At the Center for Critical Care Nephrology, researchers have spent countless hours in the lab searching for more answers about acute kidney injury and its mechanisms, risks, and recovery. One valuable way they find these answers is through the observation of biomarkers, which can be any molecule that indicates the presence of a specific physiological condition in an organism. Win Kulvichit, MD--a visiting scholar from Thailand--has explored these molecules in the form of exosomes, which are vesicles secreted from almost all cells in the human body.
What sparked your interest in nephrology research, specifically AKI renal recovery and biomarkers, above other topics? What inspired this specific study?
I had been interested in AKI and renal recovery when I was a 5th year medical student. At that time, I had taken care of a patient with septic shock who developed AKI. Without any absolute indications for RRT, our medical team decided to withhold RRT and observe the progression of the disease. Unfortunately, the patient’s clinical status deteriorated rapidly. When the indication for RRT was fulfilled, the patient was already in a state of beyond help. So, I began to wonder whether how can one can predict renal recovery from AKI. After reviewing some literature, I found that renal recovery prediction can be performed by using several biomarkers, but it was still on the quest to search for the best biomarkers. I also came across a paper that showed the utilization of exosomes as biomarkers for several diseases including AKI. That is when I was sparked to do research of this topic.
What is the significance in choosing to study the Ezrin and Moesin proteins?
Ezrin and Moesin are both members of ERM family proteins (Ezrin-Radixin-Moesin). ERM proteins crosslink actin filaments with plasma membranes. From our previous proteomic study, we discovered that urinary exosomal Ezrin and Moesin were both significantly upregulated in patients with renal recovery at an early time point, demonstrating that these two biomarkers might play a critical role in renal recovery process. It is well established that actin filament and their linkers, including Ezrin and Moesin, disrupt at early stages of kidney injury, and they also recover at an early stage of renal recovery. Therefore, these two proteins have high potential for being predictive biomarkers of renal recovery.
You mentioned that exosomes are like “biomarker treasure chests”. Can you elaborate on this point and how it was important in your research?
Exosomes are extracellular nanovesicles secreted from almost every cell in human body. They contain many functional molecules such as proteins, DNA, and mRNA. In the past, they were viewed as a cellular trash bin, excreting unimportant things out of the cell. However, we now know that they are different from other extracellular vesicles like apoptotic blebs. Since they are very small, this means that significant energy is required to produce exosomes. It is now well known that exosomes play crucial roles in cellular communication. All in all, molecular content of exosomes can represent the physiologic and pathologic state of the cells which they were secreted from. Therefore, they are like biomarker treasure chests because new relevant biomarkers might be discovered in exosomes.
Did you come across any obstacles during the study? How did you overcome them?
In my opinion, the biggest obstacle is the limited time I have for this visiting scholarship. Data retrieving and analysis are very time consuming. One year is an extremely short period of time to conduct a good study. I tried my best to use my limited time as effectively and productively as possible.
Having been involved in medicine in both Thailand and the United States, how has this influenced your career? Are there any major differences in the research or clinical aspects?
Being involved in medicine in Thailand and the United States gives me a wider perspective and understanding in the clinical and research standpoints of both different settings. The United States has major advantages of having a better systematic approach of conducting research, much larger databases, a better multidisciplinary system, and, most importantly, higher research funding. Being a part of CCCN provides me with great insight of how great research should be conducted. This opportunity and experience will influence how I view medical research on a global scale and also how I set the future goals of myself as a medical researcher in the future.
Author: Bridget Kotek
Sepsis research and sepsis coverage in the news and media has skyrocketed in recent years, with intensivists dedicated to find more answers to the mechanisms and realities behind the disease. Sepsis induced-AKI falls under this umbrella, and Shengnan Li, MD—a Center for Critical Care Nephrology visiting scholar from China—has delved into researching this topic in an effort to find more answers and improve life for patients in the long run.
What is your role in the Center for Critical Care Nephrology?
I am doing clinical research on surgery associated AKI with Dr. Kellum and doing basic research on SA-AKI with Dr. Wen.
What inspired your interest in sepsis and sepsis-induced AKI research above other topics? What inspired this specific study?
