New avian model of experimental glomerulonephritis consistent with mediation by cellular immunity. Nonhumorally mediated glomerulonephritis in chickens.

The present study examined the role of cell-mediated immunity (CMI) in the production of experimental autoimmune glomerulonephritis (EAG) in chickens deficient in humorally mediated immunity (HMI). Cyclophosphamide bursectomized (Bsx) and normal control chickens were used. Bsx chickens were used only if they had severe depression of HMI, which was evidenced by marked reduction in bursal weights (0.89 +/- 0.23 vs. 2.92 +/- 0.9 g), decreased serum IgG to less than or equal to 10% of normal, and total lack of HMI to immunization with sheep red blood cells. EAG was produced by immunizing chickens with bovine glomerular basement membrane (GBM) in complete Freund's adjuvant. CMI manifested by wattle thickness increments to PPD was not different, 3.89 +/- 0.45 mm for Bsx compared with 3.73 +/- 0.75 mm for controls. No circulating antibodies to GBM developed in 68% of Bsx chickens, and the anti-GBM titers were less than 1:312 in those Bsx chickens positive for antibody compared with greater than 2,000 for controls. GBM deposits of IgG by fluorescence were much decreased, 0.53 +/- 0.16 compared with 2.19 +/- 0.32 for controls, and were absent in 64% of Bsx chickens. Nonetheless, proliferative nephritis with crescents was present and was even more severe in Bsx chickens than in controls, with glomerular sizes of 20.8 +/- 0.6 U for Bsx-GBM, 19.8 +/- 1.2 for control-GBM, 14.9 +/- 1.5 for Bsx, and 13.6 +/- 0.8 for normal chickens. Nephritic eluates did not produce disease in normal chickens, while administration of sensitized cells with [H3]thymidine to naive birds was associated with increased mesangial grain counts by autoradiography. These findings suggest that CMI plays a major role in the pathogenesis of EAG in chickens in the absence of HMI. By implication, CMI may be crucial in the development of other types of glomerulonephritis as well.

Massive proteinuria and acute renal failure in a patient with acute silicoproteinosis.

Acute pulmonary silicoproteinosis, massive proteinuria and fatal renal failure developed in a 23 year old male sandblaster. Examination of the kidney by immunofluorescence revealed granular deposits of immunoglobulin M (IgM) and the third component of complement (C3) along the glomerular basement membrane. Light microscopy disclosed mild proliferative glomerulonephritis with loss of colloidal iron staining for sialoprotein, and electron microscopy disclosed an increased density of epithelial cytoplasm, altered lysosomes and endothelial cell microtubular structures. The silicon content of the kidney was 264 parts per million (ppm), but particles of silicon were not demonstrated by electron microscopy. No primary or systemic causes of renal diseases were elucidated. The renal dysfunction apparently resulted from acute renal silicon toxicity, a new complication of acute pulmonary silicoproteinosis.

Ventriculojugular shunt nephritis with Corynebacterium bovis. Successful therapy with antibiotics.

A patient with hydrocephalus and a ventriculojugular shunt presented with acute nephritis, nephrotic syndrome (proteinuria 10 g/24 hours), decreased complement levels, circulating immune complexes and diminished creatinine clearance (41 ml/min). Seven blood cultures grew Corynebacterium bovis. A renal biopsy specimen revealed mesangiocapillary glomerulonephritis by light microscopy, and thickened glomerular basement membranes with areas of increased granular density by electron microscopy. Immunofluorescent examination of the biopsy specimen demonstrated 2+ granular glomerular basement membrane deposits of immunoglobulin M (IgM), with trace third component of complement (C-3), fourth component of complement (C-4) and immunoglobulin G (IgG). Rabbits immunized with C. bovis produced a line of partial identity in agar with patient serum against a sonicate of C. bovis. Indirect fluorescein staining of the biopsy specimen with the rabbit antiserum demonstrated 1+ granular glomerular basement membrane deposits. Potassium thiocyanate microelution of sections prior to examination markedly diminished staining with antihuman antiserum, but did not affect staining with rabbit antiserum. Following initial therapy with intravenous penicillin for six weeks the bacteremia cleared, serum complement levels returned to normal, proteinuria decreased and creatinine clearance increased. A relapse occured four weeks later with decreased complement levels, increased proteinuria and decreased creatinine clearance. Blood cultures were again positive for C. bovis. Following therapy with erythromycin and rifampin, the bacteremia cleared and there was a sustained improvement of all parameters. To our knowledge, this is the first time an association has been noted between C. bovis ventriculojugular shunt infection and glomerulonephritis. These findings support the potential role of C. bovis as an etiologic agent in human renal disease and further define the immune complex nature of shunt nephritis.

