Haemolytic uraemic syndrome: therapeutic effect of plasma infusion.

The therapeutic effect of plasma infusion was evaluated in 10 children and seven adults with haemolytic uraemic syndrome. All but one patient responded to this treatment with rapid disappearance of haematological abnormalities. The patient who apparently failed to respond to plasma infusion obtained complete remission of the disease after plasmapheresis. Although 15 of the 17 patients were anuric or oliguric on admission, renal function recovered completely in eight children and two adults. Seven patients showed residual chronic renal failure and two required long-term maintenance haemodialysis. Treatment with plasma was also successful in patients with relapses or recurrent episodes. Plasma infusion is a promising therapeutic approach for the haemolytic uraemic syndrome and deserves further study in clinical trials.     

Management of uraemic pericarditis.

Of 250 patients undergoing haemodialysis from 1967 to 1974 17 presented with uraemic pericarditis. Seven of these patients who had been transferred early enough to peritoneal dialysis treatment were cured without pericardiectomy (mean survival 18 months (range 6-36); no deaths). Only one patient was cured from his pericarditis by "aggressive haemodialysis." In seven out of 10 patients treated with haemodialysis, pericardiectomy finally had to be performed because of pericardial tamponade (postoperative survival 20 months (range 8-36); one death). Two patients died from pericardial tamponade before surgery. In patients with evidence of uraemic pericarditis frequent peritoneal dialysis with high fluid withdrawal is the treatment of choice, but in cardiac tamponade pericardiectomy should follow a preoperative pericardiocentesis with limited fluid aspiration. Of possible significance in the aetiology of pericarditis were the findings that 10 of the 17 patients had hypertension with cardiac enlargement and that 14 presented with evidence of underdialysis, possibly due to the reuse of dialysis components.     

Acute Asymmetrical Neuritis Associated with Rapid Ultrafiltration Dialysis

Three patients with chronic renal failure treated by haemodialysis developed acute asymmetrical sensory and motor neuropathies when ultrafiltration was induced to treat oedema. The neuropathies were characteristic of acute mononeuritis multiplex rather than uraemic polyneuritis, and we give our reasons for believing that they were not caused by toxic uraemic metabolites but by an ischaemic process due to vasoconstriction resulting from ultrafiltration.     

Cimetidine for duodenal ulceration in patients undergoing haemodialysis.

Peptic ulcer is a common problem in advanced renal failure, but most drugs for ulcers are hazardous in this condition. In a small open study cimetidine was given to nine patients with acid hypersecretion and endoscopically diagnosed duodenal ulceration who were undergoing haemodialysis. The patients obtained good pain relief and suffered no serious side effects. Both basal and stimulated acid output fell considerably and the plasma gastrin response to food increased during treatment. Two patients with recurrent vomiting during haemodialysis had a striking response to cimetidine, which suggested that such vomiting may be acid-mediated in some patients. These preliminary results suggest that cimetidine may prove to be an advance in the management of peptic ulcer in uraemic patients.     

Plasma thromboxane B2 in haemodialysed patients

Plasma thromboxane B2 (TXB2) concentration was measured in 7 cases of terminal renal failure before and after haemodialysis. The TXB2 levels were higher in the investigated group than in the control group (p less than 0.05). Haemodialysis induced a further increase in the TXB2 concentration. Increased thromboxane production may play a part in the pathogenesis of accelerated atherosclerosis in uraemic patients treated with chronic haemodialysis.     

