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REVIEW Preventing and Treating Acute Kidney Injury Among Hospitalized Patients with Cirrhosis and Ascites: A Narrative Review Elliot B. Tapper, MD,a Alan Bonder, MD,a Andres Cardenas, MD, MMSc, PhDb a Division of Gastroenterology/Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass; bGI/Liver Unit, Hospital Clinic, Institut de Malalties Digestives i Metaboliques, University of Barcelona, Spain. ABSTRACT Acute kidney injury in the setting of ascites and cirrhosis is a medical emergency characterized by significant morbidity and mortality. Clinicians other than gastroenterologists are often the front line against acute kidney injury for patients with ascites. Owing to the specifics of cirrhotic physiology, the treatment and prevention of acute kidney injury in the setting of ascites has unique features, widespread knowledge of which will benefit our patients with cirrhosis. Early detection and treatment of infection, maximization of cardiac output, and avoidance of medications that limit cardiorenal adaptations to arterial underfilling are part of a multipronged strategy to protect the renal function of our patients with cirrhosis and ascites. Ó 2016 Elsevier Inc. All rights reserved. The American Journal of Medicine (2016) 129, 461-467 KEYWORDS: Hepatorenal syndrome; Hospitalist; Liver disease; Paracentesis; Spontaneous bacterial peritonitis Cirrhosis is a common comorbidity among hospitalized patients in the US. As up to 50% of patients with cirrhosis develop ascites,1 it is, unsurprisingly, a common factor in many admissions. In 2012 alone, there were more than 380,000 hospital discharges for patients with cirrhosis and ascites at American hospitals.2 Owing to unique aspects of cirrhotic hemodynamics and renal physiology, patients with ascites are highly vulnerable to acute kidney injury. Importantly, the definition of renal injury in the setting of cirrhosis and ascites is based largely on changes relative to the patient’s baseline. Given the frequency of sarcopenia in this population, relying on serum creatinine levels alone may overestimate renal function.3,4 Funding: EBT was supported by a grant from the Carl J. Shapiro Institute for Education and Research. No other authors received any financial support for this study. Conflict of Interest: No author has any conflicts of interest to disclose. Authorship: EBT is the guarantor of this article. Concept and writing: EBT; acquisition of data: EBT, AB, AC; critical revision: AB, AC. All authors approved this manuscript. Requests for reprints should be addressed to Elliot B. Tapper, MD, Division of Gastroenterology/Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA 02115. E-mail address: [email protected] 0002-9343/$ -see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2015.12.006 The most devastating complication of ascites is an extreme form of renal injury termed “type 1 hepatorenal syndrome.” Type 1 hepatorenal syndrome occurs with an 8% annual incidence among patients with ascites and heralds a median survival of 2 weeks without treatment.5 It is defined in part by recently adjusted criteria that include an acute increase in the serum creatinine by at least 0.3 mg/dL or a 50% increase from the patient’s baseline (ie, stage 1 acute kidney injury) that is unresponsive to standard therapy for prerenal azotemia.3 The rapidity and severity of type 1 hepatorenal syndrome is contrasted with the so-called type 2 hepatorenal syndrome, which is felt to reflect the same underlying physiology but is characterized by a slower, lower increase in creatinine and increased risk for type 1 hepatorenal syndrome6,7 (Table). Compared to patients with ascites without renal injury, those with type 2 hepatorenal syndrome have reduced overall survival (6 months).6 In many hospitals, nongastroenterologists admit the majority of patients with ascites and are therefore the front line against renal injury.8 What transpires for these patients early in their hospital course may prove critical to their renal function. Early