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SUMMARY In 48 patients undergoing renal biopsy there was a strong correlation (X2 11-45 (P < 0 01)) between the demonstration of circulating and deposited immune complexes. Serial studies of circulating immune complex levels have shown fluctuations which only sometimes appear to coincide with clinical changes in individual patients.The presumed importance of circulating immune complexes (CIC) in the pathogenesis of glomerulonephritis in man is based on comparisons with animal models (Wilson and Dixon, 1976).There is much indirect evidence suggesting the activity of immune complexes in human glomerulonephritis from (i) demonstration of granular deposits of immunoglobulins and complement components in renal biopsy sections by immunofluorescence, (ii) changes in serum complement levels, and (iii) detection of complement breakdown products in the circulation as well as cryoglobulins and rheumatoid factor. A number of workers have described varying levels of CIC in several histological types of glomerulonephritis (Johnson et al., 1975;Rossen et al., 1976; Stuhlinger et al., 1976;Ooi et al., 1977;Woodroffe et al., 1977;Cohen et al., 1978;Levinsky et al., 1978;Onyewotu and Mee, 1978;Pussell et al., 1978). The purpose of this study was (a) to investigate whether CIC could be detected at the time of renal biopsy and correlated with histological findings, and (b) to see if serial measurements of levels of CIC indicated any correlation with the clinical course. Methods DETECTION OF CIRCULATING IMMUNE COMPLEXESBlood samples were taken in the morning and allowed to clot at room temperature. Sera were stored at -70'C; 05 ml volumes were mixed with 0-1 ml of a 12% solution of polyethylene glycol (PEG) in 60 mM EDTA, pH 7 5, and left at 4°C for Received for publication 2 January 1979 18 hours. The precipitate was washed with 2 % PEG and redissolved in 0-5 ml of barbitone buffered saline. IgG, Clq, and IgA were measured in the dissolved pellet (Clayton et al., 1977) as was the remaining Clq in the supernatant after the first centrifugation. Results were expressed as the amount of the total Clq and immunoglobulin precipitated, and the normal range was constructed from a study of healthy adult donors. Results were considered abnormal if the precipitated value was more than 2 standard deviations greater than the mean for normal controls. The laboratory studies were all carried out without knowledge of the clinical details of the patients studied.

The constitutive cyclooxygenase (COX)-1 enzyme has been considered the physiologically important isoform for prostaglandin synthesis in the normal kidney. It has, therefore, been suggested that selective inhibitors of the ‘inducible’ isoform (COX-2) may be free from renal adverse effects. We studied the renal effects of the predominantly COX-2 antagonist nabumetone in isolated perfused kidneys. As compared with controls, kidneys removed after in vivo administration of oral nabumetone (15 mg/kg) disclosed altered renal function with reduced glomerular filtration rate, filtration fraction, and urine volume and enhanced hypoxic outer medullary tubular damage. By contrast, renal function and morphology were not affected in vivo by nabumetone or its active metabolite 6-methoxy-2-naphthylacetic acid. The latter agent (10–20 mg/kg i.v.) did not significantly alter renal microcirculation, as opposed to a selective substantial reduction in medullary blood flow noted with the nonselective COX inhibitor indomethacin (5 mg/kg i.v.). In a rat model of acute renal failure, induced by concomitant administration of radiocontrast, nitric oxide synthase, and COX inhibitors, the decline in kidney function and the extent of hypoxic medullary damage with oral nabumetone (80 mg/kg) were comparable to a control group, and significantly less than those induced by indomethacin. In rats subjected to daily oral nabumetone for 3 consecutive weeks, renal function and morphology were preserved as well. Both nabumetone and 6-methoxy-2-naphthylacetic acid reduced renal parenchymal prostaglandin E₂ to the same extent as indomethacin. It is concluded that while nabumetone adversely affects renal function and may intensify hypoxic medullary damage ex vivo, rat kidneys are not affected by this agent in vivo, both in acute and chronic studies. COX selectivity may not explain the renal safety of nabumetone.

In a recent study of 1,263 children with acute leukaemia at the Children's Cancer Research Foundation in Boston we observed two patients with undifferentiated leukaemia and multiple neurofibromatosis.5 This frequency is not significantly higher than the estimated incidence of neurofibromatosis in the general population (one case per 2,500-3,300 births).2 The association of neurofibromatosis with leukaemia has occurred in two other children in the same clinic (not in our series) and has been described in three case reports from France.3-5 In one instance the combination of diseases affected siblings.4 The eight reported cases of neurofibromatosis and childhood leukaemia are of great interest, but the evidence is not sufficient as yet to indicate that the high cancer risk in neurofibromatosis extends to leukaemia.-I am, etc., JOSEPH F. FRAUMENI, JR.