Septic AKI is associated with a higher risk of in-hospital mortality. A study investigated 192,980 patients with severe sepsis from seven US states, and it demonstrated that AKI occurred in 22% and was associated with a mortality rate of 38.2%. The Sepsis Occurring in Acutely Ill Patients (SOAP) cohort study recruited patients admitted to 198 ICUs across Europe. Of 3147 patients, 37% had sepsis, and AKI occurred in 51% of cases and was associated with an ICU mortality of 41%. From the above, we may have the impression that sepsis associated(SA)-AKI is a severe disease with high incidence. However, the mechanism of sepsis-AKI described in literature and in reality are complicated and unclear, so I think a large unknown space is waiting for us to explore.
What main ideas do you want readers to take away from this study?
AKI was a risk factor for CKD in previous clinical studies; I think we found a pathological evidence for this phenomenon in our animal model. Usually, we defined complete recovery as sCr returned to less than 1.5 baseline level. We observed that histological damage as well as maladaptive repair existed, even though sCr had completely recovered to baseline level. The definition of complete recovery should be refined in the future. Second, treatment with UPHD186 inhibited fibrosis as well as other histological injury in our model, which may provide evidence for a new therapeutic strategy for renal recovery following SA-AKI.
Your research poster explained how treatment with UPHD186 did not significantly improve survival, but it did produce less histological damage, less renal fibrosis, and inhibition of macrophage infiltration. Going from rodent model to human patient, what could this mean for AKI treatment?
UPHD 186 not significantly improving survival may attributed to the following factors: First, sample size in our study is relatively small. It is difficult to show significant improvement with relatively small simple size. Second, even though the improvement in survival is not significant according to present data, it did promote renal recovery. Improving the quality of life without prolonging the lifespan should also be meaningful for patients.
Did you face any challenges during this study? If so, how did you overcome them?
Yes, we did. Some of the data we gained could not be explained at the beginning. The effective time point conflicted with the one we expected. However, after we stopped, checked a lot of literature, and decided to add another small part on our experiments and tried again, we seemed to figure out the resolutions.
Based on your findings, what areas do you think need further research? Are there any future plans currently in the works?
The active component of UPHD186 is a histone deacetylase inhibitor, which has been looked into a lot in cancer research. We can further study its specific regulating mechanisms and more specific signal pathways.
Having been involved in medicine and research in both China and the United States, how has this influenced your career and perspective?
The main reason I came to US was to improve my research ability and be a scientist in the future. The two- year training has helped me to accumulate experience in doing clinical and basic research, know more about the happiness of success and sorrow of complications in science. It also helped me to confirm that I will continue to do research on AKI after I return to China.
Author: Bridget Kotek
"There's a way to do it better – find it." Thomas Edison.
The "it" of interest for our purposes is identifying, diagnosing, predicting, and preventing acute kidney injury (AKI). And researchers are constantly innovating new techniques or developing new technology, determined to do it better. Traditionally, AKI is identified and diagnosed by monitoring and assessing serum creatinine levels and urine output. But the clinical value of these methods is being undermined; novel biomarkers are upstaging serum creatinine in the ICU. AKI biomarkers have been found to be "sensitive, specific, and highly predictive" allowing for earlier identification of this deadly condition. Additionally, they provide critical information in predicting renal recovery and post-transplant outcomes. These positive results led to a surge in biomarker research and the development of medical tools to exploit their predictive powers. But many diseases and conditions beginning to move their fields toward biomarker-oriented medicine, do not have well understood causes and mechanisms. And AKI is no exception. Before novel AKI biomarkers can be utilized to their fullest potential in helping heal the severely ill, it is important to understand their chemistry as well as roles and mechanisms in AKI.
The Center for Critical Care Nephrology is concerned with the underlying mechanisms of AKI and researchers at the center are conducting pioneering research on the characterization of novel biomarkers. David Emlet, PhD, is one of our dedicated faculty members logging countless hours in the lab to unlock the secrets of AKI biomarkers, specifically, IGFBP7 and TIMP2. Hard work paid off in December of 2016, when the American Journal of Physiology - Renal Physiology first published the article titled, "Insulin-like growth factor binding protein 7 and tissue inhibitor of metalloproteinases-2: differential expression and secretion in human kidney tubule cells" that filled knowledge gaps in the molecular basis of these markers and proposes their potential role in the pathogenesis of acute kidney injury, paving the way for ensuing investigations. Emlet, first author on this paper, has over 15 years of PhD experience focusing his expertise in cellular and molecular biology, with an emphasis on signal transduction. He was kind enough to break down this study in order to highlight the importance of biomarker research and the potential these molecules have in the future of medicine, as well as the value of the model systems for further investigation of these AKI biomarkers. But before diving into the science, let’s get to know this month’s spotlighted researcher.
