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Hepatorenal syndrome in children

 Sindromul hepatorenal la copii

First published: 03 iunie 2024

Editorial Group: MEDICHUB MEDIA

DOI: 10.26416/Pedi.73.1.2024.9650

Abstract

Hepatorenal syndrome (HRS) is a severe complication of end-stage cirrhosis and portal hypertension. In children with chronic liver diseases, the incidence of HRS is 5%, a fact established before receiving a liver transplant. Cur­rently, there are only sporadic studies that would con­firm new therapeutic modalities usable in the treat­ment of HRS in the pediatric population, which can offer both the chance of improving the quality of life of these patients and the chance of reducing the dis­­abi­­li­­ties of HRS in adults. In this paper, we present some general data regarding the physiopathology, clas­si­fi­ca­tion and diagnosis of hepatorenal syndrome, as well as the main treatment modalities.

Keywords
hepatorenal syndrome, cirrhosis, children

Rezumat

Sindromul hepatorenal (HRS) este o complicaţie severă a ci­ro­zei în stadiul terminal şi a hipertensiunii portale. La copiii cu afecţiuni hepatice cronice, incidenţa HRS este de 5%, fapt sta­bi­lit înainte de a primi un transplant de ficat. În prezent exis­tă doar studii sporadice care confirmă noi modalităţi te­ra­peu­tice utilizabile în tratamentul HRS la populaţia pediatrică, ce pot oferi atât şansa unei îmbunătăţiri a calităţii veţii acestor pacienţi, cât şi şansa reducerii dizabilităţilor HRS la adulţi. În această lucrare, prezentăm câteva date generale cu privire la fiziopatologia, clasificarea şi diagnosticul sindromul he­pa­to­renal, cât şi la principalele modalităţi de tratament. 

Introduction

Hepatorenal syndrome (HRS) is a severe complication of end-stage cirrhosis and portal hypertension, which is characterized by increased splenic blood flow, a state of reduced central volume, but especially renal blood flow and glomerular filtration rate (GFR)(1). After the first year of diagnosis, more than 20% of patients with advanced liver cirrhosis will develop HRS, and 40% within five years(2). In children with chronic liver disease, the incidence of HRS is 5%, which was established before they received a liver transplant(3,4). HRS comes in two types. Type I is an acute but rapidly progressive condition. The given form develops predominantly after a precipitating factor such as gastrointestinal hemorrhage, bacterial peritonitis etc. Type II presents a slowly progressive form of renal failure that often occurs spontaneously in patients with chronic ascites(5). Some studies have reported conclusive data that vasoconstrictor therapy with vasopressin analogues, mainly terlipressin, can improve kidney function, as well as survival in adults(5). However, there are limited studies evaluating the efficacy of this treatment in children. Studies show that liver transplantation is so far the only treatment option that ensures the long-term survival in children(6).

Pathophysiology

The pathogenesis of HRS is multifactorial. In children, there are limited studies and, as a result, the pathophysiological mechanisms are based on those provided by adult patients(6,7).

It is confirmed that the onset of the disease is caused by both the clinical picture of cirrhosis, various etiologies in children and adolescents, the most common cau­ses being biliary atresia, choledochal cysts, viral hepatitis B (HBV), but also hepatitis C (HCV) and autoimmune hepatitis, etc(6).

Hypoxia due to circulatory changes in the portal mesenteric area, as well as in the hepatic microcirculation, contributes to the development of liver parenchymal and endothelial cell damage and reperfusion through the elimination of endooxides, other mediators, etc.

As a result, portal hypertension occurs in liver cirrhosis as a result of increased intrahepatic flow resistance while stasis and release of vasodilator mediators in the hepatic vascular bed lead to vasodilatation of splenic arteries and systemic hypotension, with the reduction of the cause of peripheral vascular resistance(8).

Ascites and endothelial cell edema in the sinusoids are the result of several mechanisms: “overflow”, which is a primary event in the renal proximal tubule, and leads to water and salt retention, causing increased hydrostatic pressure and fluid extravasation (Figure 1). On the other hand, “underfilling” was proposed by Schrier et al. in 1988, who believe that portal hypertension as a result of hypovolaemia and the compensatory response of the kidneys promotes water and salt retention(9).

