The extrapyramidal syndromes of chronic kidney disease and dialysis (EPS-CKDD): diagnostic criteria, risk factors and prognosis.

BACKGROUND: Acute extrapyramidal movement disorders in dialysis patients are rare, inconsistently defined and have uncertain aetiology and prognosis. AIM: Define diagnostic criteria, prognosis and risk factors. DESIGN AND METHODS: Retrospective case series review of 20 patients (14 female, mean age 62 years) receiving dialysis for a median of 15 (interquartile range 4-35) months who presented with acute parkinsonism (AP = 11) or chorea/athetosis (CA = 9). RESULTS: All patients had type 2 diabetes (HbA1c 6.8 ± 1.0) and had received metformin. Lactic acidosis was present in 2 patients at presentation and serum lactate was elevated in 7/15 patients tested. No patient had abnormal copper or thyroid metabolism and 5/8 patients tested returned marginal abnormalities in heavy metal screening. Magnetic resonance imaging (MRI) revealed characteristic bilateral symmetric T2 hyperintensity of the basal ganglia (BG), predominantly putamen and globus pallidus (the lentiform nucleus) and more extensive involvement of the external and internal capsules in patients with AP presentation. Post-mortem demonstrated cytotoxic necrosis of the BG. Therapy included thiamine, intensive dialysis and cessation of metformin. Two patients died acutely, nine recovered and nine had residual symptoms. Median survival did not differ by presentation: AP 24 [95% confidence interval (CI) 21-27] and CA 33 (95% CI 32-35) months, P = 0.21. CONCLUSIONS: There are two distinct clinical extrapyramidal movement disorders associated with specific diagnostic MRI imaging that support the diagnosis of the extrapyramidal syndromes of chronic kidney disease and dialysis. The associations with diabetes, metformin and metabolic acidosis suggest a common pathogenic mechanism but require additional study. Early recognition and treatment may improve outcomes.

The effect of radiological imaging on treatment delay and hospitalisation in patients with peritoneal dialysis-related peritonitis: A secondary analysis of the PROMPT study.

BACKGROUND: In peritoneal dialysis-related peritonitis (peritonitis), delayed antibiotic therapy is associated with adverse outcomes. Identifying barriers to timely treatment may improve outcomes. AIM: To determine the impact of radiological investigations on treatment delay and predictors of hospitalisation and length of stay (LOS). METHODS: Retrospective review of patients with presumed peritonitis in Western Australia. RESULTS: In 153 episodes of peritonitis, 79 (51.6%) resulted in admission with a median LOS of 3 days (Q1, Q3: 1, 6). In a multivariable model, significant predictors of admission were abnormal exit-site (odds ration (OR) 5.7; 95% confidence interval (CI): 1.4, 23.6; p = 0.02), failure to detect a cloudy bag (OR 11.9; 95%CI: 3.2, 44.7; p < 0.001), female sex (OR 3.3; 95% CI: 1.4, 9.7; p = 0.027), radiological imaging within 24 h (OR 8.8; 95% CI: 2.2, 34.8; p = 0.002) and contact with ambulant care facility (OR 0.32, 95% CI: 0.11, 0.98; p = 0.04). Imaging within 24 h of presentation occurred in 41 (27%) episodes of peritonitis, mostly plain X-rays (91%), of which 83% were clinically irrelevant. Imaging performed within 24 h of presentation increased the median time to antibiotic treatment (2.9 h (Q1, Q3: 1.6, 6.4) vs 2.0 h (Q1, Q3: 1, 3.8; p = 0.046)). Imaging performed prior to administering antibiotics significantly increased the median time to treatment (4.7 h (Q1, Q3: 2.9, 25) vs 1.5 h (Q1, Q3: 0.75, 2.5; p < 0.001)) in those where imaging followed antibiotic treatment. CONCLUSIONS: Half of all presentations with peritonitis result in hospital admission. Radiological imaging was associated with an increased risk of hospitalisation, potentially contributes to treatment delay, and was mostly clinically unnecessary. When required, imaging should follow antibiotic therapy.

