Journal of the American Society of Nephrology
2008 JASN IMPACT FACTOR 7.505 HOME   AUTHOR INFO   EDITORIAL BOARD   SUBSCRIBE   FEEDBACK   ALERTS   HELP 
    advanced
CURRENT ISSUE ARCHIVES JASN Express ONLINE SUBMISSION


This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Shah, V. O.
Right arrow Articles by Zager, P. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shah, V. O.
Right arrow Articles by Zager, P. G.
J Am Soc Nephrol 14:1320-1329, 2003
© 2003 American Society of Nephrology

Epidemic of Diabetic and Nondiabetic Renal Disease among the Zuni Indians: The Zuni Kidney Project

Vallabh O. Shah*, Marina Scavini{dagger},{ddagger}, Christine A. Stidley§, Francesca Tentori*,¶, Thomas K. Welty*, Jean W. MacCluer#, Andrew S. Narva%, Arlene Bobelu{dagger},@, Carleton P. Albert@, David S. Kessler||, Antonia M. Harford*, Craig S. Wong**, Alexis A. Harris{dagger}{dagger}, Susan Paine§ and Philip G. Zager*

*Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico; {dagger}Dialysis Clinic Inc., Albuquerque, New Mexico; {ddagger}Istituto Scientifico H San Raffaele, Milan, Italy; §Department of Family and Community Medicine, University of New Mexico, Albuquerque, New Mexico; Universita’ degli Studi di Milano, Scuola di Specializzazione in Nefrologia, Milan, Italy; #Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Texas; %Indian Health Service, Albuquerque, New Mexico; @Zuni Pueblo; Zuni PHS Hospital, Zuni, New Mexico; **Department of Pediatrics, University of New Mexico, Albuquerque, New Mexico; {dagger}{dagger}Department of Pathology, University of New Mexico, Albuquerque, New Mexico.

Correspondence to Dr. Philip G. Zager, University of New Mexico, Dept. of Internal Medicine, Nephrology ACC5, Albuquerque, NM 87131-5271. Phone: 505-272-4750; Fax: 505-272-2349;


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
ABSTRACT. There is an epidemic of renal disease among the Zuni Indians. The prevalence of end-stage renal disease among the Zuni Indians is 18.4-fold and 7.4-fold higher than among European Americans and American Indians/Alaskan Natives, respectively. In contrast to other American Indian tribes, nondiabetic renal disease accounts for a significant percent of the renal disease burden among the Zuni Indians. To explore this hypothesis, a community epidemiologic study of the Zuni Pueblo was conducted. A questionnaire was administered, blood and urine samples were collected, and BP, height, and weight were measured. Neighborhood household clusters were used as the sampling frame to maximize ascertainment and minimize bias. Age and gender distributions in the sample (n = 1483) were similar to those of the eligible Zuni population (n = 9228). The prevalence, age-adjusted and gender-adjusted to the Zuni population, of incipient (0.03 <= UACR < 0.3) albuminuria (IA) (15.0% [95% confidence interval, 13.1 to 16.9%]), and overt (UACR >= 0.3) albuminuria (OA) (4.7% [3.6 to 5.8%]) was high. The prevalence estimates for IA and OA were higher among diabetic participants (IA: 33.6% [27.6 to 39.7%]; OA: 18.7% [13.7 to 23.7%]) than nondiabetic participants (IA: 10.8% [9.0 to 12.6%]; OA: 1.8% [1.0 to 2.5%]). However, there were more nondiabetic participants; therefore, they comprised 58.0% [51.4 to 64.6%] and 30.9% [20.0 to 41.7%] of participants with IA and OA, respectively. In contrast to most other American Indian tribes, nondiabetic renal disease contributes significantly to the overall burden of renal disease among the Zuni Indians. E-mail: pzag@unm.edu


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The burden of renal disease is increased among Native Americans (1). The prevalence of albuminuria varies significantly among American Indian tribes (2). There is an epidemic of diabetic renal disease among the Pima Indians (3,4). Less widely recognized is the epidemic of renal disease in the Zuni Indians. In contrast to the epidemic in the Pima Indians, the epidemic among the Zuni Indians is attributable to high rates of diabetic and nondiabetic renal disease (5–7). Among the Zuni Indians, the age- and gender-adjusted prevalence of end-stage renal disease (ESRD) (17,400 per million population) (8) is 18.5-fold, 4.1-fold, and 5.3-fold higher than that among European Americans, African Americans, and Native Americans, respectively (1). The incidence of ESRD at Zuni is increasing rapidly. The average number of new ESRD patients per year treated at the Zuni Dialysis Center increased from 10.4 between 1992 and 1996 to 15.6 from 1997 to 2001 (ESRD Network 15, personal communication). The Zuni Kidney Project (ZKP) is a community-based, collaborative research program established to reduce the burden of renal disease (8). We describe the population-based, cross-sectional survey (PBCSS) conducted by the ZKP to estimate the prevalence of albuminuria and related risk factors.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Population
The pueblo contains over 2000 households and has approximately 10,000 tribal members (9). The median age is 26 yr. Only 8% of the Zuni Indians are >= 60 yr of age. Major occupations include jewelry making, farming, sheep-herding, and government jobs. Low immigration and emigration rates indicate that the population is relatively endogamous.

