Kidney-Immune System Crosstalk in AKI

Summary: Acute kidney injury (AKI) now is recognized as a systemic disease. It occurs frequently in critically ill patients and has profound effects on morbidity and mortality. Recent research efforts have shown a bidirectional interplay between AKI and the immune system. Both innate and adaptive immune responses mediate renal injury as well as recovery from AKI. Dendritic cells, monocytes/macrophages, neutrophils, T lymphocytes, and B lymphocytes all play specific roles in the development of AKI. M2 macrophages and regulatory T cells also are pivotal in controlling inflammation, tissue remodeling, and repair after AKI. Conversely, existing evidence also suggests that increased production and decreased clearance of cytokines as well as dysfunction of immune cells, in particular neutrophils, can contribute to immune dysfunction and impaired bacterial clearance during AKI. Clinical data indicate that AKI is a risk factor for infections after various forms of critical illness, including cardiac surgery, malignancies, or severe trauma.Available evidence does not suggest that standard renal replacement therapies improve outcome from AKI beyond control of fluid balance and azotemia. Thus, novel approaches likely will be necessary to prevent or treat AKI-induced dysregulation of the inflammatory response. Summary: Acute kidney injury (AKI) now is recognized as a systemic disease. It occurs frequently in critically ill patients and has profound effects on morbidity and mortality. Recent research efforts have shown a bidirectional interplay between AKI and the immune system. Both innate and adaptive immune responses mediate renal injury as well as recovery from AKI. Dendritic cells, monocytes/macrophages, neutrophils, T lymphocytes, and B lymphocytes all play specific roles in the development of AKI. M2 macrophages and regulatory T cells also are pivotal in controlling inflammation, tissue remodeling, and repair after AKI. Conversely, existing evidence also suggests that increased production and decreased clearance of cytokines as well as dysfunction of immune cells, in particular neutrophils, can contribute to immune dysfunction and impaired bacterial clearance during AKI. Clinical data indicate that AKI is a risk factor for infections after various forms of critical illness, including cardiac surgery, malignancies, or severe trauma. Available evidence does not suggest that standard renal replacement therapies improve outcome from AKI beyond control of fluid balance and azotemia. Thus, novel approaches likely will be necessary to prevent or treat AKI-induced dysregulation of the inflammatory response. Extensive clinical and experimental research over the past decade has indicated that acute kidney injury (AKI) is a systemic disease,1Singbartl K Kellum JA AKI in the ICU: definition, epidemiology, risk stratification, and outcomes.Kidney Int. 2012; 81: 819-825Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar and the interactions between AKI and the immune system have gained particular interest.2Singbartl K Joannidis M. Short-term effects of acute kidney injury.Crit Care Clin. 2015; 31: 751-762Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar AKI affects more than 50% of all critically ill patients and has detrimental effects on both short- and long-term patient outcomes.1Singbartl K Kellum JA AKI in the ICU: definition, epidemiology, risk stratification, and outcomes.Kidney Int. 2012; 81: 819-825Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar, 3Hoste EA Bagshaw SM Bellomo R Cely CM Colman R Cruz DN et al.Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study.Intensive Care Med. 2015; 41: 1411-1423Crossref PubMed Scopus (1345) Google Scholar AKI can be caused by septic or aseptic insults (eg, nephrotoxic, or ischemia–reperfusion injury [IRI]), but almost always involves inflammatory changes (Fig. 1).4Bonavia A Singbartl K. A review of the role of immune cells in acute kidney injury.Pediatr Nephrol. 