When thoracic organ recipients become abdominal organ donors: sharing the risks and benefits of transplantation: a case report.

INTRODUCTION: The increasing demand for organ donation has resulted in the use of expanded-criteria donors. Solid organ transplant recipients and potential recipients represent a unique pool of selected organ donors that may help to meet this demand. CASE REPORT: We present 2 cases, a lung transplant recipient and a patient on the lung transplant waiting list, who became kidney donors to 4 recipients. CONCLUSIONS: These donations illustrate the interrelated risks and benefits for transplant recipients who themselves can become unintended, but effective donors.

Trajectory Learning for Robot Programming by Demonstration Using Hidden Markov Model and Dynamic Time Warping.

The main objective of this paper is to develop an efficient method for learning and reproduction of complex trajectories for robot programming by demonstration. Encoding of the demonstrated trajectories is performed with hidden Markov model, and generation of a generalized trajectory is achieved by using the concept of key points. Identification of the key points is based on significant changes in position and velocity in the demonstrated trajectories. The resulting sequences of trajectory key points are temporally aligned using the multidimensional dynamic time warping algorithm, and a generalized trajectory is obtained by smoothing spline interpolation of the clustered key points. The principal advantage of our proposed approach is utilization of the trajectory key points from all demonstrations for generation of a generalized trajectory. In addition, variability of the key points' clusters across the demonstrated set is employed for assigning weighting coefficients, resulting in a generalization procedure which accounts for the relevance of reproduction of different parts of the trajectories. The approach is verified experimentally for trajectories with two different levels of complexity.

Prospective randomized clinical trial assessing the efficacy of Denamarin for prevention of CCNU-induced hepatopathy in tumor-bearing dogs.

BACKGROUND: Increases in liver enzymes occur in up to 86% of dogs receiving CCNU and can result in treatment delay or early discontinuation of treatment. Denamarin contains S-adenosylmethionine and silybin, both of which have been investigated as treatments for various liver diseases. HYPOTHESIS: Dogs on CCNU receiving Denamarin have lower alanine aminotransferase (ALT) activity than dogs not receiving Denamarin. Dogs on Denamarin are less likely to require treatment delay because of hepatopathy and are more likely to complete their prescribed course of CCNU. ANIMALS: Dogs with lymphoma, mast cell tumor, or histiocytic sarcoma that were prescribed CCNU with or without corticosteroids and with normal ALT activity were eligible for enrollment. METHODS: Dogs were prospectively randomized to receive either concurrent Denamarin during CCNU chemotherapy or to receive CCNU alone. Liver-specific laboratory tests were run before each dose of CCNU. RESULTS: Increased liver enzyme activity occurred in 84% of dogs receiving CCNU alone and in 68% of dogs on concurrent Denamarin. Dogs receiving CCNU alone had significantly greater increases in ALT, aspartate aminotransferase, alkaline phosphatase, and bilirubin and a significantly greater decrease in serum cholesterol concentrations than dogs receiving concurrent Denamarin. Dogs receiving CCNU alone were significantly more likely to have treatment delayed or discontinued because of increased ALT activity. CONCLUSIONS: Increased liver enzyme activity occurs commonly in dogs receiving CCNU chemotherapy. These results support the use of concurrent Denamarin to minimize increased liver enzyme activity in dogs receiving CCNU chemotherapy. Denamarin treatment also increases the likelihood of dogs completing a prescribed CCNU course.

Hypercoagulability in chronic kidney disease is associated with coagulation activation but not endothelial function.

