Lipid abnormalities in red blood cell and plasma phospholipids in cyclosporine-treated heart transplant recipients.
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Biomedical subjects
Publications and source records attributed to H R Powell.
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OBJECTIVE: To determine the outcome of patients with end-stage chronic renal failure treated by live donor renal transplantation at the Royal Melbourne Hospital and Royal Children's Hospital between 1973 and 1991, during which time two distinct immunosuppressive regimens were used. DESIGN: Data about live donor renal transplant recipients were retrieved from the Australian and New Zealand Dialysis and Transplantation Association Registry, to which we have submitted data on all transplant recipients at six monthly intervals since the commencement of our dialysis and transplant programs. PATIENTS: Seventy-two patients with chronic renal failure who received live donor renal transplants during the 19 years from February 1973 to February 1992 were included. MAIN OUTCOME MEASURES: Patient survival, transplant survival, transplant function, change in prednisolone requirements, and duration of hospital stay. RESULTS: The first 32 patients were treated with immunosuppressive regimens based on combinations of prednisolone and azathioprine ("dual therapy"), while the next 40 patients were treated with combinations of cyclosporin, prednisolone and azathioprine ("triple therapy"). Survival of patients in each group five years after transplantation was 97%. Actuarial graft survival at 5, 10 and 15 years in the dual therapy group was 58%, 52% and 47%, compared with a 5-year actuarial graft survival in the triple therapy group of 96%. There was no statistically significant difference in renal transplant function between the two groups within the first 6 years after transplantation. Twelve of 26 patients (46%) treated initially with triple therapy were able to stop treatment with prednisolone within 12 months of transplantation. Median hospital stay was 12 (range, 6-35) days during the period 1973-1985 and 8 (range, 5-20) days for the 1985-1992 period. CONCLUSION: Live donor renal transplantation has provided a highly satisfactory means of treating patients with end-stage chronic renal failure in the short and long term. Our recent experience indicates that excellent patient and graft survival and adequate renal function can be achieved by treating live donor renal transplant recipients with a triple immunosuppressive regimen of low dose cyclosporin, prednisolone and azathioprine.
Two cases of anti-neutrophil cytoplasmic antibody (ANCA)-associated necrotizing and crescentic glomerulonephritis are reported. A 12-year-old girl and a 10-year-old boy presented with polyarthritis, anaemia, haematuria, proteinuria, impaired renal function, anorexia, nausea, marked loss of weight and lethargy. The boy also had a vasculitic rash and anterior uveitis. Both children had diffuse cytoplasmic ANCA identified by indirect immunofluorescence and confirmed by specific enzyme-linked immunosorbent assay. Renal biopsies showed severe focal and segmental necrotizing glomerulonephritis with 100% crescents. They were treated with plasma exchange, prednisolone, cyclophosphamide and heparin. Within 1 month of commencing treatment, both had normal serum creatinine concentrations and ANCA was not detectable. Renal biopsies 6 weeks following commencement of treatment revealed quiescent disease, although up to 40% of glomeruli were sclerosed or had fibrous crescents. Following cessation of cyclophosphamide and heparin after 7 months and reduction in steroid dose, a biopsy at 10 months in the boy revealed quiescent disease, but the girl had recurrent disease associated with reappearance of a low titre of ANCA and small cellular crescents in 20% of the glomeruli. These cases reflect the potential usefulness of ANCA determination for categorizing paediatric patients, helping in the selection of therapy and as a possible marker of disease activity, similar to the experience in adults.
Collagen studies in newborn rats with incomplete ureteric obstruction were performed to describe and quantify changes in collagen deposition resulting from urinary tract obstruction at an early developmental age. Incomplete ureteric obstruction was created in three-day-old rats by placing the left ureter in a tunnel formed by the psoas muscle, and sham-operated controls underwent a laparotomy. The rats were sacrificed at 10, 17, 24 or 31 days. Collagen types I, III, IV, and V were localized by indirect immunofluorescence microscopy, the total collagen content of the kidney was quantitated using hydroxyproline analysis, and collagen types I and III were quantitated using cyanogen bromide (CNBr) peptide analysis. Increased immunofluorescent staining for all of the collagens was found in the diffusely widened medullary interstitium of the obstructed kidney, and more focally in the cortical interstitium. Collagen types I, III and V, but not collagen type IV, were also found in bands in the interstitium at the junction of the cortex with the medulla. Increased staining for collagen type IV was found in thickened and tortuous tubular basement membranes (TBM) of the obstructed kidneys. The total collagen content of the obstructed kidney was significantly increased compared to the amounts in both the contralateral kidneys and in the kidneys from sham-operated controls at 24 and 31 days of age (P < 0.01 in each case, Wilcoxon matched pairs rank sum test and Mann Whitney U-test, respectively). The amount of collagen in the kidneys correlated with the degree of hydronephrosis (Spearman correlation test, r = 0.78, P < 0.02). CNBr peptide analysis demonstrated that over 50% of the collagen in the normal neonatal rat kidney was collagen type I and approximately 25% was collagen type III. In the obstructed kidneys most of the collagen was also collagen type I and collagen type III, although the proportion of total collagen comprised by these collagen types was decreased compared with the controls. The amount of collagen type III in the contralateral kidneys was reduced compared to that in the controls. Thus, the neonatal renal response to obstruction resulted in increased amounts of a range of collagens in the interstitium and TBM, and the extent of this response was partially related to the degree of hydronephrosis.
