PMC9831939_01
Renal tissue morphology. Panel a shows a low-power micrograph of the renal cortex using a periodic acid-Schiff stain. Glomeruli are histologically normal, and there is no tubule necrosis or interstitial inflammation. Original magnification x100. Panel b shows hematoxylin and eosin-stained section and demonstrates focal proximal tubule vacuolization. Original magnification x400. Panel c shows PAS-stained tissue and also demonstrates proximal tubule cytoplasmic vacuolization. Original magnification x400. Panel d shows Jones Silver-stained tissue with dramatic proximal tubule cytoplasmic vacuolization (original magnification x630). Panel e shows a transmission electron micrograph of the apical region of the proximal tubule. Substantial subapical cytoplasmic vacuolization is present (original magnification x15,000). Panel f shows transmission electron micrograph of the basal region of the proximal tubule. Diffuse basal vacuolization is present (original magnification x15,000).
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A kidney biopsy, performed 2 months after the last dose of ICI therapy and while RTA was still present, showed no evidence of tubulitis, interstitial nephritis, or interstitial inflammation (Figure 1a). However, significant vacuolization of the proximal tubule was evident by light microscopy and by ultrastructural analysis (Figure 1b-f).
Immunohistochemistry examination for critical acid-base transporters. Panels a and b show expression of the electrogenic sodium bicarbonate cotransporter, isoform 1. Panel a shows intact basolateral sodium bicarbonate cotransporter, isoform 1 immunolabel in proximal tubule segments in this patient. Panel b shows sodium bicarbonate cotransporter, isoform 1 immunolabel expression in control tissue. Sodium bicarbonate cotransporter, isoform 1 immunolabel does not differ detectably between case and control tissues. Panels c and d show immunohistochemistry for H+-ATPase in the case and control tissues, respectively. In both, intact H+-ATPase expression with apical polarization in type A intercalated cells is not detectably different between case and control tissues. Panels e and f show Rhesus C glycoprotein immunolabel expression in the case and control tissue. Panels e and f show Rhesus C glycoprotein immunolabel expression in the case and control tissues, respectively. Apical and basolateral Rhesus C glycoprotein immunolabel in intercalated cells is present in both and does not differ detectably between case and control tissues.
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We used standard immunohistochemistry techniques described previously.S2 Immunohistochemistry for sodium bicarbonate cotransporter 1, the proximal tubule's primary basolateral bicarbonate transporter, whose expression is necessary for normal ammonia metabolism,,S3,S4 showed normal proximal tubule expression not evidently different from control tissue (Figure 2a and b). H+-ATPase, critical for collecting duct H+ secretion, exhibited normal expression and localization in collecting duct type A intercalated cells that did not differ detectably from control tissue (Figure 2c and d). Rhesus C glycoprotein is an ammonia transporter critical for collecting duct ammonia secretion and showed normal apical and basolateral expression and intensity not detectably different from control tissue (Figure 2e and f).