What is your role in the Center for Critical Care Nephrology?
Shortly after the center was established, John brought me on board to develop an in vitro model systems program in the Center’s wet lab, to serve as a stand-alone system for cellular and molecular discovery, as well as to complement the established animal models. To accomplish this, I established a collaboration with the local Organ Procurement Organization to receive human kidneys that were deemed not suitable for transplant. The kidneys are processed for several different experimental methods, to include isolation and culture of viable cells of proximal and distal tubule origin. We continue to expand the tissue/cell repository, work on developing more physiologically relevant systems to include organoid culture, and of course perform experimentation for biological discoveries as in this current paper.
When/how did you decide you wanted to get a PhD and conduct research? (Is there something else you thought you would be when you were younger?)
I knew very early on that I wanted to be a biologist, within my freshman or sophomore years in High School, so I majored in biology in college. An internship and my independent research project in college were both focused on studies at the molecular and cellular level, and through those experiences I realized that this was the niche for me. My first science related job out of college was as a Research Technician in a cancer research laboratory that focused on Tyrosine Kinase signal transduction, and that led to my Ph.D. in molecular pharmacology.
There was indeed something else I was interested in doing, that was being a part of the military. My father was a Seabee in World War II, and also an avid aviation buff. Both influences must have affected me strongly, as I entered the military (Army) out of High School, where I served in the Aviation and Medical Service Corps branches. I retired in 2013 after 25 years of service, having had the opportunity to experience all my childhood aspirations.
When you’re not at the office or the lab, how do you like to do in your spare time?
Spare time, that’s funny. When I do have some spare I always enjoy time with my daughter. In the fall I like to be outdoors, either hunting or just enjoying the environment, and in the spring and summer I enjoy vegetable gardening. Lastly, and way too infrequently, I blow the dust off my banjo, and remind myself how terrible I am at playing it.
And now to transition from banjo to biomarker: what inspired this specific study?
In 2013, John and others published a clinical study on the discovery and validation of two novel AKI biomarkers, IGFBP7 and TIMP2, demonstrating that these new biomarkers, alone and in combination, are earlier and superior predictors to existing biomarkers for the of the onset of AKI in critically ill patients. Many subsequent clinical studies have supported the initial finding, and have further demonstrated that these biomarkers can also be useful for predicting AKI after surgery, predicting renal recovery, and are associated with long term outcomes after AKI. Despite the success of these markers clinically, there was and remains, very little information available regarding the expression and/or function of these markers in the kidney. The purpose of this study was to take the first step in answering these very questions.
What are the salient points of this paper?
First, we demonstrated that indeed both IGFBP7 and TIMP2 are expressed and secreted from human primary kidney proximal and distal tubule epithelial cells in vitro and in vivo. Additionally, we discovered a very intriguing differential expression pattern between the two markers, where IGFBP7 is equally expressed across tubule cell types yet preferentially secreted by cells of proximal tubule origin, and TIMP-2 is both expressed and secreted preferentially by cells of distal tubule origin. In primary tissue samples, we identified that the expression of these markers was in part separate from expression of the kidney injury markers kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin, suggesting the possibility for differential mechanistic and/or temporal profiles of regulation of these early AKI biomarkers from known markers of injury. Last, an in vitro model of ischemia-reperfusion showed enhancement of secretion of both markers early after reperfusion, demonstrating that these biomarkers are indeed modulated by clinically relevant insults, and that our model systems are useful tools the further investigate the potential roles of these biomarkers in AKI.
Now that we have begun to understand the very basics of IGFBP7 and TIMP2 in the kidney, and have demonstrated the usefulness of our primary cell model systems, the next logical steps are to use the system to test other clinically relevant kidney insults that are etiologic to AKI, and to investigate the potential biological role of these biomarkers in the disease with the hope and intent that we might be able to uncover new avenues for therapy. We are in the process of developing in vitro models for sepsis, nephrotoxicity, and surgery/cardiopulmonary bypass/trauma, and will be sharing new data soon. Additionally, we are in an ongoing process of establishing collaborations with numerous other kidney researchers at the University of Pittsburgh to share this valuable and primary resource for more studies on AKI as well as other kidney related diseases.