detection and treatment of infection, maintaining a balanced hyperdynamic circulation, and avoidance of medications that limit cardiorenal adaptations to arterial underfilling are part of a multipronged strategy to protect the 462 The American Journal of Medicine, Vol 129, No 5, May 2016 renal function of patients with cirrhosis and ascites. Herein, we will review a physiology-driven approach to the prevention and treatment of renal injury in patients with cirrhosis and ascites. Diminished venous return results in an instantaneous decrease in stroke volume that is addressed immediately through 3 coordinated cardiorenal mechanisms (Figure 1). First, carotid baroreceptors fire in response to volume/ pressure changes, causing catecholamine release to compensate via chronotropic and inotropic adaptations.13 FROM PHYSIOLOGY TO Indeed, even at rest, the heart of THERAPY a patient with cirrhosis is hyperCLINICAL SIGNIFICANCE dynamic,14 often at a rate Progressive hepatic injury and exceeding that of noncirrhotic fibrosis leads to cirrhosis, which is Patients with cirrhosis complicated by controls.15 Second, the same broadly characterized by 2 feaascites are at markedly increased risk of baroreceptor reflex leads to a tures: architectural disruption with renal failure. nonosmotic release of antidiuretic resultant interference with intra All patients with ascites must be hormone to facilitate water recaphepatic blood flow (portal hyperture in the kidney as well as peassessed for spontaneous bacterial tension) and diminished metabolic ripheral vasoconstriction.16,17 The capacity of the liver. Resistance to peritonitis with a paracentesis immediresult is increased plasma volume intrahepatic blood flow caused by ately upon admission. even while arteries remain underfibrosis and intrahepatic endothe The new definition of acute renal failure filled.6 Third, a lower sensed lial dysfunction,9 in turn, leads to in patients with cirrhosis is an increase arterial volume leads to the actiportal hypertension and the forin serum creatinine 0.3 mg/dL within vation of the renin-angiotensin mation of varices with portosys48 hours or 50% from baseline. system to induce further renal temic shunting and therefore, salt avidity and peripheral vasodecreased delivery of blood to the Hold beta-blockers if a patient with constriction, which is active prevena cava.10 Portal hypertension cirrhosis and ascites develops kidney dominantly in the efferent also leads to gut-barrier dysfuncinjury. glomerular arterioles, thereby tion complicated by the transmaintaining intraglomerular location of bacterial products into perfusion pressures.6 the splanchnic vasculature11 with consequent production of This balance between cardiac stimulation and vasoconinflammatory cytokines and splanchnic nitric oxide.12 striction is precarious. Many patients do well without Additionally, abnormal liver metabolism leads to increased complications. Over time, however, cardiac reserve fades or splanchnic concentrations of vasodilatory neurotransmitters vasodilation progresses and the result is an inability to derived from the enteric nervous system.6 This cirrhotic maintain sufficient cardiac output. Peripheral water retention double hit produces one immediate consequence: decreased progresses, and chronic renal insufficiency ensues, typified venous return. Table Definition of Terms Term Definition Acute kidney injury (AKI)* Stage 1 Stage 2 Stage 3 Type 1 hepatorenal syndrome (HRS)* Type 2 hepatorenal syndrome Spontaneous bacterial peritonitis a. b. c. d. e. Increase in serum creatinine 0.3 mg/dL within 48 hours or 50% from baseline Increase in serum creatinine two- to threefold from baseline Increase in serum creatinine > threefold from baseline or 4 mg/dL Cirrhosis and ascites are present AKI, as above No creatinine response after 2 days of held diuretics and albumin challenge Absence of shock, no recent nephrotoxins (eg, nonsteroidal antiinflammatory drugs, iodinated contrast) Exclusion of structural renal disease: tubular necrosis, glomerulonephritis, proteinuria, or