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.
Q: Why do a review focused on septic AKI over other etiologies? How does it differ from other AKI etiologies such as ischemic AKI?
A: 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.
Q: 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?
A: 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.
Q: In your own words, can you summarize the main points of the vital developments in septic AKI covered in the review?
A: 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.
Q: Of the novel biomarkers receiving attention from researchers, which do you believe to have the greatest potential in improving outcomes?
A: 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.
Q: What pathophysiologic theory currently has the most evidence to support it? Which do you believe researchers should be focusing on?
A: 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.
Q: If aggressive fluid administration is not beneficial in septic AKI patients, could it still be beneficial in patients with other AKI etiologies?
A: 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.
Q: What obstacles and limitations do researchers face when studying septic AKI?
A: 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.
Q: 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?
A: 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.
Q: If an ICU clinician diagnoses septic AKI what would you recommend for treatment? What would you advise against?
A: 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 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 the condition in the ICU. 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 renal microcirculation rather than the previous notion of macrocirculation and renal vasculature. The latter is the conventional wisdom Kellum cites as the greatest limitation. As research continues to expand in this area, it remains crucial to keep the medical community accurately informed. Despite overwhelming evidence against conventional wisdom in recent years, many still strongly believe its truth. In this interview, Kellum stresses that we must listen to the data and let go of previously misinformed notions in order to see immediate improvement in the care of the critically ill resulting in increased long-term patient survival. Unfortunately, firmly held believes from outdated sources blocking the path of progress is no new narrative. In his 1950 publication Scientific Autobiography and Other Papers, Max Plank, the father quantum mechanics, famously said "An important scientific innovation rarely makes its way by gradually winning over and converting its opponents. What does happen is that its opponents gradually die out, and that the growing generation is familiarized with the ideas from the beginning." Perhaps the ease technology provides in sharing and accessing information will allow this message and others like it to reach more people. By educating a greater population and emphasizing the data, there is hope that we can change this cycle.
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!
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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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