RESUMEN
Atacicept is a first-in-class, dual anti-B-cell Activation Factor-A Proliferation-Inducing Ligand fusion protein in clinical evaluation for treatment of IgA nephropathy. To compare efficacy and safety of atacicept versus placebo in patients with IgAN, this randomized, double-blind, placebo-controlled phase 2b clinical trial ORIGIN enrolled 116 individuals with biopsy-proven IgA nephropathy. Participants were randomized to atacicept 150, 75, or 25 mg versus placebo once weekly for up to 36 weeks. Primary and key secondary endpoints were changes in urine protein creatinine ratio based on 24-hour urine collection at weeks 24 and 36, respectively, in the combined atacicept 150 mg and 75 mg group versus placebo. The primary endpoint was met at week 24 as the mean urine protein creatinine ratio was reduced from baseline by 31% in the combined atacicept group versus 8% with placebo, resulting in a significant 25% reduction with atacicept versus placebo. At week 36, the key secondary endpoint was met as the mean urine protein creatinine ratio reduced from baseline by 34% in the combined atacicept group versus a 2% increase with placebo, resulting in a significant 35% reduction with atacicept versus placebo. The reduction in proteinuria was accompanied by stabilization in endpoint eGFR with atacicept compared to a decline with placebo at week 36, resulting in significant between-group geometric mean difference of 11%, approximating an absolute difference of 5.7 mL/min/1.73m2. Endpoint galactose deficient IgA1 levels significantly decreased from baseline by 60% versus placebo. The safety profile of atacicept was like placebo. Thus, our results provide evidence to support a pivotal, phase 3 study of atacicept in IgA nephropathy.
Asunto(s)
Creatinina , Glomerulonefritis por IGA , Proteínas Recombinantes de Fusión , Humanos , Glomerulonefritis por IGA/tratamiento farmacológico , Glomerulonefritis por IGA/orina , Glomerulonefritis por IGA/diagnóstico , Método Doble Ciego , Femenino , Masculino , Proteínas Recombinantes de Fusión/uso terapéutico , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/administración & dosificación , Adulto , Persona de Mediana Edad , Creatinina/orina , Creatinina/sangre , Resultado del Tratamiento , Proteinuria/tratamiento farmacológico , Proteinuria/orina , Receptores Fc/uso terapéutico , Adulto Joven , Tasa de Filtración Glomerular/efectos de los fármacosRESUMEN
AIM: People with chronic kidney disease experience high rates of cardiovascular disease. Cholesterol-lowering therapy is a mainstay in the management but there is uncertainty in the treatment effects on patient-important outcomes, such as fatigue and rhabdomyolysis. Here, we summarise the updated CARI Australian and New Zealand Living Guidelines on cholesterol-lowering therapy in chronic kidney disease. METHODS: We updated a Cochrane review and monitored newly published studies weekly to inform guideline development according to international standards. The Working Group included expertise from nephrology, cardiology, Indigenous Health, guideline development and people with lived experience of chronic kidney disease. RESULTS: The guideline recommends people with chronic kidney disease (eGFR ≥15 mL/min/1.73 m2) and an absolute cardiovascular risk of 10% or higher should receive statin therapy (with or without ezetimibe) to reduce the risk of cardiovascular events and death (strong recommendation, moderate certainty evidence). The guidelines also recommends a lower absolute cardiovascular risk threshold (≥5%) for Aboriginal and Torres Strait Islander Peoples and Maori with chronic kidney disease to receive statin therapy (with or without ezetimibe) (strong recommendation, low certainty evidence). The evidence was actively surveyed from 2020-2023 and updated as required. No changes to guideline recommendations were made, with no new data on the balance and benefits of harms. CONCLUSIONS: The development of living guidelines was feasible and provided the opportunity to update recommendations to improve clinical decision-making in real-time. Living guidelines provide the opportunity to transform chronic kidney disease guidelines.
