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Faculty/Presenter Disclosure Faculty: Dr. Donna Birbrager Relationships with commercial interests: – Speakers Bureau/Honoraria: Merck, Astra-Zeneca, Eli.

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Presentation on theme: "Faculty/Presenter Disclosure Faculty: Dr. Donna Birbrager Relationships with commercial interests: – Speakers Bureau/Honoraria: Merck, Astra-Zeneca, Eli."— Presentation transcript:

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 CFPC CoI Templates: Slide 1

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

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

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5 Overview and Objectives 1. What constitutes a true renal emergency? 2. Management of gout in CKD 3. Appreciate that we often over treat BP in CKD.  Review the 2012 CHEP guidelines for HT targets in Non DM CKD 4. Review the results of ESA in CKD and review the 2012 KDIGO Anemia Guidelines in CKD 5. 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  Fam Hx: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 = 96ACR > 100, UA bland 24 H Urine 8 g/d TG = 4.0, HDL = 2.1 LDL = 5.1, TC = 7.0  PMH:Nil, Pipe smoker  Fam Hx: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 = 96ACR > 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  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? 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  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. 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”

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18 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:

19 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  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: Zhang W. et al. Ann Rheum Dis. 2006; 65:

20 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 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: Kim SY. et al. Arth Care & Res. 2010; 62: 170–180. Krishnan E. et al. Arch Intern Med. 2008;168: Kou D-F.et al. Rheumatology 2010;49:141–146.

21 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  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:

22 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: eGFR 50+ mL/min: 0.6 mg BID eGFR mL/min: 0.6 mg once daily eGFR mL/min: 0.6 mg every 2 days eGFR <15 mL/min: not recommended  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: eGFR 50+ mL/min: 0.6 mg BID eGFR mL/min: 0.6 mg once daily eGFR mL/min: 0.6 mg every 2 days eGFR <15 mL/min: not recommended

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

24 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  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

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26 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  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

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28 Chronic ULT Management options in 2014  DIET  MEDICATIONS:  Allopurinol  Febuxostat  Uricosuric  Probenecid, Losartan, High Dose ASA  DIET  MEDICATIONS:  Allopurinol  Febuxostat  Uricosuric  Probenecid, Losartan, High Dose ASA

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30 Chronic Gout Management Benefits of Serum Urate < 360 µmol/L 1. Shoji A. et al. Arthritis Rheum. 2004;51: Perez-Ruiz F. et al. Arthritis Rheum. 2002;47: Mean Serum Urate, µmol/L Percentage of Patients With Gout Flare Recurrence Reduction in Acute Flares in Years 2 and 3 of Treatment Serum Urate, mg/dL Tophus Reduction, mm/month Allopurinol (n = 24)Benzbromarone (n = 25) Combined (n = 14) Tophus Size Reduction 2 N = 267

31 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  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

32 Allopurinol  Half-life of allopurinol and oxypurinol are prolonged in renal failure  Reduce the starting allopurinol dose  eGFR < 60 allopurinol 200 OD  eGFR < 30 allopurinol 100 OD  eGFR < 15 consider discontinuing  Half-life of allopurinol and oxypurinol are prolonged in renal failure  Reduce the starting allopurinol dose  eGFR < 60 allopurinol 200 OD  eGFR < 30 allopurinol 100 OD  eGFR < 15 consider discontinuing

33 Chronic Gout Management Febuxostat  Non-purine analog that selectively inhibits xanthine oxidase to reduce uric acid production 1  Rapidly and well absorbed with no accumulation  Extensive hepatic metabolism  Renal excretion  No dose adjustments needed in people with decreased renal function  Non-purine analog that selectively inhibits xanthine oxidase to reduce uric acid production 1  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 Pacher P. et al. Pharmacol Rev. 2006;58: Emmerson BT. N Engl J Med. 1996;334:

34 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  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

35 Chronic Gout Management Febuxostat  Non-purine analog that selectively inhibits xanthine oxidase to reduce uric acid production 1  Rapidly and well absorbed with no accumulation  Extensive hepatic metabolism  Renal excretion  No dose adjustments needed in people with decreased renal function  Non-purine analog that selectively inhibits xanthine oxidase to reduce uric acid production 1  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 Pacher P. et al. Pharmacol Rev. 2006;58: Emmerson BT. N Engl J Med. 1996;334:

36 Acute Flare Goal -> Resolve rapidly to suppress pain and inflammation Acute Flare Goal -> Resolve rapidly to suppress pain and inflammation NSAID (including coxibs) ± PPI or Colchicine or Corticosteroid (i.a., oral, i.m., i.v.) Other options: Centrally acting analgesic, opioids NSAID (including coxibs) ± PPI or Colchicine or Corticosteroid (i.a., oral, i.m., i.v.) Other options: Centrally acting analgesic, opioids Treat as soon as possible Review at weeks Assess lifestyle factors Check serum urate, Check blood pressure, Renal function & Glucose in all patients Review at weeks Assess lifestyle factors Check serum urate, Check blood pressure, Renal function & Glucose in all patients Further attacks (or risk factors +++) Treat acute attack Consider Serum Urate Lowering Therapy when acute attack resolved if: 1.>2 acute attacks per year or 2. 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 Further attacks (or risk factors +++) Treat acute attack Consider Serum Urate Lowering Therapy when acute attack resolved if: 1.>2 acute attacks per year or 2. 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 Resolution All patients Optimize weight Increase exercise Modify diet Reduce alcohol intake Maintain fluid intake Treat underlying cardiovascular risk factors All patients Optimize weight Increase exercise Modify diet Reduce alcohol intake Maintain fluid intake Treat underlying cardiovascular risk factors Acute Gout Management Pathway 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:

37 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 If CrCl mL/min Start ALLOPURINOL ( 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 Check renal function Anti-inflammatory prophylaxis for up to 6 months Check sUA regularly Maintain sUA lowering therapy to achieve and maintain sUA <360 μmol/L Acute attack resolved Chronic Gout Management Pathway

38 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??

39 X. Treatment of Hypertension in Patients with Non Diabetic Chronic Kidney Disease Chronic kidney disease and proteinuria * ACEI/ARB: Bilateral renal artery stenosis ACEI or ARB Combination with other agents Additive therapy: Thiazide diuretic. Alternate: If volume overload: loop diuretic Target BP: < 140/90 mmHg * 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

40 XI. Treatment of Hypertension in Patients with Renovascular Disease 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. Does not imply specific treatment choice Renovascular disease Caution in the use of ACEI or ARB in bilateral renal artery stenosis or unilateral disease with solitary kidney

41 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) x 2006: REMOVED recommendation – REIN-2. Target of 130/80 still supported based on AASK, MDRD The ups and downs of BP targets in CKD revisiting the AASK followup data: little support for lower targets except (maybe) for those with proteinuria…. Triggering revisiting of overall recommendation

42 Studies of BP targets in CKD patients Upadhyay, Ann Intern Med. 2011;154: MDRDAASKREIN-2 N Target BP~125/75 ~125/75 130/80 vs.~140/90vs.~140/90vs. x/90 1 o outcomechange in GFRcompositeESRD MortalityNDNDND CVD eventsNDNDx GFR declineNDNDND ESRDNDNDND

43 In 2012, CHEP revisited the CKD BP targets following publication of significant new data CHEP 2011 CHEP 2012 For patients with nondiabetic chronic kidney disease, target BP is <130/80 mm Hg (Grade C). For patients with nondiabetic chronic kidney disease, target blood pressure is <140/90 mm Hg (Grade B).

44 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?

45  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 3 RCTs Designed to Address Whether Anemia Correction in CKD May Improve CV Morbidity and Mortality

46 Conclusion The use of darbepoetin alfa 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

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

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49 Frequency of Anemia Testing in CKD CKD 3CKD 4-5NDCKD 5HD and 5PD CKD patients without anemia At least annually At least twice per year At least every 3 months CKD patients with anemia but not treated with an ESA At least every 3 months At least monthly in 5HD and at least every 3 months in 5PD Adults and children >15 years old Hemoglobin (g/l) Male<130 Female<120

50 Investigation of anemia in 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 B 12 and folate levels

51 Iron Studies Not Super Useful in CKD: Sensitivity and specificity of TSAT and serum ferritin (ferritin) and their combination (TSAT þ ferritin) and bone marrow iron (BM iron) to identify correctly a positive erythropoietic response (Z1- g/dl [Z10-g/l] increase in Hb [DHb]) to intravenous iron in 100 nondialysis patients with CKD (areas under the ROCs).