2018; 33: 1629-1639Crossref PubMed Scopus (66) Google Scholar Inflammation and recruitment of leukocytes are key mediators during all phases of renal injury (ie, from initiation, to maintenance, and to resolution of AKI).4Bonavia A Singbartl K. A review of the role of immune cells in acute kidney injury.Pediatr Nephrol. 2018; 33: 1629-1639Crossref PubMed Scopus (66) Google Scholar Shortly after endothelial or tubular epithelial cell damage, activation of resident renal inflammatory cells occurs, followed by recruitment and subsequent infiltration with different subsets of leukocytes. Virtually all immune cells appear to be involved in the pathogenesis of AKI.4Bonavia A Singbartl K. A review of the role of immune cells in acute kidney injury.Pediatr Nephrol. 2018; 33: 1629-1639Crossref PubMed Scopus (66) Google Scholar The majority of invading cells (ie, neutrophils, monocytes, and dendritic cells), are thought to be deleterious. However, some leukocyte subsets seem to exert protective effects (eg, T-regulatory cells). Some circulating leukocytes show opposing properties, depending on the phase of the disease process. For example, M1 macrophages promote inflammation in the early phase, whereas M2 macrophages show anti-inflammatory effects after IRI and facilitate renal recovery. Available data suggest that systemic inflammation also plays a role in the pathogenesis of AKI, at least in some forms. Increased levels of proinflammatory cytokines (eg, interleukin 6 [IL6]), have been associated with the development of AKI after cardiac surgery or during sepsis.5Zhang WR Garg AX Coca SG Devereaux PJ Eikelboom J Kavsak P et al.Plasma IL-6 and IL-10 concentrations predict AKI and long-term mortality in adults after cardiac surgery.J Am Soc Nephrol. 2015; 26: 3123-3132Crossref PubMed Scopus (113) Google Scholar, 6Chawla LS Seneff MG Nelson DR Williams M Levy H Kimmel PL et al.Elevated plasma concentrations of IL-6 and elevated APACHE II score predict acute kidney injury in patients with severe sepsis.Clin J Am Soc Nephrol. 2007; 2: 22-30Crossref PubMed Scopus (147) Google Scholar, 7Murugan R Karajala-Subramanyam V Lee M Yende S Kong L Carter M et al.Acute kidney injury in non-severe pneumonia is associated with an increased immune response and lower survival.Kidney Int. 2010; 77: 527-535Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar Systemic inflammation also influences recovery from AKI with higher levels of cytokines associated with nonrecovery.8Murugan R Wen X Keener C Pike F Palevsky PM Unruh M et al.Associations between intensity of RRT, inflammatory mediators, and outcomes.Clin J Am Soc Nephrol. 2015; 10: 926-933Crossref PubMed Scopus (24) Google Scholar Conversely, AKI itself has profound immune-suppressive effects (Fig. 2). Patients with AKI show a higher risk for infections after cardiac surgery or trauma and during hematologic malignancies.9Bihorac A Baslanti TO Cuenca AG Hobson CE Ang D Efron PA et al.Acute kidney injury is associated with early cytokine changes after trauma.J Trauma Acute Care Surg. 2013; 74: 1005-1013Crossref PubMed Scopus (53) Google Scholar, 10Thakar CV Yared JP Worley S Cotman K Paganini EP. Renal dysfunction and serious infections after open-heart surgery.Kidney Int. 2003; 64: 239-246Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 11Tumbarello M Spanu T Caira M Trecarichi EM Laurenti L Montuori E et al.Factors associated with mortality in bacteremic patients with hematologic malignancies.Diagn Microbiol Infect Dis. 2009; 64: 320-326Crossref PubMed Scopus (74) Google Scholar Patients requiring renal replacement therapy (RRT) are particularly affected by infections.12Reynvoet E Vandijck DM Blot SI Dhondt AW De Waele JJ Claus S et al.Epidemiology of infection in critically ill patients with acute renal failure.Crit Care Med. 2009; 37: 2203-2209Crossref PubMed Scopus (50) Google Scholar Nearly 50% of the infections become apparent shortly before commencement of RRT, 40% during RRT, and approximately 10% in the period after discontinuation of RRT. Thus, commencement of RRT during AKI does not appear to affect the AKI-associated risk of infection. Importantly, the kidneys play a major role in cytokine homeostasis.9Bihorac A Baslanti TO Cuenca AG Hobson CE Ang D Efron PA et al.Acute kidney injury is associated with early cytokine changes after trauma.J Trauma Acute Care Surg. 2013; 74: 1005-1013Crossref PubMed Scopus (53) Google Scholar, 13Zager RA Johnson AC Lund S Hanson S. Acute renal failure: determinants and characteristics of the injury-induced hyperinflammatory response.Am J Physiol Renal Physiol. 