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UPDATE IN NEPHROLOGY Christopher Valentine, MD Division of Nephrology Wexner Medical Center at The Ohio State University October 26, 2012.

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Presentation on theme: "UPDATE IN NEPHROLOGY Christopher Valentine, MD Division of Nephrology Wexner Medical Center at The Ohio State University October 26, 2012."— Presentation transcript:

1 UPDATE IN NEPHROLOGY Christopher Valentine, MD Division of Nephrology Wexner Medical Center at The Ohio State University October 26, 2012

2 Disclosure I am the Site Co-PI for Symplicity HTN – 3, a clinical trial of renal denervation to treat resistant hypertension sponsored by Medtronic Ardian LLC, Mountain View, CA.

3 Outline New Biomarker for Idiopathic Membranous Nephropathy New data regarding high protein diet and the kidneys Lowering LDL in CKD (SHARP Study) Prevention of contrast induced nephropathy (ACT Trial) Long Interdialytic Interval and Mortality Hypertension updates New name for Wegeners granulomatosis New drug - Rituximab

4 BIOMARKER FOR IDIOPATHIC MEMBRANOUS NEPHROPATHY

5 Figure 1 Schematic view of an M type secretory phospholipase A2 receptor expressed on the surface of a podocyte Rees, A. and Kain, R. (2009) A watershed in the understanding of membranous nephropathy Nat. Rev. Nephrol. doi: /nrneph

6 Anti PhosphoLipaseA2 Receptor antibody Membranous nephropathy is relatively common - accounts for up to one third of biopsy diagnoses of nephrotic syndrome in non diabetic adults. Most cases are the idiopathic form rather than secondary to hepatitis B, autoimmune disease, malignancy, captopril, NSAIDS.

7 APLA2R antibody Beck LH et al. NEJM 2009; 361: 11. M type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. PLA2R is a transmembrane receptor in glomerular podocytes. 26/37 or 70% of patients with idiopathic MN had circulating auto Ab to PLA2R. Circulating auto Ab were associated with disease activity. The auto Ab was not seen in healthy controls, secondary MN, or other proteinuric diseases.

8 APLA2 R Antibody A specific receptor on the surface of the podocyte has been identified as an antigen in membranous nephropathy. We should soon have a clinically available lab test that may allow for non invasive diagnosis of this disease as well as monitoring response to treatment.

9 HIGH PROTEIN DIET

10 High Protein Diet Comparative Effects of Low- Carbohydrate High-Protein vs. Low-Fat Diets on the Kidney. AN Friedman et. al. CJASN July Low carbohydrate high protein diets are popular and effective for weight loss, but little is known about adverse renal effects. Concerns with high protein diet include increased GFR, increased proteinuria, acid-base or electrolyte disorders.

11 High Protein Diet Design: 307 obese adults were randomized to LCHP or low fat diet for 24 months. LCHP diet from Dr. Atkins New Diet Revolution (2002). Low fat diet was cal/day 55% CHO, 30% fat, 15% protein. Exclusion Criteria: diabetes mellitus, HTN, statin therapy.

12 High Protein Diet Baseline Characteristics Age 45 68% women 75% white, 22% black Weight 104 kg (229 lb) and BMI 36 Serum Cr 0.8 to 0.9 mg/dl

13 High Protein Diet Results: changes at 24 months. No obvious renal toxicity. LCHPLow Fat Weight- 6.6 kg- 7.8 kg Serum Cr+ 0.1%- 1.6% Urine volume+ 228 ml/day- 40 ml/day Cr Clearance+ 3.7 ml/min- 3.5 ml/min Urine albumin- 21%-24%

14 High Protein Diet Conclusion: In healthy obese individuals, a LCHP weight loss diet over two years was not associated with noticeably harmful effects on GFR, albuminuria, or fluid/electrolyte balance compared with a low fat diet.