Therapy of the idiopathic nephrotic syndrome with alternate day steroids.

Eighty-one adult patients with the idiopathic nephrotic syndrome were treated with prednisone, 60 to 120 mg, on alternate days. Treatment was continued with diminishing drug doses for up to 10 years. Biopsy specimens were categorized as showing lipoid nephrosis 36 per cent, focal sclerosis 12 per cent, diffuse proliferative 22 per cent and membranous nephropathy 30 per cent. Patients with systemic causes of the nephrotic syndrome were excluded. Proteinuria decreased to normal or to less than or equal to 3 g with a greater than or equal to 50 per cent decrease from base line in 83 per cent of the patients with lipoid nephrosis, 30 per cent of the patients with focal sclerosis, 50 per cent of the patients with diffuse proliferative nephritis and 71 per cent of the patients with membranous nephropathy. Improvement occurred in those with focal sclerosis, diffuse proliferative nephritis and membranous nephropathy only after prolonged treatment (14 to 15 months). Stable or improved renal function occurred in 97 per cent of those with lipoid nephrosis, 50 per cent of those with focal sclerosis, 73 per cent of those with diffuse proliferative nephritis and in 83 per cent of those with membranous nephropathy. Death or dialysis occurred in 12 per cent of the patients, and complications coincident with treatment occurred once every 12 patient years. Compared to other series of patients with the idiopathic nephrotic syndrome, therapy of our patients with prolonged alternate day steroids resulted in (1) decreased protein excretion, (2) maintenance of good renal function and (3) decreased number of complications of therapy.

Cold-reactive alloantibodies and allograft malfunction occurring immediately posttransplant.

Certain kidney allografts function promptly, whereas others subjected to similarly optimal procurement and preservation methods do not. Previous reports have indicated that such unexplained allograft malfunction (AM) could be due to the presence of cold-reactive IgM alloantibodies (i.e., lymphocytotoxins and agglutinins) present in renal transplant recipients. These investigations were undertaken to determine whether the presence of such alloantibodies was associated with any histological abnormalities. Pretransplant and 1-hr posttransplant biopsies were analyzed from 49 cadaveric renal allografts that came from ideal donors and were subjected to "optimal" preservation. First, no correlation could be made between AM and the severity of renal tubular cell disruption. However, glomerular lesions in the posttransplant biopsy correlated significantly with the development of AM. Segmental glomerular intracapillary red blood cell aggregates and fibrin deposition were present in 71% of biopsies in the 21 allografts with AM, whereas such lesions were present in 29% of biopsies in the 28 allografts with immediate function (P less than 0.005). Development of glomerular lesions correlated significantly with the presence of cold-reactive lymphocytotoxins (CRL) in the recipient (60% vs. 9%). Sera containing CRL were found to also have IgM antiendothelial cell antibody. These observations suggest that another possible mechanism for lack of prompt allograft function is a self-limiting vascular injury, that occurs in the cold and is immune-mediated.

Transforming growth factor-beta levels in human allograft chronic fibrosis correlate with rate of decline in renal function.