52 Iron Therapy in CKD Choice of FE Rx Patient Type Clinical Parameters Treatment Plan Adult CKD patients with anemia not on iron or ESA therapy - If an increase in HB concentration without ESA treatment is desired* and -TSAT is ≤30% and ferritin is ≤500µg/l We suggest a trial of IV iron or in CKD ND patients alternatively a 1-3 month trial of oral iron therapy (2C) Adult CKD patients on ESA therapy, not receiving iron supplementation - If an increase in HB concentration** or a decrease in ESA dose is desired*** and -TSAT is ≤30% and ferritin is ≤500µg/l We suggest a trial of IV iron or in CKD ND patients alternatively a 1-3 month trial of oral iron therapy (2C)  Select the route of iron administration based on: The severity of iron deficiency  Availability of venous access  Response to prior oral iron therapy  Side effects with prior oral or IV iron therapy  Patient compliance  Cost

53 We recommend using ESA therapy with great caution, if at all, in:  CKD patients with active malignancy, in particular when cure is the anticipated outcome (1B)  CKD patients with a history of stroke ( 1B)  CKD patients with a history of malignancy (2C)

54 ESA in CKD ND Hb < 100 Hb >100  We suggest that the decision whether to initiate ESA therapy be individualized based on (2C):  The rate of fall of Hb concentration  Prior response to iron therapy  The risk of needing a transfusion  The risks related to ESA therapy  The presence of symptoms attributable to anemia  We suggest that ESA therapy not be initiated (2D)

55 ESA in CKD 5D  We suggest that ESA therapy be used to avoid having the Hb concentration fall below 90 g/l by starting ESA therapy when the hemoglobin is between g/l (2B)  In general, we suggest that ESAs not be used to maintain Hb concentration above 11.5 g/dl (115 g/l) in adult patients with CKD. (2C)  In all adult patients, we recommend that ESAs not be used to intentionally increase the Hb concentration above 13 g/dl (130 g/l). (1A)

56 Case 5 Mr C.O.  Mr O. is a 48-year-old with hypertension, high chol  Medications include CCB, statin.  Presents to MD for flank pain NYD  US : Cysts +++  LAB: Cr 130 with eGFR = 52  No Family History  Referred to for ? PKD 56

57 Genetic Renal Cystic Disease Non-Genetic Renal Cystic Disease  ARPKD (Autosomal Recessive PKD)  ADPKD (Autosomal Dominant PKD)  Juvenile Nephronophthisis – Medullary CD  Juvenile Nephronophthisis (autosomal recessive)  Medullary Cystic Disease (autosomal dominant)  Congenital Nephrosis (autosomal recessive)  Familial Hypoplastic Glomerulocystic Disease (autosomal dominant)  Others – e.g. Cystic Fibrosis, VHL  Multicystic Dysplastic Kidney  Benign Multilocular Cyst (Cystic Nephroma)  Simple Cysts – Bosniak Classification  Medullary Sponge Kidney  Sporadic Glomerulocystic Kidney Disease  Acquired Renal Cystic Disease  Calyceal Diverticulum  Cystic Renal Cell Carcinoma

58 Genetic Renal Cystic Disease Non-Genetic Renal Cystic Disease  ARPKD (Autosomal Recessive PKD)  ADPKD (Autosomal Dominant PKD)  Juvenile Nephronophthisis – Medullary CD  Juvenile Nephronophthisis (autosomal recessive)  Medullary Cystic Disease (autosomal dominant)  Congenital Nephrosis (autosomal recessive)  Familial Hypoplastic Glomerulocystic Disease (autosomal dominant)  Others – e.g. Cystic Fibrosis, VHL  Multicystic Dysplastic Kidney  Benign Multilocular Cyst (Cystic Nephroma)  Simple Cysts – Bosniak Classification  Medullary Sponge Kidney  Sporadic Glomerulocystic Kidney Disease  Acquired Renal Cystic Disease  Calyceal Diverticulum  Cystic Renal Cell Carcinoma

59 Simple Cysts (or not) Observed frequently in normal kidneys. 65 to 70 percent of cases of “renal masses” Prevalence:  30 to 49 — 1.9; 1.4  50 to 69 — 15; 6.7  >70 — 32.3; 14.6 Signs/Symptoms: None. Rarely, rupture (hemorrhage), hematuria, pain, abdominal mass, infection, and/or hypertension. Imaging: Simple renal cysts have characteristic changes on US and CT DDx: polycystic kidney disease, complex cysts, and solid masses (such as a renal carcinoma or abscess). Treatment: The vast majority of simple cysts require no treatment. Therapy may rarely be required for symptoms, signs, and/or complications.

