UPDATE IN NEPHROLOGYChristopher Valentine, MD

Division of Nephrology

Wexner Medical Center at The Ohio State University

October 26, 2012

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.

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

BIOMARKER FOR IDIOPATHIC MEMBRANOUS NEPHROPATHY

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 nephropathyNat. Rev. Nephrol. doi:10.1038/nrneph.2009.167

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.

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.

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.

HIGH PROTEIN DIET

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.

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 1200-1800 cal/day 55% CHO, 30% fat, 15% protein.

• Exclusion Criteria: diabetes mellitus, HTN, statin therapy.

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

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%

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.

LDL LOWERING IN CKD

SHARP (Study of Heart and Renal Protection)

• C Baigent et. al. Lancet 2011; 377: 2181-92.

• 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.

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.

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

SHARP• Exclusions: Known coronary heart disease.

• Adherence: 2/3 patients randomized to simvastatin/ezetimibe took it as prescribed.

SHARP - Results

Simvastatin/Ezetimibe n=4650

Placebon=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% 3.4% 0.12

CHD Death 2% 1.9% 0.95

Any major atherosclerotic event

11.3% 13.4% 0.0021

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 30-40 major atherosclerotic events/1000 patients/5 years.

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.

CONTRAST INDUCED NEPHROPATHY

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; 124:1250-59.

• Funded by Brazilian Ministry of Health.

ACT• Previous studies of NAC for CIN have given inconsistent

results, and current guidelines disagree.

• Median study size has been 80 patients.

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

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.

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.

INTERDIALYTIC INTERVAL

Interdialytic Interval and Mortality• Long Interdialytic Interval and Mortality among Patients

Receiving Hemodialysis.

RN Foley et.al. NEJM 2011; 365:1099-107.

USRDS and University of Minnesota

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.

Interdialytic Interval• Baseline Characteristics

• Average age 62

• Median 2.5 years on dialysis

• 45% female• 36% Black• 14% Hispanic

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%

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

Interdialytic Interval• More hospitalizations after the 2 day interval for :

• MI• CHF• Stroke• Dysrhythmia

Interdialytic Interval• No cost data collected

• What is the cost to Medicare of these hospitalizations compared to the cost of more frequent dialysis?

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

UPDATES IN HYPERTENSION

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

JNC VIII• Will tell us:

• When to initiate drug therapy

• How low to go

• Which classes of drugs to use

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.

Thiazides

• ALLHAT : JAMA December 18, 2002.• 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%

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

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.

Bedtime Medication for HTN• MAPEC:Hermida RC et al, Chronobiol Int. 2010 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.

Bedtime Medication for HTN• Non Dipping is predominant in:

• Elderly• Diabetics• Resistant HTN• Secondary HTN

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.

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.

MAPEC ResultsAM Medication Bedtime

MedicationP value

Clinic SBP 144 142 NS

Clinic DBP 81 81 NS

48hr mean SBP 122 121 NS

48hr mean DBP 72 72 NS

Asleep mean SBP 116 111 < 0.001

Asleep mean DBP 65 63 < 0.001

Sleep time relative SBP decline

7% 11% < 0.001

Sleep time relative DBP decline

12% 17% < 0.001

MAPEC ResultsAll Meds AM Bedtime

MedicationP value

Non Dipping 62% 34% < 0.001

CVD events N=187 N=68 <0.001

CV Death/MI/Stroke

N=55 N=18 <0.001

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.

RENAL DENERVATION

Resistant Hypertension

1. Calhoun DA, et al. Circulation. 2008;117;e510-e526.2. Makris A, et al. Int J Hypertens. 2011;doi: 10.4061/2011/598694.3. Papademetriou V, et al. Int J Hypertens. 2011;doi:10.4061/2011/196518.

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

However, a majority of patients with

resistant hypertension and

no identifiable secondary causes have an activated

sympathetic nervous system and

increased sympathetic

outflow3

Secondary Causes of Hypertension1,2

Obstructive sleep apnea

Primary aldosteronism

Renal artery stenosis

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;54:1195-1201.

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;54:1195-1201.

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

Data on file. Medtronic, Inc.

• Standard interventional technique• 4-6 120-second treatments per artery

Renal Nerve Anatomy Allows a Catheter-Based Approach

57

Symplicity Staged Evaluation in Hypertension and Beyond

First-in-Man1

Symplicity HTN-12

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

Series of Pilot Studies

Symplicity HTN-23 EU/AU Randomized Clinical Trial

Sources:1. Krum H, et al. Lancet. 2009;373:1275-1281.2. Symplicity HTN-1 Investigators. Hypertension. 2011;57:911-917.

3. Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909.4. Data on file, Medtronic.

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;376:1903-1909.

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

*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;376:1903-1909.

Change in Office Blood Pressure6-mo post

randomization12- mo post

randomization

6-mo post-RDNCrossover Pts*

6-mo post-RDN*

12-mo post-RDN*

-24

-8-10

6-mo Controls†

-12

+7 0

BP

ch

ang

e(m

mH

g)

P=0.15Esler, 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, 2012. Chicago, IL

-32-35

-30

-25

-20

-15

-10

-5

0

5

10

RDN SBP

RDN DBP

Cross over SBPCross over DBP

-28

P=0.16

*P<0.001 for BP Change post RDN †P=0.026 for SBP change from baseline

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.

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 18-80 years • Enrolling now

• christopher.valentine@osumc.edu• 614-293-4997

Source: Data on file, Medtronic.

NEW NAME FOR WEGENER’S GRANULOMATOSIS

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.

A NEW DRUG Rituximab for ANCA associated vasculitis and lupus nephritis

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).

RAVE Trial• Rituxan vs. Cytoxan/Azathioprine for ANCA associated

vasculitis. • JH Stone et al. NEJM 2010. 363 (3): 221-232

RTX CTX/AZA

Remission 64% 53% RTX non inferior

Response in relapsing disease

67% 42% P < 0.01

RAVE Trial• Conclusion: RTX is as effective as cyclophosphamide in

inducing remission of ANCA associated vasculitis and may be more effective in relapsing disease.

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. 1215-1226.