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 Wegener’s granulomatosis
New drug - Rituximab

4. Biomarker for Idiopathic Membranous Nephropathy

5. Nat. Rev. Nephrol. doi:10.1038/nrneph.2009.167
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 2012.
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.
LCHP
Low 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.
9270 patients and median follow up 4.9 years.
3023 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
44-49 months
-32 mg/dl
-3 mg/dl
Ischemic Stroke
2.5%
3.4%
0.0073
Coronary revascularization
3.2%
4.4%
0.0027
Non fatal MI
2.9%
0.12
CHD Death 2%
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 2010
10th 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, 2002. SHEP: JAMA June 26, 1991.
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, 1991.
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.
2156 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 17% AM Medication Bedtime Medication P value Clinic SBP
144
142 NS
Clinic DBP 81
48hr mean SBP
122
121
48hr mean DBP 72
Asleep mean SBP
116
111
< 0.001
Asleep mean DBP 65 63
Sleep time relative SBP decline 7%
11%
Sleep time relative DBP decline
12%
17%

50. MAPEC Results All Meds AM Bedtime Medication P value Non Dipping 62%
34%
< 0.001
CVD events
N=187
N=68
<0.001
CV Death/MI/Stroke
N=55
N=18

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
Causes of Pseudoresistant Hypertension1,2
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
Secondary Causes of Hypertension1,2
Obstructive sleep apnea
Primary aldosteronism
Renal artery stenosis
However, a majority of patients with resistant hypertension and
no identifiable secondary causes have an activated sympathetic nervous system and increased sympathetic outflow3
Purpose:
To provide an overview of resistant hypertension and its potential causes; what to look for in the diagnosis of resistant hypertension.
Key Points:
The etiology of resistant hypertension is multifactorial1,2
Several factors associated with pseudoresistance can be identified and corrected, including poor adherence prescribed medication, suboptimal dosing of antihypertensive agents, white coat effect, suboptimal BP measurement technique, and physician inertia
Other factors associated with resistant hypertension that can be modified or minimized include lifestyle factors (obesity, dietary salt, heavy alcohol intake), and medications that interfere with BP control
Secondary causes can be identified and addressed
The majority of patients with resistant hypertension and no identifiable secondary causes have an activated sympathetic nervous system and increased sympathetic outflow3
Clinical data shows that older age, obesity, aldosterone excess, and obstructive sleep apnea are correlated with increased sympathetic nervous system activity via multiple mechanisms4
Although the mechanisms that link these conditions to resistant hypertension are not clearly defined, sympathetic nervous system hyperactivity appears to play a crucial role in the pathophysiology of treatment resistance4
Sources:
Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Circulation. 2008;117:e510-e526.
Makris A, Seferou M, Papadopoulos DP. Resistant hypertension workup and approach to treatment. Int J Hypertens. 2011;doi: /2011/
Papademetriou V, Doumas M, Tsioufis K. Renal sympathetic denervation for the treatment of difficult- to-control or resistant hypertension. Int J Hypertens. 2011;doi: /2011/
Tsioufis C, Kordalis A, Flessas D, et al. Pathophysiology of resistant hypertension: the role of sympathetic nervous system. Int J Hypertens. 2011;doi: /2011/
Calhoun DA, et al. Circulation. 2008;117;e510-e526.
Makris A, et al. Int J Hypertens. 2011;doi: /2011/
Papademetriou V, et al. Int J Hypertens. 2011;doi: /2011/ 53

54. Renal Nerves and the SNS
Mandatory
Efferent Sympathetics
Afferent Renal Sympathetics
Purpose:
To explain sympathetic afferent and efferent signaling between the kidneys and the CNS.
Key Points:
Efferent signals from the CNS, specifically the hypothalamus, control physiology of the viscera. In the case of the kidneys, these signals promote the renin system and sodium retention, while inhibiting RBF and GFR
These components are stimulated in disease states characterized by SNS hyperactivation and contribute to increased BP in hypertension
Pharmacologic strategies to inhibit the effects of renal SNS activity include:
Beta-blockers (to reduce renin release)
Angiotensin-converting enzyme inhibitors (ACEIs) and receptor blockers (ARBs) (to block the actions of angiotensin II and aldosterone which lead to renin release)
Diuretics (to counter the renal sympathetic-mediated water and sodium retention)
Efferent nerves terminate in blood vessels, the juxtaglomerular apparatus, and renal tubules
Renal sensory afferent nerves relay sensory information back to the CNS, and directly affect sympathetic outflow to the kidneys and other organs, such as the heart and peripheral vasculature
Source:
Schlaich MP, Sobotka PA, Krum H, et al. Renal denervation as a therapeutic approach for hypertension: novel implications for an old concept. Hypertension. 2009;54:
Sympathetic signals from the CNS modulate the physiology of the kidneys
The kidney is a source of central sympathetic activity, sending signals to the CNS
Adapted from Schlaich MP, et al. Hypertension. 2009;54: 54

