#978 Interstitial fibrosis and tubular atrophy of immune checkpoint inhibitor-related interstitial nephritis associate mortality and kidney prognosis
Authors: Matsubara Takeshi , Yamamoto Shinya , Kuwabara Takashige , Miyazawa Shuma , Miyasato Yoshikazu , Sawa Naoki , Sugiyama Hitoshi , Maruyama Shoichi , Mukoyama Masashi , Yanagita Motoko 
Published: May 2024

Abstract

Background and Aims
Several studies have been conducted on immune checkpoint inhibitor (ICI)-associated nephrotoxicity. However, current clinical analyses for nephrotoxicity are inadequate owing to the diagnostic criteria, which are mostly based on an increase in serum Cre levels rather than on renal pathology. In addition, many studies have focused on the incidence of ICI-associated nephrotoxicity, and few have focused on its prognosis and effects on overall survival. One of the major pathological findings of ICI-associated nephrotoxicity is known to show tubulointerstitial nephritis (TIN). Therefore, this study aimed to clarify the clinical and pathological characteristics of biopsy-proven ICI-TIN and their effects on the clinical remission of kidney injury and renal or cancer prognosis using the nationwide database of the Japan Renal Biopsy Registry (J-RBR) of the Japanese Society of Nephrology.

Method
This is a multicenter study using J-RBR named “SUrvey of renal Biopsy database and Anti-cancer dRUg therapy in Japan (SUBARU-J)”. Fifty-four patients with renal biopsy-proven ICI-TIN, registered in the J-RBR between 2018 and 2021 was analyzed. We collected patient clinical characteristics, pathological scores of renal biopsy including glomerulosclerosis, interstitial fibrosis, tubular atrophy (IFTA), and cellular infiltration, as well as data on the clinical remission of kidney injury during the acute phase, defined as a recovery of serum Cre to &lt;1.5 × above baseline within 90 days from renal biopsy, then performed a multivariable analysis to investigate factors associated with clinical remission of kidney, and finally calculated the adjusted hazard ratio of each factor for overall survival, progression-free survival (PFS) of cancer, and major kidney adverse events (MAKE), consisting of the composite endpoint of death, renal replacement therapy dependence, or a decrease in estimated glomerular filtration rate to &lt;50% of baseline.

Results
The median (interquartile range) time from the initiation of immune checkpoint inhibitors to renal biopsy was 134 (IQR: 56.5–364) days. Extrarenal immune-related adverse events occurred in 10 (18.5%) patients and 44 (81.5%) patients were treated with steroids. Clinical remission of kidney injury was achieved in 28 (51.8%) patients. A shorter interval (within seven days) between renal biopsy and steroid treatment was independently associated with the clinical remission of kidney injury (OR 35.3, p = 0.0301). The observation period from renal biopsy was 415 (IQR 140-844) days, with one-year overall survival of 62.5% and two-year overall survival of 42.4%. Hypertension (aHR 0.37, 95% CI: 0.17-0.82, p = 0.0144), IFTA (aHR 2.50, 95% CI: 1.12-5.57, p = 0.0251), and clinical remission of kidney injury (aHR 0.43, 95% CI: 0.19-0.94, p = 0.0355) were independently associated with overall survival. Hypertension (aHR 0.31, 95% CI: 0.15-0.64, p = 0.0018) and clinical remission of kidney injury (aHR 0.47, 95% CI: 0.23-0.96, p = 0.0391) also had a significant association with PFS although IFTA did not (aHR 2.03, 95% CI: 0.98-4.21, p = 0.0560). Furthermore, Hypertension (aHR 0.37, 95% CI: 0.18-0.77, p = 0.0075), IFTA (aHR 2.40, 95% CI: 1.14-5.06, p = 0.0210), and clinical remission of kidney injury (aHR 0.39, 95% CI: 0.19-0.81, p = 0.0123) were independently associated with the incidence of MAKE.

Conclusion
These data suggested that the pathological IFTA score of ICI-TIN, along with hypertension and clinical remission of kidney injury during the acute phase, could be associated not only with kidney prognosis but also with overall survival.