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To assess the prevalence of microalbuminuria and kidney dysfunction in low-income countries and in the USA.
Cross-sectional study of screening programmes in five countries.
Screening programmes in Nepal, Bolivia, the USA (National Health and Nutrition Examination Survey (NHANES) 2005–2008) Bangladesh and Georgia.
General population in Nepal (n=20 811), Bolivia (n=3436) and in the USA (n=4299) and high-risk subjects in Bangladesh (n=1518) and Georgia (n=1549).
Estimated glomerular filtration rate (eGFR)<60ml/min/1.73 m2 and microalbuminuria (defined as urinary albumin creatinine ratio values of 30–300 mg/g) were the main outcome measures. The cardiovascular (CV) risk was also evaluated on the basis of demographic, clinical and blood data.
The prevalence of eGFR<60ml/min/1.73 m2 was 19%, 3.2% and 7% in Nepal, Bolivia and the USA, respectively. In Nepal, 7% of subjects were microalbuminuric compared to 8.6% in the USA. The prevalence of participants with predicted 10-year CV disease (CVD) risk ≥10% was 16.9%, 9.4% and 17% in Nepal, Bolivia and in the USA, respectively. In Bangladesh and Georgia, subjects with eGFR<60 ml/min/1.73 m2 were 8.6% and 4.9%, whereas those with microalbuminuria were 45.4% and 56.5%, respectively. Predicted 10-year CVD risk ≥10% was 25.4% and 25% in Bangladesh and Georgia, respectively.
Renal abnormalities are common among low-income countries and in the USA. Prevention programmes, particularly focused on those with renal abnormalities, should be established worldwide to prevent CVD and progression to end-stage renal disease.
Chronic kidney disease (CKD) has emerged as one of the strongest cardiovascular (CV) risk factors. In the general population, glomerular filtration rate (GFR) lower than 60 ml/min/1.73 m2 and albuminuria—one of the earliest manifestations of CKD—are associated with an independent risk of CV morbidity and mortality.1–3 Importantly, albuminuria reduction through ACE inhibitor or angiotensin receptor blocker therapy is associated with a slower renal disease progression and decreased CV mortality and morbidity.4 5 Thus, since measurement of renal function and albuminuria is easy and relatively inexpensive, kidney-targeted detection and prevention programmes seem to offer a valuable opportunity to establish early prevention strategies that go beyond traditional cardioprotective approaches.
Nonetheless, data on the prevalence of renal dysfunction and microalbuminuria from population screening programmes in developed countries are scarce. Even fewer information is available from low-income countries, where incidence of renal and CV risk factors such as obesity and diabetes are increasing at an even higher rate than in developed nations.6
In 2005, the International Society of Nephrology (ISN) established a Global Outreach Program (formerly called the Commission on Global Advancement of Nephrology (COMGAN)) aimed at building global capacity for preventing CKD in developing nations. In 2007, the ISN funded the establishment of an electronic database (Kidney Disease Data Center (KDDC)) to support the collection and analysis of data obtained through ISN-sponsored prevention programmes. In the two coordinating centres in Nepal and Bolivia, these programmes have been developed as general population screenings, providing the unique opportunity to assess prevalence of renal dysfunction and microalbuminuria/proteinuria in these areas. In the present study, we analysed general-population data from these two low-income country centres and from the National Health and Nutrition Examination Survey (NHANES), which provides data from a representative sample of the US civilian non-institutionalised population. Moreover, we reported data from screening programmes established in two other centres in Bangladesh and Georgia that focused on high-risk populations, such as subjects with hypertension, diabetes mellitus (DM), prior kidney disease or CV (heart/stroke) disease.
Given variability in local resources, the programmes were implemented differently in each location. Details of the single screening programmes, including numbers of screening centres within each country are listed in table 1. Programmes established in Nepal and Bolivia included general populations. The programme established in Nepal included subjects ≥18 years old and was conducted in the community in Dharan, a city in eastern Nepal as follows. Dharan has 19 wards and the screening started from ward 1 and progressed sequentially to ward 2, ward 3 and so on.
