Chronic kidney disease: Stemming the global tide

EDITORIALS

Chronic Kidney Disease: Stemming the Global Tide

C

HRONIC KIDNEY DISEASE (CKD) is rapidly becoming a major public health problem globally, with more than 1 million patients on renal replacement therapy (RRT) worldwide and an expected 2 million patients by 2010.1,2 To a large extent, this may be the result of the forthcoming global epidemic of diabetes mellitus (154 million patients with diabetes in 2000, increasing to 370 million in 2030), as well as the aging of the population, with a much greater prevalence of end-stage renal failure (ESRF) in those older than 65 years. There is a clear and direct relationship between a nation’s gross national product and the availability of RRT.3 Approximately 90% of patients with ESRF come from developed nations.3 Conversely, there is limited access to RRT in developing countries, where the low gross national product is unable to meet the increasing demands of health care and the growing burden of ESRF.4 This is reflected in the relatively low prevalence of ESRF in emerging countries compared with high-economy states (Table 1). However, during the next decade, even the most affluent of nations will struggle to meet the demands of expanding ESRF programs; in the United States, the annual expenditure on ESRF has been estimated to reach US $39 billion by 2010.2,5 It is therefore highly imperative to shift the emphasis of the global approach to CKD from provision of RRT to early detection and prevention. Although the management of patients with ESRF consumes the totality of renal health care budgets, they represent less than 0.5% of the total number of patients with CKD. In the United States, the Third National Health and Nutrition Examination Survey (NHANES III) estimated that 11% of the adult American population (19 million persons) may have CKD, with only 345,000 patients reaching ESRF.6 In the United Kingdom, a recent survey estimated the prevalence of CKD to be approximately 5,554 patients per million population (pmp), with only 626 patients pmp on RRT.7 Identification of individuals with early CKD and prevention of progression of their disease are likely to be key factors in alleviating the future burden of ESRF. In addition, such an approach may reduce the morbidity

and mortality of such underlying conditions as hypertension and diabetes, related directly to either the presence of albuminuria or degree of renal function impairment.8 The HOORN study in The Netherlands showed that renal function was associated inversely with all-cause and cardiovascular mortality in the general population; the relative risk for cardiovascular death was 1.26 for each decrease in glomerular filtration rate (GFR) of 5 mL/min/1.73 m.9 This editorial examines some of the strategies applied worldwide for the early detection and prevention of CKD and their potential impact. CHRONIC KIDNEY DISEASE: SCREENING STRATEGIES AND PROGRAMS

To identify patients at risk for CKD, a number of screening strategies have been implemented. Some screening and early-detection programs focused on the entire population, whereas others targeted a specific at-risk group within the population (Table 2). The US-based NHANES III was a nationally based health survey carried out from 1988 to 1994, involving 15,626 adult participants, to ascertain the prevalence of various stages of CKD by using spot urine albumin and calibrated serum creatinine values.6 The overall prevalence of CKD was 11% (⬃19 million persons). The prevalence distribution pattern across the National Kidney Foundation (NKF)–Kidney Disease Outcomes Quality Initiative stages of CKD was stage 1, 3.3% (⬃6 million persons); stage 2, 3.0% (⬃5.3 million persons); stage 3, 4.3% (7.6 million persons); stage 4, 0.25% (400,000 persons); and stage 5/ESRF, 0.2% (⬃345,000 persons). This study pointed to a very large number of cases of asymptomatic CKD in the presumably healthy general population. Received July 2, 2004; accepted in revised form September 17, 2004. Address reprint requests to A. Mequid El Nahas, PhD, FRCP, Sheffield Kidney Institute, Sheffield Teaching Hospital NHS Trust, Northern General Hospital Campus, Sheffield, United Kingdom. E-mail: [email protected] © 2004 by the National Kidney Foundation, Inc. 0272-6386/04/4501-0024$30.00/0 doi:10.1053/j.ajkd.2004.09.005

American Journal of Kidney Diseases, Vol 45, No 1 (January), 2005: pp 201–208

201

202

NWANKWO, BELLO, AND EL NAHAS

Table 1. International Comparisons of the Incidence and Prevalence of ESRF

Country

United States (overall) White African American American Indian United Kingdom Europe Australia Overall Aboriginal population Russia China India Nigeria

Incidence (pmp/y)

Prevalence (pmp/y)

336 256 982 514 101 135–173

1,403 1,004 4,432 3,540 626 600–800

94 420 15 102 34–240 Unknown

658 1,895 79 Unknown Unknown 2.5

NOTE. Most data are for 2000 to 2003.

