Therapeutic approach to cerebrovascular disease in patients with chronic

kidney disease

Ligia Petrica1, M. Petrica2, D.C. Jianu2

‘Victor Babes’ University of Medicine and Pharmacy, County

Emergency Hospital, 1Dept. of Nephrology, 2Dept. of

Neurology

Timisoara, ROMANIA

Background

chronic kidney disease (CKD) is associated with a high

prevalence of cerebrovascular disorders such as stroke,

white matter diseases, intracerebral microbleeds and

cognitive impairment

this situation has been observed not only in end-stage

renal disease patients but also in patients with mild or

moderate CKD

Background

stroke is the third most common cardiovascular cause of

death in CKD patients and patients with end-stage renal

disease (ESRD)

a 4- to 10-fold greater risk of hospitalization for

ischaemic and haemorrhagic stroke [Seliger SL, et al. Kidney Int 2003; 64: 603–609]

an increased risk of cognitive impairment and dementia [Murray AM. Adv Chronic Kidney Dis 2008; 15:123–132;

Seliger SL, et al. J Am Soc Nephrol 2004; 15: 1904–1911]

poor long-term poststroke prognosis when compared

with non-ESRD patients[Iseki K, et al. Nephrol Dial Transplant 2000; 15: 1808–1813]

Background

the prevalence of asymptomatic silent cerebral

infarctions is four to five times greater in dialysis

patients than in age- and gender-matched controls

[Nakatani T, et al. Am J Nephrol 2003; 23: 86–90]

patients on dialysis with cognitive impairment appear to

have a high number of cortical defects reminiscent of

multiple infarct-related damages

[Lass P, et al. Clin Nucl Med 1999; 24: 561–565]

Background

ischaemic and haemorrhagic strokes

leukoaraiosis, silent cerebral infarcts and cerebral

microbleeds

increasing risk for both ischaemic and haemorrhagic

strokes with decreasing eGFR and the presence of

micro- or macroalbuminuria

several meta-analyses also indicate that a low eGFR

(30 mg/g)

are associated with greater risk of stroke

[Lee M, et al. BMJ 2010; 341: c4249;

Lee M, et al. Stroke 2010; 41: 2625-2631;

Lee M, et al. Cerebrovasc Dis 2010; 30: 464-469;

Ninomiya T, et al. Am J Kidney Dis 2009; 53: 417-425]

The cerebral vesselsRemodelling

The neurons - amazing cells!!!Plasticity

Reprogramming?

Neuroprotection - acute; chronic

Neuroplasticity

Treatment

treatment

treatment

treatm

en

t

Target blood pressure levels?

ACCORD in diabetic patients with CKD enrolled in the Action to

Control Cardiovascular Risk in Diabetes (ACCORD) trial,

a SBP < 120 mmHg as compared to < 140 mmHg did

not reduce the composite outcome of fatal and non-fatal

major cardiovascular events

at a significance level of

Target blood pressure levels?

SPRINT randomized trial of intensive versus standard blood

pressure control targeting a SBP < 120 mmHg as

compared to < 140 mmHg.

lower rates of fatal and non-fatal cardiovascular events

and death from any cause

even in subgroup analyses

Critique:

excluded persons with diabetes, proteinuria >1000mg/g, and

prior stroke

intensive BP control caused a higher risk of a 30% decline in

eGFR, more AKI events [Textor SC, et al. J Am Soc Nephrol 2017;28:2561-2563]

Target blood pressure levels?

lowering elevated BP to a target of < 140 mmHg

and possibly closer to 130/80 mmHg could

improve cardiovascular outcomes in patients

with CKD

RAA system in the brain

ACE and AT receptors in the cerebral microcirculation and cerebral vessels

endogenous angiotensin II modulates cerebral blood flow

[Tsutsumi K et al, Am J Physiol 1991; 261: H667-H670]

cerebrovascular remodelling arterial stiffness

vascular compliance

↓ infarction size

[London et al, Circulation 1994; 90: 2786-2796;

Shim et al, Blood Pressure 1995; 4:241-248;

Walters MR et al, Stroke 2001; 32: 473-478]

ACEIs

Blood pressure, LVH, proteinuria

target levels (kidney,brain,heart)

▶130/80mmHg

▶125/75mmHg(DM)

BUT!!!!

ACEIs

severe cerebrovascular remodelling arteriolosclerosis

small vessel disease

▶ 140/90mmHg

HOPE (The Heart Outcomes Prevention Evaluation

Study)- ramipril

↓ 32% the risk of incident cerebrovascular events

[Heart Outcome Prevention Evaluation Study Investigators.