55. Renal Denervation  Neurohormones  Blood Pressure
Purpose:
To illustrate the scientific concept behind use of RDN.
Key Points:
Hyperactivation of the SNS leads to increased BP through cyclic signaling between the CNS and kidneys
RDN provides an opportunity to disrupt the renal nerves, breaking the cycle and simultaneously reducing both efferent and afferent effects
Source:
Schlaich MP, Sobotka PA, Krum H, et al. Renal denervation as a therapeutic approach for hypertension: novel implications for an old concept. Hypertension. 2009;54:
Disrupt the renal nerves,
break the cycle
Simultaneously reduce both efferent & afferent effects
Adapted from Schlaich MP, et al. Hypertension. 2009;54: 55

56. Targeting Renal Nerves
Mandatory
Nerves arise from T10-L2
The nerves arborize around the artery and primarily lie within the adventitia
Vessel
Lumen
Media
Purpose:
To review the location and anatomy of the renal nerves.1
Key Points:
This slide shows the primary location of the renal nerves within the adventitia1
The renal nerves arise from spinal levels T10-L22
The renal nerves expand around the artery and are primarily found within the adventitia or the outer layer1
Sources:
Data on file. Medtronic, Inc.
Doumas M, Faselis C, Papademetriou V. Renal sympathetic denervation and systemic hypertension. Am J Cardiol. 2010;105:
Adventitia
Renal Nerves
Data on file. Medtronic, Inc. 56

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

58. Symplicity Staged Evaluation in Hypertension and Beyond
Mandatory
Symplicity Staged Evaluation in Hypertension and Beyond
First-in-Man1 
Symplicity HTN-12
Series of Pilot Studies 
Symplicity HTN-23 
EU/AU Randomized Clinical Trial
Purpose:
To provide a brief overview of Symplicity® Renal Denervation System™ clinical trials.
Key Points:
Symplicity HTN-1 and Symplicity HTN-2 assessed the safety and efficacy of catheter-based RDN in patients with treatment-resistant hypertension1-3
SYMPLICITY HTN-3 is a US-based randomized, double-blind, controlled trial commencing this year to further explore the safety and efficacy of RDN4
A global registry is currently being planned4
In addition to hypertension, other conditions of sympathetic excess are being explored4
Sources:
Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet ;373(9671):
Symplicity HTN-1 Investigators; Krum H, Barman N, Schlaich M, et al. Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months. Hypertension. 2011;57(5):
Symplicity HTN-2 Investigators; Esler MD, Krum H, Sobotka PA, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet. 2010;376(9756):
Data on file, Medtronic.
USA
SYMPLICITY HTN-34
US Randomized Clinical Trial
(enrolling)
Approved Geographies
Other Areas of Research:4
Global SYMPLICITY Registry,
Insulin Resistance, HF,
Sleep Apnea, More
Sources:
1. Krum H, et al. Lancet. 2009;373:
2. Symplicity HTN-1 Investigators. Hypertension. 2011;57:
3. Symplicity HTN-2 Investigators. Lancet. 2010;376:
4. Data on file, Medtronic. 58

59. Symplicity HTN-2 Trial: Overview
Mandatory
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
Purpose:
To present top-line information regarding the design, enrollment, treatment and outcomes pertinent to the Symplicity HTN-2 trial.
Key Points:
The Symplicity HTN-2 trial was a 6-month, multicenter, randomized, controlled study of 106 patients with treatment-resistant hypertension who were randomized between June 9, 2009 and January 15, 20101
The 24 sites were located in Europe, Australia, and New Zealand1
This trial established the efficacy and safety profile of RDN in the comparative context of a control group1
Of the 106 patients, 52 were randomized to RDN plus baseline antihypertensive medications and 54 were randomized to continue baseline antihypertensive medications alone1
For those assigned to the intervention group, RDN was performed as described in the Symplicity HTN-1 trial2
The primary endpoint of the Symplicity HTN-2 trial was between-group changes in office SBP at 6 months1
Secondary endpoints focused on short- and long-term safety, as well as additional measurements of BP reduction1
Symplicity HTN-2 Investigators. Lancet. 2010;376: 59

