Renal dysfunction is a frequent complication in decompensated cirrhosis with its ominous significance reflected in inclusion of serum creatinine (sCr) in the Model for End-stage Liver Disease (MELD). Because of the latter's role in organ allocation, the number of patients with renal dysfunction undergoing liver transplantation (LT) has increased compared with the pre-MELD era (1).
PATHOPHYSIOLOGY OF RENAL DYSFUNCTION IN CIRRHOSIS
Renal dysfunction in cirrhosis can be classified into 2 broad categories: (i) renal dysfunction reflecting circulatory disturbances characteristic of decompensated cirrhosis (i.e., hepatorenal syndrome [HRS]), and (ii) renal dysfunction independent of hemodynamic derangements of cirrhosis (i.e., volume depletion, drug-induced nephrotoxicity, glomerulopathies).
Decompensated cirrhosis is associated with marked splanchnic vasodilatation, decreased effective arterial blood volume, renal hypoperfusion, and activation of the renin-angiotensin system. This in turn induces nonosmotic hypersecretion of antidiuretic hormone with intrarenal vasoconstriction and sodium and free-water retention. Intercurrent events such as hypovolemia (i.e., gastroesophageal variceal hemorrhage, excessive diuresis, profuse lactulose-induced diarrhea) or further vasodilatation (i.e., infections) can disturb the delicate compensatory hemodynamic balance in patients with cirrhosis leading to a rapid decline of renal function.
Nonalcoholic fatty liver disease and chronic kidney disease share risk factors, most notably diabetes mellitus and hypertension; however, recent data suggest that nonalcoholic fatty liver disease per se may be an independent risk factor for renal dysfunction even in the absence of cirrhosis (2). Potential mechanisms may include activation of the renin-angiotensin system, pro-inflammatory cytokines, and oxidative stress.
Glomerulopathies associated with hepatitis B and C such as membranous and membranoproliferative glomerulonephritis and vasculitidies (polyarteritis nodosa and mixed cryoglobulinemia) may be responsible for renal dysfunction. Presence of proteinuria, hematuria, and/or abnormal sediment on urinalysis is an important diagnostic clues, and additional testing includes serum cryoglobulins, complement levels, rheumatoid factor, and occasionally renal biopsy (3).
DEFINITIONS OF ACUTE AND CHRONIC RENAL DYSFUNCTION IN CIRRHOSIS
Although there are several definitions for acute kidney injury (AKI), the most widely used in cirrhosis includes increase in sCr by ≥0.3 mg/dL within 48 hours or ≥1.5 times baseline within 7 days (4,5). Importantly, clinicians must recognize that a sCr of 0.9 mg/dL (within normal range) may represent AKI if the level was 0.5 mg/dL or lower within the previous 48 hours (because it represents an increase by 0.4 mg/dL or 1.8 times the baseline). AKI in cirrhosis is stratified into 3 stages (Table 1).
sCr as a measure of renal function has important limitations in cirrhosis. Diminished muscle mass and increased tubular secretion of creatinine result in spuriously low sCr levels, potentially significantly overestimating renal function. Furthermore, hyperbilirubinemia interferes with estimation of sCr levels by some widely used commercial assays. Similar to the general population, sCr levels are lower in women than in men, and this physiologic variation is not accounted by the MELD score, resulting in sex disparities in LT and waitlist mortality (6). Commonly used formulas to estimate the glomerular filtration rate (GFR) such as the Modification of Diet in Renal Disease, chronic kidney disease-Epidemiology Collaboration, and the Cockroft-Gault include sCr and consequently frequently overestimate renal function in patients with cirrhosis (7). Although accurate markers of GFR exist, their applicability in clinical practice is limited (Table 2).
HRS is defined as renal dysfunction in patients with cirrhosis in the absence of an identifiable cause. The criteria for diagnosing HRS is summarized in Table 3.
MANAGEMENT OF RENAL DYSFUNCTION IN PATIENTS WITH CIRRHOSIS
Management of AKI in cirrhosis and HRS type 1 is summarized in Figure 1. Prompt identification of potential causes of renal dysfunction permits implementation of specific interventions that mitigate its clinical course (Table 4). Initial workup should include ultrasonography to evaluate the renal parenchyma and rule out urinary obstruction, urine studies (urinalysis, sediment, culture, urine electrolytes, urine protein, and urine creatinine), and blood cultures.
Diuretics, vasodilators, nonsteroidal anti-inflammatory drugs, and nephrotoxic agents should be discontinued immediately on recognition of AKI. If profuse diarrhea has occurred from lactulose therapy (or other laxatives), the dose and/or frequency of administration of this agent should be reduced.
Cautious expansion of intravascular blood volume is recommended with the type of fluid used dictated by the etiology of AKI: crystalloids for volume depletion due to diarrhea or excessive diuresis, and albumin for hypoperfusion due to infections, HRS type 1, or when the cause of AKI is unclear. The use of vasoconstrictors in addition to volume expansion with intravenous albumin reduces short-term mortality in patients with HRS type 1 compared with albumin alone (8). The choice of vasoconstrictor depends on availability of these agents, familiarity, and the level of care: midodrine and octreotide are commonly used in nonintensive care settings, whereas norepinephrine infusion requires intensive care monitoring and central venous access. Some evidence suggests that albumin in combination with norepinephrine may be superior to albumin plus midodrine and octreotide in reversing HRS type 1 (8). Although not licensed in the United States, the vasopressin analogue terlipressin appears to be more effective in reversing HRS type 1 when used in combination with albumin compared with midodrine and octreotide (9). The role of terlipressin for treatment of HRS type 2 is less well-defined.