2006; 291: F546-F556Crossref PubMed Scopus (8) Google Scholar AKI can lead to altered cytokine levels, especially during concomitant systemic inflammation. The decrease in renal function during AKI can increase cytokine levels in some cases.8Murugan R Wen X Keener C Pike F Palevsky PM Unruh M et al.Associations between intensity of RRT, inflammatory mediators, and outcomes.Clin J Am Soc Nephrol. 2015; 10: 926-933Crossref PubMed Scopus (24) Google Scholar Moreover, kidneys themselves can become a site of cytokine production during AKI, further increasing local and systemic cytokine concentrations.14Bijuklic K Jennings P Kountchev J Hasslacher J Aydin S Sturn D et al.Migration of leukocytes across an endothelium-epithelium bilayer as a model of renal interstitial inflammation.Am J Physiol Cell Physiol. 2007; 293: C486-C492Crossref PubMed Scopus (41) Google Scholar AKI also has direct effects on some leukocyte subsets, in particular neutrophils.15Singbartl K Bishop JV Wen X Murugan R Chandra S Filippi MD et al.Differential effects of kidney-lung cross-talk during acute kidney injury and bacterial pneumonia.Kidney Int. 2011; 80: 633-644Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 16Singbartl K Miller L Ruiz-Velasco V Kellum JA. Reversal of acute kidney injury-induced neutrophil dysfunction: a critical role for resistin.Crit Care Med. 2016; 44: e492-e501Crossref PubMed Scopus (29) Google Scholar AKI impairs intracellular F-actin polymerization and thus interferes with key neutrophil functions, such as bacterial killing and recruitment to sites of infection/inflammation. This review discusses the details and clinical relevance of kidney-immune system crosstalk. Sepsis or noninfectious sources of inflammation lead to AKI (Fig. 1). Septic AKI is the consequence of foreign antigens binding to innate immune receptors, subsequently activating inflammasome components, and ultimately leading to the release of proinflammatory cytokines, both systemically and locally. Aseptic AKI can result from a variety of exposures (eg, nephrotoxins or renal IRI). Both pathogen invasion during sepsis and organ damage via aseptic insults first activate the innate immune system.17Duann P Lianos EA Ma J Lin PH. Autophagy, innate immunity and tissue repair in acute kidney injury.Int J Mol Sci. 2016; 17Crossref PubMed Scopus (70) Google Scholar Damage-associated molecular patterns (DAMPs) represent intracellular components released from necrotic cells. Pathogen-associated molecular patterns (PAMPs) are conserved molecular motifs expressed in invading microorganisms. Both DAMPs and PAMPs bind to and activate membrane-bound Toll-like receptors, instigating a host-specific cascade during the early defense phase of innate immunity. This cascade includes transcription of pro-IL18 and pro-IL1β, acting as the initial signal in a complex signaling process: the inflammasome.18Hauenstein AV Zhang L Wu H. The hierarchical structural architecture of inflammasomes, supramolecular inflammatory machines.Curr Opin Struct Biol. 2015; 31: 75-83Crossref PubMed Scopus (44) Google Scholar The inflammasome comprises receptors of the innate immune systems and sensors, inducing inflammation. Here, the inflammasome itself amplifies the activation of pro-IL18 and IL1β to form the mature forms of these cytokines. Recent evidence has indicated that innate immunity itself is sufficient to cause AKI. This was shown in a zebrafish model of sepsis in larvae at 78 to 82 hours after fertilization when only innate immunity has developed.19Wen X Cui L Morrisroe S Maberry D Emlet DR Watkins SC et al.A zebrafish model of infection-associated acute kidney injury.Am J Physiol Renal Physiol. 