Dynamic QT interval analysis in uraemic patients receiving chronic haemodialysis

OBJECTIVE: To analyse the duration of the QT interval and its relationship with heart rate changes in patients with uraemia, before and during haemodialysis. METHODS: QT and RR intervals were measured automatically using a dedicated algorithm with 24-h Holter recordings in 29 patients (15 women) receiving chronic haemodialysis. QT corrected for heart rate (QTc) and the slope of QT/RR linear regression were calculated. Arterial blood pressure (ABP) was measured before and during haemodialysis. Plasma concentrations of K+, Mg2+ and Ca2+ were assessed before and after haemodialysis. RESULTS: ABP decreased significantly from baseline (102.7 +/- 11.0 mmHg) during the first (100.6 +/- 8.8 mmHg, P < 0.05), second (95.6 +/- 10.6 mmHg, P < 0.05), and third (94.9 +/- 10.3 mmHg, P < 0.05) hours of haemodialysis. QTc was longer during haemodialysis than during a 4-h period of no dialysis (447 +/- 28 ms compared with 429 +/- 22 ms, P < 0.001), and increased progressively during haemodialysis, with the greatest value during the last hour of haemodialysis (454 +/- 32 ms compared with 426 +/- 22 ms, P < 0.001). QT/RR slopes and correlation coefficients were lower during haemodialysis than during the period of no dialysis (0.13 +/- 0.08 compared with 0.20 +/- 0.07, P < 0.001 and 0.48 +/- 0.30 compared with 0.81 +/- 0.20, respectively; P < 0.001), suggesting a reduced ability to adapt the QT interval in response to changes in heart rate. The effects of haemodialysis on QT interval and the QT/RR relationship were greater in women than in men. QTc variations during dialysis were not correlated with changes in ABP, but were inversely related to changes in Ca2+ concentration (r2 = 0.35; P = 0.001). CONCLUSIONS: In patients with uraemia, the haemodialysis session induces a progressive increase in QT interval and modifies its relationship with heart rate. These effects may predispose some individuals to ventricular arrhythmias at the end of and immediately after the haemodialysis session.     

Impaired high-shear-stress-induced platelet aggregation in patients with chronic renal failure undergoing haemodialysis

We investigated shear-induced platelet aggregation (SIPA) in 30 patients with chronic renal failure (CRF) undergoing haemodialysis. 26 patients showed a significant decrease in SIPA at high shear stress but no change in SIPA at low shear stress. The former reaction reflects the interaction between plasma von Willebrand factor (vWF) and its platelet receptors, glycoprotein (GP) Ib-IX and lIb/ IlIa complex, whereas the latter is assumed to involve the binding of plasma fibrinogen to GP IIb/IIIa complex. These SIPA profiles in CRF patients after haemodialysis showed almost no change compared to those before haemodialysis.
The ratio of ristocetin cofactor/vWF antigen in plasma was slightly lower in CRF patients than in controls (P<0.01). However, the level of GPIb antigen in the platelets of these patients was significantly reduced (42.1±20-3% of normal platelets), with partial destruction of GPIb antigen. The number of vWF receptors on the GPIb molecule was quantitated using the GPIb-binding protein alboaggregin-B (AL-B), purified from the snake venom of Trimeresurus albolabris. AL-B bound to GPIb at a total of 48 760±9944 molecules per normal platelet and a K_d of 85.44±15.70 nM at saturation. In contrast, binding in CRF platelets was 22 980±6395 molecules per platelet and K_d was 50.08±13.83 nM. Taking these results together, we conclude that the impaired SIPA found in CRF patients is due to both abnormalities in plasma vWF and in its platelet GPIb receptor.     