INTRODUCTION: Patients with chronic kidney disease exhibit features of a hypercoagulable state and have endothelial dysfunction, which may contribute to their increased cardiovascular risk. We examined the relationship between coagulation activation and vascular function in patients with chronic kidney disease. MATERIALS AND METHODS: We measured parameters of the tissue factor pathway of blood coagulation (tissue factor, factor VIIc and factor X); natural inhibitors (tissue factor pathway inhibitor, protein C, free and total protein S, antithrombin III) and markers of coagulation activation (thrombin-antithrombin complexes, prothrombin fragment 1+2) in 66 stage 4&5 chronic kidney disease patients and 36 healthy controls. Their relationship with markers of vascular function (flow mediated dilatation, soluble E-selectin and thrombomodulin) and a mediator of inflammation (interleukin-6) was determined. RESULTS: Up-regulation of the tissue factor pathway (increased tissue factor and factor VIIc), increased prothrombin fragment 1+2 and significant reductions in antithrombin III and the ratio of free protein S: total protein S were found in patients compared to healthy controls. Increased tissue factor antigen was significantly and independently correlated with creatinine and interleukin-6 (P<0.001). Factor X and antithrombin III were both reduced in chronic kidney disease and correlated (r=0.58; P<0.001). Changes in coagulation and anti-coagulation were independent of all measures of endothelial function. CONCLUSIONS: Significant activation of the TF pathway of coagulation and depletion or reduction of some natural anticoagulants in chronic kidney disease was correlated with the degree of renal dysfunction, but not correlated with the abnormalities of vascular function. These data are consistent with a hypercoagulable state in chronic kidney disease that may be independent of endothelial based regulation but associated with an inflammatory state.

Post-transplant HLA class II antibodies and high soluble CD30 levels are independently associated with poor kidney graft survival.

HLA-specific antibodies (HSA) and soluble CD30 (sCD30) were measured in 208 renal transplant recipients with functioning grafts at least 1 year after transplantation (median 8.2 years) to investigate the predictive value of HSA and sCD30 on subsequent graft outcome. HSA (class I and class II) were detected by both ELISA LAT-M and Luminex LabScreen assays. Data on graft outcome was collected with a median follow-up time of 3.5 years after antibody and sCD30 measurement. Recipients with post-transplant HLA class II antibodies had particularly poor graft outcome with a hazard ratio (HR) of 7.8 (p < 0.0001) when detected by ELISA, and a HR of 6.0 (p < 0.0001) when detected by Luminex. A high post-transplant sCD30 level >or=100 U/mL was associated with increased risk of subsequent graft failure (HR 2.7, p = 0.03). sCD30 and HSA had an independent and additive association with graft outcome. Recipients with HLA class II antibody and high sCD30 had the highest risk of subsequent graft failure (HR 43.4, p < 0.0001 and HR 18.1, p = 0.0008 for ELISA and Luminex, respectively). These data show that detection of HSA and serum sCD30 measured at least 1-year post-transplant provides valuable and predictive information regarding subsequent graft outcome.

A review of the current treatment of renal artery stenosis.

PURPOSE: Atherosclerotic renal artery stenosis (ARAS) is associated with morbidity and mortality consequent to progressive ischemic renal failure and the cardiovascular consequences of hypertension. There is considerable uncertainty concerning the optimal management of patients with this condition. This review considers the aetiological factors and the physiologic consequences of ARAS and compares the results of clinical studies of medical and endovascular therapies on blood pressure control and preservation of renal function. RESULTS: Although, in patients with fibromuscular disease the results of percutaneous transluminal angioplasty (PTA) are clearly superior to medical therapy and surgery, in asymptomatic patients with ARAS the antihypertensive benefits and preservation of renal function of endovascular, surgical and medical therapies appear similar. In selected symptomatic patients interventions may, however, be life-saving. Surgery is generally reserved for arterial occlusions with preserved renal parenchyma and function. CONCLUSIONS: The results of larger, multicentre, randomised, controlled trials are required to clearly clarify the role of interventional therapy in asymptomatic patients.