2018; 315: F291-F299Crossref PubMed Scopus (19) Google Scholar Neutrophils are attracted to the site of renal inflammation by interacting with endothelial chemokines and adhesion molecules (eg, E-selectin, L-selectin, P-selectin, and integrin).20Singbartl K Green SA Ley K. Blocking P-selectin protects from ischemia/reperfusion-induced acute renal failure.FASEB J. 2000; 14: 48-54Crossref PubMed Scopus (179) Google Scholar, 21Singbartl K Ley K. Protection from ischemia-reperfusion induced severe acute renal failure by blocking E-selectin.Crit Care Med. 2000; 28: 2507-2514Crossref PubMed Scopus (120) Google Scholar, 22Zarbock A Schmolke M Bockhorn SG Scharte M Buschmann K Ley K et al.The Duffy antigen receptor for chemokines in acute renal failure: a facilitator of renal chemokine presentation.Crit Care Med. 2007; 35: 2156-2163Crossref PubMed Scopus (37) Google Scholar Neutrophils produce and secrete cytotoxic compounds (eg, reactive oxygen species), while adhering to the endothelium and infiltrating into the inflamed tissue.23Leliefeld PH Wessels CM Leenen LP Koenderman L Pillay J. The role of neutrophils in immune dysfunction during severe inflammation.Crit Care. 2016; 20: 73Crossref PubMed Scopus (171) Google Scholar Cytotoxic substances are of utmost importance in eliminating invading microorganisms but also can injure healthy host tissue. During IRI, there is also margination of neutrophils to the vascular endothelium in the renal medulla, causing vascular congestion and ultimately impeding renal medullary blood flow.20Singbartl K Green SA Ley K. Blocking P-selectin protects from ischemia/reperfusion-induced acute renal failure.FASEB J. 2000; 14: 48-54Crossref PubMed Scopus (179) Google Scholar, 21Singbartl K Ley K. Protection from ischemia-reperfusion induced severe acute renal failure by blocking E-selectin.Crit Care Med. 2000; 28: 2507-2514Crossref PubMed Scopus (120) Google Scholar Renal neutrophil recruitment, including transmigration, peaks at approximately 24 hours after injury.20Singbartl K Green SA Ley K. Blocking P-selectin protects from ischemia/reperfusion-induced acute renal failure.FASEB J. 2000; 14: 48-54Crossref PubMed Scopus (179) Google Scholar, 21Singbartl K Ley K. Protection from ischemia-reperfusion induced severe acute renal failure by blocking E-selectin.Crit Care Med. 2000; 28: 2507-2514Crossref PubMed Scopus (120) Google Scholar Neutrophils show reduced levels of cytokines after transmigration, suggesting prior cytokine release to further stimulate leukocyte recruitment and increase vascular permeability.24Awad AS Rouse M Huang L Vergis AL Reutershan J Cathro HP et al.Compartmentalization of neutrophils in the kidney and lung following acute ischemic kidney injury.Kidney Int. 2009; 75: 689-698Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar In human beings, more common forms of AKI, such as septic AKI, do not show signs of extensive neutrophil recruitment or other histologic signs of overt inflammation.25Langenberg C Bagshaw SM May CN Bellomo R. The histopathology of septic acute kidney injury: a systematic review.Crit Care. 2008; 12: R38Crossref PubMed Scopus (199) Google Scholar Renal neutrophil infiltration during cisplatin-induced AKI is facilitated by caspase 1–dependent proinflammatory cytokines (eg, IL1β, IL18, and IL6). Blockade of these proinflammatory mediators limits neutrophil infiltration during cisplatin-induced AKI but is not sufficient to prevent nephrotoxic AKI completely.26Ramesh G Reeves WB. TNFR2-mediated apoptosis and necrosis in cisplatin-induced acute renal failure.Am J Physiol Renal Physiol. 2003; 285: F610-F618Crossref PubMed Scopus (239) Google Scholar, 27Ramesh G Reeves WB. TNF-alpha mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity.J Clin Invest. 