Evidence against enhanced platelet activity in sickle cell anaemia

S ummary . Although numerous studies have provided indirect evidence for enhanced platelet activity in sickle cell anaemia, little attention has been directed to examination of platelet alpha and dense granule release in the sickling disorders. We simultaneously measured by radioimmunoassay plasma levels of the alpha granule constituents β-thromboglobulin (β-TG) and platelet factor 4 (PF₄) in 43 children with sickle cell anaemia in steady state and 24 patients during severe vaso-occlusive crisis. β-TG levels during steady state (50 ± 3.6 ng/ml, mean ± SEM) were greater ( P <0.001) than in normal controls (36 ± 1.6), but there was no additional significant rise during crisis (55 ± 5.9). PF₄ levels were similar ( P = 0.12) in both steady state (10 ± 1.2 ng/ml) and crisis (9.3 ± 2.3) to those of normal controls (6.0 ± 0.8). The similarity of β-TG/PF₄ ratios in normal and sickle cell anaemia patients as well as the positive correlation ( P <0.05) between platelet count and β-TG and PF₄ suggested that an artefactual in vitro platelet activation was responsible for some of the observed increased β-TG and PF₄ levels. Further evidence against enhanced platelet activity in these sickle cell patients included normal intraplatelet content of the dense granule constituent 5-HT and a normal ATP/ADP ratio. From this data we conclude that platelet activation in children with sickle cell anaemia appears minimal.     

Electrolyte concentration during haemodialysis and QT interval prolongation in uraemic patients.

AIMS: To assess the effect of different combinations of potassium and calcium concentrations on QT interval in the dialysis bath in uraemic patients. METHODS AND RESULTS: Sixteen haemodialysis (HD) patients underwent a 24 h Holter recording before and during HD sessions with six randomized combinations of electrolytes concentrations of the dialysis bath (K(+), 2 and 3 mmol/L; Ca(2+), 1.25, 1.5, and 1.75 mmol/L). The effect of different dialysis baths on QT interval was significant (P < 0.05). The longest mean QTc was observed with the lowest K(+) (2 mmol/L) and Ca(2+) concentrations (1.25 mmol/L), whereas the shortest mean QTc was observed with the highest K(+) (3 mmol/L) and Ca(2+) concentrations (1.75 mmol/L). QTc was >440 ms in 9 of 16 patients (56%) at the lowest Ca(2+) and K(+) concentrations, and in 3 of 16 patients (18%) at the highest electrolytes level. Changes in QTc during the HD sessions were inversely correlated with that in total Ca and Ca(2+) plasma concentrations (P < 0.0001). CONCLUSION: Changes in ventricular repolarization duration associated with HD largely depend on the concentrations of Ca(2+) and K(+) in the dialysis bath. These findings may have important implications for the choice of the electrolytes concentration of the dialysis bath during the HD session.     

Serotyping and genotyping of hepatitis C virus in Taiwanese patients with type C chronic liver disease and uraemic patients on maintenance haemodialysis

BACKGROUND: To evaluate a recombinant immunoblot hepatitis C virus (HCV) serotyping assay, which determines HCV serotypes 1, 2, and 3 by detecting type-specific antibodies to core-and NS-4-derived peptides. METHODS: Immunoreactivity of type-specific antibodies among 173 chronic hepatitis C patients and 43 haemodialysis patients in Taiwan was examined and the serotyping results were compared with genotyping by Okamoto's method. Serial specimens from 29 patients undergoing interferon-alpha therapy were also evaluated. RESULTS: Of the 205 specimens for which genotyping data were available, 51.2% were of serotype 1, 31.7% of serotype 2, 1.0% of serotype 3, 2.4% of either serotype 1 or 3, and the remaining 13.7% were untypable. The serotypable rate was significantly lower in haemodialysis patients than in chronic hepatitis C patients (70.0% vs 94.9%; P < 0.001). Serotyping of genotype 2b specimens was significantly more dependent on core peptide bands than other genotypes. Using genotyping as the reference, the overall sensitivity, specificity and concordance of the recombinant immunoblot HCV serotyping assay were 86.3%, 97.2% and 83.9%, respectively. However, the serotyping assay had significantly lower sensitivity (69.2%), specificity (77.8%) and concordance (53.8%) for genotype 2b specimens. Of nine HCV complete responders, one lost type-specific antibodies 6 months after the cessation of interferon-alpha treatment. CONCLUSIONS: These results suggest that, except for less than optimal performance with immunocompromised or genotype 2b patients, the HCV serotyping assay is a practical and useful method for HCV typing in the clinical setting in Taiwan.     

