 Thank you to the organizers for having me here today. These are my disclosures. I'm going to go over definitions of renal and liver impairment, review some of the available data or lack of data from the pivotal clinical trials, review individual targeted agents and the manufacturer's recommendations, and finish off with a phase one data for safety of targeted agents and patients with renal and liver dysfunction. So just starting off, this is the National Kidney Foundation definition of chronic kidney disease defined as a GFR of less than 60 ml per minute per 1.73 meter square. You'll see here on the table the various stages, and I have listed here the CTCAE grades that correlate to the various stages with grade two, three, and four. In terms of renal insufficiency in kidney cancer patients, it occurs in up to about 50% of patients. This is what I've seen in the literature. These are patients that are older, median age of 65 years. These patients have chronic kidney disease from comorbidities such as diabetes, hypertension, and the majority of these patients have undergone nephrectomy. This is adapted from the CTCAE four, just looking at the grades of liver toxicity, ALT, AST, and bilirubin, I'm not going to go into the various grades, but this is what we typically use to grade our patients' toxicities. And the child pu classification is used to get a better understanding of severity of patients' liver disease. This uses clinical and lab criteria such as encephalopathy, ascites, bilirubin, albumin, and prothrombin time. You give points according to the various grades, and then there's class A, class B, and class C listed below based on the points which correspond to the least severe liver disease, moderately severe, and also most severe. So looking at just first line treatment of kidney cancer, I just added the serum creatinine here on the right and liver function criteria that were necessary to participate in these studies. And looking at the study of synetineb, the two studies of bevizizumaps, serraphanib phase two study, pazophanib, and tensorolimus, it excluded patients with significant renal insufficiency or liver function. If you think of CTCAE for all of these inclusion criteria, you're looking at about grade one. The synetineb expanded access trial, similarly, serum creatinine had to be less than two times upper limit of normal. And looking at the liver function, this is about CTCAE grade two. And the serraphanib expanded access trial excluded patients with renal impairment who required hemodialysis. So just to go through the various drugs, starting off with bevizizumap, the metabolism is nonspecific in clearance, varies by body weight, gender, and tumor burden. There is no recommended dose reductions provided by the manufacturer's labeling, either for renal insufficiency or hepatic insufficiency. It does recommend to suspend for proteinuria as described here, and discontinue in patients with nephrodic syndrome. For TEMS serolimus, this is metabolized by the liver by CIF3A4 to serolimus and for minor metabolites. It's excreted via feces, less than 5% eliminated via urinary excretion. There is no dose adjustment necessary in renal impairment. This hasn't been studied in patients with on dialysis. In liver dysfunction, these are the recommendations that are made. It's contraindicated in moderate to severe liver dysfunction. For synitinib and its metabolite, primarily metabolized by the liver as well, excreted via feces with approximately 16% of the drug eliminated by urinary excretion. There is no dose adjustment necessary for renal dysfunction if it's mild, moderate, or severe. For dialysis patients, there is no initial dose adjustment necessary, although there is a recommendation that you can increase the dose of synitinib because patients on dialysis seems to get less exposure by about 47% of the drug when they take it. Everyone's well aware of the black box warning for synitinib for hepatotoxicity. Hepatotoxicity has been observed in clinical trials and post-marketing experience. This hepatotoxicity can be severe and deaths have been reported. There is no dose adjustment necessary if the liver dysfunction is mild or class A. Moderate class B has not been studied in class C patients. And the studies that have looked at synitinib excluded patients with ALTs, ASTs, elevations as depicted here. For pazopinib also metabolized primarily by the liver, it's excreted via the feces with less than 4% of the drug eliminated by urinary excretion. There's no dose adjustment necessary for renal dysfunction. We're all very aware of the black box warning for hepatotoxicity for pazopinib. There have been severe and fatal hepatotoxicity observed in clinical trials. And there is a recommendation by the manufacturer label that I use always to monitor herpatic function and interrupt reduced or discontinued dosing as recommended. And I listed that here. So when you initiate patients on pazopinib, you want to monitor liver tests before treatment start, followed by weeks 3, 5, 7, and 9. Thereafter, you monitor at month 3 and at month 4. And as clinically indicated, for isolated ALT elevation as listed here, you may continue the drug with weekly monitoring of LFTs until the ALT returns to grade 1 or baseline. For isolated ALT elevations greater than 8 times the upper limit of normal, you should interrupt the drug until grade 1 or baseline. And reduce the dose to 400 milligrams with weekly LFTs for 8 weeks. If you do get another elevation in the ALT-AST, you should discontinue the drug. And discontinue permanently if ALT elevation is greater than 3 times upper limit of normal, plus Billy Rubin's elevation is greater than 2 times upper limit of normal. Finally, seraphonib predominantly metabolize in the liver excreted via the feces with about 20% of the drug eliminated by urinary excretion. There is no dose adjustment necessary for renal dysfunction if mild, moderate, severe. And I'm going to finish off with going over phase one and the pharmacokinetic study that looked at seraphonib in patients with hepatic or renal dysfunction. This was the CALGB60301, which looked at 102 parts to it. The first part looked at 138 patients. These patients had different tumor types. There were about 30 plus patients with kidney cancer, hepatocellular patients, and others. Study part two looked at 124 patients, and this was a phase one dose escalation study. They looked at nine different cohorts. These are the cohort definitions for the study cohort one looked at total Billy Rubin that was normal, and also renal function that was normal. And these patients were started at 400 milligrams BID. And then on the middle column looks at the hepatic cohorts and the, my slides keep advancing. The renal column looked at different cohorts as well, based on mild, moderate, severe, or very severe dysfunction. And I've highlighted here what the starting doses were for each cohort. Looking at just the hepatic cohorts, this table just breaks down the cohort by mild, moderate, severe, and very severe dysfunction and LFT abnormalities associated with each. The number of patients entered an accessible, the number of DLTs. And finally, the recommended starting dose for each cohort provided by the authors. And looking at the renal cohorts, same broken down by mild dysfunction, moderate, severe, very severe dysfunction. The number of patients entered an, sorry, this thing keeps going forward, accessible, number of DLTs, and the recommended starting dose for patients with mild, moderate, severe, and very severe renal dysfunction. As you can see, going back to the hepatic cohort six, patients, they didn't even tolerate a very low dose of seraphonib that was given every three days, as did the severe dysfunction cohort seven here. And this looks at the, it's a dot plot of the area under the curve for AUC of seraphonib by cohort. And there was no, no difference across all cohorts and AUC. So in, in conclusion, patients with renal and liver dysfunction are excluded from clinical trials. Patients with various degrees of dysfunction may be treated safely with targeted agents. It is important to modify doses and frequently monitor these patients as recommended. Prospective studies, including patients with renal and liver dysfunction are key in providing guidance to the treating physician. Thank you.