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.

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.

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.

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 (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 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 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.

Intracellular free magnesium concentrations in skeletal muscle in chronic uraemia.

Low intracellular free magnesium concentrations ([Mg2+]i) are associated with essential hypertension and may reflect a disordered cellular ionic environment. 31P magnetic resonance spectroscopy was used to study skeletal muscle [Mg2+]i in a group of chronic renal failure (CRF) patients and data were compared with a group of control subjects of similar age. Other data including the patients' blood pressure, medication and plasma biochemistry were collected. There was a significant inverse correlation of [Mg2+]i with systolic (p < 0.001) and diastolic blood pressure (p < 0.05) in the CRF population. In CRF [Mg2+]i was similar (0.52 +/- 0.01 mM, SEM) to controls (0.53 +/- 0.01 mM; p = 0.20), even if just the normotensive patients and controls were compared. There was no correlation of [Mg2+]i with plasma parathyroid hormone, total [Mg2+] or [Ca2+]. Similar to studies in subjects with essential hypertension, these data support a role for [Mg2+]i specifically, and an abnormal intracellular environment more generally, in the pathophysiology of hypertension in CRF.

Environmental and genetic determinants of the hypercoagulable state and cardiovascular disease in renal transplant recipients.

BACKGROUND: Fibrinogen and factor VII coagulant activity (VIIc), risk factors for cardiovascular disease (CVD) in the general population, could contribute to CVD risk in renal transplant recipients (RTR). METHODS: We measured fibrinogen and VIIc in 38 RTR and 31 controls, along with prothrombin fragment F1 + 2 and D-Dimer (markers of coagulation and fibrinolytic activation), plasma lipids and the acute phase response cytokine, interleukin 6. The effect of genetic polymorphisms of beta-fibrinogen (G/A-455) and factor VII (Arg/Gln353) was explored. RESULTS: F1 + 2, D-Dimer, and fibrinogen were increased in all RTR, indicating a chronic prothrombotic state. Fibrinogen correlated with age. F1 + 2, and trough cyclosporin A (CsA). RTR carriers of the A-455 allele had a greater increment in plasma fibrinogen concentration and correlation with CsA than homozygotes for the G-455 allele. Interleukin 6 was increased in RTR confirming that a persistent lowgrade acute-phase response could contribute to increased fibrinogen. Differences in plasma VIIc were associated with factor VII genotype, disease status, and blood lipids. Carriers of the Gln353 allele had 30% lower VIIc when compared with Arg353 homozygotes, which could confer a reduced thrombotic risk. The 12 RTR with CVD or metabolic complications (RTR+) were more hyperlipidaemic and had higher fibrinogen and VIIc than the 26 RTR free of disease complications (RTR-), or the controls. CONCLUSIONS: Long-term RTR manifest features of a chronic prothrombotic and persistent inflammatory state. Alterations in fibrinogen and VIIc in RTR arise in part as a result of interactions between common genetic and environmental factors, and these changes could contribute to the increased risk of CVD in RTR.

Plasminogen activator inhibitor-1 activity in chronic renal disease and dialysis.