Figure 1. Pathophysiological hypothesis of acute decompensation and development of organ dysfunction in patients with liver cirrhosis(10)
Figure 1. Pathophysiological hypothesis of acute decompensation and development of organ dysfunction in patients with liver cirrhosis(10)

Splenic vasodilation

Splenic vasodilation is one of the most important manifestations of HRS. The primary pathophysiological mechanism is still incompletely elucidated, even though it is directly related to the reduction of intrahepatic vascular resistance, opening of portosystemic shunts and minor arteriovenous fistulas(11).

Several biochemical mediators have been proposed to estimate the vasodilator effect, such as nitric oxide, glucagon, carbon monoxide, prostaglandins (prostaglandin I2), epoxyeicosatrienoic acids, endogenous cannabinoids and adrenomedullin, enzyme concentrations, carbohydrate metabolism, protein, coagulation system, etc. It has been shown that the prognosis of liver failure is also related to the degree of dysfunction of other organs and systems such as lungs, kidneys, digestive tract, central nervous system, etc.

Hyperdynamic circulation states
and subsequent cardiac dysfunction

Decreased peripheral vascular resistance of blood pressure results in hyperdynamic circulation as a mechanism to restore homeostasis. Several studies have demonstrated the existence of hyperdynamic circulation in humans and rats with portal hypertension, as long as a portosystemic shunt is present(12,13).

Cyrotic cardiomyopathy is characterized by reduced systolic and diastolic contraction in response to ventricular hypertrophy and dilatation of the heart chamber(7). The main mechanisms include: loss of adrenergic signaling, changes in myocardial plasma membrane, and increased levels of cardiac depressants, including bile acids, endotoxins, cytokines, NO, and carbon monoxide(14).

Mechanisms of vasoconstriction

Neurohormonal mechanisms are activated to decrease hypovolemia caused by peripheral vasodilation, with the aim of restoring circulatory homeostasis. These mechanisms act on cutaneous, muscular and cerebral circulation.

Systemic inflammation

Recent studies have reported that systemic inflammation – and, thus, hyperinflammatory states – also play a role in the pathophysiology of HRS. Systemic inflammatory response syndrome has been detected in more than half of HRS-LRA patients, independent of the presence of actual infection(15).

It has been shown that the most extensive initial systemic inflammation also had the highest risk of developing liver failure and death(16).

Plasma levels of proinflammatory cytokines (interleukin 6 [IL-6] and tumor necrosis factor a [TNF-a]) and urinary levels of monocyte chemoattractant protein-1 (MCP-1) are higher in patients with HRS-LRA than in those with decompensated cirrhosis without acute kidney injury (AKI) and in those with AKI secondary to prerenal azotemia(17).

Bacterial translocation is a process that occurs continuously and indicates the passage of viable bacteria through the mucosa and lamina propria of the digestive tract to extraintestinal locations such as mesenteric lymph nodes, liver, spleen, peritoneum or bloodstream. Thus, one of the main mechanisms by which the systemic inflammatory state contributes to the pathogenesis of HRS is the translocation of intestinal bacteria from the gut to the mesenteric lymph nodes due to altered intestinal permeability(18).

There is yet another subject of debate that represents a biopathological entity with variable clinical expressions, encompassing separate pathological phenomena. Advances in molecular biology have allowed the detailing of defence mechanisms, but also bacterial translocation with a hyperpermeability of the intestinal mucosa and maintenance or even amplification of the inflammatory process. There are numerous scientific arguments to assert that endotoxic and inflammatory causes not only hemodynamic, metabolic, acid-base and immunological, but also bacterial translocation alterations. Bacterial translocation induces increased levels of proinflammatory cytokines, especially IL-6 and TNF-a, but also of other vasodilatory factors such as NO(19,20).

Diagnosis

In 1996, the International Club of Ascites (ICA) defined HRS as a decline in renal function in patients with acute decompensated liver disease and portal hypertension, characterized by severe circulatory dysfunction. At the same time, the criteria were revised in 2007, which allowed the classification of HRS into two distinct subtypes: type 1 HRS and type 2 HRS(21,22).