Biomarkers represent progressive tools for earlier, and possibly more definitive detection of AKI, with the potential of leading to therapeutics that could increase survival and decrease cost. This study, and others like it, shed light on the mechanisms of development and progression of and/or protection/recovery from AKI, which, in turn, translate into diagnostic, therapeutic, and clinical significance. Dave's dedication to this kind of research, at the most basic, molecular level, when I am sure he would rather be gardening with his daughter, provides the necessary knowledge for effective healthcare treatments that target the cause of a disease. And, if I may get away with two notorious (debatably trite) quotes in one article, as influential philosopher, Avicenna, said, "therefore in medicine we ought to know the cause of sickness and health."
Author: Megan Treu
"Fluids should be treated as drugs" has become a common saying in the critical care community as the evidence of deleterious effects of fluid overload on organ function is becoming public knowledge. Fluid balance in the critically ill, and specifically in those with AKI, has become a widely researched topic. Results from studies investigating fluid balance in critically ill with acute kidney injury have fostered a movement to consider fluids like any other drug, advocating for a more cautious approach to their administration. Traditionally, these studies looked at survival rates and renal recovery in those with either positive or negative fluid balance. Consistently, the results found that exposure to positive FB, compared with negative FB, is associated with increased mortality and impaired renal recovery. Thus, conventional practice for ventilated patients became a "drying out" of the individual as negative fluid balance seemed better than the outcomes of positive fluid balance. But the CCCN, in collaboration with multiple University of Pittsburgh groups, sought to fill some of the gaps in the existing literature. Looking at the data from a new perspective, the article "Both Positive and Negative Fluid Balance May Be Associated With Reduced Long-Term Survival in the Critically Ill" published in Critical Care Medicine in August 2017, reports novel findings. The principle investigator and the corresponding author of the study, Dr. Ragi Murugan, offers his insight on this article, the world of fluids, and his personal experience.
What inspired this specific study?
First, we considered that many studies had been conducted looking at the association between fluid balance and mortality among the critically ill but they had only considered outcomes in a short period of time – no study had looked at the associations of fluid balance on long-term out comes. So, we wanted to look at mortality rates between positive and negative fluid balance up to one year after admission to the ICU.
A second inspired thought appeared during fluid analysis. We saw that there were a third group of patients who were in even fluid balance. These patients could be thought of as euvolemic, or in the normal, physiological state for fluid balance. Both positive and negative are pathological states. Comparing a physiological condition to the pathological seemed intuitive to us but upon revisiting the existing literature we realized that even fluid balance was rarely mentioned; it was unclear whether positive or negative fluid balances were associated with poor outcome compared to euvolemia and so we investigated.
Why do you think past studies have not used even fluid balance as a comparator? This study compares positive, negative, and even FB. What is the reasoning behind this?
No one thought even fluid balance would offer any enlightening information on mortality of AKI patients and wasn't considered significant enough to include in the research. Positive and negative fluid balance had interesting implications that researchers wanted to look at. Positive fluid balance had been associated with an increase in mortality and keeping fluid balance negative showed promise for decreasing time a patient spent on the ventilator. And when the two are compared, positive seemed to be very bad while negative looks really good. But we thought it made more sense to compare each of these pathological states to the physiological state of even FB. When we looked at this third group in comparison both positive and negative FB resulted in higher risk of death. This was an important finding to report because it contradicts current fluid recommendations in the ICU.
What do you want researchers/readers to take away from this study? What are the most important observations & conclusions? Did any of the findings surprise you?
We found that both positive and negative fluid balance were associated with a decrease in long-term survival compared to even fluid balance. Additionally, patients with positive FB who received RRT had lower mortality compared to patients with even FB suggesting that once fluid overload has occurred, mechanical fluid removal may lower long-term risk of death.
I expected to see an increased risk of death in the short- and long-term for positive FB, but not for negative FB. That was a surprise. We estimated that negative fluid balance would be beneficial for short-term survival then neutral in the long-term. As it turns out, it does increase short-term survival BUT in the long term it is associated with a higher risk of death than the euvolemic patients. Even fluid balance is the best bet for survival - this challenged the prior knowledge on the subject.