All subjects older than 18 years were considered eligible for the evaluation in Bolivia. The screening programme was conducted in the community in the city of La Paz and El Alto located in Murillo province of the same department. The screening camp was organised in the Unit Nephrology Service at Hospital Juan XXIII. On the day of screening people were asked to come to the centre.
On the day of the screening, the subjects were enrolled after being informed on the objective of the survey, the procedures, the information that could be drawn for the survey and the potential benefits of such screening.
Entry criteria for Bangladesh and Georgia included known hypertension, DM, prior kidney or CV (heart/stroke) disease. Information from the NHANES screening programme of the US population is reported in table 1. Further details are available at http://www.cdc.gov/nchs/nhanes.htm.
Data from low-income countries were collected prospectively by the staff of the screening programmes, using the same cut-off points for clinical and laboratory parameters and the same web-based database and the same cut-off criteria at all participating sites. Data quality was monitored by the bioengineer team of the Clinical Research Center for Rare Diseases, ‘Aldo e Cele Dacco’’, Bergamo, Italy.
Baseline data obtained from each participant included age, gender, marital and employment status, education level, smoking status, alcohol use, DM status and personal history of hypertension and kidney disease. Height and weight were measured and used to calculate body mass index (BMI). Systolic (SBP) and diastolic blood pressures (DBP) were measured by trained personnel using manual sphygmomanometers after participants rested quietly for at least 5 min.
Blood and urine specimens were provided by participants according to local protocols determined by the availability of resources (table 1). Urinary protein/albumin excretion was assessed, respectively, by dipstick and urinary albumin creatinine ratio (ACR) in Nepal and Georgia, by dipstick alone in Bolivia and by ACR alone in the USA. The screening programme in Bangladesh evaluated albumin excretion by Albustick. Results of urinalysis were interpreted by trained and experienced personnel working in appropriate conditions. Follow-up of abnormalities identified during screening varied, depending on local resources (table 1). Screening was carried out under research protocols approved in advance by the relevant institutional review boards.
Microalbuminuria was defined as urinary ACR values of 30–300 mg/g. Subjects with ACR lower than 30 mg/g were defined as normoalbuminuric, those with more than 300 mg/g as macroalbuminuric. Positive Albustick identified patients with microalbuminuria. Results of dipstick urinalysis were considered to indicate macroalbuminuria if they showed protein of 1+ or more. Hypertension was classified according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure scheme.7 Participants were classified as having DM if they reported a history of or were currently treated for DM. Serum creatinine was used to estimate GFR using the Modification of Diet in Renal Disease (MDRD) Study equation in all participants.8 Because the MDRD Study equation is less accurate at higher levels of true GFR, participants were classified regarding the presence or absence of estimated GFR (eGFR)<60 ml/min/1.73 m2 (termed ‘decreased eGFR’). Participants’ BMI was classified according to the current WHO9 scheme as follows: <18.49 (underweight), 18.5–24.9 (reference range), 25–29.9 (preobese) and ≥30 kg/m2 (obese).
The likelihood of a serious CV outcome (death, myocardial infarction, stroke, heart failure or coronary revascularisation) during the next 10 years was estimated by using WHO charts for each studied country (available at http://www.ish-world.com/Documents/colour_charts_24_Aug_07.pdf).
Descriptive statistics were tabulated by country using count and percentage with CI or median and IQR, as appropriate. Missing values were not analysed and case-wise deletion did not occur; therefore, the total number of participants varied by variable. Outcomes of interest included hypertension, proteinuria, eGFR<60 ml/min/1.73 m2, DM, BMI and CV risk. According to the WHO charts, the 10-year risk of a fatal or non-fatal CV event considered the following parameters: age (years), gender, smoking habit, SBP (mm Hg) and presence/absence of DM. A SAS V.9.1 code was constructed to generate the 10-year CV risk class for each participant. Results were stratified by gender, age, prior DM status and prior CV disease (CVD) status. Differences in listed variables between genders were analysed using Cochran-Mantel-Haenszel test—analysis of variance type or χ2 test, as appropriate.
Age-adjusted eGFR<60ml/min/1.73 m2 and ACR>30 prevalence estimates were adjusted by the direct method to the year 2000 US Census population using the age groups 18–24, 25–34, 35–44, 45–54 and 55 years and older. The 95% CIs were calculated using Taylor series linearisation.
