Hello, everyone. I'm Ankit Sakooja, and I will be talking on this very exciting topic, the med, the myth. These are my conflicts of interest, nothing relevant to the current talk. The learning objective of this talk is to examine the evidence surrounding contemporary controversies of potentially nephrotoxic medications. And there are two specific medications that we'll be talking about. One is the combination therapy of vancomycin with piperosalintazobactam or PIPTAZ, and the other one being furosemide. So let's talk about the first medication, the combination of vancomycin with PIPTAZ. So what's the myth? Well, the myth surrounding this combination therapy is that the addition of PIPTAZ to vancomycin increases the risk of acute kidney injury. Now, if true, this has huge implications because in a recent study of over 500 hospitals in the U.S., vancomycin and PIPTAZ were noted to be the two most common antibiotics used in the country. Given how commonly they are prescribed, a huge complication such as AKI would be very, very concerning. And a report corroborated by multiple studies is even more concerning, right? Now, in this meta-analysis of 47 studies, authors found that the combination therapy with vancomycin and PIPTAZ resulted in significantly higher rates of nephrotoxicity than vancomycin monotherapy alone, or a combination of vancomycin with cefepime or a combination of vancomycin with miropinem. So this sounds pretty concerning. Now, I was part of a study that took a closer look at this issue. This study included over 3,000 critically ill patients who received up to three days of combination therapy with either vancomycin and PIPTAZ or vancomycin with other medications like cefepime, miropinem, etc. And we found that though there was an increase in the rates of acute kidney injury, it was predominantly restricted to mild AKI or stage 1 AKI. So that was very interesting. Now, looking further, we found that there was, in fact, no increased risk of moderate to severe or stage 2 to stage 3 AKI with PIPTAZ and vancomycin combination when compared to either vancomycin, cefepime, or vancomycin, miropinem in both an adjusted and unadjusted analysis. Now, the caveat of the study is that we looked at only up to 72 hours of exposure of these medications. Now, the fact that more severe AKI is not seen with this combination has been confirmed with other studies, though. As shown here, this recent meta-analysis found that though there is an increased risk of acute kidney injury with this combination, there was really no increased risk for a need for acute dialysis or for mortality for that matter. It's pretty interesting, right? So the literature so far pointed to the fact that the increased risk is only for mild or stage 1 AKI. When that happens, you know, that kind of makes you feel like putting your detective face on, the game face on, and trying to take this further. And really, the question becomes, if this is only mild AKI measured by creatinine that happens, then is this even a real risk, or are these just some perturbations in creatinine due to other reasons? So when it happens, let's go back to basics. Now, let's see how creatinine is actually handled in the kidneys. Now, creatinine is secreted from blood into the tubular lumen by organic anion transporters, specifically the OAT-1 and OAT-3, as shown over here in this figure. Now, this is then further secreted into the urine by MATE-1 and MATE-2K. Now, PIPTAS is a very interesting medication, which is a substrate for both OAT-1 and OAT-3, and it does competitively inhibits creatinine secretion into urine. Now, when that happens, the levels of the creatinine in blood go up. So all the AKI that we have seen so far really just reflects...is a function of the rise in creatinine, right? And may thus just be all hogwash, because we can clearly see that PIPTAS increases the serum creatinine levels by competitively inhibiting its secretion through the OAT-1 and OAT-3 receptors in the tubules. Now, to confirm that this is truly what it is, what we need is a substance that can tell us about kidney injury but is predominantly unaffected by tubular secretion. Voila! As it turns out, we have just something like that in testatin C. It is a substance which is filtered at the glomerulus and absorbed in the tubules but does not undergo any tubular secretion. And in fact, in comparison to creatinine, testatin C has a much better correlation with and area under the curve to predict GFR across multiple studies, as shown in this figure over here. So a recent study looked into how the vancomycin and PIPTAS combination affects testatin C levels, among other things. This was a study of 739 critically ill patients at UPenn with a diagnosis of severe sepsis or septic shock who received antibiotics for at least 48 hours. And the antibiotics that they looked at specifically were the combination of vancomycin and PIPTAS combination and the combination of vancomycin and cefepime as the control group. They then looked at the kidney function markers, which were creatinine, BUN, and testatin C levels at day 0 and day 2 after the initiation of treatment. As you can see over here, there were 297 patients in the vancomycin and