The study suggests that maintenance of an even fluid balance should be favored despite current advocacy for negative fluid balance for earlier liberation from the ventilator as negative FB, though associated with short-term survival and liberation from the ventilator, it has been associated with increased long-term harm.
What are your recommendations when it comes to fluid administration or mechanical removal in critically ill patients based on these findings?
I advise cautious use. Think with every bag of fluid, is this really necessary? How will this effect outcomes? Do not use inappropriate fluids. Keep the patient in even FB is possible. Euvolemic state is hard to assess but critical judgement should be used. Also using RRT usually happens very late – once it gets desperate – but whether earlier use in FO patients may be beneficial, need further research.
What barriers/obstacles did you face when researching this and how did you overcome them?
Our biggest proponent was the clock; data analysis is very time consuming and it took a while to obtain all the variables, define groups, etc.. There was a lot of back and forth with databases and reviewing literature. I have to give a lot of credit to my Critical Care fellow and lead author, Dr. Vikram Balakumar, for his involvement and commitment to this preliminary process.
Based on this study, what areas need further research? Are you looking into any of the questions that it brought up?
This study brought up some good questions that may lead in several directions. Observational studies like this give important clues to what may be happening, but they cannot identify the cause. The mechanisms of action are unknown and a greater understanding may aid in improving treatment. Further research also needs to be done to determine which treatment is associated with the more favorable outcome: even fluid balance or treating positive fluid balance with RRT. Research on technologies for treatment that can limit fluid overload effectively remove fluid once FO has happened. The timing of such procedures to determine when fluid should be taken out and how much. It may be advantageous to look at the relative relationship between benefit and harm in negative fluid balance. The only study that could potentially show that a practice of restricting fluid may be associated with better outcomes would be a randomized trial comparing usual care of normal fluid administration to limit fluid administration.
Do you agree with shifting clinical perceptions that advocate for the consideration of fluids as drugs?
Yes – Only 50% of patients will even respond to fluid. Fluid may not be the answer for everyone with low BP. Vasopressors may be more beneficial – this is especially true if you have AKI or FO.
You have studied in India, the United States, and the United Kingdom. Are there any significant distinctions between research and/or clinical focuses? How has this influenced you and your career?
Yes there is definitely a distinction between the focuses across the schools in these countries. Both India and the UK emphasized clinical skills and you were expected to make a diagnosis from an examination without equipment or expensive tests. The United States, on the other hand, is very technology based and relies on such equipment and tests to ensure diagnosis. The US also has extensive support teams, including specialists and a nursing staff to aid in all steps of patient care. I remember thinking how much easier it was to practice in the US for these reasons.
Critical care is also a much greater field in the US than India or the UK. Indian public hospitals may not even have critical care clinics and the private hospitals may be too expensive for an extended stay. In the UK there is national health care so severely ill patients will be admitted to an ICU if necessary. However, the trade off is that there is a small, limited number of ICU beds so what counts as "necessary" differs across these countries.
Growing up, I always knew I wanted to do medicine but I had no idea where that path would end up leading. I attended medical school, immediately after high school, in India and after receiving my MD I worked with an intensivist in India who was trained in Pittsburgh. After that experience I did not want to do anything else but critical care. After completing my fellowship, I began working with John [Kellum] and he became my mentor. He introduced me to the great research opportunities in Pittsburgh and that is when I got interested in research.
What are your main research areas of interest? What drew you to these fields?
I have been involved in research in many domains of critical illness including acute kidney injury, sepsis, mechanisms of recovery, and organ transplantation. But recently I have been interested specifically in fluid in the ICU. Fluid is the “elephant in the room.” About 1/3 of patients are fluid overloaded in the ICU. But of those patients who have AKI, that number doubles to 2/3 being fluid overloaded. Patients usually do not come into the ICU with fluid overload. It is a curious topic to investigate that has important translatable implications in clinical practice. I am also interested in AKI biomarkers as well as contrast-induced AKI.
Treatment of patients in the ICU is a delicate transaction of weighing options, careful considerations, and calculated decision making for every specific case. Severely ill patients often lose significant amounts of fluids before admission to the ICU. Fluid administration may be beneficial, even necessary, in some cases but not all. Conventional judgement already advocates against over use of fluids that may result in a harmful fluid overdose. But there is data also suggests not administering enough fluids may lead to long-term risk. While we wait for further research in this area, it may not be a bad idea to strive for Goldilocks precision in the ICU – not too much or too little, but just right.