Beta2-microglobulin causes abnormal phosphatidylserine exposure in human red blood cells

The exposure of the aminophospholipid phosphatidylserine on the external leaflet of red blood cell plasma membrane can have several pathophysiological consequences with particular regard to the processes of cell phagocytosis, haemostasis and cell-cell interaction. A significant increase in phosphatidylserine-exposing erythrocytes has been reported in chronic haemodialysis patients and found to be strongly influenced by the uraemic milieu. To identify uraemic compound(s) enhancing phosphatidylserine externalization in erythrocytes, we fractionated by chromatographic methods the ultrafiltrate obtained during dialysis, and examined by flow cytometry the effect of the resulting fractions on phosphatidylserine exposure in human red cells. Chromatographic procedures disclosed a homogeneous fraction able to increase erythrocyte phosphatidylserine exposure. The inducer of such externalization was identified by monodimensional gel electrophoresis and mass spectrometry investigations as beta2-microglobulin. To confirm the beta2-microglobulin effect and to examine the influence of protein glycation (as it occurs in uraemia) on phosphatidylserine erythrocyte exposure, erythrocytes from normal subjects were incubated with recombinant beta2-microglobulin (showing no glycation sites at mass analysis), commercial beta2-microglobulin (8 glycation sites), or with in vitro glycated recombinant beta2-microglobulin (showing multiple glycation sites). Elevated concentrations of beta2-microglobulin (corresponding to plasma levels reached in dialysis patients) increased slightly but significantly the protein's ability to externalize phosphatidylserine on human erythrocytes. Such an effect was markedly enhanced by glycated forms of the protein. Beta2-microglobulin is recognized as a surrogate marker of middle-molecule uraemic toxins and represents a key component of dialysis-associated amyloidosis. Our study adds further evidence to the potential pathophysiologic consequences of beta2-microglobulin accumulation in chronic uraemic patients.     

Congestive cardiomyopathy in uraemic patients on long term haemodialysis.

Five uraemic patients who developed progressive cardiac failure with clinical evidence of congestive cardiomyopathy at the start or during haemodialysis treatment were studied. The diagnosis of cardiomyopathy, for which there was no apparent cause, was confirmed by angiocardiographic and haemodynamic studies. These showed a significant increase in left ventricular end-diastolic volume over normal values obtained in 12 patients without uraemia. The mean velocity of myocardial fibre shortening was significantly decreased, as was the index of normalised rigidity. Three of the five patients presented the complete picture of the disease. The other two also had considerable ventricular dilatation and a decreased index of normalised rigidity but normal ejection fraction and only moderately decreased myocardial contractility indices. This suggests that there may be primary involvement of normalised heart muscle rigidity followed by secondary changes in myocardial contractility in uraemic patients with congestive cardiomyopathy.     

Arteriovenous hemofiltration as an adjuvant therapy in peritoneal dialysis and hemodialysis in a patient with terminal renal failure]

In the uraemic patient regularly treated with peritoneal dialyses occurring peritonitis caused a decrease of ultrafiltration and transfer abilities of the peritoneum. Other symptoms dangerous for life also appeared: uraemic pericarditis and significant overhydration. Peritoneal dialyses lost its effectiveness. Therefore they were supplemented by arterio-venous haemofiltration. Haemofiltration was also conducted at the beginning of haemodialysis treatment, which was initially unregular. Application of haemofiltration enabled the patient to survive during the time of waiting for regular haemodialyses. It may be useful to consider such a treatment, when the adequacy of proper renal substitutive management of uraemia by other methods is impossible to obtain.     

Spleen size in chronic renal failure.

To investigate the cause of clinically detectable splenomegaly, which is common in patients receiving regular haemodialysis, splenic volume was assessed by isotopic scanning using intravenously injected technetium-99m microspheres in 34 controls and 149 patients with chronic renal failure. Of the patients, 16 had never received dialysis, 10 were undergoing continuous peritoneal dialysis, 94 were undergoing regular haemodialysis, and 29 had undergone successful renal transplantation more than nine months previously. Mean splenic volume was increased only in the patients who were receiving haemodialysis. Splenic enlargement was probably not due to iron overload as it occurred in all patients who had received haemodialysis, 14 of whom had not received intravenous iron. No patient had had hepatitis. Splenic enlargement was probably related to the process of haemodialysis itself and may have been due either to red cell damage produced by haemodialysis or to an immunological reaction induced by a component of haemodialysis, possibly ethylene oxide.     

Cholestyramine in treatment of postvagotomy diarrhoea--double-blind controlled trial.

