Etiology of Acute Kidney Injury

Most cases of AKI in patients with cirrhosis are “pre‐renal,” due to reduced glomerular perfusion on top of reduced renal blood flow. This is frequently precipitated by infection (46%), including bacterial peritonitis or relative hypovolemia (32%), such as when there is variceal bleeding or paracentesis without adequate albumin replacement (Table 12.2). Prolonged or severe pre‐renal AKI may progress to acute tubular necrosis (ATN). Less commonly, primary renal parenchymal disease may cause AKI. Associations of liver disease with glomerulonephritis are outlined in Table 12.3. Bile‐cast nephropathy leading to AKI or a Fanconi‐like proximal tubulopathy (characterized by low serum uric acid and phosphate) is associated with severe hyperbilirubinemia. Particular attention should be paid to management of medication as patients with cirrhosis are at risk from nephrotoxic medications.

Cause	Frequency (%)	Precipitants
Infection associated	46	Sepsis
		Spontaneous bacterial peritonitis
Hypovolemia associated	32	Diuretic overuse
		Gastrointestinal bleeding (including variceal bleeds)
		Lactulose and infection‐related diarrhea
		Large‐volume paracentesis (without adequate albumin replacement)
Hepatorenal syndrome	13	Decompensated liver cirrhosis
Parenchymal renal disease	9	Acute tubular necrosis
		Interstitial nephritis
		Bile‐cast nephropathy
		Glomerulonephritis

Disease	Association
Alcoholic cirrhosis	Immunoglobulin A nephropathy
Hepatitis B	Membranous nephropathy (most common)
	Polyarteritis nodosa
	Membranoproliferative glomerulonephritis
Hepatitis C	Membranoproliferative glomerulonephritis with or without cryoglobulins (most common)
	Membranous nephropathy
	Fibrillary glomerulonephritis
Primary biliary cholangitis	Membranous nephropathy
	Anti‐neutrophilic cytoplasmic antibody vasculitis
Autoimmune hepatitis	Immune complex glomerulonephritis
	Membranous nephropathy
	Membranoproliferative glomerulonephritis
Alpha‐1‐antitrypsin deficiency	Membranoproliferative glomerulonephritis

Acute Kidney Injury Hepatorenal Syndrome

“AKI ”, previously referred to as “type 1 HRS,” is a diagnosis of exclusion, resulting from the renal physiological changes seen in advanced liver cirrhosis, in the absence of structural or parenchymal renal disease (Figure 12.1).

Development of portal hypertension leads to increased release of vasodilatory mediators into the splanchnic arterial circulation (nitric oxide, prostacyclin, carbon monoxide, and endogenous cannabinoids). Pooling of blood within the splanchnic system causes “effective arterial hypovolemia” and reduced renal perfusion. The simultaneous release of damage‐associated molecular patterns from cirrhotic liver tissue and pathogen‐associated molecular patterns from bacterial translocation in the gut are thought to activate circulating innate immune cells, triggering a systemic inflammatory response and release of cytokines (including tumor necrosis factor alpha and interleukin‐6) into the circulation, which may further exacerbate circulatory dysfunction.

In the earlier stages of chronic liver disease, a compensatory increase in cardiac output helps to maintain adequate renal perfusion. As hepatic dysfunction progresses, however, this compensatory mechanism is overwhelmed, exacerbated by the presence of “cirrhotic cardiomyopathy” (characterized by systolic and diastolic dysfunction, seen in up to 50% of patients with cirrhosis). Compensatory activation of the sympathetic nervous system, the renin–angiotensin–aldosterone system, and vasopressin release in addition may lead to intense renal vasoconstriction and a decline in GFR, alongside increased sodium and water retention, contributing to ascites formation.

Investigation

Initial evaluation to determine the underlying cause of AKI should include a detailed history and examination, including review of the drug treatment chart. Important investigations include:

• Septic screen, including C‐reactive protein, blood and urine cultures, chest x‐ray and ascitic tap to diagnose spontaneous bacterial peritonitis.
  
• Endoscopy in cases where gastrointestinal bleeding is suspected.
  
• Urine analysis: hematuria or proteinuria may suggest a glomerular pathology. Laboratory urine protein quantification (spot urine albumin : creatinine ratio or protein : creatinine ratio) is advised.

In patients where the cause of AKI remains unclear or if patients are slow to respond to initial resuscitation, the following additional investigations are suggested:

• Ultrasound of the urinary tract to define renal size, exclude obstructive uropathy or other structural urinary tract abnormalities.
  
• Urine microscopy: granular casts may be observed in patients with both AKI‐HRS and ATN, but renal tubular epithelial cell casts are more specific to ATN. Red‐cell casts can indicate active glomerulonephritis and bile acid casts may be associated with development of bile‐cast nephropathy (Figure 12.2).
  
• Urinary sodium: in ATN, renal tubular function is impaired, leading to high urinary sodium concentration (> 40 mEq/l), raised fractional sodium excretion (> 2%), and low urine osmolality (< 350 mOsm/kg). Conversely, patients with AKI‐HRS have low urinary sodium (< 20 mEq/l), low fractional excretion of sodium (< 1%), and elevated urine osmolality (> 500 mOsm/kg). Caution is advised, however, as these findings can frequently be misleading, especially when patients are receiving diuretic therapy.
  
• A renal immunology screen should be requested for all patients with proteinuria or hematoproteinuria, where glomerulonephritis is suspected from history or examination, or the cause of AKI remains unclear (Box 12.2; Figure 12.3; Table 12.4).
  
• Renal biopsy allows definitive histological diagnosis of AKI etiology, especially when intrinsic renal disease is suspected. It is important to note, however, that, due to coagulopathy, patients with cirrhosis are at especially high risk of bleeding complications and a decision to biopsy should only be made following careful risk–benefit assessment and correction of any ascites and coagulopathy.

  

Management

A step‐by‐step approach to management of AKI in patients with liver disease is outlined in (Figure 12.4). For patients with AKI, it is important stop any nephrotoxins such as non‐steroidal anti‐inflammatory drugs, aminoglycosides, or angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers. Vasodilator agents and laxatives should be discontinued in patients with severe diarrhea. Where intravascular volume depletion is present, diuretics should be withheld, and cautious fluid resuscitation, initiated with crystalloids or blood products (if hemoglobin < 70 g/l), followed by volume expansion with albumin (1 g/kg/day for 48 hours) if renal impairment persists. There should be a low threshold for commencing antibiotic therapy in cases of suspected infection. Assessment to guide continuing resuscitation is notoriously difficult, requiring regular clinical review in the setting of a high‐dependency environment. Strict fluid balance, daily weight and measurement of postural blood pressure, hourly urine output, and central venous pressure may facilitate this process.

Key diagnostic criteria for AKI‐HRS are outlined in (Box 12.3). Following albumin replacement, persistent AKI‐HRS may be treated with splanchnic vasoconstriction using, for example, terlipressin. Terlipressin has been shown to reduce mortality risk in patients with AKI‐HRS and to increase the proportion of patients who recover their renal function. Of note, terlipressin is not yet licensed for this indication in many countries, and caution is advised regarding its adverse effect profile, including severe abdominal pain and diarrhea, increased risk of cardiovascular events and respiratory failure. Alternative vasoconstrictors such as noradrenaline or midodrine/octreotide may be used, but there is increasing evidence to suggest that the latter are less effective therapies. Patients with AKI‐HRS require close monitoring to prevent fluid overload and progressive hyponatremia [5, 6],