2002; 110: 835-842Crossref PubMed Scopus (711) Google Scholar An influx of neutrophils into the cortical and medullary peritubular capillaries of kidneys occurs during sepsis/septic shock.28Singbartl K Bockhorn SG Zarbock A Schmolke M Van Aken H. T cells modulate neutrophil-dependent acute renal failure during endotoxemia: critical role for CD28..J Am Soc Nephrol. 2005; 16: 720-728Crossref PubMed Scopus (29) Google Scholar, 29Herter JM Rossaint J Spieker T Zarbock A. Adhesion molecules involved in neutrophil recruitment during sepsis-induced acute kidney injury.J Innate Immun. 2014; 6: 597-606Crossref PubMed Scopus (50) Google Scholar It remains controversial whether or not these neutrophils directly contribute to kidney damage in sepsis. However, we recently indicated that impairments in renal microcirculation, a hallmark of sepsis, also increase renal transit time for activated neutrophils even if they do not invade the renal parenchyma.30Gomez H Ince C De Backer D Pickkers P Payen D Hotchkiss J et al.A unified theory of sepsis-induced acute kidney injury: inflammation, microcirculatory dysfunction, bioenergetics, and the tubular cell adaptation to injury.Shock. 2014; 41: 3-11Crossref PubMed Scopus (488) Google Scholar This prolonged exposure increases the concentration of inflammatory mediators released from neutrophils in the peritubular capillary and accentuates inflammation extending into the tubules, thus combining with mediators filtered at the glomerulus. Monocytes/macrophages are pivotal in both kidney injury and renal repair, including fibrosis after injury. Monocytes are rare in the healthy kidney but greatly increase in number shortly after injury. After recruitment into injured kidneys, monocytes differentiate into functionally different macrophage subsets, characterized in vitro as M1 or M2 cells.31Ysebaert DK De Greef KE Vercauteren SR Ghielli M Verpooten GA Eyskens EJ et al.Identification and kinetics of leukocytes after severe ischaemia/reperfusion renal injury.Nephrol Dial Transplant. 2000; 15: 1562-1574Crossref PubMed Scopus (307) Google Scholar Here, binding of DAMPs and PAMPs to surface pattern recognition receptors activates M1 macrophages, partaking in the innate immune response.32Huen SC Cantley LG. Macrophage-mediated injury and repair after ischemic kidney injury.Pediatr Nephrol. 2015; 30: 199-209Crossref PubMed Scopus (107) Google Scholar M1 macrophages release chemokines, proinflammatory cytokines, and inducible nitric oxide synthase, forming cytotoxic peroxynitrites.32Huen SC Cantley LG. Macrophage-mediated injury and repair after ischemic kidney injury.Pediatr Nephrol. 2015; 30: 199-209Crossref PubMed Scopus (107) Google Scholar Thus, renal macrophages can add to renal inflammation during AKI. Blocking macrophage function is not sufficient to prevent AKI in all cases.33Lu LH Oh DJ Dursun B He Z Hoke TS Faubel S et al.Increased macrophage infiltration and fractalkine expression in cisplatin-induced acute renal failure in mice.J Pharmacol Exp Ther. 2008; 324: 111-117Crossref PubMed Scopus (85) Google Scholar M2 macrophages are involved in wound healing and immunoregulation. These immunoregulatory macrophages release anti-inflammatory mediators (eg, IL10 and transforming growth factor-β), limiting the inflammatory response.34Fadok VA Bratton DL Konowal A Freed PW Westcott JY Henson PM. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF.J Clin Invest. 1998; 101: 890-898Crossref PubMed Scopus (2553) Google Scholar, 35Filardy AA Pires DR Nunes MP Takiya CM Freire-de-Lima CG Ribeiro-Gomes FL et al.Proinflammatory clearance of apoptotic neutrophils induces an IL-12(low)IL-10(high) regulatory phenotype in macrophages.J Immunol. 2010; 185: 2044-2050Crossref PubMed Scopus (155) Google Scholar The exact stimuli and mechanisms causing differentiation into M1 versus M2 macrophages remain unclear. M2 macrophages generate extracellular matrix. Dysregulated wound healing macrophages play an important role in kidney fibrosis.32Huen SC Cantley LG. Macrophage-mediated injury and repair after ischemic kidney injury.Pediatr Nephrol. 