obstructive nephropathy (could all be seen in or comorbid with HRS) a. Cirrhosis and ascites are present b. Limited response to diuretics (refractory ascites) c. Moderate, steady decrease in renal function, typically occurring over months with creatinine <2.5 mg/dL Paracentesis with a neutrocytic ascites (cell count >250 neutrophils/mm3) or ascitic fluid culture positive. *New definitions as of 2015: see reference.3 Tapper et al Protecting Cirrhotic Kidneys Figure 1 463 Cirrhotic hemodynamics and the response to arterial underfilling. by diuretic resistant or refractory ascites and the slow increase in serum creatinine described as Type 2 hepatorenal syndrome.1 Type 1 hepatorenal syndrome, on the other hand, is a rapid injury that reflects a catastrophically upset hemodynamic balance.5,6 Spontaneous bacterial peritonitis is a frequent inciting event.7,18 A common infection among patients with cirrhosis, spontaneous bacterial peritonitis induces profound splanchnic and peripheral vasodilation, further exacerbating deficits in venous return. Inotropic stimulation cannot compensate for such deficits in preload. When sudden arterial underfilling is addressed through further vasoconstriction, the result is a rapid and severe renal injury. Leveraging the pathophysiology of renal injury in this setting allows the clinician to quickly and, it is hoped, effectively address it. To maintain renal perfusion, one must ensure adequate circulating blood volume with a favorable balance between cardiac output and vasoconstriction. APPLYING THE THEORY When hospitalized, patients with ascites either have or are at risk for acute kidney injury. There are multiple generic ways in which one can forestall the development of renal injury by maintaining the patient’s effective circulating volume (Figure 2). First and foremost, all patients with ascites should have a paracentesis on admission to exclude spontaneous bacterial peritonitis.19-22 Spontaneous bacterial peritonitis can present very subtly and often asymptomatically.1,23 Furthermore, prompt recognition and therapy is critical to prevent hepatorenal syndrome and shock—a delay in diagnosis by as little as 12 hours is associated with a 2.7-fold increased risk of in-hospital death.24 When spontaneous bacterial peritonitis is diagnosed, whether by neutrocytic ascites (> 250 neutrophils per cubic millimeter) or culture positivity, immediate provision of appropriate antibiotics is essential (eg, 2 grams of ceftriaxone daily for empiric treatment of communityacquired spontaneous bacterial peritonitis).25 Beyond that, while those with jaundice will benefit most, all patients at present should receive albumin for hepatorenal syndrome prophylaxis using 1.5 g/kg on day 1 and 1 g/kg on day 3 of diagnosis.26 Second, patients with cirrhosis and ascites are at increased risk of contrast nephropathy and therefore, benefit from efforts to prevent exposure to or reduce the volume of iodinated contrast exposure.27 Third, routine monitoring of urine output and temporary withholding of diuretics during times of low oral intake are generally indicated. Fourth, prevention of spontaneous bacterial peritonitis can help patients avoid hepatorenal syndrome. Although somewhat controversial given the risk for developing resistant organisms, well-selected patients with elevated bilirubin (> 3 mg/dL) and low ascitic total protein (< 1.5 g/dL) may benefit from antibiotic prophylaxis, usually with a fluoroquinolone.28,29 When a patient with ascites presents with acute kidney injury, multiple maneuvers are needed (Figure 2). First, consideration of the broader differential diagnosis is crucial.30 Evaluation of the urine sediment and withholding potentially nephrotoxic agents should be routine. 464 The American Journal of Medicine, Vol 129, No 5, May 2016 Figure 2 A therapeutic approach to the patient with ascites. ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; g/kg ¼ grams per kilogram; GI/Liver ¼ Gastroenterology; NGAL ¼ neutrophil gelatinase-associated lipocalin; NSAIDS ¼ nonsteroidal antiinflammatory drugs. Nonhepatorenal syndrome acute kidney injury has a more favorable outcome.31 However, the distinction between hepatorenal syndrome or prerenal azotemia and acute tubular necrosis can be difficult. Unfortunately, urine microscopy is often inconclusive or nonspecific.32 There is considerable interest and promise in urinary biomarkers such as neutrophil gelatinase-associated lipocalin, a protease expressed in the distal convoluted tubule. Fagundes et al33 demonstrated that patients with tubular necrosis had urinary neutrophil gelatinase-associated lipocalin concentrations that were several-fold higher than those with hepatorenal syndrome. Patients with tubular necrosis had a median of 417 mg/g creatinine, compared with 30 mg/g in volume-depletion-related azotemia and 76 mg/g in patients with hepatorenal syndrome. Further research is needed to confirm the optimal cutoffs in the setting of changing definitions of acute kidney injury and heterogeneous populations, particularly in view of frequent concentration overlap between etiologies.3,31,33,34 Second, it is critical to distinguish between simple prerenal azotemia and hepatorenal syndrome. Functionally, this distinction is based on the outcome of volume expansion. An “albumin challenge” is therefore recommended. Common scenarios prompting this presentation include largevolume paracentesis (particularly without prophylactic albumin infusion), complications of diuresis, infection, and resolved gastrointestinal bleeding. Recently revised recommendations from the International Club of Ascites suggest as initial therapy the withholding of diuretics and 2 days of albumin infusion at 1 g/kg.3 Given the risk of pulmonary edema and respiratory failure after albumin infusion,35,36 caution is warranted. We recommend serial cardiopulmonary examinations and consideration of albumin dosereductions patients with known cardiomyopathy and significant renal failure. The magnitude of creatinine elevation at the time of presentation is associated directly with the odds of renal injury resolution and survival, implying that pretreatment factors partially determine patient outcomes.37 Specifically, the prehospital duration of renal injury is prognostic, as are baseline creatinine levels.37 Additionally, there is no incremental survival benefit to earlier albumin infusion within the first 48 hours.36 Therefore, with sufficient time for a thorough evaluation and careful exclusion of other causes, a deliberate approach to renal injury is safe and effective. Third, a thoughtful examination of the medication list on admission is essential to be sure to hold diuretics, discontinue angiotensin-converting enzyme inhibitors, alpha-antagonists (eg, tamsulosin), and avoid nonsteroidal antiinflammatories (NSAIDs).1 Pain should never be treated with NSAIDs in patients with ascites. Renal prostaglandin production may be the only counterbalance to catecholamine- and angiotensin-induced Tapper et al Protecting Cirrhotic Kidneys glomerular vasoconstriction in the afferent arteriole; NSAIDs reduce prostaglandin production, which, for patients with ascites, will reduce glomerular filtration rate.38,39 Finally, cardiac compensation may be essential to renal recovery. For example, the purpose of albumin infusion is the preservation of cardiac output by supporting stroke volume in the setting of arterial underfilling, especially in the setting of infections.10,26 Beta-blockade, however, limits chronotropic and inotropic cardiac compensation and may, therefore, defeat the purpose of volume expansion. Increasingly, beta-blockade is viewed as possessing a therapeutic index.40 Eventually, the benefits, be it primary prophylaxis of variceal hemorrhage or prevention of spontaneous bacterial peritonitis, are outweighed by the risks of decreased cardiac output, particularly acute kidney injury.40-42 The development of spontaneous bacterial peritonitis is likely the most clear-cut example of an event that heralds diminishing returns and increased risks of beta-blockade. Indeed, as shown by