Tushar Issar1, Ria Arnold2, Natalie C G Kwai3, Susan Walker1, Aimy Yan1, Adeniyi A Borire1, Ann M Poynten4, Bruce A Pussell5, Zoltan H Endre5, Matthew C Kiernan6, Arun V Krishnan7. 1. Prince of Wales Clinical School, UNSW Sydney, NSW 2031, Australia. 2. School of Medical Sciences, UNSW Sydney, NSW 2052, Australia. 3. Prince of Wales Clinical School, UNSW Sydney, NSW 2031, Australia; Department of Exercise Physiology, UNSW Sydney, NSW 2052, Australia. 4. Department of Endocrinology, Prince of Wales Hospital, Sydney, NSW 2031, Australia. 5. Department of Nephrology, Prince of Wales Hospital, Sydney, NSW 2031, Australia. 6. Brain and Mind Centre, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia. 7. Prince of Wales Clinical School, UNSW Sydney, NSW 2031, Australia. Electronic address: arun.krishnan@unsw.edu.au.
Abstract
OBJECTIVE: Chronic kidney disease (CKD) caused by diabetes is known as diabetic kidney disease (DKD). The present study aimed to examine the underlying mechanisms of axonal dysfunction and features of neuropathy in DKD compared to CKD and type 2 diabetes (T2DM) alone. METHODS: Patients with DKD (n = 30), CKD (n = 28) or T2DM (n = 40) and healthy controls (n = 41) underwent nerve excitability assessments to examine axonal function. Neuropathy was assessed using the Total Neuropathy Score. A validated mathematical model of human axons was utilised to provide an indication of the underlying causes of nerve pathophysiology. RESULTS: Total neuropathy score was significantly higher in patients with DKD compared to those with either CKD or T2DM (p < 0.05). In DKD, nerve excitability measures (S2 accommodation and superexcitability, p < 0.05) were more severely affected compared to both CKD and T2DM and worsened with increasing serum K+ (p < 0.01). Mathematical modelling indicated the basis for nerve dysfunction in DKD was an elevation of extracellular K+ and reductions in Na+ permeability and the hyperpolarisation-activated cation current, which was similar to CKD. CONCLUSIONS: Patients with DKD manifested a more severe neuropathy phenotype and shared features of nerve dysfunction to that of CKD. SIGNIFICANCE: The CKD, and not diabetes component, appears to underlie axonal pathophysiology in DKD.
OBJECTIVE:Chronic kidney disease (CKD) caused by diabetes is known as diabetic kidney disease (DKD). The present study aimed to examine the underlying mechanisms of axonal dysfunction and features of neuropathy in DKD compared to CKD and type 2 diabetes (T2DM) alone. METHODS:Patients with DKD (n = 30), CKD (n = 28) or T2DM (n = 40) and healthy controls (n = 41) underwent nerve excitability assessments to examine axonal function. Neuropathy was assessed using the Total Neuropathy Score. A validated mathematical model of human axons was utilised to provide an indication of the underlying causes of nerve pathophysiology. RESULTS: Total neuropathy score was significantly higher in patients with DKD compared to those with either CKD or T2DM (p < 0.05). In DKD, nerve excitability measures (S2 accommodation and superexcitability, p < 0.05) were more severely affected compared to both CKD and T2DM and worsened with increasing serum K+ (p < 0.01). Mathematical modelling indicated the basis for nerve dysfunction in DKD was an elevation of extracellular K+ and reductions in Na+ permeability and the hyperpolarisation-activated cation current, which was similar to CKD. CONCLUSIONS:Patients with DKD manifested a more severe neuropathy phenotype and shared features of nerve dysfunction to that of CKD. SIGNIFICANCE: The CKD, and not diabetes component, appears to underlie axonal pathophysiology in DKD.
Authors: Jeremy Chung Bo Chiang; Ria Arnold; Roshan Dhanapalaratnam; Maria Markoulli; Arun V Krishnan Journal: Pharmaceuticals (Basel) Date: 2022-05-15
Authors: Tushar Issar; Susan Walker; Ria Arnold; Ann M Poynten; Zoltan H Endre; Arun V Krishnan Journal: Muscle Nerve Date: 2022-02-23 Impact factor: 3.852