29/11/2017

1

Does this patient have ‘flash’

pulmonary oedema?

Philip A Kalra

Professor of Nephrology,

Salford Royal Hospital and University of Manchester, UK

Case 1

73 yr old lady; type 2 Diabetes 10 yrs; PVD; hypertension

Acute presentation with 3 day history of pulmonary oedema and anuria (April 2005)

Creatinine 712 mol/l (eGFR 3 ml/min), K 6.1 mmol/l

Needed urgent haemodialysis

Renal U/S : no obstruction, left K 10 cm

Suspected diagnosis : acute left RA occlusion

Serial Creatinine Measurements

0

200

400

600

800

1000

9.4

10.4

10.4

11.4

11.4

13.4

19.4

20.4

21.4 4.

512

.8

Date

Creatinine

Stented

Dialysed

Dialysed

Dialysed

mol/l

2005

British Society for Heart Failure Hypertension/renovascular disease Fibromuscular disease

(FMD) Fibromuscular disease (FMD)

Up to 10% of all renovascular disease

Greatest incidence in women (9:1) aged < 35 years (but also elderly – Pascual, AJKD 2005)

75% have renal involvement, bilateral in 35%; 3% have renal impairment

Associated with pathology in other arterial systems eg carotids (15%)

Familial clustering

Prevalence : data from angiography in kidney donors (3181 patients in 3 studies) – range 3.8%-6.6% (average 4.4% : Cragg et al. 1989; Neymark et al. 2000; Andreoni et al. 2002)

FMD : management

Clinical presentation usually :

hypertension (may be

‘accelerated’) + preserved

renal function

Lesions tend not to progress

over time

Hypertension ‘cure’ rate of

15-30% with angioplasty

(Slovut & Olin 2004), but no

RCT comparing medical

therapy

Angioplasty recommended for

– young

– FMD diagnosed soon after

hypertension onset

– malignant hypertension

– renal impairment

– bilateral disease

Other patients : renin angiotensin

blockade + low dose aspirin (Olin &

Sealove 2011; Plouin et al 2007)

Atherosclerotic renovascular disease

(ARVD) CVS co-morbidity and ARVD

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

CAD CCF PVD AAA CVA

% with RAS

Harding

JASN 1990 MacDowall

Lancet 1998

Choudri

BMJ 1990

Olin

AmJ Med

1990

Kuroda

Stroke 2000

29/11/2017

2

Other CKD

ARVD

Survival after

haemodialysis start

Other CKD

ARVD

Survival – non-dialysis CKD (eGFR 33 ml/min in both groups)

ARVD 2016 : prognosis

still very poor

Why would we consider renal

revascularization in ARVD?

Cardiac

‘Flash’ pulmonary

oedema

Improve ‘congestion’

(cardio-renal disease)

Pre-coronary or

carotid surgery

Blood pressure

Control of severe

hypertension

Renal

Acute kidney injury

Prevention of severe

RAS → RAO

‘Rapid’ deterioration

in renal function

Patients who need

RAA blockade but are

intolerant

Case 2 65 yr old lady with 3 episodes of acute pulmonary

oedema in 12 months

BP 220/88 on 3 agents

Echo – moderate to severe systolic dysfunction (EF 35%) and LVH

Claudication; right carotid stenosis but no history of IHD

↓GFR from 60 to 22 ml/min in 15 months

MRA bilateral 80-90% RAS; right kidney 9 cm, left 11cm

Changes in isoSK-GFR and

cardiac MR parameters

0

5

10

15

20

25

30

35

Left

GFR

Right

GFR

Pre

Post

Pre-

revasc

4

months

EF (%) 42 53

LVEDV

(ml)

200 106

LV mass

(g) 201 133

GFR

(ml/min)

Case 3 : 76 yrs old male

Bilateral 90% RAS – 2 x attempts at revascularization 5 yrs earlier by cardiologists in London

referred with deteriorating renal function

BP 127/53 on verapamil, candersartan, indapamide

Urine PCR 2 g/mol

USS kidneys : right 9.5cm, left 10 cm

creatinine eGFR

– 2 yrs earlier 147 46

– May 2011 203 31

– August 219 26

Case 3 : Renal revascularization August

2011

0

5

10

15

20

25

30

35

40

45

50

2009 Aug-11

eGFR

ml/min

Case 4

Male aged 53

Hypertension (175/90)

Serum creatinine 180mol/l

Kidney sizes : L 9.8cm;

