Background and motivation
Diabetic kidney disease (DKD) constitutes a major global health burden, significantly contributing to chronic kidney disease (CKD) and end-stage renal failure (ESRF). Due to the incurable nature of DKD, its management remains largely conservative, emphasising glycaemic and blood pressure control, alongside lifestyle modifications. Although the emergence of sodium–glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor agonists (GLP1RAs), and non-steroidal mineralocorticoid receptor antagonists (nsMRAs) has shown particular benefit in type 2 diabetes mellitus (T2DM), the prevalence of DKD has remained relatively unchanged over the past three decades. The pathophysiology of DKD is closely linked to other diabetes-related microvascular and macrovascular complications, including neuropathy, retinopathy, and peripheral vascular disease. One such complication is diabetic autonomic neuropathy (DAN), often presenting as cardiac autonomic neuropathy (CAN), which is diagnosed using cardiovascular autonomic reflex tests (CARTs).
Aims of the PhD
The overall aim is to investigate whether magnetic resonance imaging (MRI) biomarkers can enhance our understanding of the association between CAN and DKD. The specific objectives are: (1) to review the current literature on the relationship between CAN and DKD; (2) to test these hypotheses in a longitudinal cohort study of individuals with type 1 diabetes mellitus (T1DM); (3) to evaluate whether simple shape metrics derived from MRI can detect early changes in DKD that are not identified through routine blood and urine analyses; and (4) to determine whether MRI-based perfusion metrics can elucidate a direct mechanistic link between CAN and DKD.
Results
A comprehensive literature review identified 27 studies (17 in T2DM) published over the past 30 years, demonstrating a clear association between CAN and DKD progression, including in patients without microalbuminuria. Ten prospective studies highlighted the predictive value of CAN for future declines in estimated glomerular filtration rate (eGFR). The review offers evidence-based recommendations for future research aimed at revealing the mechanisms of autonomic renal regulation, which are essential for understanding CAN’s contribution to DKD progression and for guiding the development of targeted therapeutic interventions.
A 15-year longitudinal study in T1DM showed that CAN severity was significantly associated with eGFR decline and increased urinary albumin creatinine ratio (UACR). CAN was linked to a higher baseline Kidney Disease: Improving Global Outcomes (KDIGO) CKD risk category and strongly predicted adverse renal outcomes, including macroalbuminuria, progression in KDIGO risk, doubling of serum creatinine, ≥ 30% eGFR decline, kidney replacement therapy initiation, or kidney disease-related death.
An investigation using MRI to assess three-dimensional shape of the kidneys identified potential biomarkers for DKD progression. Reduced kidney compactness correlated with irregular shape, despite similar eGFR values, suggesting subclinical early DKD changes, such as hyperfiltration, in structurally deformed kidneys. These findings indicate that MRI-based structural assessments may detect disease progression that routine biomarkers overlook, offering potential for improved DKD risk stratification and management.
Further research using dynamic contrast-enhanced MRI (DCE-MRI) assessed the impact of CAN on renal perfusion. No significant differences in MRI-derived renal blood flow were found between participants with and without CAN, consistent across T1 and T2DM, eGFR grades, and CAN severity. These findings suggest that CAN may not directly influence renal perfusion in these populations.
Overall conclusion
This research investigated the role of MRI biomarkers to improve the understanding of the relationship between CAN and DKD progression. By exploring renal structural changes and perfusion metrics, the studies seek to identify early subclinical DKD changes that may be overlooked by conventional biomarkers. Ultimately, these findings could contribute to more precise risk stratification and better management strategies for DKD, particularly in patients with coexisting CAN.
Outlook
The work presented in this thesis contributes evidence regarding the impact of CAN on DKD, the potential utility of renal imaging in DKD research and clinical practice and generates future research directions to investigate renal perfusion in populations with CAN and DKD. These insights may enhance the understanding of the interplay between CAN and renal function decline, ultimately advancing DKD management strategies
