Diabetic kidney disease in the elderly: prevalence and clinical correlates

Kidney dysfunction is rising worldwide in parallel with population ageing [1], being diagnosed in about 25% of people aged 65–74 years, and in > 50% of those aged > 75 years [2]. Senescence is associated with a progressive decline of estimated glomerular filtration rate (eGFR) of about 1–2 ml/min per year, depending on ethnic, genetic and environmental factors, which may limit renal reserve and make this organ more susceptible to damage by several factors, including type 2 diabetes mellitus (T2DM) [3‐6].

T2DM is a progressive disease [7] whose prevalence also increases with age [8], thus exposing elderly patients to an increased risk of long-term diabetic complications, including diabetic kidney disease (DKD).

Low eGFR and albuminuria are the central features for the diagnosis of DKD, and they may be present together in 12% of T2DM subjects or as isolated forms in 35% of them: 24% as albuminuria with preserved eGFR values, and 11% as isolated low eGFR values (< 60 ml/min) [9].

In the large cohort of the Italian Association of Clinical Diabetologists (AMD) Annals Initiative, we have recently demonstrated that low eGFR and albuminuria may have different associations with clinical variables and risk factors for cardiovascular disease (CVD) [9].

However, in spite of the large prevalence of DKD among elderly T2DM patients, it is still unclear whether ageing modifies the associations of low eGFR and albuminuria with CVD risk factors, a particularly relevant issue when considering that DKD is associated with an enormous CVD burden, even at older ages [10, 11].

Furthermore, quality of diabetes care should be carefully considered in elderly patients with DKD, since management of diabetes and its associated CVD risk factors may be different at different ages.

Therefore, here we explored the prevalence of low eGFR and albuminuria and their associations with CVD risk factors and quality of care indicators in a large cohort of T2DM patients participating to the AMD Annals Initiative, stratified according to a wide age-range.

In the present report, we analyzed the data set of electronic medical records, collected between 1 January and 31 December 2011, from 157,595 patients with T2DM followed-up at 207 diabetes centers included in the Italian Association of Clinical Diabetologists (AMD) Annals Initiative. Details on database and data collection have been reported elsewhere [12‐14]. Data were collected and centrally analyzed anonymously, and the results were internally approved by the AMD Annals scientific committee. This initiative includes measuring and monitoring of major metabolic laboratory parameters, anthropometric measures, systolic and diastolic blood pressure (BP), as well as the use of specific classes of cardiovascular drugs. In particular, kidney function was assessed by serum creatinine and urinary albumin excretion measurements. eGFR was estimated for each patient using a standardized serum creatinine assay and the CKD-EPI formula. Increased urinary albumin excretion was diagnosed as: i) microalbuminuria if UAE rate was > 20 and ≤ 200 μg/min, or if urinary albumin-to-creatinine ratio (ACR) was > 2.5 mg/mmol in men and > 3.5 mg/mmol in women and ≤30 mg/mmol in both genders, or if urinary albumin concentration was > 30 and ≤300 mg/l; ii) macroalbuminuria if UAE rate was > 200 μg/min, or if ACR was > 30 mg/mmol in both genders, or if urinary albumin concentration was > 300 mg/l. Albuminuria indicated patients with either micro- or macroalbuminuria.

Diabetes care in elderly patients is challenging because of several epidemiological, clinical and economic issues, which are amplified in presence of chronic complications.

The prevalence of diabetes is high in older subjects, affecting more than 20% of subjects > 65 years [17]. Our data, on a large sample of outpatients with T2DM with a wide age-range, showed that renal complications affect 41.3% of this population, and more than 60% of those aged > 75 years.

These prevalence figures are comparable to those reported both in non-diabetic and diabetic cohorts, although with some disparities imputable to differences in study design, disease duration, and T2DM management.

In non-diabetic cohorts, the prevalence of renal disease parallels the ageing process, affecting up-to 56.1% of subjects aged > 75 years [18‐21]. However, the NHANES study underlined how diabetes has a stronger impact on renal function than ageing itself, showing that the increasing prevalence of renal impairment in the US population in the period 2005–2008 was related to the increasing trends of diabetes, while the age distribution of that population did not change during the observation [10].

Available data on DKD prevalence among elderly T2DM cohorts are also varying, with a DKD prevalence of 15.1% reported in older adults in the Republic of Ireland [22], whereas, in theT2DM patients aged > 75 years in the ZODIAC-24 study [23], the prevalence of low eGFR was 42% and that of albuminuria 52%. These data are similar to our findings and those reported in the Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study (RIACE) cohort [24].

The overall high prevalence of DKD in elderly T2DM patients is likely to be the result of two opposite trajectories, i.e. the high frequency of T2DM in this age-group, and the decreased mortality rate due to a better control of the disease, which may have contributed to increase patients survival, allowing sufficient time to develop chronic diabetes complications [25‐28].

The physiological decline of renal function with age may have also played a role, since senescence is associated with a gradual decline of eGFR [3, 4], an observation that was confirmed by our study, wherein the impairment of eGFR across age-strata was much more pronounced than the occurrence of albuminuria (Fig. 1) .

Similarly, in the UK Prospective Diabetes Study (UKPDS) study, older age was a significant predictor for the onset of low eGFR but not of albuminuria, whose prevalence was comparable to our findings: 24.9% in the UKPDS vs. 25.6% in our study subjects in the corresponding age-range (< 65 years old) [29, 30].