Survey Design
The PBCSS (8) was conducted from February 1999 to April 2002. All Zuni Indians >= 5 yr of age (n = 9228) were eligible to participate. A household sampling frame within neighborhood clusters was used to maximize participation and reduce the potential for bias associated with differential sampling. Demographics of survey participants were compared with the 2000 Zuni Tribal Census (9). The study was approved by the University of New Mexico Human Research Review Committee, the Indian Health Service (IHS) Institutional Review Board, and the Zuni Tribal Council.

We administered a questionnaire (8) that is based on the Behavioral Risk Factor Surveillance System (10) and Strong Heart Study (11) questionnaires. It contained sections on demographics, medical history, social history, risk factors, and family structure. The reliability and validity of the instrument have been demonstrated (8). BP was measured according to American Heart Association guidelines (12). Height and weight were measured. Serum glucose, total cholesterol, and urine creatinine were measured by colorimetric methods (13). Glycosylated hemoglobin (HbA1c) was measured by latex immunoagglutination inhibition. Urine albumin was measured in spot urine samples by rate nephelometry (14) and expressed as urine albumin to creatinine ratio (UACR) (15).

Classification of Participants
To control costs, enhance efficiency, and maximize recruitment, we utilized validated epidemiologic screening tools (e.g., single spot urine samples for UACR and HbA1c to screen for diabetes) (15,16). Albuminuria was classified according to American Diabetes Association (ADA) guidelines as normal (UACR < 0.03), incipient (IA) (0.03 <= UACR < 0.3), or overt (OA) (UACR >= 0.03) (17).

We also considered using the gender-specific UACR cut-points suggested by Warram et al. (18). We measured urinary creatinine, albumin, and UACR in nondiabetic male participants (n = 416) and female participants (n = 397), aged 15 to 39 yr, and without a history of kidney disease. Median urinary creatinine concentration (mg/dl) was higher among male participants (161.1) than female participants (144.0) (P < 0.05). The ratio of the mean urinary creatinine for female to male participants (0.89) was higher than that (0.68) previously reported (18). Neither the median urinary albumin (mg/dl) or UACR differed between the genders (albumin: 0.82 versus 0.89 [P = 0.76]; UACR: 0.006 versus 0.006 [P = 0.50], male versus female participants, respectively). We thus followed ADA guidelines (17), but we also estimated rates of albuminuria using the gender-specific cut-points recommended by Warram et al. (18).

Participants were classified as diabetic if they had a prior history of diabetes, random glucose >= 200 mg/dl (19), or HbA1c > 7.0% (16). Among Pima Indians without a prior diagnosis of diabetes, the probability of having diabetes was 50% for individuals with HbA1c of 6.0 to 6.9% and 98% for individuals with HbA1c of 7.0 to 7.9% (20). Therefore, we classified participants with HbA1c between 6.0 and 7.0%, a random glucose < 200 mg/dl, and no prior history of diabetes, as having an "indeterminate" diabetes status. Assessing the prevalence of IA and OA in the diabetic and indeterminate groups enabled us to obtain conservative estimates of the prevalence of albuminuria among the remaining participants who had a low probability of being diabetic.

Participants >= 20 yr of age were classified as overweight if their body mass index (BMI) was >= 25 and < 30, and obese if BMI >= 30 (21). Among participants five to 19 yr of age, BMI percentiles were obtained from gender-specific growth charts (22). Participants were classified as overweight if the BMI was >= the 85th and < 95th percentiles and obese if the BMI was >= 95th percentile (23). Participants >= 18 yr of age were classified as hypertensive if they had a prior history of hypertension, a systolic BP (SBP) >= 140 mmHg, or a diastolic BP (DBP) >= 90 mmHg (24). Participants < 18 yr of age were classified as hypertensive if they had a prior history, or a SBP or DBP >= 95th percentile for age and height (25). Among participants < 20 yr and >= 20 yr hypercholesterolemia was defined as total cholesterol >=170 and >= 200 mg/dl, respectively (26,27).

Statistical Analyses
Analyses were conducted using data from the first 1483 ZKP participants for whom UACR, HbA1c, random glucose, history of diabetes, gender, and age were available. Prevalences of albuminuria and potential risk factors were expressed as percentages with 95% confidence intervals (95% CI). Estimates of the variances and covariances were obtained using Taylor series linearization. When appropriate, estimated prevalences of albuminuria and related risk factors were age-adjusted (5-yr intervals) and gender-adjusted using the 2000 Zuni Tribal Census (9), with variance estimates adjusted by the finite population correction factor. Associations of putative risk factors (diabetes, BMI, hypertension, and hypercholesterolemia) for albuminuria were assessed in models that controlled for dependencies created by the sampling design. UACR and putative risk factors were modeled as continuous and categorical variables.

We constructed univariate and multivariate models, using logistic and linear regression, to test for associations of putative risk factors for albuminuria among participants >= 20 yr. Separate models were constructed for diabetic and nondiabetic participants and for the aggregate group. We constructed separate models for IA, OA, and IA and OA combined. All models included adjustments for age and gender.

