Transcript Update in Nephrology - American College of Physicians

UPDATE IN
NEPHROLOGY
Christopher 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 nephropathy
Nat. 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
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%
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 Results
AM Medication
Bedtime
Medication
P 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 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
<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
Causes of Pseudoresistant
Hypertension1,2
Secondary Causes of
Hypertension1,2
Suboptimal dosing of antihypertensive
agents
Obstructive sleep apnea
White coat effect
Primary aldosteronism
Suboptimal BP
measurement technique
Renal artery stenosis
Physician inertia
Lifestyle factors
Medications that interfere with BP
control
Pseudoresistance caused
by poor adherence to prescribed
medication
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.
However, a majority
of patients with
resistant
hypertension and
no identifiable
secondary causes
have an activated
sympathetic
nervous system and
increased
sympathetic
outflow3
Renal Nerves and the SNS
Efferent Sympathetics
Afferent Renal Sympathetics
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;54:1195-1201.
Renal Denervation
 Neurohormones
Disrupt the renal nerves,
break the cycle
Adapted from Schlaich MP, et al. Hypertension. 2009;54:1195-1201.
 Blood Pressure
Simultaneously reduce both
efferent & afferent effects
Targeting Renal Nerves
• Nerves arise from T10-L2
• The nerves arborize around the artery
and primarily lie within the adventitia
Vessel
Lumen
Media
Adventitia
Renal
Nerves
Data on file. Medtronic, Inc.
Renal Nerve Anatomy Allows a Catheter-Based
Approach
• Standard interventional technique
• 4-6 120-second treatments per artery
57
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
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;373:1275-1281.
3. Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909.
2. Symplicity HTN-1 Investigators. Hypertension. 2011;57:911-917. 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
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.
*Inclusion/exclusion
Change in Office Blood Pressure
12- mo post
randomization
6-mo post
randomization
10
6-mo
post-RDN*
6-mo
Controls†
12-mo
post-RDN*
6-mo post-RDN
Crossover Pts*
BP change
(mmHg)
5
+7
0
0
-5
RDN SBP
-10
-15
-8
-10
-12
-20
RDN DBP
Cross over SBP
Cross over DBP
-25
-28
-30
-35 -32
P=0.16
-24
*P<0.001 for
BP Change post RDN
†P=0.026 for
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, 2012. Chicago, IL
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
• [email protected]
• 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.