A double-blind controlled trial was performed to assess the effectiveness of cholestyramine in treating severe continuous postvagotomy diarrhoea. Each patient and a clinician assessed the results, and those treated with cholestyramine showed a considerable improvement over those given placebo. There were no significant side effects or changes in laboratory values in the cholestyramine group. Although the numbers were too small for statistical analysis, these results suggest that cholestyramine may be of value in the management of some patients with severe continuous postvagotomy diarrhoea who are unresponsive to other forms of treatment.     

Parenchymal destruction and arterial changes (haemodialysis intimal fibrosis) of glomerulonephritic kidneys in chronic intermittent haemodialysis.

The kidneys of 13 chronic diffuse glomerulonephritis patients who had been subjected to chronic intermittent haemodialysis were compared with those of 6 patients treated in the conservative way. Their renal parenchyma was examined with a semiquantitative histological method and advanced complete destruction of the glomeruli was demonstrated in the dialysed cases. There was no perceptive difference in the distribution of the various grades of damage of the recognizable glomeruli and tubules. With the exception of the chronic lobular glomerulonephritis cases, a marked obliterative mucoid intimal proliferation ("haemodialysis-intimal-fibrosis") had developed in the dialysed glomerulonephritis patients. It affected the renal arteries of all size from the segmental to the interlobular arties. Haemodialysis-intimal-fibrosis did not develop in the additionally examined 13 dialysed chronic pyelonephritis cases nor in 8 such treated conservatively. The change seems to be characteristic, but not specific, for chronic diffuse glomerulonephritis treated by chronic intermittent haemodialysis.     

Evaluation of monocyte chemotactic responsiveness in uraemic patients undergoing haemodialysis with different dialytic membranes

Recent data show that monocyte chemotactic peptide-1 (MCP-1), a chemotactic factor specific for monocytes, may play a central role in regulating the activation of these cells. For this reason, the production of MCP-1 in peripheral blood mononuclear cell (PBMC) cultures of eight healthy subjects, six chronic uraemic subjects under conservative treatment and six chronic uraemic patients undergoing haemodialysis (HD), was assessed. In the latter group of individuals, complement-activating membranes such as cuprophan (CU) were used for 1 month followed by biocompatible non-complement-activating membranes, like polymethylmetacrylate (PMMA) for the next 30 days. The chemotactic index (CI) elicited by PBMC supernatants from patients undergoing dialysis was found to be significantly higher than that obtained by supernatants recovered from normal subjects or uraemic patients on conservative therapy. Furthermore, the CI from PBMC supernatants having had contact with CU membranes was higher than that obtained from PBMC activated by PMMA. Finally, the increased chemotactic ability in the supernatants was closely correlated with the augmented MCP-1 gene expression and production, as assessed by in vitro hybridization studies.     

Observations on the Antipruritic Effect of Guanethidine in Atopic Dermatitis

Guanethidine, 0.75 to 1.25 mg. per kg. per day, was found to alleviate the pruritus of acute atopic dermatitis in 19 out of 20 patients. It was not effective in patients with other dermatoses. An apparent partial tolerance to this treatment developed in six out of 10 patients re-treated. It had little or no therapeutic effect in 10 patients with a variety of other pruritic dermatoses, suggesting that this drug has a specific antipruritic action in patients with atopic dermatitis. In a double-blind study, 11 of 12 patients with atopic dermatitis treated with guanethidine experienced relief of pruritus. Four out of 12 patients using a placebo had complete or partial relief. Guanethidine, 1% to 10%, used topically was therapeutically no more effective than placebo. In view of the reported side effects and the anesthetic hazard encountered with guanethidine, further long-term studies are indicated before this drug is adopted for clinical use in the treatment of atopic dermatitis. The findings support the hypothesis that atopic dermatitis may be a manifestation of a hereditary defect in cutaneous noradrenaline binding.     

Continuous ambulatory peritoneal dialysis and renal transplantation: a five year experience.

