Age-related Associations of Hypertension and Diabetes Mellitus with Chronic Kidney Disease

Tareq M Islam; Caroline S Fox; Devin Mann; Paul Muntner

Disclosures

BMC Nephrology 

In This Article

Discussion

In the current study, associations were present between diagnosed diabetes mellitus and stage 3 or 4 CKD for all age groups. Additionally, although not statistically significant among the youngest age group, associations were present between hypertension and stage 3 or 4 CKD. However, for both hypertension and diagnosed diabetes, these associations were stronger among younger adults. Also associations between hypertension and diagnosed or undiagnosed diabetes mellitus with albuminuria were present across the adult lifespan but were stronger for younger adults. Also, a substantial proportion of adults = 70 years of age who were free of diabetes mellitus and hypertension had stage 3 or 4 CKD or albuminuria.

Recent studies have investigated differences in ESRD and mortality across age grouping among patients with stage 3 through 5 CKD not on dialysis.[5,6] In a study of over 2 million US veterans, the relative risk of mortality associated with lower eGFR was substantially higher for younger, compared to older, adults.[5] In a separate analysis of data for 209,622 patients with eGFR <60 ml/min/1.73 m2 not on dialysis, the crude rates and multivariable-adjusted hazard ratios of ESRD within each eGFR strata was lower at older age.[13] Also, in a study from Southampton and South-West Hampshire, United Kingdom, the standardized mortality ratio of mortality was lower at older age for adults with persistent elevated serum creatinine (≥1.7 mg/dL for six months or longer).[14]

While several studies have investigated risk factors for CKD and albuminuria, few data are available on these associations by age group. In an analysis of the Cardiovascular Health Study, an observational study of community-dwelling adults ≥65 years of age at baseline, hypertension and cigarette smoking were associated with a decline in renal function among individuals who were free of diabetes mellitus.[15] In the Coronary Artery Risk Development in Young Adults study, a study of adults 18 to 28 years of age at baseline, glucose levels and change in systolic blood pressure were associated with elevated serum creatinine after 15 years of follow-up among both men and women. Also, among 2122 Bogalusa Heart Study participants with a mean age of 26.0 to 26.5 years, higher systolic and diastolic blood pressure was associated with an increased risk of albuminuria.[16] The current study extends these previous studies by demonstrating the importance of hypertension and diabetes mellitus as risk factors for stage 3 or 4 CKD and albuminuria across the full adult lifespan from age 20 through ≥80 years in a large nationally representative sample of US adults.

The weaker association of hypertension and diabetes mellitus with stage 3 or 4 CKD and albuminuria at older age and high prevalence of these conditions among older adults without hypertension or diabetes mellitus suggests that other factors may contribute to the high prevalence of kidney disease in older adults. For example, nephrotoxic agents that adults are exposed to over their life course may explain the higher rate of kidney disease as people age. Previous studies have reported environmental exposures including lead and cadmium are more common at older age and are associated with the development of kidney disease.[17,18] Also, older adults have higher rates of exposure to potentially nephrotoxic medications (e.g., acetaminophen) and medical tests (e.g., angiograms) that may increase their risk of kidney disease.[19–21] Additionally, local obstructive processes are more common in older adults and may play a role in the development of CKD and albuminuria.[22] Atherosclerosis is another possible factor contributing to the high burden of stage 3 or 4 CKD and albuminuria among older adults. Atherosclerosis is very common among older adults and can affect the renal vasculature resulting directly in renal damage..[23,24] Also, the presence of more severe atherosclerosis may be a marker for developing heart failure resulting in decreased renal perfusion. A study by Shlipak and colleagues found, after multivariable adjustment, among adults ≥ 65 years of age without a history of clinical cardiovascular disease, an ankle-brachial index <0.9 was associated with a 1.61 times higher risk of a rapid decline in eGFR defined as ≤ -3 ml/min/1.73 m2/year..[25] Additionally, participants in their study with a common carotid intima-medial thickness ≥ 1.19 and internal carotid intima-medial thickness ≥ 1.82 were 1.34 and 1.41 times more likely to have a rapid decline in eGFR, respectively. The current study did not have data on sub-clinical atherosclerosis, precluding investigation of increased levels of this risk factor on the development of stage 3 or 4 CKD and albuminuria.

As prevalence ratios depend on the baseline disease risk (i.e., the risk of disease in the unexposed group), the attenuation of prevalence ratios at older age may be a statistical anomaly resulting from the high prevalence of stage 3 or 4 CKD and albuminuria among older adults. However, the absolute difference in the prevalence of hypertension and diabetes mellitus for those with and without stage 3 or 4 CKD and albuminuria was also larger among younger versus older adults. The consistency of larger associations of hypertension and diabetes mellitus with stage 3 or 4 CKD and albuminuria among younger adults, (i.e., using absolute differences or prevalence ratios) highlights the importance of these risk factors among younger adults. Furthermore, the age-dependent association between hypertension and diabetes with CKD suggests that it may be a different physiologic condition when present in younger versus older adults. Future studies are needed to evaluate these differences by age.

The results of the current study demonstrate the importance of hypertension and diabetes mellitus on kidney disease in young adults. However, its important to recognize the low prevalence of stage 3 or 4 CKD among adults < 50 years of age with hypertension or diabetes mellitus. While a previous analysis showed population-wide screening for albuminuria was not cost-effective, there was a clear beneficial cost-effectiveness ratio for screening adults with hypertension or diabetes mellitus regardless of their age.[26] Also, a scientific advisory statement from the American Heart Association, developed in conjunction with the National Kidney Foundation, recommended measuring serum creatinine, to screen for stage 3 or 4 CKD, for all adults with hypertension or diabetes mellitus including those under 50 years of age.[27]

Limitations and Strengths

The relatively small number of NHANES 1999–2004 study participants under 50 years of age with stage 3 or 4 CKD is a major limitation of the current analysis. As such, adequate statistical power was not available to detect small associations of risk factors with stage 3 or 4 CKD in this age group. An additional limitation is the cross-sectional study design of NHANES 1999–2004. Although we studied established risk factors for stage 3 or 4 CKD, caution should be taken when inferring causality based on the results of the current study. Also, as with any large-scale epidemiologic study, NHANES 1999–2004 relied on the MDRD study equation to estimate GFR and determine the presence of stage 3 or 4 CKD. Rule and colleagues reported that the MDRD underestimates GFR in healthy individuals.[28] The differential impact of the MDRD study equation on classifying CKD by age group warrants further study. Finally, we relied on fasting plasma glucose and not an oral glucose tolerance test to define the presence of diabetes mellitus. Therefore, we may have underestimated the prevalence of undiagnosed diabetes mellitus in our sample. However, it is unlikely that this occurred differentially by age grouping.

One of the major strengths of the current study was its large sample which permitted us to perform analyses for three separate age categories. In addition, NHANES 1999–2004 provides data that represents the non-institutionalized civilian US population that were collected following standardized protocols and data were available to analyze stage 3 or 4 CKD and albuminuria, separately. Few epidemiologic data are available on the presence of albuminuria among older adults. The consistency of the trends of lower prevalence ratios for both stage 3 or 4 CKD and albuminuria at older age is noteworthy.

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