In Europe, the Prevention of Renal and Vascular End Stage Disease (PREVEND) study undertaken in the Dutch city of Groningen screened and followed up (⬃3 years) almost half the population (⬃40,000 persons) to assess the prevalence of microalbuminuria (increased urine albumin-creatinine ratio [ACR]) in the general population.10 Approximately 7% of those screened had albuminuria. During follow-up, individuals with the greatest level of albuminuria were found to have the greatest incidence of cardiovascular death, thus confirming the association between albuminuria and cardiovascular morbidity and mortality. In Iceland, a study of 18,912 adults found the prevalence of increased serum creatinine levels to be very low (0.22%) compared with other studies.11 This may reflect the use of serum creatinine as the sole measure of renal function, thus potentially overlooking a significant number of individuals with early stage 1 to 2 CKD (GFR ⬎ 60 mL/min). In the Far East, studies have been undertaken in Australia, Japan, Singapore, and India. The Australian Diabetes, Obesity and Lifestyle (AusDiab) study is a population-based crosssectional survey to determine the prevalence of diabetes mellitus, obesity, cardiovascular risk factors, and indicators of kidney disease in Australian adults.12 A representative sample of the Australian adult population comprising 11,247 participants was studied from May 1999 to December 2000, showing 11.2% to have significant renal impairment (GFR ⬍ 60 mL/min) and 2.4%

to have proteinuria.12 The Okinawa screening program evaluated approximately 106,000 adult Japanese individuals between 1983 and 1984 for early markers of kidney disease (proteinuria by dipstick urinalysis and blood pressure measurement) and followed them up for 17 years.13 The study identified obesity, dyslipidemia, and smoking as significant risk factors for the development of albuminuria. It also identified proteinuria14 and obesity15 as major risk factors for the development of ESRF. NKF Singapore has set up a comprehensive program for CKD prevention, initiated in 2000, with more than 450,000 Singaporeans recruited to date.16 The program detected significant urinary abnormalities (proteinuria, 0.8%; hematuria, 9.1%) in the general population.16 In southern India, the Chennai community screening program, screened approximately 25,000 individuals and detected around 6% with previously undiagnosed hypertension and 4% with diabetes mellitus.17 When applied to this community, intensive management of patients with hypertension and diabetes with readily available and inexpensive drugs achieved target values in the majority of patients.17 Some screening programs targeted specific at-risk populations, such as the Australian aborigines18 and the Zuni Indians in the southwestern United States.19 The inhabitants of the Tiwi islands are Australian aborigines, for whom a quarter of all deaths are attributed to ESRF.18 They have an annual incidence of ESRF 5 times that of the Australian population (Table 1). This may explain their very high incidence of cardiovascular mortality; 5-fold that of the general population. In the Tiwi screening program, the overall prevalence of albuminuria was a staggering 44%, and when followed up longitudinally, it highlighted all future risks for renal and cardiovascular deaths. Of interest, intervention in this high-risk group with angiotensin-converting enzyme inhibition significantly reduced blood pressure, proteinuria, and overall mortality.18 The Zuni Indians also have a very high prevalence of ESRF (17,400 pmp; 2% of the population), mainly caused by chronic mesangioproliferative glomerulonephritis and diabetic nephropathy.19 The Zuni Pueblo community study showed a prevalence of albuminuria of approximately 20%.19

