Are there any proven therapies available for the treatment of his disease?

Transcription

1 ACOI 2010

2 Case ADPCKD Shortly after being elbowed in the flank during a pickup basketball game, a 35-year-old healthy man has severe, colicky abdominal pain followed by gross hematuria. He is hospitalized, and a renal ultrasound scan reveals bilateral polycystic kidneys and liver cysts, previously unknown to the patient. The blood pressure is 160/100 mm Hg. The serum creatinine concentration is 0.9 mg per deciliter (80 µmol per liter). The pain subsides in 2 days with analgesics, rest, and fluids; the gross hematuria resolves in 4 days, although microscopic hematuria persists. How should his case be further evaluated and managed? Are there any proven therapies available for the treatment of his disease?

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4 Most common serious genetic disease in the world (1 in 800, 500K US and 10% dialysis) Autosomal dominant with complete penetrance (spontaneous in 5%) PKD1 and PKD2 genes Leads to massive enlargement of the kidneys with hypertension and renal failure

5 Structure of Polycystic Kidney Disease Proteins Wilson P. N Engl J Med 2004;350:

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7 Volume Progression in Polycystic Kidney Disease Jared J. Grantham, M.D., Vicente E. Torres, M.D., Arlene B. Chapman, M.D., Lisa M. Guay-Woodford, M.D., Kyongtae T. Bae, M.D., Ph.D., Bernard F. King Jr., M.D., Louis H. Wetzel, M.D., Deborah A. Baumgarten, M.D., Phillip J. Kenney, M.D., Peter C. Harris, Ph.D., Saulo Klahr, M.D., William M. Bennett, M.D., Gladys N. Hirschman, M.D., Catherine M. Meyers, M.D., Xiaoling Zhang, M.S., Fang Zhu, M.D. and John P. Miller, A.B. N Engl J Med Volume 354;20: May 18, 2006

8 Radiologic Features of Autosomal Dominant Polycystic Kidney Disease Grantham J. N Engl J Med 2008;359:

9 Total Kidney Volume (Panel A) and Total Cyst Volume (Panel B) in Relation to Age in Women (Blue) and Men (Red) Grantham, J. et al. N Engl J Med 2006;354:

10 Log-Transformed Total Kidney Volume (Panel A) and Total Cyst Volume (Panel B) in Relation to Time Grantham, J. et al. N Engl J Med 2006;354:

11 Relation between Changes in Total Kidney Volume and Total Cyst Volume (Panel A) and between Changes in Left and Right Kidney Volumes (Panel B) in Individual id Patients t over Three Years Grantham, J. et al. N Engl J Med 2006;354:

12 Relationship between Total Kidney Volume and Glomerular Filtration Rate Grantham, J. et al. N Engl J Med 2006;354:

13 Total Kidney Volume in Relation to Age in the 185 Patients with Identified PKD1 (Red) or PKD2 (Blue) Mutations Grantham, J. et al. N Engl J Med 2006;354:

14 Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive enlargement of cyst-filled kidneys A magnetic-resonance-based method was used to determine the rates of change in total kidney volume and cyst volume and iothalamate clearance over a three-year period in patients with ADPKD without azotemia Higher rates of kidney enlargement were associated with more rapid decreases in renal function

15 Kidney enlargement resulting from the expansion of cysts in patients with ADPKD is continuous and quantifiable and is associated with the decline of renal function Higher rates of kidney enlargement are associated with a more rapid decrease in renal function 1500cc volume is the cut off for progression

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17 Altered PKD gene lead to abnormal intracellular Ca (decreased) of the tubular microvilli (mechanosensors) Low intracellular Ca leads to up regulation of cell growth, fibrosis, and inflammation by means of mtor Cyclic AMP concentrations are stimulated by vasopressin and nonvasopressin mechanisms

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22 Total Kidney Volume and Other Measures of Renal Function of the Study Patients with Autosomal Dominant Polycystic Kidney Disease. Walz G et al. N Engl J Med 2010;363:

23 Serra AL et al. N Engl J Med 2010;363: Total Kidney Volume.

28 Tolvaptan current phase III trial TEMPO ¾ ongoing mtor Inhibitors sirolimus and everolimus treatment of CKD 2 /3 may slow cyst growth in bigger kidneys and lower GFR. No GFR benefit Octreotide slows liver and kidney growth and improves health h perception. No GFR benefit

29 Tolvaptan diabetes insipidus mtor Inhibitors high drop out rate due to stomatitis, thrombocytopenia, and proteinuria Octreotide GI symptoms (injection) Cost Tolvaptan $250/d, sirolimus $20/d, Octreotide $100/d

30 45 yo woman with Type I DM presents to the office for ongoing management. She is on lisinopril 80 qd for proteinuric (U P/C 10) Stage 3 CKD (egfr 54 ml/min Repeat UP/C 6 mg/mg g She follows a low salt diet and BP 136/88 What are her options for therapy?

