Relative contributions of diabetes and chronic kidney disease to neuropathy development in diabetic nephropathy patients.

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.

Potassium control in chronic kidney disease: implications for neuromuscular function.

In Australia, approximately 1.7 million adults have evidence of chronic kidney disease (CKD). This complex disease can result in a multitude of complications, including hyperkalaemia, which is common and well recognised. The advent of new therapeutics aimed at lowering serum potassium has raised the possibility of optimising potassium control to enable greater use of renin-angiotensin-aldosterone system inhibitors in the management of CKD. Recent studies suggest that hyperkalaemia also has implications for peripheral neuropathy in CKD, a complication that substantially contributes to patient morbidity. This review examines evidence of the relationship between potassium and peripheral neuropathy, with a discussion of clinical implications. We searched PubMed for original and review articles using pre-specified key words, clinical guidelines and population data. The major findings were that contemporary CKD cohorts demonstrate a high prevalence of peripheral neuropathy, even in stage 3-4 CKD, including those without diabetes. The severity of the problem has been emphasised by an ominous rise in foot complications and amputation rates in dialysis patients, highlighting the need for increased awareness of the condition in earlier stages of CKD and targeted treatment strategies. It is likely that the pathophysiology of peripheral neuropathy in CKD is multifaceted, with potential influences from potassium, vascular abnormalities, diabetes, inflammation and unknown middle molecules. Despite these complexities, the relationship between potassium and nerve function in dialysis has been well established, and recent research in stage 3-4 CKD suggests that assertive potassium control may improve neuromuscular outcomes in CKD. These small studies should be confirmed in large, multicentre settings.

The utility of the Total Neuropathy Score as an instrument to assess neuropathy severity in chronic kidney disease: A validation study.

OBJECTIVE: To demonstrate construct validity of the Total Neuropathy Score (TNS) in assessing peripheral neuropathy in subjects with chronic kidney disease (CKD). METHODS: 113 subjects with CKD and 40 matched controls were assessed for peripheral neuropathy using the TNS. An exploratory factor analysis was conducted and internal consistency of the scale was evaluated using Cronbach's alpha. Construct validity of the TNS was tested by comparing scores between case and control groups. RESULTS: Factor analysis revealed valid item correlations and internal consistency of the TNS was good with a Cronbach's alpha of 0.897. Subjects with CKD scored significantly higher on the TNS (CKD: median, 6, interquartile range, 1-13; controls: median, 0, interquartile range, 0-1; p < 0.001). Subgroup analysis revealed construct validity was maintained for subjects with stages 3-5 CKD with and without diabetes. CONCLUSIONS: The TNS is a valid measure of peripheral neuropathy in patients with CKD. SIGNIFICANCE: The TNS is the first neuropathy scale to be formally validated in patients with CKD.

Effects of hemodialysis on intraneural blood flow in end-stage kidney disease.

INTRODUCTION: We quantified intraneural blood flow (INBF) in 18 patients with end-stage kidney disease (ESKD) and examined its relationship with nerve size, neuropathy severity, and nerve excitability parameters. METHODS: Sonographic measurements of the median nerve were performed at the same site before and after hemodialysis. INBF was quantified by analyzing power Doppler sonograms to obtain the vessel score (VSc) and maximum perfusion intensity (MPI). Corresponding median motor nerve excitability studies were performed. Neuropathy severity was assessed using Total Neuropathy Score. RESULTS: A total of 39% of ESKD patients had detectable INBF compared with none in the control group (P < 0.0001). Patients with detectable INBF had larger nerves and more severe neuropathy (P < 0.01). INBF parameters were significantly reduced after a session of dialysis (VSc: P < 0.01; MPI: P < 0.01). A significant relationship was found between interdialytic change in INBF and changes in nerve excitability. CONCLUSIONS: Increased INBF is a potential marker for neuropathy severity in ESKD patients. Muscle Nerve 57: 287-293, 2018.

Randomized, Controlled Trial of the Effect of Dietary Potassium Restriction on Nerve Function in CKD.