Mandorfer et al,43 beta-blockers increase transplant-free survival in patients with a history of ascites but not spontaneous bacterial peritonitis, while the risk of death is increased for patients who continue betablockers after a first episode of spontaneous bacterial peritonitis. In order to maximize cardiac output and mean arterial pressure during renal failure, beta-blockers, including those prescribed for variceal bleeding prophylaxis, should be held at least temporarily.40,42,44,45 TREATMENT OF HEPATORENAL SYNDROME A failure to respond to volume expansion and exclusion of nephrotoxic agents and other causes of renal injury merits initiation vasoconstrictor therapy (Table).1,3 The underlying premise of vasoconstrictor therapy is that splanchnic vasodilation prevents the intended improvements in effective arterial volume related to albumin infusion. In this setting, agents that constrict the splanchnic vasculature augment cardiac output by enhancing cardiac venous return and improve renal perfusion.46 Vasoconstrictor therapies include midodrine (an oral alpha-agonist and vasopressor) and octreotide (a serotonin antagonist that likely reverses some splanchnic vasodilation), norepinephrine (a vasopressor), or terlipressin (a vasopressor) where available with additional volume expansion.29 All vasoconstrictors should include cotherapy with 10-20 grams of albumin daily.1 Terlipressin delivered in a continuous infusion without a bolus at 3 mg/24 hours up-titrated to 12 mg/24 hours if the serum creatinine failed to decrease by > 25% of the initial value provides significant benefit to patients with hepatorenal syndrome, with a superior rate of renal recovery in a randomized trial compared with midodrine and octreotide.35 This study was stopped early for efficacy when 48 Italian patients with mean model for end-stage liver disease scores of roughly 30 were enrolled; 55.5% of patients receiving terlipressin achieved reversal of renal failure, compared with 4.8% on midodrine/octreotide. As nonresponders were offered a rescue therapy, many patients 465 randomized to midodrine/octreotide ultimately received terlipressin. In general, the factors associated with poor response include total bilirubin 10 mg/dL, failure to increase mean arterial pressure > 5 mm Hg, or lack of an absolute serum creatinine reduction > 0.5 mg/dL by the third day of therapy.47 Terlipressin, however, is not approved for use in the US. This is partly because a randomized, double-blind, placebocontrolled trial that employed bolus dosing with 1 mg of terlipressin administered by slow intravenous push every 6 hours or matching placebo failed to achieve a survival advantage over albumin monotherapy in this population.48 Furthermore, while early trials were suggestive of significant benefits,49,50 they also highlighted the risk of side effects on treatment, including abdominal cramps and ischemic extremities. These risks may be more likely in the setting of bolus delivery, as opposed to continuous infusions, as continuous terlipressin use was not associated with risks over octreotide/midodrine.35 Side effects leading to treatment discontinuation occur in roughly 7% of cases. Nevertheless, a meta-analysis of prior trials including bolus therapy still demonstrated a mortality benefit over albumin monotherapy or no intervention (relative risk 0.76; 96% confidence interval, 0.63-0.91).51 Three studies have evaluated the role for norepinephrine infusions in the treatment of hepatorenal syndrome,52-54 2 in comparison with terlipressin in randomized controlled trials.52,54 In the largest study, 46 patients were randomized to receive terlipressin or norepinephrine (with albumin).54 Norepinephrine was provided in continuous infusion, 0.5 mg/h initially, with stepwise increases every 4 hours up to a maximum of 3 mg/h, with the goal of a 10-mm Hg increase in mean arterial pressure or a 200-mL increase in the 4-hour urine output. Responses were achieved in 39.1% and 43.4% of patients receiving terlipressin and norepinephrine, respectively. Unfortunately, terlipressin