Statistical analyses were performed using Stata software, V.12.0 (StataCorp, www.stata.com) for low-income countries and SAS-callable SUDAAN statistical software V.10.0 (Research Triangle Institute, Research Triangle Park, North Carolina, USA) to account for the complex survey sample design for the USA.
Table 2 shows demographic and clinical characteristics of the 31 613 participants.
Median age of participants and gender distribution were similar between the two general population screening cohorts in Nepal and Bolivia and in the USA. Levels of education were variable across nations, with people from Bolivia and the USA showing the highest fraction of subjects with more than 10 years of education. Prevalence of smoking habit was lower than 15% in both low-income countries, whereas it approximated 25% in US subjects. Levels of activity, vegetable intake and alcohol consumption were variable. Bolivian subjects had the highest prevalence of positive familiar history for CKD, hypertension, CVD and diabetes. At physical examination, US participants showed highest levels of BMI, whereas median blood pressure levels were within the normal range for all countries.
High-risk subjects included in Bangladesh and Georgia programmes were older than in general population screenings and more frequently female. Level of education was relatively low in both countries, with people from Bangladesh showing the lower fraction of subjects with more than 10 years of education. Prevalence of smoking habit was almost 30% in Bangladesh and 10% in Georgia. Level of activity was high, with more than 70% of subjects in Bangladesh and 50% in Georgia doing more than 1 h/day of physical activity. Vegetable intake and alcohol consumption were variable. Georgian subjects had the highest prevalence of family history of CKD, hypertension, CVD and diabetes. By physical examination, they also showed the highest levels of BMI, whereas those from Bangladesh had the highest levels of blood pressure.
Within general population screening programmes, Nepalese participants had the highest prevalence of hypertension (assessed at the clinical visit). In each general population programme, the prevalence of hypertension was higher in participants who were male, older than 60 years, or had a history of DM or CVD (table 3).
The prevalence of eGFR<60 ml/min/1.73 m2 was highly variable, ranging from 3.2% in Bolivia to 19% in Nepal. The fraction of US participants with eGFR<60 ml/min/1.73 m2 was 7%. In these nations, the prevalence of eGFR<60 ml/min/1.73 m2 was higher in male subjects and in participants older than 60 years and in those with prior DM or CVD.
The prevalence of microalbuminuria was similar between Nepal and the USA. Only a minority of patients (13.3%) with microalbuminuria in Nepal was positive for proteinuria (≥1+) at urinary dipstick. To take into account for the difference in the age distributions of the programmes examined, we performed age-adjusted prevalence estimates of eGFR<60 ml/min/1.83 m2 and ACR>30. As shown in table 4, age-adjusted analyses confirmed crude data of the prevalence of renal dysfunction in these countries.
Roughly the same prevalence of proteinuria (≥1+) was found in Nepal and Bolivia. In analogy with hypertension, the higher prevalence of microalbuminuria and proteinuria was found within subjects who were male, older than 60 years, or who had a history of DM or CVD.
The proportion of participants who had both eGFR<60 ml/min/1.73 m2 and microalbuminuria or macroalbuminuria was 2.1% and 1.4% in Nepal and Bolivia, respectively. The proportion of participants with both heavy proteinuria (≥3+) and eGFR<60 ml/min/1.73 m2 was markedly lower (Nepal 0.1%, Bolivia 0.5%).
Subjects included in the high-risk population screenings had a high prevalence of hypertension, with almost one-fourth of those in Georgia with stage 2 hypertension. The prevalence of hypertension was higher in male participants and in those older than 60 years, or with a history of DM or CVD (table 3).
In Bangladesh, 45.4% of screened subjects had positive albumin dipstick. More than 50% of screened subjects in Georgia had microalbuminuria and 14% had proteinuria (≥1+). Male gender, older age and a history of DM or CVD were associated with higher levels of proteinuria in both nations. The proportion of participants who had both eGFR<60 ml/min/1.73 m2 and microalbuminuria or macroalbuminuria was 4.8% in Bangladesh and 2.9% in Georgia. The proportion of participants with both heavy proteinuria (≥3+) and eGFR<60 ml/min/1.73 m2 was markedly lower in Georgia (0.5%) where both these measurements were performed.
