hoboken) 2017 Mar 30;9(3):69-72. Epub 2017 Mar 30.

Departments of Internal Medicine and Surgery, Hepatology and Critical Care Medicine University of Kansas Medical Center Kansas City KS.

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http://dx.doi.org/10.1002/cld.621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467146PMC
March 2017

Sustained Reduction of Blood Pressure With Baroreceptor Activation Therapy: Results of the 6-Year Open Follow-Up.

Hypertension 2017 May 20;69(5):836-843. Epub 2017 Mar 20.

From the Department of Medicine, Maastricht University Medical Center and Cardiovascular Research Institute Maastricht (CARIM), The Netherlands (P.W.d.L., A.A.K.); Department of Medicine, Zuyderland Medisch Centrum, Sittard, The Netherlands (P.W.d.L.); Department of Medicine, University of Rochester, NY (J.D.B.); Department of Medicine, University of Chicago Medicine, IL (G.L.B.); Department of Medicine, University of Southern California, Los Angeles (M.K.N.); and Department of Nephrology, Medizinische Hochschule Hannover, Germany (H.H.).

Baroreflex activation therapy is a novel technique for treating patients with resistant hypertension. Although short-term studies have demonstrated that it lowers blood pressure, long-term results have not yet been reported. The aim of the present study is to assess the long-term efficacy and safety of baroreflex activation therapy. Long-term follow-up data were analyzed from all patients who had been included in 1 of the 3 trials that focused on treatment-resistant hypertensive patients. Altogether, 383 patients were available for analysis: 143 of these had completed 5 years of follow-up and 48 patients had completed 6 years of follow-up. In the entire cohort, office systolic blood pressure fell from 179±24 mm Hg to 144±28 mm Hg (<0.0001), whereas office diastolic pressure dropped from 103±16 mm Hg to 85±18 mm Hg (<0.0001). Heart rate fell from 74±15 beats per minute to 71±13 beats per minute (<0.02). The effect of baroreflex activation therapy is greater than average in patients with signs of heart failure and less than average in patients with isolated systolic hypertension. In ≈25% of patients, it was possible to reduce the number of medications from a median of 6 to a median of 3. Temporary side effects, related to either the surgical procedure or the cardiovascular instability, do occur, but they do not require specific measures and resolve over time.After a follow-up of 6 years, baroreflex activation therapy maintains its efficacy for persistent reduction of office blood pressure in patients with resistant hypertension without major safety issues.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.117.09086DOI Listing
May 2017