J.S. Cameron

THE IMPORTANCE OF THIOPURINE METHYLTRANSFERASE ACTIVITY FOR THE USE OF AZATHIOPRINE IN TRANSPLANT RECIPIENTS

The immunosuppressive efficacy of azathioprine is related to its rapid metabolism in vivo to 6-mercaptopurine (6MP), with subsequent conversion to thioguanine nucleotides by an anabolic route involving hypoxanthine-guanine phosphoribosyltransferase. Two alternative catabolic routes exist: oxidation to 6-thiouric acid via xanthine oxidase and methylation to 6-methylmercaptopurine via the enzyme thiopurine methyltransferase (TPMT). Catabolism via either route would restrict formation of the active metabolites.We analyzed TPMT activity in erythrocyte lysates of 25 controls, 25 uremic patients on dialysis, and 68 transplanted patients. Median activity was lower in controls (31.0 pmol/hr/mg Hb, range 16.2–43.0) and transplanted patients receiving only cyclosporine and prednisolone (31.7 pmol/hr/mg Hb, range 12.7–43.5) than in the azathioprine treated group, (36.1 pmol/hr/mg Hb, range 16.1–71.3), or the uremic group on dialysis, (35.5 pmol/hr/mg Hb, range 18.6–62.6) suggesting that both azathioprine and uremia induce the enzyme, but CsA does not.

Lupus nephritis in childhood and adolescence.

Lupus nephritis in childhood usually presents after the age of 10 years, and presentation under 5 years is very rare. More males (F∶M ratio 4.5∶1) are affected than in adult-onset cases, but the ratio is the same in prepubertal and pubertal children. The incidence of clinically evident renal disease is greater at onset than in adults (82%), the usual presentation being with proteinuria, 50% having a nephrotic syndrome. Half the children show World Health Organisation class IV nephritis in renal biopsies. Neuropsychiatric lupus is present at onset in 30%, may complicate 50% at some point and remains a major problem. Prognosis has improved greatly over the past 30 years, at least in part the result of immunosuppressive treatment. Treatment of the initial phase may be guided by the severity of the renal biopsy appearances, more aggressive treatment including cytotoxic agents, i.v. methylprednisolone and perhaps plasma exchange, although the value of exchange is not established. Controversy persists as to the most effective cytotoxic treatment in the acute phase, both oral and i.v. cyclophosphamide and azathioprine being used in different units. In the chronic maintenance phase it seems established both clinically and histologically that addition of a cytotoxic agent improves outcome, but again the drug and route of administration are contentious. Azathioprine has the advantage of being safe for pregnancy and not gonadotoxic, whilst i.v. cyclophosphamide has been demonstrated to improve results over prednisolone alone in controlled trials and has advantages in non-compliant patients. No trial comparing the two regimes has been carried out, and one is needed. Today children much less commonly go into renal failure, and the main causes of actual death (15% of patients over 10 years) are now infections and extra-renal manifestations of lupus, principally neurological. Morbidity of the disease and the treatment remain a major problem, especially when treatment exacerbates complications of the disease itself, such as infections, osteonecrosis, thrombosis, vascular disease and possibly neoplasia.

Why the persistently high mortality in acute renal failure.

Abstract Data from 109 patients in established Summary acute renal failure, referred during the period January, 1969, to April, 1971, have been analysed. Mortality in this group of patients was distressingly high (57%) despite intensive dialysis and intensive general care. Sepsis still remains a major problem both as a precipitating and complicating factor in acute renal failure. Milder forms of renal failure were rarely referred to the unit during this period; most patients being older, more severely ill, and with prolonged oliguria. Since mortality increases with age, irrespective of precipitating cause, the greater age of the series probably accounts for much of the high mortality. Survival from acute renal failure in old patients who had just had surgical operations was rare, and it is in this area that most remains to be done. 29 patients with urine hypo-osmolar or isoosmolar plasma were given frusemide 500 mg. or 250 mg. intravenously; only 7 showed a diuresis, and this was sustained in only 3.

