Good morning. Good morning. Thank you for this kind invitation to join this symposium. I have nothing to disclose regarding this presentation. And my task will be to explain, to explore the pathogenesis of hepatorenal syndrome according to new developments and new advances in this syndrome. And I think that this should be done under the light of the new paradigms that have been observed, that have been developed in cirrhosis, that I would summarize in three points. First, cirrhosis is a dynamic disease and a dynamic process that evolves in the stages which have the potential for reversibility upon control of etiology. Second, cirrhosis should not be longer considered a disease limited to the liver, but extends beyond the liver due to the presence of circulatory dysfunction, organ failure, and systemic inflammation. And ACLF has emerged at a new entity within cirrhosis defined by the presence of acute decompensation, organ failure, high short-term mortality, which is driven by high-grade systemic inflammation. And in this talk, I will first explain the systemic inflammation hypothesis, which should be viewed as an extension and not opposing to the previous peripheral vasodilation hypothesis. Thereafter, I will explain the recent evidences that challenge the classical concepts of hepatorenal syndrome, and I will contrast this evidence with the previous concepts in this rather old syndrome. And I finally will explain the mechanisms of renal damage in non-classical hepatorenal syndrome. And increased portal pressure and increased peripheral vasodilation, this is systemic circulatory dysfunction, drives the transition from the compensated to decompensated cirrhosis and hepatorenal syndromes. The worse the systemic circulatory dysfunction, as addressed by the level of plasma renin activity, the worse the prognosis, as it was shown almost four decades ago. But recently, the concept or the entity of ACLF is being defined, and ACLF mainly differs from traditional acute decompensation by high short-term mortality. High short-term mortality that relates to the severity of ACLF, as addressed by the number of organ failures, and also is closely related, the severity, the mortality, to the presence of systemic inflammation. And this was already observed in the first descriptions in the canonical study of ACLF as measured by the white blood cell count. In a more recent study, it has been shown that the serum concentration levels of pro and anti-inflammatory cytokines in patients with ACLF parallels the levels, the serum levels parallels the severity of the syndrome. In contrast, the severity of circulatory renal dysfunction, as measured by plasma renin concentration, is similar across the different ACLF grades. And this is further shown in the graphic on the right hand, in which the level of interleukin-8 is greater in non-survivors than in survivors with ACLF. But the levels of plasma renin concentration are equally distributed between both groups, indicating that the systemic inflammation is the driver of the disease in ACLF, and not severe, and not systemic circulatory dysfunction. It is important to remark that systemic inflammation is not exclusively present in patients with ACLF. Low-grade systemic inflammation appears, even in the compensated cirrhosis stage, and increases as the disease progresses, as cirrhosis progresses in the compensated stage, being especially higher in those patients with cirrhosis, ascites, and high LVP, as used as a surrogate marker of bacterial translocation. It is important also to point out that when you achieve bowel decontamination with norfloxacin in these patients with cirrhosis, ascites, and high LVP, you reduce systemic inflammation, and you improve systemic hemodynamic. Indicating first that the activation of the immune system is mainly due to an enteric bacterial stimulus. And second, that the systemic inflammation contributes to the hemodynamic derailment of cirrhosis of the decompensated patients with cirrhosis. Therefore, as the peripheral vasodilation hypothesis stated, that the driver of the disease in the decompensated patients was peripheral vasodilation and systemic circulatory dysfunction. Low-grade inflammation in the decompensated patients contributed to worsening systemic circulatory dysfunction by increasing nitric oxide production. In contrast, high-grade systemic inflammation seems to be the driver of disease in patients with CLCLF, and leads to organ failure by mechanisms that I will explain thereafter. And it is in this context of systemic circulatory dysfunction where the classical concept of hepatorenal syndrome fits. And in this situation, there is marked effective arterial hypovolemia, which is mainly caused by splenic arterial vasodilation with the contribution of a reduced cardiac output. This leads to renal vasoconstriction, intense renal vasoconstriction, reduction in renal blood flow as