BACKGROUND: Long-term renal transplant function is limited primarily by a progressive scarring process loosely termed "chronic rejection, chronic allograft nephropathy, or allograft fibrosis." Although the etiology of transplant fibrosis is uncertain, several possible factors including chronic cyclosporin A (CsA) exposure may contribute to its pathogenesis. CsA stimulates renal fibrosis perhaps through the induction of the potent pro-sclerotic growth factor, transforming growth factor beta (TGFbeta). Previously, we demonstrated that, in human transplant biopsies, acute CsA toxicity but not acute tubular necrosis is associated with elevated levels of renal TGFbeta protein. We now examine whether long-term CsA treatment (>1 year) is associated with elevated levels of intra-allograft TGFbeta and whether heightened expression of TGFbeta is clinically significant. METHODS: Using immunohistochemical techniques, we determined the relative level of expression of intrarenal TGFbeta protein in transplant biopsies. We studied biopsies obtained from 40 CsA-treated patients that were diagnosed as having chronic allograft fibrosis. Biopsies were scored as having minimal or high levels of TGFbeta. RESULTS: Seventy-two percent of patients expressed high levels of intra-allograft TGFbeta. This group of patients lost renal function at an average rate of -19.5+/-17.3 ml/min/year. In contrast, patients with minimal or no TGFbeta expression experienced a decline of only -6.2+/-4.1 ml/min/year (P=0.01). CONCLUSIONS: These results suggest that the majority of CsA-treated patients with biopsy proven chronic fibrosis have elevated levels of intra-graft TGFbeta that correlates with an increased rate of decline in renal function.

Isolated xanthomatosis of the small bowel.

A case of xanthomatosis of the small bowel is described. Beginning with the proximal jejunum, an 85-cm segment of small bowel was distorted by regularly spaced nodular accumulations of lipid-laden macrophages that expanded the submucosa and muscularis and extended to the serosal surface. The conditions often associated with xanthomatosis were not found in this patient.

Congo red-negative amyloidosis-like glomerulopathy.

Three cases of amyloidosis-like glomerulopathy are presented in which renal amyloidosis was initially diagnosed on the basis of ultrastructural findings, despite negative Congo red staining. The histologic and immunofluorescence findings and, on careful examination, ultrastructural features of this amyloidosis-like glomerulopathy all serve to distinguish it from true amyloidosis. The clinical behavior suggests that it is a primary glomerulopathy since, with time, no other systems become involved.

Influence of the interview on the evaluation of applicants to medical school.

PURPOSE: To determine whether medical school admission interviewers change their evaluations and impressions of applicants as a direct result of the interview. METHOD: In 1991-92, 419 applicants to the University of Virginia School of Medicine were interviewed by members of the admission committee in two separate half-hour sessions. After reviewing each applicant's folder, interviewers rated the applicant before the interview on six objective scales. After the interview, ratings were again made on the same six scales, on the same form, below the ratings made before the interview. Data were examined using paired t-tests, Pearson correlations, and stepwise multiple-regression analysis. RESULTS: Of the six scales, only the ratings of Commitment to Serve Others were not significantly changed by the interview; the ratings of Familiarity with Issues in Medicine changed the most (p < .01 by paired t-test). The ratings of Overall Impression increased for accepted applicants and decreased for rejected applicants. CONCLUSION: The interview did influence interviewers' ratings made before the interview, and in the direction consistent with admission decisions, which supports the continued use of the interview. Although the magnitude of the changes was not large, the changes validate the conviction that the interview aids in the selection of individuals for medical school.

Aortic dissection: surgical and nonsurgical treatments compared. An analysis of seventy-four cases at the University of Virginia.

During the eleven year period from 1965 to 1976, aortic dissection was diagnosed in seventy-eight patients treated at the University of Virginia Medical Center. The seventy-four cases that comprise the present report were confirmed by aortography, surgery, or autopsy. Forty patients (54 per cent) were surgically treated by interruption of the origin of dissection and insertion of a Dacron prosthesis. The remaining thirty-four (46 per cent) were treated according to the Wheat regimen or by nonspecific supportive measures. The overall survival at one year was 28 per cent. One year survival for patients with type I dissections treated surgically was 19 per cent compared with 8 per cent one year survival for nonsurgically treated patients. Sixty per cent of patients with type II dissections treated surgically were alive at the end of one year, whereas no patients with type II dissection treated nonsurgically survived beyond one year. Half the patients with type III dissections treated surgically were alive at one year compared with 35 per cent of those nonsurgically treated. These data suggest that surgery is the treatment of choice for all types of aortic dissections, but particularly for type II. Patients with type I dissections have a very poor prognosis regardless of therapy.