15 LDL LOWERING IN CKD

16 SHARP (Study of Heart and Renal Protection) C Baigent et. al. Lancet 2011; 377: The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with CKD: a randomized placebo-controlled trial patients and median follow up 4.9 years were dialysis patients. Simvastatin/ezetimibe vs. placebo.

17 SHARP Background: LDL lowering with statins reduces risk of MI, ischemic stroke, and need for coronary revascularization in people without kidney disease, but effects in moderate to severe CKD are unclear. To avoid risk of myopathy a low dose (20mg) of simvastatin was combined with ezetimibe 10 mg daily.

18 SHARP Baseline Characteristics 63% men 72% white Average age 62 33% on dialysis, remainder had average GFR of 26ml/min BP 139/79 23% diabetic BMI 27 Total cholesterol 189 LDL 107

19 SHARP Exclusions: Known coronary heart disease. Adherence: 2/3 patients randomized to simvastatin/ezetimibe took it as prescribed.

20 SHARP - Results Simvastatin/Ezetimibe n=4650 Placebo n=4620 P value Change in LDL at months -32 mg/dl-3 mg/dl Ischemic Stroke2.5%3.4% Coronary revascularization 3.2%4.4% Non fatal MI2.9%3.4%0.12 CHD Death2%1.9%0.95 Any major atherosclerotic event 11.3%13.4%0.0021

21 SHARP Conclusion: Lowering LDL with simvastatin plus ezetimibe safely reduces risk of ischemic stroke and coronary revascularization in patients with CKD. Full compliance is predicted to reduce risk of events by 25% and prevent major atherosclerotic events/1000 patients/5 years.

22 SHARP Why does this differ from 4D and AURORA which showed no significant benefit for hemodialysis patients? Much smaller numbers of patients and of modifiable vascular events in earlier studies. Over 50% of the primary outcomes in 4D and AURORA were vascular deaths, which were not prevented by treatment in SHARP. 75% of the primary outcomes in SHARP were non fatal atherosclerotic events for which there is benefit.

23 CONTRAST INDUCED NEPHROPATHY

24 Acetylcysteine for Prevention of Contrast Induced Nephropathy? Acetylcysteine for Prevention of Renal Outcomes in Patients Undergoing Coronary and Peripheral Vascular Angiography. (Acetylcysteine for Contrast induced nephropathy Trial). Circulation 2011; 124: Funded by Brazilian Ministry of Health.

25 ACT Previous studies of NAC for CIN have given inconsistent results, and current guidelines disagree. Median study size has been 80 patients.

26 ACT ACT randomized 2308 patients undergoing angiography to acetylcysteine 1200mg bid for 4 doses vs. placebo. At least one risk factor for CIN: Age >70 Cr > 1.5 DM CHF or EF < 45% Hypotension

27 ACT Exclusions: Dialysis, STEMI Interventions: 98 % received IV 0.9% saline 1 ml/kg/hr for 6 hrs pre and 6 hrs post angiography for both groups. 75% received low osmolarity contrast. 50% received > 100ml contrast.

28 ACT Primary endpoint was 25% elevation in Cr at 48-96hrs. Primary endpoint occurred in 12.7% of both groups. In the largest trial to date Acetylcysteine does not reduce the risk of CIN for at risk patients undergoing coronary and peripheral vascular angiography.

29 INTERDIALYTIC INTERVAL

30 Interdialytic Interval and Mortality Long Interdialytic Interval and Mortality among Patients Receiving Hemodialysis. RN Foley et.al. NEJM 2011; 365: USRDS and University of Minnesota

31 Interdialytic Interval Dialysis patients have a high prevalence of cardiovascular disease and limited tolerance of volume and metabolic deviation from normal. Hypothesis is that a long interdialytic interval is associated with adverse events. Schedules are Mon/Wed/Fri or Tue/Thr/Sat Retrospective data for 32,065 U.S. hemodialysis patients.