The activity of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of fibrinolysis, is associated with insulin resistance (IR) and the risk of venous and arterial thrombotic cardiovascular disease (CVD) in the general population, and may behave as an acute-phase reactant. PAI-1 activity was measured in 124 patients with chronic renal disease, and its relationship with alterations in metabolic, lipid, and cytokine parameters and the prevalence of CVD complications was explored. Patients with chronic renal disease not requiring dialysis were divided into a low proteinuric ([LP]n = 30) or high proteinuric ([HP]n = 31) group and compared with patients on continuous ambulatory peritoneal dialysis ([CAPD]n = 32) or hemodialysis([HD]n = 31) and with 31 healthy controls. Patients on HD had significantly lower PAI-1 activity than HP, CAPD, and control groups, but no group had significantly higher values than the controls (AU/mL: 7.4 +/- 3.8 HD, 11.2 +/- 8.4 CAPD, 9.4 +/- 5.4 LP, 12.1 +/- 8.0 HP, 11.4 +/- 6.6 controls, P = .04). Interleukin-6 (IL-6), the mediator of the acute-phase response, was determined in a subset of patients and was significantly increased in HD, CAPD, and LP groups compared with the controls (median, pg/mL: 4.6 HD, 4.0 CAPD, 2.9 LP, 2.4 HP, and 1.5 controls, P < .001), but did not correlate with PAI-1. PAI-1 independently correlated with body mass index (BMI), triglycerides, and lipoprotein(a) [Lp(a)] in stepwise regression for all patients. Dividing the whole patient group by tertiles of triglycerides and BMI, increased PAI-1 was confined to the subgroup of patients with both obesity (BMI > 26.7 kg/m2) and hypertriglyceridemia (triglycerides > 2.5 mmol/L). These data suggest that PAI-1 activity in chronic renal disease and dialysis was more strongly associated with the common metabolic abnormalities of obesity and hypertriglyceridemia than with renal disease status, dialysis, or a chronic inflammatory state. This study does not support but does not exclude a major role for increased PAI-1 activity in CVD risk in chronic renal disease.

Presentation and survival of patients with severe renal failure and myeloma.

We reviewed the clinical features and outcome of 56 patients with myeloma and severe renal failure managed in a single institution over a 15-year period. Renal failure was recognized within 2 months of the diagnosis of myeloma in 75% of patients, and was the initial presentation of myeloma in 50%. Patients were staged by the Durie and Salmon classification. Light-chain and IgD myeloma accounted for 46% of cases, and Bence-Jones proteinuria was identified in > 90%. In 43%, a potential precipitant of renal failure was identified, usually hypercalcaemia or a non-steroidal anti-inflammatory agent. A preserved corrected calcium at presentation was characteristic (2.40 +/- 0.15 mmol/l, n = 42), even after excluding those with hypercalcaemia requiring specific intervention (n = 14, 2.76 +/- 0.51; p < 0.01): this finding in patients with unexplained acute renal failure should alert clinicians to the possibility of myeloma. Forty-seven patients (84%) required dialysis. Only seven (15%) ever regained renal function. Median survival (all patients) was 8 months. One-third died within 3 months of referral and one-third survived > 1 year. Hypoalbuminaemia and reduced platelet count at presentation were associated with reduced survival, but hypercalcaemia, infection, dialysis, (urgent or long-term), and dialysis modality were not. Chemotherapy was associated with increased survival, but progression of myeloma and infection were the two most frequent causes of death. Severe renal failure was associated with advanced myeloma stage and light-chain/IgD paraproteinaemia. Survival was related to severity of myeloma and not requirement for dialysis per se.

The effects of gemfibrozil upon the hypercoagulable state in dyslipidaemic patients with chronic renal failure.

BACKGROUND: The dyslipidaemia of chronic renal disease could contribute to a hypercoagulable state by activation of blood coagulation and/or impairment of fibrinolysis, thereby increasing cardiovascular disease (CVD) risk. METHODS: We measured the coagulation activation marker prothrombin fragment F1 + 2 (F1 + 2), fibrinogen, plasminogen activator inhibitor-1 activity (PAI1), interleukin-6 (IL6), insulin, lipids and lipoprotein(a) (Lp(a)), in 12 patients with chronic renal disease before and after gemfibrozil. RESULTS: Gemfibrozil significantly reduced triglycerides by 44% and increased HDL-cholesterol by 31% without significant change in LDL cholesterol. Before treatment, patients had increased F1 + 2, fibrinogen and IL6, but similar PAI1 compared with the controls, consistent with a hypercoagulable and persistent inflammatory state. Following treatment, F1 + 2 decreased to within the normal range and this reduction correlated with the decrease in triglycerides and inversely with the increase in HDL-cholesterol. A non-significant decrease in fibrinogen was inversely correlated with a significant increase in albumin. However, Lp(a) and PAI1 activity significantly increased whilst insulin and IL6 were unchanged. CONCLUSIONS: Gemfibrozil improved the uraemic dyslipidaemia and hypercoagulable state by reduction in activation of blood coagulation, indirectly suggesting a reduction in lipid-dependent extrinsic pathway activity which should contribute to reduced risk of thrombosis and CVD. Reduced fibrinogen and increased albumin are consistent with a reduction in the acute phase response. Increased PAI1 and Lp(a) could impair fibrinolysis and potentially increase CVD risk, although the mechanism for these effects is uncertain but does not appear related to cytokine or insulin mediated mechanisms and requires further study. Large prospective studies are required to determine if gemfibrozil can reduce CVD events in uraemia.

