Biomedical subjects
Publications and source records attributed to J S Cameron.
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Orotic acid excretion was normal when tested by three methods in adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency. These results do not support the speculation, based on the oroticaciduria observed by others, that the immunodeficiency in these disorders results from the inhibition of pyrimidine biosynthesis. An alternative hypothesis is discussed.
Forty consecutive patients whose biopsies showed focal and segmental sclerosis were studied for 6 to 16 years to establish the long-term prognosis of this group of patients. By the end of a decade 21 were dead, on regular dialysis or transplanted; only one death was unrelated to renal failure. A further 8 patients had a GFR of less than 60 ml/min/1.73 m2. Only 11 patients had normal renal function, and of these eleven only four had no urinary abnormality. Actuarially calculated survival was 75% at 5 years, 50% at 10 years, and 38% at 15 years. There was no difference between the 28 adults and the 12 children in terms of evolution. Patients with a nephrotic syndrome at presentation had a poorer prognosis than those never nephrotic. Twenty nephrotic patients were treated with prednisone, and 14 of these with cyclophosphamide in addition. One patient responded with loss of proteinuria within two months to both drugs, and another lost proteinuria when treated with cyclophosphamide. Thirteen patients received allografted kidneys; a nephrotic syndrome recurred in three patients, with histological evidence of recurrent disease in two.
We have made a blind retrospective analysis of 334 renal biopsies, each containing more than 10 glomeruli, from adults and children with glomerulonephritis, in order to assess the clinicopathological significance of segmental lesions. These were defined as endocapillary proliferation and/or sclerosis involving capillary loops, and a less than half the glomerular tufts. On optical microscopy of paraffin-embedded material, 57 biopsies containing segmental lesions were independently classified by two observes as "focal proliferative glomerulonephritis" or "focal segmental glomerulosclerosis". These results were then reviewed with immunofluorescence, electron microscopic and clinical data and an "executive" diagnosis reached. Scarred focal proliferative glomerulonephritis could not be reliably distinguished from focal segmental glomerulosclerosis by optical microscopy alone. Some cases of focal proliferative glomerulonephritis are not associated with systemic disease and may have negative immunofluorescence findings, and we were unable to distinguish scarring in these patients from the lesion of focal segmental glomerulosclerosis with any of the tools at our disposal. Some patients with scarred focal proliferative glomerulonephritis showed profuse proteinuria, a nephrotic syndrome and progression to renal insufficiency. These cases cannot therefore be differentiated from focal segmental glomerulosclerosis by their clinical features. It would seem that the morphological lesion of focal segmental glomerulosclerosis should be regarded as focal segmental glomerular scarring from a variety of insults, rather than a distinct disease entity.
We describe 11 patients whose renal biopsies showed minimal changes with focal segmental glomerulosclerosis. These patients, in contrast to the majority of patients with similar renal histology, went into renal failure within 2 1/2 years of clinical onset. All were young, severely nephrotic, most hypertensive, with microscopic hematuria, non-selective proteinuria and extreme hypercholesterolemia. Treatment with corticosteroids and cytotoxic drugs was without effect in any patient. Despite rapid decline in renal function, profuse proteinuria and a nephrotic syndrome persisted into terminal uremia and continued even after dialysis had begun. Seven patients were given nine allografts; four grafts failed because of immediate vascular complications, and a persistant nephrotic syndrome was evident in two of the five surviving grafts. This did not, however, lead to graft failure. Two patients died on dialysis because of myocardial problems. These patients with rapid decline in renal function constitute a distinct clinical subgroup amongst those with focal and segmental glomerulosclerosis; it is possible that they have a different primarily vascular pathogenesis in contrast to other patients with similar renal biopsy appearances.
The first home dialysis was carried out from Guy's Hospital in London in 1968. Since then, 141 patients have been treated in this manner. The age of the patients ranged from 4 to 64 years. 24 patients have died (cerebrovascular accidents, myocardial infarction, pulmonary edema, sepsis, peritonitis, hyperkalemia etc.). Some of the deaths were due to a slackening of discipline on the part of the patients and nursing staff during the years of constant dialysis. Of 60 adults 52 were able to start work again; full rehabilitation still seems possible in 6 cases. Nevertheless, many patients cannot lead a normal life because their social and sexual activity is greatly restricted. The present economic crisis led to financial limitations in the National Health Service. In future, home dialysis may have to be reduced and more transplantations performed.