32 Interdialytic Interval Baseline Characteristics Average age 62 Median 2.5 years on dialysis 45% female 36% Black 14% Hispanic

33 Interdialytic Interval Baseline Characteristics 44% had Diabetes as cause ESRD 44% AVF, 27% AVG, 21% catheter for access Median predialysis weight 77kg Median interdialytic weight gain 3.6%

34 Interdialytic Interval Over 2.2 years, 41% of patients died. Events more common after the 2 day interval: Death of any cause Cardiac death Infectious death Cardiac arrest Myocardial infarction All P values highly significant

35 Interdialytic Interval More hospitalizations after the 2 day interval for : MI CHF Stroke Dysrhythmia

36 Interdialytic Interval No cost data collected What is the cost to Medicare of these hospitalizations compared to the cost of more frequent dialysis?

37 Interdialytic Interval Longer interval is associated with deaths, MI, CHF, arrhythmias, strokes. Potential Solutions: Dialysis literally every other day instead of M/W/F or T/R/S? Reduce missed or shortened treatments Peritoneal dialysis Home hemodialysis 5-6 days a week Renal Transplant

38 UPDATES IN HYPERTENSION

39 JNC VIII JNC VII published 2003 JNC VIII committee has been meeting since 2008 Planning to issue guidelines based on high quality evidence Screening thousands of articles from 1966 to present Coming Soon

40 JNC VIII Will tell us: When to initiate drug therapy How low to go Which classes of drugs to use

41 Thiazides HCTZ 47.8 million prescriptions in th most prescribed drug in the US Half life of 5-14 hours Half life of chlorthalidone is 40 hrs.

42 Thiazides ALLHAT : JAMA December 18, Chlorthalidone was superior to amlodipine and lisinopril for control of SBP. Chlorthalidone was superior to lisinopril for the outcomes of stroke and heart failure. SHEP: JAMA June 26, In patients age 60 and above chlorthalidone reduced incidence of stroke by 36%

43 Thiazides Based on potency, duration of action, and clinical trial results – use chlorthalidone. Chlorthalidone doses > 12.5 mg daily have minimal to no additional impact on blood pressure, but increase probability of adverse effects including: Hypokalemia Hyponatremia Hyperglycemia Hyperuricemia Dizziness

44 Thiazides After starting a thiazide, check lytes/BUN/CR in 10 days. Na and K balance change over the first 7-10 days but then equilibrium is established.

45 Bedtime Medication for HTN MAPEC:Hermida RC et al, Chronobiol Int Sep. Ambulatory monitoring of BP and CV events ABPM correlates better with target organ damage and CV events than office BP. Most people have a morning increase in BP and lowering with nocturnal rest. Normal dipping is at least 10% lower than awake BP. Some people are non-dippers or even risers at night. Most HTN patients take all of their medications in the AM.

46 Bedtime Medication for HTN Non Dipping is predominant in: Elderly Diabetics Resistant HTN Secondary HTN

47 Bedtime Medication for HTN MAPEC Study First prospective evaluation of bedtime treatment for BP patients randomized and followed for 5.6 years. Randomized to all meds on awakening or at least one medication at bedtime. 48hr ABPM done at baseline and then annually.

48 Bedtime Medication for HTN MAPEC Methods: Single center in Spain. HTN defined as ABPM awake mean > 135/85 or asleep mean > 120/70. Mean age 55. Office BP 155/88 at baseline. 55% AM group and 53% Bedtime group were Non Dippers at baseline. Accepted first line drugs were ARB, ACEI, amlodipine or nifedipine, beta blocker, torsemide.