the hemodynamic hallmark of hepatorenal syndrome. According to this concept, classical hepatorenal syndrome is a functional disease caused by systemic circulatory dysfunction, by the hemodynamic derangement of cirrhosis. And there, and you will know them, several evidence that support this point of view, mainly the favorable response to vasoconstrictors, to terliprasine in many of these patients, and also the absence of renal histological changes in the kidney of these patients, although this has not definitively proven among other evidences. However, there are several evidences that are challenging this classical view of non-hepatorenal syndrome. And the first can be the response to terliprasine if we see the bottle half full. Only 50% of the patients respond to terliprasine and albumin. And increased serum bilirubin as a marker of hepatic failure has been identified as an important and independent factor of non-response to terliprasine in this patient. And the cutoff value used in this study was 10 milligrams, which is close to the value of hepatic failure that is used in the modified SOFA score of the CLIF consortium. Also in this study, there was a trend for an independent prediction of non-response in patients with systemic inflammation, as addressed, as measured, by the white blood cell count. And indeed, systemic inflammation is present in patients with hepatorenal syndrome. And a recent study, also from the Canonic series, in which it has been measured the heat map of systemic inflammatory biomarkers in different phenotypes of patients with acute decompensation. Increased serum levels of different cytokines are increased in patients with renal dysfunction. Also, it is important to highlight that the in-hospital mortality in patients with cirrhosis, decompensation, and hepatorenal syndrome is twice as high in those with cirrhosis than in those without systemic inflammatory response. Even in the 30% of patients who show it in this study, cirrhosis, but did not have bacterial infection. Therefore, there are several evidence that indicate that systemic inflammation is contributing to the development of hepatorenal syndrome. But this still can fit with the splenic vasodilation or the peripheral vasodilation hypothesis. Since, as I told you before, systemic inflammation worsens systemic circulatory dysfunction by increasing nitric oxide, by increasing the production of nitric oxide. Although, systemic inflammation can also impair glomerular filtration rate by causing kidney tissue injury. And there are some, they are limited, but some evidences regarding that this fact can be true. And one is a study that evaluated renal finding in 80 patients with cirrhosis with increased creatinine and without proteinuria and hematuria that seemed to have functional renal failure. Observing the presence of renal parenchymal damage in more than 50% of them, including tubal interstitial inflammation. Therefore, patients with cirrhosis and that supposedly can have functional renal failure could have in liver, in renal biopsy, parenchymal damage. And the question that arises is to what extent the presence of kidney inflammation, kidney damage driven by systemic inflammation could impair and could contribute to impair the response to vasoconstrictors. And in this regard, ACLF and the number of organ failure, this is the severity of ACLF, which correlate with systemic inflammation, is as independent predictor of non-response in patients with this syndrome, with ACLF. And this is further shown in this slide, in which also in the canonic series, the degree of systemic inflammation as measured by the value of interleukin 8 and product of oxidative stress as oxidized albumin are significantly greater in patients with kidney dysfunction than in those without kidney dysfunction. Although the values of plasma renin concentration are similar or are also similar in both groups, indicating again that the systemic inflammation in these circumstances could be the main driver of kidney dysfunction in this setting. And another question is what are the mechanisms leading to renal damage in these patients with non-classical hepatorenal syndrome? And I would highlight mainly the mechanism of systemic inflammation, including the renal immune response to pumps and dams, and also with a potential contribution of bile acids, which has been called cholemic nephropathy. And in this setting of high-grade systemic, this setting of ACLF with high-grade systemic inflammation, it can lead to organ and kidney failure by two mechanisms. One is immunopathology and the other one is immune metabolism disturbance. And regarding the first one, you should take into account that the massive release of inflammatory mediators such as cytokines, oxidative products, and even the recruitment of activated immune cells by peripheral tissues can lead to peripheral tissue damage. And the second mechanism is