We compared the prevalence estimates of albuminuria and putative risk factors among the Zuni Indians with those in the US population and the Strong Heart Study. Estimates for the US population were obtained from the third National Health and Nutrition Examination Survey (NHANES III) (28). Albuminuria prevalence among Strong Heart Study participants was derived from published data (29). Reproducibility of laboratory data was assessed using percent agreement and the weighted kappa statistic. The ZKP database was maintained in MS Access (Microsoft, Redmond, WA) and converted to SAS (SAS Institute, Inc., Cary, NC), SUDAAN (RTI, Research Triangle Park, NC), and StatXact (Cytel Software Corporation, Cambridge, MA) for statistical analyses. The level of statistical significance was P < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
We compared the population sample with the eligible Zuni Tribal Population (ZTP). Female participants comprised 52.2% (95% CI, 49.7 to 54.7) of ZKP survey participants versus 51.9% of the eligible ZTP. Among those >= 25 yr of age, high school graduates comprised 61.9% (58.7 to 65.1) of survey participants versus 58.7% of the ZTP. The percentages of people >= 40 yr of age were similar among survey participants (28.9% [26.6 to 31.7]) and the ZTP (29.5%). Although the sample was similar to the eligible ZTP with regard to age, gender, and educational attainment, there may have been important unrecognized differences that resulted in unrecognized selection bias. For example, the high level of anxiety associated with renal disease may have resulted in a sampling bias due to underrepresentation of Zuni Indians with serious renal disease.

Reproducibility of the albuminuria classification was validated by analyzing split samples (n = 462) in two laboratories (UNM Health Sciences Center and NIDDK-Phoenix). Results were categorized as normal, incipient, and overt, and were compared. Percent agreement was 95% (92 to 97), and the weighted kappa was 0.85 (0.78 to 0.93). Due to the high percentage of participants in the normal category, the kappa statistic was more sensitive to disagreements than when the categories are equally distributed.

Prevalence estimates of IA and OA, stratified by age and gender, are shown (Table 1). Overall, the age- and gender-adjusted prevalences of IA and OA were 15.0% [13.1 to 16.9] and 4.7% [3.6 to 5.8], respectively. The prevalences of IA and OA, respectively, were similar among female and male participants. Among male and female participants >= 45 yr of age, only 54.4% (44.6 to 64.2) and 57.7% (50.9 to 64.4) had normal UACR values. The use of gender-specific cut-points (18) resulted in slightly higher prevalence estimates of albuminuria compared with those obtained using the single cut-points specified above. Specifically, the prevalence of albuminuria among male participants using the single cut-point was 20.7% [17.5 to 23.9] versus 28.2% [24.7 to 31.8] using gender-specific cut-points. Among female participants, the prevalence estimates of albuminuria were 18.8% [16.0 to 21.7] and 20.5% [17.6 to 23.4] using single versus gender-specific cut-points, respectively.


View this table:
[in this window]
[in a new window]

  		Table 1. Prevalence (%) of albuminuria, stratified by age and gender, among Zuni Indians >= 5 yr of agea
 
We estimated the prevalence of albuminuria among survey participants, stratified by diabetes status (Table 1). The percentages of male and female participants with IA and OA were higher among diabetic than nondiabetic participants. However, nondiabetic participants comprised 58.0% [51.4 to 64.6] of those with IA and 30.9% [20.0 to 41.7] of those with OA. Among all participants with albuminuria, 51.6% [45.6 to 57.5] were nondiabetic, 42.9% [37.0 to 48.7] were diabetic, and 5.6% [1.9 to 9.7] had an indeterminate diabetes status.

The distribution of the UACR values among ZKP participants was skewed. Both the medians and geometric means were significantly lower than the raw, untransformed means. The geometric mean values, stratified by age and gender, are shown (Table 2). The geometric means tended to increase with advancing age among both female and male participants.


View this table:
[in this window]
[in a new window]

  		Table 2. Geometric means of urinary albumin to creatinine ratio (UACR), stratified by age and gender, among survey participantsa
 
There was significant gender disparity in the prevalence of selected risk factors (Table 3). The prevalence estimates for obesity and diabetes were higher among female participants (P < 0.001). Hypertension (P < 0.001) and hypercholesterolemia (P < 0.01) were both more common among male than female participants.


View this table:
[in this window]
[in a new window]

  		Table 3. Age-adjusted prevalence (%) of being overweight, obesity, high cholesterol, hypertension, and diabetes, stratified by age and gender, among Zuni Indians >= 5 yr of agea
 
We examined the relationships between age and the prevalence estimates for albuminuria and putative risk factors. The prevalence of albuminuria tended to increase with advancing age. Among female Zuni Indians (Table 1), the prevalence of both IA and OA was higher in those >= 45 yr of age than in any other age group (P < 0.05). Among male participants in the aggregate group, the prevalence estimates of IA and OA tended to be higher among those >= 45 yr of age, although these differences did not attain statistical significance. The effect of advancing age on the prevalence of albuminuria appeared to be greater among nondiabetic versus diabetic (Table 1) participants. Among female participants, the prevalence of hypertension was highest in those >= 45 yr of age (P < 0.05; Table 3). Among male participants, the prevalence of hypertension tended to increase with advancing age, but these changes did not reach statistical significance. The prevalence of obesity did not increase after age 25 yr among either male or female participants.

The results of our modeling are discussed below. Because the results from the univariate models were similar to those from the multivariate models, only the latter are presented. We present only those models in which UACR and the continuous risk factors were categorized and generalized estimating equations used. This decision was made for the following reasons: (1) in some instances, e.g., BMI, the assumption of a linear association between the predictor and the outcome variables was violated; (2) the distribution of UACR was very skewed, resulting in observations with extreme influence; and (3) none of the models with continuous variables were more informative than those with discrete variables.

