In this community-based longitudinal study of adults, the risks related to a faster decline in eGFR were different among age groups. In relation to hypertension, proteinuria, and smoking status, faster declines in eGFR were observed in the older group. Other risk factors, including anemia and diabetes mellitus, were related to a similar rate of eGFR decline among the age groups.
Age is one of the most fundamental considerations for providing personalized care. The risk factors for kidney dysfunction have been evaluated in cohort studies or interventional trials [5, 23]. For example, a study of a general Japanese population showed that the relationship between blood pressure and GFR slopes varied across age groups . However, age-adjusted risks, rather than age-stratified risks, have usually been evaluated, and thus, reported risk factors are limited. To achieve more personalized care, we conducted an age-stratified risk assessment of comprehensive risk factors for loss of kidney function.
Clinical significance and study implications
In this study, higher systolic blood pressure was related to a faster loss of kidney function in older people. This result was consistent with those of previous studies reporting that the absence of hypertension was related to a slower progression of kidney disease in older people [24, 25]. A possible mechanism underlying this association might be glomerular hypertension by hyalinization of afferent arterioles  that may affect the autoregulation of glomerular blood flow . Because active treatment of hypertension is a risk factor for kidney failure , a study of renal outcome regarding hypertension treatment in older people is required to evaluate the balanced target of blood pressure treatment in older people.
Current smoking is a known risk factor for the loss of kidney function in middle-aged or older people . Interestingly, this relationship with smoking was observed, even in the participants aged ≥80 years. Current smoking was not associated with reduced kidney function in young people; however, this result should be carefully interpreted because smoking may transiently increase eGFR . In addition, the elevated eGFR observed in individuals with proteinuria aged 40 to 49 years should be interpreted with caution because it may be related to single-nephron hyperfiltration , which could result in kidney dysfunction.
In this study, higher BMI was related to a slightly faster loss of kidney function in older people. However, no age-dependent trend was observed. Moreover, the effect sizes related to higher BMI were minimal in each age group. Considering that most participants had BMI <30 kg/m2, this result was consistent with those of other studies that reported that a BMI of 25 to 30 kg/m2 was not related to a faster loss of kidney function in any age group .
Interestingly, a history of stroke or coronary disease did not relate to the loss of kidney function in younger people. A study by Esposito et al. reported a faster loss of kidney function in younger people with CKD than in the elderly . Considering the differences in the study design, the stable kidney function observed in younger people in our study may be because many of them had better kidney function (only 2% had an eGFR of <60 ml/min/1.73 m2) and fewer complications of hypertension (7%) or diabetes (2%). Similarly, it may be because of the strict medical treatments after the event of stroke or coronary disease. In contrast, the rate of decline in kidney function in older people did not differ significantly from that in previous studies. For example, a US study reported annual rates of eGFR decline of 0.8 and 1.4 mL/min/1.73 m2 in non-diabetic men and women aged 66 years and older, respectively .
Due to the large sample size, this study might have detected a minimal difference in the GFR slope. However, most of the significantly different risk factors observed in this study had a difference of -0.10 mL/min/1.73 m2 from the mean slope. Considering that the mean slope was -0.39, the presence of multiple factors could lead to a clinically significant loss of kidney function. Furthermore, risk factors that increased in association with older age might become more important over time, which is shown in Figure 2.
Strengths and limitations
More than 50,000 Japanese people aged 40 to 80 years or older participated in this study. The participants may not be different from the typical Japanese population. The mean eGFR slope in the study population was -0.39 mL/min/1.73 m2 per year, which was almost the same as that reported in a nationwide study in Japan . Furthermore, the wide range of characteristics may contribute to the generalizability of the results.
Another strength of this study was the inclusion of >8,000 participants aged ≥80 years. Old-age populations are usually not stratified because of either their limited number or they are not the target population. The population of people aged ≥80 years is increasing worldwide . The results of this study provide basic information about the risk factors of loss of kidney function in older people. Interventional trials, including those comprising people of this age group, are warranted to validate the results of this study.
This study has several limitations. First, drug classes for the treatment of hypertension or diabetes mellitus were not considered in the analysis. Some medications, including angiotensin II receptor blockers or sodium-glucose cotransporter-2 inhibitors, may affect kidney function . Second, we did not investigate the underlying diseases of kidney dysfunction that might affect the progression of the disease. Possibly, primary diseases that were not examined in this study, such as polycystic kidney disease, might have had a significant impact on renal function . Furthermore, the high prevalence of kidney dysfunction and proteinuria in the elderly might indicate that the effects of disease-related treatments could not be fully adjusted. Third, smoking history was not included in the questionnaire. Because the questionnaire asked about the current smoking status at the time of examination, the risks related to smoking in older people may have been underestimated. Fourth, previous studies of kidney function have observed that annual changes in eGFR over a 3-year follow-up period can be used as a surrogate outcome for assessing the risk of ESKD, even in those with preserved kidney function [37, 38]; however, the short median follow-up period of 2.8 years in the youngest age group may affect the ability to detect changes in eGFR. Fifth, this study was not a cluster-randomized observational study, and the limited number of participants, especially those in their 40s, might have led to a selection bias toward those with health problems. Sixth, kidney dysfunction and proteinuria observed in the elderly might have been associated with all-cause and cardiovascular mortality , which could cause a bias towards attenuating a decline in kidney function.