INTERLINKING CARDIOVASCULAR DISEASE, CHRONIC KIDNEY DISEASE, AND OBESITY JOSHUA K. KAYIMA ASSOCIATE PROFESSOR DEPT. OF CLINICAL MEDICINE AND THERAPEUTICS UNIVERSITY OF NAIROBI
Introduction According to projections carried out by WHO, the world will experience a substantial shift in the distribution of deaths from communicable diseases to non-communicable disease during the next 25 years Main reason Increased aged population Chronic morbidities such as Chronic kidney disease Cardiovascular diseases
CKD and CVD (1) Patients with chronic renal failure carry one of the heaviest burden of CV disease CV disease frequently leads to death before ESRD CVD risk is higher than that contributed by hypertension, DM, obesity, dyslipidemia and smoking (the traditional CKD risk factors that are also common in CKD patients)
CKD and CVD (2) Mortality among patients with CKD higher than general population ESRD 45% of all mortality is related to cardiovascular event 25% of all mortality related to sudden cardiac death Even moderate reductions in GFR are associated with increased risk of cardiac events, hospitalization and death.
CKD and CVD (3) In CKD patients, coronary heart disease occurs earlier in life, progresses more rapidly, and is associated with medical calcification, artherosclerosis and reduced vascular compliance. Vascular disease more resistant to treatment with statins
Non traditional risk factors (1) Regardless of cause, uremic caries an increased risk of CVD related mortality. Non traditional risk factors associated with uraemic state include Micro albuminuria and proteinuria Anaemia Altered mineral metabolism and hyperparathyroidsm Increased vascular calcification Hyper homocysteinaemia
Non traditional risk factors (2) Chronic inflammatory state with elevated CRP Oxidative stress Endothelial dysfunction Malnutrition Carnitine deficiency Low vitamin C Sympathetic nervous system overactivity High lipoprotein (a) levels and small apolipoprotein (a) size Chronic volume overload
As shown in the chart below, a GFR of less than 15 ml/min/1.73 m2 to be associated with the greatest risk for cardiovascular events was shown Adapted from Go et al, N Engl J Med, 2004.
The Distribution of the Causes of Death in Patients With End-Stage Renal Disease in the U.S. Between 2003 and 2005 Hage, F. G. et al. J Am Coll Cardiol 2009;53:2129-2140 Copyright 2009 American College of Cardiology Foundation. Restrictions may apply.
The Association Between Chronic Kidney Disease and Cardiovascular Events Hage, F. G. et al. J Am Coll Cardiol 2009;53:2129-2140 Copyright 2009 American College of Cardiology Foundation. Restrictions may apply.
Chronic Kidney Disease CKD is common and has an increasing prevalence The prognosis is generally poor with many experiencing progression Co-morbidities are usually associated Recognising the factors associated with CKD progression enables identification of high-risk patients, who are given more intensive treatment
Epidemiology Total prevalence of CKD (USA) 13% EUROPE NKF-KDOQI- USA EUROPE Stage 1 6.3% 5 7% Stage 2 Stage 3 5.5% 4.6% Stage 4 0.6% 0.7% Stage 5 0.6% 0.7%
Epidemiology Prevalence is Asia & Australia higher in Africa, much higher Prevalence continues to increase. USA 1990 2000, prevalence increased by 30%
End-stage Renal Disease (ESRD) Incidence varies widely between countries 100 150 / million pop. Europe 300 / million pop. USA / Mexico 400 / million pop. Taiwan 90 120 / million pop. (1990 s) Africa, sub Sahara
Many risk factors and markers for the development and progression of CKD exist. The cost of treatment of ESRD is a major concern. Early recognition and management of CKD may slow progression of CKD
Initiating Factors Age Gender Ethnicity Family history of CKD Diabetes mellitus Metabolic syndrome Hyperfiltration state High normal urinary albumin excretion Dyslipidemia Nephrotoxins Primary kidney disease Urological disorders Cardiovascular disease
Traditional progression factors or markers African American ethnicity Proteinuria Hypertension High protein intake Obesity Anemia Dyslipidemia Smoking Nephrotoxins Cardiovascular disease
Emerging progression factors or markers ADMA FGF23 Phosphate PTH Adrenomedullin ANP NT-proBNP L-FABP KIM-1 NGAL ApoA-IV Adiponectin Genetic polymorphisms
Obesity, inflammation and kidney disease Obesity is associated with a wide range of well known co-morbidities Cardiovascular disease Dyslipidemia Hypertension Diabetes mellitus Metabolic syndrome and Recently renal involvement
Epidemiological data suggest the existence of relationship between obesity and CKD. There is a description of an obesity related glomerulopathy glomerulo sclerosis glomerulo megaly + proteinuria
Other glomerular lesions increased mesangial matrix mesangial proliferation podocyte hypertrophy Glomerulomegaly FSGS Lesions associated with weight and not hypertension, or hyperglycaemia
Adopose tissue is active Produces a variety of factors involved in a wide variety of biologic processes. Factors Adipocytokines (TNF, IL6, resistins, leptins, adiponectin. Acylation stimulating protein Plasminogen activator inhibitor I Angiotensinogen They play a role in energy homeostasis, insulin insensitivity and vascular disease
The metabolic syndrome phenotype results from multiple factors targeting glucose metabolism and the vascular system. DYSREGULATION OF ADIPOSE METABOLISM due to i) overnutrition ii) sedentary lifestyle = initial obligatory insult INSULIN RESISTANCE = inappropriate response to insulin by adipose, muscle, and liver cells. 2 to circulating cytokines TNF, IL-6
ENDOTHELIAL DYSFUNCTION Aortic stiffness Carotid intimal-medial thickening Hypertension LVH ATHEROGENIC DISEASE and vascular damage to kidneys and other organs evidenced by MICROALBIMINURIA
UPREGULATION OF PROTHROMBOTIC and PROINFLAMMATORY PROCESSES Pro-CKD Pro-CVD Inflammatory process contributes to CKD and artherosclerosis ( CRP, Proinflammatory cytokines e.g. TNF, IL-6)
PROCOAGULANT STATE Increased concentration of fibrinogen and factor VII Decreased fibrinolytic activity including plasminogen activator inhibitor-i Affect endothelial function GLOMERULAR HEMODYNAMIC ALTERATIONS Occur, with glomerular hyperfiltration, microaltuminuria and consequent CKD
HYPERURICAEMIA Also seen in most patients with metabolic syndrome linked to CVD, hypertension and renal disease. Hyperuricaemia implicated in Endothelial dysfunction and Increased production of inflammatory mediators e.g. CRP There is no hard evidence yet that treatment of asymptomatic hyperuricaemia reduces CVD, and CKD risk
In human studies correlating inflammatory factors, with obesity and renal lesion are emerging, though difficult to interprete BMI is correlated to leptin, adiponectin and TNF-, but glomerular lesions are not always correlated. There is increasing evidence of an important relationship between MS and obesity with albuminuria and CKD (Chenet al) MS favours the emergency of type 2 DM, CVD, microalbuminuria and CKD Treating the initial stages of obesity, may prevent obesity related co-morbidities
Prevalence of Chronic Kidney Disease and Microalbuminuria among Persons with and without Components of the Metabolic Syndrome. Chen J et al. Ann Intern Med 2004;140:167-174 2004 by American College of Physicians
Prevalence of chronic kidney disease (top) and microalbuminuria (bottom) by number of the metabolic syndrome components. Chen J et al. Ann Intern Med 2004;140:167-174 2004 by American College of Physicians
statins Inhibit 3-hydroxy-3-methyl-glutaryl-CoA reductase Cholesterol synthesis Isoprenoid compound formation e.g. farnesylpyrophosphate geranylgeranylpyrophosphate. Isoprenylation blockade is implicated in statin pleitropic effects Modulation/prevention of endothelial dysfunction, inflammatory process oxidative stress Statin may also reduce renal injury associated with hypertension In CKD, statins reduce CRP, ILI-, TNF-, indepent of cholesterol reduction
STATINS AND CKD Primary and secondary prevention trials with statins have shown that reducing lipid concentration is accompanied by a reduction in risk of all major vascular events Evaluation effect of statins in patients with CKD-limited.
Post hoc analysis of large trials (e.g. The anglo scandinavian cardiac outcomes trial, The cholesterol and Recurrent Event Study, and Pravastatin Pooling Project) suggest that statins reduce cardiovascular outcomes in patients with CKD stage 2, 3 Benefit increases as renal function declines.