CHRONIC KIDNEY DISEASE: AS A CARDIOVASCULAR RISK EQUIVALENT

AN OVERVIEW

Prof A Akinsola OAU Ile-Ife

MAGNITUDE OF CKD
Stage 1 Description Kidney damage with normal or increased GFR Kidney damage with mildly decreased GFR Moderately decreased GFR Severely decreased GFR Kidney failure GFR ml/min/1.73m2 ? 90 US prevalence, 1000s 5900 US prevalence % 3.3

60 89

5300

3.0

3 4 5

30 59 15 29 < 15 or dialysis

7600 400 300

4.3 0.2 0.1

Australia 18% had one indicator of CKD Nigeria: only hospital data late stages of CKD :28% medical admission,300 400/million

Cardiovascular burden of CKD is enormous: CV Mortality in CKD Vs General Population

Approximate Prevalence of CVD in the General Population and CKD

Ischemic Heart Disease (Clinical) General Population 8 13 (Age 55-64) CKD stages 3-4 NA (diabetic and nondiabetic kidney disease) CKD stage 1-4 (kidney transplant recipients) CKD stage 5 (heamodialysis) 15 LVH ( Echo) 20 25-50 (varies with level of kidney functions) 50-70 Heart failure (Clinical) 3 6 NA

NA

40

75 75

40 40

CKD stage 5 40 (peritoneal dialysis)

THE BURDEN OF CARDIOVASCULAR (CV) EVENTS IN CKD ALSO ENORMOUS

Primary cause of morbidity/premature mortality in CKD patients Only 16% of CKD patients have normal ECG at first dialysis Majority have LVH, Systolic dysfunction/LV dialtation 50% of deaths have a CV cause Dialysis population have a 10-20 fold higher risk than the general population for CV mortality

 Risk for cardiac mortality in patients <45yr old is 100 x higher in CKD than general population Direct observation of elevated relative risk of vascular events in Hyper treatment studies [HOT & MRF, T] JNC VII listing of microalls & GFR < 60 as 2 major CV risk factors & as target organ disease

SPECTRUM OF CVS DISEASE IN CKD

MYOCARDIAL Pathophysiology: Pressure/volume overload due to HT, Anaemia, Hyperdynaemic circulation, PTH, elevated SNS activity, inflammation Structural alterations Ventricular remodelling LVH LVH (concentric (Pr); Eccentric (volume overload) HF (occuring in 30-50%, [CKD stages 3 & 4]

Spectrum of CV Disease in CKD

BLOOD V V: Pathophysiology: Heamodynamic/metabolic changes (A) Arterial remodelling collagen, calcification, extracellular matrix, arteriosclerosis arterial stiffening (B) Intimal arteriosclerotic plaque formation coronary artery disease 1 HD * (finding of CAD in >50% of CKD stage 5 by coronary angio

PROPOSITIONS
Increased prevalence of traditional/non traditional CV rf in CKD CKD itself, is an independent risk equivalent CV rf are also risk factors for progression of CKD Presence of Cardiovascular Disease is also a risk factor for CKD

Proposition 2:
The 2 major marlers of CKD ie Microalbuminuria GFR < 60 ml/mn are both independent risk factors for CV disease Reduced GFR: Increased levels of non-traditional risk factors May mirror severity of vascular disease May be a measure of residual confounding traditional risk factors May compromise optimal treatment (aspirin, b-blockers, ACET)

 Microalbuminuria:
A maker of generalised endothelial dysfunction and vascular permeability May be associated with other risk factors or surrogates Predictor for early or incipient renal failure

Proposition 2: Cardiovascular Risk Factors are prevalent in CKD

Traditional: specified by Framingham Heart study patient ( see table) Table Non-traditional: uraemia related increases in prevalence with declining GFR RF for LVH older age, Higher Systolic BP, Lower Hb and decreased GRF RF for atherosclerosis: DM, Higher total cholesterol, lower high density, LP cholesterol, smoking, higher systolic BP

Others:
Inflammation: An integral part in the pathogenesis of atherosclerosis. Markers: C- reactive problem (CRP) independent predictor of all cause mortality and CV disease, mortality [MDRD study] Rates CRF > 2.2mg/l increases as GFR CRR (1L-6, TNF reception I & II are assoctiated with increased odds for coronary events[nurses health study]

OXIDATIVE STRESS

A common pathway for inflammation, insulin resistance etc. in the pathogenesis of atherosclerosis Evidence from studies: Antioxidants in secondary prevention of cardiovascular disease in CKD [SPACE]

METABOLIC SYNDRONME abdominal fat accumulation, HT, triglyceride, HDL Glucose Major components of metabolic syndrome hyperinsulinaemia and insulin resistance are present in CKD and this is associated with increased CV disease risk.

HYPERHOMOCYSTEINAEMIA + OTHER THIOLS

HC- is associated with CV disease risk in the general population; similarly so in kidney failure Studies lacking for early CKD Lowering with Acetyl cystein, folic acid/Vit B6, 12 may be beneficial

Endothelial cell dysfunction and

injury Abnormal endothelium- dependent vasodilation - is a predictor of CV disease events and mortality in kidney failure, it is independent of arterial stiffness in LVH

RISK FACTORS FOR ARTERIOSCLEROSIS

Impaired endothelium dependent vasodilatation contributes to arterial structural alterations in patients with CKD Abnormal Ca and PO4 metabolism: Increased risk of mortality and 20 PTH in Dx occurs when >6.5mg/dl PO4 AND Ca++ x PO product > 72mg2/dl2. Recommendation PO4 2.5-6.5mg/dl; Ca x PO4 < 72mg2/dl2.

 Abnormal Ca and PO4 metabolism: Increased risk of mortality and 20 PTH in Dx occurs when PO4 >6.5mg/dl Ca++ X PO4 product > 72mg2/dl2. Recommendation PO4 2.5-6.5mg/dl; Ca x PO4 < 72mg2/dl2.

Mortality from hyperphosphataemia

 Leads to large vessel calcification: (i) arterial stiffening (ii) increased pulse pressure (iii) decreased coronary perfusion (iv) LVH
2 Types of calcification Intimal develop in 80-90% of atherosclerotic plaques that protrude into vessel lumen ischaemia and necrosis

 Media calcification (Monckenberg sclerosis) occurs diffusely in the tunica media (common in CKD and diabetics) vascular rigidity, decreases compliance systolic hypertension + increase pulse, wave velocity, contributes to LVH and compromised diastolic coronary flow. ? deficit of a glycoprotein fetuin a potent inhibitor of calcification in CKD??

ANAEMIA: as a cardiovascular risk factor Prevalence of anaemia = 25% in pts with CrCl > 50ml/min; with CrCl (35 49ml/min = 44% (25 34ml/min = 51% (< 25ml/min = 44% A decline in Hb starts at a GFR 70min/min, in males and 50ml/min in females

 Physiological alterations: CO, cardiomegaly, LVH, CHF A close relationship between LVH and aneamia EPO treatment has led to partial regression Correction of aneamia improves survival

DYSLIPIDAEMIA: NHNES data have linked the metabolic syndrome and dyslipidaemia to development of CKD Endothelial dysfunction and atherosclerosis of the renal vasculature possibly a major component of both diabetic and non-DM CKD

 Smoking an independent risk factor for both CVD and CKD ces CV disease death rates in CKD Nicotin + components of tar upregulation of adhesion molecules Promotes oxidation and entry of LDL cholesterol into the vascular subendothelium

 Increased Sympathetic N.S activity: Renal Ischaemia, Ang.II, cerebral NO contribute to stimulation of symp. Activity Renal and Cardiac injury form SNS activity may be enhanced by NO and oxidative stress

Conclusion: CKD, even in the early stage constitutes a major CV risk equivalent and thus poses a great challenge perhaps greater than that of RRT.