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Anticolesterolemiantes , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Insuficiencia Renal Crónica , Humanos , Anticolesterolemiantes/uso terapéutico , Anticolesterolemiantes/efectos adversos , Australia/epidemiología , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Ezetimiba/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Nueva Zelanda/epidemiología , Guías de Práctica Clínica como Asunto , Brechas de la Práctica Profesional , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/complicacionesRESUMEN
BACKGROUND: Patients with early-stage chronic kidney disease (CKD) must make lifestyle modifications and adhere to treatment regimens to prevent their progression to end-stage kidney disease. The aim of this study was to elicit the perspectives of patients with stage 1-4 CKD about their disease, with a specific focus on their information needs in managing and living with CKD and its sequelae. METHODS: Patients with CKD stages 1-4 were purposively sampled from three major hospitals in Sydney, Australia to participate in focus groups. Transcripts were thematically analysed. RESULTS: From nine focus groups including 38 participants, six major themes were identified: medical attentiveness (shared decision-making, rapport, indifference and insensitivity); learning self-management (diet and nutrition, barriers to physical activity, medication safety); contextualizing comorbidities (prominence of CKD, contradictory treatment); prognostic uncertainty (hopelessness, fear of disease progression, disbelief regarding diagnosis); motivation and coping mechanisms (engage in research, pro-active management, optimism, feeling normal); and knowledge gaps (practical advice, access to information, comprehension of pathology results and CKD diagnosis, education for general practitioners). CONCLUSION: Patients capacity to slow the progression of CKD may be limited by their lack of knowledge about the disease, its comorbidities, psychosocial influences and their ability to interact and communicate effectively with their health-care provider. Support from a multidisciplinary care team, combined with provision of comprehensive, accessible and practical educational resources may enhance patients' ability and motivation to access and adhere to therapeutic and lifestyle interventions to retard progression of CKD.
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Conocimientos, Actitudes y Práctica en Salud , Fallo Renal Crónico/prevención & control , Educación del Paciente como Asunto , Insuficiencia Renal Crónica/terapia , Adaptación Psicológica , Adulto , Anciano , Actitud del Personal de Salud , Comunicación , Costo de Enfermedad , Progresión de la Enfermedad , Femenino , Grupos Focales , Alfabetización en Salud , Humanos , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/etiología , Masculino , Persona de Mediana Edad , Motivación , Nueva Gales del Sur , Cooperación del Paciente , Relaciones Médico-Paciente , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/psicología , Factores de Riesgo , Conducta de Reducción del Riesgo , Autocuidado , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
Despite its initially defined role as a T-helper type 1 cell (Th1)-inducing cytokine, interleukin-27 (IL-27) has complex roles in vivo. The role of IL-27 receptor (IL-27R) was defined in experimental crescentic glomerulonephritis induced by a foreign antigen, sheep globulin, which is planted in glomeruli. This lesion is dependent on a Th1 effector cellular response. Twenty-one days after the administration of sheep anti-mouse glomerular basement membrane antibody, wild-type mice developed histologic and functional inflammatory renal injury. Injury was attenuated in the absence of IL-27R α chain (IL-27Rα), the unique component of the IL-27R complex. In contrast to the attenuated renal injury on day 21, Il27ra(-/-) mice exhibited enhanced systemic immune responses, including Th1 responses, with increased IL-2-dependent interferon-γ (IFN-γ) production. However, earlier in the development of the nephritogenic immune response, IFN-γ production was decreased, with reduced early immune responses translating into attenuated renal injury. Having demonstrated decreased early Th1 systemic immune responses, followed by enhanced nephritogenic Th1 immune responses, renal injury was studied at later time points. On days 28 and 35 after injection of the nephritogenic antigen, renal injury was enhanced in Il27ra(-/-) mice compared with wild-type mice in an at least partially IFN-γ-dependent manner. In Th1-dependent autoinflammatory lesions, IL-27Rα has a biphasic role in vivo, initially pathogenic, but ultimately playing a protective role by regulating immune responses and attenuating disease.
