Thank you very much, Professor Kapoor. It is a great honor to be here. I would like to thank organizing committee and SCCM for the invitation. Kidneys, obviously, my most favorite organ. I think the kidneys are the most sophisticated dialysis machine that we carry with ourselves, and I hope that all of you have emptied your effluent bags so we can sit here for 80 minutes and enjoy the next talk, not my talk. So, this next 40 minutes, we'll focus on kidney and lung interaction, have no conflict of interest, and this is the outline of next 40 minutes. We know that there is a good communication between heart and lung and kidney. Obviously, heart and lung is very well-defined. With heart failure, you get pulmonary congestion. In addition, with lung disease, you get pulmonary hypertension. There is a well-defined relationship between the two. Kidney and heart also is very well-defined, cardiorenal syndrome. The role of kidney and lung interaction is less defined. I try to make a sense of literature. In addition, a few years ago in Austria, we had an AdKey meeting on kidney and lung relationship that some of the slides that I present is from that AdKey meeting. So, we all know cardiorenal syndrome is defined based on the impact of each organ on the other organ, based on the chronicity. So, acute heart failure or acute cardiac event would result in acute kidney injury or chronic cardiovascular diseases can lead to diseases in the kidney. Vice versa, in type 3 and 4, acute and chronic kidney disease can lead to cardiac or cardiovascular events. And type 5 is when systemic diseases engage these two together. When it comes to kidney and heart, kidney and lung, the definition of that is a little fuzzy. We all know pulmonary renal syndrome. As this was defined a long time ago, it is when we have diffuse alveolar hemorrhage in the lung and with the different degrees. And we have acute germinophritis. Sometimes it's present with RPGN and often it's immune-mediated process. However, this is not the whole story between access of kidney and lung. I would like to make a suggestion that we should think about it similar to cardiorenal syndrome as far as the pathophysiology is concerned. So, type 1 and type 2 are when acute and chronic lung disease would impact kidney function and causes kidney disease. Type 3 and 4, when acute and chronic kidney disease would result in damage to the lung, present some of the cases. And type 5 is basically pulmonary renal syndrome that systemic diseases engage both organs at the same time. Now, a little bit about epidemiology. We know that acute kidney injury is the most common organ failure in patients with ARDS. Whenever ARDS and acute kidney injury are coinciding, a need for mechanical ventilation is almost certain. 70 to 85% of these patients need mechanical ventilator. In addition, acute kidney injury in a patient with ARDS prolongs the hospitalization and therefore the cost. Acute exacerbation of COPD also increases the risk of acute kidney injury, on the other hand. This is a prospective multicenter cohort of the state of Washington. They looked into all patients who had acute lung injury. This was a little older definition than Berlin definition for ARDS. So, they all had acute lung injury. 65 of them had acute lung injury due to severe trauma. 89 of them found to have severe oliguric acute kidney injury. And comparison with the whole cohort of 1,000 patients, as you can see, mortality of patients with oliguric acute kidney injury is even significantly more than patients with severe trauma. As a matter of fact, median survival for these patients is between 7 to 10 days. Half of these patients die within 7 to 10 days when acute lung injury and acute kidney injury coincide. This is another epidemiology studies of about 2,000 patients that's a stratified patients based on presence of acute kidney injury and severity of acute kidney injury. As you can see, there is a dose response relationship between acute kidney injury and survival. Those without acute kidney injury survive the best, have the best survival. More severe acute kidney injury, they have the worst survival. Same cohort, as you can see, there is a dose response relationship between rising serum creatinine despite all the limitations of serum creatinine is a good prognostic marker. Rising serum creatinine and mortality to the point that creatinine more than 1.2 is associated with about 60% higher rate of mortality. When patients need dialysis, then their mortality is four times as much. So, there is a good connection between acute lung injury and kidney failure. We also know that chronic kidney disease is associated with increased risk of CKD with a 60% higher chance of development of CKD. And the more severe emphysema we have, in this study particularly, the lower GFR we have. Any 10% increase in emphysema translates to about 4.5 TC per kg per 1.73 square meter body surface area of decline in GFR. So, there is a good correlation between progressive COPD and progressive CKD. In this cohort, in the country of Taiwan, a whole country was evaluated. About 8,000 patients were found to have COPD. About 15,000 patients had no COPD. As you can see, in 12-year follow-up, there is a significant separation of the Kaplan-Meier curves in development of chronic