BACKGROUND AND OBJECTIVES: Neuromuscular complications are almost universal in CKD by the time that a patient commences dialysis. Recent studies have indicated that chronic hyperkalemia may contribute to the development of neuropathy in CKD. This study was undertaken to determine whether dietary restriction of potassium intake may be a neuroprotective factor in CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A 24-month prospective, single-blind, randomized, controlled trial was undertaken in 47 consecutively recruited patients with stages 3 and 4 CKD. The intervention arm (n=23) was prescribed a diet focusing on potassium restriction to meet a monthly serum potassium level of ≤4.5 mEq/L, with oral sodium polystyrene sulfonate provided if dietary advice failed to achieve the target. The control arm (n=24) received dietary advice regarding general nutrition. The primary outcome was the change in the total neuropathy score evaluated by a blinded observer. Secondary outcomes included electrolyte levels, gait speed, neurophysiologic parameters, and health-related quality of life scores. Five patients withdrew before initiation of treatment, and final analysis consisted of n=21 in each group. RESULTS: There was a greater increase in total neuropathy score from baseline to final assessment in the control arm compared with the intervention arm (6.1±6.2-8.6±7.9 controls; 7.8±7.4-8.2±7.5 intervention; change 2.8±3.3-0.4±2.2, respectively; P<0.01). The intervention significantly reduced mean serum potassium compared with controls (4.6±0.1-4.8±0.1 mEq/L mean recorded every 6 months over the trial duration; P=0.03). There were no adverse changes in other nutritional parameters. Improved gait speed was also noted in the intervention arm compared with the control arm, with a mean increase of 0.15±0.17 m/s in the intervention group versus 0.02±0.16 m/s in the control group (P=0.01). CONCLUSIONS: Our results provide important preliminary evidence that dietary potassium restriction confers neuroprotection in CKD and should be confirmed in a larger multicenter trial.

Haemodialysis alters peripheral nerve morphology in end-stage kidney disease.

OBJECTIVE: We explored the nerve ultrasound (US) characteristics of 15 patients with end-stage kidney disease (ESKD) and correlated these findings with clinical severity and electrophysiological parameters of neuropathy. METHODS: 15 ESKD patients on thrice-weekly high-flux haemodialysis and 15 healthy controls were enrolled. Sonographic and electrophysiologic studies were conducted before and after a single session of haemodialysis. Serial measurements of median nerve cross-sectional area (CSA) and hypoechoic fraction (HF) were performed at the same non-entrapment site in the mid-forearm. Neuropathy severity was quantified using the total neuropathy score (TNS). RESULTS: 86.7% of the ESKD cohort had neuropathy (TNS>1). ESKD patients had significantly higher baseline CSA (8.9±1.2mm2 vs 7.5±1.0mm2, p<0.05) and HF (56.0±1.0% vs 54.0±1.1%, p<0.05) compared with the control group. The CSA correlated significantly with TNS (r=0.826; p<0.0001) and other electrophysiological parameters. There was a reduction in both the CSA (8.3±1.4mm2; p<0.01) and HF (55.0±1.6%; p<0.05) after a single session of HD. A significant relationship was also found between the change in CSA and change in serum K+ after dialysis (r=0.782, p<0.01). CONCLUSIONS: This study shows that peripheral nerves in ESKD patients are larger and more hypoechoic and that these morphological abnormalities may be reversed by dialysis. SIGNIFICANCE: US may be useful as an early marker of neuropathy in ESKD.

Neurological complications in chronic kidney disease.

Patients with chronic kidney disease (CKD) are frequently afflicted with neurological complications. These complications can potentially affect both the central and peripheral nervous systems. Common neurological complications in CKD include stroke, cognitive dysfunction, encephalopathy, peripheral and autonomic neuropathies. These conditions have significant impact not only on patient morbidity but also on mortality risk through a variety of mechanisms. Understanding the pathophysiological mechanisms of these conditions can provide insights into effective management strategies for neurological complications. This review describes clinical management of neurological complications in CKD with reference to the contributing physiological and pathological derangements. Stroke, cognitive dysfunction and dementia share several pathological mechanisms that may contribute to vascular impairment and neurodegeneration. Cognitive dysfunction and dementia may be differentiated from encephalopathy which has similar contributing factors but presents in an acute and rapidly progressive manner and may be accompanied by tremor and asterixis. Recent evidence suggests that dietary potassium restriction may be a useful preventative measure for peripheral neuropathy. Management of painful neuropathic symptoms can be achieved by pharmacological means with careful dosing and side effect considerations for reduced renal function. Patients with autonomic neuropathy may respond to sildenafil for impotence. Neurological complications often become clinically apparent at end-stage disease, however early detection and management of these conditions in mild CKD may reduce their impact at later stages.

Comparative study to evaluate the effects of peritoneal and hemodialysis on peripheral nerve function.

