Nephropathy in human immunodeficiency virus-1 transgenic mice is due to renal transgene expression.

HIV-associated nephropathy (HIVAN) is a progressive glomerular and tubular disease that is increasingly common in AIDS patients and one of the leading causes of end stage renal disease in African Americans. A major unresolved issue in the pathogenesis of HIVAN is whether the kidney disease is due to renal cell infection or a "bystander" phenomenon mediated by systemically dysregulated cytokines. To address this issue, we have used two different experimental approaches and an HIV-1 transgenic mouse line that develops a progressive renal disease histologically similar to HIVAN in humans. In the murine model, kidney tissue expresses the transgene and in heterozygous adults, renal disease develops shortly thereafter. We demonstrate by terminal deoxynucleotide transferase-mediated dUTP-biotin nick-end labeling assay that similar to the disease in humans, apoptosis of renal tubular epithelial cells is a component of the molecular pathogenesis. To determine whether apoptosis is due to transgene expression or environmental factors, we treated fetal kidney explants (normal and transgenic) with UV light to induce transgene expression. Apoptosis occurred in transgenic but not normal littermates after stimulation of transgene expression. To confirm a direct effect of HIV expression on the production of HIVAN, we transplanted kidneys between normal and transgenic mice. HIVAN developed in transgenic kidneys transplanted into nontransgenic littermates. Normal kidneys remained disease free when transplanted into transgenic littermates. Thus, the renal disease in the murine model is intrinsic to the kidney. Using two different experimental approaches, we demonstrate a direct effect of transgene expression on the development of HIVAN in the mouse. These studies suggest that in humans, a direct effect of HIV-1 expression is likely the essential cause of HIVAN, rather than an indirect effect of cytokine dysregulation.

Laparoscopic management of gastrointestinal stromal tumors.

BACKGROUND: Surgery remains the standard for nonmetastatic gastrointestinal stromal tumors (GISTs). Laparoscopic surgery should be considered for these tumors as their biologic behavior lends them to curative resection without requiring large margins or extensive lymphadenectomies. METHODS: A retrospective review was performed of patients who underwent laparoscopic treatment of GISTs by surgeons at the Mount Sinai Medical Center from 2000-2005. Records were reviewed with respect to patient demographics, medical history, diagnostic workup, operative details, postoperative course, and pathologic characteristics. RESULTS: Laparoscopic surgery was attempted in 43 patients with GISTs. The average age was 65 years and 21 were women. Fifty-six percent of patients presented with anemia or gastrointestinal bleeding. The tumors were located in the stomach (65%) and in the small bowel (35%). The mean tumor sizes were 4.6 cm (stomach) and 3.7 cm (small bowel). Gastric operations included laparoscopic wedge (29%), sleeve (21%), and partial (29%) gastrectomies. The three gastric conversions were due to local invasion of tumor into adjacent organs or proximity to the gastroesophageal junction. Small bowel operations included laparoscopic resections with extracorporeal (47%) and intracorporeal anastamoses (33%). Conversion in small bowel operations was associated with coincidental pathology in addition to the GIST. This consisted of an associated bowel perforation and a synchronous colonic carcinoma. There was one mortality and a 9% morbidity rate, including an evisceration requiring reoperation. All tumors were pathologically confirmed with CD117 immunohistochemistry. CONCLUSIONS: In light of their biologic behavior, GISTs should be considered for laparoscopic resection. This minimally invasive approach to these tumors can be performed safely and reliably.

Pulmonary metastatic leiomyosarcoma coexisting with pulmonary chondroma in Carney's triad.

The diagnosis of Carney's triad requires the coexistence of at least two of three rare disorders, including gastric epithelioid leiomyosarcoma, pulmonary chondroma, and functioning extra-adrenal paraganglioma. Seventeen cases have been reported so far, occurring predominantly in young female patients. We report herein the 18th case of this entity and the first case, to our knowledge, where pulmonary metastases from a gastric leiomyosarcoma coexisted in a patient with benign pulmonary chondromas.

Hepatitis-B-associated glomerulonephritis: pathology, pathogenesis, and clinical course.

