Pathophysiology of Acute Kidney Injury By JOSEPH V. BONVENTRE, MD, PhD The term “acute renal failure” (ARF) has traditionally been used to describe a syndrome with a rapid decline in glomerular filtration rate (GFR) occurring over a period of hours to weeks as the key feature. Recently, a consortium of nephrologists and inten- sivists, the Acute Kidney Injury Network (AKIN), representing many of the professional societies involved in the care of critically ill patients, recommended that the term “acute kidney injury” (AKI) replace ARF. This term includes the entire spectrum of ARF and recognizes that minor changes in kidney function (reflected by a change in serum creati- nine [SCr] of 0.3 mg/dL) can portend worse patient outcome, 1 whereas the term “failure” is reserved for those patients whose renal functional impairment is so severe that replace- ment therapy is indicated, or at least considered. The previous issue of Nephrology Rounds reviewed the epidemiology, diagnosis, and treatment of AKI in various settings. This issue of Nephrology Rounds examines the pathophysiological underpinnings of AKI. In addition to the prognostic indications, a number of other reasons contributed to the change in terminology from ARF to AKI. Telling patients that they have acute kidney injury is much less ominous than describing their condition as acute renal failure. Furthermore, the population gener- ally recognizes “kidney” more than “renal” in referring to this organ. The AKIN network proposed that AKI be defined as “an abrupt (within 48 hours) reduction in kidney function, currently defined as an absolute increase in SCr of >0.3 mg/dL ( >25 μmol/L), a percentage increase of 50%, or a reduction in urine output (documented oliguria of < 0.5 mL/kg/hr for >6 hours).” 2 There are numerous potential causes of AKI; many relate to a mismatch between oxygen and nutrient delivery to the nephrons, and energy demand of the nephrons. The causes of AKI have been traditionally divided into prerenal, intrinsic renal, and postrenal. In prerenal azotemia, there is a decrease in GFR with changes in SCr, but no tubular injury. Intrinsic renal causes can be asso- ciated with ischemia, toxins, or primary interstitial or glomerular disease. It is important to recog- nize that relative oxygen deprivation often is not generalized, but because of the complexity of vascular and tubular relationships in the kidney, functional consequences of localized tubular injury may be amplified. Other causes relate to direct toxic effects of substances on the vasculature or epithelium. The kidney is particularly susceptible to toxic effects from many environmental or therapeutic substances, since many of these compounds are concentrated by the tubule as the filtrate moves down the nephron. In humans, acute injury is often superimposed on chronic kidney disease (CKD); as a result, AKI is increasingly recognized as an important precipitant in the progression to end-stage renal disease (ESRD). AKI is frequently associated with multiple organ failure and sepsis. Despite advances in preventive strategies and support measures, this syndrome continues to be associated with significant morbidity and mortality. The pathogenesis of AKI is complex and, to some extent, varies based on the particular cause; however, many convergent processes lead to tissue injury and organ dysfunction. Causes asso- ciated with toxins also have a final common pathway contributing to local or generalized ischemia. Figure 1 summarizes the complex interplay between vascular and tubular processes that ultimately lead to organ dysfunction. AKI is a state often characterized by enhanced intrarenal vasoconstric- tion; it is also associated with enhanced renal-nerve activity and increased tissue levels of vasocon- strictive agents, such as angiotensin II and endothelin. A decreased responsiveness in the resistance vessels to vasodilators, such as acetylcholine, bradykinin, and nitric oxide (NO), as well as lower production levels of some vasodilators can enhance the impact of these vasoconstrictive agents. These effects on the resistance vessels are complemented by endothelial damage, enhanced leuko- cyte-endothelial adhesion (particularly in the postcapillary venules), and activation of coagulation pathways; together, these processes result in small-vessel occlusion and further activation of the leukocytes causing increases in inflammation and providing a positive-feedback network. The inflammation produces increased levels of mediators expanding the interactions between leuko- cytes and endothelial cells, and activating the coagulation pathways. The resultant effects on oxygen and nutrient delivery to the epithelial cells result in damage to those cells; furthermore, damaged tubular cells also generate proinflammatory mediators. Repair involves the replacement of lost cells in the tubule by mechanisms that are not completely understood. 3 The editorial content of Nephrology Rounds is determined solely by the Nephrology Division of Brigham and Women’s Hospital. Co-Editors Joseph V. Bonventre, M.D., Ph.D., (Division Director) Barry M. Brenner, M.D., F.R.C.P., (Director Emeritus) Nephrology Division Brigham and Women’s Hospital Reza Abdi, M.D. M. Javeed Ansari, M.D. Jessamyn Bagley, Ph.D. Sangeeta Bhattia, M.D., Ph.D. Joseph V. Bonventre, M.D., Ph.D. Barry M. Brenner, M.D. Anil K. Chandraker, M.B., M.R.C.P. David M. Charytan, M.D. Mary Choi, M.D. Kenneth B. Christopher, M.D. Gary C. Curhan, M.D., Sc.D. Bradley M. Denker, M.D. Jeremy Duffield, M.D., Ph.D. John P. Forman, M.D. Markus H. Frank, M.D. Indira Gulena, M.D. Dirk M. Hentschel, M.D. Andreas Herrlich, M.D., Ph.D. Li-Li Hsiao, M.D., Ph.D. Benjamin D. Humphreys, M.D., Ph.D. John J. Iacomini, Ph.D. Takaharu Ichimura, Ph.D. Vicki Rubin Kelley, Ph.D. Julie Lin, M.D., M.P.H. Edgar L. Milford, M.D. David B. Mount, M.D. Nader Najafian, M.D. Jagdeep Obhrai, M.D. Shona Pendse, M.D. Martin R. Pollak, M.D. Mohamed H. Sayegh, M.D. Julian L. Seifter, M.D. Jagesh V. Shah, Ph.D. Alice M. Sheridan, M.D. Ajay K. Singh, M.B., M.R.C.P. (U.K.) Theodore I. Steinman, M.D. Eric N. Taylor, M.D. Chaorui Tian, M.D., Ph.D. John K. Tucker, M.D. Vishal Vaidya, Ph.D. Sushrut S.Waikar, M.D. Wolfgang C. Winkelmayer, M.D., Sc.D. Xueli Yuan, M.D., Ph.D. Kambiz Zandi-Nejad, M.D. Jing Zhou, M.D., Ph.D. Brigham and Women’s Hospital Website: www.brighamandwomens.org/renal AUGUST/SEPTEMBER 2008 Volume 6, Issue 7 NEPHROLOGY Rounds AS PRESENTED IN THE ROUNDS OF THE NEPHROLOGY DIVISION OF BRIGHAM AND WOMEN’ S HOSPITAL BOSTON, MASSACHUSETTS ® HARVARD MEDICAL SCHOOL TEACHING AFFILIATE Nephrology Rounds is approved by the Harvard Medical School Department of Continuing Education to offer continuing education credit www.nephrologyrounds.org