Renal replacement therapy, usually in the form of dialysis, may be considered for selected patients with HRS type 1 who fail to respond to medical therapies and are candidates for LT (as a bridge to this intervention) or for those expected to recover from a reversible form of liver injury.
Transjugular intrahepatic portosystemic shunt may improve sCr and GFR in patients with HRS; however, its benefit is only short-term, particularly in HRS type 1, and complications are a major concern.
Effective antiviral therapy for hepatitis B or C typically improves renal function in patients with glomerulopathies related to these viruses (10). Importantly, selection of antiviral regimens must be guided by the severity of renal dysfunction and renal clearance of individual antiviral agents.
PROGNOSIS OF PATIENTS WITH CIRRHOSIS AND RENAL DYSFUNCTION
Renal dysfunction is associated with diminished survival of patients with cirrhosis, although there are striking differences depending on specific renal insults. HRS type 1 is associated with the worst median survival in the absence of LT: 34 weeks for patients with MELD scores <20 and 4 weeks for those with MELD scores ≥20 (11). Restoration of hepatic function after LT is associated with resolution of HRS type 1 in 76% of patients. The duration of dialysis before transplantation appears to be the only reliable predictive factor for nonreversal of HRS following LT, with a 6% increased risk of nonreversal with each additional day on dialysis (12). HRS type 2 follows a more protracted clinical course and is associated with a median survival of 6 months (13). Similar to the general population, acute tubular necrosis in patients with cirrhosis can reflect various renal insults; however, it is associated with much higher 6-month mortality in patients with cirrhosis not undergoing LT (14).
INDICATIONS FOR SIMULTANEOUS LIVER-KIDNEY TRANSPLANTATION
Renal insufficiency is an important predictor of poor outcomes after isolated LT; thus, it is imperative to identify candidates who are best served by simultaneous liver-kidney (SLK) transplantation during the evaluation process (15). Current criteria for SLK transplantation are summarized in Table 5.
Renal dysfunction from various causes is commonly encountered in patients with cirrhosis and is associated with markedly diminished survival. Efforts must be directed at avoiding renal insults in this population and promptly identifying potentially reversible causes of renal dysfunction. HRS, particularly type 1, is associated with extremely poor survival in the absence of LT but frequently resolves after transplant. Medical therapy with volume expansion and vasoconstrictors may improve or reverse HRS, typically serving as a bridge to LT. Specific criteria have been set to determine eligibility for SLK transplantation and should be followed in clinical practice.
CONFLICTS OF INTEREST
Guarantor of the article: Paul Martin, MD, FACG.
Specific author contributions: A.F.C. and P.M. drafted the entire manuscript including tables and figures and approved the final version.
Financial support: None.
Potential competing interests: None.
1. Gonwa TA, McBride MA, Anderson K, et al. Continued influence of preoperative renal function on outcome of orthotopic liver transplant (OLTX) in the US: Where will MELD lead us? Am J Transplant 2006;6(11):2651–9.
2. Huh JH, Kim JY, Choi E, et al. The fatty liver index as a predictor of incident chronic kidney disease in a 10-year prospective cohort study. PLoS One 2017;12(7):e0180951.
3. Shah AS, Amarapurkar DN. Spectrum of hepatitis B and renal involvement. Liver Int 2018;38(1):23–32.
4. Palevsky PM, Liu KD, Brophy PD, et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for acute kidney injury. Am J Kidney Dis 2013;61(5):649–72.
5. Angeli P, Ginès 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. J Hepatol 2015;62(4):968–74.
6. Mindikoglu AL, Regev A, Seliger SL, et al. Gender disparity in liver transplant waiting-list mortality: The importance of kidney function. Liver Transplant 2010;16(10):1147–57.
7. MacAulay J, Thompson K, Kiberd BA, et al. Serum creatinine in patients with advanced liver disease is of limited value for identification of moderate renal dysfunction: Are the equations for estimating renal function better? Can J Gastroenterol 2006;20(8):521–6.
8. Facciorusso A, Chandar AK, Murad MH, et al. Comparative efficacy of pharmacological strategies for management of type 1 hepatorenal syndrome: A systematic review and network meta-analysis. Lancet Gastroenterol Hepatol 2017;2(2):94–102.
9. 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):567–74.
10. Yang Y, Ma YP, Chen DP, et al A meta-analysis of antiviral therapy for hepatitis B virus-associated membranous nephropathy. PLoS One 2016;11(9):e0160437.
11. Wiest R, Garcia-Tsao G. Bacterial translocation (BT) in cirrhosis. Hepatology 2005;41(3):422–33.
12. Wong F, Leung W, Al Beshir M, et al. Outcomes of patients with cirrhosis and hepatorenal syndrome type 1 treated with liver transplantation. Liver Transplant 2015;21(3):300–7.
13. Alessandria C, Ozdogan O, Guevara M, et al. MELD score and clinical type predict prognosis in hepatorenal syndrome: Relevance to liver transplantation. Hepatology 2005;41(6):1282–9.
14. Allegretti AS, Parada XV, Eneanya ND, et al. Prognosis of patients with cirrhosis and AKI who initiate RRT. Clin J Am Soc Nephrol 2018;13(1):16–25.
© The American College of Gastroenterology 2019. All Rights Reserved.
15. Fede G, D'Amico G, Arvaniti V, et al. Renal failure and cirrhosis: A systematic review of mortality and prognosis. J Hepatol 2012;56(4):810–8.