kidney disease. And interestingly, majority of Kaplan-Meier curves, after the initial presentation, they become parallel at the end. But as you can see, these two curves continue to diverge. So, if you have COPD, chances of development of CKD continues to increase in comparison with non-COPDers. Now, how the pathophysiology works, obviously, patients with acute lung injury or pneumonia, they are very high risk. They have significant increase in inflammatory cytokines. They also have pulmonary hypertension that results in RV failure and the renal venous hypertension. Neurohumoral activation would impact kidney function. And also, there were toxins that we use for antibiotics, for treatment of pneumonia, or other potential medications could potentially lead to acute kidney injury. On the other hand, acute exacerbation of COPD follows the same suit. A lot of these patients receive medications like antibiotics in order to treat infection that would be nephrotoxic as well. And then, acute exacerbation often follows the same suit as increased cytokines that can lead to damage to the kidney. Hypoxemia decreases renal blood flow, particularly more severe hypoxemia. In addition, oxygen delivery goes down as oxygen saturation decreases. So, not only renal blood flow goes down, oxygen saturation is lower, therefore, oxygen delivery is lower. Hypercapnia has several different impacts on the kidney, and that would be one is changing auto-regulation activity of the kidney. Kidney cannot regulate its perfusion in a setting of severe hypercapnia. In addition, residual volume increases, and that will lead to increasing the abdominal pressure. That is a risk factor for acute kidney injury. So, interthoracic hypertension and intra-abdominal hypertension is a very well-described risk of acute kidney injury that happens in the setting of acute lung diseases, both in lung injury or COPD exacerbation. Now, add to this need for mechanical ventilator, non-invasive or invasive, and all of these could potentially lead to further damage. So, with non-invasive, sometimes we get barotrauma and risk of hyperinflation, intra-abdominal hypertension. On the other hand, mechanical ventilator that I'll show you some data how it impacts kidney function, also can cause barotrauma, increase cytokines, and exaggerate what other lung diseases can do to the kidney. So, we know that mechanical ventilator can be associated with significant decrease in raw blood flow, GFR, sodium excretion, and urine output. This is a very interesting study that C stands for control time, and then the first intervention in yellow arrow is when PEEP was set as plus 10 centimeter water, and then green arrow is when negative PEEP was applied, minus 6 centimeter water. As you can see, renal blood flow decreases significantly from more than 400 mL per minute to around 200 mL per minute. Then patients go to control phase again, and then with negative PEEP, you can see there's a significant increase in renal blood flow. Same can be seen in urine output. Urine volume significantly decreased with higher PEEP. With negative PEEP, urine output increases, similar to inulin clearance, which is measured GFR. Measured GFR decreases significantly in high PEEP, and then increases significantly with negative PEEP. In addition to that, mechanical ventilator cause some significant neurohormonal changes. So, for example, positive pressure ventilation would lead to decreased venous return, and that would create the perception of decreased effective blood volume in carotid bodies and baroreceptors that would lead to increased antidiuretic hormone. And that can mitigate ability of kidney to get rid of extra water. So, free water clearance decreases. On the other hand, by a similar mechanism, there is a significant activation of renal angiotensin aldosterone system that would lead to significant vasoconstriction of an artery, or that would lead to further decline in GFR. Now, we know based on multiple studies, including this systematic review, that absence of mechanical ventilator in an acute lung injury is associated with less risk of acute kidney injury. So, when mechanical ventilator was not present, risk of acute kidney injury was about four times less than when patients were on acute kidney injury. So, all of this mechanism that I mentioned can translate to higher risk of acute kidney injury. Now, going back to this, the more severe lung disease is, the higher chance of acute kidney injury is present. And in this scheme, the primary concept of acute kidney injury, which is a process, patients at high risk, they come in, they get exposed to multiple factors, not only by lung injury or COPD exacerbation, but also by mechanical ventilator. They go through the process of damage, decreased GFR, and eventually kidney failure, resulting in some death and also resulting in some cases that recover lung, the function can be associated with recovery, but often the recovery is partial. Even if GFR goes back to baseline, which often does, the residual reserve kidney function disappears. These patients cannot endure the same damage in the next round of recurrence of lung injuries. So, to summarize pathophysiology, there are some hemodynamic changes in lung disease. Increased pulmonary artery pressure would result in