Infection in immunosuppressed transplant recipients.
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Biomedical subjects
Publications and source records attributed to S M Mauer.
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Pancreatic tissue fragments from neonatal inbred Lewis rats were distributed throughout the peritoneal cavities of isologous diabetic recipients receiving prednisolone on a schedule similar to that used in clinical transplantation beginning 9-44 days before transplantation. Plasma glucose levels in six of seven diabetic rats receiving prednislone returned to normal levels 3 weeks after transplantation. Plasma insulin levels in the animals with successful transplants reached, at 1 week after transplantation, levels measured in normal control rats, but never attained the high insulin levels observed in the normal control animals receiving steroids. As with glucose the insulin levels remained in the normal range, and the animals steadily gained weight. During i.v. glucose tolerance tests (IVGTTs) in the rats with successful transplants at 4, 11-14, and 26-29 weeks after transplantation, the glucose levels were similar to those observed during IVGTTs in the control animals before and during corticosteroid therapy. In contrast, insulin levels during the IVGTTs were lower in the rats with successful transplants than in the control rats with or without steroids; however, insulin release during the IVGTTs was rapid in all animals, both with successful transplants and controls. These observations demonstrate that islet tissue implanted in the peritoneal cavities of diabetic rats receiving immunosuppressive chronic corticosteroid therapy can respond with a rapid and sufficient release of insulin to reverse diabetes as documented by normal glucose levels under stimulated and nonstimulated conditions.
Diabetes was induced in Lewis rats with streptozotocin. Six to eight months later glomeruli showed mesangial thickening: IgG, IgM and C3 were seen in large quantities in the mesangium by immunofluorescent microscopy. Ten animals then had successful pancreatic transplantation resulting in normal glucose and insulin levels within one to three weeks. Biopsies obtained within the first two weeks following transplantation demonstrated a significant reduction in mesangial thickening and in mesangial staining for IgG, IgM and C3. Three to four weeks after transplantation C3 staining was no longer detected. A gradual reduction in mesangial IgG and IgM localization continued so that by nine weeks following islet transplantation only minimal staining for immunoglobulins was present. Although mesangial thickening was reduced, this abnormality could still be detected in most animals six to nine weeks after transplantation. Three rats showed improvement in glomerular morphology within two weeks despite persistent hyperglycemia. These rats had normal insulin levels at this time. Islet transplantation in inbred diabetic rats effectively returns glucose and insulin levels to normal and results in rapid regression of the light microscopic and immunopathologic glomerular lesions. These studies support the concept of reversible mesangial dysfunction in diabetic rats.
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Unilateral renal perfusion with the aminonucleoside of puromycin (60 mg. per kilogram) was used to produce unilateral renal disease in rats characterized by marked proteinuria, hypoalbuminemia, and hypercholesterolemia. Urine albumin excretion increased from 0.21 plus or minus 0.16 mg. per 24 hours prior to perfusion to 126 plus or minus 30 mg. on the fourteenth day after perfusion. If the perfused kidney was removed after 10 days, urine albumin excretion immediately decreased to normal, whereas marked proteinuria continued after contralateral nephrectomy. Immunofluorescent studies revealed abundant protein reabsorption droplets (beta1C and albumin) in proximal tubules of aminonucleoside-perfused kidneys but not in contralateral kidneys thus indicating that the increased proteinuria was of unilateral origin. Less marked proteinuria was observed following unilateral renal perfusion with lower doses of aminonucleoside. Glomerular mesangial function was studied 10 days after renal perfusion. Renal specimens were obtained 12 hours after intravenous injection of 37.5 mg. per 100 Gm. of body weight of aggregated human IgG and evaluated by immunofluorescent microscopy. Glomerular mesangial staining for human IgG in aminonucleoside-perfused kidneys was markedly increased when compared to contralateral kidneys. In contrast, mesangial staining in kidneys perfused with saline was equal to that of contralateral kidneys and proteinuria following perfusion with saline was not increased. These studies provide further evidence that increased proteinuria following administration of aminonucleoside to rats is the result of a rapid direct on the kidney and that alterations of glomerular mesangial function are related to renal factors rather than changes in systemic milieu.