Hepatitis-B-associated glomerulonephritis (HBGN) is a distinct entity occurring frequently in hepatitis-B-prevalent areas of the world. The disease affects both adults and children who are chronic hepatitis-B-virus (HBV) carriers with or without a history of overt liver disease. The diagnosis is established by serologic evidence of HBV antigens/antibodies, presence of an immune complex glomerulonephritis, immunohistochemical localization of 1 or more HBV antigens, and pertinent clinical history, when available. In this study we present clinicopathologic and follow-up findings in 12 patients (7 children, 5 adults) with hepatitis-B-associated glomerulonephritis. Twelve patients provided 15 renal biopsies and 1 specimen of kidney tissue, obtained at autopsy; these were examined by light microscopy, electron microscopy, and immunohistochemical methods. Membranous glomerulonephritis (MGN) with or without mesangial proliferation was noted in 7 biopsies, mesangiocapillary (membranoproliferative) glomerulonephritis (MCGN) in 5 biopsies, and proliferative glomerulonephritis with or without membranous changes in 2 biopsies. Tubulointerstitial changes were minimal except in 3 adults, in whom they were attributable to arterionephrosclerosis. Ultrastructural findings included the presence of considerable amounts of focal or diffuse granular electron-dense deposits in the glomeruli, in the subepithelial, subendothelial, and mesangial locations, occasionally destroying or replacing the lamina densa of the basement membrane. Variable mesangial proliferation was also observed, with interposition, with focal irregular reduplication of the basement membranes and rare clusters of spherical particles, probably representing viral particles in the deposits. In addition, granular deposits along tubular basement membranes were seen in 1 case. The glomerular deposits stained for 2 or more immunoglobulins, the predominant one being IgG, and variably also for complement components (C3, C4 and C1q). Hepatitis B viral antigens (HBsAg, HBcAg, HBeAg) were demonstrated using acid elution techniques in the deposits in all biopsies where frozen tissue was available, singly or in a variety of combinations and intensities. There were deposits of IgG, C3, C1q, and HBsAg along the tubular basement membranes in 1 case. Follow-up biopsies in 2 cases, 2 and 5 years apart, showed a transformation from a diffuse MGN to MCGN with segmental membranous features. Follow-up biopsy after 3 years in the third patient, who went into clinical remission, revealed partially resolving glomerular lesions. Renal lesions secondary to chronic liver disease, parasitic diseases, certain tropical nephropathies, and lupus nephritis are some of the diseases that may morphologically resemble HBGN. Recognition and differentiation of HBGN from other entities may have significant prognostic and therapeutic implications.(ABSTRACT TRUNCATED AT 400 WORDS)

Amyloidosis and inflammatory bowel disease. A 50-year experience with 25 patients.

Amyloidosis is a rare but serious complication of inflammatory bowel disease (IBD), especially Crohn's disease (CD). It occurred in 15 of our 1709 patients with CD (0.9%) (706 with ileocolitis, 310 with colitis, and 693 with enteritis), but in only 1 of our 1341 patients with ulcerative colitis (UC) (0.07%), admitted to The Mount Sinai Hospital between 1960 and 1985. Eleven of the patients with CD who had amyloidosis had ileocolitis, 2 colitis, and 2 ileitis; these figures represent a frequency within each group of 1.6%, 0.6%, and 0.3%, respectively. Amyloidosis was thus associated 4.4 times more often with CD of the colon than with pure small bowel disease. We have added to this group of 15 patients the 5 cases of CD that were originally reported by Werther et al in 1960, plus another 4 (2 with UC and 2 with CD) who have been seen since 1985, making a total of 25 patients in this series, 22 with CD and 3 with UC. There was a striking male preponderance, 16 of 22, among patients with CD, although 2 of the 3 patients with UC were female. Amyloid disease was diagnosed at a mean age of 40 years, 15 years (range, 1-42) after the onset of CD. Six major forms of amyloidosis occurred: nephropathy, enteropathy, cardiomyopathy, hepatosplenomegaly, thyroid mass, and generalized amyloidosis. Renal disease with proteinurea and/or renal insufficiency occurred in 18 of the 22 patients with CD and in all 3 with UC. Nephropathy was by far the most common lethal manifestation of IBD-associated amyloidosis in this series. Nephrotic syndrome developed in 15 patients with CD and was accompanied by renal failure, the major contributor to mortality, in 10 of the 13 patients who died. Amyloidosis may be associated with suppurative or other extraintestinal manifestations of IBD. Fifteen of the 22 patients with CD who had amyloidosis also had suppurative complications of their bowel disease, although the other 7 had no recognizable suppuration. Extraintestinal manifestations were also common in this series, occurring in 12 of 22 patients with CD and in 2 of the 3 patients with UC; 6 of the 18 patients with nephrotic syndrome also had arthritis. However, there is no evidence that patients with IBD with amyloidosis have extraintestinal manifestations more frequently than do IBD patients without amyloidosis. Earlier reports of amyloid associated with IBD came from autopsy series. In recent years, biopsy has allowed diagnosis to be made during life.(ABSTRACT TRUNCATED AT 400 WORDS)