The odds ratios (OR) for IA, OA, and IA and OA combined for selected risk factors among participants, stratified by diabetes status, are shown (Table 4). There were significant differences in the magnitude of the OR between diabetic and nondiabetic participants. Among diabetic participants, there were no significant increases in the OR for IA associated with being overweight or obese. Hypertension and hypercholesterolemia tended to have increased OR for albuminuria among diabetic participants, but these did not attain statistical significance. Among nondiabetic participants, being overweight, hypertensive, or hypercholesterolemic were associated with increased OR for IA and OA combined.


View this table:
[in this window]
[in a new window]

  		Table 4. Odds ratios for incipient and overt albuminuria, adjusted for age and gender, among survey participants aged >= 20 yr, stratified by diabetes statusa
 
The OR for IA, OA, and IA and OA combined among diabetic and nondiabetic participants in aggregate are shown (Table 5). These models demonstrated multiple interactions between diabetes status, BP, and BMI. Diabetes was associated with an increased OR for IA and OA combined with or without hypertension and/or a high BMI. Hypertension was associated with an increased OR for IA and OA combined among nondiabetic but not among diabetic participants. Hypercholesterolemia was associated with an increased OR for IA and OA combined.


View this table:
[in this window]
[in a new window]

  		Table 5. Odds ratios for incipient and overt albuminuria, adjusted for age and gender, among survey participants aged >= 20 yr (n = 952)a
 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study documents an epidemic of albuminuria among the Zuni Indians (7,30). It also demonstrates associations of diabetes, a high BMI, hypertension, and hypercholesterolemia with albuminuria. Among individuals >= 15 yr of age, the Zuni Indians had a higher prevalence of albuminuria (22.9% [20.5 to 25.3]) than the US population (8.5% [7.9 to 9.2]) (28). The prevalence of albuminuria among Zuni Indians was higher than among American Indians from Oklahoma and the Dakotas but lower than those from Arizona (29) (Figure 1A). A comparison of prevalence of putative risk factors for albuminuria among the Zuni Indians and the US population is shown (Figure 1B). Obesity, diabetes and hypertension were significantly more common among the Zuni Indians than in the US population of similar age. In contrast, hypercholesterolemia was more frequent in the US population (28). The findings in the Zuni Indians are similar to those in an Australian Aboriginal community where the prevalence estimates for IA and OA were 26% and 24%, respectively (31).



View larger version (26K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Figure 1. (A) Prevalence of albuminuria (UACR >= 0.03) among Zuni Indians and Strong Heart Study participating tribes (age, 45 to 74 yr). {blacksquare}, all; {square}, diabetic participants; {blacksquare} nondiabetic participants. (B) Prevalence of obesity, diabetes, high cholesterol, and hypertension among Zuni Indians and U.S. population (age >= 20 yr). {blacksquare}, Zuni Indians; {square}, US population.

 
The prevalence of albuminuria among nondiabetic Zuni Indians is among the highest reported among nondiabetic American Indians (32). Two distinct types of renal disease, e.g., diabetic nephropathy and mesangiopathic glomerulonephritis (Mes GN), occur among the Zuni (5–7,33). In 1986 to 1987, the prevalence of proteinuria among self-selected members of the Zuni Pueblo (n = 1627) was 7.1%, and only a third of the cases were attributed to diabetes (30). Between 1973 and 1983, diabetic nephropathy and chronic glomerulonephritis accounted for 24% and 40%, respectively, of ESRD (6). A high proportion of renal biopsy specimens have shown Mes GN, frequently with IgA positivity on immunoflourescence and electron dense deposits on electron microscopy (7,33).

In concert with the tribe’s wishes, the ZKP did not perform renal biopsies. Clinically indicated biopsies were performed by the IHS nephrologist (AN). Photomicrographs from renal biopsies in two patients illustrate two distinct types of renal disease, e.g., diabetic nephropathy (DN) and IgA nephropathy (IgAN). Figures 2A and 2B are from the patient with DN. Figure 2A demonstrates a glomerulus with prominent Kimmelsteil-Wilson sclerotic nodules and prominent arteriolar hyalinosis. Figure 2B demonstrates marked thickening of the basement membrane, mesangial expansion, and the absence of immune deposits. Immunoflourescence (not shown) revealed that there was no granular staining in the glomeruli with antisera specific against IgG, IgA, or IgM. Figures 2C and 2D are from the patient with IgAN. Figure 2C shows a mild mesangial hypercelluarity and an increase in mesangial matrix. Figure 2D demonstrates a mild increase in mesangial matrix and deposition of immune complexes. Immunofluorescence was positive (3+) for IgA (not shown). In conjunction with previous reports (7,33), these photomicrographs suggest that at least two distinct types of renal disease occur among the Zuni Indians. Other causes of albuminuria, e.g., focal sclerosing glomerulonephritis, membranous glomerulopathy, and amyloid among the Zuni Indians have been reported (7,33).



View larger version (152K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Figure 2. (A) Diabetic glomerulosclerosis with large Kimmelsteil-Wilson nodule formation and prominent arteriolar hyalinosis (periodic-acid Schiff stain, x40 magnification). (B) Diabetic glomerulosclerosis with marked thickening of basement membranes, mesangial expansion, and absence of immune deposits (electron microscopy, x5000 magnification). (C) IgA nephropathy with mild focal mesangioproliferative glomerulonephritis, mild increase in mesangial matrix with mild mesangial hypercellularity (hematoxylin and eosin stain, x40 magnification). (D) IgA nephropathy with mild increase in mesangial matrix and occasional mesangial immune deposits (electron microscopy, x6000 magnification).

