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Faculty/Presenter Disclosure

CFPC CoI Templates: Slide 1. Faculty/Presenter Disclosure. Faculty: Dr. Donna Birbrager Relationships with commercial interests: Speakers Bureau/Honoraria: Merck, Astra-Zeneca, Eli Lilly, Boehringer-Ingelheim , Impres Pharma Consulting Fees: Takeda, Otsuka.

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Faculty/Presenter Disclosure

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  1. CFPC CoI Templates: Slide 1 Faculty/Presenter Disclosure • Faculty: Dr. Donna Birbrager • Relationships with commercial interests: • Speakers Bureau/Honoraria: Merck, Astra-Zeneca, Eli Lilly, • Boehringer-Ingelheim, ImpresPharma • Consulting Fees: Takeda, Otsuka

  2. CFPC CoI Templates: Slide 2 Disclosure of Commercial Support • I have no industry-related financial conflicts of interest to declare

  3. CFPC CoI Templates: Slide 3 Mitigating Potential Bias No particular drugs are being discussed in this program content

  4. CLINICAL PEARLS: CASE BASED EXAMPLES OF IMPORTANT ISSUES NEPHROLOGY 2014 Donna Birbrager MD, FRCPC Nephrologist, Lakeridge Health May 14, 2014

  5. Overview and Objectives • What constitutes a true renal emergency? • Management of gout in CKD • Appreciate that we often over treat BP in CKD. • Review the 2012 CHEP guidelines for HT targets in Non DM CKD • Review the results of ESA in CKD and review the 2012 KDIGO Anemia Guidelines in CKD • Review the role of Tolvaptan in PKD. • Review the results of the Tempo 3:4 trial

  6. Case 1: Mr. C.K. 57 y.o. • PMH: Nil, Pipe smoker • FamHx: Dad died 69 of MI • MEDS: None • HPI: 2 weeks of increased SOA Facial edema in AM Feels weak and unwell • O/E: BP 110/74, 92 kg JVP low, 3+ edema Chest clear, dull bases Nil else • Lab: Cr = 86 eGFR = 96 ACR > 100, UA bland 24 H Urine 8 g/d TG = 4.0, HDL = 2.1 LDL = 5.1, TC = 7.0

  7. Case 1 : Edema Low Albumin Proteinuria > 3g High Cholesterol (Lipiduria) Dx: Nephrotic Syndrome This is a renal emergency!!!

  8. What Are Renal Emergencies / Urgencies? • Urgent: • Sudden rise in Cr > 25% • New Dx of CKD 5 (or high risk CKD 4) • Accelerated HT • Hyperkalemia • Nephrotic Syndrome • Systemic illness with hematuria and proteinuria with rising Cr (need to r/o RPGN) • Immediate: (Go to ER) • HT Emergency / Malignant HT • ARF/AKI • Hyperkalemia > 7

  9. Case 2 : Mr. G.C. 54 y.o. Teacher PMH: Obesity, T2DM, CKD 2, HT, OA, Gout x 4 years – no Rx, exsmoker, nil else Last seen 3 months ago routine: • BP 120/76 • A1C = 6.1, Lipids Optimal, UA 522 • Cr 110, eGFR = 49, No change x 4 ys • ACR = 2.1 Meds: Ramipril 10, Atorvastatin 10, Metformin 500 BID, ASA 81 Seen in ER after recent syncope episode: • ECG: Sine wave arrhythmia  emergent management • Cr = 490, K+ = 7.6 • Treated by ER doc, ``shift therapy`` Question: • What are you thinking here?

  10. Hyperkalemia EKG

  11. Case Further Hx: • 1 week ago – Gout Flare right forefoot • Seen at W.I.C • Rx: Indocid 50 BID and colchicine • Developed diarrhea followed by Nx and Vx last few days • Continued to take ACEi during this period • DISCUSSION/Outcomes

  12. “SICK DAY” MEDICATION ADVICE: Dear Patient: If you become acutely ill, especially if you have diarrhea or vomiting, the following types of medication should be held until you are better. These drugs are good at protecting the kidney and the heart as well as for blood pressure control, but paradoxically they can be harmful if you are dehydrated. ACE-inhibitors -Ramipril (Altace) -Fosinopril (Monopril) -Enalapril (Vasotec) -Perindopril (Coversyl) -Lisinopril (Zestril) -Cilazapril (Inhibace) -Trandolopril (Mavik) Angiotensin Receptor Blockers -Telmisartan (Micardis) -Candesartan (Atacand) -Olmesartan (Olmetec) -Valsartan (Diovan) -Losartan (Cozaar) -Irbesartan (Avapro) -Eposartan (Teveten) Direct Renin Inhibitors -Aliskerin (Rasilez) Diuretics (“Water Pills”) -Furosemide (Lasix) -Indapamide (Lozide) -Hydrochlorothiazide (HCTZ) -Chlorthalidone -Spironolactone (Aldactone) You can restart your medications again as soon as you feel better. If your illness requires holding these medications for over a week, contact your MD.

