My task this morning is to discuss with you the pathophysiology of sodium retention and kidney dysfunction in cirrhotic ascites. These are my disclosures. When a patient first develops cirrhosis at the pre-ascites stage, there is already subtle sodium retention, mostly occurring in the upright posture. Then somewhere along the natural history, decompensation occurs when a patient has obvious sodium retention. At the early stage of ascites, the patient is responsive to diuretics. However, as the cirrhotic process progresses, the ascites becomes increasingly difficult to treat until eventually refractory ascites occurs, at which time avid sodium retention occurs. The patient is prone to develop chronic kidney disease, hyponatremia, and if there is any precipitating factor, the patient can then develop acute kidney injury and eventually develop functional renal failure. The pathophysiology of renal dysfunction is linked to the pathophysiology of sodium retention. I will just go back to some basic physiology. In a patient with cirrhosis, the distortion of the liver architecture leads to increased resistance to portal flow, and that is related to various mechanical factors, such as the laying down of fibrous scar tissues or the development of regenerative nodules. In addition, in patients with ongoing inflammation, there is hepatocyte swelling, and eventually the sinusoids develop a basement membrane, and that's called capillarization of sinusoids. However, the mechanical factors are only responsible for approximately two-thirds of the increased resistance to flow. Underneath the sinusoids, you have these dally cells, which, when they contract, will narrow down the sinusoidal diameter further. In addition, within the microcirculation of the liver, there is increased response to vasoconstrictors and decreased response to vasodilator. The sum of all of these factors will produce an increased resistance to portal flow. And so, when you have obstruction to portal flow, this is portal hypertension. When the presence of portal hypertension will increase the shear stress on the portal vessel, the end result is an increased production of vasodilators. In addition, there is this process called bacterial translocation, where you have increased amount of gut bacteria as well as bacterial products, many of which have got vasodilatory properties, which will lead to vasodilatation in the splenic circulation. In addition, hyporesponsiveness of the splenic vessel, as well as increased metenteric angiogenesis, will also contribute to the splenic vasodilatation. Because your circulatory capacitance in the splenic circulation is increased, there is increase in portal flow, perpetuating the portal hypertension. And so, when you have portal hypertension, there is opening up of preexisting portal systemic shunt, shunting some of the vasodilators in the splenic circulation into the systemic circulation, causing systemic arterial vasodilatation. So there is this concept of reduction in the effective arterial blood volume. Imagine that you and I, who have no liver disease, our circulatory volume will totally fill up the capacitance. This is a cirrhotic patient with vasodilatation. So the capacitance is increased without actually losing any intravascular volume. The body senses that there is reduction in circulatory volume, and that concept is known as a reduction in the effective arterial blood volume. So when you have a reduction in the effective arterial blood volume, the physiological response is the activation of various vasoconstrictor systems, including the activation of the renin, angiotensin, aldosterone system, sympathetic nervous system, and also non-osmotic release of arginine vasopressin. All of these activated vasoconstrictor systems will try to reduce the extent of the systemic arterial vasodilatation. However, the kidneys are particularly sensitive to the increased levels of these vasoconstrictors, and as a result, we have decreased GFR, decreased renal blood flow, and the body is also trying to increase the intravascular volume by retaining more salt and water. And these two factors will then predispose the cirrhotic patient with ascites to renal failure. And the reason why we know that a reduction in the effective arterial blood volume exists comes from some very old study. This is a... I'm going to show you the results from a study that's fairly old, but it still applies today. We don't do this procedure called head-out water immersion anymore. However, if you do put a patient in a pool, the external water exerts hydrostatic pressure on the vascular columns of the body, and it forces the blood from the lower extremities into the intrathoracic vascular compartment, and it lowers the levels of the sodium-retaining neurohormonal systems. And it's been worked out that the pressure exerted increases by 22.4 millimetres of mercury for every foot depth of water. And the end result is actually a massive naturesis and a diuresis. However, as soon as the person comes out of the pool, sodium retention returns. And the other way of decreasing the extent of reduction in the effective arterial blood volume is by putting some intravascular volume. And this is a study which shows that patients who receive alderman infusion for a month, you can see a significant increase in the urinary sodium excretion as well as in the urinary volume. And so by decreasing the mismatch between the intravascular volume and the capacitance that holds it, you can actually improve the sodium retention, decrease the sodium retention, and decrease the risk for developing renal dysfunction. And this summarises very well what happens to a cirrhotic patient during the natural history of cirrhosis. At the level of compensated cirrhosis, you do not have a lot of vasodilatation. And initially, the body functions very well by increasing sodium to fill the effective blood volume. However, as the cirrhotic process progresses, your vasodilatation increases, your effective arterial blood volume decreases, and you have activation of various vasoconstrictor systems. And the renal circulation is particularly sensitive to the presence of the elevated levels of vasoconstrictor systems. And therefore, you have renal vasoconstriction predisposing the patient to renal failure. And this study shows that by having worsening hemodynamics, you are actually predisposing the patient to a reduced GFR. So as the mean arterial blood pressure falls, the GFR also falls. And in patients who cannot maintain the hemodynamics, the renal plasma flow and the glomerular filtration rate are also decreased. Now there is something known as renal autoregulation. It is a physiological mechanism that we all have, that as the renal perfusion pressure decreases, the renal blood flow usually is maintained. However, in a cirrhotic patient, as the renal perfusion pressure decreases, there is inability of the patient to maintain a renal blood flow. And that seems to be a function of