PIPTAS group and 442 patients in the vancefepime group. Now, the caveat of the study is that testatin C measurement was only available in 192 patients, with 72 in the vancomycin and PIPTAS group and 120 in the vancefepime group. The outcomes that they looked at were the creatinine-defined AKI and dialysis, in addition to the levels of the creatinine and testatin C. And the creatinine-defined AKI and dialysis they looked at were through day 14. They also looked at mortality through day 30. What they found was that there was, in fact, an increase in the level of creatinine and the increase was quantified to be 8% and increase in the rates of AKI as measured by the creatinine levels through day 14. But there was really no change in the levels of testatin C in that timeframe, rates of dialysis or mortality for that matter. So, based on these studies, I think it's fair to say that the addition of PIPTAS to vancomycin does not truly increase the risk of AKI. Yes, it may cause some elevation in creatinine, but that is not AKI. And this is truly a myth. Now, let's look at a case from the past. A patient comes in with septic shock and you, being a very diligent intensivist, give this person a full substance bundle and the antibiotic therapy you chose was a combination of vancomycin and PIPTAS. Now, not only does this patient get better, you actually get accolades from your colleagues in infectious disease, nephrology, and pharmacy. Stuff of legends. All right, moving on. The next potentially nephrotoxic medication that we'll talk about is furosemide. And the myth surrounding this medication is that furosemide causes AKI. Now, this study done about 10 years back now looked at 344 critically ill patients and showed that those who received furosemide had higher elevations in serum creatinine. Those shown to contribute to rise in creatinine in few studies. It has been shown by multiple studies that use of furosemide does not lead to any increase in need for acute dialysis. As shown in this meta-analysis over here. Or in mortality, for that matter, again, as shown in this meta-analysis over here. In fact, in patients with heart failure, it has been shown that a mere rise in serum creatinine is not reflective of tubular injury as identified by a lack of rise in other biomarkers as shown in these graphs over here. On the contrary, we all know that fluid overload is bad. In fact, multiple studies have shown that each liter of increase in fluid balance in critically ill patients increases mortality. In this meta-analysis of these studies, each liter increase in cumulative fluid balance increased the adjusted risk of mortality by 19 percent. Not only that, literature also shows that increased risk for infections, dialysis, and even increased need for vasopressors with increasing fluid overload. So, avoiding or treating fluid overload should be good and is important. Now, in fact, a recent randomized control trial compared a strategy of conservative fluid administration and active de-resuscitation with usual care in 179 critically ill patients. And as you can see in this graph over here, that the intervention clearly led to less fluid overload by day five in these patients. But more interestingly, there was no increased rates of AKI or worsening AKI using the strategy. So, giving less fluids and giving diuretics to these patients did not really lead to any new or worsening AKI. Additionally, we have shown that diuretics work even in patients on vasopressors. So, this was a study that I was part of, in which we looked at patients who were critically ill and getting vasopressors for one reason or the other. We had excluded patients with heart failure. And you can clearly see in this graph over here that patients who got diuretic had higher urine But more importantly, we also showed that giving diuretics to these patients did not really cause any hemodynamic perturbations as noted by no real changes in doses of vasopressors. And these are all in norepinephrine equivalent doses. We also found no difference in the rates of AKI within seven days of exposure and need for acute dialysis. And finally, a recent study of over 14,000 critically ill patients from MIMIC3 database, which looked at diuretic administration within 48 hours of ICU admission, actually found that patients who got diuretics had higher rates of renal recovery and association, which persisted even on capacity-matched analysis. So, I think it's fair to say that the myth that furosemide causes AKI is just that, a myth. And we have successfully bursted this myth over here today. Now, going back to our case, where that patient came in with septic shock, and you gave this patient the sepsis bundle, and the patient was feeling better. But being the diligent intensivist, you see that the patient's all edematous. After this talk over here today, you take a leap of faith and give that patient diuretics. The patient diuresis very well. The edema improves, and the patient feels fantastic. And you get high fives from nephrology. I told you, stuff of legends. Well, thank you so much, everybody. Have a great day.

nephrotoxic medications

vancomycin with piperosalintazobactam

furosemide

acute kidney injury

fluid overload