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Glomerulonefritis/inmunología , Glomerulonefritis/patología , Receptores de Citocinas/metabolismo , Células TH1/inmunología , Animales , Especificidad de Anticuerpos/inmunología , Antígenos/inmunología , Glomerulonefritis/genética , Inmunidad/inmunología , Mediadores de Inflamación/metabolismo , Interferón gamma/biosíntesis , Interleucina-2/biosíntesis , Interleucinas/genética , Interleucinas/metabolismo , Riñón/inmunología , Riñón/patología , Ratones , Ratones Endogámicos C57BL , Pruebas de Neutralización , Receptores de Citocinas/genética , Receptores de Interleucina , Ovinos , Factores de Tiempo , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: A reduction in estimated glomerular filtration rate (eGFR), and/or the presence of proteinuria, are the predominant manifestations of chronic kidney disease (CKD), which is common in the elderly population. OBJECTIVE: This article outlines the clinical significance of CKD in the elderly and summarises recently updated recommendations for its assessment, staging and management. DISCUSSION: Most elderly patients with CKD present asymptomatically. Despite this, it is clinically significant as it is one of the most potent risk factors for cardiovascular disease. Even modest reductions in eGFR are associated with an increased prevalence of CKD-related complications such as anaemia and hyperphosphataemia. Early detection is an important strategy and should include all three components of the kidney health check (blood pressure measurement, a blood test for serum creatinine and eGFR, and a urine test for albumin:creatinine ratio). Treatment is guided by the patient's stage of CKD, based on kidney function (eGFR) and kidney damage (degree of albuminuria), and control of blood pressure to recommended levels with appropriate medications. The majority of elderly patients with CKD will not ultimately require, or desire, renal replacement therapy and may be safely managed in general practice.
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Insuficiencia Renal Crónica/diagnóstico , Anciano , Presión Sanguínea , Creatinina/sangre , Tasa de Filtración Glomerular , Humanos , Proteinuria , Insuficiencia Renal Crónica/clasificación , Insuficiencia Renal Crónica/terapiaRESUMEN
Introduction: The slow transformation of new research findings into clinical guidelines is a barrier to providing evidence-based care. The Caring for Australians and New Zealanders with Kidney Impairment (CARI) guidelines are developing models to improve guideline production, one methodology involves more functional concordance between trial groups, such as the Australian Kidney Trials Network (AKTN) and CARI. The objective of this project was to rapidly produce an evidence-based guideline on urate-lowering therapy in patients with chronic kidney disease (CKD), in response to new clinical trial publications on the topic by the AKTN. Methods: To produce a guideline as rapidly as possible, an existing systematic review was utilized as the evidence base, and then updated with the inclusion of clinical trials that had been published subsequently. A Work Group was convened to review the evidence and compose an appropriate guideline using CARI/GRADE methodology. The group met 3 times over 45 days to formulate the guideline. Results: The result was a strong recommendation against the use urate-lowering therapies in individuals with CKD (not receiving dialysis) and asymptomatic hyperuricemia. The process of identifying an appropriate existing systematic review, updating the literature search, and synthesizing the evidence, was done by 2 individuals over 15 days. The Work Group was formulated and composed the guideline over 45 days. In all, a new guideline incorporating the most up-to-date evidence was formulated in 60 days. Conclusion: This method of guideline development represents a potentially new way of releasing guidelines that encapsulates all available evidence in a time-efficient manner.
RESUMEN
A 62-year-old woman presented with acute renal failure, hematuria, proteinuria, and increased C-reactive protein level. She was positive for antineutrophil cytoplasmic antibodies (ANCAs) directed against myeloperoxidase (MPO) and negative for anti-glomerular basement membrane antibody. Kidney biopsy confirmed a diagnosis of pauci-immune crescentic glomerulonephritis with no immunoglobulin G staining. Remission was induced with prednisolone and intravenous cyclophosphamide, followed by maintenance therapy with azathioprine, during which MPO-ANCA results became negative. Nine months after the initial presentation, kidney function rapidly deteriorated again in association with hematuria, proteinuria, and increased C-reactive protein level. A second kidney biopsy again showed crescentic glomerulonephritis; however, on this occasion, direct immunofluorescence showed prominent linear staining of the glomerular basement membrane with immunoglobulin G. Test results were strongly positive for glomerular basement membrane antibody, but remained negative for MPO-ANCA. HLA-DR typing showed HLA-DRB1*15011, an allele strongly associated with anti-glomerular basement membrane disease. To our knowledge, this is the only reported case of 2 distinct forms of crescentic glomerulonephritis characterized by separate autoantibody profiles developing sequentially in a patient with proved HLA susceptibility. We speculate that glomerular damage caused by the initial renal insult resulted in a subsequent autoimmune response to autoantigen presented on the HLA-DR susceptibility allele.