  13. “The Gout”

  14. Pathophysiology of Gout: Acute Flares Common Sites • Frequency: • Big toe 76% • Ankle/foot 50% • Knee 32% • Finger 25% • Elbow/wrist 10% • >1 site simult.11% Mandell BF. Cleve Clin J Med. 2008;75:S5-S8. Gibson T. In Rheumatology. 4th ed. Mosby Elsevier limited 2008:1829-1837

  15. sUA Levels as a Diagnostic Marker • sUA levels may be normal ~50% of the time during a flare • Normal sUA at the time of a flare does not rule out a gout diagnosis!!! • Measure sUA after a flare resolved(may take up to 2 weeks) • Laboratories often report hyperuricemia based on population norms Urano W. et al. J Rheumatol. 2002; 29:1950-3. Zhang W. et al. Ann Rheum Dis. 2006; 65:1301-11.

  16. Risk Factors and Associated Comorbidities Comorbidities • Hypertension • Cardiovascular disease • Chronic kidney disease • Diabetes mellitus • Dyslipidemia • Metabolic syndrome Lifestyle • Obesity (high BMI) • Diet rich in meat and seafood • High alcohol intake • Frequent consumption of high-fructose corn syrup Medications • Thiazide diuretics • Low-dose aspirin • Cyclosporine • Nicotinic acid • Levodopa Demographic Factors • Advanced age • Male • Postmenopause in women Link between gout and higher risk of death from all causes including CVD Choi HK, et al. Ann Intern Med. 2005;143:499-5161. Kim SY. et al. Arth Care & Res. 2010; 62: 170–180. Krishnan E. et al.Arch Intern Med. 2008;168:1104-1110. Kou D-F.et al. Rheumatology 2010;49:141–146.

  17. Resolve the Acute Flare Rapidly • Rapidly initiate a sufficient dose of anti-inflammatory therapy • NSAIDs • Colchicine • Corticosteroids (IA/PO/IV/IM) • Consider drug limitations due to comorbidities • Evaluate NSAIDS gastropathy risk • Remember: anti-inflammatory agents do not treat the underlying cause of the disease Zhang W. et al. Ann Rheum Dis 2006;65:1312-1324.

  18. Colchicine • Effective but limited by adverse effects (nausea, vomiting, diarrhea) • Clearance of colchicine is reduced in patients with CKD, increasing the risk of neuromyopathy and bone marrow supporssion • Acute flare in CKD: • Usual dose is 0.6 mg TID for 6 doses • Reduce to 0.6 mg daily in CKD 3-5 • Prophylaxis: eGFR50+ mL/min: 0.6 mg BID eGFR 30-50 mL/min: 0.6 mg once daily eGFR 15-30 mL/min: 0.6 mg every 2 days eGFR <15 mL/min: not recommended

  19. Gout Flares during Urate Lowering Therapy Effect of Concomitant Anti-Inflammatory Prophylaxis *P = 0.022 vs. Colchicine; †P = 0.033 vs. Colchicine; ULT = urate-lowering therapy; BID = twice daily Borstad GC. et al. J Rheumatol. 2004;31:2429-2432.

  20. Indomethacin/NSAIDs • Renal impairment: NSAID use may compromise existing renal function • Patients with impaired renal function, especially those taking diuretics, and ACE-i/ARB/DRI, are at greater risk of renal toxicity. • Hyperkalemia

  21. Prednisone • Prednisone 30 to 50 mg daily for 3-5, no taper needed but may rebound – so for severe attacks may taper over 10 to 14 days • Usually add colchicine to prevent rebound • More potent than NSAIDs

  22. Chronic ULT Management options in 2014 • DIET • MEDICATIONS: • Allopurinol • Febuxostat • Uricosuric • Probenecid, Losartan, High Dose ASA