N Engl J Med 2000; 342: 145-153]

PROGRESS (The Perindopril PROtection

AGainst REcurrent Stroke Study)

↓ 28% the risk of recurrent stroke

[PROGRESS Colaborative Group, Lancet 2001; 358: 1032-1041]

ACEIs

SBP DBP[Ninomiya T et al, Kidney Int 2008; doi10.1038/ki 2008.5]

PROGRESS

(The Perindopril PROtection

AGainst REcurrent Stroke Study)

ACEIs

SBP DBP[Ninomiya T et al, Kidney Int 2008; doi10.1038/ki 2008.5]

PROGRESS

(The Perindopril PROtection

AGainst REcurrent Stroke Study)

ACEIs

BUT!!!

FOSDIAL (The Fosinopril in Dialysis)ESRD and LVH

Fosinopril ↓ the prevalence of incident stroke through BP control

The J-shaped curve of

BP control vs. stroke prevention

[Zannad F, et al. Kidney Int 2006; 70: 1318-1324;

Kessler M, et al. Nephrol Dial Transplant 2007; 22:3573-3579]

ACEIs

neuroprotection through blockade of AT1

and stimulation of AT2 and AT4[Fournier A et al, Curr Hypertens Rep 2004; 6: 182-189]

IDNT (Irbesartan Diabetic

Nephropathy Trial) diabetic nephropathy + serum creatinine ≤ 3 mg%

protection against stroke - BP=120/85mmHg

NOT below this level → hypoperfusion !!!

[Berl T et al, J Am Soc Nephrol 2005; 16: 2170-2179]

ARBs

LIFE (Losartan Interventin For End Point Reduction in Hypertension Study)

↓ 39% risk for major cardio- and cerebrovascular events, and of cardiovascular and non-cardiovascular mortality

[Dahlof B et al, Lancet 2002; 359:995-1003]

RENAAL (The Reduction in Endpoints with

the Angiotensin Antagonist Losartan)

↓ 21% combined risk for stage 5-CKD, cardio- and cerebrovascular events

[Kowey PR et al, Clin Cardiol 2005; 28: 136-142]

ARBs

ACCESS (Acute Candesartan Cilexetil

Therapy in Stoke Survivors)

↓ risk of fatal and non-fatal stroke

[Schrader J et al , Stroke 2003; 34: 1699-1703]

improved the outcome of acute stroke

[Schrader J et al, Am J Cardiovasc Drugs 2007; 7: 25-37]

ARBs

Meta-analyses ACEIs vs. ARBs ARBs are superior to ACEIs in primary

and secondary stroke prevention

[Fournier A et al, J Am Coll Cardiol 2004; 43: 1343-1347; Boutitie F et al, J Hypertens 2007; 25: 1543-1553]

↓ stroke severity in patients treated with ARBs before the cerebrovascular event

[Ovbiagele B et al, Neurology 2005; 65: 851-854]

ARBs

Association ACEIs and ARBs

ONTARGET/TRANSCEND (The Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease )

Not superior in stroke prevention[The TRANSCEND/ONTARGET Investigators, Am Heart J 2004; 148: 52-61]

ARBs

beyond cholesterol- lowering effects

pleiotropic effects

↓carotid artery IMT

up-stream and down-stream effects

[Vaughan CJ et al, Stroke 1999;30: 1969-1973]

↓ cerebral infarction size atorvastatin

rosuvastatin[Gorelick PB et al, Stroke 2002; 33: 862-875 ;

Sironi L et al, Arterioscler Thromb Vasc Biol 2005; 25: 598-603 ]

Statins

CARE (The Cholesterol and Recurrent Events)

4159 participants with a history of miocardial infarction(1711 patients with mild renal insufficiency)- pravastatin

↓ 31% incident ischaemic stroke Not in the post-hoc analysis in patients with severe

renal insufficiency!!!

No influence on haemorrhagic stroke

[Tonelli M et al, for the Cholesterol and Recurrent Events (CARE) Trial Investigators,

Ann Intern Med 2003; 138:98-104]

Statins

reverse epidemiology in dialysis patients[Kalantar-Zadeh K et al, Kidney Int 2003; 63:793-808]

4D Study (The German Diabetes and

Dialysis Study) 1225 ESRD patients; atorvastatin -20 mg/day; 3-year follow-up

global risk of cardiovascular death, non-fatal miocardial infarction, fatal and non-fatal stroke

↑ risk of fatal şi non-fatal stroke in treated patients vs. non-treated patients !!!