EDITORIAL

203 Table 2. Prevalence of Markers of CKD in Various Screening Studies

Study

Design

No. of Patients

Target Group

NHANES III6 KEEP20 PREVEND10 Iceland11 Ausdiab12 Singapore16 Chennai17 Tiwi18 Zuni19

CS CS/L CS R CS CS CS CS CS

15,625 11,246 40,856 18,912 11,247 450,000 25,000 237 1,483

GP HR GP GP GP GP GP HR HR

CKD Prevalence (%)

Proteinuria/ Albuminuria (%)

Hematuria (%)

11 47.4 — — 16

6.3 27 7.2 — 2.4 0.8

3 — — 4.6 9.1

44 19.7

— 17.8

HT, 6; DM, 4 56 37.5

GFR ⬍ 60 mL/ min (%)

ESRF (%)

4.3 16 — 0.22 11.2

0.20 0.30 —

12 —

— —

Abbreviations: Ausdiab, Australian Diabetes, Obesity and Lifestyle study; PREVEND, Prevention of Renal and Vascular End-Stage Disease Study; Singapore, NKF Singapore Program; Chennai, Prevention of Renal Failure at the Community Level Program in India; Tiwi, Australian Aboriginal Community Study; Zuni, Zuni Pueblo Community Study; CS, crosssectional analysis; R, retrospective evaluation; GP, general population; HR, high-risk individuals; HT, hypertension; DM, diabetes mellitus.

The Kidney Early Evaluation Program (KEEP) was piloted in 1997 to 1999 by the NKF to determine the prevalence of early stages of CKD in the at-risk US population.20 KEEP is ongoing, and by the end of 2003, it had recruited more than 22,000 participants. KEEP had a high yield, with an overall prevalence of the different stages of CKD of approximately 50%. Of these, 27% had albuminuria, approximately 16% had elevated serum creatinine concentrations, and 3% had other asymptomatic urinary abnormalities, including hematuria.20 As in the NHANES III, KEEP identified socioeconomic deprivation as an additional risk for the development of CKD. Different communities probably will have to adopt different methods for screening and detecting CKD that best suit their environment, taking into consideration such factors as health awareness and availability of human and material resources. Targeted population screening may best suit well-developed health systems with accurate medical records and databases. Conversely, whole-population surveys may increase health awareness in countries with less sophisticated health systems and could have good yields in the pick-up of first time diabetic and hypertensive individuals. The latter also may have the added advantage of improving the quality of care of those with diabetes and hypertension, thus hopefully minimizing their renal and cardiovascular complications.

CHRONIC KIDNEY DISEASE: RISK FACTORS/MARKERS IN THE COMMUNITIES

A range of common risk factors/markers have been identified that are associated with increased susceptibility to both renal and cardiovascular diseases. These include albuminuria/proteinuria, hypertension, dyslipidemia, and obesity (Tables 2 and 3). In an attempt to identify predictors of newonset kidney disease, 2,585 healthy participants of the Framingham Offspring Study attended a baseline examination in 1978 to 1982 and a follow-up examination 20 years later.21 Of those, 244 persons (9.4%) developed CKD, for whom identifiable risk factors were increasing age (odds ratio [OR], 2.36/10-y increment), GFR less than 90 mL/min/1.73 m2 (OR, 3.01), increased body mass index (OR, 2.60), diabetes (OR, 2.38), smoking (OR, 1.42), and hypertension (OR, 1.57) (21). Similar observations were made in the Okinawa screening program, in which obesity, smoking, and hypertriglyceridemia predicted the onset of proteinuria.13 Proteinuria,14 as well as obesity,15 also predicted the development of ESRF. The Multiple Risk Factors Intervention Study (MRFIT), studying more than 300,000 male US citizens, also showed that hypertension, obesity, and hyperlipidemia were associated with a greater risk for developing CKD.22 The study also identified low socioeconomic status as a risk factor for the development of renal insufficiency.

