Acute Kidney Injury (AKI)—The Toxicologic Pathologist’s Constant Companion

Abstract

This article provides a brief overview of the second scientific session of the 37th Annual Symposium of the Society of Toxicologic Pathology in Indianapolis, Indiana, on June 18, 2018. The session was entitled “Acute Kidney Injury (AKI): The Toxicologic Pathologist’s Constant Companion” and was co-chaired by Drs. Zaher Radi and Torrie Crabbs. The fundamentals of tubule and interstitial anatomy were covered by Dr. Kevin McDorman, followed by a review of International Harmonization of Nomenclature and Diagnostic Criteria, Standard for Exchange of Nonclinical Data, and Drug-Induced Kidney Injury terminology, which was presented by Dr. Torrie Crabbs. Dr. Bruce Molitoris gave a talk on renal hemodynamics, microcirculation, and ischemia. Advances and challenges on new therapies and clinical targets of AKI were presented by Dr. Brad Rovin, and the session ended with a review from Dr. Zaher Radi on immunopathology of AKI.

The second scientific session, entitled “Acute Kidney Injury (AKI): The Toxicologic Pathologist’s Constant Companion,” was co-chaired by Drs. Zaher Radi and Torrie Crabbs. This session began with a presentation on the “Fundamentals of Renal Tubule and Interstitial Anatomy and Physiology” by Dr. Kevin McDorman of Charles River Laboratories, Inc., which was followed by a review of International Harmonization of Nomenclature and Diagnostic Criteria (INHAND), Standard for Exchange of Nonclinical Data (SEND), and Drug-Induced Kidney Injury (DIKI) nomenclature by Dr. Torrie Crabbs of Experimental Pathology Laboratories, Inc. (EPL). Dr. McDorman briefly reviewed the complex anatomy and physiology of the kidney and presented several background findings commonly seen in toxicity studies, such as mononuclear cell infiltrates, hyaline casts, and renal tubular mineralization. In addition, he discussed that the relevance and usefulness of historical control data is dependent on the quality and consistency of the histopathology, particularly with regard to the use of thresholds, lumping versus splitting, and standardized terminology. Dr. Crabbs gave a brief overview of the INHAND initiative, how to utilize the GoReni website (www.goreni.org), and how/why SEND is applicable to toxicologic pathologists. In addition, she covered the diagnostic features of numerous renal INHAND terminologies, focusing on three of the most common renal tubular histologic findings associated with DIKI (vacuolation, degeneration, and necrosis), in addition to several complicated terms (e.g. differentiating between renal tubule basophilia, hyperplasia, regeneration, and chronic progressive nephropathy).

As a leading expert in AKI pathogenesis, Dr. Bruce Molitoris from Indiana University gave a presentation on “Renal Hemodynamics, Microcirculation, and Tubular Ischemia: It’s All about the Blood Flow,” which focused on endothelial injury mediators, interactions, and targets for therapy as they pertain to AKI. The audience was reminded that the kidney is comprised of a heterogeneous population of cells, with anatomically distinct structures, that function together to perform a number of tightly regulated, complex, and interdependent processes. AKI disrupts these cellular structure–function relationships and accelerates the progression of chronic kidney disease to end-stage kidney disease with subsequent microvascular dropout. Endothelial cells play a key role in initiating and propagating the inflammatory response following ischemia, infection, and/or sepsis. Situated in the key position between epithelial cells and white blood cells (WBCs), endothelial cells interact and respond to signals from both cell types, mediating coagulation, WBC adherence, migration into the interstitium, microvascular flow rates, and permeability. In addition, associated pericytes mediate fibrosis, when activated. Renal proximal tubule cells, which are often the primary target of nephrotoxins, ischemia, damage-associated molecular patterns (DAMPs), and pathogen-associated molecular patterns (PAMPs), directly signal to endothelial and interstitial cells. Thus, the multifactorial nature of the etiology and pathophysiology of AKI, in addition to limitations of current diagnostic techniques, hinders the translation of preclinical therapeutic success. During this talk, Dr. Molitoris stressed that evolution of the importance and understanding of epithelial, endothelial, and inflammatory cell interactions and individualization of care are necessary for eventual success of AKI treatment.

After a short break, Dr. Brad Rovin, from The Ohio State University, gave a seminar discussing the “Advances and Challenges on New Therapies and Clinical Targets of AKI.” This presentation covered the clinical syndromes of AKI, its epidemiology, and its consequences. For most types of AKI, especially those causing acute tubular injury which manifest as acute tubular necrosis histologically, there are no specific treatments; treatment that is available is either preventative or supportive. Barriers to developing new AKI therapies were discussed and several biomarkers of AKI were reviewed. In addition, the most recent failed AKI trial was discussed to enable the audience to appreciate areas of improvement for future clinical trials of AKI.

The final presentation of the session was an in-depth review by Dr. Zaher Radi of Pfizer, on the “Immunopathology of AKI.” Pathophysiologically, the classification of AKI can be divided into three categories: (1) prerenal (e.g., hypovolemia), (2) intrinsic (e.g., renal aseptic ischemia/reperfusion injury), and (3) postrenal (e.g., obstruction). Intrinsic AKI can be further subdivided into having glomerular, tubular, interstitial, or renovascular origins. Emerging evidence supports the involvement of renal tubular epithelial cells, in addition to the innate and adaptive arms of the immune system, in the pathogenesis of intrinsic AKI. Proinflammatory DAMPs, PAMPs, hypoxia-inducible factors, toll-like receptors, complement system, oxidative stress, adhesion molecules, apoptosis, resident renal dendritic cells, neutrophils, T and B lymphocytes, macrophages, natural killer T cells, cytokines, and chemokines all contribute to the immunopathogenesis of AKI; each of these components was discussed in detail.