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We studied the clinical and biochemical manifestations of complete adenine phosphoribosyltransferase deficiency in the kindred of a male homozygous child excreting stones of 2,8-dihydroxyade-nine. Abnormal amounts of adenine, 8-hydroxyade-nine and 2,8-dihydroxyadenine (25 per cent of total purine metabolites) appeared in the urine of the propositus and his clinically normal brother, but not in heterozygotes or a control. Adenine phosphoribosyl-transferase activity in erythrocytes was less than 1 per cent of normal in both homozygotes and varied from 20 to 57 per cent of normal in six heterozygotes. Heterozygotes exhibited neither hyperuricemia nor gout. Treatment of the propositus with allopurinol and a low purine diet stopped stone formation. In addition, excretion of 2,8-dihydroxyadenine decreased. An autosomal recessive mode of inheritance with variable expression in the phenotype is indicated. Homozygotes may be detected by their raised urinary adenine levels or absence of detectable erythrocyte adenine phosphoribosyltransferase activity (or both).
All the survivors of a series of 88 patients with Henoch-Schönlein nephritis were examined after a follow-up of six and a half to 21 years (mean 9-9). Sixty-one patients had no demonstrable abnormality; six had minor urinary abnormalities; five had hypertension without urinary abnormally or renal dysfunction; four had heavy proteinuria; eight were in chronic renal failure, three of whom were on regular dialysis; and four patients had died within 25 months of onset. Neither corticosteroids nor immunosuppressive drugs alone or in combination appeared to influence the outcome. A clinical presentation with a combination of acute nephritis and a nephrotic syndrome and a high proportion of crescents in renal biopsy specimens was associated with a poor outcome. Neither the clinical presentation nor the renal morphology were, however, precise determinants of outcome. Outcome was not related to age, associated streptococcal infection, or recurrences of the rash. The clinical state two years after presentation was compared with the state six and a half years or more after presentation in 76 patients. The clinical state had changed in 32 patients, in 17 of whom it had deteriorated. It was not possible to identify with any certainty the patients who would deteriorate (or improve). Patients who have had Henoch-Schönlein nephritis should be followed up for at least five years.
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Raised levels of circulating soluble immune complexes were found in sera of 21 of 29 patients with lupus nephritis. They correlated well with clinical disease activity in the group as a whole and with the course of individual patients. In 2 patients, high-dose methylprednisolone reduced levels of immune complexes and led to clinical improvement. The size of the IgG complexes was studied in 7 patients. The complexes were very large (2-5-4X10(6) M.W.) in 6, but only the 4 with diffuse proliferative glomerulonephritis had medium-sized IgG complexes (1-1-5X10(6) M.W.) as well.
During 1971-5, 72 episodes of acute renal failure were treated in 70 children aged up to 16 years. The commonest causes were renal hypoperfusion (31 cases), haemolytic-uraemic syndrome (12), glomerulonephritis (9), septicaemia (5), and congenital abnormalities (6). Though referral from other hospitals was generally prompt, 10 out of 51 patients had been observed for up to seven days before transfer. Dailysis was used in 44 cases, the most common complications of which were peritonitis in those treated with peritoneal dialysis and acute changes in fluid balance in those treated with haemodialysis. Altogether 37 patients fully recovered, 10 were discharged with chronically impaired renal function, 17 died, and six entered the dialysis and transplantation programme. The mortality fell from 33% in 1972 to 20% in later years, which was due solely to maintenance dialysis being available. Though all patients with irrevocable kidney failure who were suitable entered the dialysis and transplantation programme, with current financial restrictions we doubt whether we shall be able to find places for all such patients in the future.
1. Adenine administered either parenterally or orally is less toxic to the pig than to other species; doses of 100 mg/kg are rapidly catabolised and excreted largely as soluble purine end-products in the urine. 2. The low toxicity is explained by the excretion of less than 1% of the dose as 2,8-dihydroxyadenine. 3. These results suggest that adenine dosages which give rise to kidney damage must be above a threshold-like level which varies in the different mammalian species, and is higher in the pig than in the rat, dog, rabbit or man.
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1. Abnormal amounts of adenine, 8-hydroxyadenine and 2,8-dihydroxyadenine are found in the urine of homozygotes for APRTase deficiency and are diagnostic of this condition. 2. The renal complication is due to the excessive amounts of 2,8-dihydroxyadenine excreted since it is removed by allopurinol which blocks 2,8-dihydroxyadenine formation. 3. Uric acid metabolism and the excretion of the other minor purine bases is normal, at least in childhood, in homozygotes for APRTase deficiency. 4. Patients with the defect appear to be very sensitive to dietary purine. At least some of the adenine metabolites may have a dietary origin.
1. The important fact which emerges from these studies both without and with dietary purine supplementation is that thiopurinol dose possess apparent in vivo xanthine oxidase inhibitory activity but the dose must be increased well above therapeutic levels for this effect to manifest. 2. The considerable reduction in total endogenous urinary purine excretion at these high doses substantiates an additional inhibitory effect of thiopurinol on de novo purine synthesis. 3. Thiopurinol, like its analogue allopurinol, is also capable of reducing the absorption of dietary purine administered in the form of guanine in the pig.