204

NWANKWO, BELLO, AND EL NAHAS

Table 3. Major Risk Factors for CKD in Communities Study

Okinawa13 FOS21 MRFIT22 ARIC23 WCS24 PHS25

Hypertension Obesity Hyperlipidemia Smoking

⫺ ⫹ ⫹ NS ⫹ NS

⫹ ⫹ ⫹ NS NS NS

⫹ NS ⫹ ⫹ NS ⫹

⫹ ⫹ ⫹ NS ⫹ NS

Abbreviations: MRFIT, Multiple Risk Factor Intervention Trial; FOS, Framingham Offspring Study; ARIC, Atherosclerosis Risk in Communities Study; WCS, Washington County Survey in Maryland; PHS, Physicians’ Health Study; Okinawa, Okinawa Screening Program; ⫹, identified risk factor; ⫺, not a risk factor; NS, not studied.

The Atherosclerosis Risk in Communities (ARIC) study investigated the relationship between plasma lipid levels and the development of renal dysfunction (0.4-mg/dL increase in serum creatinine level) in 12,728 participants with baseline serum creatinine values between 1.8 and 2 mg/dL (159 and 177 ␮mol/L).23 The study reported that high serum triglyceride levels and low high-density lipoprotein cholesterol levels predicted an increase in serum creatinine level during a 3-year period.23 The Washington County survey in Maryland prospectively followed up 23,534 men and women during a 20-year period.24 Baseline blood pressure, cigarette smoking (hazard ratios, 2.4 in men and 2.9 in women), and treated diabetes (hazard ratios, 5 in men and 10.7 in women) were risk factors for the development of CKD.24 The Physicians’ Health Study followed up 4,483 initially healthy men for 14 years and observed that elevated total cholesterol and low high-density lipoprotein cholesterol levels were associated with an increased risk for developing renal dysfunction.25 Common risk factors clearly appear to be associated with both renal and cardiovascular diseases in developed countries. Early detection and prevention may have an impact on the outcome of both renal and cardiovascular morbidity and mortality. In developing countries, the riskfactor profile for CKD may be determined by the extent of Westernization of the society. Westernized societies acquire a risk profile similar to that of the developed world, with diabetes and hypertension leading the risk factors for CKD. It is relevant in that respect to note that the preva-

lence of diabetes is due to increase significantly more in the developing world (3-fold between 2000 and 2030) compared with developed nations (50% increase). However, developing countries continue to experience the burden of infectious diseases and associated CKD; the global burden of human immunodeficiency virus infection, with 40 million infected individuals; hepatitis C (170 million); malaria (300 million cases/ y); schistosomiasis (200 million); and tuberculosis (200 million) is compounded by the high incidence of CKD in affected individuals and the increased morbidity and mortality associated with renal involvement. Programs for the detection and prevention of CKD in the emerging world will have to keep the infectious disease burden in mind in any targeted screening of at-risk individuals. CHRONIC KIDNEY DISEASE: HOW TO SCREEN?

Many of these studies relied on the measurement of urinary albumin or protein for the detection of patients at risk of kidney diseases. However, some have questioned the value of mass screening of the population for proteinuria in isolation, reasoning that its yield of treatable diseases, especially in young adults, is too low to warrant the exercise.26 Orthostatic proteinuria, diet, menstruation, transient fever, hydration status, and physical activity are all factors that may affect the level of proteinuria and undermine the outcome of an untargeted randomly selected mass proteinuria screening exercise. In addition, reliance on proteinuria as the sole marker of CKD can be confounded by its variation with time and the sensitivity of methods used to measure it. In the NHANES III, only 63% of positive results on initial testing for microalbuminuria could be confirmed on repeated testing.6 NHANES III also showed variability in urinary albumin excretion rates with age, with abnormal albuminuria levels varying from 7% in the 20- to 39-year-year-olds group to approximately 30% in those older than 70 years.27 The NordTrondlerg Health study in Norway showed that 3 urine samples positive for an elevated ACR were superior to a lower number of samples in predicting proteinuria.28 However, the Nord-Trondlerg Health study group concluded that in a randomly selected apparently healthy population, as a re-

