Michael C. Gelfand

The Glomerular Complement Receptor in Immunologically Mediated Renal Glomerular Injury

We examined 25 renal-biopsy specimens to determine whether there is a relation between immunologically mediated renal diseases and the activity of complement receptors that selectively bind antigen-antibody complexes containing activated third component of complement (C3b). These receptors have been termed glomerular complement receptors. Renal lesions associated with in vivo deposition were associated with a loss of receptor sites as demonstrated by reduced or absent in vitro binding of C3b-coated test reagents by glomerular complement receptor. These findings suggest that binding of complement containing immune complexes to glomerular complement receptors in human subjects may participate in the immunopathologic processes of certain immune-complex-mediated renal diseases.

The natural history and immunopathology of outbred athymic (nude) mice

Abstract An original colony of inbred athymic (nu/nu) mice on a BALB/c background was crossbred with outbred Swiss NIH mice to obtain a line of greater health, vigor, and fertility. Outbred nu/nu mice remain healthy and active under laboratory conditions up to 1 yr without resorting to antibiotic treatment, and can be raised successfully using either nu/nu or nu/+ mothers. The histopathology of these mice as well as their lymphoid surface markers and mitogen responsiveness confirms their “T-less” state. Unlike inbred athymic strains, they show no evidence of autoantibody formation and they have almost normal levels of IgA. They freely accept skin allografts throughout their life but do develop θ positivity and the ability to reject skin allografts after allogeneic thymic transplants. Of particular interest were elevated IgM levels and greatly elevated splenic IgM PFC background activities to a variety of synthetic chemical haptens. The cause of death of these mice was almost invariably due to extensive hepatic necrosis and fibrosis. In the total population at risk of over 1000 nu/nu mice, at least 150 of which were followed until 1 yr of age, not one spontaneous de novo cancer was noted.

QT prolongation and near fatal cardiac arrhythmia after intravenous tacrolimus administration: a case report.

BACKGROUND The use of immunosuppressant agents is mandatory in the long-term management of transplant recipients. Herein, we report a case of near fatal cardiac arrhythmia related to the use of intravenous tacrolimus in a 35-year-old woman undergoing renal transplantation. METHODS The patient had no previous history of cardiac disease, but an initial electrocardiogram demonstrated slightly prolonged QT and QTc intervals and normal sinus rhythm. Postsurgical immunosuppression included intravenous tacrolimus and methylprednisolone. During intravenous tacrolimus infusion, marked QT prolongation occurred. The patient suffered recurrent runs of torsade de pointes, refractory to aggressive medical management and requiring numerous defibrillations. Rapid atrial pacing eventually controlled the arrhythmia. RESULTS We note not only a temporal association, but also a direct linear relationship, between this arrhythmia and blood tacrolimus levels. CONCLUSION We believe this case presents a little recognized hazard associated with the use of intravenous tacrolimus and points to the need for careful predrug screening for QT prolongation. Tacrolimus has been shown to effect intracellular calcium and to prolong the action potential duration experimentally. This suggests that an increase in the intracellular calcium may underlie torsades de pointes associated with intravenous tacrolimus.

Captopril-Associated Cholestatic Jaundice

Captopril, the competitive inhibitor of angiotensin-converting enzyme, is of considerable benefit in difficult-to-manage forms of hypertension. Its use has been associated with various untoward effects, but hepatic injury has not been widely reported. We treated a patient with captopril-associated cholestatic jaundice; a review of cases reported to the drug manufacturer and a review of the literature showed 13 additional cases of hepatic injury associated with captopril. In 9 of these the jaundice was categorized as cholestatic, and in 4 of the remaining 5 as mixed cholestatic-hepatocellular. These findings show that jaundice may be an idiosyncratic side effect of captopril, and that captopril-associated jaundice characteristically has strongly cholestatic features.

Binding sites for immune complexes containing IgG in the renal interstitium.

Abstract In immunologically mediated interstitial renal disease, immunoglobulin and complement are often localized in involved areas of the kidney. The mechanism by which these immune components localize in renal tubulo-interstitial sites is not known. Here, we describe the presence of binding sites for the Fc fragment of IgG in the renal interstitium of man and in a variety of other species. These binding sites were demonstrated in vitro by the specific adherence of IgG-coated sheep or human red blood cells to frozen sections of renal tissue. Binding was specifically blocked by IgG and not by IgM, IgA, or other human and animal proteins. Reagent RBC coated with the (Fab′)2 fragment of IgG were not bound. In contrast to the previously described human glomerular complement receptors, these interstitial IgG-Fc receptors are present in man and in all animal species studied. Such receptor sites may be involved in the deposition of antigen-antibody complexes in renal interstitial areas.