venous congestion and intra-abdominal hypertension. Pro-inflammatory, anti-inflammatory cytokines would be associated with higher risk of acute kidney injury. Acid-based disorder, in order to correct acid-based disorder, kidneys start kind of consuming more oxygen. In a setting of decreased neural blood flow, decreased oxygen saturation, then that would make a mismatch between oxygen supplement and demand. In gas exchange, hypercapnia, as I mentioned, is associated with a decreased auto-regulation and severe hypoxemia decreases neural blood flow. Neuromotor changes, we alluded to that as well. Now, add mechanical ventilator to the topic, it increases intrathoracic pressure even more, so cardiac output can decrease and pulmonary venous, renal venous hypertension increase and also some injurious mechanical ventilation strategies could lead to increase in cytokines and therefore cause proximal tubular cell apoptosis. Now, how do we monitor that? We can certainly use hemodynamic variables, central venous pressure, mean arterial pressure, cardiac output measurement. Renal perfusion pressure, which is mean arterial pressure minus CVP, could be potentially used. It's been shown that renal perfusion pressure is associated predictor of acute kidney injury. Cumulative fluid balance, amount of PEEP that we apply, tidal volume and peak inspiratory pressure all could indicate risk of acute kidney injury. Measurement of inflammatory markers, arterial pH and oxygen CO2 in arterial ABG and also some measurements in order to assess fluid balance like BMP could be helpful. Now, how ARDS management would impact acute kidney injury? What is the relationship between what we do for ARDS patient and impact development of acute kidney injury? We know that lung protecting mechanical ventilation strategies often used within our ICUs. In this study of about 1,100 patients, they found that output of mechanical ventilator can predict severity of acute kidney injury. So if we look into static compliance of the lung, there is significant correlation between severe acute kidney injury and declining compliance. As you can see, the rate of severe acute kidney injury increases to 40% in compliance in single digits. If you recall from the COVID time, a lot of these patients were in teens and single digits in compliance. They had a very significant rate of acute kidney injury. In addition to that, that PEEP could be also associated with severe acute kidney injury. Higher PEEP, as I mentioned, can impact renal blood flow and that can lead to higher rate of acute kidney injury. How about prone positioning? As you well know, a very well done randomized clinical trial showed that prone positioning would be associated with improvement in survival. In similar studies, when patients are prone, as you can see, intra-abdominal pressure increases. And if we consider intra-abdominal pressure as a risk factor of acute kidney injury, we can expect chances of higher acute kidney injury rate. And also, renal blood flow index decreases over time when we have higher intra-abdominal pressure. So by association, we can potentially expect higher rates of acute kidney injury on patients who are prone. However, this has not been seen in the literature, mainly because the effects are so small. We need the larger studies on prone patients in order to see any effect. But I'm sure that these physiological changes would increase risk of acute kidney injury. How about use of nartric oxide, inhaled nartric oxide? So in this systematic review of 10 randomized clinical trial with more than 1,300 patients who use the nartric oxide, risk of acute kidney injury was higher for about 40%. Risk of need for dialysis was higher by about 50%. In a cohort study of 500 patients, the 200 patients received inhaled nartric oxide and 300 didn't. And again, hazard ratio for acute kidney, renal replacement therapy was twice as much after the propensity matching decreased to 60%, similar to what systematic review showed. How about neuromuscular blockade? We all remember AcuraSys trial, 340 patients were randomized between C-satachorium and placebo. These patients had early and severe ARDS-FET PF ratio less than 150. Primary outcome was 90-day mortality, which showed benefit of using paralytic agents. And when we look into the renal failure free days, it seems the C-satachorium arm had significantly larger renal failure free days in comparison with the placebo group. In a ROSE trial, this wasn't seen. So 1,000 patient, similar group of patient, moderate to severe ARDS, C-satachorium versus placebo, primary outcome the same. And this study was discontinued due to futility. And if you look into the renal outcomes, you can see that the renal failure free days in day 28 was the same in the two arms. So kind of jury is out, is not out yet in this topic. However, we have to be very careful. These patients who go on a paralytic agents, often they have significant muscle mass loss. And all of these studies looked at renal failure, judging based on serum creatinine, which is very unreliable in this patient population. Now we all remember FACT trial, this landmark trial on management of ARDS, conservative versus liberal group. The primary outcome of FACT trial was not significantly different, 60 day mortality. However, length