There is large body of evidence indicating that HRS is of functional origin, such as the absence of significant histological kidney abnormalities, the reversibility of HRS after liver transplant, and the improvement or normalization of kidney function after pharmacological treatment with vasoconstrictors and albumin.

The main cause of functional kidney impairment in cirrhosis is impairment in circulatory function characterized by a reduction in systemic vascular resistance due to splanchnic arterial vasodilation related to portal hypertension [1, 2, 5] (Fig. 15.1). In early stages of the disease, when patients are still asymptomatic, portal hypertension is moderate and there is only slight decrease in systemic vascular resistance. In this stage of cirrhosis, effective arterial blood volume and arterial pressure are maintained within normal levels by an increase in cardiac output. However, in advanced stages of cirrhosis, there is a progressive splanchnic arterial vasodilation leading to a marked reduction in effective arterial blood volume that cannot be balanced by the increase in cardiac output. In this context, in order to maintain arterial pressure within normal levels there is activation of systemic vasoconstrictor systems, including renin–angiotensin system, sympathetic nervous system, and in late stages, non-osmotic hypersecretion of vasopressin. The activation of vasoconstrictor systems have positive effects as they help maintain effective arterial blood volume but they have negative effects in the kidney, particularly sodium and solute-free water retention leading to the development of ascites and edema and hypervolemic hyponatremia . In advanced cirrhosis, the increased activity of vasoconstrictor systems induces an intense renal vasoconstriction leading to the reduction of glomerular filtration rate and the development of HRS. In these stages, there is also a decrease in cardiac output, probably related to cirrhotic cardiomyopathy, which also contributes to extreme arterial underfilling characteristic of HRS [1, 2, 5].

Finally, there is also evidence that inflammation may also play a role in the pathophysiology of HRS. Bacterial translocation (i.e., passage of bacteria from the intestinal lumen to the mesenteric lymph nodes) may play an important role in the impairment of circulatory function leading to the development of HRS. Bacterial translocation induces an inflammatory response, with an increased production of proinflammatory cytokines and vasoactive factors (i.e., nitric oxide) in the splanchnic area leading to a further vasodilation of the splanchnic circulation [6].

Besides HRS, patients with cirrhosis may develop kidney failure due to different etiologies such as hypovolemia, bacterial infections, intrinsic acute kidney injury (iAKI), and administration of nephrotoxic agents such as nonsteroidal anti-inflammatory drugs or parenchymal kidney disease [7]. The differential diagnosis of the cause of kidney failure is highly important, as the management and prognosis are completely different. There is no objective variable for the diagnosis of HRS. As described above, the diagnosis of HRS is made after exclusion of other causes of kidney failure.

As described in Chap. 3, in recent years, neutrophil gelatinase-associated lipocalin (NGAL) has emerged as a new biomarker potentially useful for the differential diagnosis of the cause of kidney failure in patients with cirrhosis. Two recent studies showed that urinary levels of NGAL (uNGAL) are significantly higher in patients with iAKI compared to patients with prerenal kidney failure or HRS. Interestingly, patients with HRS have uNGAL levels intermediate between prerenal kidney failure and iAKI [8, 9]. Therefore, if these results are validated in further studies, uNGAL could be incorporated in the daily clinical practice as an objective variable for the differential diagnosis of kidney failure in patients with cirrhosis.

According to the severity and progression of kidney failure, there are two types of HRS. Type 1 HRS is presented as an acute kidney failure with a rapid increase in serum creatinine with a final value above 2.5 mg/dL. It is associated with a dismal prognosis with a median survival of only 2 weeks without treatment. In contrast with type 1 HRS, patients with type 2 HRS develop a moderate kidney failure with serum creatinine levels ranging from 1.5 to 2.5 mg/dL. In patients with type 2 HRS, kidney failure is less progressive and remains stable for some period of time. Type 2 HRS is typically associated with refractory ascites. These patients have a slightly better prognosis with a median survival of 6 months (Fig. 15.2). Finally, during follow-up, patients with type 2 HRS may develop type 1 HRS either spontaneously or associated with a precipitating factor, particularly bacterial infections.

HRS may develop spontaneously without an identifiable precipitating factor. However, in other patients, HRS occurs associated with conditions leading to a further impairment in the circulatory function. The most frequent precipitating events leading to HRS are bacterial infections and, particularly, spontaneous bacterial peritonitis (SBP). Up to one third of patients with SBP develop HRS during or after infection [10, 11]. In approximately one third of these patients, HRS is reversible with the control of infection; however, in the remaining patients, kidney failure is persistent or progressive. Bacterial infections other than SBP may also trigger HRS; however, its frequency and severity is usually low [12, 13].

Gastrointestinal bleeding is another complication of cirrhosis that may also act as a precipitating factor of kidney failure. Nevertheless, kidney failure in the setting of gastrointestinal bleeding is uncommon (approximately 10 %) and usually related to hypovolemia and not HRS [14].

Finally, another condition that may also act as a precipitating event is large-volume paracentesis without intravenous albumin administration. This situation may trigger the development of HRS in approximately 15 % of patients and is associated with poor prognosis [15]. One of the main reasons for the administration of intravenous albumin after large-volume paracentesis is the prevention of development of HRS.

General management of patients with HRS depends on the severity of kidney function. Patients with type 1 HRS on the waiting list for liver transplantation (LT) should be treated in an intensive care unit. Patients should be monitored closely in order to early diagnose associated complications of cirrhosis that may occur, particularly bacterial infections. In contrast with patients with type 1 HRS, patients with type 2 HRS without associated complications should be managed as outpatients. In this chapter, we will focus on the management of patients with type 1 HRS.