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Enfermedad por Anticuerpos Antimembrana Basal Glomerular/inmunología , Anticuerpos Anticitoplasma de Neutrófilos , Glomerulonefritis/inmunología , Antígenos HLA/inmunología , Femenino , Glomerulonefritis/tratamiento farmacológico , Humanos , Persona de Mediana Edad , Inducción de RemisiónRESUMEN
The autoantigen in Goodpasture disease is the noncollagenous domain of alpha3 type IV collagen [alpha3(IV)NC1]. We previously demonstrated that IL-12p40(-/-) mice are protected from experimental autoimmune anti-glomerular basement membrane (anti-GBM) glomerulonephritis, seemingly defining a role for IL-12 in this disease; however, the recent identification of IL-23, a heterodimer composed of IL-12p40 and IL-23p19 subunits, raises the possibility that IL-23, rather than IL-12, may modulate this disease instead. We immunized wild-type, IL-12p35(-/-) (IL-12 deficient, IL-23 intact), IL-12p40(-/-) (deficient in both IL-12 and IL-23), and IL-23p19(-/-) (IL-12 intact, IL-23 deficient) mice with recombinant mouse alpha3(IV)NC1. Wild-type mice developed autoreactivity to alpha3(IV)NC1: Humoral responses, cellular responses, renal histologic abnormalities, leukocyte accumulation, autoantibody deposition, and IL-17A mRNA expression (a cytokine produced by the IL-23-maintained Th17 subset). IL-23 but not IL-12 was detected in the immune system. Regardless of the presence of IL-12, mice deficient in IL-23 were protected, but mice with IL-23 were not. Both IL-23-deficient strains exhibited lower autoantibody titers, reduced cellular reactivity, diminished cytokine production (IFN-gamma [Th1], IL-17A [Th17], TNF, and monocyte chemoattractant protein 1), and less renal disease and glomerular IgG deposition. The deficient responses in the absence of IL-23 were not due to increased regulatory T cells; IL-12p40(-/-) and IL-23p19(-/-) mice did not show increased proportions of CD4(+)CD25(+)FoxP3(+) cells or IL-10 levels early in the immune response. In conclusion, autoreactivity to the Goodpasture antigen is directed primarily by IL-23, absence of which results in hyporeactivity including but extending beyond a deficient Th17 response.
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Enfermedad por Anticuerpos Antimembrana Basal Glomerular/inmunología , Interleucina-17/inmunología , Interleucina-23/inmunología , Animales , Formación de Anticuerpos , Autoantígenos/inmunología , Autoinmunidad , Modelos Animales de Enfermedad , Adyuvante de Freund/inmunología , Inflamación/inmunología , Interleucina-12/deficiencia , Interleucina-12/inmunología , Interleucina-17/genética , Interleucina-23/deficiencia , Interleucina-23/genética , Ratones , Ratones Noqueados , ARN Mensajero/genética , Valores de Referencia , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunologíaRESUMEN
AIM: Statins are widely used for their cholesterol-lowering effects and for prevention of cardiovascular disease. Evidence indicates that these drugs also have immunomodulatory and other non-lipid lowering effects, with studies suggesting benefit in some animal models of immune (particularly T helper (Th)1)-mediated inflammatory disease and their corresponding human disease counterparts. We sought to evaluate the immunomodulatory effects and therapeutic potential of atorvastatin in experimental crescentic glomerulonephritis, a Th1-predominant animal model of glomerulonephritis. METHODS: Autologous phase, anti-glomerular basement membrane glomerulonephritis was induced in C57BL/6 mice by intravenous injection of sheep anti-mouse glomerular basement membrane globulin. Mice were administered atorvastatin (10 or 100 mg/kg) or control (phosphate-buffered saline) daily by oral gavage. Immune responses and renal injury were assessed after 21 days. RESULTS: Compared with control-treated mice, treatment with atorvastatin did not alter renal injury (serum creatinine, proteinuria, glomerular crescent formation) or glomerular leukocytic infiltration (CD4(+) T cells or macrophages). Atorvastatin resulted in a dose-related increase in circulating serum antibody to the disease-inducing antigen but no differences in antigen-stimulated splenocyte production of Th1/Th2 cytokines. At the higher dose, atorvastatin also led to a significant reduction in apoptosis of splenic CD4(+) T lymphocytes. CONCLUSION: This study demonstrates that statins modulate humoral responses and alter splenic CD4(+) T cell apoptosis. However, atorvastatin does not lead to significant changes in T helper cell polarization or renal injury in experimental crescentic glomerulonephritis.