of mechanical ventilation and ICU length of stay was significantly shorter when conservative arm was used. However, renal failure in day seven, then 28, was not different between the two arms. And also, the analysis was not statistically significant, although you can see numerically, patients who were on liberal arm had higher need for dialysis in comparison with the others. There is a follow-up of this study, FACT-LITE trial, which compared these two arms with the other ARDS-Net trial patients that they had a protocolized fluid management. So in conservative group in this arm, usually they were slightly negative, 100 cc negative. In a liberal arm, there were six liters positive. In FACT-LITE, there were about two liters positive. And there was no difference between conservative and FACT-LITE group. However, there were significantly higher acute kidney injury in the liberal arm. Now, switching the gear, going from acute kidney injury, how it impacts lung. We know that acute kidney injury is not a boom. It is a process that results in increased damage in the kidneys that are vulnerable, and that would result in process that results in apolarization of tubular cells. Eventually, these cells, if we cannot reverse the damaging situation, would go to death process through necrosis or apoptosis. And eventually, in maladaptive repair of this kidney, you can see significant progression of fibrosis. Now, in acute kidney injury, you can see changes, first of all, fluid retention, and changes in humeral or cellular function could potentially lead to increased risk of lung injury. So, to be more specific, then kidney function, regardless of injury or not, when kidney function goes down, there are several things happen that increases risk of acute lung injury or acute respiratory failure. First of all, fluid overload can lead to cardiogenic pulmonary edema. However, patients, if you don't treat them really fast enough, they can have significant chemotactic factors, cytokine release, and they eventually go to non-cardiogenic pulmonary edema. Uremic toxins have several different roles. One is they paralyze, uremic toxins, they paralyze water exchange across the pneumocytes. Therefore, removal of fluid from alveoli to the circulation, despite recovery of the underlying source, may be significantly delayed. Acidosis alkalosis changes respiratory drive and decreased cytokine clearance by the kidney would result in further damage and injury to the lung. Now switching to kidney injury, these are the first group where only kind of changes in function, but injury also can cause lung injury. So these patients obviously because of kidney injury they have poor inflammatory cytokines elevation and that would result in upregulation of pulmonary adhesion molecules and chemotaxis and that will lead to entrapment of a lot of neutrophils and non-cardiogenic pulmonary edema. Immunoparalysis as a result of severe inflammatory states significant due to acute kidney injury would result in a higher risk of infection, therefore acute lung injury. And obviously when cells in the kidney, proximal tubular cells particularly die, it releases significant number of particles including DNA, RNA, mRNAs, other microparticles and also mitochondrial disease associated molecular patterns that can all cause inflammatory state in distant organs including lungs. Now we know that fluid overload can cause pulmonary congestion. If you can see on the left side of the panel, you can see significant intra-alveolar fluid however there is no inflammatory state, there is no significant fluid. In this kind of condition if you remove volume, respiratory status recovers very quickly. You wait a little longer, inflammatory state starts building up and at this time removing fluid although impacts lung function but it would be less evident from those patients that come to us with flash pulmonary edema, you diurese them or you put them on ultrafiltration, get fluid off them. And finally when inflammation is full-blown in the lung, removal of fluid has very minimal impact in recovery of lung function. Now outside of that, patients with acute kidney injury may need renal replacement therapy. There is a significant impact of renal replacement therapy on lung function. I'll kind of go over some data. Timing of dialysis initiation, the modality that you use, intensity of dialysis, how much antibiotics are removed with dialysis or not, biocompatibility of the dialysis filter with the body that results in a complement activation or cytokine release could all impact lung function. In addition, when patients have severe respiratory failure, we use ECMO. There is a crosstalk between dialysis and ECMO that I'll try to allude later on and each one of these devices can impact the relationship between acute kidney injury and lung. So as you can see, there is a very complex relationship between these two organs. Now we talked about the connection or access between heart and lung and kidney, but we need to also say that there are some relationships between the devices that support the failure of these organs with each other. So in acute kidney injury and mechanical ventilation, we know that patients who have acute kidney injury, they have longer mechanical ventilation duration for about three days