Five life threatening complications of percutaneous femoral vein catheterization for hemodialysis (Shaldon Technique) are presented. They occurred over a period of five years during which 700 uneventful catheterizations were carried out. In three instances femoroiliac vein thrombosis occurred, and on one occasion this was complicated by pulmonary embolism. In two other instances perforation of the inferior vena cava occurred with profuse bleeding. These complications can be aboided by early removal of the catheters after dialysis and by cautiously manipulating the wireguide when resistance or obstruction is encountered during insertion.
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Thirteen children, aged between one and five years, received transplants and 11, all related-donor recipients, are alive (mean follow-up 2.2 yr). Five had congenital nephrotic syndrome, 5 had hypoplastic-dysplastic kidneys and one each had polycystic kidneys, nephroblastoma and glomerulonephritis. One child died of peritonitis and one died following irrevocable rejection. Two children required retransplantation. The present serum creatinine of the survivors is 0.67 +/- 0.23 (x +/- SD)mg/100ml. Eight of the 11 survivors have shown catch-up growth. Thus we conclude that related-donor transplantation is warranted in children having reached the age of one year and six kilograms in body weight.
Transplantation of islets of Langerhans into the peritoneal cavity of diabetic rats returns the recipients to a normal metabolic state and provides the capability to respond to a glucose stimulation with a rapid release of insulin. Of the two groups of transplanted diabetic rats studied, each had normal nonfasting glucose levels and normal glucose profiles following intravenous glucose tolerance tests. However, one group had significantly lower insulin levels than normal controls both under nonfasting conditions and 4 minutes following glucose stimulation. The other group demonstrated insulin levels greater than those of the normal controls when drawn under nonfasting conditions and essentially identical to the levels of the normal controls following a glucose load. Each transplanted group responded similarly to normal rats with a rapid release of insulin following glucose administration.
Immunoglobulins and complement are deposited in the glomerular mesangium of rats with progressive glomerulosclerosis secondary to chemically induced diabetes mellitus. Isotransplantation of a kidney from a rat diabetic for 6 mo into a normal recipient results within 2 mo in the disappearance of IgG, IgM, and beta(1)C from the mesangium and arrest or reversal of the light microscopic glomerular lesions. Kidneys isotransplanted from normal donors into diabetic rats developed mesangial matrix thickening and deposition of IgG, IgM) and beta(1)C in the mesangium. No glomerular changes occur upon transplantation of a normal kidney into a normal rat. These findings indicate that diabetic glomerular changes in the rat are reversible and are secondary to the diabetic state rather than to the inducing agent.
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These studies were designed to explore the effects of nephrotoxic serum (NTS) in rats on the uptake and processing by the glomerular mesangium of intravenously administered protein macromolecules (radiolabeled aggregated human IgG, [125I]AHIgG). Measurements of [125I]AHIgG levels in preparations of isolated glomeruli correlated well with qualitative estimates of glomerular IgG deposition seen by immunofluorescent microscopy. Rats given 2 ml NTS received 25 mg/100 g body wt [125I]AHIgG 48 h later and were sacrificed at varying time intervals thereafter. NTS-treated animals demonstrated a marked increase in glomerular uptake of [125I]AHIgG as compared with concurrent controls but a normal ability to clear [125I]AHIgG from the mesangium over 72 hr. Animals given 1.0, 0.5, and 0.25 ml NTS had neither proteinuria nor significant light microscopic changes, yet had increased uptake of [125I]AHIgG of 4.4, 3.0, and 2.1 times control values, respectively at 8 h after the infusion of aggregates. Rats given 1 ml NTS and 12.5, 6.25, and 3.125 mg [125I]AHIgG/100 g body wt had increased glomerular uptake at 8 h, but there was, within both NTS and control groups, a disproportionate decrease in uptake at lower [125I]AHIgG doses. Rats given cobra venom factor (CoF) followed by a NTS shown to be complement dependent (proteinuria reduced by prior complement depletion with CoF) had less mesangial [125I]AHIgG uptake than NTS controls but greater uptake compared with normal controls. CoF itself had no effect on mesangial or reticuloendothelial system [125I]AHIgG uptake. These studies demonstrate a striking change in glomerular mesangial activity after fixation of nephrotoxic antibodies to the glomerular basement membrane, even in the absence of proteinuria and suggest that subtle alterations of the filtration surface can influence mesangial function. The effect of NTS on the mesangium is due, in large part, to the glomerular injury and proteinuria which nephrotoxic antibodies produce.
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