A cell-free binding assay maps the LSP1 cytoskeletal binding site to the COOH-terminal 30 amino acids.

The leukocyte specific protein 1 or LSP1 is a multi functional protein involved in such divers biological processes as the regulation of neutrophil motility, chemotaxis, adhesion and membrane immunoglobulin M (mIgM) mediated apoptosis of B-lymphocytes. The 330-amino-acid mouse LSP1 protein contains a high-affinity F-actin binding site and in intact cells localizes to the F-actin filament containing cytoskeleton. Here we use a high-speed F-actin co sedimentation assay and transfection experiments in the LSP1- T-lymphoma cell line BW5147 to show that LSP1 interacts with F-actin and the cytoskeleton through residues downstream of amino acid residue 230. We then designed a novel cell-free cytoskeleton binding assay in which a set of GST-LSP1 fusion proteins are allowed to bind to the cytoskeleton in NP-40 soluble lysates of BW5147 cells and are recovered in the low-speed detergent insoluble pellet. Using this assay the cytoskeleton binding site of mouse LSP1 maps to the 300-330 interval. These results will allow the design of LSP1 mutants that do not bind to the cytoskeleton to determine the importance of LSP1 cytoskeleton binding for the diverse functions of LSP1.

Oxidant stress in nephrotic syndrome: comparison of F(2)-isoprostanes and plasma antioxidant potential.

BACKGROUND: The nephrotic syndrome (NS) is associated with an increased risk of coronary heart disease. Increased oxidant stress may contribute to this by means of hyperlipidaemia and/or hypoalbuminaemia. In this study we assessed the contributory role of oxidant stress, as measured by F(2)-isoprostanes and plasma oxygen radical absorbance capacity (ORAC), in subjects with NS. METHODS: We studied 14 subjects with NS and 17 age- and sex-matched healthy non-proteinuric controls. Measurement of plasma and urinary F(2)-isoprostanes was carried out using a combination of silica and reverse-phase cartridges, high-performance liquid chromatography, and gas chromatography mass spectrometry using electron-capture negative ionization. The plasma ORAC assay measured the decrease in fluorescence of phycoerythrin added to plasma in the presence of a free-radical generator. The ORAC value (microM) was calculated as the ratio of the area under the fluorescence decay curve for plasma to the area under the fluorescence decay curve for a Trolox standard. RESULTS: Plasma ORAC was significantly lower in NS patients compared with controls: mean (standard error) NS patients 3306 microM (286); controls 4882 microM (496), P=0.011. In univariate linear regression analysis, plasma albumin was significantly positively correlated with plasma ORAC (r=0.40, P=0.03). Plasma and urinary F(2)-isoprostanes did not differ significantly between NS and control groups. CONCLUSIONS: This study demonstrates that in the NS there is decreased free-radical trapping capacity of plasma that is inversely correlated with hypoalbuminaemia, but no increase in plasma and urinary F(2)-isoprostanes. Decreased total plasma antioxidant potential in combination with hyperlipidaemia may contribute to the increased risk of cardiovascular disease seen in NS.

Vascular function of the peripheral circulation in patients with nephrosis.

