Herbert S. Diamond

Evidence for a Postsecretory Reabsorptive Site for Uric Acid in Man

The effects of administration of drug combinations on uric acid excretion were studied in order to test the hypothesis that a portion of renal tubular reabsorption of uric acid occurs distal to the uric acid secretory site. Oral administration of pyrazinamide (3 g) during probenecid uricosuria (probenecid 500 mg every 6 h) decreased urate excretion from 463 mug/min following probenecid medication alone to 135 mug/min following probenecid plus pyrazinamide (P < 0.01). When a greater uricosuric effect was induced with a 2 g oral dose of probenecid, the decrement in urate excretion which followed pyrazinamide administration (3 g) was more pronounced (2,528 mug/min following probenecid alone, 574 mug/min following probenecid plus pyrazinamide). Results were similar when an 800 mg oral dose of sulfinpyrazone was given in place of probenecid (1,885 mug/min following sulfinpyrazone alone, 475 mug/min following sulfinpyrazone plus pyrazinamide). Thus, apparent urate secretion (measured as the decrease in excretion of urinary uric acid resulting from pyrazinamide administration) appeared to vary, depending upon the degree of inhibition of reabsorption produced by probenecid or sulfinpyrazone. When small doses of aspirin were administered in place of pyrazinamide to produce secretory inhibition, the results were similar. Neither probenecid nor pyrazinamide significantly altered urate excretion when administered to patients with serum salicylate levels above 14 mg/100 ml. These results are interpreted as suggesting that renal tubular reabsorption of uric acid occurs at least in part at a postsecretory site and that a portion of secreted urate is reabsorbed. During maximum probenecid- or sulfinpyrazone-induced uricosuria, inhibition of urate secretion with either pyrazinamide or low doses of aspirin resulted in a decrease in uric acid excretion which exceeded total urinary uric acid during control periods by two- to fourfold. This suggests that renal tubular secretion of urate may greatly exceed uric acid excretion and that a large fraction of secreted urate is reabsorbed. The pyrazinamide suppression test underestimates urate secretion. Uricosuria induced by some drugs, including probenecid, sulfinpyrazone, and iodinated radioopaque dyes, appears to represent, at least in part, inhibition of postsecretory urate reabsorption.

Progression of Mesangial and Focal to Diffuse Lupus Nephritis

Abstract The finding of a focal glomerular lesion in systemic lupus erythematosus has been considered a good prognostic sign because the disease rarely progresses to a more severe histologic lesion and renal insufficiency. In 7.5 years, 110 of 165 such patients evaluated had clinical renal involvement, with biopsy in 69; 31 had a mesangial or focal lesion, 24 diffuse nephritis, and 14 membranous nephritis. The renal status of nine patients with an initial mesangial or focal lesion deteriorated one to 12 years later and progressed to diffuse nephritis. There was no difference between the groups with and without histologic progression in clinical severity of disease at the time of first biopsy, nor in the initial pattern of immunofluorescent or electron microscopical deposits within the glomerulus. It appears that mesangial, focal, and diffuse nephritis represent a continuum of increasingly advanced renal disease in systemic lupus erythematosus. (N Engl J Med 291:693–696, 1974)

Exacerbation of systemic lupus erythematosus after withdrawal of azathioprine therapy.

Abstract In a controlled clinical trial of withdrawal of long-term azathioprine medication from nine patients with systemic lupus erythematosus, exacerbation of the disease occurred in seven of the...

Human cartilage lysozyme

The lysozyme content of human cartilage was measured by incubation of lyophilized, powdered cartilage in a variety of buffers and salt solutions, and the factors controlling the binding of lysozyme within cartilage were studied. Lysozyme was extracted from hyaline cartilage by buffers of pH greater than 9.0 by solutions 1 M in monovalent cations, and by solutions 0.12-0.40 M in divalent cations. The ability of cations to extract lysozyme from cartilage agreed with their known affinities for binding to chondroitin sulfate. The total extractable lysozyme content of five samples of human costal cartilage ranged from 1.45 to 3.36 mug lysozyme per mg of cartilage; for five samples of hyaline cartilage from peripheral joints the range was 0.80-3.03 mug lysozyme per mg of cartilage. Cartilage incubated in excess exogenous lysozyme could bind 0.053 equivalents of lysozyme per equivalent of chondroitin sulfate. Fibrocartilage and synovium from knee joints yielded no detectable lysozyme, despite the fact that synovium, a tissue rich in lysosomes, contained measurable quantities of beta-glucuronidase. Lysozyme extraction from cartilage was not augmented by incubation with streptolysin S. When incubation was carried out with mild extraction techniques, lysozyme extraction from cartilage tended to parallel uronic acid release, both as a function of time and from one specimen to another. The active material as lysozyme. Lysozyme occurs in human hyaline cartilage as a counterion to polyanionic glycosaminoglycans. Carextracted from cartilage met five criteria for identification tilage lysozyme appears to be extracellular and nonlysosomal. Degradation of cartilage may contribute to the increased serum and synovial fluid lysozyme levels often present in patients with rheumatoid arthritis.

