Acute Kidney Injury in Patients with Liver Disease

Abstract

AKI is commonly encountered in patients with decompensated cirrhosis, and it is associated with unfavorable outcomes. Among factors specific to cirrhosis, hepatorenal syndrome type 1, also referred to as hepatorenal syndrome-AKI, is the most salient and unique etiology. Patients with cirrhosis are vulnerable to traditional causes of AKI, such as prerenal azotemia, acute tubular injury, and acute interstitial nephritis. In addition, other less common etiologies of AKI specifically related to chronic liver disease should be considered, including abdominal compartment syndrome, cardiorenal processes linked to cirrhotic cardiomyopathy and portopulmonary hypertension, and cholemic nephropathy. Furthermore, certain types of GN can cause AKI in cirrhosis, such as IgA nephropathy or viral hepatitis related. Therefore, a comprehensive diagnostic approach is needed to evaluate patients with cirrhosis presenting with AKI. Management should be tailored to the specific underlying etiology. Albumin-based volume resuscitation is recommended in prerenal AKI. Acute tubular injury and acute interstitial nephritis are managed with supportive care, withdrawal of the offending agent, and, potentially, corticosteroids in acute interstitial nephritis. Short of liver transplantation, vasoconstrictor therapy is the primary treatment for hepatorenal syndrome type 1. Timing of initiation of vasoconstrictors, the rise in mean arterial pressure, and the degree of cholestasis are among the factors that determine vasoconstrictor responsiveness. Large-volume paracentesis and diuretics are indicated to relieve intra-abdominal hypertension and renal vein congestion. Direct-acting antivirals with or without immunosuppression are used to treat hepatitis B/C-associated GN. In summary, AKI in cirrhosis requires careful consideration of multiple potentially pathogenic factors and the implementation of targeted therapeutic interventions.

Keywords: Critical Care Nephrology and Acute Kidney Injury Series; acute kidney injury; cirrhosis; hepatorenal syndrome; liver failure.

Figure 1.

Etiology of AKI in cirrhosis. Hepatorenal syndrome type 1 (HRS-1) is one of many potential causes of AKI. Prerenal azotemia can be caused by gastrointestinal fluid losses induced by laxatives prescribed for prophylaxis for hepatic encephalopathy (HE), urinary losses caused by diuretics prescribed for ascites, or poor cardiac output due to hepatocardiorenal syndrome 1 (HCRS-1). Ischemic acute tubular injury (ATI) can be caused by prolonged prerenal azotemia, hemorrhagic shock (e.g., due to gastrointestinal bleeding [GIB]) or septic shock (e.g., due to spontaneous bacterial peritonitis [SBP]). Toxic ATI can be caused by cholemic tubulopathy (bile acids) or certain drugs commonly prescribed in this setting, such as fluoroquinolones (FQs) or vancomycin. Renal vein congestion can cause AKI, as seen in abdominal compartment syndrome (ACS) caused by tense ascites, congestive heart failure from cirrhotic cardiomyopathy (CCM), or right ventricular failure from portopulmonary hypertension (PoPHTN). Acute GN can be caused by IgA nephropathy (IgAN) or hepatitis C (HCV)– or hepatitis B (HBV)–associated membranoproliferative GN (MPGN), often cryoglobulinemic. Acute interstitial nephritis can be caused by antibiotics prescribed for infections (e.g., FQ or penicillin [PCN]) or proton pump inhibitors (PPIs). Obstructive uropathy is rare in cirrhosis, but it can occur in patients treated for HRS-1 with midodrine.

Figure 2.

Determinants of HRS-1 reversal. (1) Timing of initiation—the earlier in the disease evolution (i.e., at lower stages of AKI), the greater the likelihood of response to therapy. (2) Effect on mean arterial pressure (MAP). There is a nearly linear correlation between the increase in MAP and the likelihood of HRS-1 reversal. Although the ideal MAP target is not clear, an increase of ≥15 mm Hg has been associated with improved outcomes. (3) The degree of underlying liver disease. Patients with an elevated total bilirubin level are less likely to respond to therapy; whether this is a direct effect of bile acid nephrotoxicity or a reflection of the underlying severity of illness is not known. (4) Reversal of the trigger. Whether infection, hemorrhage, or other trigger, removal and treatment of the trigger dictate clinical outcomes. (5) Underlying CCM or PoPHTN plays an important role in determining if a patient will respond to vasoconstrictor therapy and have HRS-1 reversal.

