A 54 year old man with a history of alcohol excess was admitted under the medical team with an upper gastro-intestinal bleed. He had a background of pulmonary fibrosis that limited his exercise tolerance to 30 yards. Antibiotics, terlipressin and fluid resuscitation, including blood, were given. An oesophago-gastro-duodenoscopy demonstrated severe portal gastropathy but no active bleeding or varices. An abdominal ultrasound demonstrated cirrhosis and some moderate ascites. On day two of the patient’s hospital admission he was admitted to the intensive care unit (ICU) with respiratory failure and non-invasive ventilation was started. Over the next few days his condition deteriorated and he required vasopressor support. By day 6 the patient was oliguric, and his creatinine had risen from 102 to 155 µmoles/l.

What is the cause for his acute kidney injury? Could it be hepatorenal syndrome? 

Dave Slessor

Epidemiology

Acute kidney injury (AKI) is a common problem for patients with cirrhosis. For patients with cirrhosis it is the 3^rd leading cause of admission to the ICU and in all patients with cirrhosis who are admitted to the ICU 49% will develop AKI.¹ In a study on patients with cirrhosis admitted to the ICU with AKI, the cause of the AKI was most commonly due to bacterial infections (40%), followed by hypovolaemia (32%), parenchymal kidney disease (15%), HRS type 2 (9%) and HRS type 1 (3%).²

Pathophysiology of HRS

In cirrhosis portal hypertension leads to an increase in vasodilator factors such as nitric oxide (NO) and carbon monoxide.³ This subsequently causes a decrease in systemic vascular resistance (SVR). To compensate the body increases the cardiac output thereby maintaining the effective arterial blood volume and arterial pressure within normal limits. In advanced cirrhosis the SVR becomes markedly reduced and cannot be compensated for leading to under filling and an effective hypovolaemia.³ This is compounded by the development of a cirrhotic cardiomyopathy.⁴ In an attempt to maintain normal blood pressure there is the activation of vasoconstrictor mechanisms including the renin-angiotensin system, the sympathetic nervous system as well as secretion of anti-diuretic hormone. Side-effects of this include sodium and solute-free water retention causing ascites and oedema, as well as intra-renal vasoconstriction and hypoperfusion leading to AKI.³

Bacterial translocation commonly occurs in patients with cirrhosis. This can cause an inflammatory response and further release of vasodilator factors in the splanchnic area, again leading to the development of AKI.³

Risk factors

The predominant risk factor for the development of HRS is bacterial infections and in particular spontaneous bacterial peritonitis (SBP).⁴ Other risk factors include gastro-intestinal bleeding and large volume paracentesis without concomitant albumin administration.⁴ Of interest the severity of liver failure as defined by the Child-Pugh score or liver function blood tests has not been shown to be a risk factor for the development of HRS.⁴

Diagnosis/evaluation

The International Club of Ascites has defined criteria for the diagnosis of HRS:⁵

1. Presence of cirrhosis and ascites
2. Serum Creatinine >133 µmoles/L despite 48 hours of diuretic withdrawal and volume expansion with albumin
3. Absence of: shock, current/recent use of nephrotoxic drugs and parenchymal kidney disease

There are two types of HRS. In type 1 there is a rapid reduction in renal function with serum creatinine doubling to a level of at least 220µmol/l in <2 weeks. Encephalopathy will often be present. Type 1 usually follows a precipitating insult, often SBP⁵. Whereas type two HRS usually develops spontaneously over a longer time frame, the creatinine level rises to >133 µmol/l, and there is often refractory ascites⁵.

Differentiating HRS from other causes of renal failure can be difficult. HRS has a similar urine chemistry to pre-renal failure with a urinary sodium of <10 in the absence of diuretics.⁶ However the clinical course of HRS will not improve with volume expansion in contrast to pre-renal failure.⁶

Urine neutrophil gelatinase-associated lipocalin levels may be helpful in differentiating HRS from pre-renal and other causes of renal failure in patients with cirrhosis. One study demonstrated a median level of 20ng/ml (Inter-quartile range 15-45) in pre-renal failure vs. 105ng/ml (27.5-387.5) in HRS vs. 325 (100-700) in intrinsic kidney disease.⁷ However the wide inter-quartile range may limit the usefulness of this test.