Resolution of renal amyloidosis.

A patient with renal amyloidosis and the nephrotic syndrome consequent to extensive infected burns demonstrated both clinical resolution of the nephrotic syndrome and morphologic regression of the renal amyloid deposits over a six year period. The regression of the amyloid deposits was associated with several changes in the glomerular capillary wall resulting in a double capillary wall contour. This case indicates that deposits of amyloid in the kidney may regress and suggests a sequence of events in this resolution.

Fatal disseminated adenovirus 11 pneumonia in an agammaglobulinemic patient.

Adenovirus type 11, an organism not previously associated with pneumonia, caused the death of a patient with infantile x-linked agammaglobulinemia who had normal cell-mediated immunity. Despite long-standing, regular therapy with immune globulin, his serum lacked neutralizing antibody to the virus. This case confronts the conventional view that viral infections are primarily resisted by cellular immune reactions and reemphasizes the importance of antibody in the host defense against adenoviruses. It further demonstrates the continued vulnerability of such patients to certain pathogens in the presence of presumably adequate standard-dose passive immunization.

Cold ischemic injury accelerates the progression to chronic rejection in a rat cardiac allograft model.

BACKGROUND: The pathogenesis of chronic rejection likely involves an interplay between immunogenic and nonimmunogenic factors. The objective of this study was to determine the influence of cold ischemic preservation injury on the rate of progression to chronic rejection in the Lewis to F344 cardiac allograft model. METHODS: To induce an ischemic injury, donor hearts were stored for 3 hr at 4 degrees C in University of Wisconsin solution before transplantation. Allografts were excised at 1, 7, and 90 days after transplantation or at rejection. Vasculopathy was graded for degree of intimal thickening based on the involvement of vascular perimeter and luminal compromise. RESULTS: The degree of vessel injury in ischemic injured allografts at 90 days was significantly greater than in nonischemic injured allografts (2.8+/-0.4 vs. 1.6+/-0.5, P<0.05). Ischemic injury in syngeneic grafts did not induce a vasculopathy. Immunoperoxidase staining with R73 (anti-T cell) and ED1 (anti-macrophage) monoclonal antibodies revealed that, in ischemic injured allografts at 90 days after transplantation, the infiltrate was composed predominantly of T cells and macrophages. Additionally, ischemic injured allografts excised at 7 days after transplantation showed cellular infiltrates composed of R73-positive T cells and rare interleukin-2 receptor-positive cells, which was not observed in nonischemic allografts or ischemic syngeneic grafts. CONCLUSIONS: The progression to chronic vasculopathy in this model is principally an immunologic process, which is accelerated by an ischemic insult to the allograft. The vascular injury is mediated in part by T cells and macrophages.

Small bowel transplantation in the rat. Effect of pretransplant blood transfusions and cyclosporine on host survival.