[Wanner C et al, N Engl J Med 2005; 353: 238-248]

Statins

AURORA (A study to evaluate the Use of Rosuvastatin in subjects On Regular haemodialysis: an Assessment of survival and cardiovascular events)

the first large-scale international trial to assess the effects of statins on cardiovascular outcomes in patients with ESRD on chronic haemodialysis

Rosuvastatin treatment significantly reduced the rates of cardiac events by 32% among hemodialysis patients with diabetes mellitus

[Fellstrom B, et al. Kidney Blood Press Res 2007;30: 314-22;

Holdaas H, et al. J Am Soc Nephrol 2011; 22 1335 11341]

Statins

SHARP The effects of lowering LDL cholesterol with

simvastatin plus ezetimibe in patients with

chronic kidney disease (Study of Heart

and Renal Protection): a randomised placebo-

controlled trial

Reduction of LDL cholesterol with simvastatin 20 mg plus

ezetimibe 10 mg daily safely reduced the incidence of the

first major atherosclerotic event in a wide range of patients

with advanced chronic kidney disease

[SHARP Investigators. Lancet. 2011; 377(9784): 2181–2192]

Statins

EPO receptors in the brain[Digicaylioglu M et al, Proc Natl Acad Sci USA1995; 92:3717-3720]

EPO synthesis by neurons and astrocytes[Marti HH et al, Eur J Neurosci 1996; 8: 666-676]

EPO is localized in the human cerebral cortex and hypoccampus

[Jumbe NL, Oncology (Huntingt) 2002; 16: 91-107]

protects neurons against ischaemic damage

↓ infarction size[Sadamoto Y et al, Biochem Biophys Res Commun 1998; 253: 26-32;

Belayev L et al, Stroke 2005; 36: 1065-1070]

Erythropoietin

Human studies short-term prognosis after stroke 100000 U rhuEPO in 3 doses iv, at the

onset of stroke, at 24h and at 48h

neuroprotective effects inhibits apoptosis

antioxidative effects by inhibiting gluthamate

anti-inflammatory effects

neurotrophic effects via BNF

stimulates neuronal stem cells

angiogenic properties stimulates release of NO

[Ehrenreich H et al. Moll Med 2002; Ehrenreich H et al, Stroke 2009; 8: 495-505]

Erythropoietin

Pre-dialysis patients

ESAs beneficial in CKD anaemia

CHOIR [Singh AK et al N Engl J Med 2006; 355: 2085-2098]

CREATE

[Drueke TB et al. N Engl J Med 2006; 355: 2071-2084]

Erythropoietin

EPO in dialysis patients

beneficial stroke prevention

improvement of cognitive function

↑ cerebral arterial oxygen content

↑ brain oxygen extraction

↑ cerebral blood volume

[Johnson W. et al, Kidney Int 1990; 38: 919-924;

Metry G et al, J Am Soc Nephrol 1999; 10: 854-863]

Erythropoietin

BUT !!!EPO in dialysis patients

overcorrection of anaemia(Hb>11.5g/dl)

may be detrimental

[Iseki K et al, Nephron 1996; 72: 30-36]

Erythropoietin

BUT !!! Erythropoiesis-stimulating agents increase the

risk of acute stroke in patients with chronic

kidney disease Seliger SL et al. Kidney Int. 2011; 80: 288-294]

We should seek to use the lowest ESA dose

required to meet the clinical goals of the patient

TREAT

Erythropoietin

[Szczech L. Nat. Rev. Nephrol. 2011; 7: 365–366]

beyond blood pressure control

athero- and arterioscleroticcerebrovascular remodelling

↓ IMT carotid artery

NORDIL (The Nordic Diltiazem Study)

↓ risk of incident stroke

[Hansson L et al, Lancet 2000; 356: 359-365]

Calcium channel blockers

PREVENT (The Prospectiv Randomized Evaluation of the Vascular Effects of Norvasc Trial)

amlodipin stabilizes the atheromatousplaque in the carotid arteries

[Byington RP et al, Am J Cardiol 1997; 80:1087-1090]

not in the post-hoc analysis-ALLHAT !!!

[Rahman M et al, Ann Intern Med 2006; 144: 172-180]

Calcium channel blockers

beyond glycaemic control ↓ prevalence of stroke in DM + CKD

[Schneider CA et al, JASN 2008; 19:182-187]

vascular remodelling

↓ IMT and arterial stiffness carotid artery[Nakamura T et al, Metabolism 2004; 53:1382-1386;

Langenfeld MR et al, Circulation 2005; 111:2525-2531]

↓ cerebrovascular resistance[Park JS et al, Metabolism 2007; 56:1081-1086]

↓ proteinuria[Miyazaki Y et al, Kidney Int 2007; 72:1367-1372;

Kincaid-Smith P et al, Nephrology(Carlton) 2008; 13:58-62]

Thiazolidinediones

Thiazolidinediones

Thiazolidinediones

Take-homemessages

The prototype patient

Multiorgan protection

Multidisciplinary approach