Hepatorenal syndrome: Paving a pathway from a fatal condition to an opportunity to preserve kidney function

Abstract

In the 19^th century, von Frerichs F and Flint A identified a type of acute renal impairment associated with advanced liver disease, characterized by oliguria, absence of proteinuria, and normal renal histology, which was later termed hepatorenal syndrome (HRS). HRS primarily affects cirrhotic patients with ascites and often follows severe infections, digestive hemorrhages, or high-volume paracentesis. Pathophysiologically, HRS involves low glomerular filtration rate, hypotension, renin-angiotensin axis activation, water clearance, hyponatremia, and minimal urinary sodium excretion. These conditions mimic those seen in decreased effective circulatory volume (ECV) scenarios such as septic shock or heart failure. HRS represents a specific form of prerenal acute kidney injury (AKI) in patients with baseline renal ischemia, where the kidney attempts to correct decreased ECV by retaining sodium and water. Intense renal vasoconstriction, passive hyperemia from ascites, and acute tubular necrosis (ATN) with specific urinary sediment changes are observed. Persistent oliguria may transition HRS to ATN, although this shift is less straightforward than in other prerenal AKI contexts. Notably, liver grafts from HRS patients can recover function more rapidly than those from other ischemic conditions. Experimental studies, such as those by Duailibe et al, using omega-3 fatty acids in cirrhotic rat models, have shown promising results in reducing oxidative stress and improving kidney function. These findings suggest potential therapeutic strategies and underscore the need for further research to understand the mechanisms of HRS and explore possible treatments. Future research should address the impact of omega-3 on survival and secondary outcomes, as well as consider the balance of therapeutic risks and benefits in severe liver disease.

Key Words: Hepatorenal syndrome; Acute kidney injury; Oliguria; Ascites; Hibernation; Cirrhosis

Core Tip: Hepatorenal syndrome involves low glomerular filtration rate, hypotension, renin-angiotensin axis activation, decreased water clearance, hyponatremia, and minimal urinary sodium excretion, similar to prerenal acute kidney injury. Notably, liver grafts from these patients can recover function more rapidly than those from other ischemic conditions. Experimental findings suggest potential therapeutic strategies and underscore the need for further research to understand the mechanisms of hepatorenal syndrome and explore possible treatments.

INTRODUCTION

In 1861, von Frerichs F, and in 1863, Flint A described the relationship between advanced liver disease and a type of acute renal impairment characterized by oliguria, the absence of proteinuria, and normal renal histology[1]. Interestingly, the French physician, Merklen PJ, in 1916 described a “similar disease”, called acute hepatonephritis, in 15 patients with acute hepatic failure, jaundice, and ascites who developed an “acute nephritis” evidenced by an oliguria that rapidly progressed to anuria and, later on, in 1937, this disease was subdivided in a “simple” and a “chronic” type. From a clinical perspective, similar cases as Fridriech and Flint’s shared some characteristics, such as: They happened in cirrhotic patients with ascites, at some point of those patient’s follow-up they suffered from a severe infection, digestive hemorrhage, or underwent a high volume paracentesis before the beginning of the acute kidney function deterioration-or acute kidney injury (AKI), as it is its known today. This pathological condition was named as hepatorenal syndrome (HRS).

Later on, in 1993, Ginès et al[2] studied cirrhotic and ascitic patients who developed HRS. They identified HRS’s main pathophysiological elements as: (1) Low glomerular filtration rate; (2) Low blood pressure; (3) Activation of the renin-angiotensin axis (RAA); (4) Severely decreased free water clearance; (5) Hyponatremia; and (6) Almost negligible urinary sodium excretion (less than 1 mEq/day).

Interestingly, those laboratory determinations resemble those occurring in patients with decreased effective circulatory volume (ECV), regardless of whether they have high, normal or decreased extracellular volume status, as seen in conditions such as diarrheal diseases, septic shock, or congestive heart failure, respectively. In all these cases, the kidney has a high capacity for reabsorbing both sodium from the proximal, distal, and thick Henle’s kidney tubules, and water from the medullary collecting ducts as consequences of RAA activation and vasopressin secretion.

HRS

In fact, HRS is a particular case of a prerenal AKI occurring in a baseline chronically prerenal or ischemic kidney. In this condition, the kidney is actively reabsorbing sodium and water in an attempt to correct the decreased ECV and the consequent accumulation of ascitic fluid in patients with liver cirrhosis, particularly those who are decompensated.

In astute clinical observations, we have learned that HRS is associated to: (1) Intense vasoconstriction of the kidney arterial tree[3]; (2) Passive hyperemia of the kidney due to venous congestion as a consequence of ascites[4], as seen in intra-abdominal hypertension[5] or decompensated congestive heart failure[6]; (3) Necrosis of proximal tubular cells, tubulorrhexis, mitochondrial abnormalities, and tubular piknotic nucleus, all of which can be clinically summarized as acute tubular necrosis (ATN)[7]. In this situation, the urinary sediment changes from bland to include bilirubin-stained renal tubular epithelial cell casts, along with scattered coarse dark granular or mudy-brown casts[8]; and (4) Reflux of proximal convoluted tubular epithelium into Bowman’s space, as seen in experimental ischemic kidney damage and severe hypotension[9].

