1. Research Project for Dialysis Patients with a Hgb >13 for 2005 Researched, Edited, and Presented by Mindy Huttu, Anatole Besarab, and Stan Frinak

2. Why are dialysis patients anemic? – Anemia is measured as a reduction in hemoglobin (Hgb), the substance in red blood cells that carries oxygen. – Chronic Kidney Disease (CKD) patients become anemic as they loose kidney function. – This results from the loss of the Kidneys’ ability to produce the red blood cell stimulating hormone Erythropoietin (EPO). – To prevent Anemia, replace EPO produced in the kidney with “artificial” (genetically engineered) EPO. – Maintaining a near constant Hgb is not easy for doctors and patients to do. Why are dialysis patients anemic? – Anemia is measured as a reduction in hemoglobin (Hgb), the substance in red blood cells that carries oxygen. – Chronic Kidney Disease (CKD) patients become anemic as they loose kidney function. – This results from the loss of the Kidneys’ ability to produce the red blood cell stimulating hormone Erythropoietin (EPO). – To prevent Anemia, replace EPO produced in the kidney with “artificial” (genetically engineered) EPO. – Maintaining a near constant Hgb is not easy for doctors and patients to do. Introduction

3. What is Dialysis? Type of therapy used to provide an artificial replacement for lost kidney function due to kidney failure. It is a life maintaining treatment. Dialysis may be used for very sick patients who have suddenly lost their kidney function or for quite stable patients who, over time, have permanently lost their kidney function. Type of therapy used to provide an artificial replacement for lost kidney function due to kidney failure. It is a life maintaining treatment. Dialysis may be used for very sick patients who have suddenly lost their kidney function or for quite stable patients who, over time, have permanently lost their kidney function.

4. What is Hemoglobin, (Hgb)? Hemoglobin is the oxygen-carrying protein in the red blood cells. In vertebrates, it transports oxygen from the lungs to the rest of the body. It also transports carbon dioxide to the lungs for removal.

5. What is EPO? Erythropoietin (EPO) is a glycoprotein hormone that is a growth factor for red blood cell precursors in the bone marrow. It is produced by the kidney, and is the hormone regulating red blood cell production. It is used in treating anemia resulting from chronic kidney disease or from cancer chemotherapy. EPO is generally injected under the skin of the patient. Several injections weekly are required for the original forms, but newer long-acting forms (Darbepoetin) may require injections only once every two to four weeks. EPO can also be injected into the blood stream directly. This route of administration is the preferred mode in dialysis patients. Erythropoietin (EPO) is a glycoprotein hormone that is a growth factor for red blood cell precursors in the bone marrow. It is produced by the kidney, and is the hormone regulating red blood cell production. It is used in treating anemia resulting from chronic kidney disease or from cancer chemotherapy. EPO is generally injected under the skin of the patient. Several injections weekly are required for the original forms, but newer long-acting forms (Darbepoetin) may require injections only once every two to four weeks. EPO can also be injected into the blood stream directly. This route of administration is the preferred mode in dialysis patients.

6. When and how was EPO developed? First postulated in 1906 based on transfusion experiments in rabbits. In 1950, the still unidentified erythropoietic factor was found to be stimulated in rats breathing a low-oxygen atmosphere. In the 1960s its source was identified as the kidneys. Human EPO was first purified from human urine by T. Miyake, C. K. Kung and E. Goldwasser at the University of Chicago in 1977. EPO has now been identified with a molecular mass of about 30,000 Daltons. It has a 165 amino acid chain with four oligosaccharide side chains and circulates in the blood plasma at about 5 pmol/L. First postulated in 1906 based on transfusion experiments in rabbits. In 1950, the still unidentified erythropoietic factor was found to be stimulated in rats breathing a low-oxygen atmosphere. In the 1960s its source was identified as the kidneys. Human EPO was first purified from human urine by T. Miyake, C. K. Kung and E. Goldwasser at the University of Chicago in 1977. EPO has now been identified with a molecular mass of about 30,000 Daltons. It has a 165 amino acid chain with four oligosaccharide side chains and circulates in the blood plasma at about 5 pmol/L.