BACKGROUND: Nephrotic syndrome is associated with abnormal lipoprotein metabolism and increased risk of coronary heart disease. Endothelial dysfunction, an early phase of atherogenesis that manifests as impaired flow-mediated dilation (FMD) of the peripheral circulation, may link these associations. METHODS: We examined endothelial function of the brachial artery and forearm resistance arteries in 15 patients with nephrosis (NP), 15 patients with primary hyperlipidemia (HL) alone, and 15 normolipidemic, nonproteinuric subjects (NC) matched for age, sex, and weight. The NP and HL groups had similar serum cholesterol and triglyceride concentrations. Post-ischemic FMD (endothelium-dependent) and glyceryl trinitrate-mediated dilation (GTNMD; endothelium-independent) of the brachial artery were studied using ultrasonography and computerized edge detection software. Postischemic forearm blood flow was also measured using plethysmography. RESULTS: Postischemic FMD of the brachial artery was significantly lower in the NP and HL groups compared with NC group (mean +/- SE): NP 4.91 +/- 0.8%, HL 4.53 +/- 0.6%, NC 8.45 +/- 0.5% (P < 0.001). There were no significant differences among the groups in baseline diameter and GTNMD of the brachial artery, nor in maximal forearm blood flow and flow debt repayment of the forearm microcirculation. Significant differences in FMD among the groups were principally related to differences in serum low-density lipoprotein cholesterol. CONCLUSIONS: Patients with NP have abnormal endothelium-dependent but preserved endothelium-independent dilation of the brachial artery following an ischemic stimulus. Postischemic forearm microcirculatory function is unimpaired. Dyslipoproteinemia is probably the principal cause of endothelial dysfunction of conduit arteries in patients with NP and the basis for their increased risk of cardiovascular disease.

Renal allograft thrombosis: can thrombophilia explain the inexplicable?

Renal allograft thrombosis remains a preventable cause of early allograft thrombosis. It should not be considered simply an unpredictable and poorly understood consequence of surgery. Extrapolated data from the general population and early data from renal patients supports the concept that the interplay of non-inherited hypercoagulability of renal disease with inherited thrombophilia, and the altered environmental milieu of transplantation predisposes to thrombosis (summarized in Figure 2). We should not accept the inevitability of a constant attrition of grafts to thrombosis and need to continue to identify risk factors and confirm appropriate screening and interventions for its prevention, almost certainly requiring collaborative multicentre trials. In the future, just as we now expand the specificity of HLA gene typing with molecular biology, genotyping for recognized thrombophilia genes in patients at risk will expand our ability to recognize and prevent thrombosis with targeted interventions drawn from the increasing array of anticoagulants now available. The contribution of thrombophilia to non-immune mechanisms of chronic allograft loss is also a potentially important but neglected area of research.

Cardiovascular disease, fibrinogen and the acute phase response: associations with lipids and blood pressure in patients with chronic renal disease.

BACKGROUND: Fibrinogen, an acute phase reactant and coagulation factor is a major independent risk factor for cardiovascular disease (CVD) in the general population and may interact with lipids to promote CVD risk. METHODS: Plasma fibrinogen, lipids and interleukin-6 were measured in 126 patients with chronic renal disease (low proteinuria (LP) and high proteinuria (HP) groups) or on maintenance dialysis (haemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD)) and 31 healthy controls (N). RESULTS: Fibrinogen was increased in all patients, and by each treatment category, when compared with the control group (421+/-143 all, 361+/-72 HD, 429+/-91 CAPD, 395+/-102 LP, 490+/-220 HP vs. 268+/-54 (N) mg/dl; P=0.0001) and correlated with urinary protein concentration, diastolic blood pressure and inversely with albumin. Interleukin-6, the mediator of the acute phase response, was increased in the combined patient group (3.2 vs. 1.5, median, pg/ml, P=.0002) and correlated with fibrinogen (r=0.32, P=0.01) and inversely with HDL-cholesterol (r=0.39, P < 0.01), consistent with a persistent inflammatory response. Patients with CVD complications (CVD +, n=46) were older, had an increased total:HDL-cholesterol ratio (7.7+/-4.3 CVD + vs. 5.9+/-1.8 CVD -, P < 0.005), but fibrinogen did not significantly differ (450+/-172 CVD + vs. 404+/-121 CVD -, P=0.09). Multiple logistic regression analysis identified categorisation of patients by values of fibrinogen and the total:HDL-cholesterol ratio greater than 95%, of the values for the controls as the only significant independent predictor of CVD complications. (Odds ratio for CVD complications of 13.5 (95%, CI 3.5-52) fibrinogen > 374 and total:HDL-cholesterol > 6.9 versus fibrinogen < 374 and total:HDL-cholesterol < 6.9). CONCLUSIONS: The significant increase in fibrinogen in all renal disease states was associated with evidence of an acute phase response, protein losing states and hypertension. Persistence of an acute phase response was also correlated with an adverse lipid profile. Fibrinogen alone was a weak discriminator of prevalent CVD disease but in conjunction with an increased total:HDL-cholesterol ratio, was associated with the prevalence of CVD complications. Hypertension and a persistent acute phase response in patients with renal disease could contribute to CVD risk by effects upon fibrinogen and lipids, but requires confirmation by prospective evaluation.