We investigated the effect of pretransplant conditioning as a way to reduce the need for the aggressive immunosuppressive therapy reportedly required in small bowel (SB) allograft recipients. LEW rats were conditioned with (1) a donor-specific blood transfusion (DST) on day -8 and a concurrent 5-day course of CsA (10 mg/kg/day); (2) a nonspecific blood transfusion and CsA; (3) CsA alone. A 10-cm segment of the host native bowel was then replaced with an equivalent segment of SB obtained from ACI rats. Postoperative treatment consisted of CsA at 2.5 mg/kg/day for 30 days. Rats conditioned with a nonspecific transfusion and CsA or with CsA alone survived for 14.1 +/- 5.8 and 18.3 +/- 5.7 days, respectively. In contrast, rats conditioned with DST and CsA survived for 60.3 +/- 36.2 days (P less than 0.001 vs. both controls). Biopsies taken from long-term survivors showed a normal bowel architecture. The function of the allografts was studied in a group of animals totally deprived of their native bowel and transplanted with a 30-cm segment of ACI SB. CsA-DST-treated recipients survived an average of 90 +/- 43 days and grew at a rate comparable to isografted animals. Treated allograft recipients had maltose absorption indistinguishable from isografted controls at all times tested. In contrast, maltose absorption was severely impaired in recipients rejecting their grafts. This study demonstrates that long-term survival of SB allograft recipients can be achieved with good functional results with low doses of CsA in recipients conditioned with DST and CsA.

Recurrence of scleroderma in a renal allograft from an identical twin sister.

A patient with scleroderma developed renal failure secondary to recurrence of scleroderma in a renal allograft from an identical twin. This report reviews the previous reports of scleroderma recurrence in renal allografts; the differential diagnosis of scleroderma renal crisis, including cyclosporine toxicity, malignant hypertension, and allograft rejection; and the pathophysiology of this disease.

Immunohistologic c-myc protein in benign breast disease and cancer.

We have studied the histopathology and differential distribution of the c-myc protein (Myc) in human breast tissues including 17 cases of infiltrating mammary carcinoma, 4 cases of fibroadenoma, 5 cases with fibrocystic changes, and 1 case of reduction mammoplasty (as a control). Using a sensitive immunohistochemical method on frozen tissue sections, both a rabbit polyclonal anti-c-myc antibody and a mouse monoclonal anti-c-myc antibody, H51C116, produced high levels of Myc staining in the nuclei of epithelial cells of infiltrating mammary carcinomas (30-90% of cells stained). In contrast, the nuclei of epithelial cells of fibroadenomas, and breast tissues with fibrocystic changes stained infrequently. We studied benign tissue surrounding the tumors in four cases; three were essentially negative, and one showed nuclear epithelial cell staining throughout the lobules. Sixteen of the tumors were examined in parallel, using formalin-fixed, paraffin-embedded samples. Immunohistological procedures for Myc produced uniform, intense epithelial cell cytoplasmic staining (8 cases); light epithelial cell cytoplasmic staining (5 cases) or were unstained (3 cases). We argue that the differences between frozen and paraffin sections are incompatible with the notion of simple displacement of nuclear Myc to the cytoplasm during fixation. Elevated levels of nuclear Myc in tumor cells and subsets of benign tissue are consistent with a role for Myc in mammary cell proliferation and tumorigenesis.

Nucleolar localization of BRCA1 protein in human breast cancer.

Both a rabbit polyclonal BRCA1 antibody, K-18, and a mouse monoclonal BRCA1 antibody, AP 16, produced nucleolar epithelial cell staining on frozen tissue sections of human infiltrating mammary carcinomas. There was much less BRCA1 antibody staining in normal tissues; however, 2 intraductal tumors and a papilloma, found in proximity to the carcinomas showed considerable nucleolar immunoreactivity. MCF-7 cells fixed in methanol and immunostained with the same two antibodies also revealed nucleolar staining, however, after 4% paraformaldehyde fixation for three minutes, there were many fewer nuclei stained. Antigen retrieval methods on formalin-fixed, paraffin-embedded specimens produced tumor cell cytoplasmic staining with AP 16 and nuclear staining in both tumor and normal epithelial cells with another BRCA1 monoclonal antibody, SG 11.

Morphologic and clinical correlates in renal amyloidosis.

