Association Between Kidney Disease Index and Decline in Cognitive Function with Mediation by Arterial Stiffness in Asians with Type 2 Diabetes

INTRODUCTION

According to the World Health Organization, there are currently more than 55 million people living with dementia globally.¹ Ten million new cases of dementia are reported each year.¹ Dementia is also the seventh leading cause of mortality and is a major contributor to disability in older people worldwide.¹ Hence there is a strong impetus to understand and prevent the development of dementia.

According to a systematic review by Biessels and Despa (2018), individuals with diabetes had relative risks of 1.53 to 2.27 of developing dementia.² Moreover, there was a high prevalence (45%) of mild cognitive impairment in patients with type 2 diabetes (T2D).³ Another emerging risk factor of dementia is chronic kidney disease (CKD)³ which is characterized by estimated glomerular filtration (eGFR) less than 60 ml/min/1.73 m² or urinary albumin-to-creatinine ratio (uACR) more than 30 mg/g.⁴ Interestingly, the brain and kidney have common hemodynamic characteristics as both are low-resistance end-organs with exposure to high blood flow and have rich vasculature.⁵ The brain tissues are penetrated by branches from anterior, middle and posterior cerebral arteries.⁵ Similarly, the kidneys have juxtamedullary afferent arterioles. These vessels depend on their autoregulation to respond to hemodynamic strain generated by large supplying arteries.⁵ It was also suggested that T2D leads to accumulation of advanced glycation end-products, chronic inflammation and oxidative stress which are substrates for development of CKD⁶ and cognitive impairment.⁷ Hence it is plausible that both kidneys and brain have shared pathophysiological pathways in patients with T2D.

While there were studies which investigated the relationship between renal function and cognitive function, the results were not consistent.⁸ Some studies found a positive association between worse kidney function and cognitive impairment, while others observed a null effect.⁸ The difference may be attributed to different measures of renal function being used.⁸ Some of the studies used categorical measures of GFR or uACR while other studies used continuous renal function as exposures of interest.⁸ A systematic review reported a positive association between worse categorical GFR and cerebral small vessel disease (cSVD) with relative risk 1.77 (95% Confidence Interval (CI) 1.40–2.24) in a pooled analysis of four studies. However, pooled analyses on studies using eGFR and uACR as separate continuous variables showed no evidence of association.⁸ The joint effect of low renal function and albuminuria on cognitive function is also unknown.

In recent years, there is an emerging interest in combining eGFR and uACR into a novel kidney disease index (KDI) which was calculated as a geometric mean of 1/eGFR and natural logarithmically transformed (ln) (100*uACR).⁹ The geometric mean is an approach which combines information from different dimensions of an underlying condition into a composite measure.¹⁰ Unlike arithmetic mean which can only combine measurements from the same scale, geometric mean can combine eGFR and uACR which come from different scales.¹⁰ The details of the calculation are covered under materials and methods. In a study by Gerstein and colleagues (2022), higher values of KDI were shown to be linearly associated with major cardiovascular events, kidney outcomes and mortality in patients with T2D.⁹ In contrast, there was a non-linear association between 1/eGFR and the outcomes in the same study.⁹ The findings suggested that KDI could aid in identifying high-risk individuals who might benefit from preventive strategies.⁹ These results provided a timely opportunity for us to examine the association between KDI and cognitive function in patients with T2D. KDI as a composite measure can better reflect two aspects of CKD: 1) abnormality of kidney function in terms of low eGFR; and 2) kidney damage as indicated by albuminuria.⁴ The dual aspects of CKD were taken into account in CKD definition and classification by 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines and classification.⁴

Besides the epidemiological link between KDI and cognitive decline in T2D, there is a strong impetus to understand the underlying pathophysiological mechanism. Of note, arterial stiffness, a hallmark of vascular aging, adversely affects the brain with high pulsatile flow damaging cerebral micro-vessels.¹¹ The study by Novak N and Colleagues (2023) also demonstrated that arteriosclerosis markers such as N-terminal pro-B-type natriuretic peptide (NT-proBNP) and Growth Differentiation Factor 15 (GDF15) mediated the association between kidney function and cognitive decline in community-dwelling individuals.¹² Hence it is plausible that arterial stiffness, which is also a marker of arteriosclerosis,¹³ mediates the relationship between KDI and decline in cognitive function.