Will Hemoperfusion Be Useful for Cancer Chemotherapeutic Drug Removal

One of the major problems in clinical cancer chemotherapy is the inability to safely administer full therapeutic doses of specific drugs in the face of dysfunction of an organ system controlling that drugs metabolism and excretion. Should efficient drug removal from blood be possible following full therapeutic doses and after tumor exposure, then theoretically, even in the presence of organ dysfunction, anticancer drug toxicity may be reduced or avoided. Preliminary experiments in our laboratory have shown that adriamycin may be efficiently removed by activated charcoal from aqueous and protein solutions and blood in vivo, and that daunorubicin is removed in vitro to the same extent. However, although methotrexate is removed efficiently in vitro and extracted 50% in vivo by charcoal hemoperfusion, its overall pharmacokinetics do not appear to be altered in comparison with the alteration in pharmacokinetics of adriamycin achieved with charcoal hemoperfusion. Computer modeling has suggested that efficient adriamycin removal is achievable, and that clinical studies are warranted. For methotrexate removal, however, previous clinical studies and our own data suggest that charcoal hemoperfusion has little utility unless a highly specific sorbent for methotrexate removal can be developed.

Ontogeny of B lymphocytes: I. In vitro appearance of Ig-bearing lymphocytes

Abstract During the immediate postnatal period, a striking increase in the fraction and number of splenic lymphocytes which bear easily detectable surface immunoglobulin (Ig) occurs in BALB/c and CDF1 mice. Thus, in mice

Cooperation of three lymphoid cells in allograft rejection

Abstract The lymphoid cell subpopulations mediating first set skin allograft rejection were studied in NZB/W and BALB/c mice. Recipient mice were deficient in skin allograft rejection by spontaneous loss of recirculating T cells and splenectomy (NZB/W) or corticosteroid pretreatment and splenectomy (BALB/c). Prompt primary allograft rejection could be restored in these immunologically deprived recipients by injection of syngeneic lymphoid cells. In each strain at least three different populations of lymphoid cells were required for prompt primary allograft rejection: two T cells and a B cell. These studies suggested that a recirculating T cell cooperates with a sessile splenic T cell as well as a B cell. The studies do not indicate in which population (s) specificity might reside.

Proliferation of mouse bone marrow-derived lymphocytes in vitro: One mechanism of response to concanavalin A and phytohemagglutinin

In mixed populations of mouse thymus-derived (T) and bone marrow-derived (B) lymphocytes, both T and B cells proliferate in response to soluble phytohemagglutinin (PHA) and conconavalin A (Con A). We have investigated one mechanism of the B cell proliferative response in vitro to Con A and PHA. Thymocytes (THY) were mitogen pulsed with Con A or PHA and metabolically poisoned with mitomycin C and cycloheximide. Mitogen-pulsed, inhibitor-poisoned THY were used to stimulate relatively pure preparations of B cells. We have shown that T cell surface-bound mitogen itself directly stimulates B cells to proliferate in vitro . In our system T cell surface-bound mitogen is relatively more important than blastogenic mediator production by mitogen coated THY in the stimulation of B cell proliferation. We propose that, in mixed populations of T and B cells cultured with soluble mitogens, mitogen bound to T cell surfaces plays a major role in the stimulation of B cell proliferation.

Charcoal Hemoperfusion: Georgetown University Hospital Experience

At Georgetown University Hospital, interest in charcoal hemoperfusion as a means of facilitating toxin removal from blood has shown a doubled peaked history. After the pioneering work of Yatzidis, et al (1) in 1965 in the treatment of barbiturate poisoning, DeMyttenaere, Maher, and Schreiner in 1967 demonstrated the effectiveness of charcoal hemoperfusion in the treatment of glutethimide overdosage in dogs (2). Unfortunately, because of the significant and potentially life threatening dangers of thrombocytopenia and charcoal embolization, charcoal hemoperfusion was not pursued as an attractive therapeutic modality for toxin removal in clinical practice.