and weaning process is longer by about 20 hours. It's one day longer mechanical ventilation weaning process takes. And since trial, as you know, this is a trial of use of sepsis associated ARDS, use of erosobastatin, and the study was discontinued due to futility. However, in post hoc analysis of 240 patients who found to have acute kidney injury, particularly those who had persistent acute kidney injury more than seven days, they had significantly longer mechanical ventilation duration and higher rate of death when lung injury, respiratory failure coincided. As you can see, weaning process is significantly shorter when oliguria does not exist. And same, the weaning process is significantly shorter when serum creatinine does not increase. So kidney injury would prolong the weaning process from mechanical ventilator. A couple of years ago, Dr. Tomasi, who was at the time a resident now is a nephrology fellow, and I, we did look into our ICU patients. We identified about 77,000 ICU patients. 47,000 of them, about 61% of them, did not have acute lung injury or ARDS, nor they had acute kidney injury. Among the other 39% of patients, majority had acute kidney injury alone. A very small percentage of patients, about 490 patients, had ARDS alone. And the rest of patients, about 1,500 patients, had both organ failure. And we tried to identify which organ can cause worse outcome when they start earlier. What we noticed is that among those patients who had any of these organ failure in comparison with no acute kidney injury or ARDS, there was significantly higher comorbid conditions and severity of illness as expected. However, those with acute kidney injury and ARDS had tremendously higher comorbid burden, and also they had severe higher severity of illness. You really need to have susceptible organs when these two organs fail together, and that is probably why we see higher mortality among this patient population. And when we looked into outcomes among the AKI patients who underwent dialysis, when ARDS was present, rate of need for dialysis was tremendously higher. And then ICU mortality and hospital mortality was higher in comparison with no AKI ARDS group when any of these organs failed. However, when these two organs failure existed at the same time, mortality was 21% in ICU and about 30% in the hospital. Length of a stay was significantly higher when these two organ failure presented at the same time. Among all the AKI patients, if ARDS was present, the duration of renal replacement therapy was significantly higher. Among all ARDS patients, when AKI was present, length of mechanical ventilation was higher. So this basically kind of verifies and provides some consistent report in comparison with literature. How about renal replacement therapy timing? Is it okay if you start early versus late? This is a systematic review looking at 28-day mortality and early versus late dialysis initiation. As you can see, it doesn't favor any timing issues. However, in a KIKI trial, which was a multi-center franchise study, looking to early versus late initiation of dialysis in ICU on patients who had acute kidney disease stage 3, mortality of ARDS patients were the same. However, the adequate urine output with renal replacement therapy was significantly more frequent than when the latest strategy was used. So early initiation of dialysis can drop urine output and increase the need for dialysis. START-AKI trial was a pragmatic randomized clinical trial of multiple continents. We were participant in START-AKI and 3,000 patients were randomized between early versus late stage 2 and 3 acute kidney injury. As you can see, median number of ventilation free days in 28 days were the same between the two arms, regardless of if dialysis started early versus late. Now, when should we start dialysis then on patients with acute lung injury? We know that patients in critical illness, they have significant higher import of osmolar impact. So they get a lot of medications, we keep giving them normal saline, and they are hypercatabolic, so they generate a lot of osmosis. In addition, we give them a lot of fluid. If kidney is normal, can handle this, but kidneys that are diseased to begin with, or they become diseased through damage through the process, they lose the capacity to make that support. So there will be a gap between supply and demand, and when the gap is large enough, dialysis is to start. So the factors that we consider when we start using dialysis is, first of all, severity of acute kidney injury based on urine outputs, creatinine trajectories, electrolyte derangements, acid-base disorders, and complications of uremia. Also severity of illness matters. If you're dealing with a patient that is on three pressors, not making a drop of urine, this patient most likely needs eventually dialysis in comparison with those who are sitting in a bed and communicating with you well off pressors. And non-renal organ dysfunction, degree of fluid overload, pre-existing comorbid condition trajectories. We also need to make sure that we consider complications that may come between our replacement therapy. And SART-HCI showed that these patients have more hyperhypotension and more hypophosphatemia if we start dialysis early. Line insertion, hypotension during dialysis, and clearance of nutrients and drugs could potentially lead to further damage. Other factors that we consider include availability of machines, staff, and relative visions of the patients and futility, as Dr. Naira mentioned really well. Now regarding to renal replacement therapy, ECMO interaction, when do we use, what indications we consider when we use ECMO and CRRT on ECMO patients. So we looked into about 200 patients in Mayo Clinic. 