7. What is Chronic Kidney Disease? Chronic kidney disease (CKD) is a slowly progressive loss of kidney function over a period of months or years and quantitated as low glomerular filtration rate. CKD that leads to severe illness and requires some form of renal replacement therapy (such as dialysis) is called end-stage renal (kidney) disease (ESRD). Chronic kidney disease (CKD) is a slowly progressive loss of kidney function over a period of months or years and quantitated as low glomerular filtration rate. CKD that leads to severe illness and requires some form of renal replacement therapy (such as dialysis) is called end-stage renal (kidney) disease (ESRD).

8. What is Anemia? Anemia is the diminution of red blood cells that contain hemoglobin. This reduces the ability of blood to carry oxygen to the tissues. Severity of anemia is measured as a decreased Hgb level below the normal range Male:13 - 18 gm/dL Female:12 - 16 gm/dL Anemia is the diminution of red blood cells that contain hemoglobin. This reduces the ability of blood to carry oxygen to the tissues. Severity of anemia is measured as a decreased Hgb level below the normal range Male:13 - 18 gm/dL Female:12 - 16 gm/dL

9. Aims of Study Question: How well do doctors regulate the Hgb of dialysis patient’s? Method: Examine the trends between EPO dose and Hgb in dialysis patients. Goal: Can the data teach us how to do a better job of managing anemia? Question: How well do doctors regulate the Hgb of dialysis patient’s? Method: Examine the trends between EPO dose and Hgb in dialysis patients. Goal: Can the data teach us how to do a better job of managing anemia?

10. A good correlation between EPO and HGB level Hgb and EPO vs Time Reducing EPO reduces Hgb three months later

11. Hgb and EPO vs Time Reducing EPO reduces Hgb three months later

12. Problems of using EPO The effect of a given EPO dose can persist for up to 3 months. Therefore, a change in EPO dosage may not alter the Hgb level to the desired level for up to several months. The effect of a given EPO dose can persist for up to 3 months. Therefore, a change in EPO dosage may not alter the Hgb level to the desired level for up to several months.

13. Defining the Project Physicians respond to Hgb levels only when limits are exceeded. Low Hgb occur for many reasons, most of which are not under the control of the physician. High Hgb, however, result from dosing by doctors and medical staff and are potentially modifiable. Physicians respond to Hgb levels only when limits are exceeded. Low Hgb occur for many reasons, most of which are not under the control of the physician. High Hgb, however, result from dosing by doctors and medical staff and are potentially modifiable.

14. Methods Extract Data from data base Sort with Access Calculate in Excel Analyze in StatView and develop graphs and study trends Suggest Improvements in dosing strategies Extract Data from data base Sort with Access Calculate in Excel Analyze in StatView and develop graphs and study trends Suggest Improvements in dosing strategies

15. Data 2005 Descriptive StatisticsMeanStd. Dev.NMinMax Hgb12.01.6348785.518.8 Roll Average12.11.4318056.4717.17 EPO Dose Corr6285.45188.854882028000 FESAT26.69.862152685 FERR438.0308.32153164260 CHR31.62.982085-31.546.3 delta Hgb-0.0101.124648-11.911.2 delta time (days)13.9009.894652-351181 slope0.16.624647-78168 Time to reach 1372.973.663682322 Time Hgb >13 g41.342.733721.7257 total duration Hgb >1381.259.711873273 EPO Increased222326846105022000 EPO Decreased-18152502810-22000-50 Hgb Increase0.90.7722630.111 Hgb Decrease-0.950.872145-12-0.1 Hgb Slope Inc (per mo)2.957.2422620.05168 Hgb Slope dec (per mo)-2.954.752145-78-0.07 MeanSDNMinMax Rolling Average (Hgb) 12.11.4318056.4717.7 EPO Increase 222326846105022000 EPO decrease - 18152502810- 22000- 50 Hgb increase 0.9 0.7722630.111 Hgb decrease - 0.950.872145- 12- 0.1 Hgb Slope Inc mo 2.957.2422620.05168 Hgb Slope Dec mo - 2.954.752145- 78- 0.07 MeanSDNMinMax Rolling Average (Hgb) 12.11.4318056.4717.7 EPO Increase 222326846105022000 EPO decrease - 18152502810- 22000- 50 Hgb increase 0.9 0.7722630.111 Hgb decrease - 0.950.872145- 12- 0.1 Hgb Slope Inc mo 2.957.2422620.05168 Hgb Slope Dec mo - 2.954.752145- 78- 0.07 Average number of times a patient Hgb exceeded 13 = 1.8 times per year