may have been under-dosed, limiting the interpretation of the data. Boluses were given at initial doses of 0.5 mg/6 hours, with stepwise increases every 3 days if a 1 mg/dL reduction in serum creatinine was not achieved. Additionally, norepinephrine use generally is restricted to the intensive care unit, increasing its cost and limiting its application. In general, patients on vasoconstrictor therapy must be monitored closely. This includes serial blood pressure and heart rate checks, particularly in view of a risk of bradycardia as well as extremity examinations. Response to treatment via serum creatinine levels should be assessed at least every 48 hours and continued for 24 hours beyond the point of a complete response or for a maximum of 14 days.35 Finally, particularly if renal function deteriorates, the risk of pulmonary edema with ongoing albumin infusions and, as such, rigorous cardiopulmonary examinations should be performed routinely.36 For centers without access to terlipressin, the standard therapy for hepatorenal syndrome should include daily infusions of albumin (10-20 grams), midodrine at doses up to 12.5 mg 3 times per day to achieve an increase in mean 466 systolic blood pressure of 15 mm Hg, and octreotide titrated from 100 to 200 mg subcutaneously 3 times daily.1 Octreotide alone is ineffective.55 As above, the expected outcomes are somewhat poor.35 However, there is still a small benefit. In a study of 87 patients with type 1 hepatorenal syndrome, 21 of whom received no intervention (66 who received midodrine/octreotide), sustained reductions in serum creatinine were observed in 40% of patients on therapy, compared with 5% of those without.56 Ultimately, for poor outcomes, hemodialysis is the major salvage therapy, particularly for patients who are transplant candidates. Beyond that, there is ongoing study about the role of a transjugular intrahepatic portosystemic shunt for highly selected patients with largely preserved hepatic function. CONCLUSION Acute kidney injury in the setting of ascites and cirrhosis is a medical emergency characterized by significant morbidity and mortality. Owing to the specifics of cirrhotic physiology, the treatment of acute kidney injury in the setting of ascites has unique features, widespread knowledge of which will benefit our patients with cirrhosis. The basic principles of cirrhotic hemodynamics inform an effective approach to the diagnosis and treatment of patients with ascites. References 1. Runyon BA. Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline management of adult patients with ascites due to cirrhosis 2012. Hepatology. 2013;57: 1651-1653. 2. U.S. Department of Health and Human Services, Agency for Healthcare Research and Quality. National statistics for ascites discharges. Available at: http://hcupnet.ahrq.gov/HCUPnet.jsp. 2012. Accessed August 1, 2015. 3. Angeli P, Gines P, Wong F, et al. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. Gut. 2015;64(4): 531-537. 4. Tapper EB, Jiang ZG, Patwardhan VR. Refining the ammonia hypothesis: a physiology-driven approach to the treatment of hepatic encephalopathy. Mayo Clin Proc. 2015;90(5):646-658. 5. Gines A, Escorsell A, Gines P, et al. Incidence, predictive factors, and prognosis of the hepatorenal syndrome in cirrhosis with ascites. Gastroenterology. 1993;105:229-236. 6. Arroyo V, Guevara M, Ginès P. Hepatorenal syndrome in cirrhosis: pathogenesis and treatment. Gastroenterology. 2002;122:1658-1676. 7. Follo A, Llovet JM, Navasa M, et al. Renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, clinical course, predictive factors and prognosis. Hepatology. 1994;20:1495-1501. 8. Mellinger JL, Volk ML. Multidisciplinary management of patients with cirrhosis: a need for care coordination. Clin Gastroenterol Hepatol. 2013;11:217-223. 9. Gupta TK, Toruner M, Chung MK, Groszmann RJ. Endothelial dysfunction and decreased production of nitric oxide in the intrahepatic microcirculation of cirrhotic rats. Hepatology. 1998;28(4):926-931. 10. Gines P, Schrier RW. Renal failure in cirrhosis. N Engl J Med. 2009;361:1279-1290. 