2015; 30: 199-209Crossref PubMed Scopus (107) Google Scholar Recent studies have shown the spleen as an important site for the cholinergic anti-inflammatory pathway, which, when activated, has been shown to be renal-protective in the setting of IRI. Stimulation of the cholinergic anti-inflammatory pathway leads to suppression of tumor necrosis factor-α (TNF-α) production, along with a shift of macrophages toward a protective M2 phenotype.36Inoue T Tanaka S Okusa MD. Neuroimmune interactions in inflammation and acute kidney injury.Front Immunol. 2017; 8: 945Crossref PubMed Scopus (23) Google Scholar There is a large number of dendritic cells (DCs) in the renal interstitium, in particular between tubular epithelium and peritubular capillaries, where they can interact directly with epithelium and endothelium as well as circulating immune effector cells. Their numbers increase further during inflammation, such as during IRI.37Lemley KV Kriz W. Anatomy of the renal interstitium.Kidney Int. 1991; 39: 370-381Abstract Full Text PDF PubMed Scopus (203) Google Scholar DCs are arranged in finger-like extensions, creating a sentinel system that surveils the surrounding tissue. DCs undergo functional changes during AKI (eg, increasing expression of inducible co-stimulator ligand).38Soos TJ Sims TN Barisoni L Lin K Littman DR Dustin ML et al.CX3CR1+ interstitial dendritic cells form a contiguous network throughout the entire kidney.Kidney Int. 2006; 70: 591-596Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar Renal DCs have two main functions: they act as antigen-presenting cells to T cells, and they release TNF-α, a major proinflammatory mediator early after injury. In cisplatin-induced nephrotoxicity, renal DCs appear to play a protective role. Depletion of DCs before or during cisplatin treatment leads to more severe renal dysfunction, tubular injury, neutrophil infiltration, and mortality in mice.39Tadagavadi RK Reeves WB. Renal dendritic cells ameliorate nephrotoxic acute kidney injury.J Am Soc Nephrol. 2010; 21: 53-63Crossref PubMed Scopus (120) Google Scholar T cells are antigen-specific adaptive immune cells. Their activation relies on the presence of co-stimulatory molecules such as CD28. T cells and their co-stimulatory molecules are critically involved in renal inflammation and AKI, even under aseptic conditions.28Singbartl K Bockhorn SG Zarbock A Schmolke M Van Aken H. T cells modulate neutrophil-dependent acute renal failure during endotoxemia: critical role for CD28..J Am Soc Nephrol. 2005; 16: 720-728Crossref PubMed Scopus (29) Google Scholar Mice deficient in both CD4+ and CD8+ T cells show reduced renal damage after IRI.40Rabb H Daniels F O'Donnell M Haq M Saba SR Keane W et al.Pathophysiological role of T lymphocytes in renal ischemia-reperfusion injury in mice.Am J Physiol Renal Physiol. 2000; 279: F525-F531Crossref PubMed Google Scholar Increased numbers of activated T cells persist for several weeks after renal IRI, suggesting a role of these effector cells in the transition from AKI to chronic kidney disease.41Ascon M Ascon DB Liu M Cheadle C Sarkar C Racusen L et al.Renal ischemia-reperfusion leads to long term infiltration of activated and effector-memory T lymphocytes.Kidney Int. 2009; 75: 526-535Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar A subset of CD4+ cells, Th17 cells, seem to mediate AKI after septic shock by releasing IL17.42Luo CJ Luo F Zhang L Xu Y Cai GY Fu B et al.Knockout of interleukin-17A protects against sepsis-associated acute kidney injury.Ann Intensive Care. 2016; 6: 56Crossref PubMed Scopus (30) Google Scholar IL17 is a proinflammatory chemokine that stimulates neutrophil migration. Th17 cells become hyperactivated in patients with septic shock, and increased levels of circulating IL17 in septic shock are associated with poor outcomes.43Maravitsa P Adamopoulou M Pistiki A Netea MG Louis K Giamarellos-Bourboulis EJ. Systemic over-release of interleukin-17 in acute kidney injury after septic shock: clinical and experimental evidence.Immunol Lett. 2016; 178: 68-76Crossref PubMed