Hyperuricosuria and increased tubular secretion of urate in sickle cell anemia.

Seven young adults with uric acid overproduction due to sickle cell anemia were normouricemic with a mean serum uric acid level of 4.9 mg/100 ml. Urate clearance was greater in these patients than in normal subjects or in patients with primary hyperuricemia due to uric acid overproduction. The increase in urate clearance was entirely accounted for by increased pyrazinamide suppressible urate clearance. Pyrazinamide administration abolished the uricosuric response to ribonucleic acid (RNA) feeding in these patients with sickle cell anemia, and maximal uricosuric response to the administration of probenecid was similar in the patients with sickle cell anemia and in normal subjects suggesting that reabsorption of both filtered and secreted urate was not impaired in sickle cell disease. Pyrazinamide suppressible urate clearance at maximal uricosuric response to probenecid was increased in patients with sickle cell disease suggesting increased tubular secretion of urate. This increase in urate secretion permits most young adults with urate overproduction due to sickle cell anemia to remain normouricemic and may account for the low frequency of secondary gout in this disease.

The Natural History of Urate Overproduction in Sickle Cell Anemia

Serum uric acid and uric acid excretion were studied in 95 patients with sickle cell anemia ranging in age from 17 months to 45 years to ascertain the natural history of urate overproduction. Hyperuricemia was infrequent in children with sickle cell anemia, but was found in 26 of 67 adults (39%). Thirty-six patients studied in a clinical research center had a mean urate clearance of 9.1 +/- 0.8 mL/min. Patients with sickle cell anemia were often normouricemic despite urate overproduction. Normouricemia was maintained by increased urate clearance, which was attributed to increased urate secretion. The hyperuricemic patients had decreased urate clearance with decreased pyrazinamide-suppressible urate clearance. Para-aminohippurate clearance was decreased to 634 mL/min in the hyperuricemic patients with sickle cell anemia compared with 853 mL/min in normouricemic hyperuricosuric subjects with sickle cell anemia. Hyperuricemia occurs only in patients who develop altered renal tubular function with diminished urate clearance secondary to diminished urate secretion.

Pregnancy and azathioprine in systemic lupus erythematosus

Five patients with systemic lupus erythematosus were receiving long-term azathioprine treatment (2.5 mg. per kilogram per day) at the time of conception. In two patients, azathioprine was discontinued prior to the twelfth week of pregnancy and they both aborted. Three patients who continued azathioprine throughout the pregnancy delivered four normal-but small-babies. Karyotype examinations, intelligence testing, and specific neurologic evaluation for the commoner forms of malformation have shown no abnormalities in any of the four babies at birth or at one-year intervals thereafter. It appears that azathioprine in our patients had no teratogenic effect.

Renal handling of uric acid in sickle cell anemia.

Hematologic disorders which result in increased cell turnover rates are frequently associated with hyperuricemia and secondary gout due to increased uric acid synthesis. Although sickle cell anemia is characterized by a 6–8 fold increase in red cell turnover, gout is thought to be an uncommon complication of this disease. Since impaired renal concentrating ability is a common and early manifestation of sickle cell disease, and other defects of renal tubular transport such as diminished tubular maxima for PAH and renal tubular acidosis have been described, the present study was designed to investigate tubular transport of urate in sickle cell anemia, and to evaluate the hypothesis that hyperuricosuria due to defective renal tubular transport of urate might protect sickle cell anemia patients against gout.

Hyperuricosuria in the Fanconi syndrome.

A patient with asymptomatic adult Fanconi syndrome with glycosuria, amino-aciduria, hypophosphatemia, and renal tubular acidosis was found to have hypouricemia (serum uric acid, 1.5-1.8 mg/100 ml) secondary to increased renal clearance of urate (urate clearance/glomerular filtration rate, 32 per cent). Increased urate clearance in this patient with multiple reabsorptive defects probably represents diminished urate reabsorption. Consistent with this, the uricosuric response to probenecid was diminished. Reabsorption of filtered urate appeared to be intact. Inhibition of urate secretion with pyrazinamide completely suppressed the uricosuria in this patient, suggesting that increased urate clearance was due to either enhanced secretion or diminished reabsorption of secreted urate. There was no direct evidence for increased urate secretion. The response of urate excretion to pharmacologic inhibitors of tubular transport of urate differs in various clinical states associated with hyperuricosuria. The responses may reflect different mechanisms of hyperuricosuria.

Recent advances in rheumatic diseases: the connective tissue diseases other than rheumatoid arthritis--1970 and 1971.

Abstract The most significant developments of clinical and pathophysiological interest in the connective tissue diseases (other than rheumatoid arthritis) during 1970 and 1971 are reviewed, with di...