109 of them were on ECMO alone, but the rest of them received some sort of CRRT at one point or another. About 30% of these patients who received CRRT had no acute kidney injury. They were initiated on CRRT solely for volume management. And the rest of them had acute kidney injury. Obviously acute kidney injury as per definition was higher in the latter group, so was acid-base electrolyte imbalances. Patients who received the CRRT for volume overload, they were older, they had higher coronary artery disease, and they had, and those who received acute kidney CRRT for acute kidney injury, they had higher rate of sepsis. After adjustment for multiple factors, demographic, and laboratory, and severity of illness common with conditions, what we noticed is that if you start CRRT on ECMO patients for volume, rate of mortality increases by 10 times. However if you start dialysis for acute kidney injury, rate of mortality increases by 20 times. This is despite the fact that absolute number of mortality, 92% of patients who initiated on dialysis because of volume overload died in comparison with 65% who initiated on dialysis for acute kidney injury. Mainly due to the fact that these patients were older, they had higher comorbid condition coronary artery disease. That's why we saw this difference. And so as you well know, this is preaching to a choir of intensivists. We all know, we all know ECMO, VE-ECMO is isolating right side of the heart in order to generate oxygenated blood. VE-ECMO is to isolating the whole heart in order to provide cardiovascular support and respiratory support in some cases. ECMO membrane, as you know, they are comprised of significant number of hollow fibers. The blood passes through them, and inside hollow fibers there is a gas flow allowing the gas exchange across the membrane. So gas flow, we can adjust FiO2 in order to change the oxygenation rate. We can adjust sweep flow to change ventilation CO2 removal. And there is also non-sterile water passes through non-permeable membranes in some other hollow fibers in order to control temperature within the membrane in order to avoid hypothermia. And finally blood flow rate that the blood passes through between these hollow fibers based on the etiology that you need ECMO can be designed as three to five liters as average per minute. So the way that these two machines can be connected are different. Sometimes we don't even use any pump. We just connect, we use differences in pressure across the circuit of ECMO in order to generate. It's like a CAVH that we used early 1990s. So there is no pump required. However there's less control on clearance and ultrafiltration. Sometimes we use negative to negative pressure. Both return and access lines are connected to negative part of circuit before the pump. And the benefit is that there is no shunt across the membrane. There is no recirculation. However return line is to negative pressure. And the analysis machines do not like it. So we have to put some adjustable clamps in order to mimic positive pressure for CRT machines. Positive to positive, so all both ports are connected to after pump. Again no risk of air embolism because membrane can catch air bubbles. Return line to positive pressure and no shunt and no recirculation. However access line is connected to very highly positive pressure. Sometimes we need to use clamps to decrease the difference between pressure in the circuit of ECMO versus pressure, positive pressure that the analysis machines can use. Positive to negative, again this the benefits are at access line to positive pressure, return line to negative pressure, no shunt or recirculation. However we need to put clamps in both arms in order to make sure that the pressures are adjusted. This is the way that we use it at our institution. We use the ports and across the membrane. And the caveat is that access is from the end of membrane and then we return blood to the venous side of the membrane. The reason is that if there is any air bubble in the blood going back to patient can be trapped in the membrane rather than going to the patient. This we found very practical, provides good clearance despite the fact that this is associated with oxygen membrane shunt and recirculation because we recirculate clean blood across the membrane. And a return line is to positive pressure which sometimes we need to put some clamps on. And this last connection is when we use a completely different line. And so these two systems become completely parallel to each other. So we can have complete control on CRRT without the shunt and recirculation but we need another line which could be done side. And we looked into our ECMO patients in 2015 to 2019. We analyzed about 200 patients. About 30% of them had no acute kidney injury. 