Lipoprotein(a) concentration in diabetes: relationship to proteinuria and diabetes control.

Diabetic patients are at increased risk of cardiovascular disease, particularly when proteinuria is present. Lipoprotein(a)[Lp(a)] levels were assessed in 37 patients with insulin dependent (IDDM) and in 75 patients with non-insulin dependent (NIDDM) diabetes who showed varying degrees of proteinuria and glycaemic control. Median Lp(a) in 112 diabetic patients was significantly greater than in 116 healthy controls (113 vs 48 mg/L; p less than 0.01). 86 of the patients had first morning urine albumin concentration less than 30 mg/L (normoalbuminuria = NA), 16 patients 30-200 mg/L (microalbuminuria = MA) and ten patients greater than 200 mg/L (albuminuria = ALB). There was no significant difference in median Lp(a) concentration between the three groups (NA = 108, MA = 163, ALB = 98 mg/L; p greater than 0.5). No significant difference in median Lp(a) or NIDDM treated with oral agents and/or diet (120, 98, 115 mg/L respectively; p greater than 0.7). When the 86 NA patients were divided on the basis of median fructosamine concentration (357 mumol/L), no significant difference was found in median Lp(a) levels between those grouped below or above this median (98 mg/L vs 118 mg/L; p greater than 0.5). Across all diabetics studied there was no significant correlation present between Lp(a) and urinary protein or glycaemic control. These cross-sectional results suggest that median Lp(a) concentration is increased in both IDDM and NIDDM patients, but this increase is not related to the degree of proteinuria or short-term glycaemic control.

Lipoprotein(a) levels in chronic renal disease states, dialysis and transplantation.

Lipoprotein(a) is an independent risk factor for cardiovascular disease. Lipoprotein(a) levels were measured in 196 patients (103 Male [M]: 93 Female [F]) with chronic renal diseases and in 116 controls. Median levels of Lipoprotein(a) [Lp(a)] were found to be significantly elevated in patients with untreated chronic renal disease (285,285 mg/L; M,F; range 30-1675 mg/L) and in those treated with continuous ambulatory peritoneal dialysis (320, 603; M,F; range 50-1450) compared with controls (70,51; M,F; range 1-750; p less than 0.01 Males, p less than 0.001 Females). Lp(a) levels in patients treated by haemodialysis (133,35; M,F; range 5-685) and renal transplantation (100,95; M,F; range 10-1700) were not significantly different from controls. Lipoprotein(a) levels correlated inversely with serum albumin in the combined dialysis group (r = -0.34, p less than 0.001), and with urinary protein loss in the combined transplant and chronic renal diseases groups (r = 0.29, p less than 0.01). This correlation of Lp(a) with protein metabolism suggests a similarity with changes in other apolipoprotein-B containing lipoproteins in nephrosis. These findings may be relevant to the increased risk of atherosclerosis in patients with chronic renal disease and to their optimum mode of renal replacement therapy.

Late presentation and development of nephrocalcinosis in primary hyperoxaluria.

A case of primary hyperoxaluria type 1 with complete deficiency of alanine:glyoxalate aminotransferase that first manifested at the age of 59 with irreversible acute on chronic renal failure is reported. Nephrocalcinosis, initially absent, developed rapidly after renal failure evolved. The possible role of hypovolaemia and contrast nephrotoxicity in precipitating the clinical onset is discussed. Primary hyperoxaluria should be considered in patients of any age presenting with unexplained renal failure, and appropriate systemic pathology of oxalosis.