49 MAPEC Results AM MedicationBedtime Medication P value Clinic SBP144142NS Clinic DBP81 NS 48hr mean SBP122121NS 48hr mean DBP72 NS Asleep mean SBP116111< Asleep mean DBP6563< Sleep time relative SBP decline 7%11%< Sleep time relative DBP decline 12% 17% < 0.001

50 MAPEC Results All Meds AMBedtime Medication P value Non Dipping62%34%< CVD eventsN=187N=68<0.001 CV Death/MI/Stroke N=55N=18<0.001

51 MAPEC Interpretation Taking 1 or more HTN medications at bedtime: Cost effectively improves BP control Decreases prevalence of non-dipping Strongly associated with lower CVD risk Asleep BP and nocturnal dipping should be therapeutic targets, as they were the most significant predictors of event-free survival.

52 RENAL DENERVATION

53 Resistant Hypertension 1.Calhoun DA, et al. Circulation. 2008;117;e510-e Makris A, et al. Int J Hypertens. 2011;doi: /2011/ Papademetriou V, et al. Int J Hypertens. 2011;doi: /2011/ Causes of Pseudoresistant Hypertension 1,2 Suboptimal dosing of antihypertensive agents White coat effect Suboptimal BP measurement technique Physician inertia Lifestyle factors Medications that interfere with BP control Pseudoresistance caused by poor adherence to prescribed medication However, a majority of patients with resistant hypertension and no identifiable secondary causes have an activated sympathetic nervous system and increased sympathetic outflow 3 Secondary Causes of Hypertension 1,2 Obstructive sleep apnea Primary aldosteronism Renal artery stenosis

54 Afferent Renal Sympathetics The kidney is a source of central sympathetic activity, sending signals to the CNS Efferent Sympathetics Sympathetic signals from the CNS modulate the physiology of the kidneys Renal Nerves and the SNS Adapted from Schlaich MP, et al. Hypertension. 2009;54: Mandatory

55 Renal Denervation Blood Pressure Neurohormones Disrupt the renal nerves, break the cycle Simultaneously reduce both efferent & afferent effects Adapted from Schlaich MP, et al. Hypertension. 2009;54:

56 Targeting Renal Nerves Vessel Lumen Media Adventitia Renal Nerves Nerves arise from T10-L2 The nerves arborize around the artery and primarily lie within the adventitia Mandatory Data on file. Medtronic, Inc.

57 Standard interventional technique second treatments per artery Renal Nerve Anatomy Allows a Catheter-Based Approach 57 Mandatory

58 Symplicity Staged Evaluation in Hypertension and Beyond First-in-Man 1 Symplicity HTN-1 2 USA SYMPLICITY HTN-3 4 US Randomized Clinical Trial (enrolling) Approved Geographies Other Areas of Research: 4 Global SYMPLICITY Registry, Insulin Resistance, HF, Sleep Apnea, More Series of Pilot Studies Symplicity HTN-2 3 EU/AU Randomized Clinical Trial Sources: 1. Krum H, et al. Lancet. 2009;373: Symplicity HTN-1 Investigators. Hypertension. 2011;57: Symplicity HTN-2 Investigators. Lancet. 2010;376: Data on file, Medtronic. Mandatory

59 Symplicity HTN-2 Trial: Overview Design Multicenter (24 sites in Europe, Australia, and New Zealand), prospective, randomized, controlled study Population 106 patients with treatment-resistant hypertension Treatment Intervention group (endovascular catheter-based RDN with the Symplicity ® Renal Denervation System plus baseline antihypertensive medications) Control group (baseline antihypertensive medications alone) Duration 6 months (for the primary endpoint) with follow-up to 3 years Outcome Measures Primary endpoint: between-group changes in average office SBP from baseline to 6 months Secondary endpoints: acute and chronic procedural safety, a composite cardiovascular endpoint, occurrence of 10 mm Hg SBP reductions, achievement of target SBP, change in 24-hour ambulatory BP, and change in home BP Symplicity HTN-2 Investigators. Lancet. 2010;376: Mandatory