Factor VII coagulant activity (VIIc) and hypercoagulability in chronic renal disease and dialysis: relationship with dyslipidaemia, inflammation, and factor VII genotype.

BACKGROUND: Factor VII coagulant activity (VIIc) is implicated in cardiovascular disease (CVD) risk in the general population. VIIc is correlated with hyperlipidaemia and influenced by a polymorphism of the factor VII gene and could contribute to thrombotic risk in patients with renal disease. METHODS: We studied VIIc in 100 patients with chronic renal disease or on maintenance dialysis and examined its relationship with dyslipidaemia, a marker of coagulation activation prothrombin fragment F1+2 (F1+2), the acute-phase reactant and coagulation factor fibrinogen, a mediator of the inflammatory response interleukin-6 (IL6), and the factor VII R353Q polymorphism. RESULTS: VIIc (186+/-58 vs 140+/-37, % standard, P<0.0001) and F1+2 (0.51 vs 0.30 nM, median, P<0.0001) were increased in the patients with renal disease compared with the control group, consistent with a hypercoagulable state. Patients and controls heterozygous for the factor VII R353Q polymorphism, had 35% lower VIIc than homozygotes for the R353 allele, indicating that the Q353 allele could confer genetic protection from thrombotic risk. There was a significant correlation between VIIc and F1+2 (r=0.26, P<0.05), total and VLDL cholesterol, and triglycerides, but the correlation with lipids did not differ by genotype. VIIc and F1+2 also correlated with increased concentration of IL6 and fibrinogen, and inversely with albumin, suggesting that a persistent inflammatory response could contribute to a hypercoagulable state, possibly via cytokine induced activation of the endothelium, or by induction of monocytes to express tissue factor. Patients with CVD complications or a history of myocardial infarction did not have higher VIIc or F1+2 than those without CVD. CONCLUSIONS: VIIc was significantly increased in renal disease states and strongly influenced by a common polymorphism of the factor VII gene, but the increase in VIIc and its correlation with lipids was not genotype specific. VIIc correlated with evidence of increased coagulation activation and persistence of an inflammatory response. A persistent inflammatory response and the dyslipidaemia of renal disease may contribute to coagulation activation and increased cardiovascular risk. Prospective studies are required to evaluate increased VIIc as a thrombotic risk factor in chronic renal disease.

The factor V Leiden mutation and risk of renal vein thrombosis in patients with nephrotic syndrome.

BACKGROUND: Acquired abnormalities of coagulation and fibrinolysis in nephrotic syndrome have been implicated in the pathogenesis of renal vein thrombosis (RVT). Whether resistance to activated Protein C due to a mutation in the gene for factor V (FV Leiden/FV506Q, the commonest inherited risk factor for venous thrombosis) could contribute to risk of RVT in patients with nephrotic syndrome is unknown. METHODS: Genotyping for the factor V Leiden mutation was undertaken in a retrospective study of 35 patients with a history of nephrotic syndrome, 10 of whom had suffered clinically significant and radiologically proven RVT. RESULTS: Two patients (6%) were heterozygous for the FV506Q mutation, a prevalence similar to studies within the general population. One heterozygote had suffered a RVT, whilst the other without a native RVT subsequently had a primary renal allograft thrombosis. CONCLUSIONS: In a retrospective study the prevalence of the FV Leiden mutation was not increased in patients with nephrotic syndrome nor associated with prevalence of clinically significant RVT. Whilst this study was insufficiently powerful to fully exclude an association, it suggests acquired rather than inherited alterations in the coagulation/fibrinolytic balance associated with nephrosis may be of greater importance in venous thrombotic risk, and that routine screening of patients with nephrosis for this mutation will not identify the majority of patients at risk for RVT. Confirmation of these results and determining whether the natural history of thrombosis or underlying renal disease in carriers of the FV Leiden mutation differs from those without this mutation, will require a large prospective study.