EDITORIAL

sult of a low positive predictive value and reduced reliability, microalbuminuria did not satisfy criteria for a good screening test.29 In addition, use of a given ACR value to define microalbuminuria may underestimate microalbuminuria in men with greater muscle mass and, possibly, in members of certain ethnicities.30 A timed 24-hour urine albumin excretion rate, considered the most accurate method of albuminuria estimation, reasonably eliminates the variability in urinary albumin concentration caused by activity and posture, but is limited because it is an arduous task for the subject, and there frequently is undercollection or overcollection of the total urinary sample. Most guidelines recommend screening individuals at increased risk in the first instance with albumin-specific dipstick, followed by confirmation by such quantitative analyses as ACR (⬎30 mg/g) before proceeding with additional diagnostic evaluation.31,32 Conversely asymptomatic individuals should be tested initially with a standard dipstick (ⱖ1⫹), to be confirmed by a measurement of total protein-creatinine ratio (⬎200 mg/g) before further evaluation.32 Some investigators suggested that testing for albuminuria and hematuria in combination may be more powerful in predicting renal parenchymal damage than proteinuria alone.33 Screening relying on the measurement of serum creatinine levels, as undertaken in Iceland,11 is limited to the detection of individuals with increased levels suggestive of moderate to severe renal insufficiency, thus underestimating the overall burden of CKD. Conversely, calculation of GFR through a range of formulas based on serum creatinine levels may improve the detection of CKD providing the required additional information is available (age, sex, weight, race, and albumin and blood urea nitrogen levels), thus allowing for potential adjustments based on these demographic and clinical factors.34 CHRONIC KIDNEY DISEASE: HOW TO STEM THE TIDE?

Prevention and Management of Chronic Kidney Disease Lifestyle modification. In attempting to stem the tide of CKD, approaches based on primary and secondary prevention have to be applied. In the West, approximately 60% of all patients with

205

ESRF have diabetes and hypertension. Worldwide, the epidemic of type 2 diabetes is threatening to increase the global burden of CKD. Therefore, approaches aimed at the primary prevention of diabetes mellitus can have major impacts on alleviating the future burden of CKD. A number of trials have shown that lifestyle modifications (diet, weight reduction, and/or exercise) can considerably reduce the incidence of type 2 diabetes in overweight individuals with impaired glucose tolerance.35,36 Lifestyle modifications can be effective in preventing hypertension.37 Smoking38 and, to a lesser extent, alcohol consumption39 and recreational drugs40 have been linked to the development of ESRF. Pharmacological approaches. These have been the subject of numerous comprehensive reviews.41,42 Briefly, control of hypertension has been shown to be the single most important intervention to reduce both albuminuria/proteinuria and the subsequent progression of CKD. In patients with CKD, target blood pressure levels less than 130/85 mm Hg have been recommended in the absence of diabetes or proteinuria and less than 125/75 mm Hg in patients with diabetes and those with proteinuria in excess of protein of 1 g/24 h.31 More recent guidelines recommend a target blood pressure less than 130/80 mm Hg in patients with nondiabetic kidney disease with a protein-creatinine ratio of 200 mg/g or greater, while considering lower systolic blood pressure levels in those with a proteincreatinine ratio greater than 500 mg/g.43 Control of albuminuria/proteinuria also is an important factor in slowing the progression of diabetic and nondiabetic CKD.41,42 For that, antihypertensive approaches based on the inhibition/blockage of the renin-angiotensin system have been recommended in proteinuric (protein-creatinine ratio ⱖ 200 mg/g) patients. Lipid level reduction with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) has been shown to be protective in experimental models of CKD, in which they may be synergistic with manipulation of the renin-angiotensin system.44 In patients with CKD, a systematic review suggested that lowering lipid levels might have a beneficial impact on the rate of progression of renal insufficiency.45 These interventions, including blood pressure control, renin-angiotensin system manipulation, statin treatment, and cessation of