Author: Megan Treu
With sepsis research gaining increasing momentum and attention from news and media, the review article, "Acute kidney injury in sepsis," published in the June 2017 issue of Intensive Care Medicine, and co-authored by the Center's very own director, John Kellum, struck me as a must read for any kidney intensivist. However, its importance to all areas of critical care medicine can be quickly realized. Sepsis and AKI go hand-in-hand in the ICU. Though the article focuses on the recent data and principal developments in epidemiology, pathology, prevention, and treatment of septic AKI, further implications can be surmised. To discuss this article in more detail, I had the pleasure of sitting down with Dr. John Kellum himself. In this exclusive interview, Kellum highlights central research themes, therapeutic implications, and the vital significance of septic AKI research.
Why do a review focused on septic AKI over other etiologies? How does it differ from other AKI etiologies such as ischemic AKI?
Sepsis is the leading cause of AKI in the critically ill and yet it’s also one of the least understood etiologies. As an intensivist and sepsis researcher, it’s a no-brainer. Each etiology of AKI is different. Sepsis causes AKI through mechanisms very different from direct ischemia-reperfusion. Early on in the study of this disease it was mischaracterized as a disease of low renal blood flow. More recently we have come to realize that the disease is more of a toxic nephropathy effecting tubular epithelium rather than a disease of the renal vasculature as we once believed.
The article provides a take home message: “Septic acute kidney injury is no longer considered a disease of the macrocirculation, but rather a disorder of the renal microcirculation with associated inflammatory tubular injury. These new ideas have profound diagnostic and therapeutic implications.” Are there any additional take-aways you think readers/researchers should get from this review?
Yes, this is the take-home but even microcirculatory changes might be a result rather than the cause of septic AKI. Functional changes occur very rapidly while vascular changes usually take more time. However, sepsis, like AKI is heterogenous and some forms of sepsis undoubtedly affect the kidney microculation directly and early on. LPS when injected into experimental animals can produce rapid change in the endothelium.
In your own words, can you summarize the main points of the vital developments in septic AKI covered in the review?
Epidemiology—perhaps the major points here are that sepsis is the leading cause of AKI and that even “mild” sepsis is a common cause of AKI. Also, most sepsis is community-acquired and AKI is already present when patients present to medical attention. Thus prevention strategies will not be possible. However, recovery of renal function is the most important determinant of long-term outcomes and so the goal of therapy should be to promote recovery.
Pathogenesis—As above, sepsis is a toxic, inflammatory injury not a disease of renal blood flow.
Prevention—Early treatment of sepsis (which requires early recognition of infection) is the only way to prevent septic AKI.
Treatment—Current treatment is aimed facilitating recovery and largely based on avoiding further injury. New therapies are being investigated to directly target the inflammatory response and its down-stream signaling pathways.
Of the novel biomarkers receiving attention from researchers, which do you believe to have the greatest potential in improving outcomes?
It’s not really a question of which markers are best. There’s no reason why multiple markers can’t be used. Each have the potential to tell us something different about what’s going on in the kidney. Damage markers like KIM-1 and NGAL can complement functional markers like creatinine and cystatin C. TIMP-2*IGFBP-7 appear to be markers of kidney stress, the earliest indication that AKI is imminent.
What pathophysiologic theory currently has the most evidence to support it? Which do you believe researchers should be focusing on?
In addition to the emphasis on inflammation and direct toxic injury to the renal tubular epithelium, the role of tubular-glomerular feedback in causing reductions in GFR and bioenergetic failure in the cells should also be emphasized. Injured cells also develop a “senescent phenotype” can remain in cell-cycle arrest and therefore incapable of proliferating to replace lost cells.
If aggressive fluid administration is not beneficial in septic AKI patients, could it still be beneficial in patients with other AKI etiologies?
Rapid reversal of intravascular volume depletion will always have role in the management of sepsis and AKI. When hypovolemia is superimposed on sepsis, under-perfused tissue beds can develop endothelial dysfunction. Pre-renal azotemia can complicate and compound kidney injury from sepsis. However, established kidney injury cannot be “washed away” with fluids and “aggressive” fluid resuscitation can lead to fluid overload further complicating tissue perfusion.
What obstacles and limitations do researchers face when studying septic AKI?
