In patients with chronic kidney disease (CKD), disordered mineral metabolism, deterioration in bone quality and extra-skeletal calcification constitute the clinical syndrome known as chronic kidney disease – mineral and bone disorder (CKD–MBD). Renal osteodystrophy (ROD) is the skeletal component of CKD-MBD, and refers to abnormalities of bone turnover, mineralisation, volume, linear growth or strength. The erosion of bone quality in CKD confers an excess fracture risk through stages of CKD, is not attenuated by kidney transplantation and can be associated with persistent hyperparathyroidism in kidney transplant recipients (KTRs). The currently available tools in clinical practice have limited utility in evaluating ROD and add to diagnostic and therapeutic uncertainty in this area. The mechanisms of bone loss after transplantation and their relationship with changes in bone structure and markers of mineral metabolism are poorly understood. Tackling these challenges requires an enhanced understanding of the pathophysiology of ROD and development of tools for accurate evaluation of renal bone disease.

The advent of high-resolution (HR) imaging and newer biomarkers has provided greater insight and generated research interest in CKD-MBD. HR imaging studies of bone microarchitecture have highlighted the contribution of cortical bone structure to overall bone strength and its association with hyperparathyroidism and bone fragility in KTRs and patients with CKD. HR magnetic resonance imaging (MRI) using customised processing techniques has proven to be an excellent non-invasive tool for studying bone microarchitecture.

My research explored prevalent bone and mineral metabolism abnormalities and the role of various contemporary imaging modalities, in particular MRI, in evaluation of ROD. Chapter 2, a cross-sectional study of histological abnormalities of bone in a relatively young cohort of potential KTRs, highlights severe deterioration of cortical microarchitecture but predominantly normal trabecular parameters, reinforcing the importance of comprehensive cortical bone evaluation in patients with CKD. Chapter 3 describes a proof-of-concept evaluation of bone microarchitecture in patients with CKD using MRI with findings correlated to those obtained by bone biopsy and other bone imaging techniques (Dual-energy X-ray absorptiometry, DXA;​ peripheral quantitative computed tomography, pQCT;​ trabecular bone score, TBS), to highlight advantages of MRI as a diagnostic tool in ROD. MRI demonstrated significant and relevant associations with important bone biopsy and DXA parameters but could not establish a reliable relationship with bone turnover. No associations were observed with bone turnover markers. This study also underlined the inherent heterogeneity of bone microarchitecture at differing skeletal sites and the pitfalls of assessing these and comparing imaging modalities with vastly different resolutions and protocols. The study described in Chapter 4 monitored changes in bone density and microarchitecture in KTRs over one year after transplantation using MRI, DXA, pQCT and TBS and biomarkers. Trabecular bone structure and connectivity deteriorated independent of changes in BMD but associated with PTH levels, complemented by significant reduction in TBS. Unlike in other contemporary studies, there was no progressive deterioration in cortical bone. Chapter 5 describes an exploration of mineral metabolism and clinical outcomes after transplantation in a large cohort of KTRs, focusing on the impact of discontinuation of cinacalcet on these parameters. Persistent post-transplantation hyperparathyroidism and hypercalcaemia, consistent with available data, was demonstrated, but the clinical significance of these mineral metabolism markers was unclear. Historically, aluminium deposition in bone was recognised as a major cause of adynamic bone disease but is now less relevant due to increasingly rare use and phasing out of aluminium-containing phosphate binders in clinical practice. However, many centres continue to routinely screen dialysis patients for aluminium levels. The study in Chapter 6 examined the utility of routine testing of serum aluminium levels in the haemodialysis population in our centre via a retrospective audit of tests performed on 755 patients over four years. Only 0.5% of 2058 test results matched criteria for toxic aluminium levels, with no evidence of clinical toxicity and progressive reduction in the proportion of elevated aluminium levels over the years. This led to cessation of routine testing of aluminium levels in our dialysis unit.

In conclusion, clinical studies presented in this thesis add to the increasing body of literature about the bone abnormalities prevalent in CKD and highlight the novel use of MRI in assessing bone quality in CKD and in KTRs. Overall, non-invasive HR imaging, particularly MRI, has the potential to close the vast gap between screening of BMD using DXA and comprehensive diagnosis by bone biopsy. This needs validation in large trials with hard clinical endpoints and should be viewed in the context of a plethora of technical caveats and issues of high cost and availability. The utility of MRI (and other HR imaging) would be enhanced by more accurate and reliable non-invasive markers of bone turnover and mineralisation. These challenges are significant, but not insurmountable. A coordinated, multidisciplinary, patient-focused effort is needed from the nephrology research community to address the unmet needs of patients with ROD and CKD-MBD.