Volume 90, Issue 3, Pages 638-647 (September 2016) Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors  Frank B. Cortazar, Kristen A. Marrone, Megan L. Troxell, Kenneth M. Ralto, Melanie P. Hoenig, Julie R. Brahmer, Dung T. Le, Evan J. Lipson, Ilya G. Glezerman, Jedd Wolchok, Lynn D. Cornell, Paul Feldman, Michael B. Stokes, Sarah A. Zapata, F. Stephen Hodi, Patrick A. Ott, Michifumi Yamashita, David E. Leaf  Kidney International  Volume 90, Issue 3, Pages 638-647 (September 2016) DOI: 10.1016/j.kint.2016.04.008 Copyright © 2016 International Society of Nephrology Terms and Conditions

Figure 1 Representative images of CPI-induced AKI. Core needle-biopsy specimens (a–c) from patient 9 show “typical” features of acute tubulointerstitial nephritis; (d) from patient 2 show granulomatous acute tubulointerstitial nephritis; (e,f) from patient 8 show acute thrombotic microangiopathy. (a) Periodic acid-Schiff stain shows diffuse interstitial inflammation and focal severe tubulitis with infiltrating lymphocytes (arrows, ×200; bar = 50 μm). (b) Hematoxylin and eosin stain shows diffuse interstitial infiltrates predominantly composed of lymphocytes, with several eosinophils (arrows, ×400; bar = 25 μm). (c) Immunohistochemistry reveals the lymphocytic infiltrates in the interstitium to be predominantly CD4+ T cells (×40; bar = 100 μm). (d) Periodic acid-Schiff stain shows a noncaseating granuloma with multinucleated giant cells (yellow arrows), severe interstitial inflammation and tubulitis (blue arrows), and severe glomerulitis (black arrow, ×200; bar = 50 μm). (e) Silver stain shows diffusely wrinkled glomerular basement membranes and “onion-skin” lesion of small arteries (arrow, ×200; bar = 50 μm). (f) Electron microscopy shows swollen endothelium and subintimal widening filled with electron-lucent “fluffy” material (arrows, ×1400; bar = 4 μm). Larger versions of these images are shown in Supplementary Figure S1. AKI, acute kidney injury; CPI, checkpoint inhibitor. Kidney International 2016 90, 638-647DOI: (10.1016/j.kint.2016.04.008) Copyright © 2016 International Society of Nephrology Terms and Conditions

Figure 2 Time course of events and response to treatment. Solid black arrows indicate initiation of steroids (dosing regimens are provided in Table 3). Open arrows indicate initiation of hemodialysis (patients 3 and 12 received 3 sessions of hemodialysis and subsequently recovered; patients 6 and 8 remained dialysis-dependent). Day 0 refers to checkpoint inhibitor initiation. Kidney International 2016 90, 638-647DOI: (10.1016/j.kint.2016.04.008) Copyright © 2016 International Society of Nephrology Terms and Conditions

Figure 2 Time course of events and response to treatment. Solid black arrows indicate initiation of steroids (dosing regimens are provided in Table 3). Open arrows indicate initiation of hemodialysis (patients 3 and 12 received 3 sessions of hemodialysis and subsequently recovered; patients 6 and 8 remained dialysis-dependent). Day 0 refers to checkpoint inhibitor initiation. Kidney International 2016 90, 638-647DOI: (10.1016/j.kint.2016.04.008) Copyright © 2016 International Society of Nephrology Terms and Conditions

Figure 3 Estimated incidence of CPI-associated AKI. *P < 0.01 for each of the following comparisons: Ipi + Nivo compared to Ipi alone, Nivo alone, and Pembro alone. AKI, acute kidney injury; CPI, checkpoint inhibitor; Ipi, ipilimumab; Nivo, nivolumab; Pembro, pembrolizumab. Kidney International 2016 90, 638-647DOI: (10.1016/j.kint.2016.04.008) Copyright © 2016 International Society of Nephrology Terms and Conditions