INTRODUCTION: There is no specific treatment for neuropathy in chronic kidney disease (CKD). We compared nerve function across hemodialysis (HD) and peritoneal dialysis (PD). METHODS: Subjects underwent neurological assessment and neurophysiological testing using nerve excitability studies. Pre- and postdialysis studies were undertaken in HD (n = 10) and PD (n = 10) patients and were compared with stage 4 CKD patients (n = 12) and healthy controls (n = 20). RESULTS: There were prominent differences in nerve excitability between the groups (P < 0.001). The HD group was significantly abnormal compared with all groups for excitability parameters, while the PD group demonstrated results similar to the CKD group. Pre- and postdialysis fluctuations were pronounced in the HD group, while the PD group showed less severe fluctuations. CONCLUSIONS: PD patients demonstrated greater normality of nerve excitability compared with the HD group despite similar duration of dialysis. These results suggest PD may provide greater homeostatic stability and may be neurologically beneficial. Muscle Nerve 54: 58-64, 2016.

Evidence for a causal relationship between hyperkalaemia and axonal dysfunction in end-stage kidney disease.

OBJECTIVE: Potassium (K(+)) has been implicated as a factor in the development of uraemic neuropathy. This study was undertaken to investigate whether hyperkalaemia plays a causal role in axonal dysfunction in end-stage kidney disease (ESKD). METHODS: Median motor nerve excitability studies were undertaken in four haemodialysis patients during a modified dialysis session. The serum K(+) level was "clamped" (fixed) for the first 3h of dialysis, whilst allowing all other solutes to be removed, this was followed by dialysis against low dialysate K(+) for a further 4 h. Blood chemistry and nerve excitability studies were undertaken prior to, during and following dialysis. Results were compared to results from the same patients during routine dialysis sessions. RESULTS: All patients demonstrated significant nerve excitability abnormalities reflective of nerve membrane depolarization in pre-dialysis recordings (p<0.01). After the 3 h clamp period, serum K(+) remained elevated (5.0 mmol/L) and nerve excitability remained highly abnormal, despite the significant clearance of other uraemic toxins. In contrast, studies undertaken during routine dialysis sessions demonstrated significant improvement in both serum K(+) and nerve function after 3 h. CONCLUSIONS: The current study has established a causal relationship between serum K(+) and axonal membrane depolarization in haemodialysis patients. SIGNIFICANCE: From a clinical perspective, strict K(+) control may help improve nerve function in ESKD.

An international comparison of the effect of policy shifts to organ donation following cardiocirculatory death (DCD) on donation rates after brain death (DBD) and transplantation rates.

During the past decade an increasing number of countries have adopted policies that emphasize donation after cardiocirculatory death (DCD) in an attempt to address the widening gap between the demand for transplantable organs and the availability of organs from donation after brain death (DBD) donors. In order to examine how these policy shifts have affected overall deceased organ donor (DD) and DBD rates, we analyzed deceased donation rates from 82 countries from 2000-2010. On average, overall DD, DBD and DCD rates have increased over time, with the proportion of DCD increasing 0.3% per year (p = 0.01). Countries with higher DCD rates have, on average, lower DBD rates. For every one-per million population (pmp) increase in the DCD rate, the average DBD rate decreased by 1.02 pmp (95% CI: 0.73, 1.32; p<0.0001). We also found that the number of organs transplanted per donor was significantly lower in DCD when compared to DBD donors with 1.51 less transplants per DCD compared to DBD (95% CI: 1.23, 1.79; p<0.001). Whilst the results do not infer a causal relationship between increased DCD and decreased DBD rates, the significant correlation between higher DCD and lower DBD rates coupled with the reduced number of organs transplanted per DCD donor suggests that a national policy focus on DCD may lead to an overall reduction in the number of transplants performed.

Socioeconomic, demographic and policy comparisons of living and deceased kidney transplantation rates across 53 countries.