Type I was characterized by a rapid deterioration of renal function, with initial serum creatinine doubling to ≥2.5 mg/dL or a 50% reduction in less than two weeks in the first 24 hours, creatinine clearance being below 20 ml/min.

Type II was characterized by the progression of renal failure that did not meet the criteria for type I. Of note, urinary sodium and oliguria have been removed from the new diagnostic criteria(23).

Therefore, in 2015, the ICA modified the previous criteria and classifications of AKI in patients with cirrhosis, which is consistent with the Kidney Disease Improving Global Outcomes (KIDGO) classification(24).

 Serum creatinine present within three months of the primary diagnosis may be used as a baseline value when a baseline level obtained within seven days is not available. Although oliguria has not been included in the definition of AKI in patients with cirrhosis, a study indicating that the amount of urine was significantly associated with adverse outcomes in patients with AKI and cirrhosis led to the revision of a new definition and, generally, to a new classification for HRS, which expands on the 2015 ICA consensus document(10,25).

New diagnostic criteria for HRS

Recently, the ICA has completely revised the nomenclature and diagnostic criteria for HRS type I, which is referred to as HRS-LRA(26,27).

Figure 2. Mechanisms of renal injury potentially involved in HRS-LRA in patients with liver cirrhosis – adapted after Angeli et al., 2019(10)
Figure 2. Mechanisms of renal injury potentially involved in HRS-LRA in patients with liver cirrhosis – adapted after Angeli et al., 2019(10)

This assumption has led to the elimination by the ICA of the minimum creatinine value for diagnosis and, therefore, HRS-LRA can be diagnosed even when serum creatinine levels are below 2.5 mg/dL. Functional kidney injury that does not meet the HRS-acute kidney injury (HRS-AKI) criteria is classiffied into HRS-non acute kidney injury (HRS-NAKI), of which NAKI is further divided into HRS-acute kidney disease (HRS-AKD) if the estimated glomerular filtration rate (eRFG) is below 60 mL/min/1.73 m2 for less than three months and HRS-chronic kidney disease (HRS-CKD) if eRFG is below 60 ml/min/1.73 m2 for more than three months (Table 1)(10).

Table 1 Classification of hepatorenal syndrome (HRS) subtypes(10)
Table 1 Classification of hepatorenal syndrome (HRS) subtypes(10)

Stages of acute kidney injury according
to the
International Club of Ascites(26)

Stage I: Increase in serum creatinine ≥0.3 mg/dL or increase in serum creatinine ≥1.5-fold to 2-fold from baseline.

Stage IA: serum creatinine <1.5 mg/dL.

Stage IB: serum creatinine ≥1.5 mg/dL.

Stage II: Increase in serum creatinine at least two to three times the baseline value.

Stage III: Increase in serum creatinine at least three times baseline or serum creatinine ≥4 mg/dL with an acute increase ≥0.3 mg/dL or initiation of renal replacement therapy.

Recent research has shown that the inclusion of urine flow in the diagnostic criteria for AKI has also significantly improved the assessment of chondral liver disease, and patients identified on the basis of urine flow criteria without increased sCr had higher mortality rates, explaining that this criterion could be important in determining the prognosis of the disease(10).

We note that urinary biomarkers, which reflect structural damage to the kidneys, are important in the differential diagnosis of AKI in patients with liver cirrhosis. Recent studies have reported that among the most promising biomarkers are neutrophil gelatinase-associated lipocalin (NGAL), interleukin-8, and albumin.

NGAL is a glycoprotein released from the injured renal tubular epithelium, which increases significantly in AKI before the rise in serum creatinine(28). Other studies have demonstrated that uNGAL (Urinary Neutrophil Gelatinase Associated Lipocalin) and interleukin 8 levels are predictive of prognosis, with increased biomarker levels being driven by higher short-term mortality(29). Literature data draw attention to the role of urinary biomarkers such as IL-18, albumin and liver fatty acid binding protein (L-FABP) in differentiating acute tubulointerstitial necrosis (ATN) and HRS. Their use has shown similar performance, indicating the highest levels in ATN compared to patients with HRS-LRA or hypovolemia-induced ALR(28).