Subjects with DM (assessed at the clinical visit) were 5.9% in Nepal, 2.6% in Bolivia and 7.9% in the USA. In all the countries, prevalence of DM progressively increased with BMI. No significant difference was found in the prevalence of DM between female and male subjects in Bolivia and in the USA. Conversely, DM was significantly more frequent among males in Nepal programme. Except for Bolivia, where all people with hyperglycaemia had a previous diagnosis of DM, 3.5% and 2.9% of subjects found hyperglycaemic during Nepal and US screening programmes did not have a previous diagnosis of DM. The prevalence of underweight was highest among Nepalese subjects, whereas that of obese subjects was highest in Bolivia (table 5). The prevalence of participants with predicted 10-year CV risk≥10% was 16.9%, 9.4% and 17.0% in Nepal, Bolivia, and the USA, respectively (table 6).
Subjects with DM were frequent both in Bangladesh (9.6%) and in Georgia (15.2%), with 8.5% and 4.4% of subjects with fasting hyperglycaemia having no previous diagnosis of DM, respectively. Prevalence of DM was similar between female and male subjects in both Bangladesh and Georgia. A complementary pattern of nutritional status was found in the two nations. Almost one-fifth of subjects in Bangladesh were undernourished, with only 1.4% of obese people in the nation. Conversely, undernourishment was seen in only 2.6% of Georgian people and 37.4% of cases were obese (table 5). The prevalence of participants with predicted 10-year CV risk≥10% was 25.4% in Bangladesh and 25.0% in Georgia (table 6).
The present large screening programmes of general populations showed a high prevalence of eGFR<60 ml/min/1.73 m2 and microalbuminuria in Nepal and Bolivia, similar to that found in the US population by NHANES. Hypertension, DM and obesity were relatively common among these populations and clustered in subjects with renal dysfunction. As expected, prevention programmes in Bangladesh and Georgia focusing on subjects with already known CVD risk factors such as DM, hypertension or previous CV events found higher prevalence of microalbuminuria. In accordance with previously published studies, male gender was associated with an increased prevalence of hypertension, reduced renal function and proteinuria.10–12
The prevalence of renal dysfunction and microalbuminuria found in Nepal and Bolivia is in line with those reported by other ISN-sponsored screening programmes in indigent residents of Guadalajara, Mexico13 or of Kinshasa, in the Democratic Republic of Congo,14 highlighting the generalisability of this approach for case detection in diverse settings around the world. Notably, the availability of the NHANES dataset allowed us to infer that the burden of CKD is similar across different populations worldwide, including both high-income and low-income countries. Importantly, data on the prevalence of albuminuria retrieved from the NHANES cohort are similar to those reported by the Prevention of Renal and Vascular ENd-stage Disease study, a large European screening programme.15 This is consistent with other evidence that chronic non-communicable diseases are now the major cause of morbidity and mortality in the entire world.16–19 Intriguingly, prevalence of CKD and of subjects with high CV risk was consistent across different countries, independent of per capita incomes (available at http://www.heritage.org/index/default). Of note, prevalence of CKD in low-income countries and in the USA was confirmed when data were corrected for different age distributions across nations. In low-income countries, levels of physical activity were higher than in the US population, whereas smoking habit and alcohol consumption tended to be lower. However, in light of progressive spread of Western lifestyles,20 incidence of DM and hypertension has been forecast to increase in these nations during the next few years, which is also expected to translate into increased CKD and CVD. This clearly highlights the importance of prevention programmes especially in low-income countries, where renal replacement therapies and coronary revascularisation procedures are available only for a minority of people.
About 15% of subjects had an estimated 10% or higher risk of developing a CV risk in the following 10 years. In consideration of the high prevalence of renal dysfunction and microalbuminuria, this risk was probably underestimated, although the net additional contribution of eGFR and albuminuria on CVD risk is still unclear. Long term outcome analysis of the present screened cohorts will allow assessing whether inclusion of albuminuria and/or reduced GFR among the variables considered in algorithms for prediction of individual CVD risk will improve the performance of current WHO prediction algorithms.