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Glomerulonefritis/tratamiento farmacológico , Ácidos Heptanoicos/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inmunidad Humoral/efectos de los fármacos , Riñón/efectos de los fármacos , Pirroles/farmacología , Animales , Atorvastatina , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Relación Dosis-Respuesta a Droga , Glomerulonefritis/inmunología , Glomerulonefritis/patología , Riñón/patología , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
T-bet is a transcription factor that is essential for T helper (Th)1 lineage commitment and optimal IFN-gamma production by CD4(+) T cells. We examined the role of T-bet in the development of experimental crescentic glomerulonephritis, which is induced by Th1-predominant, delayed-type hypersensitivity-like responses directed against a nephritogenic antigen. Anti-glomerular basement membrane (GBM) glomerulonephritis was induced in T-bet(-/-) and wild-type C57BL/6 mice. Compared with wild-type controls, renal injury was attenuated in T-bet(-/-) mice with glomerulonephritis, evidenced by less proteinuria, glomerular crescents, and tubulointerstitial inflammation. Accumulation of glomerular CD4(+) T cells and macrophages was decreased, and was associated with reduced intrarenal expression of the potent Th1 chemoattractants CCL5/RANTES and CXCL9/Mig. Supporting the pro-inflammatory nature of T-bet signaling, assessment of systemic immunity confirmed that T-bet(-/-) mice had a reduction in Th1 immunity. The kinetic profile of T-bet mRNA in wild-type mice supported the hypothesis that T-bet deficiency attenuates renal injury in part by shifting the Th1/Th2 balance away from a Th1 phenotype. Expression of renal and splenic IL-17A, characteristically expressed by the Th17 subset of effector T cells, which have been implicated in the pathogenesis of autoimmune disease, was increased in T-bet(-/-) mice. We conclude that T-bet directs Th1 responses that induce renal injury in experimental crescentic glomerulonephritis.
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Enfermedad por Anticuerpos Antimembrana Basal Glomerular/metabolismo , Interleucina-17/metabolismo , Riñón/patología , Proteínas de Dominio T Box/metabolismo , Células TH1/fisiología , Animales , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/inmunología , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/patología , Antígenos CD19/metabolismo , Apoptosis/fisiología , Linfocitos B/metabolismo , Linfocitos B/fisiología , Proliferación Celular , Citocinas/metabolismo , Riñón/metabolismo , Activación de Linfocitos/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , ARN Mensajero/metabolismo , Bazo/metabolismo , Células TH1/metabolismoRESUMEN
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.