Recent studies have demonstrated that both congenital hypoplasia and acquired scarring are involved in the parenchymal lesions associated with reflux nephropathy. Medical therapy can prevent symptomatic infection. While there is no proof that either medical or antireflux surgery prevents acquired scarring, paradoxically there is evidence that surgery adds no benefit to medical therapy, and that the results of medical therapy and surgical therapy are similar in children with isolated severe reflux. The group at most severe risk of renal scarring is infants and the effects of medical and surgical therapy in preventing acquired renal injury in this group have not been sufficiently investigated. On the basis of this information it has been our practice to maintain urine sterility using continuous antibiotic prophylaxis throughout infancy and early childhood. Following the development of reliable urine toilet habit and the ability to collect midstream urine specimens, antibiotics are given according to the frequency of urine infection, and weekly testing of morning urine with nitrite strips at home is used for early detection of infection and prevention of symptomatic infection. Antireflux surgery is mandatory for those children with complicated VUR (such as urinary tract obstruction) and should otherwise be reserved for those having persistent breakthrough infections in infancy and early childhood.
Four cases of peritonitis caused by the filamentous fungus Paecilomyces variotii in patients on continuous ambulatory peritoneal dialysis are reported. Removal of the Tenckhoff catheter and antifungal chemotherapy led to resolution of symptoms in all cases. Possible contaminating events are discussed, and reported infections with P. variotii are reviewed.
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Recurrence of haemolytic-uraemic syndrome (HUS) after renal transplantation may occur in both cyclosporin A (CyA) and non-CyA-treated patients, and in patients receiving anti-lymphocyte globulin. We report a case of recurrent HUS in an 8-year-old boy who received Orthoclone (OKT3) combined with prednisolone and azathioprine therapy on receipt of his first cadaveric renal allograft. Despite avoidance of CyA therapy irreversible HUS occurred.
Polymeric IgA (PIgA) and immune complex concentrations in IgA-related renal disease were measured in cross sectional and longitudinal studies to establish the relationship between these parameters and both mucosal infection and renal dysfunction. These studies were performed in 50 patients with IgA nephropathy (IgAN), 17 patients with Henoch Schönlein purpura nephritis (HSPN), 11 control patients with IgA negative, diffuse mesangial proliferative glomerulonephritis (DMPGN) and 50 healthy controls. Total PIgA (PIgAT) and PIgA subclass concentrations were measured using a secretory component binding enzyme immunoassay and isotype specific immune complex concentrations were measured using conglutinin (K) binding immunoassays. In cross sectional studies patients with IgAN were found to have increased concentrations of PIgAT, PIgA1, K-IgA1 and K-IgA2 compared to controls. In the longitudinal studies controls and patients had significant increases in PIgAT and PIgA1 concentrations during infection. However, in patients with IgAN, the increases were greater, persisted for longer, and PIgA2 concentrations were also increased. K-IgA1 and K-IgA2 concentrations increased significantly during episodes of infection in IgAN patients in contrast to controls. Patients with HSPN had results similar to those of IgAN patients. No significant correlation was found between PIgA or K-IgA concentrations, and either serum creatinine concentrations or the degree of hematuria. The results indicate that patients with IgA-related renal disease have abnormal regulation of PIgA and immune complexed IgA, and that these abnormalities are exaggerated during mucosal infection.
The concentrations of serum IgG and IgM antibodies to polyclonal IgA (IgAp), IgA1, and IgA2 were determined by enzyme immunoassay in 31 patients with IgA nephropathy and 30 healthy controls. Patients with IgA nephropathy had significantly raised concentrations of serum IgA compared to controls (Mann-Whitney U test, P = 0.001) and increased concentrations of conglutinin-binding IgA immune complexes (P = 0.024). No differences in the median concentrations of IgG and IgM anti-IgA antibodies were found between the patients and the controls. In serum samples from healthy controls there was a significant positive correlation between IgM anti-IgAp and IgA immune complex concentrations (P = 0.05), which contrasted with the finding of an inverse correlation between IgM anti-IgAp and IgA immune complex concentrations in patients with IgA nephropathy (P less than 0.05). In addition, the concentrations of conglutinin binding IgM immune complexes in serum were found to correlate with the concentration of IgM anti-IgAp (0.010 less than P less than 0.025), IgM anti-IgA1, and IgM anti-IgA2 (P much less than 0.005 for both) in patients with IgA nephropathy but not in controls. IgM anti-IgA antibodies may be important in augmenting the clearance of IgA immune complexes from the serum of patients with IgA nephropathy.