Serum cystatin C, which is produced by nucleated cells, is an important marker in detecting renal function in patients with liver cirrhosis. Thus determination of RFG based on serum cystatin C compared to serum creatinine allows the accurate and earlier diagnosis of chronic kidney disease(22).

A noninvasive tool that allows early diagnosis of HRS as one of the selected renal biomarkers is the assessment of the serum metabolomic profile, a factor that can predict the response to HRS treatment and the status of renal function after liver transplantation. However, at present, the clinical significance of the metabolomic profile is still unclear, warranting further studies in this area(27).

Clinical manifestations

The etiopathogenetic study revealed the following aspects in HRS: children with hepatorenal syndrome present with a variety of nonspecific symptoms, such as fatigue, abdominal pain, general feeling of sickness, but also with symptoms indicative of advanced liver disease, including ascites, jaundice of the tegument, splenomegaly or hepatomegaly.

Thus, type I hepatorenal syndrome is characterized by a rapid reduction of the renal function with progression to renal failure with generalized edema, decreased diuresis, but also more likely to develop hepatic encephalopathy, causing confusion, drowsiness, acute liver failure, etc. Type II hepatorenal syndrome represents the severe and unpredictable course of renal dysfunction which generally progresses much more slowly than type I, and children are less likely to develop jaundice, may not develop hepatic encephalopathy, but predominantly develop accumulation of intraabdominal ascitic fluid, and do not respond to diuretic treatment.

Treatment

We believe that there are currently sporadic studies that would confirm new therapeutic modalities usable in the treatment of HRS in the pediatric population, that may offer both the chance of an improvement in the quality of life of these patients and the chance of reducing HRS disability in adults(30).

Research in the field but also our clinical results regarding the use of some drugs in the treatment of hepatorenal syndrome reveal that, in children, the use of agents that induce nephrotoxicity should be discontinued, as well as nonsteroidal anti-inflammatory drugs and diuretics(31). In highly experienced centres speciali­zing in hepatorenal pathologies, good results are reported with the use of albumin in combination with terlipressin (vasopressin analogue), norepinephrine, but also a combination of midodrine and octreotide (somatostatin analogue). It is certain that albumin alone and terlipressin give good results(31).

Pharmacological vasoconstrictor therapy

Analysing the results of several studies, but also according to the latest guidelines, terlipressin is a vasopressin analogue which is a V1/V2 receptor selective drug, being considered the first-line treatment for HRS in Europe according to the European Association for the Study of the Liver (EASL) and the Asian Pacific Association for the Study of the Liver (APASL)(32-34).

Most recently, the FDA approved the use of injectable terlipressin to treat adults with hepatorenal syndrome with rapidly declining renal function(32,34-36). Even though important progress has been made, it still remains a topic of discussion in the literature. A recent meta-analysis, which included the analysis and synthesis of 24 articles with 1429 participants, is now recommending that terlipressin in combination with albumin represents a successful combination in the treatment of HRS(31).

Currently, there is literature with inconclusive results re­gar­ding the use of terlipressin in children. On the other hand, only one series of patients with hepatorenal syndrome followed a single average dose of 15 to 20 mcg/kg every 4 hours, with terlipressin preparation used in con­ti­nuous infusion at 30 mcg/kg/day(5).

In these circumstances, several meta-analyses conducted in children have evaluated and compared the efficacy of vasoconstrictors, the data revealing that terlipressin in combination with intravenous albumin showed greater efficacy(37,38).

It was performed a study on 16 patients with a mean age of 10 years old (6.1-14.4) and 21 records of terlipressin administered initially as a bolus, and then either as a bolus, or as infusion, all cases receiving the mean dose of 5.2 (3.8-6.7) mcg/kg/hour. The results of the study demonstrated that after treatment there was a sustained increase in mean arterial pressure, improvement in serum creatinine (Cr) (at 24 hours; p=0.386), and an increase in urine output, predominantly in patients with hepatorenal syndrome (HRS-LRA)(39).