The use of pregabalin in the treatment of uraemic pruritus in haemodialysis patients

We evaluated the effect of pregabalin in the treatment of uraemic pruritus not due to secondary hyperparathyroidism. Sixteen haemodialysis patients suffering from uraemic pruritus resistant to conventional treatment started on pregabalin 25 mg/day orally. The parameters recorded were age, time on haemodialysis, haematocrit, Ca, PO₄, Ca × PO₄ product, PTH, spKt/V, eosinophil counts and IgE. The effectiveness of pregabalin on uraemic pruritus was evaluated by using visual analogue scale before and after one month of treatment. Visual analogue scale consisted of a 10‐cm horizontal line scored from 0 (no itch) to 10 (worst imaginable itch). Four patients discontinued treatment due to side effects and therefore were excluded from the study. The mean age of the remaining 12 patients was 61.2 ± 12.8 years, and the time on haemodialysis was 38 ± 39.1 months. The haematological and biochemical profile of the patients remained without significant change at the end of the observation period. There was a statistically significant difference between visual analogue scale values before and after the one month treatment period (7.44 ± 2.01 and 1.7 ± 1.31, respectively), p < 0.0003. Uraemic pruritus is a common and distressing symptom in patients undergoing haemodialysis. Pregabalin appears to be an effective alternative treatment.     

Evidence for a defect in pituitary secretion of luteinizing hormone in chronic alcoholic men.

To characterize the defect in the hypothalamic-pituitary-gonadal axis of alcoholic men, acute and chronic LRF responses were evaluated in 22 chronic alcoholic men with varying degrees of biochemically and histologically confirmed liver disease. In addition, acute LRF responses in 14 normal men, before and at the end of 72 h of administration of 2 ml/kg/day 95% ethanol, were evaluated. The alcoholics hd significantly reduced basal testosterone and elevated gonadotropin levels (both FSH and LH) compared to the normal volunteers (P less than 0.02). Serum concentrations of estradiol and PRL did not differ between alcoholics and normal volunteers. A 100-micrograms bolus of LRF resulted in a 3-fold increase of LH in alcoholic men as compared to a 6-fold increase of serum LH in normal volunteers. No significant difference in the LRF-induced FSH responses was observed. When the response of normal volunteers to LRF before and after ethanol administration was evaluated, basal levels of both gonadotropins were increased after alcohol administration and a reduced LRF-induced LH response was observed. Based upon these results, we conclude that: 1) the central hypothalamic-pituitary defect known to exist for LH secretion is in part due to inadequate pituitary secretion and 2) acute alcohol ingestion in normal men suppresses the LRF-induced LH but not the FSH response.     

Pegylated-interferon alpha 2a treatment for chronic hepatitis C in patients on chronic haemodialysis

AIM: To evaluate the response to pegylated-interferon alpha 2a in chronic hepatitis C patients on chronic haemodialysis. METHODS: Ten patients with chronic C hepatitis were enrolled in this study. All had increased aminotransferases for more than 6 mo, positive antiHCV antibodies and positive PCR HCV-RNA. We administrated Peg-Interferon alpha 2a 180μg/wk for 48 wk. After 12 wk of treatment we evaluated the biochemical and early virological response (EVR). At the end of the treatment we evaluated the biochemical response and 24 wk after the end of the treatment we evaluated the sustained virological response (SVR). We monitored the side-effects during the treatment. RESULTS: Two patients dropped out in the first 12 wk of treatment and 2 after the first 12 wk of treatment. After 12 wk of treatment, 7 out of 8 patients had biochemical response and EVR and 1 had biochemical response but persistent viremia. We had to reduce the dose of pegylated-interferon to 135μg/wk in 2 cases. Three out of 6 (50%) patients had SVR 24 wk after the end of the treatment. Intention-to-treat analysis showed that 3 out of 10 patients (30%) had SVR. Side-effects occurred in most of the patients (flu-like syndrome, thrombocytopenia or leucopoenia), but they did not impose the discontinuation of treatment. CONCLUSION: After 12 wk of treatment with Peg-Interferon alpha 2a (40 ku) in patients on chronic haemodialysis with chronic C hepatitis, EVR was obtained in 87.5% (7/8) of the cases. SVR was achieved in 50% of the cases (3/6 patients) that finished the 48 wk of treatment.     

Factor XI deficiency and a platelet defect

A patient with a lifelong bleeding tendency of moderate severity was found to have both factor XI deficiency and a long bleeding time. There was a significant deficiency of platelet factor 3, but other parameters of platelet function were normal. Infusion studies showed that both fresh plasma and platelet concentrate were required for complete correction of the haemostatic abnormalities, suggesting that these two defects were inherited coincidentally.     