11. Reiberger T, Ferlitsch A, Payer BA, et al. Non-selective betablocker therapy decreases intestinal permeability and serum levels of LBP and IL-6 in patients with cirrhosis. J Hepatol. 2013;58:911-921. The American Journal of Medicine, Vol 129, No 5, May 2016 12. Epstein FH, Martin P-Y, Ginès P, Schrier RW. Nitric oxide as a mediator of hemodynamic abnormalities and sodium and water retention in cirrhosis. N Engl J Med. 1998;339:533-541. 13. Henriksen J, Ring-Larsen H, Kanstrup I, Christensen N. Splanchnic and renal elimination and release of catecholamines in cirrhosis. Evidence of enhanced sympathetic nervous activity in patients with decompensated cirrhosis. Gut. 1984;25:1034-1043. 14. Kowalski HJ, Abelmann WH. The cardiac output at rest in Laennec’s cirrhosis. J Clin Invest. 1953;32:1025-1033. 15. Møller S, Wiinberg N, Henriksen JH. Noninvasive 24-hour ambulatory arterial blood pressure monitoring in cirrhosis. Hepatology. 1995;22: 88-95. 16. Gines P, Berl T, Bernardi M, et al. Hyponatremia in cirrhosis: from pathogenesis to treatment. Hepatology. 1998;28:851-864. 17. Sigal SH. Hyponatremia in cirrhosis. J Hosp Med. 2012;7:S14-S17. 18. Barreto R, Fagundes C, Guevara M, et al. Type-1 hepatorenal syndrome associated with infections in cirrhosis: natural history, outcome of kidney function, and survival. Hepatology. 2014;59:1505-1513. 19. European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol. 2010;53(3):397-417. 20. Ghaoui R, Friderici J, Desilets DJ, et al. Outcomes associated with a mandatory gastroenterology consultation to improve the quality of care of patients hospitalized with decompensated cirrhosis. J Hosp Med. 2015;10(4):236-241. 21. Brooling J, Ghaoui R, Lindenauer PK, Friderici J, Lagu T. Use of paracentesis in hospitalized patients with decompensated cirrhosis and ascites: Opportunities for quality improvement. J Hosp Med. 2014;9: 797-799. 22. Ghaoui R, Friderici J, Visintainer P, Lindenauer PK, Lagu T, Desilets D. Measurement of the quality of care of patients admitted with decompensated cirrhosis. Liver Int. 2014;34:204-210. 23. Runyon BA. Monomicrobial nonneutrocytic bacterascites: a variant of spontaneous bacterial peritonitis. Hepatology. 1990;12:710-715. 24. Kim JJ, Tsukamoto MM, Mathur AK, et al. Delayed paracentesis is associated with increased in-hospital mortality in patients with spontaneous bacterial peritonitis. Am J Gastroenterol. 2014;109:1436-1442. 25. Mazer L, Tapper EB, Piatkowski G, Lai M. The need for antibiotic stewardship and treatment standardization in the care of cirrhotic patients with spontaneous bacterial peritonitisea retrospective cohort study examining the effect of ceftriaxone dosing. F1000Res. 2014;3, Available at: http://f1000research.com/articles/3-57/v2, Accessed January 2, 2016. 26. Sort P, Navasa M, Arroyo V, et al. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med. 1999;341:403-409. 27. Traub SJ, Kellum JA, Tang A, Cataldo L, Kancharla A, Shapiro NI. Risk factors for radiocontrast nephropathy after emergency department contrast-enhanced computerized tomography. Acad Emerg Med. 2013;20(1):40-45. 28. Fernández J, Navasa M, Planas R, et al. Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology. 2007;133:818-824. 29. Bonder A, Botero ML, Cardenas A. Current therapies for hepatorenal syndrome. Curr Hepatol Rep. 2014;13:74-80. 30. Cooper CM, Fenves AZ. Before you call renal: acute kidney injury for hospitalists. J Hosp Med. 2015;10(6):403-408. 31. Fagundes C, Barreto R, Guevara M, et al. A modified acute kidney injury classification for diagnosis and risk stratification of impairment of kidney function in cirrhosis. J Hepatol. 2013;59:474-481. 32. Perazella MA, Coca SG, Kanbay M, Brewster UC, Parikh CR. Diagnostic value of urine microscopy for differential diagnosis of acute kidney injury in hospitalized patients. Clin J Am Soc Nephrol. 2008;3:1615-1619. 33. Fagundes C, Pépin M-N, Guevara M, et al. Urinary neutrophil gelatinase-associated lipocalin as biomarker in the differential diagnosis of impairment of kidney function in cirrhosis. J Hepatol. 