 
The causes of the high rates of diabetic and nondiabetic renal disease are not readily apparent. Diabetes had the strongest association with albuminuria. The prevalence of diabetes among adult ZKP participants was higher than among the US and composite American Indian populations (34,35), but similar to that among Strong Heart Study participants from Oklahoma and the Dakotas (36). Among diabetics, the Zuni Indians may have a higher risk for developing nephropathy than other American Indians.

Other putative risk factors, e.g., hypertension, hypercholesterolemia, and obesity, may also contribute to the epidemic. Similar to a recent report by Hoehner et al. (32), hypertension was associated with IA among nondiabetic participants. Hypertension was also associated with OA among diabetic participants. Although the association of hypercholesterolemia with IA and OA among diabetics was in concert with previous reports (37,38), the cross-sectional survey of the present study precluded determining if the hypercholesterolemia preceded the onset of albuminuria. Recent epidemiologic (39) and experimental (40,41) studies support a role for hypercholesterolemia as a risk factor for susceptibility and progression of renal disease. There are conflicting reports regarding the putative role of obesity as a risk factor for renal disease. An association between massive obesity and the nephrotic syndrome has been reported (42). However, previous studies in American Indians did not demonstrate independent associations between obesity and renal disease (29,43). Although there was no evidence of a strong association between obesity and albuminuria in the present study, this may reflect survivor bias due to decreased mortality among non-obese subjects.

It is unlikely that the high rates of albuminuria among the Zuni Indians can be accounted for solely by established risk factors. It is thus reasonable to postulate that genetic factors, possibly acting in concert with established risk factors, contribute to the increased risk for albuminuria (44,45). Among the Zuni Indians, there is familial aggregation of diabetic and nondiabetic renal disease (7). An apparent autosomal dominant mode of inheritance has been reported for IgAN among a Zuni pedigree (46). These findings are consistent with the hypothesis that genetic factors may modulate the risk for both diabetic and nondiabetic renal disease. Reports of familial clustering of renal disease in other populations are consistent with the existence of renal failure susceptibility genes (47). Freedman et al. (47–49) observed clustering of ESRD of diverse causes (diabetic nephropathy, HIV nephropathy, hypertension, and glomerulonephritis) within large African-American families.

The age-related increases in the prevalence estimates of albuminuria, diabetes, and hypertension observed in the present study are consistent with the hypothesis that the metabolic syndrome ("Syndrome X") and clinical diabetes predispose to the development of diabetic and nondiabetic renal disease among the Zuni Indians. It is likely that some nondiabetic participants had albuminuria that could be attributed to the metabolic syndrome. Hoy et al. (31) reported that albuminuria in an Australian Aboriginal community was associated with obesity and hypertension and thus may be part of the metabolic syndrome. Isomaa et al. (50) demonstrated that among Swedish patients with type 2 diabetes mellitus (T2DM), the prevalence of albuminuria was higher in those with versus those without the metabolic syndrome. In a multiple logistic regression analysis, the metabolic syndrome was associated with microalbuminuria (RR, 3.99; P = 0.01).

Freedman et al.(49) observed a familial predisposition to nephropathy among African Americans with T2DM. Among index cases with T2DM and ESRD, 37% reported a close relative with ESRD. In contrast, only 7% of age- and gender-matched individuals with T2DM without nephropathy reported ESRD in a close relative. These investigators subsequently reported that asymptomatic elevations in serum creatinine and urinary albumin excretion were frequently present in diabetic siblings of African Americans with T2DM and diabetic nephropathy (51). Similarly, Brancati et al. (52) reported that diabetes mellitus was a risk factor for both diabetic and nondiabetic ESRD among a cohort of men screened for the Multiple Risk Factor Intervention Trial (MRFIT).

The design of this study enhanced economy, efficiency, and recruitment, but it imposed significant limitations. Although use of a single UACR determination may have led to the misclassification of some participants, it was unlikely to cause systematic bias in the overall prevalence estimate. Several epidemiologic studies have relied on a single UACR determination to estimate albuminuria prevalence (3,29,31,32,53). UACR was measured irrespective of medications. Angiotensin-converting enzyme inhibitors (ACEi) and/or angiotensin II receptor antagonists (ARBs) are standard of care for diabetic patients (17) and nondiabetic patients (54) with albuminuria. ACEi and ARBs may reduce proteinuria by 30 to 50% (55). Since these drugs were not withdrawn before UACR determination, the prevalence of albuminuria may have been significantly underestimated. The classification of diabetes status relied on self-report, random serum glucose, and HbA1c. We did not perform oral glucose tolerance tests; therefore, we could not detect impaired glucose tolerance (IGT). The prevalence of albuminuria may be increased among individuals with IGT (3,29). Albuminuria may precede the onset of clinical T2DM in Whites (56) and American Indians (57). Thus, IA in some nondiabetic ZKP participants may be attributable to IGT. Some participants who did not meet the criteria for diabetes mellitus at the time of the survey will do so later in life.

