SUrvey of renal Biopsy registry database and Anticancer dRUg therapy in Japan (SUBARU-J study)

Abstract

Background: Kidney complications associated with anticancer drug therapy have greatly increased recently. We aimed to investigate the real-world clinical outcomes of anticancer drug therapy-associated renal complications in Japan using the national kidney biopsy database, Japan Renal Biopsy Registry (J-RBR).

Methods: From 2018 to 2021, 449 cases from 49 facilities identified as 'drug-induced' histopathology in the J-RBR were screened, of which a total of 135 were confirmed as anticancer drug-related cases and included in the analysis. Overall survival rates were estimated using the Kaplan-Meier method and compared by logrank test. The Cox regression model was used to evaluate the association between variables and deaths.

Results: The most common primary sites of malignancies were the lung (33.3%), followed by gastrointestinal (16.3%) and gynaecological (11.1%) cancers. Tubulointerstitial nephritis (TIN; 47.4%) and thrombotic microangiopathy (TMA; 35.6%) were the most frequent diagnoses. All immunoglobulin A nephropathy, minimal change disease and crescentic glomerulonephritis (CrGN) cases were immune checkpoint inhibitor related. All CrGN cases were anti-neutrophil cytoplasmic antibody negative. Antibiotics were most frequently used concomitantly with anticancer drugs in TMA cases among subgroups (TMA versus others: 62.5 versus 27.5%; P < .001). Among TMA cases, the serum lactate dehydrogenase level tended to be higher in cytotoxic agent-associated TMA (CTx-TMA) than in other TMAs, but was not significant between groups (415.5 versus 219.0 U/l; P = .06). Overall survival was worse in CTx-TMA than in other TMAs (P = .007). The Cox model demonstrated proton pump inhibitor (PPI) use (hazard ratio 2.49, P = .001) as a significant prognostic factor, as well as the presence of metastasis and serum albumin level.

Conclusions: Our registry analysis highlighted various presentations of biopsy-proven kidney complications associated with anticancer drug therapy. Clinicians should be aware of worse outcomes associated with CTx-TMA and the prognostic role of PPI use.

Keywords: PPI use; anticancer drug therapy; kidney biopsy registry database; thrombotic microangiopathy.

Graphical Abstract

Figure 1:

Flow chart of patient selection for final analysis.

Figure 2:

Distribution of the histopathological diagnoses by a causative agent. Pie charts show the histopathological distributions in (A) total subjects and subgroups of (B) anticancer drugs, (C) non-anticancer drugs and (D) causative agent unidentified. FSGS: focal segmental glomerulosclerosis.

Figure 3:

Kaplan–Meier curves for overall survival in (A) TIN and (B) TMA. Cases with missing overall survival data were excluded from this analysis. Conventional CTx: conventional cytotoxic agents; targeted Tx: targeted therapy.

Figure 4:

Kaplan–Meier curves for overall survival in the CTx-TMA and others-TMA subgroups in elevated LDH TMA cases. TMA cases with LDH >220 IU/l were employed in this analysis. Cases in a subgroup with a combination treatment of cytotoxic agents and anti-angiogenic agents (CTx + AAG) were excluded from this analysis.