Jack S.C. Fong

Hemolytic-uremic syndrome. Current concepts and management.

This article reviews recent observations that help to explain the complex pathogenesis of hemolytic-uremic syndrome, discusses the epidemiology, etiology, and the clinical picture of the syndrome, explores approaches to management, and looks at the few long-term follow-up studies of this difficult disorder.

Thyroid antigen-antibody nephritis.

Abstract A patient with autoimmune thyroiditis developed nephrosis. Light, immunofluorescence, and electron microscopic examination of renal biopsy tissue demonstrated epimembranous nephropathy. Thyroglobulin and thyroid microsomal antigen were demonstrable in her glomeruli by indirect immunofluorescence microscopy.

Treponemal Antigens in Congenital and Acquired Syphilitic Nephritis: Demonstration by Immunofluorescence Studies

Two patients, a 4-month-old infant girl with congenital syphilis and a 45-year-old man with secondary syphilis, had the nephrotic syndrome with glomerulonephritis. Immunoglobulins and treponemal antigenic material were seen in the glomeruli of both patients by immunofluorescence microscopic studies of renal tissue. Electron micrographs showed subepithelial electron dense deposits along the glomerular basement membrane. This confirms earlier suggestions that the renal injury is of an immune-complex type.

Muscle extract infusion in rabbits. A new experimental model of the crush syndrome.

Previous studies provide inconclusive data concerning the nephrotoxicity of myoglobin following muscle injury. We investigated the possibility that released muscle constituents other than myoglobin may be associated with renal damage, and studied accompanying hematological and coagulation changes. An extract of homologous or autologous muscle was infused intravenously in rabbits in a dose of 100 mg of muscle extract protein/kg; equine myoglobin was given to control animals. Experimental animals developed proteinuria, cylindruria, and a 50% reduction in glomemlar filtration rate. Leukopenia, thrombocytopenia and evidence of intravascular coagulation also were seen. The muscle extract was shown to have thromboplastlc activity; however inhibition of this by phospholipase C did not prevent the changes induced by muscle extract infusion possibly because the intrinsic coagulation pathway still was activated. Although moderate hypotension and ECG changes developed in some rabbits, these were not consistent and the renal functional changes appeared to be independent of these factors. Pulmonary and glomerular microthrombi were seen in experimental animals and there was vacuolation of the renal proximal tubular cells. These studies indicate that a number of biological systems are activated following muscle extract infusion and that these may be more important than the nephrotoxicity of myoglobin in the pathogenesis of the renal injury.

Renal injury after muscle extract infusion in rats: Absence of toxicity with myoglobin

A crude muscle extract infused into rats produced oliguria, a precipitous drop in total hemolytic complement, and in circulating white cell and platelets counts. A mild vaso-depressor effects was noted. These changes were not produced by myoglobin or saline infusion. Muscle constituents other than myoglobin are responsible for the systemic and renal nephrotoxic effects observed.

Turner’s Syndrome, 46X, del (X) (p 11), Persistent Complement Activation and Membranoproliferative Glomerulonephritis

An adolescent girl with short stature and learning disability was found to have an unusual variant of Turners syndrome, 46X, del (X) (p 11) and an abnormal urinary sediment. Further studies demonstrated persistent depression of C3 and histologic evidence of membranoproliferative glomerulonephritis (MPGN). The occurrence of MPGN in this case may have been a manifestation of the known tendency for Turner patients to develop immunologic disease.

Colchicine reduces proteinuria in passive Heymann nephritis.

Colchicine was given to rats in the heterologous phase of passive Heymann nephritis to see whether this drug could reduce proteinuria. Treatment with 0.06 mg/day for 14 days caused significant reductions in proteinuria and albuminuria. Administration of dimethyl sulfoxide (DMSO) alone or in combination with colchicine also reduced protein and albumin excretion. In a long-term experiment, rats treated with colchicine had significantly less proteinuria. After stopping therapy, urine protein excretion was similar to controls. No differences in glomerular C3 and IgG deposition were found between treated and control rats 24 h, 3,7 and 14 days after immunization. Depressed serum C3 levels were measured at 24 h in colchicine-treated rats. No difference in serum-circulating immune complexes was detected between the two groups. Concurrent administration of indomethacin and colchicine to rats with passive Heymann nephritis (PHN) partially reversed the reduction in proteinuria and albuminuria seen in rats treated with colchicine alone. The G.F.R, however, was significantly reduced in colchicine-treated rats as well as in rats treated with colchicine and indomethacin. Serum cholesterol and triglyceride levels were significantly lower in colchicine-treated rats than in controls. Serum cholesterol concentrations in rats given both colchicine and indomethacin were similar to control values. These findings suggest that colchicine reduces urine protein and albumin excretion, and hyperlipidemia in PHN. The finding that indomethacin partially blocks the effects of colchicine suggests that renal prostaglandin stimulation by colchicine may have been involved in the reduction in proteinuria.