AIM: There are more than 1.7 million sufferers of end stage kidney disease (ESKD) worldwide and for many a donated kidney provides the only chance of regaining independence from dialysis. Unfortunately, the demand for kidneys for transplantation far exceeds the available supply. It is important, therefore, that we understand the factors that may influence kidney donation rates. While certain socio-demographic factors have been linked to kidney donation rates, few studies have examined the influence of multiple socio-demographic factors on rates of both living and deceased kidney transplantation (KT) and none have examined their comparative effect in large numbers of culturally and socio-politically diverse countries. METHOD: In this study, we performed univariate and multivariate analyses of the influence of 15 socio-economic factors on both the living donor (LD) and the deceased donor (DD) kidney transplantation rates (KTR) in 53 countries. RESULTS: Our analyses demonstrated that factors such as UN HDI (United Nations Human Development Index), religion, GDP, education, age, healthcare expenditure, presumed consent legislation and existence of a nationally managed organ donation program were associated with higher deceased KTR. In contrast, the only factors associated with living KTR were a highly significant negative association with presumed consent and variable associations with different religions. CONCLUSION: We suggest that by identifying factors that affect kidney transplantation rates these can be used to develop programs for enhancing donor rates in individual countries where those rates are below the leading countries.

Effects of hemodiafiltration and high flux hemodialysis on nerve excitability in end-stage kidney disease.

OBJECTIVES: Peripheral neuropathy is the most common neurological complication in end-stage kidney disease. While high flux hemodialysis (HFHD) and hemodiafiltration (HDF) have become the preferred options for extracorporeal dialysis therapy, the effects of these treatments on nerve excitability have not yet been examined. METHODS: An observational proof-of-concept study of nerve excitability and neuropathy was undertaken in an incident dialysis population (n = 17) receiving either HFHD or HDF. Nerve excitability techniques were utilised to assess nerve ion channel function and membrane potential, in conjunction with clinical assessment and standard nerve conduction studies. A mathematical model of axonal excitability was used to investigate the underlying basis of the observed changes. Nerve excitability was recorded from the median nerve, before, during and after a single dialysis session and correlated with corresponding biochemical markers. Differences in nerve excitability were compared to normal controls with longitudinal follow-up over an 18 month period. RESULTS: Nerve excitability was performed in patient cohorts treated with either HFHD (n = 9) or online HDF (n = 8), with similar neuropathy status. Nerve excitability measures in HDF-treated patients were significantly closer to normal values compared to HFHD patients obtained over the course of a dialysis session (p<0.05). Longitudinal studies revealed stability of nerve excitability findings, and thus maintenance of improved nerve function in the HDF group. CONCLUSIONS: This study has provided evidence that nerve excitability in HDF-treated patients is significantly closer to normal values prior to dialysis, across a single dialysis session and at longitudinal follow-up. These findings offer promise for the management of neuropathy in ESKD and should be confirmed in randomised trials.

Supramaximal elevation in B-type natriuretic peptide and its N-terminal fragment levels in anephric patients with heart failure: a case series.

INTRODUCTION: Little is known about the responses of natriuretic peptides to developing congestive heart failure in 'anephric' end-stage kidney disease. CASE PRESENTATION: We present three consecutive cases of surgically-induced anephric patients in a critical care environment: a 28-year-old Caucasian woman (with congestive heart failure), a 42-year-old Caucasian woman (without congestive heart failure), and a 23-year-old Caucasian woman (without congestive heart failure). Our limited study data indicate that cut-off values advocated for B-type natriuretic peptide and its N-terminal fragment to 'rule out' congestive heart failure in two of our end-stage kidney disease patients (without congestive heart failure) are largely appropriate for anephric patients. However, our index (first) patient developed congestive heart failure accompanied by the phenomenon of massive and persistent elevation of these natriuretic levels. CONCLUSION: Our findings suggest that patients from the anephric subclass suffering from congestive heart failure will develop supramaximal elevation of B-type natriuretic peptide and its N-terminal fragment, implying the need for dramatically higher cut-off values with respective magnitudes of the order of 50-fold (B-type natriuretic peptide ~5780pmol/L; 20,000ng/L) to 100-fold (N-terminal fragment ~11,800pmol/L; 100,000ng/L) higher than current values used to 'rule in' congestive heart failure. Further research will be required to delineate those cut-off values. The role of our devised 'Blood Volume - B-type natriuretic peptide feedback control system' on 'anatomical' and 'functional' anephric patients led to significant mathematically-enriched arguments supporting our proposal that this model provides plausible explanations for the study findings, and the model lends support to the important hypothesis that these two groups of anephric patients inflicted with congestive heart failure should effectively have similar natriuretic response behavior.

Fluctuations in haemoglobin levels in haemodialysis, pre-dialysis and peritoneal dialysis patients receiving epoetin alpha or darbepoetin alpha.