70% of them had acute kidney injury. Acute kidney injury started before ECMO in about one-third of patients and after ECMO about two-third. These are patients that are exposed to hemodynamic changes associated with ECMO nephrotoxin and so forth. 60% of patients with acute kidney injury received dialysis. And among those who had allergic acute kidney injury, 60% of them received diuretics. What we noticed that hospital mortality is not associated with when acute kidney injury has started. These patients on ECMO die so much that acute kidney injury does not have a lot of impact on their outcomes. If they live long enough then acute kidney injury impact on outcome you can see. Although there was a trend in difference in incidence of acute kidney injury between VA and VV ECMO but it wasn't statistically seen. It can likely due to small sample size. And we also noted that patients who had acute kidney injury before ECMO, they had higher severity of illness and also a higher respiratory rate and also higher risk of infection. Durations when acute kidney injury was present in comparison with no acute kidney injury was tremendously higher. ECMO duration, mechanical ventilation duration, ICU and hospital stay. Use of diuretics in day one was a statistically significant in generating more urine. So if you are dealing with volume overload patient, please feel free to use diuretics. Although day two and three did not reach a statistical significance but you can see 400 cc versus 1,400 cc, 600 cc versus 1,600 cc. So there are still kind of more urine output. This is just a smaller sample size didn't reach statistical significance. Now a few words on E-Core. We know respiratory acidosis when ventilation is jeopardized, CO2 accumulation is observed. The 10% of CO2 is dissolved in plasma, 20% in protein bound and the rest is in a form of bicarbonate. Determinant of CO2 is basically ventilation production. When lungs do not have ability to ventilate or production is increased due to exercise hypercatabolic state or keep pushing keep pushing the bicarbonate or using high bicarbonate batting dialysis, we increase production of which is handled by us. Our lungs are able to handle a lot of CO2 production but when patients do not have a lot of capacity to ventilate and then that becomes problem on those patients that results in respiratory acidosis. In management we try to make a balance. Sometimes we use mechanical ventilator to increase ventilation. Dialysis, there are some animal studies using dialysis that removes the CO2 and finally using extracorporeal and CO2 removal is possible. So the goal is to minimize to minimize hypercapnia, decrease right ventricular afterload and cardiac output and also minimize lung stress by improvement in setting of the mechanical ventilator to avoid death and multi-organ failure. ECOR as you can see it can be therefore extracorporeal CO2 removal is a device that is not FDA approved in the United States but we started using it for patients that we feel that are important. There are differences between ECMO and ECOR. Obviously ECMO requires large catheters, ECMO center, a lot of expertise, large blood volume. ECOR does not require that. We can do it in regular ICUs without much expertise and so ECMO you really need to have a huge blood flow rate. In ECOR about three to four hundred CC per minute which is in this range that we can achieve with dialysis machines. You can provide adequate CO2 removal. This is animal studies five pigs. The optimum CO2 removal was observed when blood flow rate was about 400 CC per minute and gas flow rate, fluid flow rate was about 10 liter per minute. So this is what what we use in our centers. And literature indicates that modern ARDS in random clinical trial ECOR was beneficial. This is a case control study of 50 COPD patients with primary outcome of intubation prevention. As you can see those who underwent ECOR PCO2 decreased, pH increased, respiratory rate decreased in this patient population. In this randomized trial of 80 patients, ECOR versus very low tidal volume of 3 CC per kg was compared with a standard 60 CC per kg tidal volume. Primary outcome was 20 and 60 day mechanical ventilation, three days. And patients with PF ratio above 150 didn't benefit but patients with very severe ARDS benefited from this. This is a feasibility study. We are able to, they were able to decrease driving pressure. There were injurious mechanical ventilator strategy. And also another feasibility study showed increase, decreased PCO2, increased pH. This is how we use it in in the venous port of dialyzer. There is a lure lock to be incorporate pediatric membrane with smaller, smaller surface area between that and between air trap in case if there is any air leak. And that we have been able to write a protocol and we use it for patients who really need very low tidal volume. Take-home points, while data is not as robust as cardio-renal syndrome, physiology relationship between lung and kidney is very clear. Limited data on biomarkers and management exist and renal replacement therapy to remove CO2 in moderate ARDS has produced some minimal benefits. With that I thank you for attention.

kidney-lung relationship

acute kidney injury

acute respiratory distress syndrome

hemodynamic changes

inflammatory cytokines

mechanical ventilation

renal replacement therapy

ECMO