Acute interstitial nephritis related to immune checkpoint inhibitors

Abstract

Background:Immune checkpoint inhibitors (anti-PD1 or anti-CTLA-4) are increasingly used in various cancers. Immune checkpoint inhibitors (ICI)-related renal disorders are poorly described (9 cases) and were only related to Ipilimumab.Methods:Retrospective collection of clinical charts of all the patients admitted for renal disorders following ICI in the University Hospital of Toulouse (France).Results:We report on adverse renal events that occurred in three patients treated with anti-PD1 (nivolumab or pembrolizumab) or anti-CTLA-4 (ipilimumab). Acute kidney injury occurred at 4–12 weeks after initiation of treatment, and harbored features of tubulo-interstitial nephritis (interstitial polymorphic inflammatory infiltrate with predominant CD3+ CD4+ T cells, associated with granuloma in one). Following withdrawal of ICI and steroid intake, estimated glomerular-filtration rate had improved in all patients.Conclusions:These data suggest that all ICI can lead to acute interstitial nephritis, possibly related to the presence of autoreactive clonal T cells. We recommend that patients receiving ICI should undergo renal monitoring every 2 weeks for 3–6 months.

Chemotherapy and Transplantation: The Role of Immunosuppression in Malignancy and a Review of Antineoplastic Agents in Solid Organ Transplant Recipients

“…Acute interstitial nephritis reported with checkpoint inhibitors is also thought to be an immune‐related adverse event. Although the mechanism needs further investigation, it is thought to be the result of enhancing autoreactive T cells, resulting in organ‐specific damage . This is of particular concern for KTRs.…”

Granulomatous and lichenoid dermatitis after IgG4 anti‐PD‐1 monoclonal antibody therapy for advanced cancer

“…The development of these reactions is based on the co‐activation of monocyte/macrophages in the organs involved . The blockade of immune checkpoints in cancer alters the ratio between cytotoxic T‐cells, but also affects Th1/Th17 and regulatory T‐cells leading to an increase in Th1 response, with secretion of TNF‐alpha, classical macrophage activation and interferon‐gamma in large amounts generating granulomas with multinucleated giant cells . Additionally, the activity of CD8+ cells on both DC and macrophages can produce cytokines favoring Th1 and Th17 cells and inducing granulomatous reaction …”

“…During cutaneous manifestations the use of antihistamines has been employed . Generally, the time to improvement ranges from 10 to 30 days after discontinuation of the medication or use of systemic steroids …”

Immune checkpoint inhibitors in the management of malignancies in transplant recipients

“…Also, reducing immunosuppression while using immune checkpoint inhibitors can directly activate memory B-cells as their surface expresses PD-1 7. In some described cases tubulointerstitial nephritis with infiltration of T-cells and granulocytes was evident on kidney biopsy 37. The possible mechanism is the reaction of immune checkpoint inhibitors with intrarenal T cells that can eventually cause inflammation confined to the kidney 38.…”

“…The possible mechanism is the reaction of immune checkpoint inhibitors with intrarenal T cells that can eventually cause inflammation confined to the kidney 38. Additionally, intrarenal T cells induce the production of autoantibodies (anti-DNA)39 or inhibit T-reg, both of which may further augment the proliferation of autoreactive T cells with selective tropism to the kidneys 37. Interestingly, this T-cell response to kidney allograft antigens can be downregulated by the expression of PD-L1 on the tubular epithelium of kidney 40.…”