Evidence is emerging that CKD and CVD have a major impact on macroeconomic development due to diminished labour supply related to premature death and disability in people of working age. According to WHO, these conditions decrease the potential annual growth rate in gross domestic product by 1–5% in developing countries experiencing rapid economic growth.21 Importantly, data from large trials have consistently shown that off-patent drugs such as ACE inhibitors can reduce albuminuria and prevent GFR decline and CV events.5 Thus, prevention programmes should identify and treat renal abnormalities early, with the primary goal to reduce CV mortality and morbidity, which, on its turn, may translate into an economical benefit.
There is little debate that screening for albuminuria should be performed in patients with DM and/or hypertension, where early intervention can slow down deterioration of renal function. However, due to the difficulty of identifying subjects at risk in low-income countries, a prescreening phase including clinical history, BP and anthropometric values might be instrumental in identifying patients in whom screening with serum and urine testing could be most cost-effective. On the contrary, data from Nepal and Bolivia showed that more than 5% of people younger than 60 years without previous history of diabetes and hypertension had microalbuminuria/proteinuria. Consistently, screening also low-risk groups, or even the general population, has been advocated to identify and treat those at risk for progressive renal disease, arguing that most persons with albuminuria and/or reduced eGFR (<60 ml/min/1.73 m2) are asymptomatic. However, concerns towards general population screenings regard not only the cost of screening itself, but, more importantly, the risk and the cost of treating false-positive subjects with no other modifiable risk factors. Thus, patients with a first positive test should be always asked to repeat the analyses and only those with confirmed positivity should be treated.22 However, when debating how to address the issue of screening for non-communicable diseases and, more in general, of health in developing nations, we should look at the problem from the perspective of the low-income and middle-income countries, not from that of industrialised nations. Indeed, there is not a unique blueprint of screening strategy even among developing countries, so that the approaches should be adapted on single-nation conditions and socioeconomic status.23
Our study has several limitations. At variance with NHANES data, showing characteristics of a cohort representative of US population, results from Bolivia cannot be taken to infer the absolute or relative prevalence of renal abnormalities in this country, since all subjects were referred to a single centre. However, in consideration of the limited availability of local resources, current data seem reasonably reliable and representative of a large fraction of people, at least those living at the altitude regions of this country. Reliability of data is supported by the fact that, in line with available evidence, prevalence of microalbuminuria was higher in older subjects and in those with hypertension or diabetes. Also data from Nepal cannot be formally considered representative of the whole Nepalese population. However, the multiple sites used for the screening, along with the large sample size and consistency with data retrieved from a previous smaller cohort of Nepalese subjects24 make the present dataset insightful of the prevalence of CKD and CVD in this nation. Importantly, data from Bolivia were similar to those found in Nepal and this suggests that these data may reflect patterns throughout the developing world. Of note, although formal comparison across different populations is prevented by different inclusion criteria and sampling strategies, use of the same cut-off points for clinical and laboratory parameters and the same web-based database for data entry and centralised data monitoring make the present analysis a unique opportunity to study prevalence of CKD and CVD in countries with different incomes.
Owing to limited resources, laboratories in developing countries were not calibrated according to the National Kidney Disease Education Program. However, each site made calibrations for creatinine measurement according to guidelines suggested by the manufacture, which should have prevented major bias in our findings. Some authors have advocated to repeat renal function measurements in screening programmes to prevent overestimation of disease prevalence.22 However, in low-income countries, repeated measurements on a standard basis would unnecessarily increase costs and could be burdened by high rate of non-compliance, which, on its turn, could reduce the number of subjects identified with renal abnormalities. In addition, the primary goal of any screening programme is to avoid false negative results that might affect the identification of subjects at risk, whereas the risk of false-positive results is of relatively limited importance since subjects erroneously identified with albuminuria can be correctly characterised at follow-up evaluation. Therefore, different assays to measure albuminuria should be titrated to single resources. Consistently, a pilot phase of National Kidney Foundation Kidney Early Evaluation Program in México City and Jalisco State25 reporting prevalence of eGFR<60 ml/min/1.73 m2 and albuminuria close to the ones we found in high-risk subjects from Georgia and Bangladesh, evaluated albuminuria levels once and used the same cut-off points considered in our analyses.
