Background: Poisoning by the mushroom ”deadly webcap”( Cortinarius sp.) causes irreversible kidney damage but there are no known effects on other organs. The fungal toxin, orellanine, selectively targets proximal tubular cells in rats and in humans by disturbing the cell metabolism causing decreased protein synthesis and apoptosis. Clear cell and papillary renal cell carcinoma (RCC) originate from proximal tubule cells. Orellanine induced concentration-dependent decline in viability in RCC cell lines and in primary cultures from human clear cell and papillary RCC. Orellanine induced apoptosis and tumour shrinkage in RCC(SKRC-17) transplanted to rats on peritoneal dialysis and the tumours become necrotic with almost no viable tissue. Based on these data a drug has been developed based on chemically synthesized orellanine (www.oncorena.com). Methods: The primary objectives of this study are to evaluate the safety and tolerability and to determine the maximum tolerable dose (MTD) of orellanine in patients with metastatic clear cell or papillary RCC and end stage renal disease who are on chronic haemodialysis and who have failed standard of care treatment. The secondary objectives are to study the pharmacokinetic (PK)profile of orellanine and to assess the efficacy of orellanine in treating these patients with respect to objective response (OR). Exploratory objectives are to access progression free and overall survival (PFS and OS) and to conduct analysis of circulating tumour specific DNA in the blood. Serum will be collected for unspecific future research which may include sequencing or genomic analyses. Orellanine will be given intravenously once monthly. A total of 6 to 20 patients will be enrolled in a dose escalation phase to determine MTD or a dose causing complete response (CR). An independent Data Review Committee (DRC) will access cumulative data and provide recommendations and decisions for every change in dose level. Once MTD has been determined up to 20 patients will be treated in a dose expansion phase to better characterize safety, tolerability and primary efficacy. CT/MRI will occur every 4 weeks (Q4W) during dose escalation phase and Q8W during the dose expansion phase. Enrollment has started and since the occurrence of end stage renal disease in patients with metastatic RCC is uncommon, patients in this first in man study are recruited both from western Europe and north America. The study is performed in the Centre for Clinical Cancer Studies (CKC) at Karolinska University Hospital, Stockholm, Sweden Reference: Lisa Buvall et. al. Orellanine specifically targets renal cell carcinoma.Oncotarget. 2017; 8:91085-91098. https://doi.org/10.18632/oncotarget.19555. Clinical trial information: NCT05287945.