60. Symplicity HTN-2 Trial: Key Inclusion/Exclusion Criteria*
Mandatory
Symplicity HTN-2 Trial: Key Inclusion/Exclusion Criteria*
Inclusion Criteria
18-85 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/1.73m2
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
Purpose:
To detail the key inclusion and exclusion criteria for participation in the Symplicity HTN-2 trial.
Key Points:
Patients, between the ages of 18 and 85, were required to display clear treatment-resistant hypertension, as evidenced by an elevated SBP despite documented compliance with at least 3 antihypertensive drugs
Patients were excluded from participation if they had an eGFR value <45 mL/min/1.73m2; type 1 diabetes; any contraindications to MRI (performed in the clinical trial setting in order to assess left ventricular mass); substantial stenotic valvular heart disease; a history of myocardial infarction, unstable angina, or cerebrovascular accident in the previous 6 months; hemodynamically or anatomically significant renal artery abnormalities, or prior renal artery intervention; or were pregnant or planned on becoming pregnant
Additional Information:
Anatomically significant renal artery abnormalities included multiple main renal arteries, or short length (<20 mm in length) or width (<4 mm in diameter) of main renal artery
Such abnormalities triggered exclusion because adequate blood flow is required for proper cooling of the catheter tip
Patients with impaired renal function were excluded as exposure to radiographic agents used during renal angiography would risk worsening of preexisting renal disease. Similarly, patients with diabetes mellitus 1 were excluded as they are at higher risk for contrast-induced decreases in renal function
Source:
Symplicity HTN-2 Investigators; Esler MD, Krum H, Sobotka PA, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet. 2010;376:
*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: 60

61. Change in Office Blood Pressure
Mandatory
6-mo post
randomization
12- mo post
randomization
6-mo
post-RDN*
6-mo
Controls†
12-mo
post-RDN*
6-mo post-RDN
Crossover Pts* 10 5 +7
BP change
(mmHg) -5
RDN SBP
-10
RDN DBP -8
-10
-15
Cross over SBP
-12
Cross over DBP
-20
-25
*P<0.001 for - 28
-30
-24 BP
Change post RDN
†P=0.026 for
-35
-32
P=0.16
SBP change from baseline
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.12 61st Annual Scientific Session & Expo; March 25, Chicago, IL

62. SYMPLICITY HTN-3: Overview
Mandatory
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
Purpose:
To present top-line information regarding the design, enrollment, and treatment pertinent to the upcoming SYMPLICITY HTN-3 trial.
Key Points:
The SYMPLICITY HTN-3 trial is a US-based, randomized, controlled, trial to further evaluate the safety and efficacy of RDN in patients with treatment-resistant hypertension1
Will utilize 60 sites across the United States1
Patient enrollment is expected to start in 2011 and will run for months1
To increase the scientific rigor, eligible patients will be randomized to a RDN arm or a control (sham procedure) arm in a blinded fashion1
This is in contrast to the Symplicity HTN-2 trial, where control patients simply continued with their antihypertensive medications, but did not undergo a sham procedure2
Randomization will occur “on the table” after renal angiogram confirms eligible anatomy1
The primary efficacy endpoint will assess office SBP changes over 6 months1
Additional Information:
Patients will undergo 2 screening phases (to assess BP and antihypertensive medication regimen compliance), a renal angiogram (to confirm eligible anatomy), and, lastly, randomization1
The renal angiogram also acts as the sham procedure for patients in the control arm1
Sources:
Data on file, Medtronic.
Symplicity HTN-2 Investigators; Esler MD, Krum H, Sobotka PA, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet. 2010;376: .
*The renal angiogram also acts as the sham procedure for patients in the control group.
Data on file, Medtronic. 62

63. SYMPLICITY HTN-3 Trial: Inclusion Criteria
Mandatory
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
MANDATORY
Purpose:
To detail the key inclusion and exclusion criteria for participation in the SYMPLICITY HTN-3 trial.
Key Points:
In general, inclusion and exclusion criteria are very similar to those defined in the Symplicity HTN-1 and Symplicity HTN-2 trials
Patients, between 18 and 80 years of age, must display clear treatment-resistant hypertension, as evidenced by an elevated SBP despite compliant treatment with at least antihypertensive drugs
1 of these antihypertensive medications must be a diuretic
Planned medications changes over a 6-month period are prohibited
Office SBP is based on an average of 3 BP readings measured at both an initial screening visit and a confirmatory screening visit
Patients are excluded from participation if they have renal artery anatomy that is ineligible for treatment, ambulatory BP monitoring 24-hour average SBP <135 mm Hg, impaired kidney function (eGFR <45 mL/min/1.73m2), >1 inpatient hospitalization for a hypertensive crisis within the past year, type I diabetes, or are pregnant, nursing, or planning on becoming pregnant
Source:
Data on file, Medtronic.
Source: Data on file, Medtronic. 63

64. New name for wegener’s granulomatosis

65. Granulomatosis with Poly Angiitis (Wegener’s)
1937 Dr Friedrich Wegener in Berlin described the disease.
1954 term Wegener’s granulomatosis introduced.
1990 he died at age 83.
2011 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.
1997 approved for non-Hodgkins B-cell lymphoma.
Potent immunosuppressant for RA.
Now approved for ANCA associated vasculitis: Churg –Strauss/MPA/GPA (Wegener’s Granulomatosis).

68. RAVE Trial
Rituxan vs. Cytoxan/Azathioprine for ANCA associated vasculitis.
JH Stone et al. NEJM (3):
RTX
CTX/AZA
Remission
64%
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