The present study also has several unique strengths. First, in contrast to previous studies (5–7,30), it was population-based. Second, it obtained precise estimates of putative risk factors (hypertension, obesity, hypercholesterolemia, and diabetes) for albuminuria. Third, it utilized univariate and multivariate logistic and linear regression models to test for associations of these risk factors with albuminuria among diabetic and nondiabetics participants, separately and combined.

In summary, the use of a highly sensitive and reliable nephelometric method for detecting albuminuria in a representative sample of the eligible Zuni Tribal population provided precise estimates of prevalence of IA and OA among the Zuni Indians. The prevalence of albuminuria was high among both diabetic and nondiabetic Zuni Indians. IGT and metabolic "Syndrome X" may contribute to the high prevalence of albuminuria among those who do not meet the criteria for clinical diabetes mellitus. Nevertheless, a significant portion of the renal disease among the Zuni Indians may be attributable to MesGN and other types of primary and secondary glomerular disease.


   Acknowledgments
 
We acknowledge the contributions and support of the Zuni Governor, M. Bowekaty, and the Zuni Tribal Council. We appreciate the dedication of the ZKP staff (J. Bobelu, E. Jamon, K. Natachu, D. Neha, and M. Waikaniwa) to the ZKP and their community. We express our sincere thanks to the Zuni people for welcoming us in their community. Without their support this project would not have been possible. We appreciate Dr. Knowler and NIDDK Phoenix for validating our UACR measurements. We also acknowledge the advice provided by the SHS investigators and the Zuni IHS staff. We recognize the excellent technical support provided by B. Brennan, D. Dalton, J. Ghahate, M. Helbert, M. Lamey, S. McClelland, W. McCurdy, T. Peynetsa, D. Solomon, and K. Utterback. This research was funded in part by the National Institutes of Health (DK 49347, 07/01/1997 to 06/30/2002), the University of New Mexico Clinical Research Center (NIH NCRR GCRC Grant 5MO1 RR OO997), National Institutes of Environmental Health (ES 09871, 04/01/1999 to 03/31/2003) and Dialysis Clinic, Inc. The opinions expressed in this paper are those of the authors and do not necessarily reflect those of the Indian Health Service.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. U.S. Renal Data System. USRDS 2000 Annual Data Report. Bethesda, MD, NIH, NIDDK, 2000
  2. Narva AS: ESRD in the American Indian population. Nephrol News Issues 10: 28–30, 1996
  3. Nelson RG, Kunzelman CL, Pettitt DJ, Saad MF, Bennett PH, Knowler WC: Albuminuria in type 2 (non-insulin-dependent) diabetes mellitus and impaired glucose tolerance in Pima Indians. Diabetologia 32: 870–876, 1989[CrossRef][Medline]
  4. Nelson RG, Morgenstern H, Bennett PH: An epidemic of proteinuria in Pima Indians with type 2 diabetes mellitus. Kidney Int 54: 2081–2088, 1998[CrossRef][Medline]
  5. Narva AS, Beaver S, Blackman D, Zack M, Freeman W: Descriptive study of renal disease at Pueblo of Zuni. Am J Kidney Dis 20: A8, 1992
  6. Pasinski R, Pasinski M: End-stage renal disease among the Zuni Indians: 1973–1983. Arch Intern Med 147: 1093–1096, 1987[Abstract/Free Full Text]
  7. Hoy WE, Megill DM, Hughson MD: Epidemic renal disease of unknown etiology in the Zuni Indians. Am J Kidney Dis 9: 485–496, 1987[Medline]
  8. Stidley CA, Shah VO, Narva AS, Dalton D, MacCluer JW, Bobelu A, Scavini M, Welty TK, Zager PG: A population-based, cross-sectional survey of the Zuni Pueblo: a collaborative approach to an epidemic of kidney disease. Am J Kidney Dis 39: 358–368, 2002[Medline]
  9. Office of the Zuni Tribal Census: Tribal Census. Zuni Pueblo, NM, Office of the Zuni Tribal Census, 2000
  10. Nelson DE, Holtzman D, Waller M, Leutzinger CL, and Condon, K: Objectives and design of the behavioral risk factor surveillance system. In: Proceedings of the Section on Survey Research Methods, Alexandria, VA, American Statistical Association, 1998, pp. 214–218
  11. Lee ET, Welty TK, Fabsitz R, Cowan LD, Le NA, Oopik AJ, Cucchiara AJ, Savage PJ, Howard BV: The Strong Heart Study. A study of cardiovascular disease in American Indians: design and methods. Am J Epidemiol 132: 1141–1155, 1990[Abstract/Free Full Text]
  12. Perloff D, Grim C, Flack J, Frohlich ED, Hill M, McDonald M, Morgenstern BZ: Human blood pressure determination by sphygmomanometry. Circulation 88: 2460–2470, 1993[Free Full Text]
  13. Burtis C, Ashwood E, Tietz N: Tietz Textbook of Clinical Chemistry, 3rd ed., Philadelphia, WB Saunders, 1999