Renal and hepatic sonography were performed in 2 neonates with glomerulocystic renal disease. One neonate had ultrasound findings of normal hypoechoic medullary pyramids, enabling differentiation from infantile polycystic renal disease. Previous case reports have highlighted the similarity of renal ultrasound findings in these two conditions.
Red blood cell phospholipid arachidonic acid concentration was determined in 38 renal transplant recipients on cyclosporine-azathioprine-prednisolone therapy and in a comparable group of 20 patients on azathioprine-prednisolone alone. Samples also were obtained from 18 normal controls and 30 patients with "classical" hemolytic uremic syndrome (HUS). The arachidonic acid content was estimated as the percentage relative to the five principal fatty acids in red blood cell phospholipids (C16:0, C18:0, C18:1 omega 9, C18:2 omega 6, C18:3 omega 6) and quoted as mean value +/- standard deviation. There was a highly significant difference between patients on cyclosporine (14.7 +/- 2.9) and non-cyclosporine-treated transplant recipients (17.1 +/- 2.5; p less than 0.002). This difference was even more significant when patients who had been on cyclosporine for less than 3 months were excluded (14.1 +/- 2.7; p less than 0.001). The mean arachidonic acid content in non-cyclosporine recipients also was significantly less than that in normal controls (19.2 +/- 1.5; p less than 0.005) whilst the HUS patients (11.2 +/- 3.6) had significantly reduced values when compared with all the other groups. Cyclosporine often causes nephrotoxicity and in some cases HUS may develop in cyclosporine-treated transplant recipients. We have found a significant negative correlation between serum creatinine levels and red blood cell phospholipid arachidonic acid levels (r = -0.45; p less than 0.01). We propose that the decreased concentration of arachidonic acid in the cyclosporine-treated group may be related to the development of nephrotoxicity in the long term and may be a useful marker in predicting the early development of nephrotoxicity in these patients.
This paper describes the clinical features of six children who developed the haemolytic-uraemic syndrome after treatment with metronidazole. These children were older and were more likely to have undergone recent bowel surgery than are other children with this condition. While the involvement of metronidazole in the aetiology of the haemolytic-uraemic syndrome is not established firmly, the action of this drug in sensitizing tissues to oxidation injury and the reported evidence of oxidation changes in the haemolytic-uraemic syndrome suggest a possible link between metronidazole treatment and some cases of the haemolytic-uraemic syndrome.
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Escherichia coli O157:H7 was isolated from a fatal case of haemorrhagic colitis with haemolytic uraemic syndrome and neurological symptoms. This strain induced diarrhoea and neurological symptoms including incoordination, ataxia, and convulsions in piglets after oral inoculation. Similar neurological signs were seen in piglets inoculated intraperitoneally with bacterial extracts containing a shiga-like toxin that is elaborated by the bacteria. Histological examination of the brains from these piglets showed vascular damage and small infarcts confined to the cerebellum. Comparable lesions were also seen in the brain of the child from whom E coli O157:H7 was isolated. We suggest that the cerebral changes in the piglets and in the patient were caused by the shiga-like toxin elaborated by E coli O157:H7. The shiga-like toxin is thought to cause neurological abnormalities by damage to cerebral blood vessels rather than by a direct effect on the neurones.
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Since June 1985 ten consecutive paediatric cadaveric renal transplant recipients (aged from 7 to 15 years) have been studied prospectively to evaluate a triple immunosuppressive regime of low-dose cyclosporin A (CyA), azathioprine (AZA) and prednisolone (PNL) with the aim of eliminating PNL from the regime within 6 months. Follow-up has been over 6-18 months. Patient and graft survival are both 100%. Median (range) serum creatinine values at 6 months were 0.09 (0.05-0.14) mmol/l (n = 10) and 0.09 (0.06-0.16) mmol/l (n = 5) at 12 months. Readily reversible acute rejection episodes occurred in five patients (50%); two of these episodes occurred soon after cessation of PNL. Six months post-transplantation, PNL had been discontinued in six patients (60%). After 12 months, three of five patients were still not receiving PNL. Complications included hypertension (seven patients), cytomegaloviral infections (three patients), labial herpes simplex (one patient), leucopenia (two patients), marked hirsutism (four patients) and transient CyA nephrotoxicity (one patient). Following transplantation, all children had growth velocities greater than 5 cm/year and seven have growth patterns which suggest that "catch-up growth" may be occurring. This preliminary study shows that a triple immunosuppressive regime of low-dose CyA, AZA and PNL allows excellent patient survival, graft survival and graft function and has been associated with few complications, including a low incidence of CyA nephrotoxicity. Growth rates are very encouraging and in a high proportion of children it has been possible to discontinue PNL completely.