AIM: To characterize the haemoglobin variability of haemodialysis, peritoneal dialysis and pre-dialysis patients treated with either epoetin alpha or darbepoetin alpha in a clinical setting where treatment was administered according to current standard Australian practice. METHODS: Data on haemodialysis, pre-dialysis and peritoneal dialysis patients were extracted from the Renal Anaemia Management database (RAM) from 1 January 2001 to 31 December 2004. The variance in haemoglobin was calculated from patient records with more than five haemoglobin observations over a period of at least 4 weeks following 9 weeks of therapy. A mixed-model was fitted to the within-patient variances and weighting was based on the number of observations minus 1 for each record. RESULTS: The mean within-patient variance in haemoglobin levels for i.v. administered erythropoietin-stimulating agents (IV) haemodialysis, s.c. administered erythropoietin-stimulating agents (SC) haemodialysis, predialysis (SC) and peritoneal dialysis (SC) patients receiving epoetin alpha were 9% (95% CI: 13% to 5%, P < 0.0001), 17% (95% CI: 32% to 0.2%, P = 0.047), 19% (95% CI: 27% to 11%, P < 0.0001) and 26% (95% CI: 33% to 18%, P < 0.0001) lower than that for patients receiving darbepoetin alpha. The mean haemoglobin levels for haemodialysis (IV), haemodialysis (sc) predialysis (SC) and peritoneal dialysis (SC) patients receiving darbepoetin alpha were 11.6 g/dL, 11.2 g/dL, 11.5 g/dL and 11.5 g/dL compared with 11.5 g/dL, 11.6 g/dL, 11.7 g/dL and 11.5 g/dL for patients receiving epoetin alpha. CONCLUSION: There was 9-26% greater within-patient fluctuation in haemoglobin levels in patients receiving darbepoetin alpha compared with epoetin alpha. The causes of haemoglobin fluctuations and the implications for patient outcomes and resource use require further study.

Neuromuscular disease in the dialysis patient: an update for the nephrologist.

Neuromuscular disease is an extremely common complication of end-stage kidney disease (ESKD), manifesting in almost all dialysis patients, and leading to weakness, reduced exercise capacity, and disability. Recent studies have suggested that hyperkalemia may underlie the development of neuropathy. As such, maintenance of serum K(+) within normal limits between periods of dialysis in ESKD patients manifesting early neuropathic symptoms may reduce neuropathy development and progression. For patients with more severe neuropathic syndromes, increased dialysis frequency or a switch to high-flux dialysis may prevent further deterioration, while ultimately, renal transplantation is required to improve and restore nerve function. Exercise training programs are beneficial for ESKD patients with muscle weakness due to neuropathy or myopathy, and are capable of improving exercise tolerance and quality of life. Specific treatments have recently been evaluated for symptoms of autonomic neuropathy, including sildenafil for impotence and midodrine for intra-dialytic hypotension, and have been shown to be effective and well tolerated. Other important management strategies for neuropathy include attention to foot care to prevent callus and ulceration, vitamin supplementation, and erythropoietin. Treatment with membrane-stabilizing agents, such as amitryptiline and gabapentin, are highly effective in patients with painful neuropathy.

Adult nephrotic syndrome: non-specific strategies for treatment.

Irrespective of aetiology, the nephrotic syndrome presents a range of potentially serious complications. These include thrombo-embolism, infection and hyperlipidaemia. Despite the prevalence of the nephrotic state among renal patients, there has been little prospective analysis of the therapeutic approach to these potentially life-threatening events even though their pathogenesis has been examined in some detail. Most of these complications are more prevalent once the albumin concentration falls below 20 g/L and it is recognized that restoration of serum albumin significantly diminishes their frequency. However, this may be difficult to achieve, especially in adults. The problems of thrombo-embolism and infection are of immediate concern but, in persistent cases, the additional issues of hyperlipidaemia and loss of bone density also require consideration for therapy. Thus, in addition to specific attempts to reduce proteinuria, it is recommended that high-risk nephrotic patients receive anticoagulation, pneumococcal vaccination and lipid lowering therapy. Strategies for the preservation of bone density should also be considered, particularly in patients who receive high-dose corticosteroids. Among a range of non-specific treatments for proteinuria, angiotensin-converting enzyme inhibitors appear best in terms of efficacy and safety. Prospective trials are required to clarify the longitudinal impact of these generic strategies on the protection of the persistently nephrotic patient.

Fluctuations in haemoglobin levels in haemodialysis patients receiving intravenous epoetin alfa or intravenous darbepoetin alfa.