  14. Watts GF, Bennett JE, Rowe DJ, Morris RW, Gatling W, Shaw KM, Polak A: Assessment of immunochemical methods for determining low concentrations of albumin in urine. Clin Chem 32: 1544–1548, 1986[Abstract/Free Full Text]
  15. Schwab SJ, Christensen RL, Dougherty K, Klahr S: Quantitation of proteinuria by use of protein-to-creatinine ratios in single urine samples. Arch Intern Med 147: 943–944, 1987[Abstract/Free Full Text]
  16. Rohlfing CL, Little RR, Wiedmeyer HM, England JD, Madsen R, Harris MI, Flegal KM, Eberhardt MS, Goldstein DE: Use of GHb (HbA1c) in screening for undiagnosed diabetes in the U.S. population. Diabetes Care 23: 187–191, 2000[Abstract]
  17. American Diabetes Association: Diabetic nephropathy. Diabetes Care 25: S85–S89, 2002[CrossRef]
  18. Warram JH, Gearin G, Laffel L, Krolewski AS: Effect of duration of type I diabetes on the prevalence of stages of diabetic nephropathy defined by urinary albumin/creatinine ratio. J Am Soc Nephrol 7: 930–937, 1996[Abstract]
  19. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 24 [Suppl 1]: S5–S20, 2001[CrossRef]
  20. Hanson RL, Nelson RG, McCance DR, Beart JA, Charles MA, Pettitt DJ, Knowler WC: Comparison of screening tests for non-insulin-dependent diabetes mellitus. Arch Intern Med 153: 2133–2140, 1993[Abstract/Free Full Text]
  21. Garrow JS, Webster J: Quetelet’s index (W/H2) as a measure of fatness. Int J Obes 9: 147–153, 1985[Medline]
  22. Kuczmarski RJ, Ogden CL, Grummer-Strawn LM, Flegal KM, Guo SS, Wei R, Mei Z, Curtin LR, Roche AF, Johnson CL: CDC growth charts: United States. Adv Data 1: 27, 2000
  23. Barlow SE, Dietz WH: Obesity evaluation and treatment: Expert Committee recommendations. The Maternal and Child Health Bureau, Health Resources and Services Administration and the Department of Health and Human Services. Pediatrics 102: E29, 1998
  24. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 157: 2413–2446, 1997[Abstract/Free Full Text]
  25. National High Blood Pressure Education Program Working Group on Hypertension Control in Children and Adolescent: Update on the task force report on high blood pressure in children and adolescent: A working group report from the National High Blood Pressure Education Program. Pediatrics 98: 649–658, 1996[Abstract/Free Full Text]
  26. American Academy of Pediatrics Committee on Nutrition: Cholesterol in childhood. Pediatrics 101: 141–147, 1998[Abstract/Free Full Text]
  27. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 285: 2486–2497, 2001[Free Full Text]
  28. Third National Health and Nutrition Examination Survey, 1988–1994, NHANES III Laboratory Data File, Household Adult Data File, and Household Youth Data File (CD-ROM). Public Use Data File Documentation no. 76200, 76300, 77560, and 77550, Hyattsville, MD, US Department of Health and Human Services (DHHS), National Center for Health Statistics, 1996
  29. Robbins DC, Knowler WC, Lee ET, Yeh J, Go OT, Welty T, Fabsitz R, Howard BV: Regional differences in albuminuria among American Indians: An epidemic of renal disease. Kidney Int 49: 557–563, 1996[Medline]
  30. Megill DM, Hoy WE: Risk factors for renal disease in a Native American community. Transplant Proc 21: 3902–3905, 1989[Medline]
  31. Hoy WE, Mathews JD, McCredie DA, Pugsley DJ, Hayhurst BG, Rees M, Kile E, Walker KA, Wang Z: The multidimensional nature of renal disease: Rates and associations of albuminuria in an Australian Aboriginal community. Kidney Int 54: 1296–1304, 1998[CrossRef][Medline]
  32. Hoehner CM, Greenlund KJ, Rith-Najarian S, Casper ML, McClellan WM: Association of the Insulin Resistance Syndrome and Microalbuminuria among Nondiabetic Native Americans. The Inter-Tribal Heart Project. J Am Soc Nephrol 13: 1626–1634, 2002[Abstract/Free Full Text]
  33. Hughson MD, Megill DM, Smith SM, Tung KS, Miller G, Hoy WE: Mesangiopathic glomerulonephritis in Zuni (New Mexico) Indians. Arch Pathol Lab Med 113: 148–157, 1989[Medline]
  34. Harris MI, Flegal KM, Cowie CC, Eberhardt MS, Goldstein DE, Little RR, Wiedmeyer HM, Byrd-Holt DD: Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. The Third National Health and Nutrition Examination Survey, 1988–1994. Diabetes Care 21: 518–524, 1998[Abstract]
  35. Burrows NR, Geiss LS, Engelgau MM, Acton KJ: Prevalence of diabetes among Native Americans and Alaska Natives, 1990–1997: An increasing burden. Diabetes Care 23: 1786–1790, 2000[Abstract/Free Full Text]
  36. Lee ET, Howard BV, Savage PJ, Cowan LD, Fabsitz RR, Oopik AJ, Yeh J, Go O, Robbins DC, Welty TK: Diabetes and impaired glucose tolerance in three American Indian populations aged 45–74 years. The Strong Heart Study. Diabetes Care 18: 599–610, 1995[Abstract]