206

smoking, have the added advantage of cardioprotection in susceptible patients with CKD. Manpower The aforementioned programs require considerable resources in terms of both manpower and funds. Implementation of far-reaching programs for the detection and prevention of CKD will require considerable infrastructure and staffing. It will depend primarily on the leadership of nephrologists worldwide. It also will depend on the training and availability of a new generation of dedicated nephrologists with an interest and training in epidemiology and public health. For that, training of nephrologists will have to be tailored to the environment and communities they serve. To achieve their objectives, nephrologists will have to rely on well-trained and motivated community health workers. The formulation of such teams has proved extremely effective and successful when applied to such projects as the prevention of renal failure at the community level in India17 or the Tiwi Islanders in Australia.18 Funding Funding of programs for the detection and prevention of CKD will have to engage governments, nongovernmental organizations, and charitable organizations, as well as the pharmaceutical industry.46 The support of local governments at regional and national levels is a prerequirement to the implementation of many such initiatives. The involvement of nongovernmental organizations and charitable organizations will have an important role in lobbying and encouraging governments to take up and support such programs. Among these, the World Health Organization integrated noncommunicable chronic disease prevention project aims at interventions that target common risk factors for chronic diseases and, by implication, CKD. This is executed through comprehensive strategies involving health care promotion, effective policy formulation and manpower training, and development for all levels of health, from primary to tertiary. Finally, the pharmaceutical industry will have to have a pivotal role in supporting programs for the detection and prevention of CKD, knowing that many of the patients identified undoubtedly will require many of their products to prevent the

NWANKWO, BELLO, AND EL NAHAS

progression of their underlying kidney diseases.46 Strategies for the primary detection and prevention of CKD, as well as the secondary prevention of ESRF, will have considerable health economic impacts. It has been predicted through mathematical modeling that slowing the decline in GFR after 1999 by 10%, 20%, and 30% may lead to cumulative direct health care savings in the United States by 2010 approximating $18.56, $39.02, and $60.61 billion, respectively.5 In conclusion, a multifaceted approach is urgently needed to stem the global tide of CKD. For that, concerted efforts and partnerships will have to be forged between the medical community and governmental agencies, international bodies, and organizations, including the pharmaceutical industry. It also will call for a rethink of medical and nephrological training and that of associated health workers to meet communitybased demands. Such an approach has already been advocated by the Chronic Kidney Disease Initiative launched in 2004 by the Council of American Kidney Societies to address the forthcoming challenge in the United States.47 A globalization of such an approach is urgently needed. Emeka Nwankwo, MBBS, BMedSci University of Maiduguri Maiduguri, Nigeria Aminu K. Bello, MBBS, MMedSci A. Meguid El Nahas, PhD, FRCP Sheffield Kidney Institute Sheffield, UK REFERENCES 1. Lysaght MJ: Maintenance dialysis population dynamics: Current trends and long-term implications. J Am Soc Nephrol 13:S37-S40, 2002 (suppl 1) 2. Xue JL, Ma JZ, Louis TA, Collins AJ: Forecast of the number of patients with end-stage renal disease in United States to the year 2010. J Am Soc Nephrol 12:2753-2758, 2001 3. Schena FP: Epidemiology of end-stage renal disease; International comparisons. Kidney Int Suppl 57:S39-S45, 2000 4. De Vecchi AF, Dratwa M, Wiedmann ME: Healthcare systems and end-stage renal disease: An international review: Costs and reimbursement/funding of ESRD therapies. Nephrol Dial Transplant 14:31-41, 1999 5. Trivedi HS, Pang MM, Campbell A, Saab P: Slowing the progression of chronic renal failure: Economic benefits and patients’ perspectives. Am J Kidney Dis 39:721-729, 2002