R 11.3cm

Angiogram : L 80% RAS; R

normal

Randomised into ASTRAL :

Successful revascularization Case 4 : Follow-up

Feb 2001 290 mol/l

March 2001 369 mol/l

April 2001 535 mol/l

May 2001 997 mol/l

June 2001 commenced

dialysis

29/11/2017

3

Renal revascularization : RCTs in ARVD

Level 1 evidence now derived from the following RCTs in ARVD :

- EMMA study (49 patients) – Plouin et al, 1998

- DRASTIC (106) – Van Jaarsfeld et al, 2000

- Scottish and Newcastle (55) – Webster et al, 1998

- STAR (160) – Beutler et al, 2009

- ASTRAL (806) – N Eng J Med, 2009

- CORAL (947) – N Eng J Med, 2013

Many single and multi-centre prospective and retrospective studies showing benefit of revascularization in a proportion of patients

New England Journal of Medicine

2009; 361 : 1953-62

PATIENT CHARACTERISTICS BY

RANDOMISED TREATMENT

Revasc. Medical P-value

Mean age (range) 70 (42 – 86) 71 (43 – 88) 0.7

Male 63% 63% 0.9

Ex-smoker 52% 55% 0.3

Current smoker 20% 22% 0.5

Diabetes 31% 29% 0.5

CHD 49% 48% 0.2

PVD 41% 40% 0.7

Stroke 18% 19% 0.4

Dialysis 0% 0.3% 0.5

LABORATORY and BP DATA BY

RANDOMISED TREATMENT Revasc. Medical P-value

SCr (μmol/l)

88 μmol/l = 1 mg/dl

179

(66 – 551)

178

(64 – 750)

0.9

Rapid increase in SCr 12% 12% 0.9

GFR (ml/min) 40.3

(5.4 – 124.5)

39.8

(7.1 – 121.7)

0.7

Albumin:Creatinine ratio 70.2

(0 – 2740)

71.7

(0 – 2466)

0.9

Systolic BP (mm Hg) 149

(87 – 270)

152

(90 – 241)

0.07

Diastolic BP (mm Hg) 76

(45 – 120)

76

(46 – 130)

0.6

Cholesterol (mmol/l) 4.68

(0.1 – 14.8)

4.71

(1.9 – 9.6)

0.8

Change in Systolic

blood pressure

Change in renal function

Average RAS = 76%;

20% non-compliance with

revascularization

Macrovascular

events

Survival

A Randomized Multicenter

Clinical Trial of Renal Artery Stenting in

Preventing Cardiovascular and Renal Events:

Results of the CORAL Study

Christopher J. Cooper, M.D., Timothy P. Murphy, M.D., Donald E. Cutlip, M.D., Kenneth Jamerson, M.D.,

William Henrich, M.D., Diane M. Reid, M.D., David J. Cohen, M.D., M.Sc., Alan H. Matsumoto, M.D.,

Michael Steffes, M.D., Michael R. Jaff, D.O., Martin R. Prince, M.D., Ph.D., Eldrin F. Lewis, M.D.,

Katherine R. Tuttle, M.D., Joseph I. Shapiro, M.D., M.P.H., John H. Rundback, M.D.,

Joseph M. Massaro, Ph.D., Ralph B. D’Agostino, Sr., Ph.D., and Lance D. Dworkin, M.D.,

on behalf of the CORAL

Investigators

CORAL : Inclusion criteria and primary

outcome measure

INCLUSION CRITERIA Clinical Syndrome:

• Hypertension ≥2 anti-hypertensive

medications, OR

• Renal dysfunction defined as Stage 3

or greater CKD

-AND-

Atherosclerotic Renal Artery Stenosis:

• Angiographic: ≥ 60% and < 100%, OR

• Duplex: systolic velocity of >300

cm/sec, OR

• Core lab approved MRA, OR

• Core lab approved CTA

PRIMARY OUTCOME

• Composite of major

cardiovascular or renal events:

– Cardiovascular or Renal

Death

– Stroke

– Myocardial Infarction

– Heart Failure Hospitalization

– Progressive Renal

Insufficiency

– Permanent Renal

Replacement Therapy

29/11/2017

4

Medical therapy

Stent plus medical therapy

HR 0.94 [0.76-1.17], p = 0.58

Stent + Medical Therapy 35.1%, 3-years

Medical Therapy 35.8%, 3-years

Results: Primary Endpoint

Clinical Events US Medicare : Trends in

revascularization 1992-2010

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1992 1994 1996 1998 2000 2002 2010

RR

In 2004 approx 30,000 renal stent procedures performed annually in US

↓

ASTRAL published

What have we learned from the RCTs?