  37. Krolewski AS, Warram JH, Christlieb AR: Hypercholesterolemia–a determinant of renal function loss and deaths in IDDM patients with nephropathy. Kidney Int Suppl 45: S125–S131, 1994[Medline]
  38. Nelson RG, Knowler WC, Pettitt DJ, Hanson RL, Bennett PH: Incidence and determinants of elevated urinary albumin excretion in Pima Indians with NIDDM. Diabetes Care 18: 182–187, 1995[Abstract]
  39. 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[CrossRef][Medline]
  40. Kasiske BL, O’Donnell MP, Schmitz PG, Kim Y, Keane WF: Renal injury of diet-induced hypercholesterolemia in rats. Kidney Int 37: 880–891, 1990[Medline]
  41. Nishimura M, Tanaka T, Yasuda T, Kurakata S, Kitagawa M, Yamada K, Saito Y, Hirai A: Collagen secretion and growth of mesangial cells require geranylgeranylpyrophosphate. Kidney Int 55: 520–528, 1999[CrossRef][Medline]
  42. Kambham N, Markowitz GS, Valeri AM, Lin J, D’Agati VD: Obesity-related glomerulopathy: An emerging epidemic. Kidney Int 59: 1498–1509, 2001[CrossRef][Medline]
  43. Nelson RG, Knowler WC, Pettitt DJ, Hanson RL, Bennett PH: Incidence and determinants of elevated urinary albumin excretion in Pima Indians with NIDDM. Diabetes Care 18: 182–187, 1995
  44. Lei HH, Perneger TV, Klag MJ, Whelton PK, Coresh J: Familial aggregation of renal disease in a population-based case-control study. J Am Soc Nephrol 9: 1270–1276, 1998[Abstract]
  45. Young EW, Mauger EA, Jiang KH, Port FK, Wolfe RA: Socioeconomic status and end-stage renal disease in the United States. Kidney Int 45: 907–911, 1994[Medline]
  46. Hsu SI, Ramirez SB, Winn MP, Bonventre JV, Owen WF: Evidence for genetic factors in the development and progression of IgA nephropathy. Kidney Int 57: 1818–1835, 2000[CrossRef][Medline]
  47. Freedman BI, Soucie JM, Stone SM, Pegram S: Familial clustering of end-stage renal disease in blacks with HIV-associated nephropathy. Am J Kidney Dis 34: 254–258, 1999[Medline]
  48. Freedman BI, Spray BJ, Tuttle AB, Buckalew VM Jr: The familial risk of end-stage renal disease in African Americans. Am J Kidney Dis 21: 387–393, 1993[Medline]
  49. Freedman BI, Tuttle AB, Spray BJ: Familial predisposition to nephropathy in African-Americans with non-insulin-dependent diabetes mellitus. Am J Kidney Dis 25: 710–713, 1995[Medline]
  50. Isomaa B, Henricsson M, Almgren P, Tuomi T, Taskinen MR, Groop L: The metabolic syndrome influences the risk of chronic complications in patients with type II diabetes. Diabetologia 44: 1148–1154, 2001[CrossRef][Medline]
  51. Satko SG, Langefeld CD, Daeihagh P, Bowden DW, Rich SS, Freedman BI: Nephropathy in siblings of African Americans with overt type 2 diabetic nephropathy. Am J Kidney Dis 40: 489–494, 2002[CrossRef][Medline]
  52. Brancati FL, Whelton PK, Randall BL, Neaton JD, Stamler J, Klag MJ: Risk of end-stage renal disease in diabetes mellitus: a prospective cohort study of men screened for MRFIT. Multiple Risk Factor Intervention Trial. JAMA 278: 2069–2074, 1997[Abstract/Free Full Text]
  53. Jones CA, Francis ME, Eberhardt MS, Chavers B, Coresh J, Engelgau M, Kusek JW, Byrd-Holt D, Narayan KM, Herman WH, Jones CP, Salive M, Agodoa LY: Microalbuminuria in the US population: third National Health and Nutrition Examination Survey. Am J Kidney Dis 39: 445–459, 2002[Medline]
  54. Ruggenenti P, Perna A, Gherardi G, Garini G, Zoccali C, Salvadori M, Scolari F, Schena FP, Remuzzi G: Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet 354: 359–364, 1999[CrossRef][Medline]
  55. Mogensen CE, Neldam S, Tikkanen I, Oren S, Viskoper R, Watts RW, Cooper ME: Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ 321: 1440–1444, 2000[Abstract/Free Full Text]
  56. Mykkanen L, Haffner SM, Kuusisto J, Pyorala K, Laakso M: Microalbuminuria precedes the development of NIDDM. Diabetes 43: 552–557, 1994[Abstract]
  57. Lee ET, Welty TK, Cowan LD, Wang W, Rhoades DA, Devereux R, Go O, Fabsitz R, Howard BV: Incidence of diabetes in American Indians of three geographic areas: the Strong Heart Study. Diabetes Care 25: 49–54, 2002[Abstract/Free Full Text]
Received for publication August 29, 2002. Accepted for publication January 18, 2003.




This article has been cited by other articles:


Home page
 CJASNHome page
M. Scavini, C. A. Stidley, S. S. Paine, V. O. Shah, F. Tentori, A. Bobelu, T. K. Welty, J. W. MacCluer, and P. G. Zager
The Burden of Chronic Kidney Disease among the Zuni Indians: The Zuni Kidney Project
Clin. J. Am. Soc. Nephrol., May 1, 2007; 2(3): 509 - 516.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Shah, V. O.
Right arrow Articles by Zager, P. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shah, V. O.
Right arrow Articles by Zager, P. G.

HOME CURRENT ISSUE ARCHIVES JASN Express ONLINE SUBMISSION AUTHOR INFO
EDITORIAL BOARD SUBSCRIBE FEEDBACK ALERTS HELP