#1883 SUrvey of renal Biopsy database and Anti-cancer dRUg therapy in Japan (SUBARU-J study)
Authors: Kuwabara Takashige , Miyasato Yoshikazu , Kanki Tomoko , Mizumoto Teruhiko , Matsubara Takeshi , Sawa Naoki , Sugiyama Hitoshi , Maruyama Shoichi , Mukoyama Masashi , Murakami Naoka , Jhaveri Kenar , Yanagita Motoko 
Published: May 2024

Abstract

Background and Aims
The frequency of consultations for renal complications associated with anti-cancer drug therapy has greatly increased in recent years, but the actual situations remain yet to be fully understood. We aimed to investigate the clinical outcomes of anti-cancer drug therapy-associated renal complications, using the Japan Renal Biopsy Registry (J-RBR), a nationwide registry system in Japan.

Method
This nationwide survey was performed in 449 cases with “drug-induced” checked in J-RBR database from 2018 to 2021. In total 449 subjects, top-ranked histopathological diagnoses were as follows, TIN (49.8%), TMA (14.5), MN (10.0), MCNS (6.5), FSGS (4.4), Vasculitis (2.2) and others (12.2). Regardless of the causative agent, TIN was the most common diagnosis. Though, it was followed by TMA or MN in anti-cancer drug (n = 139)- or non-anticancer drug (n = 190)-related cases, respectively. Because there was also TMA included as 2nd highest in causative-agent unidentified cases (n = 120), we employed total 259 subjects of anti-cancer drug-related and causative-agent unidentified for this survey. Our surveillance files investigating on renal pathology, medications and cancer prognosis were distributed. Of the 224 cases with a file uploaded, a total of 135 anti-cancer drug-related cases confirmed by the information were analyzed. Patients’ clinical data collected at pre- and post-biopsy as well as histopathological diagnoses were used for epidemiological and clinicopathological analyses. Mann-Whitney U test or chi-square test was used for continuous or categorical variables. Overall survival (OS) was estimated using Kaplan–Meier method and compared by log-rank test.

Results
In total 135 subjects, top-ranked histopathological diagnoses were as follows: tubulointerstitial nephritis (TIN; 64 cases), thrombotic microangiopathy (TMA; 48), focal segmental glomerulosclerosis (FSGS; 5), IgA nephropathy (IgAN; 4), acute tubular necrosis (ATN; 3), minimal change nephrotic syndrome (MCNS; 3), crescentic glomerulonephritis (CrGN; 2), membranoproliferative glomerulonephritis (MPGN; 2) and others (4). 80% of TIN and 75% of TMA, the most frequent diagnoses in our survey, were associated with immune-checkpoint inhibitors (ICI) and anti-angiogenic therapy (AAG), respectively. All IgAN, MCNS and CrGN cases were ICI-related. Proton pump inhibitors and antibiotics were used concomitantly in TIN (p = 0.054) and TMA (p &lt; 0.001), respectively. Among cases with TIN, their OS in the subgroups of targeted therapy (Tx), and the combination with Tx and conventional cytotoxic agents (Combi) seemed to be worse than that of cytotoxic agents alone (CTx); it may be due to more cases in the Tx and Combi subgroups with treatment response category of progressive disease (by RECIST criteria). In contrast, among TMA cases, OS in each of the three subgroups of Tx, CTx, and Combi seemed to be overlapped, suggesting the prognostic impact of TMA on OS. The serum LDH level was higher in TMA associated with CTx (CTx-TMA) than that with others (Fig. 1: 393.2 vs. 225.1 U/L, p = 0.06). Of note, Kaplan-Meier curves for OS in TMA cases with increased LDH (&gt;220 U/L) showed poor prognosis in CTx-TMA than in others-TMA (Fig. 2: p = 0.018).

Conclusion
Our nationwide survey using J-RBR registry database with renal biopsy data provides a snapshot of kidney complications associated with anti-cancer drug therapy. Higher LDH in CTx-TMA cases may be associated with systemic TMA, probably leading to the poor prognosis. To explore the detail of anti-cancer drug-associated TMA and other complications, further research employing more sample size is warranted in the future.