This study aimed to compare the within-patient variability in haemoglobin levels in haemodialysis patients receiving intravenous epoetin alfa or intravenous darbepoetin alfa. Data on haemodialysis patients were extracted from the Renal Anaemia Management database from 2003 to 2004. The variance in haemoglobin was calculated for each patient with more than five haemoglobin observations (n = 3619). A mixed model was fitted to the within-patient variances and weighting was based on the number of observations minus 1 for each patient. The model took into account the situation where patients had data on both agents and could therefore act as their own control. The mean within-patient variance in haemoglobin levels for patients receiving darbepoetin alfa was 24% (95% CI: 18%, 31%) greater than that for patients receiving epoetin alfa (P < 0.0001). The mean haemoglobin level for patients receiving darbepoetin alfa was 11.33 g/dL (95% CI: 11.27, 11.40) compared with 11.43 g/dL (95% CI: 11.39, 11.46) for patients receiving epoetin alfa (P < 0.01). There was greater within-patient fluctuation in haemoglobin levels in patients receiving darbepoetin alfa compared with epoetin alfa. The implications of haemoglobin fluctuations on patient outcomes and resource use require further study.

Dose of epoetin alfa used in haemodialysis patients when switching from subcutaneous to intravenous administration.

AIM: To determine whether there is a change in the dose of epoetin alfa when switching from subcutaneous (SC) to intravenous (IV) administration in Australian haemodialysis patients. METHODS: Validated data from 2214 haemodialysis patients at 16 Australian hospitals who switched from SC to IV administration of epoetin alfa from January 2002 to September 2003 were extracted from the Renal Anaemia Management database provided by Janssen-Cilag. Of these patients, 806 had dosing data for at least 1 month before switch through to 6 months post switch (6 month cohort). RESULTS: In the 6 month cohort, the mean dose was 10 776 IU/week (95% CI: 10 235, 11 317) at switch compared with 12 008 IU/week (95% CI: 11 447, 12 569) 6 months post switch, an increase in a dose of 1232 IU/week (95% CI: 868, 1596). The mean haemoglobin levels at switch were 11.55 g/dL (95% CI: 11.45, 11.66) compared with 11.59 g/dL (95% CI: 11.49, 11.68) 6 months after switch. Centre and dosing frequency of epoetin alfa before switch were determinants of increased dose. CONCLUSION: Changing from SC to IV administration of epoetin alfa resulted in an 11% increase in mean dose to maintain haemoglobin levels in Australian haemodialysis patients.

Australian haemodialysis patients on intravenous epoetin alfa or intravenous darbepoetin alfa: how do they compare?

AIM: The purpose of the present study was to determine whether Australian haemodialysis patients receiving intravenous epoetin alfa are comparable to those receiving darbepoetin alfa with respect to a range of demographic and clinical characteristics. METHODS: Data on haemodialysis patients were extracted from the Renal Anaemia Management database for the period from July 2003 to March 2004. RESULTS: Patients on haemodialysis were more likely to receive epoetin alfa than to receive darbepoetin alfa (n = 1898 vs n = 603, respectively). Patients receiving epoetin alfa were marginally older than patients receiving darbepoetin alfa (61 +/- 15 vs 59 +/- 15, mean +/- SD; P < 0.05). Patients were similar in terms of proportion of males, incidence of diabetes, and angiotensin-converting enzyme inhibitor and antihypertensive use. However, patients receiving epoetin alfa had higher haemoglobin (116 +/- 13 g/L vs 113 +/- 15 g/L), serum ferritin (582 +/- 414 mug/L vs 461 +/- 350 mug/L) and transferrin saturation levels (29 +/- 13% vs 26 +/- 14%), and better dialysis adequacy test results, as measured by urea reduction ratio (URR) or Kt/V, than patients on darbepoetin alfa (P < 0.001 in all cases). The frequency of dosing was higher in the epoetin alfa group (1.7 +/- 0.7 doses/week vs 1.0 +/- 0.4 doses/week, P < 0.001). Using the 240:1 dose ratio recommended in the Australian prescribing information for darbepoetin alfa, epoetin alfa was administered at a lower dose compared with darbepoetin alfa (164 +/- 116 IU/kg per week vs 192 +/- 152 IU/kg per week, P < 0.001). CONCLUSION: This cross-sectional sample of Australian clinical practice suggests that there are differences in the haematological parameters of patients receiving epoetin alfa compared with patients receiving darbepoetin alfa.

Ischaemia induces paradoxical changes in axonal excitability in end-stage kidney disease.

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.