title: Ischaemia induces paradoxical changes in axonal excitability in end-stage kidney disease.
abstract: Peripheral neuropathy is present in 65% of patients with end-stage kidney disease (ESKD). No cause is yet established: nerve excitability studies have shown that axons are chronically depolarized, primarily owing to hyperkalaemia, but in vitro studies have suggested a role for axonal Na+/K+ pump dysfunction. To investigate Na+/K+ pump activity in vivo, lower limb ischaemia was induced in five ESKD patients and six healthy controls by a sphygmomanometer cuff, inflated to 200 mm Hg and maintained for 13 min. The peroneal nerve was stimulated at the fibular neck and excitability parameters were recorded from tibialis anterior (TA) and extensor digitorum brevis (EDB) before, during and after the ischaemic period. Baseline excitability studies in ESKD patients demonstrated reductions in threshold electrotonus and superexcitability and increased refractoriness, consistent with membrane depolarization. During ischaemia, threshold increased in ESKD patients [by +23.6 +/- 5.0% (TA); +32.1 +/- 7.3% (EDB)] in contrast to the persistent threshold reduction observed in normal controls [-2.4 +/- 5.2% (TA); -13.0 +/- 8.2% (EDB); P < 0.01]. These changes were accompanied by increased refractoriness and reduced superexcitability in both ESKD and control groups, consistent with ischaemic depolarization. Conversely, there was reduction in strength-duration time constant towards the end of ischaemia. Following release of ischaemia, the marked increase in threshold observed in normal controls was not evident in ESKD patients, but the rapid return of threshold to baseline argues against significant Na+/K+ pump dysfunction. The abnormal pattern of response to ischaemia in the ESKD patients was not fully explained by the hyperkalaemic membrane depolarization and suggests that another dialysable factor affects nerve excitability in ESKD patients, most likely H(+) ions, but that this factor only becomes evident during ischaemia. Blockade of persistent Na+ conductances by H+ would also explain the reduction in strength-duration time constant observed during ischaemia.
authors.affiliation: Prince of Wales Medical Research Institute and Prince of Wales Clinical School, University of New South Wales, Randwick, Sydney, Australia.
authors.forename: Arun V
authors.initials: AV
authors.lastname: Krishnan
authors.forename: Richard K S
authors.initials: RK
authors.lastname: Phoon
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Pussell
authors.forename: John A
authors.initials: JA
authors.lastname: Charlesworth
authors.forename: Hugh
authors.initials: H
authors.lastname: Bostock
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Kiernan
mesh_terms: D000293:Adolescent; D000328:Adult; D001369:Axons / Q000502:physiology*; D003250:Constriction; D004558:Electric Stimulation; D006801:Humans; D007511:Ischemia / Q000378:metabolism / Q000503:physiopathology*; D007676:Kidney Failure, Chronic / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D007866:Leg / Q000098:blood supply*; D008297:Male; D008564:Membrane Potentials; D008875:Middle Aged; D009431:Neural Conduction; D010523:Peripheral Nervous System Diseases / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D010543:Peroneal Nerve / Q000503:physiopathology; D011188:Potassium / Q000097:blood; D000254:Sodium-Potassium-Exchanging ATPase / Q000502:physiology
chemical_list: D000254:Sodium-Potassium-Exchanging ATPase; D011188:Potassium