2. Disclosure Verification for: Name: Jon Klein, MD PhD The presenter listed above: ___ Does not have any significant financial relationships to disclose _x_ Has disclosed the following relationships: __Research Grants __Speakers Bureau Patent holder x __Consultant for fee _x_Stock/Ownership Employment x Partnership __Advisory Committee/Board ___Other _x_ Has disclosed this activity will not include discussion of unapproved/investigational uses of products or devices __ Has disclosed this activity will include discussion of unapproved/investigational uses of products or devices Was this activity Supported by an educational grant or received in-kind support? __ Yes Name of Company: _X_No
3. Goals Define the problem of anemia in end-stage renal disease (ESRD). Review the rise of recombinant erythropoietin (rEPO) as a therapy. Review the emerging doubts about rEPO and subsequent changes in dosing. Describe proteomic data of biomarkers of rEPO response. Describe the merger of biomarkers with a model predictive control tool to adjust rEPO dose.
4. The Golden Age of Anemia Treatment The WHO defines anemia as a Hgb < 13 in males and < 12 in premenopausal females By this definition > 90% of patients with kidney disease are anemic Beginning in 1989, kidney patients began receiving FDA approved rEPO. EPO use in cancer and HIV patients soon followed
6. The Golden Age Begins to End NlHct = 42 Low Hct = 30 N Engl J Med. 1998 Aug 27;339(9):584-90.
7. N Engl J Med 2006;355:2085-98. Conclusions The use of a target hemoglobin level of 13.5 g per deciliter (as compared with 11.3 g per deciliter) was associated with increased risk and no incremental improvement in the quality of life.
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9. The Golden Age Ends WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE Chronic Kidney Disease: • In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL (5.1). • No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks. • Use the lowest Epogen dose sufficient to reduce the need for red blood cell (RBC) transfusions (5.1). “Clinicians should use the lowest dose of ESA sufficient to reduce the need for red blood cell transfusions”
10. Clinicians’ Response EPO weekly dose fell 12.5% in 2 years. Hgb targets are shifted from 10-13 to 10-11 g/dl
27. Conclusions The treatment of anemia in ESRD remains challenging. Concerns about unbridled EPO treatment have emerged. Proteomic analysis revealed serum biomarkers of EPO resistance and susceptibility The use of intelligent control methods (MMPC) provided personalized EPO dosing with results superior to standard protocols The combination of proteomic biomarkers and MMPC shows promise in guiding individualized EPO dosing.
Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR)4 and Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE)
The standard control protocol was based on an interpretation of national anemia guidelines from The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (5) and the package insert for EPOGEN
For this example I am using OSMR as the biomarker of choice since the OSMR data seem to correlate much nicer with Epo Resistance Index (ERI), hence are more illustrative. Here you see the data plot of ERI vs. total OSMR abundance with a nice “exponential” curve fit to show the relationship between the two. Using this fit, I was able to calculate Epo responsiveness for different levels of OSMR abundance (not shown here). ERI = EPO Dose/Hgb 1 month later
This is hypo-responder simulation when no OSMR value is provided at the beginning