16. Percent Hgb (g/dL) 0 2 4 6 8 10 12 14 4567891011121314151617181920 Hgb Distribution for 2005 207 Patients with a Hgb Value >13 (g/dL) 13≤ Hgb <15 (24%) Hgb <11 (23%) Hgb ≥15 (3%) N = 4862 11≤ Hgb <13 (50%)

17. Mean Hgb Time (mo) 6 7 8 9 10 11 12 13 14 15 16 0123456789101112 Mean Hgb measurements for all dialysis patients with a Hgb >13 for 2005 (time in months) (684) N=(4878) (445) (467) (442) (313) (541) (355) (222) (492) (336) (279) (291)

18. Percent 0 0 5 5 10 15 20 25 - 6 - 4 - 2 0 0 2 2 4 4 N = 4644 Mean = 0.0 ±1.1 Change Hgb (g/dL) Change in Hgb Between Measurements 2005 Data Std. Deviation (±1.12)

19. Patient Data for Hgb ≤ 13 vs. Hgb > 13 P <.0003 EPO Dose Mean Diff: 621 0 2000 4000 6000 8000 10000 12000 14000 Hgb > 13 Hgb ≤ 13 6445 5824 Hgb ≤ 13 Hgb > 13 11.3 14.0 0.0 2.0 4.0 6.0 8.0 10.0 12.0 14.0 16.0 P <.0001 Hgb

20. Patient Data for Hgb ≤ 13 vs. Hgb > 13 FESAT 28.3 25.9 0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 Hgb > 13Hgb ≤13 P <.0001 FERR 448 412 0 100 200 300 400 500 600 700 800 900 Hgb ≤ 13Hgb > 13 P <.0154 CHR 31.5 31.9 0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 Hgb > 13 P <.0065 Hgb ≤ 13

21. Hgb (g/dL) Hgb (g/dL) Time (in Days) Hgb Values for an Individual Dialysis Patient 5 6 7 8 9 10 11 12 13 14 15 16 17 18 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 0306090120150180210240270300330 EPO units EPO units 42 days above Hgb 13 150 days to increase above Hgb 13 77 days above Hgb 13

22. Suggest Improvements in dosing strategies A patients EPO dose should not be changed every month, because EPO effects can last up to 3 months or more. A trend analysis (graph) of the patient’s data may be very useful in making dosing decisions. A patients EPO dose should not be changed every month, because EPO effects can last up to 3 months or more. A trend analysis (graph) of the patient’s data may be very useful in making dosing decisions. A computerized anemia management system that recommends dosing change according to a set protocol could improve results. Reducing EPO reduces Hgb three months later

23. Hemoglobin Distribution EPO vs. Darbepoetin Using Computerized Anemia Management Program Pre Dialysis Patients on Darbepoetin Last Monthly HGB N = 265 0 4 8 12 16 20 24 Percent 5791113151719 Hgb (g/dL) 63%

24. The study showed that an individual patients Hgb can change over a wide range and the Hgb level did not always correspond to the patients EPO dose. There are many things other than just the Hgb in which the doctors must look at to decide the amount of EPO which might be right for the patient. The current Hgb level, the current EPO dose and the patients iron status measure by FERR, TSAT, and CHR levels. A trend analysis (graph) of the patient’s data may be very useful in making decisions. A computerized anemia management program that uses a database to track changes in Hgb and EPO dose may help regulate Hgb levels in dialysis patients. The study showed that an individual patients Hgb can change over a wide range and the Hgb level did not always correspond to the patients EPO dose. There are many things other than just the Hgb in which the doctors must look at to decide the amount of EPO which might be right for the patient. The current Hgb level, the current EPO dose and the patients iron status measure by FERR, TSAT, and CHR levels. A trend analysis (graph) of the patient’s data may be very useful in making decisions. A computerized anemia management program that uses a database to track changes in Hgb and EPO dose may help regulate Hgb levels in dialysis patients. Conclusions