What happens if oliguria caused by these pathophysiological abnormalities persists over time?

Sodium can no longer be reabsorbed and begins to be excreted in the urine at levels well above 30-40 mEq/day. It is almost the same that happens in ATN observed in other clinical situations. Interestingly, HRS prognosis correlates with liver function, and ATN with the resolution of kidney ischemia, implying that kidney replacement therapy is less useful in HRS than in ATN. Nevertheless, this transition from HRS to ATN is not as straightforward as it is observed in pre renal AKI from other etiologies; it has been observed that kidney grafts from patients experiencing HRS can recover function and, if it occurs, it happens much faster than with grafts from other donors who are not as severely ischemic[10].

In fact, it seems that HRS is a pathophysiological state similar to kidney hibernation, akin to what occurs in hibernating mammals: (1) Glomerular filtration rate; (2) Sodium; and (3) Water excretion almost “disappear” and all return to normal once torpor ends. This is similar to the recovery observed when a liver graft is successfully implanted from a patient with HRS[11].

In 1990 decade, Kidney Disease: Improving Global Outcomes defined two types of HRS, type 1, corresponding to the Merklen’s “hepatonephritis simple” and type 2, Merklen’s “chronic hepatonephritis” that today we understand as HRS-AKI and HRS Chronic Kidney Disease, respectively[3].

The intimate mechanisms of all those phenomena have not yet been elucidated, but some of them could be related to the experience of Duailibe et al[12]. They induced biliary cirrhosis after biliary duct ligation (BDL) in 24 male Wistar rats; in this validated model, they observed cirrhosis, portal hypertension, ascites, and reduced glomerular filtration rate 4 weeks after surgery, as it occurs in HRS. The experimental intervention was the administration of 1 g/kg/day of omega-3 fatty acids. Their main findings were that omega-3 significantly reduced all of the following: (1) The generation of free radicals and the lipoperoxidation; (2) The mitochondrial membrane potential; (3) The activity of antioxidant enzymes; and (4) The activity of antioxidant enzymes and ameliorated DNA damage and enhanced cell survival in the kidneys of the cirrhotic rats[12]. All of these findings, which are certainly related to the known pathogenesis of HRS, could help us understand that in HRS there are cellular alterations promoting kidney dysfunction[13]. Additionally, they open the door to exploring whether omega-3 supplementation can modify the clinical outcome of biliary cirrhosis specifically, or even other types of acquired liver disease, such as non-alcoholic fatty liver disease[14] or drug or toxic induced liver diseases[15,16]. Moreover, they raise the possibility that, in potential kidney donors, the phenomenon observed in hibernating mammals could serve as a “controlled ischemia-reperfusion model”[17].

What are the next steps? In Duailibe et al’s experience, all rats were killed after 4 weeks following BDL, so we do not know if omega-3 can improve rats survival or impact other secondary clinical outcomes of interest[12]. There is some evidence that cholestasis induced toxins can affect kidney cell physiology[18]; for example, liver tissue examination reveals the presence of intratubular bile acid casts in 18%-75% of patients with HRS-AKI and urinary bilirubin and urobilinogen may be present as well, moreover, serum bilirubin concentrations above 10 mg/dL have been associated with a lower rate of response to vasoconstrictors in patients with AKI-HRS compared lower intensity hyperbilirubinemia[18] implying that icterus and cholestasis could increase kidney damage by themselves. At the same time, it is interesting to note that norursodeoxycholic (NorUDCA) acid can have therapeutic potential in the same experimental model of BDL[19]. In fact, in this experiment performed also in the BLD model, NorUDCA-fed mice had significantly lower levels of AKI biomarkers, such as serum urea and urinary neutrophil gelatinase-associated lipocalin levels and less severe cholemic nephropathy as demonstrated by normal urine cytology, significantly less tubulointerstitial nephritis, and renal fibrosis as compared to controls[19].

A dose of 1 g/kg/day of omega-3 is a substantial dose, particularly for severe liver disease; could the “remedy be worse than the disease”? Certainly, there is no definitive answer to this rhetoric question because most experience have been conducted with much lower doses and there is still a gap between the observed metabolic and anti-inflammatory benefits of omega-3 and clinical outcomes in this and other models of HRS.

CONCLUSION

Nevertheless, experiences like the one from Duailibe et al[12] must be congratulated because it may open closed doors in clinical situations like HRS itself, ischemia induced AKI, and kidney preservation for organ transplantation. I think that a rocky path could be paved with astute experimental and clinical observations like the one from Duailibe et al[12].