  23. Tophus Size Reduction2 Allopurinol (n = 24) Benzbromarone (n = 25) Combined (n = 14) 8 6 Serum Urate, mg/dL 4 2 0 0 0.5 1 1.5 2 2.5 Tophus Reduction, mm/month Chronic Gout ManagementBenefits of Serum Urate < 360 µmol/L Reduction in Acute Flaresin Years 2 and 3 of Treatment1 100 N = 267 80 Percentage of Patients With Gout Flare Recurrence 60 40 20 0 540 300 330 360 390 420 450 480 570 600 510 1. Shoji A. et al. Arthritis Rheum. 2004;51:321-325. 2. Perez-Ruiz F. et al. Arthritis Rheum. 2002;47:356-360. Mean Serum Urate, µmol/L

  24. Allopurinol • Initiation during an acute attack can theoretically worsen the arthritis, although the absolute risk is not clear • Considerable interpatient variation in the daily dose required to achieve control of the serum urate concentration

  25. Allopurinol • Half-life of allopurinol and oxypurinol are prolonged in renal failure • Reduce the starting allopurinoldose • eGFR < 60 allopurinol 200 OD • eGFR < 30 allopurinol 100 OD • eGFR < 15 consider discontinuing

  26. Chronic Gout ManagementFebuxostat • Non-purine analog that selectively inhibits xanthine oxidase to reduce uric acid production1 • Rapidly and well absorbed with no accumulation • Extensive hepatic metabolism • Renal excretion • No dose adjustments needed in people with decreased renal function 1. Allopurinol Prescribing Information, Watson Pharmaceuticals, Inc., Corona, CA. 2006. 2. Pacher P. et al. Pharmacol Rev. 2006;58:87-114. 3. Emmerson BT. N Engl J Med. 1996;334:445-451.

  27. Febuxostat Efficacy Conclusions • 80 mg effectively lowers and maintain sUA <360 µmol/L • 80 mg superior to allopurinol 300mg • 80 mg is effective in subjects with renal impairment without dose adjustment • Maintenance of sUA <360 µmol/L is critical to decreases in gout flares and tophi resolution

  28. Chronic Gout ManagementFebuxostat • Non-purine analog that selectively inhibits xanthine oxidase to reduce uric acid production1 • Rapidly and well absorbed with no accumulation • Extensive hepatic metabolism • Renal excretion • No dose adjustments needed in people with decreased renal function 1. Allopurinol Prescribing Information, Watson Pharmaceuticals, Inc., Corona, CA. 2006. 2. Pacher P. et al. Pharmacol Rev. 2006;58:87-114. 3. Emmerson BT. N Engl J Med. 1996;334:445-451.

  29. Acute Gout Management Pathway Acute Flare Goal -> Resolve rapidly to suppress pain and inflammation Treat as soon as possible NSAID (including coxibs) ± PPI or Colchicine or Corticosteroid (i.a., oral, i.m., i.v.) Other options: Centrally acting analgesic, opioids Review at 4 - 6 weeks Assess lifestyle factors Check serum urate, Check blood pressure, Renal function & Glucose in all patients Resolution • Further attacks (or risk factors +++) • Treat acute attack • Consider Serum Urate Lowering Therapy when acute attack resolved if: • >2 acute attacks per year or • any of the following: • Tophi, • sUA >360 μmol/L, • combined gout and urolithiasis, • severe or difficult to treat acute attacks of gout, • chronic persistent gouty arthritis • All patients • Optimize weight • Increase exercise • Modify diet • Reduce alcohol intake • Maintain fluid intake • Treat underlying cardiovascular risk factors Adapted from Jordan KM, Cameron JS, Snaith M, Zhang W, Doherty M, Seckl J et al. British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of gout. Rheumatology (Oxford) 2007;46:1372-4.

  30. Chronic Gout Management Pathway Acute attack resolved • Frequent gout attacks (>2 per year) or any of the following: • Tophi (detected clinically or by imaging) • Uric acid overproduction (sUA >360 μmol/L • Combined gout and urolithiasis • Severe or difficult to treat acute attacks of gout • Chronic persistent gouty arthritis Check renal function If CrCl 30-100 mL/min Start ALLOPURINOL (100-250 mg QD) or Start FEBUXOSTAT (80 mg QD*) *No dose adjustments need for reduced renal function If CrCl >100 mL/min Start ALLOPURINOL (300 mg QD^) or Start FEBUXOSTAT (80 mg QD) or if CrCl >60 ml/min start PROBENECID (1-3 g BID or TID) ^Upward dose titration may be needed to achieve target Anti-inflammatory prophylaxis for up to 6 months Check sUA regularly Maintain sUA lowering therapy to achieve and maintain sUA <360 μmol/L

  31. Case 3: Mr. S.S. 66 y.o. retired salesman History of: Hypercholesterolemia Erectile dysfunction Osteoarthritis Hypertension CKD / HT Meds: Atorvastatin 20 ASA 81mg • BP 152/89 mmHg • Cr = 129, eGFR = 52 • ACR = 31 mg/mmol WHAT IS THE TARGET BP??