1617 PREVENTION BY DMSO OF GLOMERULAR INJURY IN NZB|[sol]|WF1 LUPUS MICE

Dimethyl sulfoxide (DMSO) was given to NZB/WF1 lupus mice from 10 weeks of age to see if proteinuria could be prevented in this model of glomerular injury.Twenty mice were randomized into saline (0.1 ml/day) and DMSO treatment groups (DMSO 4 mg/gm/day). Significant differences in urine protein excretion between controls and treated groups were evident at 5 months (DMSO: 5.5 ± 0.46 mg/24 hrs; Controls: 7.35 ± 0.59 mg/24 hrs; p < 0.05) and at 6.5 months of age (DMSO: 6.75 ± 0.73 mg/24 hrs; Controls: 15 ± 2.15 mg/24 hrs; p < 0.01). By 7 and 7.5 months, the protein excretion was not significantly different (DMSO: 18 ± 8.3 mg/24 hrs; Controls: 41 ± 8.7 mg/24 hrs; p > 0.05); 7.5 months: DMSO: 20 ± 7.4 mg/24 hrs; Controls: 29 ± 5.7 mg/24 hrs; p > 0.05. However, the urine protein:creatinine ratio was significantly reduced in DMSO treated mice compared to controls at 6.5 months (DMSO: 13.4 ± 1.32; Controls: 24.4 ± 4.2; p < 0.05), at 7 months (DMSO: 46.7 ± 23; Controls: 101 ± 28; p < 0.05), and at 7.5 months of age (DMSO: 37 ± 13; Controls: 88 ± 31; p < 0.05). The mean serum creatinine values were significantly lower at 7.5 months of age in DMSO treated mice (0.41 ± 0.08 mg/dl) compared to controls (0.91 ± 0.56 mg/dl; p < 0.05). By 7.5 months of age, 5/6 treated mice had relatively normal renal histology on light microscopy, while 6/8 untreated had focal proliferative glomeruloneprhtis, crescents and glomerular obsolescence (p <0.02).These findings demonstrate that DMSO has a protective effect on the progression of glomerular injury in this model.

COLCHICINE AND DMSO AS PROBES FOR STUDYING PROTEINURIA IN PASSIVE HEYMANN NEPHRITIS

In previous studies, we have shown that DMSO reduces proteinuria in passive Heymann nephritis (PHN). We have now extended these studies to include the use of colchicine (C), a known inhibitor of microtubule function. In addition, colchicine alters the shape of glomerular epithelial cells. Rats were treated with saline (controls) or C (0.05 mg/kg/d i.p. × 28 days). Controls excreted 105 ± 22 and C-treated rats, 37 ± 6 mg/d, p <0.05. Onset of treatment during the autologous phase did not reduce proteinuria. Concomittant treatment with indomethacin abolished the beneficial effect of C. Whereas low doses of DMSO alone, and C alone reduced proteinuria, a combination of the same doses of C plus DMSO provided no added advantage over each alone. These studies demonstrate that C and DMSO can reduce proteinuria in PHN possibly via a common mechanism. We have thus identified two probes which may be useful in studying the pathogenesis of proteinuria in this model.

Thrombocytopenia in Hemolytic-Uremic Syndrome

Thrombocytopenia, unlike acute hemolysis and acute nephropathy, does not occur in every patient with hemolytic uremic syndrome (HUS). The mechanism whereby thrombocytopenia occurs is not known, the pathogenetic role of platelets in HUS has not been clearly defined, the duration of thrombocytopenia is variable and the level to which the platelets fall has no prognostic value (1–3). Thrombocytopenia, however, is such a dramatic laboratory observation that much attention has been directed at this finding and, although the role of platelets in the pathogenesis of HUS has been unclear, a variety of therapeutic agents has been advocated on the assumption that normalization of the platelet count may be beneficial. None, unfortunately, has of value and enthusiasm has waned for the use of heparin, aspirin and dipyridamol (4–11).