Interestingly, our data also show that not all T2DM patients will eventually develop renal impairment even at very old age; indeed a large group of subjects aged > 75 years (n = 16.984, 48.5%) were still normo-albuminuric with preserved eGFR values, thus confirming that DKD in elderly patients is not only consequent to the loss of renal function of the ageing kidney. Furthermore, elderly subjects without DKD (mean age 80 years, diabetes duration 14 years) showed an optimal glucose control (mean HbA1c 7.1%), with lipid and BP values close to recommended targets and no weight loss, indicating the importance of controlling major risk factors in order to prevent renal complications even late in life.

CVD risk factors control is another important issue in elderly patients, especially in those with DKD. Thus, the health and economic burden associated with DKD is largely related to the high risk for CVD morbidity and mortality and its evolution to end stage renal disease [31‐34], which does not spare the elderly population [10, 11]. In the Atherosclerosis Risk in Communities (ARIC) Study, both eGFR and albuminuria were associated with CVD outcomes, although age and other demographic variables had a modulating effect on these associations [10]. Furthermore, other studies and recent meta-analyses confirmed that the relationship between renal function and CVD mortality is largely consistent across age-categories [35‐38].

Accordingly, our data show that both low eGFR and albuminuria are associated with a worst CVD risk factors profile in all the considered age-groups, and this was also evident for parameters such as BMI, triglycerides and smoking habit that progressively decrease at older age.

Our data also confirm that, independently of age, the strength of the associations of CVD risk factors is different when considering low eGFR and albuminuria, as previously demonstrated in our and in other cohorts [9, 24, 30]. These differences were particularly evident for gender, BP and glucose control.

Gender has been reported to have consistent and specific associations with DKD features, with potential implications in terms of CVD risk [39‐41]. As expected, in the overall population, female gender was more prevalent at older ages, likely because of the female survival advantage. However, gender differences in DKD were maintained even at older age, with T2DM women being more prevalent in the low eGFR group, and men in the albuminuric group.

This finding is in line with several reports showing gender- differences in renal disease both in non-diabetic [42, 43] and diabetic cohorts [9, 29, 44]. Consistent with our findings of male gender being a risk factor for albumuminuria, in the UKPDS (The United Kingdom Prospective Diabetic Study) male gender was a predictor for the incidence of albuminuria, but not of low eGFR values [29]. Similarly, both in the RIACE study [44] and in previous reports from the AMD Annals Initiative [9], the albuminuric phenotype was more frequent in T2DM men, whereas the low eGFR phenotype was more prevalent in women. Furthermore, male gender seems to be a risk factor for DKD progression towards ESRD [45‐49], whereas once on dialysis treatment, mortality risk seems to be higher in the female T2DM population [50‐53].

In spite of these epidemiological findings, the pathophysiological bases of these gender differences remain still largely unknown, although it should be kept in mind that formulas commonly used for eGFR calculation are influenced by gender [54, 55].

Notably, although glucose control was overall good in all age-groups (mean HbA1c 7.2%), a larger percentage of subjects in the youngest group showed out-of-target HbA1c values (> 8.5%), compared to subjects > 65 years, whereas the higher prevalence of HbA1c between 7.5–8.5% at older age in our cohort could be interpreted in the light of current guidelines that suggest to mitigate glucose targets in the elderly [28, 38].

Age had an influence on these associations, attenuating the relationship between renal features and the examined CVD risk factors. This was particularly evident for BP control and anti-hypertensive treatments, that were positively and strongly associated with low eGFR values in the < 65 years group and progressively less at older ages. Also smoking habit, that was positively associated with albuminuria and negatively with low eGFR was influenced by age.

When evaluating quality of diabetes care, through the Q score [15, 16], we found an overall good quality of care (mean values of 29–30) at different age- and DKD strata, and these data are in line with the findings of other diabetic cohorts in Italy [15, 16]. However, older subjects (> 75 years) and those with albuminuria (Alb+) showed lower Q score values compared to the other groups. Notably, the QUASAR study [15] showed that the risk of developing CVD events was 84% greater in patients with a score of < 15 (incidence rate ratio: 1.84; 95% CI 1.29–2.62) and 17% higher in those with a score between 15 and 25 (incidence rate ratio: 1.17; 95% CI 0.93–1.49), as compared with those with a score of > 25 [15]. Our data extended those observations indicating that, irrespectively of age, low Q-score values are a risk factor also for albuminuria, a widely recognized risk factor for CVD.

Several limitations of the study should be acknowledged. Among these, the potential influence of geriatric conditions, which may affect quality of care and DKD outcomes, was not specifically considered; moreover, we did not take into account that the management of DKD in elderly patients is complicated by the higher exposure to drugs’ side effects, including hypoglycemia, and frequent co-morbidities [28, 34, 56]. Also, we did not explore the potential associations of the available classes of drugs with low eGFR and/or albuminuria phenotypes specifically in the elderly population, although a previous analysis of this cohort showed an high percentages of patients treated with those drugs that should be limited or contraindicated by impaired renal function [57, 58].

In conclusion, in this representative sample of outpatients with T2DM, DKD prevalence, especially low eGFR, was very high in subjects > 65 years old. Both low eGFR and albuminuria were associated with a worst CVD risk factor profile, although these associations changed according to the specific outcome examined and were generally attenuated at older ages. Quality of diabetes care was overall good even at older age, however, when impaired (Q score < 15), it was associated with a higher risk of albuminuria. These data indicate that DKD in elderly patients is still a high-risk condition that deserves full clinical consideration, in order to implement a targeted treatment and improve its outcomes.