In my view, conventional wisdom has represented a major barrier. Conventional wisdom has it that AKI is first and foremost a disease of ischemia whereas in reality its rarely that. It’s not the ischemia doesn’t cause AKI, it does, but it’s rarely the cause in critically ill patients where the kidney is using hyper not hypo perfused. As a consequence, the first therapy is often to give fluid when it can make matters worse if the patient is already fluid overloaded.
Timing of treatment in sepsis has been a highly publicized topic with recent findings showing “faster is better,” “minutes matter,” and the sooner the three-hour-bundle is started the higher rate of survival. The article states, "if it is true that early (first 24–48 h) septic AKI represents functional changes in the microvasculature and tubules, then early intervention and prevention of progression acquire great importance.” Do you know if these recent studies found pathophysiological evidence of functional changes in the microvasculature/tubules?
We know that while the changes in histology are quite minimal in the early stages of septic AKI this belies a vast array of molecular changes. The fate of tubular epithelial cells might be sealed very early in the sepsis. This will definitely require rapid recognition and treatment.
If an ICU clinician diagnoses septic AKI what would you recommend for treatment? What would you advise against?
The main thing is rapid diagnosis and treatment of sepsis with appropriate antibiotics and source control. After that, the management is largely focused on avoiding further injury. [In treatment] fluids should be used with caution as should nephrotoxic drugs and contrast.
Sepsis is the leading cause of AKI, and according to the National Institute of General Medical Sciences, the most expensive condition treated in U.S. hospitals that results in death for 15-30% of those infected. Medically and economically, studying septic AKI for intensivist is - to quote Kellum - "a no-brainer." Developing innovative methods and
investigating novel biomarkers and mechanisms are crucial in decreasing prevalence of and mortality from this condition. But, it is first necessary to understand the causes and mechanisms of septic AKI. It is now thought that AKI is primarily a disease of the renal microcirculation and tubules rather than the previous notion of macrocirculation and renal vasculature. The latter is the conventional wisdom Kellum cites as an important barrier to progress.
Author: Megan Treu
What inspired this study?
I first learned of the concept of RIPC 7 years ago as a 1st year pediatric nephrology fellow in Rochester, NY. At that time I came across a paper that showed a reduction in contrast-induced AKI with the use of RIPC when trying to find an article to present for our journal club. Since that I time I remained intrigued by the idea that ischemia in one area of the body could offer protection to a remote organ. My interest was sparked once again as a pediatric critical care fellow when John Kellum discussed with me the findings of the Zarbock et al. (2016) paper showing a reduction in AKI for adult patients receiving RIPC prior to cardiac surgery. It made me question what kind of work has been done in this area in pediatrics.
What do you want researchers/readers to take away from this study?
After publication of this paper, I realized that a number of my colleagues had not heard of the use of RIPC for kidney or cardiac protection. We wanted to provide a summary of the literature thus far on the topic as it pertains to pediatric critical care. Although as discussed in the paper, despite over 20 years of published studies on RIPC, it is not used routinely in pediatric or adult clinical practice. We wanted to discuss reasons for this and, most importantly, opportunities for future research. Hopefully this paper will generate increased interest in the study of RIPC in pediatrics. Specifically, I would like to see future study on the use of biomarkers in order to stratify patients into risk groups prior to the use of RIPC.
What do you like to do in your spare time?
Spending time with my husband and other family members in Pittsburgh. I have gotten into running over the past 5 years as a wonderful way to process stress. A book that I read a few years back by Christopher McDougall has a quote I think of often before a run: “If you don’t have answers to your problems after a four-hour run, you ain’t getting them”. Although there isn’t much time for four-hour runs these days, I think that the thought applies to much shorter runs as well!
For Original Article Click Here
What inspired this study?
The number of patients with diabetes mellitus has dramatically increased in the last few years, and it is one of the most prevalent causes of renal disease worldwide. The role of renal biopsy in diabetic patients is currently an object of debate. Typically, patients with a long history of diabetic disease (10-20 years) develop classic diabetic nephropathy (DN), characterized by specific histopathological damage. This condition causes a slow and progressive worsening of renal function and the need of substitutive treatments (dialysis, transplantation, ect.) over the years. However, there is evidence that diabetic patients with atypical clinical features, such as short duration of diabetic disease or absence of other diabetic signs (i.e. retinopathy) may have different histological patterns classified as non-diabetic renal disease (NDRD) or mixed conditions. The only way to discriminate these conditions is to perform a renal biopsy. Hence, with this study we wanted to describe the frequency of these conditions through a systematic review and meta-analysis of the current literature, aiming to define if renal biopsy is useful in this setting.