60 Symplicity HTN-2 Trial: Key Inclusion/Exclusion Criteria * Inclusion Criteria years of age Elevated office SBP 160 mm Hg (or 150 mm Hg for type 2 diabetics) Documented compliance with 3 antihypertensive medications Exclusion Criteria eGFR <45 mL/min/1.73m 2 Type 1 diabetes mellitus Contraindications to MRI Substantial stenotic valvular heart disease Pregnancy or planned pregnancy during the study Myocardial infarction, unstable angina, or cerebrovascular accident in previous 6 mo Hemodynamically or anatomically significant renal artery abnormalities or prior renal artery intervention * Inclusion/exclusion criteria in the trial settings were stringent and conservative in order to ensure a homogenous population – in clinical practice, individual patient characteristics and physician judgment should guide patient selection. Symplicity HTN-2 Investigators. Lancet. 2010;376: Mandatory

61 Change in Office Blood Pressure 6-mo post randomization 12- mo post randomization 6-mo post-RDN Crossover Pts* 6-mo post-RDN* 12-mo post-RDN* mo Controls BP change (mmHg) P=0.15 Esler, M. Renal Sympathetic Denervation for Treatment of Resistant Hypertension: One-Year Results from the Symplicity HTN-2 Randomized Controlled Trial. Presented at: ACC st Annual Scientific Session & Expo; March 25, Chicago, IL RDN SBP RDN DBP Cross over SBP Cross over DBP -28 P=0.16 *P<0.001 for BPChange post RDN P=0.026 for SBP change from baseline Mandatory

62 SYMPLICITY HTN-3: Overview Design Multicenter (90 sites in the United States), prospective, randomized, blinded, controlled study Population 530 patients with treatment-resistant hypertension Treatment Treatment group (endovascular catheter-based RDN with the Symplicity ® Renal Denervation System plus baseline antihypertensive medications) Control group (sham procedure * plus baseline antihypertensive medications) Primary Outcome Measures Change in office SBP from baseline to 6 months Safety * The renal angiogram also acts as the sham procedure for patients in the control group. Data on file, Medtronic. Mandatory

63 SYMPLICITY HTN-3 Trial: Inclusion Criteria Average SBP 160mmHg (measured per guidelines) On stable medication regimen of full tolerated doses of 3 or more antihypertensive meds, with one being a diuretic No changes for a minimum of 2 weeks prior to screening No planned medication changes for 6 months Age years Enrolling now Source: Data on file, Medtronic. Mandatory

64 NEW NAME FOR WEGENERS GRANULOMATOSIS

65 Granulomatosis with Poly Angiitis (Wegeners) 1937 Dr Friedrich Wegener in Berlin described the disease term Wegeners granulomatosis introduced he died at age disease name changed to Granulomatosis with polyangiitis due to his WWII affiliation. Falk R et al, Ann Rheum Dis 2011; 70:704.

66 A NEW DRUG Rituximab for ANCA associated vasculitis and lupus nephritis

67 Rituximab Monoclonal antibody to CD20 on B cells approved for non-Hodgkins B-cell lymphoma. Potent immunosuppressant for RA. Now approved for ANCA associated vasculitis: Churg – Strauss/MPA/GPA (Wegeners Granulomatosis).

68 RAVE Trial Rituxan vs. Cytoxan/Azathioprine for ANCA associated vasculitis. JH Stone et al. NEJM (3): RTXCTX/AZA Remission64%53%RTX non inferior Response in relapsing disease 67%42%P < 0.01

69 RAVE Trial Conclusion: RTX is as effective as cyclophosphamide in inducing remission of ANCA associated vasculitis and may be more effective in relapsing disease.

70 Rituxan for Lupus nephritis: LUNAR Trial. 144 patients with active proliferative LN. RTX + MMF + steroids vs. placebo + MMF + steroids. Response 57% in RTX arm vs. 46% in standard therapy, which is not statistically significant. Trend to better response with RTX in African Americans and Hispanics. Consider Rituxan in certain ethnic groups, relapsing disease, intolerance to other therapies. BH Rovin et al. Arthritis Rheum, 64 (4) 2012, pp


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