Figure 3.

Assessment of the existing evidence for cholemic tubulopathy as a cause of AKI in cirrhosis. Some studies showed that the greater the elevation of serum bilirubin concentration, the lower the likelihood of response to vasoconstrictors in HRS-1. However, this observation is not uniform across studies. Kidney tubular epithelial cell casts (RTECCs) are found more commonly among patients with elevated serum bilirubin concentrations. However, the correlation of high serum bilirubin level and abundance of RTECCs has also been reported in the absence of AKI, thus challenging the notion that RTECCs present in the urinary sediment of patients with cirrhosis and AKI are necessarily reflective of the AKI pathogenesis. In an animal model of cirrhosis, amelioration of tubulointerstitial injury in mice lacking receptors for bile acids (farnesoid X receptor knockout [FXR-KO] mice) was observed. However, seminal studies of HRS-1 showed mostly intact kidney parenchyma. Bile acids have been shown to elicit splanchnic vasodilation. However, splanchnic vasodilation occurs regardless of serum bile acid or bilirubin (T Bili) concentration. Autopsy studies reported high prevalence of bile casts filling the tubular lumen of patients with cirrhosis who died with a diagnosis of HRS-1. However, the presence of bile casts in tubular lumen does not prove causality and may merely reflect tubular stasis and severely reduced GFR.

Figure 4.

Algorithm to guide the diagnosis and management of in-hospital AKI in the context of cirrhosis. Discontinuation of nonsteroidal anti-inflammatory drugs (NSAIDs), β-blockers, and renin-angiotensin system inhibitors (RASis) applies to all cases. Upon recognition of AKI, objective assessment of volume status should incorporate point-of-care ultrasonography (POCUS) coupled with a careful review of diagnostic elements suggestive of HRS-1 not restricted to those listed as the International Club of Ascites (ICA) criteria. Clinical history and findings in urinary sediment microscopy (uSedi), urine sodium (uNa), and fractional excretion of sodium (FENa) should then guide the next steps in the differential diagnosis. History of volume loss and POCUS findings can point to prerenal azotemia (PrerAz). In those cases, discontinuation of diuretics, volume expansion (Vol Ex) with intravenous (IV) albumin, and/or packed red blood cells (PRBCs), when appropriate, are warranted. Evidence of intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) should prompt therapeutic large-volume paracentesis (LVP). Echocardiography, POCUS findings, and pulmonary congestion by imaging may suggest cardiorenal syndrome type 1 (CRS-1) resulting from cirrhotic cardiomyopathy, high-output heart failure, or severe portopulmonary hypertension. In those cases, diuretics may be indicated. When all ICA criteria are met and other phenotypical elements consistent with HRS-1 are present (i.e., hyponatremia [hypo Na] and MAP denoting “low normal” BP), HRS-1 must be considered, and vasoconstrictor therapy should be initiated (with norepinephrine [NE] or terlipressin [Terli], MAP rise goal of ≥15 mm Hg). There is insufficient evidence supporting the use of the combination of midodrine and octreotide in HRS-1. Presence of abundant “muddy brown” granular casts (MBGCs) and/or waxy casts (WxCs) in uSedi is consistent with ATI that can originate from ischemic (shock, prolonged PrerAz, or PrerAz that fails Vol Ex) or toxic (nephrotoxins or cholemic) insults. In those cases, supportive care is the cornerstone of management. It is important to recognize the possibility of overlap of ATI and HRS-1 physiology or of HRS-1 and CRS-1 (HCRS-1). Sterile pyuria in the context of exposure to a drug should raise suspicion for acute interstitial nephritis (AIN) and should be managed by drug discontinuation and consideration for corticosteroids (CSs). Dysmorphic erythrocyturia and/or cellular casts in uSedi and viral or autoimmune serology may suggest acute GN. Percutaneous kidney biopsy (PKB) may be needed to guide the need for immunosuppression therapy (IST) and/or antiviral therapy. Obstructive uropathy can rarely occur in patients exposed to midodrine or due to other causes unrelated to cirrhosis. Bladder catheterization (cath) and consultation with urology are appropriate in this setting. After a therapeutic intervention has been executed, it is critical to assess the clinical response to the intervention, liver transplantation eligibility, need for KRT, and risks and benefits of each intervention to be able to choose the optimal treatment approach at this stage. Thus, hospice care may be the most appropriate step in some cases.