Qualitative platelet defect in a case of heparin-induced thrombocytopenia

A qualitative platelet defect was demonstrated in a patient with heparin-induced thrombocytopenia. His platelets showed impaired aggregation to collagen and arachidonate and absent second wave aggregation to adenosine diphosphate and epinephrine but normal response to ristocetin. These aggregation abnormalities were similar to those reported in idiopathic thrombocytopenia and systemic lupus erythematosus. This platelet function defect may contribute to haemorrhagic complications which appear to be common in heparin-induced thrombocytopenia.     

Studies on the platelet defect in alcoholism.

Platelet ultrastructure, protein composition, and adenine nucleotide metabolism were studied in patients ingesting ethanol to elucidate the mechanism of ethanol-induced changes in platelet function and survival. Serial measurements were made in 2 patients who maintained blood ethanol levels in excess of 300 mg/100 ml for 3 to 4 weeks. No major changes in structure or metabolism were detected in platelets from the patient whose platelet counts remained stable during the ingestion period. By contrast, the development of thrombocytopenia in the other patient was associated with significantly reduced intracellular ADP, increased ATP/ADP ratio, decreased release of ADP, increased specific radioactivity of intracellular ATP and ADP, and increased formation of hypoxanthine. Additionally, platelets from this patient varied markedly in size, contained giant granules, and possessed a poorly defined microtubular system. After stimulation with ADP or collagen, centripetal granule migration was retarded, and the aggregates formed were small and loose. Several large proteins were absent from the supernatant fraction of sonicated platelets from the thrombocytopenic patient. Exposure of normal platelets to ethanol in vitro resulted in no detectable change in platelet ultrastructure. The data indicate that the ethanol-related abnormalities of platelet function are due in part to subnormal amounts of intracellular ADP and a deficit in the storage pool of ADP. Additionally, the results suggest that impairment in the release mechanism to the observed defect in the release reaction.     

Studies on platelet surface carbohydrates in normal and uraemic platelets using 125I-labelled lectins

Summary Binding studies with six different purified ¹²⁵I-labelled lectins, concanavalin A (con A), wheat germ agglutinin (WGA), Ricinus communis agglutinin II (RCA II), Dolichos biflorus (DB), Tetranolobus purpureus (TP) and P-phytohemagglutinin (P-PHA), were used to investigate the surface topography of carbohydrates in platelets from uraemic and normal subjects. Compared with normal the uraemic platelets, bear significantly decreased (more than 2.5-fold) numbers of receptors for P-PHA (N-acetyl D-galactosamine specifity) and Con A (specifity glucose, mannose). The number of WGA, RCA, II, DB and TP receptors in uraemic platelets did not differ from the number in normal platelets. Binding studies with ¹²⁵I-labelled lectins provide further evidence of molecular defects in uraemic platelets. Moreover, this method might provide a fast and reliable technique for identifying abnormalities in the surface topography of carbohydrates on platelets in several pathological states.     

Deficiency of platelet membrane glycoprotein Ia associated with a decreased platelet adhesion to subendothelium: a defect in platelet spreading

A bleeding disorder with absent collagen-induced platelet aggregation and adhesion has been described in a patient whose platelets failed to express surface glycoprotein Ia. We studied the interaction of her platelets with subendothelium in an annular perfusion chamber and the interaction with purified human collagen type III in a rectangular perfusion system under flow conditions. Platelet adherence was almost completely absent both at low and high shear rates. The few platelets which adhered remained in the contact stage without subsequent spreading and aggregate formation. Addition of a monoclonal antibody, which was directed against the von Willebrand moiety of FVIII-VWF, to the blood, completely abolished platelet adherence at high shear rates and had a partial effect at low shear rates. These data indicate that von Willebrand factor plays a role in the initial attachment (contact stage) of platelets to subendothelium. We conclude that the bleeding disorder and excessively prolonged bleeding time in our patient are caused by a new specific defect of the platelet-vessel wall interaction.     

Cushing's disease with cure by resection of a pituitary adenoma. Evidence against a primary hypothalamic defect

A patient with Cushing's disease was treated by transphenoidal resection of a pituitary adenoma. Pituitary-adrenal suppressibility, responsiveness to metyrapone and circadian rhythm were observed postoperatively. Reversion to physiologic regulation after resection of an adenoma implies that the lesion secreted ACTH autonomously (primary hyperpituitarism). Current evidence favors the pituitary adenoma, when present, as the primary etiologic factor in pituitary-dependent Cushing's syndrome. Since adenomas occur in a majority of cases, initial therapy is best directed at the pituitary.