a disturbance, and these are very recent data, a disturbance of metabolism, a switch of anabolic processes of anabolic processes in immune system cells in detriment of catabolic processes in peripheral tissue cells that I will explain thereafter. And regarding the first mechanism, there are some data that indicate specific data in patients with kidney dysfunction that indicate that this situation, that this hypothesis is true. And in a short series of patients with alcoholic cirrhosis, it was shown that patients with non-classical hepato-renal syndrome, in contrast to patients with hepato-renal syndrome, so it increases pressure of toll-like receptor 4 in the renal tubules along with cell tubular damage. In these patients with non-classical hepato-renal syndrome, especially in those with marked systemic inflammatory response syndromes, there was an increased urinary excretion of toll-like receptor 4. Therefore, the most likely hypothesis could be or likely hypothesis could be that the circulating pumps could reach the tubular lumen, be recognized by tubular cells which behave as antigen-presenting cells leading to an activation of the inflammatory cascades that leads to renal tubular damage. This has also been shown in experimental models of biliary cirrhosis receiving sublethal doses of LPS. And in this study, it further shows that abrogating the enteric bacteria's stimulus with norfloxacin reduces or reverses these inflammatory changes in the kidney. And previously Dr. Wong also emphasized the relevance of micro vesicles and extracellular vesicles in renal damage in patients with cirrhosis. And I want just to draw your attention of this study that we presented in the Sunday Parallel Cellcion regarding the distinctive micro RNA expression in certain exosomes of patients with cirrhosis and refractory ascites in analysis made on vesicles obtained from the secretome of primary human hepatocytes. And regarding the second hypothesis, this is immune metabolism. This is changing metabolism in patients with high-grade systemic inflammation. I want to show some data also obtained from a high-throughput metabolomic study in blood from patients from the canonic series. Patients with acute decompensation and patients with ACLF. In this metabolomic study, it has been undertaken in 137 metabolites and the Cliff Consortium has been able to identify 83 metabolites that compose a distinctive blood fingerprint, which is similar across all the ACLF phenotypes independent of the organ failure and independent of the precipitating event, whose intensity, the intensity of these metabolomic fingerprints correlate with the severity of ACLF and with systemic inflammation. And to summarize the many data obtained from this study, it showed that there is a change in metabolic behavior of the peripheral, in the cells of the peripheral tissues in a critical situation such in ACLF. With an increased glucose metabolism through aerobic glycolysis, with decreased, with simultaneous decrease in oxidative phosphorylation, along with decreased mitochondrial fatty acid beta oxidation. And the final point would be a mitochondrial dysfunction due to a switch in the metabolic programs that move from or switch in the peripheral tissues to an upregulation of catabolic programs and anabolic programs in the in the activated immune system cells. And therefore, by these two mechanisms, immunopathology and energetic crisis chain immune metabolism are the hypothetical mechanisms by which high-grade systemic inflammation lead to cell death, cell mitochondrial, cell dysfunction by mitochondrial dysfunction and also probably microtrombosis and activation of the coagulation system. Just a final word by polemic nephropathy, which has been an entity which has experienced a renaissance in recent years. Although from my point of view, the data, the current data, are rather limited. In an autopsy study, 85% of patients with hepato-renal syndrome show tubular bile gas and in a renal biopsy study in patients with different forms of liver disease, including only 22% of those with cirrhosis, the researchers found polemic nephropathy only in two patients. In conclusion, hepato-renal syndrome includes a continuous spectrum of kidney injury from acute decompensation of cirrhosis to ACLF. Hepato-renal syndrome spectrum extends from a predominantly functional disorder driven by systemic circulatory dysfunction, which could be called classical hepato-renal syndrome, to another one associated with parenchymal damage driven by systemic inflammation, which we could call non-classical hepato-renal syndrome. Immune pathology and immune metabolism are the mechanisms by which high-grade systemic inflammation could mediate kidney tissue damage in non-classical hepato-renal syndrome. And thank you very much for your attention.

hepatorenal syndrome

cirrhosis

ACLF

systemic inflammation

renal damage

immunopathology