It is believed that aquaretic agents (vaptans) promote water excretion and increase diuresis, which leads to dilution of urine, blockade of V2-mediated vasodilation and, therefore, these agents may improve hyponatremia, ascites and increase plasma vasopressin concentrations. Recent studies have also demonstrated that vaptans may play an important role in increasing serum sodium concentration in patients with liver cirrhosis(40).

Extracorporeal kidney replacement therapies

Extracorporeal renal replacement therapies are useful in the treatment of HRS. Hemodialysis is the most recommended in critically ill and pre-transplant patients who do not respond to other therapies. It can be intermittent or continuous, depending on the severity of the patient(41). But, at the same time, in some patients, it can also cause a number of complications, especially in critically ill patients with cardiovascular, kidney or lung instability.

Tandem plasmapheresis and hemodialysis (TPH) is useful in critically ill pediatric patients with grade 3 hepatic encephalopathy and/or liver failure and severe coagulation changes(42).

Recently, the Molecular Adsorbent Recirculation System (MARS) has been developed as an extracorporeal system which combines high-flow hemodialysis, filtration and adsorption using a dialyzed albumin-enriched substance to remove toxins. Studies in adult patients have demonstrated benefits on both renal function and survival in patients with acute liver failure, but such studies in children are not reported(43).

Another innovative and encouraging extracorporeal system is Prometheus® (Fresenius Medical Care, Bad Homburg, Germany), which is based on the principles of high-flow HD plasma separation fractionation that contributes to a significant reduction of toxins, including ammonia, urea, as well as bilirubin and cytokines (hence, markers of inflammation). On the other hand, coagulation system factors and platelets are not altered. Reviewing recent research, we note that the use of the given method in children is at an early stage, and attempts are being made to accumulate new data and to know the potential benefits in children(44).

Other therapeutic options could include transjugular intrahepatic portosystemic shunt (TIPS). Prospective randomized studies have shown that this procedure can increase preload as well as cardiac output and leads to a reduction of blood pressure in the portal system, one of the underlying conditions of HRS(45). Although the beneficial effects of TIPS in reducing mortality rates have been demonstrated in patients with type I and type II HRS, there are a large number of contraindications, as well as an increased risk of complications, especially hepatic encephalopathy(46).

Liver transplantation

As far as surgical treatment in hepatorenal syndrome is concerned, the operation of choice remains liver and kidney transplantation. Thus, liver transplantation remains the definitive treatment in HRS. Although simultaneous liver and kidney transplantation (SKLT) presents the surgical technique of choice in patients who will not recover the native renal function after liver transplantation, the decision to perform SKLT versus liver transplantation remains a challenge. The outcome of recovery of impaired renal function remains a challenge due to a multitude of factors; in particular, the duration and severity of renal injury primarily contribute to renal prognosis(47).

European guidelines conclude and recommend that patients with end-stage liver disease and presenting with chronic kidney disease (CKD) G4 or G5, defined as eGFR<30 ml/min/1.73 m2, or HRS type 1 requiring renal replacement therapy more than 8-12 weeks, and patients with renal biopsy in which histological samples show more than 30% glomerulosclerosis and fibrosis should receive SLKT(48).

However, approximately 10% of patients receiving liver transplantation may have persistent or progressive renal dysfunction even after a successful transplantation(49).

In conclusion, hepatorenal syndrome in children is a serious condition, incompletely elucidated in terms of etiopathogenesis and incompletely studied in children, which is why medical and surgical treatment modalities are constantly changing, and are not standardized.   

 

Corresponding author: Elena Ţarcă E-mail: elatarca@gmail.com

Conflict of interest: none declared.

Financial support: none declared.

This work is permanently accessible online free of charge and published under the CC-BY licence.

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Infarctul renal acut la copii şi adolescenţi este un eve­ni­ment rar, asociat de obicei cu anomalii cardiace, cu status hiper­coa­gu­lant, boli cu ...

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Intoxicaţiile acute la grupa de vârstă pediatrică reprezintă una dintre principalele cauze de mortalitate şi de morbiditate, cu impact major în cee...

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