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Axones/fisiología , Isquemia/fisiopatología , Fallo Renal Crónico/fisiopatología , Pierna/irrigación sanguínea , Adolescente , Adulto , Constricción , Estimulación Eléctrica , Humanos , Isquemia/metabolismo , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/metabolismo , Masculino , Potenciales de la Membrana , Persona de Mediana Edad , Conducción Nerviosa , Enfermedades del Sistema Nervioso Periférico/etiología , Enfermedades del Sistema Nervioso Periférico/metabolismo , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Nervio Peroneo/fisiopatología , Potasio/sangre , ATPasa Intercambiadora de Sodio-Potasio/fisiologíaRESUMEN
OBJECTIVE: To investigate the mechanisms underlying peripheral neuropathy and to provide insights into axonal Na(+)/K(+) pump function in patients with end-stage kidney disease (ESKD). METHODS: Nerve excitability was assessed in 10 ESKD patients before and after a single session of haemodialysis and in 29 age-matched control subjects. Changes in excitability were recorded at baseline and following maximal voluntary contraction (MVC) of abductor pollicis brevis (APB) for 60s. Serum concentrations of putative neurotoxins including potassium, urea, parathyroid hormone and beta-2-microglobulin were also measured. RESULTS: Baseline excitability values were consistent with axonal depolarisation prior to dialysis. Following maximal voluntary contraction (MVC), there was an increase in threshold, which was associated with reduced strength-duration time constant and increased superexcitability, consistent with axonal hyperpolarisation. These changes were quantitatively similar for patients and controls, arguing against any significant reduction in the axonal Na(+)/K(+) pump in ESKD. Following dialysis, activity-dependent changes were less in ESKD, which suggests greater Na(+)/K(+) pump activity prior to dialysis, the opposite of the changes expected with reduced Na(+)/K(+) pump function. The reduced post-contraction threshold change in post-dialysis recordings is likely to be secondary to relative hyperpolarisation of the axonal membrane following dialysis and reduction in K(+) concentration. CONCLUSIONS: Our findings suggest that Na(+)/K(+) pump function is not impaired in patients with ESKD. SIGNIFICANCE: Pre-dialysis excitability changes in ESKD patients may be explained on the basis of hyperkalaemia. Alteration in Na(+)/K(+) pump function does not appear to be a contributing factor to the development of neuropathy in ESKD patients.
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Axones , Fallo Renal Crónico/metabolismo , Fallo Renal Crónico/fisiopatología , Conducción Nerviosa/fisiología , Enfermedades del Sistema Nervioso Periférico , ATPasa Intercambiadora de Sodio-Potasio/fisiología , Adolescente , Adulto , Anciano , Axones/patología , Axones/fisiología , Estudios de Casos y Controles , Estimulación Eléctrica/métodos , Femenino , Humanos , Fallo Renal Crónico/patología , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Actividad Motora , Contracción Muscular/fisiología , Hormona Paratiroidea/sangre , Enfermedades del Sistema Nervioso Periférico/metabolismo , Enfermedades del Sistema Nervioso Periférico/patología , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Potasio/sangre , Diálisis Renal/métodos , Seroglobulinas/metabolismo , Urea/metabolismoRESUMEN
Although multiple toxins have been implicated in the development of uraemic neuropathy, no causative agent has been identified. In the present study, the excitability properties of lower limb motor nerves in patients with end-stage kidney disease treated with haemodialysis were measured before, during and after a standard 5 h haemodialysis session, in an attempt to explore the pathophysiology of uraemic neuropathy. Compound muscle action potentials were recorded from tibialis anterior and extensor digitorum brevis, following stimulation of the common peroneal nerve in 14 patients. Measures of excitability were assessed in relation to changes in serum levels of potential neurotoxins, including potassium, calcium, urea, uric acid, parathyroid hormone and beta-2-microglobulin. Before dialysis, measures of nerve excitability were significantly abnormal in the patient group for axons innervating tibialis anterior and extensor digitorum brevis, consistent with axonal depolarization: refractoriness was increased and superexcitability and depolarizing threshold electrotonus were reduced. Pre-dialysis excitability abnormalities were strongly correlated with serum K+. Correlation was also noted between the severity of symptoms and excitability abnormalities. Haemodialysis normalized the majority of nerve excitability parameters. In conclusion, lower limb motor axons in uraemic patients are depolarized before dialysis. The correlation between serum K+ and excitability measures indicates that hyperkalaemia is primarily responsible for uraemic depolarization, and a likely contributing factor to the development of neuropathy.