EDITORIAL

6. Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS: Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis 41:112, 2003 7. John R, Webb M, Young A, Stevens PE: Unreferred chronic kidney disease: A longitudinal study. Am J Kidney Dis 43:825-835, 2004 8. Ritz E, McClellan WM: Overview: Increased cardiovascular risk in patients with minor renal dysfunction: An emerging issue with far-reaching consequences. J Am Soc Nephrol 15:513-516, 2004 9. Henry RM, Kostense PJ, Bos G, et al: Mild renal insufficiency is associated with increased cardiovascular mortality: The HOORN Study. Kidney Int 62:1402-1407, 2002 10. Hillege HL, Fidler V, Diercks GF, et al, Prevention of Renal and Vascular End Stage Disease (PREVEND) Study Group: Urinary albumin excretion predicts cardiovascular and non-cardiovascular mortality in general population. Circulation 106:1777-1782, 2002 11. Magnason RL, Indridason OS, Sigvaldason H, Sigfusson N, Palsson R: Prevalence and progression of CRF in Iceland: A population-based study. Am J Kidney Dis 40:955963, 2002 12. Chadban SJ, Briganti EM, Kerr PG, et al: Prevalence of kidney damage in Australian adults: The AusDiab Kidney Study. J Am Soc Nephrol 14:S131-S138, 2003 (suppl 2) 13. Iseki K: The Okinawa screening program. J Am Soc Nephrol 14:S127-S130, 2003 (suppl 2) 14. Iseki K, Ikemiya Y, Iseki C, Takishita S: Proteinuria and the risk of developing end stage renal disease. Kidney Int 63:1468-1474, 2003 15. Iseki K, Ikemiya Y, Kinjo K, Inoue T, Iseki C, Takishita S: Body mass index and the risk of development of end-stage renal disease in a screened cohort. Kidney Int 65:1870-1876, 2004 16. Ramirez SP, Hsu SI, McClellan W: Taking a public health approach to the prevention of end-stage renal disease: The NKF Singapore Program. Kidney Int Suppl 63:S61S65, 2003 17. Mani MK: Prevention of chronic renal failure at the community level. Kidney Int Suppl 63:S86-S89, 2003 18. McDonald SP, Maguire GP, Hoy WE: Renal function and cardiovascular risk markers in a remote Australian Aboriginal community. Nephrol Dial Transplant 18:15551561, 2003 19. Stidley CA, Shah VO, Narva AS, et al: A populationbased, cross-sectional survey of the Zuni Pueblo: A collaborative approach to an epidemic of kidney disease. Am J Kidney Dis 39:358-368, 2002 20. Brown WW, Peters RM, Ohmit SE, et al: Early detection of kidney disease in community settings. The Kidney Early Evaluation Program (KEEP). Am J Kidney Dis 42:22-35, 2003 21. Fox CS, Larson MG, Leip EP, Culleton B, Wilson PW, Levy D: Predictors of new-onset kidney disease in a community-based population. JAMA 291:844-850, 2004 22. Klag MJ, Whelton PK, Randall BL, Neaton JD, Brancati FL, Stamler J: End-stage renal disease in African-