Continuous ambulatory peritoneal dialysis is a new and increasingly popular method of routine dialysis, but its effect on renal transplantation is uncertain. A non-randomised comparison was made of the outcome of grafting in patients who had been treated before transplantation with continuous ambulatory peritoneal dialysis with that in patients treated with haemodialysis. During the five years, 1979-84, after continuous ambulatory peritoneal dialysis was introduced to Newcastle upon Tyne 220 patients have received transplants after either continuous ambulatory peritoneal dialysis (61 patients) or haemodialysis (159 patients). During follow up no significant differences occurred in survival of patients or grafts between the two treatment groups. One year after transplantation the percentages of survivors who had received continuous ambulatory peritoneal dialysis and haemodialysis were 88% and 91% respectively, and overall graft survival was 66% and 72%, respectively. A multiple regression model was used to allow for differences among patients--for example, duration of dialysis and number of preoperative transfusions--on the survival of grafts. When only first cadaver grafts were considered (in 152 patients) graft survival (non-immunological failures excluded) was not significantly different between the patients treated with continuous ambulatory peritoneal dialysis and haemodialysis. Continuous ambulatory peritoneal dialysis is not a risk factor in renal transplantation, and its continued use in treatment of potential renal graft recipients is recommended.     

Targeting the Neurokinin Receptor 1 with Aprepitant: A Novel Antipruritic Strategy

Background

Chronic pruritus is a global clinical problem with a high impact on the quality of life and lack of specific therapies. It is an excruciating and frequent symptom of e.g. uncurable renal, liver and skin diseases which often does not respond to conventional treatment with e.g. antihistamines. Therefore antipruritic therapies which target physiological mechanisms of pruritus need to be developed. Substance P (SP) is a major mediator of pruritus. As it binds to the neurokinin receptor 1 (NKR1), we evaluated if the application of a NKR1 antagonist would significantly decrease chronic pruritus.

Methods and Findings

Twenty hitherto untreatable patients with chronic pruritus (12 female, 8 male; mean age, 66.7 years) were treated with the NKR1 antagonist aprepitant 80 mg for one week. 16 of 20 patients (80%) experienced a considerable reduction of itch intensity, as assessed by the visual analog scale (VAS, range 0 to 10). Considering all patients, the mean value of pruritus intensity was significantly reduced from 8.4 VAS points (SD +/−1.7) before treatment to 4.9 VAS points (SD +/−3.2) (p<0.001, CI 1.913–5.187). Patients with dermatological diseases (e.g. atopic diathesis, prurigo nodularis) had the best profit from the treatment. Side-effects were mild (nausea, vertigo, and drowsiness) and only occurred in three patients.

Conclusions

The high response rate in patients with therapy refractory pruritus suggests that the NKR1 antagonist aprepitant may indeed exhibit antipruritic effects and may present a novel, effective treatment strategy based on pathophysiology of chronic pruritus. The results are promising enough to warrant confirming the efficacy of NKR1 antagonists in a randomized, controlled clinical trial.     

Benefits and risks of protracted treatment with human recombinant erythropoietin in patients having haemodialysis.

Fourteen patients with uraemic anaemia and having regular haemodialysis were given human recombinant erythropoietin in increasing doses, beginning with 24 U/kg thrice weekly. One patient was dropped from the study because of recurrent thrombosis of vascular access sites. In the other 13 patients, followed up for a mean of 9.1 months (range 8-11), haemoglobin concentrations increased from 62 (SD 8) to 105 (9) g/l. No antierythropoietin antibodies were detected during the study. The correction of anaemia was associated with a tendency to hyperkalaemia and a mild increase of unconjugated bilirubinaemia. In eight previously hypertensive patients antihypertensive treatment had to be reinforced, but in normotensive patients blood pressure did not change. Thrombosis of arteriovenous fistulas occurred in two patients and a cerebral ischaemic lesion in one. Protracted treatment with human recombinant erythropoietin evidently can maintain normal haemoglobin concentrations in uraemic patients over time. Full correction of anaemia, however, may trigger some vascular problems, particularly in hypertensive patients and those with a tendency to thromboembolism.     