the severity of the liver dysfunction. So for a pre-acidic cirrhotic patient, your renal perfusion pressure can come down to about 50 millimeters of mercury. You can still maintain an adequate renal blood flow. In patients with diuretic sensitive ascites, the curve starts going down at a lower renal perfusion pressure. And in patients who have hepatorenal syndrome, even at a good renal perfusion pressure, the renal blood flow is significantly reduced, and this is related to an increased activity of the sympathetic nervous system. So hemodynamic abnormalities form the basis of sodium retention and renal dysfunction in patients with cirrhosis. However, several years ago, Professor Bernardi said, hey, there is more to just renal hemodynamic abnormalities in cirrhotic patient. He brought in the idea of inflammation in cirrhosis, and the concept of bacterial translocation, it's something that we've known for a long time, and that sets up local and or systemic inflammation, which will contribute to splenic vasodilatation, can also contribute to cardiac dysfunction, which ultimately will contribute to kidney dysfunction. What is bacterial translocation? It's the passage of bacteria through the gut lumen into the splenic circulation. And this occurs because portal hypertension can lead to mucosal congestion and eventual epithelial apoptosis, making the cirrhotic gut leaky. In addition, there is decreased bile acid production in cirrhosis, which favors the overgrowth of pathological bacteria. Bacterial translocation actually occurs to a small extent under normal circumstances, but becomes pathological when there is increased quantity or rate of translocation. And that can lead to enhanced pro-inflammatory response and release of various reactive oxygen species and nitric oxide. And so this is a pictorial representation of what happens. Bacterial translocation can occur through loose and tight junctions, and they also can occur through the epithelial cells. And in the sinusoid, they will activate various inflammatory mediators, and when they get transferred into the sinusoid, they can recruit a lot of the immune cells, causing further damage. And this is to show you that as the cirrhotic disease progresses, you actually have increasing amount of bacterial translocation, increasing production of nitric oxide and reactive oxygen species, causing damage and inflammation. But inflammation can also occur without the presence of bacteria, and this is what we call sterile inflammation. And so various factors can also damage liver cells, such as alcoholic hepatitis, a flare viral hepatitis, drug-induced liver injuries. By causing hepatocyte necrosis, you actually produce these molecules known as damage-associated molecular pattern. And bacteria will produce what we call pathogen-associated molecular pattern, and they can all activate various immune cells to produce inflammatory markers. And all the inflammatory markers, such as increased chemokines, cytokines, and nitric oxide, will cause further changes in the hemodynamics of the patient. And looking particularly at the kidneys, and you will see all these stamps and pumps and inflammatory mediators being filtered by the glomeruli, and in the peritubular microcirculations, they actually can cause oxidative stress, leading to microthrombi, and also cause death of the tubular cells, and therefore contributing to the development of renal failure. And this is just to show you some experimental data in patients who have got systemic inflammatory response syndrome factors. The patients who have got SERS markers were more likely than patients without SERS markers to develop AKI. And this study was done in patients with alcoholic cirrhosis. And in another study, once again, the patients who have got AKI, a higher proportion of these patients were likely to have SERS compared to patients without AKI. In fact, the more SERS components you have, the more likely the patient is to develop AKI. And so just to summarize the pathophysiology of renal dysfunction in cirrhosis. So this is what's been known for a long time, patients with cirrhosis with obstruction to the portal flow, leading to the development of portal hypertension. And this will lead to an increase in shear stress to the splenic vessels, leading to increased production of vasodilators. And therefore, there is splenic vasodilatation, leading to a reduction in the effective arterial blood volume. And in addition, when you have altered renal response to the activation of the vasoconstrictor systems, such as the altered auto-regulation response. In addition, when you have bacterial translocation with the bacteria causing an increased amount of PAMPs, and sterile inflammation causing an increased amount of DAMPs, and all of these will activate the immune system, causing an inflammatory response, making the cirrhotic patient likely to develop renal failure. And this is just to show you that the use of albumin can actually significantly decrease all these inflammatory markers, and therefore, there are studies now showing that the use of chronic infusion of albumin may actually reduce the likelihood of these patients developing renal failure, most likely through reduction in the inflammatory marker levels, as well as filling in the effective arterial blood volume. Now I just want to spend a minute or two to talk about these extracellular vesicles. These are tiny particles excreted by all cell types, and depending on their size, they can either be called exosomes, microvesicles, that next one should be microparticles, ectosomes, or oncosomes. These microparticles, their job is to communicate between cells. They actually package some molecules and transfer them between cells, and therefore, they may be involved in the communication between different parts of the kidney, as indicated in this cartoon. So here you have communication between glomerular cells, between tubular cells, and also, so this is between glomerular cells, between glomerular and tubular cells, and also between mesangial cells and the glomerular cells. So what they do is they could package some PAMs or DAMs, and involved in initiating the fibrotic process, and also initiating the inflammatory process, thereby contributing to the renal damage. So the pathophysiology of renal dysfunction is complex. It's no longer just a change in the hemodynamics, although hemodynamic abnormalities set the stage for renal functional changes, including renal sodium retention. Inflammation also contributes to renal damage and cirrhosis. Bacterial translocation is important in initiating inflammatory process. Sterile and or infective causes of inflammation exaggerate renal dysfunction induced by bacterial translocation. And now we know that extracellular vesicles may prove to be important in mediating further renal damage, and thank you for your attention.

pathophysiology

sodium retention

kidney dysfunction

cirrhotic ascites

portal hypertension

renal dysfunction