2012;57:267-273. Tapper et al Protecting Cirrhotic Kidneys 34. Verna EC, Brown RS, Farrand E, et al. Urinary neutrophil gelatinaseassociated lipocalin predicts mortality and identifies acute kidney injury in cirrhosis. Dig Dis Sci. 2012;57:2362-2370. 35. Cavallin M, Kamath PS, Merli M, et al. Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: a randomized trial. Hepatology. 2015;62(2): 567-574. 36. Afinogenova Y, Tapper EB. The efficacy and safety profile of albumin administration for patients with cirrhosis at high risk of hepatorenal syndrome is dose dependent. Gastroenterol Rep (Oxf). 2015;3(3): 216-221. 37. Piano S, Rosi S, Maresio G, et al. Evaluation of the Acute Kidney Injury Network criteria in hospitalized patients with cirrhosis and ascites. J Hepatol. 2013;59:482-489. 38. Zipser RD, Radvan GH, Duke IR, Little TE, Kronborg J. Urinary thromboxane B2 and prostaglandin E2 in the hepatorenal syndrome: evidence for increased vasoconstrictor and decreased vasodilator factors. Gastroenterology. 1983;84:697-703. 39. Boyer TD, Zia P, Reynolds TB. Effect of indomethacin and prostaglandin A, on renal function and plasma renin activity in alcoholic liver disease. Gastroenterology. 1979;77:215-222. 40. Phillip SG, Runyon BA. The changing role of beta-blocker therapy in patients with cirrhosis. J Hepatol. 2014;60:643-653. 41. Sersté T, Francoz C, Durand F, et al. Beta-blockers cause paracentesis-induced circulatory dysfunction in patients with cirrhosis and refractory ascites: a cross-over study. J Hepatol. 2011;55: 794-799. 42. Sersté T, Melot C, Francoz C, et al. Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites. Hepatology. 2010;52:1017-1022. 43. Mandorfer M, Bota S, Schwabl P, et al. Nonselective b blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis. Gastroenterology. 2014;146(7):1680e1-1690e1. 44. Wong F, Salerno F. Beta-blockers in cirrhosis: friend and foe? Hepatology. 2010;52:811-813. 467 45. Krag A, Bendtsen F, Henriksen JH, Møller S. Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites. Gut. 2010;59:105-110. 46. Cárdenas A. Hepatorenal syndrome: a dreaded complication of endstage liver disease. Am J Gastroenterol. 2005;100:460-467. 47. Nazar A, Pereira GH, Guevara M, et al. Predictors of response to therapy with terlipressin and albumin in patients with cirrhosis and type 1 hepatorenal syndrome. Hepatology. 2010;51:219-226. 48. Sanyal AJ, Boyer T, GarciaeTsao G, et al. A randomized, prospective, double-blind, placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome. Gastroenterology. 2008;134:1360-1368. 49. Moreau R, Durand F, Poynard T, et al. Terlipressin in patients with cirrhosis and type 1 hepatorenal syndrome: a retrospective multicenter study. Gastroenterology. 2002;122:923-930. 50. Ortega R, Gines P, Uriz J, et al. Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: results of a prospective, nonrandomized study. Hepatology. 2002;36:941-948. 51. Gluud LL, Christensen K, Christensen E, Krag A. Terlipressin for hepatorenal syndrome. Cochrane Database Syst Rev. 2012;9: CD005162. 52. Alessandria C, Ottobrelli A, Debernardi-Venon W, et al. Noradrenalin vs terlipressin in patients with hepatorenal syndrome: a prospective, randomized, unblinded, pilot study. J Hepatol. 2007;47:499-505. 53. Duvoux C, Zanditenas D, Hézode C, et al. Effects of noradrenalin and albumin in patients with type I hepatorenal syndrome: a pilot study. Hepatology. 2002;36:374-380. 54. Singh V, Ghosh S, Singh B, et al. Noradrenaline vs. terlipressin in the treatment of hepatorenal syndrome: a randomized study. J Hepatol. 2012;56:1293-1298. 55. Pomier-Layrargues G, Paquin SC, Hassoun Z, Lafortune M, Tran A. Octreotide in hepatorenal syndrome: a randomized, double-blind, placebo-controlled, crossover study. Hepatology. 2003;38:238-243. 56. Esrailian E, Pantangco ER, Kyulo NL, Hu K-Q, Runyon BA. Octreotide/midodrine therapy significantly improves renal function and 30-day survival in patients with type 1 hepatorenal syndrome. Dig Dis Sci. 2007;52:742-748.