Cholestyramine and medium-chain triglyceride in prolonged management of patients subjected to ileal resection or bypass

The pathophysiology of cholerrheic enteropathy is described and a series of patients reviewed. Of 11 patients with chronic disabling diarrhea and steatorrhea after ileal resection or bypass, two had recurrent ileitis, three had lactose intolerance and six of those operated on five years or more previously had vitamin B₁₂ deficiency. Cholestyramine was given alone or with medium-chain triglyceride (MCT) or Portagen (MCT and lactose). The maximal response occurred when cholestyramine was given with Portagen — significantly reduced stool frequency and weight in all patients and stool fat in five. Restudy of five patients four to 11 months later showed the same pattern of response: cholestyramine with 70% MCT abolished symptoms in four patients (ileectomy) and 100% MCT alone greatly improved the condition of the fifth (extensive small bowel resection).     

Factor VIII complex in uraemia and effects of haemodialysis.

Levels of the factor VIII complex were found to be raised in patients with chronic renal failure and further raised by regular dialysis. Increased fibrinogen concentrations were also found. These results suggest the existence of a prothrombotic state in uraemia that is exacerbated by haemodialysis. Ristocetin-induced platelet agglutination, however, was depressed in uraemia and worsened by dialysis. This defect may be transferred to normal platelets from dialysed uraemic plasma, suggesting the existence of an inhibitor of the interaction between factor VIII and platelet glycoprotein. These results may help to explain the anomaly of a prolonged bleeding time together with accelerated atherogenesis that is found in patients with uraemia receiving dialysis.     

Effect of rosuvastatin on outcomes in chronic haemodialysis patients – design and rationale of the AURORA study

Background

Patients with end-stage renal disease (ESRD) are at high risk of cardiovascular events. Multiple risk factors for atherosclerosis are present in ESRD and may contribute to the increased risk of cardiovascular mortality in this population. In contrast to patients with normal renal function, the benefits of modifying lipid levels on cardiovascular outcomes in patients with ESRD on haemodialysis have yet to be confirmed in large prospective randomised trials. A study to evaluate the Use of Rosuvastatin in subjects On Regular haemodialysis: an Assessment of survival and cardiovascular events (AURORA) will be the first large-scale international trial to assess the effects of statin therapy on cardiovascular morbidity and mortality in ESRD patients on chronic haemodialysis.

Methods

More than 2,750 ESRD patients who have been receiving chronic haemodialysis treatment for at least 3 months have been randomised (1:1), irrespective of baseline lipid levels, to treatment with rosuvastatin 10 mg or placebo. The primary study endpoint is the time to a major cardiovascular event (first occurrence of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke). Secondary endpoints include all-cause mortality, major cardiovascular event-free survival time, time to cardiovascular death, time to non-cardiovascular death, cardiovascular interventions, tolerability of treatment and health economic costs per life-year saved. Study medication will be given until 620 subjects have experienced a major cardiovascular event.

Conclusion

Our hypothesis is that results from AURORA will establish the clinical efficacy and tolerability of rosuvastatin in patients with ESRD receiving chronic haemodialysis and guide the optimal management of this expanding population.     

Haemodialysis in Poisoning by Sea-snake Venom

Myoglobinuria, renal failure, and muscular weakness or paralysis were noted in two patients following sea-snake bite. A pathological study by biopsy showed renal tubular necrosis and myonecrosis. Both patients were treated by haemodialysis, and there was a remarkable improvement in the muscular symptoms. Recovery was complete in both cases. It is believed that muscular paralysis was the effect of hyperkalaemia and uraemia on the muscles sensitized by the toxic effect of the sea-snake venom. Removal of potassium and uraemic factors by dialysis thus led to the rapid improvement of the muscular activity. Haemodialysis seems to be a useful alternative method to sea-snake antivenom in the treatment of sea-snake bite poisoning.