  32. X. Treatment of Hypertension in Patients with Non Diabetic Chronic Kidney Disease Target BP: < 140/90 mmHg Chronic kidney disease and proteinuria * ACEI or ARB Additive therapy: Thiazide diuretic. Alternate: If volume overload: loop diuretic Combination with other agents ACEI/ARB: Bilateral renal artery stenosis * albumin:creatinine ratio [ACR] > 30 mg/mmol or urinary protein > 500 mg/24hr Monitor serum potassium and creatinine carefully in patients with CKD prescribed an ACEI or ARB Combinations of a ACEI and a ARB are specifically not recommended in the absence of proteinuria

  33. XI. Treatment of Hypertension in Patients with Renovascular Disease Does not imply specific treatment choice Close follow-up and intervention (angioplasty and stenting or surgery) should be considered for patients with: uncontrolled hypertension despite therapy with three or more drugs, or deteriorating renal function, or bilateral atherosclerotic renal artery lesions (or tight atherosclerotic stenosis in a single kidney), or recurrent episodes of flash pulmonary edema. Renovascular disease Caution in the use of ACEI or ARB in bilateral renal artery stenosis or unilateral disease with solitary kidney

  34. The ups and downs of BP targets in CKD • 1999: ADDED new recommendation lowering BP targets in CKD– MDRD • For patients with proteinuria that is greater than 1 g/day, target blood pressure is lower than 125/75 mm Hg (MAP 92) (GRADE C) • 2006: REMOVED recommendation – REIN-2. Target of 130/80 still supported based on AASK, MDRD 2010- revisiting the AASK followup data: little support for lower targets except (maybe) for those with proteinuria…. Triggering revisiting of overall recommendation

  35. Studies of BP targets in CKD patients Upadhyay , Ann Intern Med. 2011;154:541-548 MDRD AASK REIN-2 N 840 1094 334 Target BP ~125/75 ~125/75 130/80 vs.~140/90 vs.~140/90 vs. x/90 1o outcome change in GFR composite ESRD Mortality ND ND ND CVD events ND ND x GFR decline ND ND ND ESRD ND ND ND

  36. In 2012, CHEP revisited the CKD BP targets following publication of significant new data

  37. Case 4: Ms R.O. • Mr R.O. is a 51-year-old with CKD 3b due to Diabetes • eGFR =35 ml/min • Medications include ACEi,CCB, HCZ,statin. Insulin • Presents to MD for physical and flu shot • Bloodwork: • Cr = 152 eGFR = 35, ACR = 22 mg/mmol • K = 4.8, Lipids optimal • A1c = 6.9% • Hb = 104 What work up does the anemia require? What treatment is indicated?

  38. 3 RCTs Designed to Address Whether Anemia Correction in CKD May Improve CV Morbidity and Mortality • CREATE (Cardiovascular risk Reduction by Early Anemia Treatment with Epoetin beta) - Completed • Determine the impact of early vs late anemia correction on mortality and cardiovascular morbidity in patients with CKD • CHOIR (Correction of Hemoglobin and Outcomes In Renal insufficiency) – Terminated Early • Determine the impact of degree of anemia correction on mortality and cardiovascular morbidity in patients with CKD • TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) - Enrolling • Determine the impact of anemia therapy (yes/no) on mortality and cardiovascular morbidity in patients with CKD and type 2 diabetes

  39. Conclusion • The use of darbepoetinalfa in patients with diabetes, chronic kidney disease, and moderate anemia who were not undergoing dialysis did not reduce the risk of either of the two primary composite outcomes (either death or a cardiovascular event or death or a renal event) and was associated with an increased risk of stroke • For many persons involved in clinical decision making, this risk will outweigh the potential benefits

  40. Treatment of Anemia with Erythropoietin Stimulating Agents (ESAs): What We Know Dialysis CKD Improvements Hb Reduces Transfusion +/- Quality of Life +/- CV Outcomes no 3 RCTs

  41. Frequency of Anemia Testing in CKD

  42. Investigation of anemiain CKD • In patients with CKD and anemia ( regardless of age and CKD stage), include the following tests in initial evaluation of anemia: • Complete blood count ( CBC) including Hb concentration, red cell indices, WBC count and differential and platelet count • Absolute reticulocyte count • Serum ferritin level • Serum transferring saturation ( TSAT) • Serum vitamin B12 and folate levels

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