60 Adult Polycystic Kidney Disease  Autosomal dominant  1-2 per 1000  Cysts present at birth, progressively enlarge to compress renal parenchyma  Occurs at variable rate, more rapid in males  4 th Common cause of ESRD ~ 5- 10%

61 Genetics  Gene PKD1 on chromosome 16 (85%)  The protein, polycystin I, is a membrane glycoprotein involved in regulation of the cell cycle, the mutation leads to fluid secretion  Gene PKD2 on chromosome 4 (most of the rest), ESRF occurs 10-15yrs later

62 Symptoms  Age  Hypertension (+ cLVH)  Renin mediated  Microscopic/ Gross hematuria  Acute loin pain/colic and haematuria  due to haemorrhage into a cyst, infection or ureteric stone  Incidental finding of liver/kidney cysts on U/S  Abdominal discomfort  due to pressure  Berry aneurysm (~5 - 10%)  Chronic renal failure  once below 50ml/min, GFR declines by ~5ml/min/year

63 Associations  Cystic change on other organs  esp. liver, spleen, pancreas  Berry aneurysms leading to SAH  prompt Ix of sudden onset or severe headaches  Mitral valve prolapse  affects 20%

64 Screening  Patients should have regular BP checks  Offer genetic counseling  Family members should be offered:  screening for intracranial aneurysms (18-40yrs)  renal screening by US (>20yrs)

65 Imaging

66 ADPKD

67 ADPKD - Treatment  Role of genetic counseling  Role of hypertension management  ACEi, ARB  Risk of infection  co-trimoxazole, quinolones  Avoid nephrotoxins  Smoking  Calculi:  percutaneous removal, lithotripsy etc.  Management of pain:  medical vs surgical  Management of meganephrosis  CRF:  dialysis and transplant

68 Polycystin and ADPKD. BRAUN W E Cleveland Clinic Journal of Medicine 2009;76:97-104

69 The Role of Vasopressin 1. Increasing fluid intake to suppress plasma vasopressin levels (> 3L/Day) 2. vasopressin V2 receptor antagonists, which lower intracellular cAMP levels  Inhibit cystogenesis and prevent renal enlargement and dysfunction  Less Epithelial Cell proliferation  Less Fluid accumulation

70 Original Article Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease Vicente E. Torres, M.D., Ph.D., Arlene B. Chapman, M.D., Olivier Devuyst, M.D., Ph.D., Ron T. Gansevoort, M.D., Ph.D., Jared J. Grantham, M.D., Eiji Higashihara, M.D., Ph.D., Ronald D. Perrone, M.D., Holly B. Krasa, M.S., John Ouyang, Ph.D., Frank S. Czerwiec, M.D., Ph.D., for the TEMPO 3:4 Trial Investigators N Engl J Med Volume 367(25): December 20, 2012

71 Study Overview In this trial, patients with autosomal dominant polycystic kidney disease were randomly assigned to tolvaptan, a vasopressin V 2 - receptor antagonist, or placebo. Tolvaptan 60 to 120 mg (divided into 60 mg in the morning and 30 mg at night). Inclusion criteria included ages 18 to 50 years (mean of 40 years), estimated creatinine clearance >60 ml/min (mean 81 mL/min) and total kidney volume >750 mL (mean 1705 mL). Over 3 years, the increase in total kidney volume in the tolvaptan group was half that in the placebo group.

72 Most Common Adverse Events and Serious Adverse Events. Torres VE et al. N Engl J Med 2012;367:

73 Conclusions Tolvaptan, as compared with placebo, slowed the increase in total kidney volume and the decline in kidney function over a 3-year period in patients with ADPKD but was associated with a higher discontinuation rate, owing to adverse events.

74 Summary of Treatments:  Increased fluid intake — 3 L/Day to suppress plasma vasopressin levels  Tolvaptan (First thing with any clinical benefit)  Somatostatin - may reduce renal and liver cyst fluid accumulation among patients with PKD Other approaches being studied: Mammalian target of rapamycin (mTOR) — (e.g. sirolimus Protein restriction does not seem to work  Methylprednisolone, urinary alkalinization, taxol, lovastatin, epidermal growth factor receptor tyrosine kinase inhibitors, peroxisome proliferator-activated receptor agonists, cyclin-dependent kinase inhibitors, and mitogen-activated protein kinase inhibitors,

75 Summary 1. Renal Emergencies  recognize that Nephrotic Syndrome is a renal emergency  Review other renal emergencies briefly 2. Gout  Acute vs Chronic management  First do no harm, many medications need dose adjusting in CKD 3. BP targets in CKD:  Diabetes = 130/80  Non DM = 140/90 4. Anemia Guidelines  No need for expensive work-up  Treat if Hb < 100 and Sx or < 90  Iron therapy +/- ESA  Goals are mainly for QOL and to avoid transfusions 5. PKD  Treat BP, avoid toxins,drink lots, promising future


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