Finally, an issue of the present study was the use of GFR-predicting equations that may not fully fit to different ethnicities, thus some participants from these countries might have been misclassified with respect to the presence of eGFR<60 ml/min/1.73 m2. This could account for the variability across different countries. On the contrary, performance of formulas is poor for high levels of GFR, whereas they tend to improve for lower values. Thus, risk of misclassification of subjects below the threshold of 60 ml/min/1.73 m2 is reasonably low. Notably, since no ad hoc formulas are available to estimate GFR more precisely in considered populations, such ISN screening programmes might offer the unique opportunity to implement formulas to fit best different ethnicities.
We found that impaired kidney function and microalbuminuria/proteinuria are common within the general population, both in low-income countries and in the USA. Although screening programmes focusing on high-risk subjects seem to be more cost-effective than general population screenings, overall these data demonstrate the feasibility of projects for early detection of CKD in low-income nations. In the light of major impact of renal abnormalities on CVD, these programmes are urgently warranted and should be implemented according to single-nation characteristics. Prospective studies are ongoing26 and will allow quantifying the benefits of such prevention strategies.
Principal investigator: Sanjib Kumar Sharma
Study group: Sanjeev Thapa, Anil Basnet, Madhav Ghimire, Bishnu Pahari, Hemanta Shrestha, Murari Barakoti, Mahesh Bhattarai M, Suchaya Parikh, Santosh Raout, Ram Chandra Kafle, Krishna Kumar Agrawal, Denish Peeyush, Khechar Paudel, Nabin Pandey, Sarita Kumari, Puru Koirala, Navaraj Paudel, Niraj Kumar Jaiswal, Vivek Kattel, Philip Urban, Sujata Rai, Sunira Karki, Mamta Dev, Bangbu Tamang, Mamit Rai, Kajiman Giri, Tofa Limbu. In addition the medical students, the nursing students and staff, the administrators of BPKIHS, various local organisations and leaders, The Redcross of Damak, Sahara Nepal of Biratamod, the media house and reporters form Dharan and Civil Society of Dharan.
Principal investigator: Rodolfo Flores Bravo
Study group: Andrea Alejandra Panozo Rivero, Rocio Adrina Alarcon Terrazas, Elizabeth Joyce Mealla Black, Rocio Miranda Choque, Agustina Anabaya, Ayde Agudo.
Principal investigator: Nazmul Islam
Study group: Mohammad Kamruzzaman, Mokbul Hussain, Tofazzal Hussain, Sujan Miah, Al-Mamun Khan, Anjan Kumar Das,Atiqul Islam, Rezwan Ahmed, Shafiqul Islam. In addition, the Patron of Abdul Khalique Borbhuiya, Shahriah Hossain Chowdhury, Mohammad Afzal Miah.
Principal investigator: Irma Tchokhonelidze
Study group: Avtandil Tataradze, Tinatin Davitaia, Lela Beglarashvili, Nino Khizanishvili, Natia Dvaladze, Lali Bibileishvili
Contributors: NP and GR coordinated the International Society of Nephrology (ISN) GO programmes in low-income countries. RFB (Bolivia), SKS (Nepal), NI (Bangladesh) and IT (Georgia) were principal investigators responsible for the screening programmes in their respective countries. PC wrote the first draft with the assistance of NP, WGC and GR. PC and NP also did the analyses of low-income country data, with statistical support from AP. CWF, JBK and PE analysed NHANES data. Other authors reviewed the report, and provided further contributions and suggestions. All authors read and approved the final report. NP is the guarantor for the above contributors.
Funding: This study was funded by a grant from the International Society of Nephrology (ISN). Additional support was provided by the Intramural Research Program and Division of Kidney, Urology and Hematology, NIDDK, NIH.
Competing interest: None.
Ethics approval: Ethics approved by IRB.
Provenance and peer review: Not commissioned; externally peer reviewed
Data sharing statement: There are no additional data available for data sharing.