Prolonged anuria and aortic insufficiency in a child with Wegener's granulomatosis.

A 16 year-old boy developed generalized Wegener's granulomatosis with rapidly progressive renal insufficiency resulting in prolonged anuria. He was treated with cyclophosphamide, prednisone and anticoagulants, and was maintained on peritoneal dialysis for seven weeks, after which he regained a GFR of 35 ml/min. Recovery of renal function following prolonged anuria has not been previously reported in a child with Wegener's granulomatosis. The patient also developed aortic regurgitation, a cardiac lesion not previously described in this disorder.

Reversible renal failure from isolated granulomatous renal sarcoidosis.

A patient presented with a 6 month history of progessive renal failure. Serum creatinine was 7.1 mg/100 ml, creatinine clearance 4 ml/minute and hematocrit 22%. Skin tests for tuberculosis, trichophyton, SK/SD and candida were all unreactive and all cultures were negative or showed normal growth. A renal biopsy revealed non-caseating epithelial granulomas and foreign body multinucleated giant cells. No deposits or micro-organisms were seen on electron microscopy. Bone marrow and lymph node biopsies were unremarkable and no lung pathology was present. Therapy with systemic prednisone produced a dramatic improvement with serum creatinine diminishing to 1.3 mg/100 ml, creatinine clearance increasing to 81 ml/minute and hematocrit improving to 39%. A search of the literature has failed to reveal similar reports of reversible renal failure from isolated granulomatous renal sarcoidosis.

Long-term oral or intravenous aluminum administration in rabbits. I. Renal and hepatic changes.

Long-term aluminum (Al) administration was studied in rabbits using intravenous (I.V.) injections of aluminum maltol or oral aluminum citrate in drinking water along with calcium. In the intravenous study, renal and liver tissue Al levels increased and were associated with proximal renal tubular pathology and with hepatic periportal Al-positive multinucleated cells. After oral Al, renal Al levels were increased in the Al-hard water group, while hepatic Al levels were not significantly increased over controls. However, cirrhosis was found in five orally-loaded animals which received Al and/or low dietary calcium or soft water. Collectively, these findings suggest that renal accumulation of Al is causally related to nephrotoxicity; that the lack of renal changes after oral loading is due to low absorption from normal adult gastrointestinal tract and normal functioning of mature kidneys; and that the elevated liver Al levels, achieved after I.V. administration, are related to the presence of hepatic Al-containing giant cells.

Disparate urinary catecholamine patterns in secondary hypertension due to unique sequential development of pheochromocytoma and neuroblastoma.

A 43-year-old white woman had a pheochromocytoma removed from her left adrenal gland, and one year later she developed a new left upper abdominal mass that was found to be a neuroblastoma. On both occasions, urinary vanillylmandelic acid level was elevated. However, urinary norepinephrine and epinephrine levels were increased only during the pheochromocytoma episode, while the urinary homovanillic acid level was elevated only when neuroblastoma developed. Despite a high suspicion of pheochromocytoma recurrence, the urinary catecholamine profile was suggestive of neuroblastoma, which was revealed by histopathologic analysis of the tumor tissue.

Poorly differentiated lymphocytic lymphoma with ectopic parathormone production: visulization of metastatic calcification by bone scan.

Metastatic soft tissue calcification is known to occur in hypercalcemia and is usually present in the kidneys, stomach and lungs. 1--3 This case presents two unusual features: 1) ectopic parathormone production in association with poorly differentiated lymphocytic lymphoma; and and 2) uptake of 99mTc-pyrophosphate in the liver in the absence of demonstrable abnormality at autopsy. The more usual sites of metastatic calcification also showed uptake of the radionuclide. We will discuss metastatic soft tissue calcification, ectopic parathyroid hormone production, hypercalcemia in malignancy and bone scan agent localization in soft tissues.