Are the results what you were hoping to find?
Yes, our pooled analysis of 48 studies reporting prevalence data on patients with diabetes undergoing renal biopsy defined the cumulative epidemiology of DN, NDRD and mixed conditions (DN + NDRD) and the likelihood of these three conditions. As expected, the prevalence of NDRD and mixed conditions is indeed high and the hypothesis that NDRD at renal biopsy is not as unlikely as commonly believed (PPVs of NDRD 36.9%, mixed forms 19.7%). IgA nephropathy was the most NDRD reported in the 48 papers analyzed. Moreover, meta-regression analysis showed that systolic blood pressure, HbA1c, diabetic duration and retinopathy are the factors explaining the heterogeneity among PPVs of NDRD between the studies.
What do you want researchers/readers to take away from this study?
A great number of nephrologists disagree with the use of renal biopsy in patients with diabetic disease, arguing that this procedure would simply confirm the presence of DN in the majority of patients. Our systematic review, instead, confirms the great variety of renal disease in patients with diabetic mellitus and encourages nephrologists to consider the possibility of performing a renal biopsy in these patients, particularly in patients with short duration of diabetic disease, rapid worsening of renal function, heavy proteinuria, absence of other typical signs of diabetic disease (retinopathy, neuropathy).
How will this research translate into clinical practice?
The ability to discriminate classical diabetic nephropathy from NRDR is very important into clinical practice, particularly for the treatment and the outcomes. Diabetic nephropathy is a chronic condition characterized by varying degrees of proteinuria and renal insufficiency. Typically, renal damage is heavily characterized by fibrotic and irreversible damage. Hence, treatment for patients with diabetic nephropathy is conservative and aims to slow the progression to end-stage renal disease through an adequate control of the most important risk factors (proteinuria, blood glucose level, blood pressure). Conversely, specific NDRD may advantage for specific treatment that can help to reduce the histopathological damage and improve renal function. IgA nephropathy is the most frequent NDRD reported among the studies and specific treatment, based on immunosuppressive drugs (corticosteroids and RAS inhibitors) may improve acute renal lesions and stabilize renal function over the years. For these reasons, a greater belief of the importance of renal biopsy in this setting may have a great impact into clinical practice.
What made you want to study this in the first place?
During my residency in Nephrology, the clinical activities gave me the possibility to focus on several hot-topics in nephrology, one of these being renal biopsy. I achieved an expertise in performing renal biopsy, but at the same time I was interested in clinical research in this setting. Hence, I wrote this project and I won a fellowship of the Italian Society of Nephrology, through which I spent six months of my residency in another beautiful Italian city, Reggio Calabria, where I worked on this project and improved my skills in systematic review and epidemiology.
What barriers/obstacles did you face when researching this and how did you overcome them?
The main problem for this research was the selection and analysis of the papers; about 1500 were screened by me and another author by title and abstract and more than 260 were selected for the full-text evaluation. Another problem was finding the full-texts for the selected studies, especially when the journals have limited access. I want to thank the European Renal Best Practice (ERBP) and ERA-EDTA Immunonephrology Working Group for the constant support of this project, particularly in this aspect. At the same time, I thank the IFC-CNR of Reggio Calabria for the statistical and methodological support.
What do you like to do in your spare time?
I like to spend my spare time with my wife, watching movies or TV series (it’s a good way to improve our English understanding), walking around the city, trying a good pizza (our typical Saturday evening is at Mineos in Squirrel Hill where we live). I love sports. I played volleyball for several years in my life and here in Pittsburgh we have an Italian team for amateur tournaments, just to enjoy together. I love running in Schenley Park, usually 5-10Km three times a week.
How is being in America different than your home country?
It’s difficult to describe all the differences that you can note between USA and Italy…all in USA is big…great space, great building, wonderful and very big parks…this city is wonderful, perfect for living, studying or working. People are very nice and helpful wherever I go. American lifestyle is completely different too, but after the first few months I got used to that. American drivers are more friendly and respectful than Italian. One of the main negative differences is the food! I miss Italian food and its quality. Similarly, I miss the wonderful taste of the Italian espresso!!!
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