Overall mortality in Pima Indians was greater with greater severity of kidney disease in both nondiabetic and diabetic subjects. The death rates in nondiabetic and diabetic subjects without kidney disease were virtually identical and increased to a similar degree with worsening kidney function in both groups, suggesting that kidney disease rather than diabetes per se is the major determinant of increased mortality among the diabetic population.
Cardiovascular disease was the leading cause of death in diabetic Pima Indians without kidney disease and in those with early kidney disease characterized by proteinuria. With progression of KD, CVD mortality increased further, but became the second leading cause of death behind DN. The greatest increase in CVD deaths occurred in subjects receiving RRT, in whom the death rate was 9 times as high as in those with normal kidney function. Indeed, the introduction and widespread use of RRT, while prolonging life and reducing deaths that would otherwise be attributable to DN, is largely responsible for the rise in deaths from cardiovascular disease in diabetic Pima Indians [11
]. These findings extend our previous observation [12
] that overall mortality in diabetic Pima Indians with clinical proteinuria was 3.5 times as high as in those without proteinuria, with the excess largely attributable to uremia and to cardiovascular disease.
Although SCr is not an ideal measurement of kidney function, the association between SCr concentration and mortality has been reported in several other studies. The choice of cut points, although arbitrary, was made to ensure that we identified an advanced stage of kidney disease. Alternative cut points did not change the overall conclusions of the study (data not shown).
The NHANES I study [13
] found that diabetic persons with moderate renal insufficiency [SCr of 122 to 177 μmol/L (1.4 to 2.0 mg/dL) in men and 104 to 146 μmol/L (1.2 to 1.7 mg/dL) in women] had higher total and CVD mortality than those without diabetes or renal insufficiency. There was, however, no significant association between serum creatinine and total or cardiovascular mortality in this population after adjustment for cardiovascular risk factors such as sex, age, hypercholesterolemia, hypertension, diabetes, and smoking. Hence, the authors suggested that the association between renal insufficiency and cardiovascular disease reported in other studies [14
], some of which excluded subjects with diabetes, was due to the co-occurrence of other established cardiovascular risk factors. The authors proposed that elevated serum creatinine was simply a marker for the presence of these risk factors. Similarly, in the Framingham community-based study [18
mild renal insufficiency [SCr of 136 to 265 μmol/L (1.5 to 3.0 mg/dL) in men and 120 to 265 μmol/L (1.4 to 3.0 mg/dL) in women] was associated with higher total mortality in men, but there was no association of KD with age-adjusted cardiovascular mortality in either sex. On the other hand, the risk of death in the US Medicare population aged 65 years and older [19
] with chronic KD but no diabetes was 11 times as high as the risk of progression to RRT, and 6 times as high as the risk of RRT for those with both diabetes and chronic KD. Likewise,
in the ARIC study [20
], the higher CVD incidence in middle-aged nondiabetic and diabetic patients with KD was strongly associated with risk factors that were more prevalent as GFR declined. The NHANES II Mortality Study [21
] found a graded relationship between proteinuria and the risk of total or CVD mortality in diabetic as well as nondiabetic subjects. In NHANES II, CVD mortality was highest among those with glomerular filtration rate (GFR) <70 mL/min. These findings suggest that higher mortality associated with KD reflects increased rates of CVD.
The independent, inverse association between estimated GFR, computed from a formula described in the Modification of Diet in Renal Disease study (MDRD formula) [22
], and mortality rates from CVD was confirmed by recent studies in 2 different populations. In a large, ethnically diverse outpatient sample of the adult population in the San Francisco Bay Area [23
], independent associations were found between lower estimated GFR and risk of cardiovascular events and death from CVD. Similarly, among patients with a previous acute myocardial infarction enrolled in the VALIANT study [24
], lower GFR was associated with higher rates of death or recurrent cardiovascular events. Nonetheless, the MDRD formula has not been validated in diabetic kidney disease or in ethnic groups other than Caucasian and African Americans and may be less accurate in persons with normal kidney function [25
]. The MDRD formula was developed from measures of GFR in people with GFR <60 mL/min/1.73m2
so its use is not recommended by the National Kidney Foundation in those with GFR ≥60 mL/min/1.73m2
]. Therefore, we chose to define stages of kidney function by SCr concentration and level of urinary protein excretion and not by the estimated GFR. When we analyzed the data using the estimated GFR instead of SCr concentration to define kidney disease, however, the overall conclusions of the study did not change.
By contrast to other populations, Pima Indians have a low incidence of fatal CVD, particularly among those without diabetes [27
]. The absence of an association between KD and CVD mortality in nondiabetic Pima Indians may be due in part to the small number of nondiabetic subjects with KD. Among diabetic Pima Indians,
CVD mortality is strongly related to diabetes duration, and diabetic Pima Indians with KD are more likely to die from CVD after the onset of kidney failure, when cardiovascular risk factors, including dyslipidemia and hypertension,
become more prevalent or worsen [28
The increased frequency of infections in subjects with KD is related to comorbidity and to depressed humoral and cellular immunity that progresses during the development of uremia [29
]. Infectious diseases accounted for 18% of all natural mortality in the nondiabetic subjects, and 18% of these deaths occurred in those with kidney disease. Pneumonia was the leading infectious cause of death, accounting for 33% of deaths in nondiabetic subjects with proteinuria and 67% in those with high SCr. In the diabetic subjects, 15% of all natural mortality was due to infectious diseases and 53% of these deaths occurred in subjects with kidney disease. Pneumonia was the leading infectious cause of death in the predialysis patients, followed by kidney infections and skin infections. In the general US population with chronic kidney disease, mortality due to infectious diseases is 3.2 times as high as in those without KD [2
]. Among patients with end-stage renal disease, infectious diseases are the second leading cause of death following CVD. Sepsis accounts nationally for 75% of these infectious deaths, followed by pulmonary infections and viral infections [2
]. In Pima Indians on RRT, infectious disease is the third leading cause of death following DN and CVD. Pneumonia was the leading infectious cause of death (34.8%), followed by coccidioidomycosis (17.4%) and urinary tract infections (13%).
Although some reports suggest that diabetes increases the risk of death from several types of cancer, a relationship between KD and deaths from malignant neoplasms has not been described [30
]. Nevertheless, a 10-fold higher risk of renal cell carcinoma has been reported [32
] in hemodialysis patients than in the nondialysis population. Notably, renal cell carcinoma was the only cause of death from malignancies among diabetic Pima Indians on RRT in this study.
Because the confounding and intermediate effects of blood pressure, body mass index, serum cholesterol concentration, and plasma glucose concentration could not be distinguished in this analysis, we chose not to control for them. Models that did control for these variables changed only the point estimates and confidence intervals, but not the overall conclusions of the study (data not shown).
The level of kidney function in this study, with the exception of RRT, was determined at research examinations. The frequency of these examinations could therefore influence whether a subject was classified appropriately at the time of death. Among those who died, all available medical records were reviewed systematically and elevations of serum creatinine concentration ≥2.0 mg/dL were noted. These data were not used in this analysis, however, because they were available only for those who died. Accordingly, mortality rates in the pre-RRT groups could be underestimated to the extent that subjects who may have developed higher levels of KD were not identified as such. Nonetheless, only 9% of the subjects classified as having normal kidney function at all exams had a serum creatinine concentration ≥2 mg/dL in the medical record before death, suggesting that the extent of kidney function misclassification was small.