Prevention

In patients with cirrhosis diagnosed with SBP, albumin administration (1.5g/kg at diagnosis and 1g/kg at 48hrs) reduces the risk of development of HRS.³ This may be due to the improvement in circulatory function as well as the antioxidant properties of albumin.³

In patients with ascites and cirrhosis gut decontamination with norfloxacin reduces the risk of HRS and improves mortality.⁸ This is thought to be due to decreasing bacterial translocation.³

Treatment

Current recommendations for type 1 HRS are resuscitation with albumin (1g/kg for two days, up to a maximum of 100g/day, followed by 20-40g/day) in combination with a vasoconstrictor, preferentially terlipressin.⁹ As well as increasing the pre-load, albumin infusions have been demonstrated to increase SVR, this may be by decreasing NO synthesis.¹⁰ Both of these mechanisms lead to an improvement in circulatory function.

Vasopressors decrease the splanchnic and systemic vasodilatation leading to improvements in circulatory function. Noradrenaline has been shown to be as effective as terlipressin in improving renal and circulatory function in patients with HRS.¹

Patients with cirrhosis have been demonstrated to have relative adrenal insufficiency⁴ and therefore when accompanied by severe sepsis may benefit from hydrocortisone administration.³

In observational studies transjugular intra-hepatic porto-systemic shunt (TIPS) has been shown to lead to an improvement in renal function in patients with type 1 and type 2 HRS, as well as improve refractory ascites in type 2 HRS.⁹ However following TIPS liver function tests may deteriorate and encephalopathy may develop.⁹

Due to the poor prognosis RRT is not recommended for type 1 HRS unless the patient is a candidate for liver transplantation or there is a reversible cause.⁹

Liver transplant should be considered if the patient has no contraindications.³ This should be performed early as severe renal failure predicts worse outcome.³ Normally the patient does not require a simultaneous renal transplant as the renal function recovers.³ However in patients who have been receiving RRT for 8-12 weeks better survival rates are reported with a combined liver-renal transplant compared with liver transplant alone.³

Extracorporeal liver support devices such as the molecular adsorbent re-circulating system have not been shown to improve mortality and are therefore only recommended if part of a clinical trial.⁹

Prognosis

Without a liver transplant the median survival for type 1 HRS is one month compared to six months in type 2 HRS.³

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References

1. Muciño-Bermejo J, Carrillo-Esper R, Uribe M, Méndez-Sánchez N. Acute kidney injury in critically ill cirrhotic patients: a review. Annals of hepatology. 2012;11(3):301.
2. Carvalho G, Regis CA, Kalil J, Cerqueira L, Barbosa D, Motta M, et al. Causes of renal failure in patients with decompensated cirrhosis and its impact in hospital mortality. Annals of hepatology. 2012;11(1):90.
3. Ginès P, Schrier RW. Renal Failure in Cirrhosis. New England Journal of Medicine. 2009;361(13):1279-90.
4. Fagundes C, Ginès P. Hepatorenal syndrome: A severe, but treatable, cause of kidney failure in cirrhosis. American Journal of Kidney Diseases. 2012.
5. International Club of Ascites [22.06.2013.]; Available from: http://www.icascites.org/about/guidelines/.
6. Betrosian AP, Agarwal B, Douzinas EE. Acute renal dysfunction in liver diseases. World Journal of Gastroenterology. 2007;13(42):5552.
7. Verna EC, Brown RS, Farrand E, Pichardo EM, Forster CS, Sola-Del Valle DA, et al. Urinary neutrophil gelatinase-associated lipocalin predicts mortality and identifies acute kidney injury in cirrhosis. Digestive diseases and sciences. 2012;57(9):2362-70.
8. Fernández J, Navasa M, Planas R, Montoliu S, Monfort D, Soriano G, et al. Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology. 2007;133(3):818-24.
9. Nadim MK, Kellum JA, Davenport A, Wong F, Davis C, Pannu N, et al. Hepatorenal syndrome: the 8th international consensus conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2012;16(1):R23.
10. Arroyo V, Fernandez J. Pathophysiological basis of albumin use in cirrhosis. Ann Hepatol. 2011;10(Suppl 1):s6-s14.

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