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The impact of chronic illnesses is being felt in developing countries for two main reasons:

the population is ageing as a result of social and medical improvements, but also rapid social and environmental changes is leading to an increase in common, preventable risk factors associated with chronic disease prevalence (World Health Organization, 2005c, Strong et al., 2005)Organization. In 2005, low-income and middle-income countries accounted for around 80% of the total burden of chronic disease mortality in developing countries, and in these countries, chronic diseases (including persistent communicablediseases such as HIV/AIDS and TB) were responsible for 50% of the total disease burden (Abegunde et al., 2007). In low- and middle-income countries, the increase in chronic non-communicable diseases (HTN and DM) is concurrent with unresolved communicable diseases (HIV/AIDS) (Strong et al., 2006). By 2020, the burden of DM and CVD will have increased by 130% in Africa alone, affecting nearly 21 million and 1.3 million people respectively, with concomitant increases in the prevalence of CKD, especially ESRD (also known as stage 5 CKD) (Schena, 2000).

The Australian Outreach program has documented that most people with chronic disease have more than one morbidity, overlapping morbidity, justifying integrated rather than disease specific programs (Hoy et al., 2005a) (Figure 12). The risk factors for CVD and CKD can be clustered into the metabolic syndrome (visceral obesity, dyslipidaemia, hyperglycaemia and HTN) or considered as separate entities. The paper by Hoy et al (2006) focuses on the value of screening people for multiple cardiovascular risk factors or if it is better to assess risk according to the metabolic syndrome definition (Hoy et al., 2006). It was found that an integrated approach, including primary and secondary prevention of all elements of the syndrome, rather diseases

specific approach was better. They also found that albuminuria had an important risk in non-renal risk, and these issues and the metabolic syndrome are discussed below.

Figure 12. Overlapping morbidities of chronic disease

Note: Adults screened in a single Aboriginal Community in the Australian Chronic Disease Outreach Program

The Metabolic Syndrome and Chronic Disease

For the past two decades the metabolic syndrome (MetS) has referred to a constellation of diseases, and highlights the risk for developing type 2 DM and an increased risk for

cardiovascular disease (Ballantyne et al., 2008). Metabolic Syndrome as an entity is recognised as a major public health challenge worldwide (Editor, 2005). It is a cause of both CVD and CKD but this term was originally recognised to help us understand how insulin resistance links with vascular disease, and if it could predict risk for developing CVD and type 2 DM (Sattar et al., 2008). There is no specific cause of this syndrome, but it includes cardiovascular risk factors and chronic conditions including visceral obesity, dyslipidaemia, HTN, and glucose intolerance or hyperglycaemia. The definition has undergone a series of changes over the last four decades, most recently by the International Diabetes Federation (International Diabetes Federation, 2005). This definition of Metabolic syndrome includes central obesity plus any two of the

Kidney Disease (46%)

Hypertension (52%) Diabetes (29%) 3%

9%

14%

3%

20%

2%

14%

34%

Screened Adults

following four factors: raised triglyceride levels or treatment for this lipid abnormality, raised cholesterol or treatment for this lipid abnormality, raised blood pressure (>130/85mmHg) or treatment of previously diagnosed hypertension, and raised fasting blood glucose (>5.6mmol/L) or previously diagnosed type 2 diabetes. Crucial to the IDF definition, to be defined as having metabolic syndrome, a person must have central obesity (waist circumference of a certain size which is ethnicity specific). No normal data for waist circumferences are available for Africa, and so European targets are used (>102cm for men and >88cm for women). The first published working definition was from the WHO and included the same cluster but also microalbuminuria (Alberti and Zimmet, 1998). Because of the regular re-evaluations of this syndrome, the central causative factor of insulin resistance has been challenged (Yudkin, 2007). The argument put forward is that central obesity, lack of exercise and tissue inflammation should be considered as the causative factors, resulting in the cascade of disease and complications. However, the clinical diagnosis of metabolic syndrome has always been in contention, since it was described by Gerald Reaven in 1988 (Reaven, 1988).

The pathogenesis of the metabolic syndrome is multi-factorial, with the major underlying risk factors being central obesity and insulin resistance (Reaven, 1988). Most patients with type 2 DM have insulin resistance, and most but not all are obese. A major contributor and possible cause is an excess of circulating fatty acids and an associated rise in cardiovascular

inflammatory markers e.g. C-reactive protein (Festa et al., 2000, Ridker et al., 2003, Rutter et al., 2004). Inflammation affecting the vascular endothelium associated with dyslipidaemia and atherosclerosis causes the increase in stroke and coronary artery disease. Albuminuria is an early and dominant element of this symptom complex, and strongly predicts all-cause and cardiovascular illnesses and deaths.

The importance of diagnosing the metabolic syndrome is that it highlights the risk associated with cardiovascular disease. The combination of risk factors further increases this risk (Expert Panel, 2001, Ballantyne et al., 2008, McNeill et al., 2005). This has been examined in several large epidemiological studies (McNeill et al., 2005). In the DECODE study (Balkau, 2000, The Decode Study Group, 2003), European men and women without diabetes, but with metabolic syndrome, had increased risk from death from all causes as well as from

cardiovascular disease. In the United States, in adults 30-70 years of age, the metabolic syndrome was associated with an increased risk of coronary heart disease and total mortality.

Those people with DM and pre-existing CVD had rates that were even higher. Even one or two metabolic syndrome risk factors confer increased risks of disease. Metabolic syndrome indicates an even worse prognosis than its individual risk factors (Meigs, 2003). Hoy et al. (2006) found that CKD and HTN were the most prominent and earliest features of the syndrome. There also appears to be gender differences; in the San Antonio Study mortality was more than twice as high in women as men (Meigs et al., 2003, Haffner, 2000). In the United States (US)

Framingham Offspring Study elevated CRP levels were related to insulin resistance and the presence of the MetS especially in women (Rutter et al., 2004). In the ARIC study, again in the US which followed a cohort with low rates of coronary heart disease, stroke or DM, the men and women with the metabolic syndrome were 1.5 times more likely to develop coronary heart disease after adjustment for established risk factors (Ballantyne et al., 2008). Evaluating metabolic syndrome in Aboriginal Australians revealed high rates of kidney disease, HTN, and DM all increasing with age, and an overlapping of these risk factors (Hoy et al., 2006).

It is argued that the metabolic syndrome is not better than other models highlighting risks for cardiovascular disease. Wannamethee (2005) argues that it was better for predicting type 2 DM than coronary artery disease, and the Framingham score was a better predictor of disease than the metabolic syndrome constellation of risk factors (Wannamethee et al., 2005). The value of the metabolic syndrome as a clinical tool remains controversial and others have also added to this debate³. Here the conclusions were that the metabolic syndrome had a weak or no

association with vascular risk in elderly populations, and defining risk for DM and cardiovascular disease had little real clinical value. It was felt that the clinical focus should remain on

establishing optimum risk algorithms for each disease. Ultimately the metabolic syndrome serves well as a simple clinical tool for identifying high-risk subjects predisposed to cardiovascular disease or type 2 DM.. Risk factors identifying people with the metabolic

3 Sattar et al (2008) argued that it was not as good as traditional algorithms that use continuous or categorical measures and which contain the key risk factors for cardiovascular disease: age, LDL cholesterol, and smoking.

syndrome may provide opportunities to intervene earlier in the development of shared disease pathways that predispose individuals to both CVD and DM.

The Metabolic Syndrome and CKD

The causes of the increased risk of CVD in CKD are most likely due to shared CVD risk factors, including DM, HTN, obesity, lipid abnormalities, and smoking (Manttari et al., 1995, Fox et al., 2004a, Muntner et al., 2000, Tozawa et al., 2007, Tozawa et al., 2002, Zoccali, 2006). It could therefore be concluded that established cardiovascular disease risk factors, or metabolic syndrome risk factors, are associated with the development of new-onset kidney disease and progression of CKD. This has been confirmed in a number of studies including among Japanese men, African Americans, Chinese and Southeast Asians (Tozawa et al., 2007, Lea et al., 2008, Kitiyakara et al., 2007, Chen et al., 2007). Interestingly, in the Southeast Asia study, the

definition used to define metabolic syndrome influenced the likelihood of predicting risk for CKD, suspected to be similar to reasons for developing CVD.

Detecting and treating metabolic syndrome early on in the community will influence kidney disease and may also delay the progression or development both of CKD and CVD. In one study, there was a linear relationship between the number of metabolic syndrome risk factors and CKD (Tanaka et al., 2006). There is evidence too that the pathogenesis of CKD is linked to inflammation, measured by a serum C-reactive protein (Lee et al., 2007, Beddhu et al., 2005, Zoccali, 2006), and in the studies by Beddhu et al. and Lee et al. the metabolic syndrome and high CRP were independently associated with increased prevalence of CKD and the odds of CKD increased in the setting of high CRP and metabolic syndrome. Inflammation is increasingly prevalent in patients with CKD (Muntner et al., 2004), and the inflammation with associated obesity and atherosclerosis is most likely the cause of kidney damage as in other organs (Beddhu et al., 2005, Rutter et al., 2004, Zoccali, 2006). The development of insulin resistance, DM and HTN further activates the cascade of kidney dysfunction (Figure 13, see also figure 8).

Thus, associations of inflammation with metabolic syndrome and its component conditions, described in the general population, are also present in patients with moderate CKD. Risk factors do not act in single organs or compartments and can be targeted with primary prevention

strategies.

Figure 13. Metabolic Syndrome and Kidney Disease

Adapted from a lecture by Dr Valerie Luyckx – Abstract South African Renal Society 2002- “Why poor people get kidney disease” (Luyckx, 2002)*