Revascularization does not

improve outcomes in majority

of unselected patients with

ARVD

These conclusions only apply

to the patient phenotype

included in the studies

Some patients do benefit

from revascularization – who

are they and can we reliably

identify them?

Don’t forget the benefits of

medical therapy

But at least no more ‘drive-by’

shootings!

Selection of cases for renal

revascularization Haemodynamically

significant RAS with:

– Recurrent unexplained

congestive heart failure (Class I, evidence level B)

– Resistant / malignant hypertension (Class IIa, evidence level B)

– Progressive CKD and bilateral RAS (Class Iia, evidence level B).

2005

Am J Kid Dis 2014; 63(2) : 186-97

Effect of renal revascularization in patients

with RAS > 70% :control versus high-risk* D Vassallo et al; BMC Nephrology (in Press)

Control

n=144; 43 PTRAS

(30%)

P value High-risk

n=131; 55 PTRAS

(43%)

P

value

Death 1.20 (0.61-2.38) 0.60 0.64 (0.33-1.26) 0.20

ESKD 1.00 (0.60-1.66) 1.00 0.64 (0.37-0.96) 0.03

CVE 1.06 (0.65-1.72) 0.82 0.66 (0.42-1.04) 0.07

Any

outcome

1.12 (0.69-1.82) 0.65 0.70 (0.45-1.09) 0.12

Flash pulmonary oedema : HR for death with PTRAS 0.38 (0.15-0.96; p=0.04)

Deteriorating renal function : HR for ESKD with PTRAS 0.44 (0.24-0.82; p=0.01)

*High risk = flash pulmonary edema, rapid deterioration in function or severe hypertension

Techniques to detect

responders to PTRAS

Pressure wire studies

Fractional flow reserve

(FFR)

Duplex ultrasound

MR perfusion imaging

– Volume : GFR

BOLD imaging

Pressure wire criteria

29/11/2017

5

MR perfusion imaging - Parenchymal Volume

(PV) : SK-GFR of stented kidneys

Number Mean PV : SK-GFR

SD Range

Deteriorated

(>15%

Deterioration

renal function)

5

4.86

1.1

3.7- 5.8

Stable (-15 to

15%)

18 6.38 2.5 3.6- 12.7

Improved

(>15%

Improvement

renal function)

7

17.49

15.2

6- 45.4

PV:isoSK-GFR characteristics in improvers (>15% improvement in isoSK-GFR) and non-improvers as compared to normal vessel or insignificant RAS group, *P < 0.05.

Cheung C M et al. Nephrol. Dial. Transplant. 2010;25:1133-1140

© The Author 2009. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

High grade proteinuria =

bad outcome in ARVD

(> 0.6 g/day)

3 main considerations prior to

possible revascularization

Does the patient have a key clinical phenotype (eg

FPE, declining function, severe hypertension)?

Is the RAS physiologically or haemodynamically

significant?

What is the state of the kidney beyond the RAS?

– Renal atrophy (< 7 cm)

– Significant proteinuria = severe parenchymal disease

– Determine kidneys with greatest ischaemic stress yet

viable tissue (‘Hibernating’ kidney tissue)

Beta-blockers

No β-blocker

With β-blocker

• ACE-I/ARB

• Statins

• Anti-platelet

also all effective

Medical therapy

Important :

Where are we now in the management

of Renal Artery Stenosis?

Patients with atherosclerotic RVD have very high

CVS risk

They should all receive comprehensive vascular

protective medication (statin, ACE-I/ARB, anti-

platelet)

An important minority of patients will benefit

from renal revascularization : it is important to

identify them

Revascularization in atherosclerotic RAS is

NOT for all but it should be for some……..

Definite indications

Severe or dialysis

dependent AKI

Patients who require/would

benefit from Renin

angiotensin blockade but

who are intolerant

Recurrent acute heart

failure

Possible indications

Very severe hypertension (eg SBP > 180 on 4+ drugs)

Rapidly deteriorating renal function : individual case basis

If rapidly deteriorating renal function and severe hypertension occur together

Emerging indications Patients with ‘hibernating’ renal

parenchyma ?

Chronic heart failure ?

Preventing renal atrophy long term?