Glomerular filtration rate measurement during platinum treatment for urothelial carcinoma: optimal methods for clinical practice.

BACKGROUND: We assessed the accuracy of four estimated glomerular filtration rate (eGFR) methods: MDRD, Cockcroft-Gault, CKD-EPI, and Wright. METHOD: The four methods were compared to measure GFR (mGFR) in patients with urothelial urinary tract cancer (T2-T4bNxMx) receiving platinum-based chemotherapy at Rigshospitalet, Copenhagen, from January 2019 to December 2021. Using standardized assays, creatinine values were measured, and mGFR was determined using Technetium-99 m diethylenetriaminepentaacetic acid (Tc-99 m-DTPA) or Cr-51-ethylenediaminetetraacetic acid (Cr-51-EDTA) plasma clearance. Patients (n = 146) with both mGFR and corresponding creatinine values available were included (n = 345 measurements). RESULTS: The CKD-EPI method consistently demonstrated superior accuracy, with the lowest Total Deviation Index of 21.8% at baseline and 22.9% for all measurements compared to Wright (23.4% /24.1%), MDRD (26.2%/25.5%), and Cockcroft-Gault (25.x%/25.1%). Bland Altman Limits of agreement (LOA) ranged from - 32 ml/min (Cockcroft-Gault) to + 33 ml/min (MDRD), with CKD-EPI showing the narrowest LOA (- 27 ml/min to + 24 ml/min and lowest bias (0.3 ml/min). Establishing an eGFR threshold at 85 ml/min-considering both the lower limit of agreement (LOA) and the minimum cisplatin limit at 60 ml/min-allows for the safe omission of mGFR in 30% of patients in this cohort. CONCLUSION: CKD-EPI equation emerged as the most suitable for estimating kidney function in this patient group although not meeting benchmark criteria. We recommend its use for initial assessment and ongoing monitoring, and suggest mGFR for patients with a CKD-EPI estimated GFR below 85 ml/min. This approach could reduce costs and decrease laboratory time for 30% of our UC patients.

Nucleotide excision repair deficiency is a targetable therapeutic vulnerability in clear cell renal cell carcinoma.

Due to a demonstrated lack of DNA repair deficiencies, clear cell renal cell carcinoma (ccRCC) has not benefitted from targeted synthetic lethality-based therapies. We investigated whether nucleotide excision repair (NER) deficiency is present in an identifiable subset of ccRCC cases that would render those tumors sensitive to therapy targeting this specific DNA repair pathway aberration. We used functional assays that detect UV-induced 6-4 pyrimidine-pyrimidone photoproducts to quantify NER deficiency in ccRCC cell lines. We also measured sensitivity to irofulven, an experimental cancer therapeutic agent that specifically targets cells with inactivated transcription-coupled nucleotide excision repair (TC-NER). In order to detect NER deficiency in clinical biopsies, we assessed whole exome sequencing data for the presence of an NER deficiency associated mutational signature previously identified in ERCC2 mutant bladder cancer. Functional assays showed NER deficiency in ccRCC cells. Some cell lines showed irofulven sensitivity at a concentration that is well tolerated by patients. Prostaglandin reductase 1 (PTGR1), which activates irofulven, was also associated with this sensitivity. Next generation sequencing data of the cell lines showed NER deficiency-associated mutational signatures. A significant subset of ccRCC patients had the same signature and high PTGR1 expression. ccRCC cell line-based analysis showed that NER deficiency is likely present in this cancer type. Approximately 10% of ccRCC patients in the TCGA cohort showed mutational signatures consistent with ERCC2 inactivation associated NER deficiency and also substantial levels of PTGR1 expression. These patients may be responsive to irofulven, a previously abandoned anticancer agent that has minimal activity in NER-proficient cells.