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Abstract
This thesis examined the pathophysiology of peripheral neuropathy across the spectrum of chronic kidney disease (CKD) using nerve excitability techniques. The purpose of these studies was to establish the prevalence and impact of neuropathy in moderate severity CKD, to investigate the causative role of potassium in the development of axonal dysfunction and to provide an evidence base concerning the differential effects of various therapies on neuropathy in this patient group.
Initial studies were undertaken in CKD patients receiving different forms of treatment, namely high-flux haemodialysis and haemodiafiltration. Compared to high-flux haemodialysis, patients who received haemodiafiltration demonstrated greater normality of nerve excitability prior to dialysis, across a single dialysis session and at long-term follow-up. In keeping with previous studies, pre-dialysis K+ was strongly correlated with measures of axonal depolarisation.
Subsequent studies were undertaken to investigate whether potassium had a causal role in mediating axonal depolarisation using a modified dialysis intervention. This study demonstrated that axonal depolarisation remained unchanged for as long as serum potassium remained elevated, despite the significant removal of other dialysable uraemic toxins. Furthermore, mathematical modelling analysis revealed that nerve excitability abnormalities in dialysis patients were profoundly worse than that expected for normal axons exposed to similarly high potassium concentrations.
Studies undertaken in renal transplant patients demonstrated differences in outcomes that were dependent on the form of post-transplant immunosuppression. Immunosuppressive regimens based on calcineurin inhibition were associated with a greater severity of neuropathy and nerve excitability abnormalities compared to patients receiving alternative immunosuppressive therapies.
In the final set of studies nerve function was assessed in diabetic and non-diabetic CKD patients and a disease control group diabetic patients without CKD. Studies in the control group demonstrated nerve excitability abnormalities in type 1 diabetic patients prior to neuropathy onset. In CKD patients, peripheral neuropathy was highly prevalent and was strongly correlated with measures of physical function and quality of life. Additionally, this study revealed that diabetic-CKD is associated with a more severe neuropathy phenotype. In total these findings demonstrate the impact of neuropathy and highlight the need for early detection and management of this condition in all stages of CKD.