In this study, we aimed to examine the association between KDI and follow-up cognitive function over time, and the role of arterial stiffness as a potential mediator in the association in patients with T2D.

MATERIALS AND METHODS

RESULTS

The baseline characteristics of patients were shown in Table 1. The mean age of the patients was 61.3±8.0 years. There was a slight male predominance at 51.0%. The distribution of patients by ethnicity was as follows: Chinese, 54.1%; Malay, 19.1%; Indian, 22.8%; and Other 3.9%. The proportion of patients with < 7 years of education was 32.1%. The median values for eGFR, uACR, and KDI were 82.1 ml/min/1.73 m² (IQR 60.4–99.2), 26.5 mg/g (IQR 7.7–123.7) and 0.30 (0.26–0.37) respectively. The proportion of CKD stage 3 and above (i.e., eGFR < 60 ml/min/1.73 m²) was 24.6%.

In Table 2, baseline KDI was positively correlated with age, GDS score, DM duration, BMI, SMM, SBP, HbA1c, FPG, TG, and PWV. It was negatively correlated with baseline RBANS scores for total and all cognitive domains.

In the unadjusted analysis in Table 3, baseline lnKDI was cross-sectionally associated with lower RBANS total score (indicative of lower cognitive function) with coefficient –5.59 (95% CI –6.97 to –4.20; p < 0.001) at baseline. The association remained in Model 1 and Model 2 with coefficients –3.55 (95% CI –4.86 to –2.24; p < 0.001) and –2.59 (95% CI –4.17 to –1.20; p < 0.001) respectively. Baseline ln(1/eGFR) and ln(ACR*100) were also cross-sectionally associated with lower RBANS total score in the unadjusted analysis with corresponding coefficients –2.81 (95% CI –3.62 to –1.99; p < 0.001) and –0.62 (95% CI –0.85 to –0.40; p < 0.001) at baseline. Their associations remained in Models 1 and 2. In the adjusted Model 2, the coefficients for ln(1/eGFR) and ln(uACR*100) were –1.53 (95% CI –2.48 to –0.59; p = 0.001) and –0.28 (95% CI –0.52 to –0.05; p = 0.019) respectively. Hence the association between lnKDI with RBANS total score appeared stronger than the associations between ln(1/eGFR) and ln(uACR*100) with RBANS total score.

In Table 3, baseline lnKDI was negatively associated with all the RBANS domain scores in the unadjusted analysis at baseline. In the adjusted Model 2, lnKDI remained significantly associated with lower RBANS score in immediate memory, delayed memory, visuo-spatial/construction and attention domains with adjusted coefficients –2.65 (95% CI –4.88 to –0.42; p = 0.020), –2.76 (95% CI –5.04 to –0.48; p = 0.018), –4.71 (95% CI –6.73 to –2.68; p < 0.001) and –2.74 (95% CI –4.89 to –0.59; p = 0.013) respectively at baseline. Ln(1/eGFR) was associated with lower RBANS scores in visuo-spatial/construction and attention, while ln(uACR*100) was associated with lower RBANS scores in delayed memory in the adjusted Model 2.

There were 590 participants who were followed up over a mean period of 5.0±1.1 years (up to 8.6 years). Table 4 showed that the mean follow-up RBANS total decreased from baseline by 2.04 from 102.8±7.6 to 100.8±8.5 (p < 0.001). Similar findings were noted for all cognitive domains.