The factor V Leiden (R506Q) mutation and risk of thrombosis in renal transplant recipients.

BACKGROUND: Renal transplantation and chronic renal failure are associated with an increased risk of venous thrombosis and myocardial infarction (MI). We investigated whether resistance to activated protein C due to a mutation in the factor V gene (FV Leiden/FV506Q) may predispose patients to thrombosis. METHODS: Three hundred patients who had undergone renal transplantation were genotyped for the FV mutation. Seventy-seven patients who had suffered thrombotic complications (42 venous, 28 arterial, and 7 both) were compared with 223 patients free of thrombosis. RESULTS: Thirty-two patients had suffered early renal allograft thrombosis (30 venous), and 33 patients had suffered MI. A higher proportion of the patients with thrombosis, compared to those without, had a family history of arterial cardiovascular disease (42% vs. 26%, P=0.04). Eighteen (6%) patients were heterozygous for FV506Q and seven (39%) of these had suffered venous thrombosis (including four primary allograft thromboses), compared with 15% of the patients without the mutation (P<0.05). The odds ratio for risk of venous thrombosis for FV506Q carriers was 3.6 (95% confidence interval: 1.3-9.9) or 4.0 (1.2-13.8) for primary allograft thrombosis. Only one of the FV506Q carriers had suffered an MI. CONCLUSIONS: Carriers of the factor V 506Q mutation with chronic renal failure who have undergone transplantation are at an increased risk of venous but not arterial thrombosis. This mutation explained 14% of all venous and 20% of primary allograft thrombosis, suggesting that other unidentified genetic and environmental factors contribute to the risk of thrombosis in renal transplant recipients.

The effect of propionyl L-carnitine on skeletal muscle metabolism in renal failure.

The effect of propionyl L-carnitine on skeletal muscle metabolism in chronic renal failure. Carnitine deficiency, resulting in defective oxidative ATP synthesis, has been implicated in the myopathy of chronic renal failure. Using 31P magnetic resonance spectroscopy we examined calf muscle metabolism in 10 dialysed patients before and after 8 weeks of propionyl L-carnitine (PLC) 2 g.p.o. daily. Resting phosphocreatine/ATP (4.41 +/- 0.20 [SEM]) decreased to normal control levels on PLC (3.98 +/- 0.14; controls 4.00 +/- 0.06). In contrast, there was no effect of PLC on aerobic and anaerobic metabolism of muscle during or following 2-10 min exercise. The maximal calculated oxidative capacity (Qmax) remained below normal (28 +/- 3 mM/min before and 24 +/- 3 mM/min after PLC; controls 49 +/- 3 mM/min). Qmax correlated positively with hemoglobin concentration ([Hb]) after PLC (p < 0.03). Oxidative capacity assessed by phosphocreatine recovery T significantly improved with PLC administration (0.93 +/- 0.1 to 0.74 +/- 0.08 min) in those patients (n = 6) with [Hb] > 10 g/dl. [Hb] was rate limiting to oxidative metabolism in recovery from exercise but only following treatment with PLC. Patients with anemia or those subjects who use relatively more non-oxidatively synthesized ATP during exercise, do not respond to PLC. Oxidative metabolism did not normalize on PLC suggesting that anemia and carnitine deficiency are not the only causes of mitochondrial dysfunction in renal failure.