31 Losartin vs. Trandolopril vs. Both in Stage 3 non diabetic CKD with > 0.3 grams proteinuria Losartin = Trandolopril Combination ARR 11% NNT 10 Side effects equal in all groups

32 Concerns were raised when a group doing a metaanalysis noted irregularities in data A review by the researcher s university found problems with consent recruitment, blinding and data Study withdrawn

33 Withdrawals due to adverse events: angiotensin-converting enzyme (ACE) inhibitors versus angiotensin II receptor blockers (ARBs).The first group is observational studies and the second group is randomized, controlled trials by American College of Physicians Matchar D B et al. Ann Intern Med 2008;148:16-29

34 Cough as an adverse event: angiotensin-converting enzyme (ACE) inhibitors versus angiotensin II receptor blockers (ARBs).The first group is observational studies and the second group is randomized, controlled trials by American College of Physicians Matchar D B et al. Ann Intern Med 2008;148:16-29

35 Successful monotherapy: angiotensin-converting enzyme (ACE) inhibitors versus angiotensin II receptor blockers (ARBs).The first group is observational studies and the second group is randomized, controlled trials by American College of Physicians Matchar D B et al. Ann Intern Med 2008;148:16-29

36 Kaplan-Meier curves for time to death and first morbid event according to presence or absence of proteinuria and CKD Anand, I. S. et al. Circulation 2009;120: Copyright 2009 American Heart Association

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39 Baseline Characteristics of the Patients The ONTARGET Investigators. N Engl J Med 2008;358:

40 Kaplan-Meier Curves for the Primary Outcome in the Three Study Groups The ONTARGET Investigators. N Engl J Med 2008;358:

41 Incidence of the Primary Outcome, Its Components, and Death from Any Cause The ONTARGET Investigators. N Engl J Med 2008;358:

42 Relative Risk of the Primary Outcome and of the Main Secondary Outcome The ONTARGET Investigators. N Engl J Med 2008;358:

43 Discontinuation of Study Medications and Selected Reasons for Permanent Discontinuation The ONTARGET Investigators. N Engl J Med 2008;358:

44 Relative Risks in Prespecified Subgroups The ONTARGET Investigators. N Engl J Med 2008;358:

45 The ONTARGET Investigators. N Engl J Med 2008;358: Secondary and Other Outcomes

46 Study Overview This large trial compared the angiotensin-receptor blocker Telmisartan, the angiotensin-converting-enzyme inhibitor Ramipril, and combination therapy with both drugs in patients with vascular disease or high-risk diabetes Outcomes were the same with Telmisartan and Ramipril, and there were more adverse events with combination therapy

47 Conclusion Telmisartan was equivalent to Ramipril in patients with vascular disease or high-risk diabetes and was associated with less angioedema Th bi i f h d i d i h The combination of the two drugs was associated with more adverse events without an increase in benefit

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54 Used combined endpoints Most had normal renal function and no proteinuria Many were normotensive Hypotension and acute dialysis Inadequately powered to answer the question in patients with CKD and proteinuria

55 Combined therapy to be reserved for patients refractory to single agent therapy who have CKD, HTN and proteinuria Close monitoring for adverse effects

57 Number of uninsured has risen to 50 million Most uninsured (90%) are low (<$22,500) and moderate income families (below 400% poverty)($88,500/ family of 4) 80% of uninsured are US citizens

58 No health insurance leads to poorer outcomes no preventative care or follow up for chronic disease Medical bills translate to debt. Uninsured pay 35% of care out-of-pocket Debt leads to the inability to afford basic necessities

59 77% of uninsured come from working families (61% full time) Cost of employee plan ($13,770) )plus increased share (30%) makes it unaffordable Medicaid enrollment is up and has filled the gap Federal restrictions prevent Medicaid and CHIP for legal immigrants who have been in US for < 5 years

60 Health expenditure per capita varies widely across OECD countries. The United States spends almost two-and-a-half times the OECD average Health expenditure is for the insured population rather than resident population. 2. Current health expenditure. Source: OECD Health Data 2009, OECD (

61 Higher health spending per capita is generally associated with higher life expectancy 2007 (or latest year available) Source: OECD Health Data 2009, OECD (

62 Expand coverage to cover 94% of US citizens Regulate insurance companies behaviors Make healthcare decrease deficit (decrease costs)(spending <<< expanded coverage) Improve patient outcomes with a flexible Improve patient outcomes with a flexible preemptive program of proven therapies

63 Coverage for all with a salary of <133% poverty Subsidies for families of 4 < 400% poverty (88K) Company of > 50 employees must provide Company of > 50 employees must provide insurance (tax credits)

64 Dependents to age 26 Health insurance exchanges and high risk pools Protection from being dropped or denied No lifetime limits

65 Dollars in billions 1000 Impact on deficit: $143 $32 $ Cost of coverage $277 expansion: 600 $ Excise tax on high-premium insurance plans Surtax on investment income for wealthy Other revenue Education system savings System improvements and savings $ $511 0 Affordable Care Act of 2010 Note: Totals do not reflect net impact on deficit because of rounding. Source: Congressional Budget Office, Letter to the Honorable Nancy Pelosi, Mar. 20, 2010.

66 1. More patients with insurance 2. Use EHR and make more money 3. Primary care increased Medicaid and Medicare reimbursement for 2 5 years 4. Surgeons in shortage areas 5. Physician owned hospitals

67 1. Increased Medicare tax on incomes > $250,00 and passive income 2. Cheaper health insurance and grants/tax breaks for you and your employees 3. Standardized insurance claims 4. Preventative services for your patients 5. Independent Payment Advisory Board

68 1. Trial programs: Accountable care organizations Bundled care Malpractice reform Medical home 2. Comparative effectiveness research

69 1. Information and Incentives 2. No substitute for SGR?? 3. Removing barriers to quality care 4. Public disclosures 5. Donald Berwick MD head of CMS

70 Unused residency slots can be shifted to primary care on state by state basis MEDPAC looking at direct and indirect Medicare payments to teaching hospitals Indirect payments (>direct) are thought to be excessive and it is proposed that some of these payments will be outcomes based. Teaching the competencies

71 Patient Care Medical Knowledge Practice-Based Learning and Improvement Interpersonal and Communication Skills Professionalism Systems-Based Practice Application to medical education and continuing medical education

72 Match Summary for 24,378 Residents in the National Resident Matching Program, Proportion of all residents in match 16-18% Iglehart JK. N Engl J Med 2010;363: