Chronic kidney disease: a research and public health priority

The growing global burden of non-communicable diseases (NCDs) worldwide has been disregarded until recently by policy makers, major aid donors and academics. However, NCDs are the leading cause of death in the world [1–3]. In 2008, there were 57 million deaths globally, of which 63% were due to NCDs. These chronic diseases are the largest cause of death, led by cardiovascular disease (17 million deaths, mainly from ischaemic heart disease and stroke) followed by cancer (7.6 million), chronic lung disease (4.2 million, including asthma and chronic obstructive pulmonary disease) and diabetes mellitus (1.3 million deaths) [4]. They share key risk factors: tobacco use, unhealthy diets, lack of physical activity and alcohol abuse [4]. The current burden of chronic diseases reflects past exposure to these risk factors, and the future burden will be largely determined by the current exposure. Actually, worldwide the prevalence of these chronic diseases is projected to increase substantially over the next decades [5]. According to WHO, the global number of individuals with diabetes in 2000 was estimated to be 171 million (2.8% of the world's population), a figure anticipated to increase in 2030 to 366 million (6.5%), 298 million of whom will live in developing countries [6]. As a consequence, predictions for the next two decades show a near 3-fold increase in the ischaemic heart disease and stroke mortality rate in Latin America, Sub-Saharan Africa and the Middle East [4]. Countries in transition in the South-East and East Asia have also witnessed a rapid deterioration of their chronic disease risk and mortality profile [7]. India, the second most populous country, has the highest number of diabetics in the world, and in 2008, the estimates for age-standardized deaths per 100 000 population due to diabetes and cardiovascular disease were 386.3 and 283.0 in males and females, respectively [7]. In China, age-specific death rates from cardiovascular disease increased between 200 and 300% in those aged 35 through 44 years between 1986 and 1999, and by more than 100% in those aged 45–54 years [8]. Of note, the 2011 WHO report on CKD Country Profiles [7] shows that globally low- and lower-middle income countries have the highest proportion of deaths under 60 years of age from NCDs. In 2008, the proportion of these premature NCD deaths was 41% in low-income and 28% in lower-middle income countries, respectively, threefold and more than twofold as compared with the proportion in the high-income countries (13%). Risk factors for chronic diseases are also escalating. Smoking prevalence and obesity levels among adolescents have risen considerably worldwide over the past decade and portend a rapid increase in chronic diseases [9, 10]. In all countries, the increased burden of NCDs is also leading to growing economic costs. For example, it has been anticipated that in the United States, cardiovascular diseases and diabetes together cost $750 billion annually [11]. In the next 10 years the United Kingdom will lose $33 billion in national income as a result of largely preventable heart disease, stroke and diabetes [12, 13]. Over the same period, the national income loss for NCDs in India and China will account for $237 and $558 billion, respectively [12, 13]. Thus, NCDs are among the most severe threats to global economic development, probably more detrimental than fiscal crisis, as underlined by the World Economic Forum's 2009 report. Chronic kidney disease (CKD) is a key determinant of the poor health outcomes for major NCDs [14]. CKD is a worldwide threat to public health, but the size of the problem is probably not fully appreciated. Estimates of the global burden of the diseases report that diseases of the kidney and urinary tract contribute with ∼830 000 deaths annually and 18 867 000 disability-adjusted life years (DALY), making them the 12th highest cause of death (1.4% of all deaths) and the 17th cause of disability (1% of all DALY). This ranking is similar across World Bank regions, but, among developing areas, East Asia and Pacific regions have the highest annual rate of death due to diseases of the genitourinary system [15]. National and international renal registries offer an important source of information on several aspects of CKD. In particular, they are useful in characterizing the population on renal replacement therapy (RRT) due to end-stage renal disease (ESRD), describing the prevalence and incidence of ESRD and trends in mortality and disease rates. One of the most comprehensive sources of information about the prevalence of ESRD worldwide is the United States Renal Data System (USRDS). We have implemented the USRDS dataset with ESRD data from renal registries identified after searches of web resources for registry databases, annual reports and published literature. According to this analysis, the most recent available data indicate that the prevalence of ESRD ranges from 2447 pmp in Taiwan to 10 pmp in Nigeria (Figure 1). However, there is paucity of renal registries globally with an international standard for registry data collection, especially in low- and middle-income countries, where, in addition, the use of RRT is scarce or non-existent, eventually making it difficult to compare ESRD results [16]. For these reasons, the reported prevalence rate of ESRD varies widely among countries, especially in the emerging world, which may be related more to the capacity of the health system to provide the costly RRT treatment than true difference in epidemiology of renal disease. Thus, in Latin America, the ESRD prevalence ranges from 1019 pmp in Uruguay to 34 pmp in Honduras, a difference that may also reflect the relationship with the gross national product [17]. Much less is known in Africa, with the highest ESRD prevalence in Tunisia (713 pmp) and Egypt (669 pmp) [18]. In relatively developed regions of China, especially in major cities, the prevalence of ESRD has been reported to be 102 pmp [19], whereas in Japan, it is more than 2200 pmp, one of the highest rates worldwide. Prevalence of ESRD (dialysis and transplantation) worldwide. Data are from the 2011 USRDS Annual Report and from national registry database and published literature. All rates are unadjusted and presented as prevalence rate per million population. Therefore, overall there are ∼1.8 million people in the world who are alive simply because they have access to one form or another of RRT [20]. Ninety per cent of those live in industrialized countries, where the average gross income is in excess of US $10 000 per capita [21]. The size of this population has been expanding at a rate of 7% per year. As an example, over the last decade, the number of those requiring dialysis has increased annually by 6.1% in Canada [22], 11% in Japan [23] and 9% in Australia [24]. However, <10% of all patients with ESRD receive any form of RRT in countries such as India and Pakistan. In India, ∼100 000 patients develop ESRD each year [25]. Of these, 90% never see a nephrologist. Of the 10 000 patients who do consult a nephrologist, RRT is initiated in 90%; the remaining 10% are unable to afford any form of RRT. Of the 8900 patients who start haemodialysis, 60% are lost to follow-up within 3 months. These patients drop out of therapy, because they realize that dialysis is not a cure and has to be performed over the long-term, ultimately causing impoverishment of their families. Patients on RRT can be regarded as the tip of the iceberg, whereas the number of those with CKD not yet in need of RRT is much greater. However, the exact prevalence of pre-dialysis CKD is not known and only rough estimates exist. In industrialized countries such as the USA, the Third National Health and Nutrition Evaluation Survey (NHANES III, 1999–2006) has shown a prevalence of CKD in the adult population of 11.5% (∼23.2 million people) [26]. A sizeable proportion of these people will experience the progression of their disease to ESRD. In Europe, the Prevention of End-Stage Renal and Vascular End-points (PREVEND) study undertaken in the city of Groningen (the Netherlands) evaluated almost 40 000 individuals in a cross-sectional cohort study [27]. It was found that no less than 16.6% had high normal albuminuria and ∼7% of those screened had microalbuminuria. If these data were to be extrapolated to the world population, the number of people with CKD could be estimated as hundreds of millions. Although data concerning the prevalence of pre-dialysis CKD in developing countries are scarce, we would expect that there are comparable numbers of patients with CKD in poor countries as in industrialized nations. To this, the International Society of Nephrology (ISN) Global Outreach (GO) funded the Kidney Disease Data Center database to house data from sponsored programmes aimed at preventing CKD and its complications in developing nations. Some examples indicate that the overall prevalence of CKD, diagnosed based on a urinary albumin/creatinine ratio ≥30 or glomerular filtration rate (GFR) ≤60 L/min/1.73 m2 (as Modification of Diet in Renal Disease, four variables), is 11 and 10.6% in urban areas, respectively, of Moldova [28] and Nepal [29]. Moreover, in the attempt to compare the burden of illness among centres in Nepal, China and Mongolia, in 11 394 adult subjects, it has been found that decreased estimated GFR (<60 L/min/1.73 m2) was present in 7.3–14% of participants across centres; proteinuria (≥1+) on dipstick (2.4–10%) was also common [30]. By a recent cross-sectional survey of a nationally representative sample of Chinese adults, the overall prevalence of CKD was 10.8% [31]. Data from India also suggest that in a developing country, the prevalence rate of CKD could vary almost 5-fold between the rural and city population [32, 33]. These observations imply that CKD would affect not only very many people in the developing world, but preferentially the poor within these countries who usually have no information about disease and risk factors, and cannot have access to healthcare. Interestingly, low socioeconomic status is associated with CKD also in developed nations, as shown in Unites States by the NHANES survey, which reported people with lower income being disproportionately afflicted with a higher burden of CKD risk factors [34]. Similarly, in Sweden [35] and the UK [36], lower income and social deprivation are associated with micro- or macro-albuminuria, reduced GFR and progressive kidney function loss. Diabetes and hypertension are the major causes of CKD leading to kidney failure in the USA, accounting for 153 and 99 pmp, respectively [37], of incident causes of ESRD. Definitely lower is the contribution of glomerulonephritis (23.7 pmp) [37]. The proportion of people with CKD not explained by diabetes and hypertension is substantially lower in the USA (28% of stage 3–4 CKD) than in developing countries [37, 38]. Indeed, in a recent study analysing screening programs in Nepal, China and Mongolia, 43% of people with CKD did not have diabetes or hypertension [30]. There is also increasing evidence that infectious diseases, still a major health problem in low-income countries, may substantially contribute to the burden of chronic nephropathies. This mainly relates to poor environmental conditions, unsafe life habit and malnutrition. Urinary tract infections, occurring in the entire population, but with particular impact on females of all ages, especially during pregnancy, may have long-term consequences over and above the direct infectious disease morbidity and mortality these infections cause. They include chronic injury of the kidney which eventually may lead to loss of renal function, development of secondary hypertension and, for pregnant women, increased risk of maternal toxaemia, neonatal prematurity and low birth weight which is usually associated with lower-than-normal nephron number anticipating the high risk for hypertension and chronic renal injury during the life time [39]. Moreover, in several regions worldwide, tuberculosis is still an endemic infection with many cases of renal tuberculosis remaining clinically silent for years while irreversible renal destruction takes place [40]. Glomerular involvement with parasitic diseases, including malaria [41], schistosomiasis [42] and leishmaniasis [43], may also pave the way to progressive renal disease. A variety of glomerular lesions, and in particular a unique form of glomerular damage, HIV-associated nephropathy, have emerged as significant forms of renal disease in HIV-infected patients [44]. With the increasing rate of this viral infection, kidney failure in HIV-infected patients will progressively become a major public health problem, particularly in Sub-Saharan Africa. Therefore, in developing countries, infectious diseases add substantial burden to non-communicable risk factors, in enhancing the global prevalence of CKDs. There are also factors that link early malnutrition with being overweight in adulthood, ultimately developing into diabetes and diabetic nephropathy [45]. A number of observational epidemiological studies have postulated that early (intrauterine or early postnatal) malnutrition causes an irreversible differentiation of the metabolic system, which may, in turn, increase the risk of certain chronic diseases in adulthood. For example, a fetus of an undernourished mother will respond to a reduced energy supply by switching on genes that optimize energy conservation. This survival strategy means a permanent differentiation of regulatory systems that result in an excess accumulation of energy (and consequently body fat) when the adult is exposed to an unrestricted dietary energy supply [45]. Because intrauterine growth retardation and low birth weight are common in developing countries or within minority groups, this mechanism may result in the establishment of a population in which many adults are particularly susceptible to developing obesity and CKD. These observations further imply that CKD would affect preferentially the poor within these countries. CKD is also linked to acute kidney injury (AKI). Thus, both the rate of progression to ESRD and all-cause mortality are increased in patients with CKD after transient increases in serum creatinine when compared with patients without CKD [46]. Moreover, up to 28% of the patients with no pre-existing kidney disease who recover from AKI develop de novo CKD [47]. Non-steroidal anti-inflammatory medications, several cardiovascular and diabetes drugs, as well as traditional medicines used in the primary-care setting in developing countries, may lead to the development of transient episodes of AKI. These findings emphasize the relevance of CKD detection and appropriate adjustments in management to optimal outcome in major NCDs. It is increasingly recognized that the burden of CKD is not limited to its implication on demands for RRT but has a major impact on the health of the overall population. Indeed, patients with reduced kidney function represent a population not only at risk for the progression of kidney disease and development of ESRD, but also at even greater risk for cardiovascular diseases. CKD is a major risk factor for cardiovascular mortality, and kidney disease is a major complication of diabetes. In ∼400 000 Medicare patients with diabetes and CKD, in USA over 2 years of follow-up, the risk of death for cardiovascular diseases (32.3%) far exceeded that of the development of ESRD (6:1) [48]. Moreover, CKD has been documented as an independent risk factor for angina, myocardial infarction, heart failure, stroke, peripheral vascular disease and arrhythmias [49, 50]. The increased risk of cardiovascular disease associated with CKD has been shown in both general [37, 51, 52] and high-risk [52] populations, in young and elderly people [53], as well as in Caucasians [49], African blacks [54] and in Asian people [55]. There is also evidence that the increased cardiovascular risk in CKD patients does not just coexist with diabetes or hypertension. Indeed, an independent and progressive association between GFR and risk of cardiovascular events and death has been found in a community-based study in more than 1 million adult subjects in the USA [56]. Similarly, a recent study in more than 6000 people followed on average 7 years has shown that the risk of cardiovascular death was increased 46% in subjects with a mild-to-moderate reduction in GFR (30–60 L/min), independent of conventional risk factors such as diabetes and hypertension [57]. The reason why CKD is a risk factor for cardiovascular outcomes is not entirely but it largely related to the excess prevalence of traditional cardiovascular risk factors, including diabetes and associated with the renal disease. In addition, factors such as of and function may become more and have relevance as CKD patients with and but still normal renal function, are at increased risk of cardiovascular morbidity and mortality studies in the general population that the of or proteinuria is associated with risk of all-cause mortality at all levels of kidney function Thus, through its impact on cardiovascular CKD may contribute to the increasing global burden of death by cardiovascular disease. 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