Gout, uric acid and purine metabolism in paediatric nephrology

Although gout and hyperuricaemia are usually thought of as conditions of indulgent male middle age, in addition to the well-known uricosuria of the newborn, there is much of importance for the paediatric nephrologist in this field. Children and infants may present chronically with stones or acutely with renal failure from crystal nephropathy, as a result of inherited deficiencies of the purine salvage enzymes hypoxanthine-guanine phosphoribosyltransferase (HPRT) and adenine phosphoribosyltransferase (APRT) or of the catabolic enzyme xanthine dehydrogenase (XDH). Genetic purine overproduction in phosphoribosylpyrophosphate synthetase superactivity, or secondary to glycogen storage disease, can also present in infancy with renal complications. Children with APRT deficiency may be difficult to distinguish from those with HPRT deficiency because the insoluble product excreted, 2,8-dihydroxyadenine (2,8-DHA), is chemically very similar to uric acid. Moreover, because of the high uric acid clearance prior to puberty, hyperuricosuria rather than hyperuricaemia may provide the only clue to purine overproduction in childbood. Hyperuricaemic renal failure may be seen also in treated childhood leukaemia and lymphoma, and iatrogenic xanthine nephropathy is a potential complication of allopurinol therapy in these conditions. The latter is also an under-recognised complication of treatment in the Lesch-Nyhan syndrome or partial HPRT deficiency. The possibility of renal complications in these three situations is enhanced by infection, the use of uricosuric antibiotics and dehydration consequent upon fever, vomiting or diarrhoea. Disorders of urate transport in the renal tubule may also present in childhood. A kindred with X-linked hereditary nephrolithiasis, renal urate wasting and renal failure has been identified, but in general, the various rare types of net tubular wasting of urate into the urine are recessive and relatively benign, being found incidentally or presenting as colic from crystalluria. However, the opposite condition of a dominantly inherited increase in net urate reabsorption is far from benign, presenting as familial renal failure, with hyperuricaemia either preceding renal dysfunction or disproportionate to it. Paediatricians need to be aware of the lower plasma urate concentrations in children compared with adults when assessing plasma urate concentrations in childhood and infancy, so that early hyperuricosuria is not missed. This is of importance because most of the conditions mentioned above can be treated successfully using carefully controlled doses of allopurinol or means to render urate more soluble in the urine. Xanthine and 2,8-DHA are extremely insoluble at any pH. Whilst 2,8-DHA formation can also be controlled by allopurinol, alkali is contraindicated. A high fluid, low purine intake is the only possible therapy for XDH deficiency.

SERUM IMMUNE COMPLEXES AND DISEASE ACTIVITY IN LUPUS NEPHRITIS

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.

Recurrence of focal segmental glomerulosclerosis in renal allografts.

Thirty-one renal allografts placed in 25 recipients with renal failure from biopsy-documented focal segmental glomerulosclerosis (FSGS) were reviewed. These represent all of the cases with this renal histology transplanted over 13 years. Recurrence of the lesion was demonstrated histologically in five recipients. A nephrotic syndrome occurred in all five patients and failure of the graft in two. Of 20 recipients who did not show a nephrotic syndrome, allograft histology in 12 did not show FSGS in any. From these data and a review of the literature, the risks of transplantation in patients with FSGS are assessed. Recipients under the age of 15 and with a course into renal failure of less than 3 years show recurrence in about 50% of cases. Of this 50%, about one-half will lose their grafts from the recurrence within 5 years, but some may show good function for many years, despite proteinuria or a nephrotic syndrome.

Tubular and interstitial factors in the progression of glomerulonephritis.

All recent studies of the outcome of different forms of progressive glomerulonephritis concur that a major factor, apparently determining outcome, is the presence and severity of tubulointerstitial changes, and not the degree of glomerular alteration. Moreover, at the time of biopsy, tubulointerstitial changes correlate much better with the glomerular filtration rate. These at first surprising findings are not only useful clinically, but should make us think about our models of how progression takes place in so-called glomerular nephritides. In fact, a major tubulointerstitial infiltrate of immune-competent cells is present in all forms of progressive glomerulonephritis, and again correlates with outcome. In addition, it is now clear the tubular epithelium is capable of synthesising and secreting a number of factors important in fibrogenesis, and of displaying major histocompatibility complex class II antigens and leucocyte-adhesion molecules. Tubular cells could thus present peptides to T helper cells and amplify, or maybe even initiate, immune reactions. Finally, fibrogenesis within the kidney is at last being studied, long after studies have been performed on liver and lung. In the past, too much attention has been paid to reversible inflammation and not enough to irreversible cirrhosis of the kidney.

RENAL TRANSPLANTATION AFTER REMOVAL AND PREVENTION OF RESYNTHESIS OF HLA ANTIBODIES

Plasma exchange and immunosuppression with prednisolone and cyclophosphamide were used to remove HLA antibodies and prevent their resynthesis in five patients awaiting renal transplantation. After treatment HLA antibody titres and reactivities against a panel of donor lymphocytes were considerably reduced and, as a result, these patients received transplants. Four of these patients have successfully functioning transplants; the other patient died as a result of septicaemia with a poorly functioning allograft.

The identification of 2,8-dihydroxyadenine, a new component of urinary stones.

Stones passed by a child homozygous for a deficiency of the enzyme adenine phosphoribosyltransferase have been identified by u.v., i.r. and mass spectrometry as 2,8-dihydroxyadenine.

DOES THE NEPHROTIC SYNDROME INCREASE THE RISK OF CARDIOVASCULAR DISEASE

Cardiovascular mortality and morbidity were assessed, after a mean follow-up period of 5 years, in an unselected series of 159 adults presenting with the nephrotic syndrome between 1972 and 1975. 60% of the deaths were attributed to terminal renal failure, and the incidence of deaths from ischaemic heart-disease (IHD) was not significantly above normal. The proportion of patients experiencing angina and intermittent claudication and the prevalence of ischaemic electrocardiographic changes did not differ significantly from those of a London control population. At follow-up, hypertension was significantly more common (p less than 0.001) in male nephrotic patients than in controls. Earlier reports of a greatly increased incidence of IHD in unselected patients with the nephrotic syndrome were not confirmed. Routine treatment of hyperlipidaemia in the nephrotic syndrome is not, therefore, recommended.