207

Americans and white men: 16-Year MRFIT findings. JAMA 277:1293-1298, 1997 23. Muntner P, Coresh J, Smith JC, Eckfeldt J, Klag MJ: Plasma lipids and risk of developing renal dysfunction: The Atherosclerosis Risk in Communities Study. Kidney Int 58:293-301, 2000 24. Haroun MK, Jaar BG, Hoffman SC, Comstock GW, Klag MJ, Coresh J: Risk factors for chronic kidney disease: A prospective study of 23,534 men and women in Washington County, Maryland. J Am Soc Nephrol 14:2934-2941, 2003 25. Schaeffner ES, Kurth T, Curhan GC, et al: Cholesterol and risk of renal dysfunction in apparently healthy men. J Am Soc Nephrol 14:2084-2091, 2003 26. Harwell TS, Nelson RG, Little RR, McDowall JM, Helgerson SD, Gohdes D: Testing for microalbuminuria in 2002. Barriers to implementing current guidelines. Am J Kidney Dis 42:245-249, 2003 27. Coresh J, Wei GL, McQuillan G, Brancati FL: Prevalence of high blood pressure and elevated serum creatinine level in the United States: Findings from the Third National Health and Nutrition Examination Survey (1988-1994). Arch Intern Med 161:1207-1216, 2001 28. Romundstad S, Holmen J, Kvenild K, Hallan H, Ellekjaer H: Microalbuminuria and all cause mortality in 2,089 apparently healthy individuals. A 4.4-year follow up study. The Nord-Trondelag Health Study (HUNT) Norway. Am J Kidney Dis 42:466-473, 2003 29. Romundstad S, Holmen J, Kvenild K, Aakervik D, Hallan H: Clinical relevance of microalbuminuria screening in self reported non diabetic/non-hypertensive persons identified in a large health screening—The Nord-Trondlerg Health Study (HUNT) Norway. Clin Nephrol 59:241-251, 2003 30. Mattix HJ, Hsu C, Shaykevich S, Curhan G: Use of the albumin/creatinine ratio to detect microalbuminuria: Implications of sex and race. J Am Soc Nephrol 13:10341039, 2002 31. National Kidney Foundation: K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, classification, and stratification. Am J Kidney Dis 39:S1S246, 2002 (suppl 1) 32. Keane WF, Eknoyan G: Proteinuria, Albuminuria, Risk Assessment, Detection, Elimination (PARADE): A position paper of the National Kidney Foundation. Am J Kidney Dis 33:1004-1010, 1999 33. Topham PS, Jethwa A, Watkins M, Rees Y, Feehally J: The value of urine screening in a young adult population. Fam Pract 21:18-21, 2004 34. Hsu C, Chertow GM, Curhan GC: Methodological issues in studying the epidemiology of mild to moderate chronic renal insufficiency. Kidney Int 61:1567-1576, 2002 35. Lindstrom J, Eriksson JG, Valle TT, et al: Prevention of diabetes mellitus in subjects with impaired glucose tolerance in the Finnish Diabetes Prevention Study: Results from a randomized clinical trial. J Am Soc Nephrol 14:S108S113, 2003 (suppl 2) 36. Molitch ME, Fujimoto W, Hamman RF, Knowler WC: The Diabetes Prevention Program and its global implications. J Am Soc Nephrol 14:S103-S107, 2003 (suppl 2)

208

37. Appel LJ: Lifestyle modification as a means to prevent and treat high blood pressure. J Am Soc Nephrol 14:S99-S102, 2003 (suppl 2) 38. Orth SR, Ritz E: The renal risks of smoking: An update. Curr Opin Nephrol Hypertens 11:483-488, 2002 39. Perneger TV, Whelton PK, Puddley IB, Klag MJ: Risk of end stage renal disease associated with alcohol consumption. Am J Epidemiol 150:1275-1281, 1999 40. Perneger TV, Klag MJ, Whelton PK: Recreational drug use: A neglected risk factor for end-stage renal disease. Am J Kidney Dis 38:49-56, 2001 41. Ruggenenti P, Schieppati A, Remuzzi G: Progression, remission, and regression of chronic renal diseases. Lancet 357:1601-1608, 2001 42. Schieppati A, Remuzzi G: The June 2003 Barry M. Brenner Comgan lecture. The future of renoprotection: Frustration and promises. Kidney Int 64:19471955, 2003

NWANKWO, BELLO, AND EL NAHAS

43. National Kidney Foundation. K/DOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease. Am J Kidney Dis 43:S1-S290, 2004 (suppl 2) 44. Zoja C, Corna D, Camozzi D, et al: How to fully protect the kidney in a severe model of progressive nephropathy: A multidrug approach. J Am Soc Nephrol 13:28982908, 2002 45. Fried LF, Orchard TJ, Kasiske BL, et al: Effects of lipid reduction on the progression of renal disease: A metaanalysis. Kidney Int 59:260-269, 2001 46. Schieppati A, Remuzzi G: Fighting renal diseases in poor countries: Building a global fund with the help of the pharmaceutical industry. J Am Soc Nephrol 15:704-707, 2004 47. Parker TF, Blantz R, Hostetter T, et al: The Chronic Kidney Disease Initiative. J Am Soc Nephrol 15:708-716, 2004