25. References http://en.wikipedia.org www.facstaff.bucknell.edu/.../ Introduction.htm http://images.search.yahoo.com/search/images/view?back=http%3A%2F%2Fimages.sear ch.yahoo.com%2Fsearch%2Fimages%3Fp%3Dkidney%2Bdialysis%26rs%3D0%26ei%3D UTF-8%26fr%3DFP-tab-img-t- t400%26vf%3D&w=427&h=331&imgurl=www.ahealthyme.com%2FImagebank%2FMedEco %2F00042705.jpg&rurl=http%3A%2F%2Fwww.ahealthyme.com%2Ftopic%2Fdialysis&siz e=24.3kB&name=00042705.jpg&p=kidney+dialysis&type=jpeg&no=5&tt=12,773&ei=UTF-8 ase.tufts.edu/biology/.../ index.asp?PP=kidneys www.sportujeme.sk www.asnanaka.com/m/.../ MedicalGlossary/images?D=D www.komsta.net/chemwalls/hemoglobin-1280.jpg http://en.wikipedia.org/wiki/Hemoglobin www.pacifichealth.com/shop/media?M=D http://www.henryfordhealth.org/ http://en.wikipedia.org www.facstaff.bucknell.edu/.../ Introduction.htm http://images.search.yahoo.com/search/images/view?back=http%3A%2F%2Fimages.sear ch.yahoo.com%2Fsearch%2Fimages%3Fp%3Dkidney%2Bdialysis%26rs%3D0%26ei%3D UTF-8%26fr%3DFP-tab-img-t- t400%26vf%3D&w=427&h=331&imgurl=www.ahealthyme.com%2FImagebank%2FMedEco %2F00042705.jpg&rurl=http%3A%2F%2Fwww.ahealthyme.com%2Ftopic%2Fdialysis&siz e=24.3kB&name=00042705.jpg&p=kidney+dialysis&type=jpeg&no=5&tt=12,773&ei=UTF-8 ase.tufts.edu/biology/.../ index.asp?PP=kidneys www.sportujeme.sk www.asnanaka.com/m/.../ MedicalGlossary/images?D=D www.komsta.net/chemwalls/hemoglobin-1280.jpg http://en.wikipedia.org/wiki/Hemoglobin www.pacifichealth.com/shop/media?M=D http://www.henryfordhealth.org/

27. Data 2005 Descriptive StatisticsMeanStd. Dev.NMinMax Hgb12.01.6348785.518.8 Roll Average12.11.4318056.4717.17 EPO Dose Corr6285.45188.854882028000 FESAT26.69.862152685 FERR438.0308.32153164260 CHR31.62.982085-31.546.3 delta Hgb-0.0101.124648-11.911.2 delta time (days)13.9009.894652-351181 slope0.16.624647-78168 Time to reach 1372.973.663682322 Time Hgb >13 g41.342.733721.7257 total duration Hgb >1381.259.711873273 EPO Increased222326846105022000 EPO Decreased-18152502810-22000-50 Hgb Increase0.90.7722630.111 Hgb Decrease-0.950.872145-12-0.1 Hgb Slope Inc (per mo)2.957.2422620.05168 Hgb Slope dec (per mo)-2.954.752145-78-0.07 MeanSDNMinMax Rolling Average (Hgb) 12.11.4318056.4717.7 EPO Increase 222326846105022000 EPO decrease - 18152502810- 22000- 50 Hgb increase 0.9 0.7722630.111 Hgb decrease - 0.950.872145- 12- 0.1 Hgb Slope Inc mo 2.957.2422620.05168 Hgb Slope Dec mo - 2.954.752145- 78- 0.07 MeanSDNMinMax Rolling Average (Hgb) 12.11.4318056.4717.7 EPO Increase 222326846105022000 EPO decrease - 18152502810- 22000- 50 Hgb increase 0.9 0.7722630.111 Hgb decrease - 0.950.872145- 12- 0.1 Hgb Slope Inc mo 2.957.2422620.05168 Hgb Slope Dec mo - 2.954.752145- 78- 0.07 Average number of times a patient Hgb exceeded 13 = 1.8 times per year