Table 5 showed the longitudinal analysis on the association between the markers of kidney disease and RBANS total score at follow-up. In Model 1 which was adjusted for follow-up period, baseline lnKDI was associated with reduced RBANS total score with coefficient –5.71 (95% CI –7.70 to –3.71; p < 0.001). The negative association between lnKDI and follow-up RBANS total score persisted in Models 2 and 3 with corresponding coefficients –4.27 (95% CI –6.16 to –2.38; p < 0.001) and –2.35 (95% CI –4.50 to –0.20; p = 0.032). Although baseline ln(1/eGFR) and ln(uACR*100) were significantly associated with lower follow-up RBANS total score in Model 1 with coefficients –3.41 (95% CI –4.71 to –2.11; p < 0.001) and –0.47 (95% CI –0.75 to –0.18; p = 0.001) respectively, their associations were attenuated and lost statistical significance in the fully adjusted Model 3.

In Table 5, lnKDI was negatively associated with follow-up RBANS score in immediate memory, delayed memory, visuo-spatial/construction and attention in Model 1 with corresponding coefficients –6.96 (95% CI –9.47 to –4.45; p < 0.001), –5.51 (95% CI –8.28 to –2.74; p < 0.001), –5.94 (95% CI –8.54 to –3.34; p < 0.001) and –8.64 (95% CI –11.44 to –5.84; p < 0.001) in Model 1. In the adjusted Model 3, the negative association between lnKDI with follow-up RBANS score for immediate memory, visuo-spatial/construction and attention domains persisted with coefficients –2.93 (95% CI –5.84 to –0.02; p = 0.049), –3.26 (95% CI –6.25 to –0.27; p = 0.033) and –4.88 (95% CI –7.95 to –1.82; p = 0.002) respectively. The association between lnKDI and immediate memory domain appeared weaker than that between lnKDI and visuospatial/construction domain or attention domain.

Supplementary Table 1 shows the results of the linear mixed model stratified by progression of kidney disease. lnKDI was associated with lower follow-up RBANS total score in patients with KDI progression with coefficients –7.41 (95% CI –9.93 to –4.89; p < 0.001), –5.30 (95% CI –7.71 to –2.89; p < 0.001) and –3.05 (95% CI –5.85 to –0.24; p = 0.034) in Models 1, 2 and 3 respectively. However, there was no evidence of association between lnKDI and follow-up RBANS total score among patients with no KDI progression. In the adjusted Model 2, lnKDI was also associated with lower follow-up RBANS total score in patients with no uACR progression but not in those with uACR progression. There was no evidence of association between lnKDI and follow-up RBANS total score in the analysis stratified by eGFR progression.

Table 5 also showed that ln(1/eGFR) and ln(uACR*100) were negatively associated with follow-up RBANS score in immediate memory, delayed memory, visuo-spatial/construction and attention domains in Model 1. However, ln(1/eGFR) remained associated with lower RBANS score in visuo-spatial/construction and attention domains in the adjusted Model 3 with corresponding coefficients –2.39 (95% CI –4.39 to –0.39; p = 0.019) and –2.58 (95% CI –4.63 to –0.52; p = 0.014). Ln(uACR*100) only remained associated with lower RBANS score in attention domain with coefficient –0.60 (95% CI –1.05 to –0.16; p = 0.007) in the fully adjustedModel 3.

In Fig. 1, mediation analysis revealed that per unit increase in baseline lnKDI was positively associated with baseline PWV with coefficient for pathway a 2.01 (p < 0.001); per unit increase in baseline PWV was negatively associated with follow-up RBANS total score with coefficient for pathway b –0.27 (p = 0.006); per unit increase in baseline lnKDI was negatively associated with follow-up RBANS total score with coefficient for pathway c –2.75 (p = 0.003), and the association between baseline lnKDI and follow-up RBANS total score was attenuated upon addition of baseline PWV to the model with coefficient for pathway c’ –2.21 (p = 0.019). Baseline PWV accounted for 19.5% of the association between baseline lnKDI and follow-up RBANS total score (p = 0.010). There was no evidence of mediation by SBP, HbA1c, LDL and TG in the association between lnKDI and follow-up RBANS total score in Supplementary Figures 1–4.

Fig. 1

Mediation of baseline PWV between lnKDI and RBANS total score at follow-up Adjusted for age, gender, ethnicity, education < 7 years, hemoglobin A1c, fasting plasma glucose, low-density lipoprotein-cholesterol, natural logarithmically transformed triglyceride, body mass index, and skeletal musclemass.

DISCUSSION

Our study demonstrated that baseline KDI, a composite index of eGFR and uACR, was independently associated with lower RBANS score globally and in the domains of immediate memory, delayed memory, visuo-spatial/construction and attention at baseline. In the longitudinal analysis, baseline KDI was also independently associated with lower follow-up RBANS score globally and in the domains of immediate memory, visuo-spatial/construction and attention. On the other hand, the reciprocal of eGFR and uACR were independently associated with RBANS total score at baseline but not at follow-up. Baseline PWV mediated the association between baseline lnKDI and follow-up RBANS total score.

The systematic review by Tang X and Colleagues (2022) showed mixed findings regarding the relationship between kidney function and cognitive impairment or dementia ⁸. Based on ten longitudinal studies conducted in the European, American and Asian populations, a decline in eGFR as a continuous variable was associated with an elevated risk of cognitive impairment and dementia with risk ratio of 1.04 (95% CI 1.00–1.08).⁸ However, there was no evidence of association between decline in eGFR with all-cause dementia (RR 1.01, 95% CI 0.97–1.06) and AD (RR 0.96, 95% CI 0.92–1.02) in subgroup analyses.⁸ On the other hand, an increase in uACR as a continuous variable was associated with an elevated risk of all-cause dementia and cognitive impairment.^8,23,24 However, another study demonstrated a null effect of uACR increase on mild cognitive impairment (RR 1.54; 95% CI 0.92–2.58).^8,25 The pooled risk ratio of these three studies on the association between continuous uACR and cognitive impairment and dementia was 1.02 (95% C 1.00–1.04) in the systematic review.⁸ Nevertheless, the few available studies for comparison were acknowledged as a limitation in the meta-analysis.⁸ Notably, eGFR and uACR were studied as separate exposures of interest in this systematic review and in other previousstudies.

To our knowledge, there is no study which examined the joint effect of eGFR and uACR on cognitive function. Hence our study has provided novel findings on the association between a composite index of renal function and albuminuria with cognitive function. Our study revealed that the association between lnKDI and cognitive function is stronger than the association between its individual components, ln(1/eGFR) and ln(uACR*100), with cognitive function at baseline and follow-up. This suggests a possible synergistic effect between renal function and albuminuria on cognitive function.

The pathophysiological mechanisms underlying the relationship between KDI and uACR remain elusive. However, there are a few proposed explanations for the relationship between eGFR and uACR with cognitive function. First, there are similarities between brain and kidney as they are both considered low-resistance end-organs with exposure to high volume of vascular flow.⁵ The vasculatures in both the brain and kidneys are therefore highly susceptible to blood pressure fluctuations.⁵ Of note, diabetes and hypertension can contribute to damage of blood vessels, compromising vascular autoregulation and vascular tone in the brain and kidneys.⁵ Thus the brain and kidneys are highly vulnerable to reduced perfusion and fluctuations in blood pressure.⁵ Second, albuminuria is considered a marker of endothelial dysfunction which damages the systemic microcirculation.⁵ Notably, endothelial damage stimulates blood-brain barrier (BBB) breakdown which itself contributes to the development of cSVD.⁵ After the occurrence of BBB breakdown, there is increased inflammation which may account for the link between albuminuria and cognitive dysfunction.⁵ Several circulating inflammatory biomarkers in the blood, such as C-reactive protein (CRP), interleukin-1 (IL-1) and tumor-necrosis factor-α (TNF-α) have been linked to both cSVD and CKD.⁵ This suggests a shared inflammatory pathway in the pathogenesis of cognitive and renal dysfunctions.⁵ Third, the loss of renal function may impede the renal clearance of amyloid-β (Aβ), resulting in accumulation of Aβ peptide which characterizes Alzheimer’s disease (AD).⁵ It is plausible that the combined effects of albuminuria and reduced renal function, as represented by KDI, exert a more detrimental impact than either component alone. This is in line with our current findings which show that the association of KDI is more marked than either component analyzed separately.

It was suggested that arterial stiffness promotes transmission of excessive pressure and flow pulsatility into the renal microvasculature, resulting in microvascular ischemia and renal damage.²⁶ Studies have demonstrated that arterial stiffness is a risk factor for kidney function decline.^26,27 There is accumulating evidence that arterial stiffness, which is measured as PWV, is a risk factor of cognitive impairment ¹¹. For the first time, we demonstrated that PWV mediated the association between KDI and cognitive function. This mechanistic pathway suggested that renal dysfunction may precede cognitive dysfunction. Furthermore, our results support an earlier study by Nowak and colleagues (2023) which revealed that the association between kidney function and cognitive dysfunction was mediated by arteriosclerosis biomarkers which included NT-proBNP and GDF15 in community-dwelling individuals.¹². These findings suggested potential vascular pathways which underline the association between kidney function and cognitive decline.¹²

The association between KDI and follow-up cognitive function was evident in patients with KDI progression but not in those without KDI progression. The results suggested that patients with KDI progression or deterioration of kidney function involving both eGFR and uACR might be more susceptible to reduction of cognitive function. This could be attributed to continuing vascular damage leading to reduction of cognitive function.

KDI was associated with decreased cognitive function in immediate memory domain though the association was weaker than that in visuospatial/construction and attention domain. The results were suggestive of cognitive changes in vascular dementia rather than those in AD where memory impairment is more pronounced.^28,29 Nevertheless, it is possible for both vascular dementia and AD to co-exist. Further studies with longer follow-up may be needed to determine the type of dementia developed. Other possible speculations are benefit of ongoing metabolic interventions (e.g., insulin has been thought to be neurotrophic³⁰) which may have mitigated progressive deterioration in some cognitive domains, and availability of prospective observation only in a smaller subset (N = 590) which may have limited the study power to observe minor effect size.

There are a few clinical implications arising from our study. First, CKD is highly prevalent in patients with T2D.³¹ Patients with T2D are also susceptible to development and progression of CKD.⁶ Hence a composite index of kidney disease may be relevant to future clinical practice as both eGFR and uACR are routinely available for monitoring of diabetic complication in patients with T2D. KDI may potentially be an inexpensive and convenient marker for monitoring cognitive function in patients with T2D. However, it is not possible to conclude if KDI can be used as a marker to predict cognitive decline or in intervention for slowing of cognitive decline. Second, arterial stiffness may be considered a potential target for preventing cognitive dysfunction in patients with T2D.

This is the first study to examine the combined effect of eGFR and uACR on cognitive function over time. The longitudinal study was conducted with a fairly long follow-up period. We also adjusted for a comprehensive range of covariates including demographics, education, APOE ɛ4 allele and clinical parameters. Nevertheless, there are some limitations in our study. First, our study was performed on patients with T2D and hence we were unable to generalize the findings to the general population. Second, we did not collect information on tau, amyloid and neurodegeneration biomarkers. Further studies are needed to study the effect of KDI on these biomarkers. Third, RBANS does not assess executive function directly. Future studies may incorporate executive function tests for a more complete cognitive evaluation. We also lacked brain imaging which can inform us on brain regions involved in cognitive function reduction.

In conclusion, KDI was associated with lower cognitive function in patients globally and in the domains of immediate memory, visuo-spatial/construction and attention. Arterial stiffness also played a mediating role in the association between KDI and cognitive decline in patients with T2D.

AUTHOR CONTRIBUTIONS

Kiat Mun Serena Serena Low (Conceptualization; Formal analysis; Investigation; Methodology; Writing – original draft); Angela Moh (Data curation; Formal analysis; Methodology); Kiat Sern Goh (Supervision; Writing – review & editing); Jonathon Khoo (Formal analysis); Keven Ang (Data curation; Project administration); Allen Yan Lun Liu (Writing – review & editing); Wern Ee Tang (Writing – review & editing); Ziliang Lim (Writing – review & editing); Tavintharan Subramaniam (Writing – review & editing); Chee Fang Sum (Writing – review & editing); Su Chi Lim (Conceptualization; Funding acquisition; Resources; Writing – review & editing).