Scopus (26) Google Scholar Moreover, renal neutrophil recruitment and apoptosis of tubular epithelial cells are reduced in IL17 knockout mice, protecting against septic AKI.42Luo CJ Luo F Zhang L Xu Y Cai GY Fu B et al.Knockout of interleukin-17A protects against sepsis-associated acute kidney injury.Ann Intensive Care. 2016; 6: 56Crossref PubMed Scopus (30) Google Scholar T cells also have emerged as potent mediators of nephrotoxic AKI.44Liu M Chien CC Burne-Taney M Molls RR Racusen LC Colvin RB et al.A pathophysiologic role for T lymphocytes in murine acute cisplatin nephrotoxicity.J Am Soc Nephrol. 2006; 17: 765-774Crossref PubMed Scopus (147) Google Scholar Renal T-cell recruitment starts within 1 hour of cisplatin administration, peaks at 12 hours, and then decreases in number by 24 hours. Mice deficient in T cells showed marked improvement in survival and renal function compared with wild-type mice, an effect that was reversed by the adoptive transfer of T cells into knockout mice. CD4 lymphocytes appear to be the predominant cells causing injury, with CD8 cells playing a lesser role, similar to the hierarchy occurring in ischemic AKI. Neutrophil and macrophage infiltration into the kidney also are attenuated in T-cell–deficient mice, indicating that T cells modulate the recruitment of phagocytic cells to the site of injury. The role of B cells in AKI remains largely unknown. To date, the role of B cells appears to be predominantly pathogenic via secretion of antibodies of the IgM class.45Linfert D Chowdhry T Rabb H. Lymphocytes and ischemia-reperfusion injury.Transplant Rev (Orlando). 2009; 23: 1-10Crossref PubMed Scopus (183) Google Scholar There is an increase in B-cell recruitment after renal IRI, which limits renal repair.46Jang HR Gandolfo MT Ko GJ Satpute SR Racusen L Rabb H. B cells limit repair after ischemic acute kidney injury.J Am Soc Nephrol. 2010; 21: 654-665Crossref PubMed Scopus (80) Google Scholar IgM antibodies also hinder kidney repair. Moreover, experimental depletion of B cells in mouse models of AKI improves kidney repair.47Burne-Taney MJ Ascon DB Daniels F Racusen L Baldwin W Rabb H. B cell deficiency confers protection from renal ischemia reperfusion injury.J Immunol. 2003; 171: 3210-3215Crossref PubMed Scopus (162) Google Scholar Regulatory T cells (Tregs), similar to macrophages, are involved in both the development of and recovery from AKI. Tregs represent a small subset of CD4+ cells that express CD25. In animal models of ischemic AKI, depletion of Tregs with anti-CD25 antibody led to more severe AKI via increases in T-cell proliferation, proinflammatory cytokine levels, and tubular damage.48Kinsey GR Sharma R Huang L Li L Vergis AL Ye H et al.Regulatory T cells suppress innate immunity in kidney ischemia-reperfusion injury.J Am Soc Nephrol. 2009; 20: 1744-1753Crossref PubMed Scopus (291) Google Scholar Anti-CD25 antibody treatment likewise impaired tubular recovery. This effect was thought to be owing to a lack of IL10-mediated suppression of the innate immune system. The CD4+ CD25+ regulatory T-cell subset (CD4+ CD25+ Tregs) also is believed to play a protective role in cisplatin-induced AKI.49Lee H Nho D Chung HS Lee H Shin MK Kim SH et al.CD4+CD25+ regulatory T cells attenuate cisplatin-induced nephrotoxicity in mice.Kidney Int. 2010; 78: 1100-1109Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar The cells migrate to the kidney shortly after exposure to cisplatin. Adoptive transfer of CD4+ CD25+ Tregs into mice lacking T cells had protective effects, including attenuated renal dysfunction, attenuated renal macrophage infiltration, and decreased levels of TNF-α and IL1β. In contrast, depletion of this cell population worsened AKI after exposure to cisplatin. AKI has profound effects on cytokine homeostasis, in particular during systemic inflammation. AKI can lead to a reduction in cytokine clearance, which becomes evident during systemic inflammation.13Zager RA Johnson AC Lund S Hanson S. 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