A case of karyomegalic interstitial nephritis without FAN1 mutations in the setting of brentuximab, ifosfamide, and carboplatin exposure.

in BMC nephrology by Matthew Leong, Tiane Dai, Lili Tong, Cynthia C Nast

TLDR

  • Karyomegalic interstitial nephritis (KIN) is a rare renal diagnosis that can be caused by genetic or medication factors. The study presented a case of a woman who developed KIN after receiving ifosfamide, carboplatin, and brentuximab treatment. The study found that brentuximab, which has a different mechanism of action, may also be associated with KIN. The study also found that drug-induced KIN can develop in the absence of FAN1 mutations, a finding not previously reported. The study's findings suggest that medication usage may not require an underlying genetic predisposition for triggering KIN or that medications alone are sufficient.

Abstract

Karyomegalic interstitial nephritis (KIN) is a rare renal diagnosis associated with both genetic and medication etiologies. The primary gene associated with KIN is the FAN1 gene which encodes a protein responsible for DNA interstrand repair. Common medication triggers of KIN are chemotherapeutic agents, especially those which disrupt DNA structure such as carboplatin. Despite overlap between these mechanisms, it has not clearly been established if medication usage requires an underlying genetic predisposition for triggering KIN or if medications alone are sufficient. This ambiguous pathogenesis can make it difficult to appropriately assess risk of KIN development when starting patients on one of the known KIN-inducing therapies. Additionally, brentuximab vedotin, an antibody-drug conjugate directed against CD30, has not been previously implicated in KIN development. We present a 49-year-old woman previously diagnosed with metastatic Hodgkin's lymphoma who was treated with doxorubicin, bleomycin, vinblastine, and dacarbazine, then 3 cycles of ifosfamide, carboplatin, etoposide, all of which were discontinued due to side effects. Following an episode of acute kidney injury, the serum creatinine was 1.09 mg/dL. She then received 2 doses of brentuximab, the serum creatinine rose, and the drug was discontinued. Kidney biopsy done 2 months after brentuximab and 5 months following ifosfamide therapies showed karyomegalic interstitial nephritis. Genetic evaluation showed no FAN1 gene mutations. The patient was started on pembrolizumab; no steroids were given due to concerns about interference with lymphoma immunotherapy. She remains with stable disease and stable chronic kidney disease. This case presents a patient who developed KIN with a progressively rising serum creatinine after ifosfamide, carboplatin and brentuximab treatment. Although ifosfamide and carboplatin have known associations with the development of KIN, this case raises the possibility that brentuximab, which has a different mechanism of action, also may be associated with KIN. Additionally, the genetic findings demonstrate that drug-induced KIN can develop in the absence of FAN1 mutations, a finding not previously reported.

Overview

  • The study focuses on karyomegalic interstitial nephritis (KIN), a rare renal diagnosis associated with genetic and medication etiologies. The primary gene associated with KIN is the FAN1 gene which encodes a protein responsible for DNA interstrand repair. Common medication triggers of KIN are chemotherapeutic agents, especially those which disrupt DNA structure such as carboplatin. The study aims to investigate the role of medication usage in triggering KIN and whether it requires an underlying genetic predisposition. The study presents a case of a 49-year-old woman who developed KIN after receiving ifosfamide, carboplatin, and brentuximab treatment. The study aims to determine if brentuximab, which has a different mechanism of action, is also associated with KIN and whether drug-induced KIN can develop in the absence of FAN1 mutations. The study's hypothesis is that medication usage requires an underlying genetic predisposition for triggering KIN or that medications alone are sufficient.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions detailed in the study. The study identifies that ifosfamide and carboplatin have known associations with the development of KIN. However, the study raises the possibility that brentuximab, which has a different mechanism of action, may also be associated with KIN. The study also finds that drug-induced KIN can develop in the absence of FAN1 mutations, a finding not previously reported.

Implications and Future Directions

  • The study's findings suggest that medication usage may not require an underlying genetic predisposition for triggering KIN or that medications alone are sufficient. The study also raises the possibility that brentuximab, which has a different mechanism of action, may also be associated with KIN. The study's findings also demonstrate that drug-induced KIN can develop in the absence of FAN1 mutations, a finding not previously reported. Future research directions could explore the mechanisms underlying the association between brentuximab and KIN and investigate the role of other genetic factors in the development of KIN. Additionally, future research could investigate the use of steroids in the treatment of KIN and their potential impact on lymphoma immunotherapy.
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