Morphologic studies and clinical correlations were undertaken in 59 patients with renal amyloidosis. Spicularly arranged amyloid deposits in the glomerular capillary wall were found in all clinical groups but were more frequent and more extensive in primary amyloidosis and multiple myeloma. The severity of proteinuria correlated with the presence of spicules and podocyte destruction rather than with the amount of amyloid in the glomerulus. The spicules were associated with morphologic and clinical evidence of rapid amyloid deposition and a fulminant clinical course. The absence of spicules and the presence of extensive new basement membrane material may produce basement membrane thickening, lamination, and double capillary wall contours, which are associated with mild proteinuria and, rarely, resolution of amyloidosis. Nodular or mixed nodular-diffuse patterns of glomerular amyloid deposits were more frequent in patients with secondary amyloidosis and a longer clinical course. Renal failure generally corresponded to severe glomerular amyloidosis and tubular atrophy. However, a relatively precipitous, usually irreversible decrease in renal function frequently occurred in patients with renal amyloidosis and did not always have a morphologic explanation. The duration of life from the time of biopsy no death in patients with primary amyloidosis (nine months) was markedly shorter than in those with secondary amyloidosis (more than 50 months).

True histiocytic lymphoma of the thymus. Report of a case and a study of the distribution of histiocytic cells in the fetal and adult thymus.

The thymus was the site of a true histiocytic lymphoma. Immunohistochemical demonstration of lysozyme and alpha-1-antitrypsin in the tumor cells indicated the histiocytic nature of the tumor. Five fetal and five adult thymus glands were studied for the presence and distribution of true histiocytic cells. Histiocytes were demonstrated predominantly in the connective tissue septa and constituted approximately 2% of cells in these thymuses. Histiocytes are therefore a normal constituent of the thymus, which may become the primary site of true histiocytic lymphoma.

The correlation of sequential changes in the distribution of pulmonary blood flow in hemorrhagic shock with the histopathologic anatomy.

Histopathologic changes were described and correlated with hemodynamic changes in a series of farm-reared dogs by a preparation and a protocol which were shown to simulate closely physiologic events in clinical hemorrhagic shock; neither anesthesia nor thoracotomy was used and flush solutions for catheters were strictly limited; a series of sham-treated controls was used for comparison. Five different isotopes were used to label microspheres to measure blood flow sequentially at the tissue level at various stages of the shock protocol. At death, multiple tissue sections were taken relative to six parallel segments of the lung arranged according to dependency so that correlations of structure and function might be related to the influence of gravity. The degrees of severity of atelectasis, hemorrhage, edema, congestion, inflammation, and hyperaeration were evaluated by rating scales. Tissues from the most dependent areas had a higher incidence and greater severity of histologic lesions. Tissues with mild histologic rating tended to have lower percentages of flow after hemorrhage, but normal or increased flow after reinfusion. The severely damaged tissue received greater than average flow throughout. Tissues with severe atelectasis paralleled the course of those with a high over-all severe pathologic rating. Tissues with severe inflammation had less blood flow in the control period, increased flow in Stages B1 and B2 and a subsequent return to control values. Those with severe edema had reduced flow in Stages B2 and B3, but high flows after reinfusion.

Epidermoid cyst of testicle. Ultrasonographic characteristics.

Epidermoid cyst is a benign lesion of the testis which represents approximately 1 per cent of all testicular tumors. We describe a case in which preoperative ultrasound of the testis suggested a benign testicular lesion, thus permitting testis-sparing surgery. The proper management of this lesion remains a source of urologic controversy, and we review the rationales for both radical orchiectomy and simple excision.

Course of gentamicin nephrotoxicity.

Metabolic balance and morphologic studies were performed on rats receiving gentamicin 100 mg/kg/day for a period of 8--10 days and during the recovery period. Daily urine flow rate increased with the administration of gentamiccin and remained elevated up to 20 days following the discontinuation of gentamicin, although BUN and plasma creatinine were virtually normal 10 days after the discontinuation of gentamicin. During the development of renal failure means daily electrolyte excretion remained normal. During the recovery period, however, sodium and potassium excretion exceeded control values while chloride and net acid excretion remained normal. Proteinuria developed during the administration of gentamicin and returned to normal 6--10 days after the discontinuation of gentamicin. Ten days of netilmicin administration (150 mg/kg/day) resulted in only mild tubular degeneration and no azotemia.

Renal biopsy: why and when.

The purpose of this paper is to emphasize the importance of information obtained by renal biopsy in the diagnosis, prognosis, and therapy of patients with renal disease. Because controversy persists regarding the value of renal biopsy as an aid in determining prognosis and in choosing appropriate therapy, there has been some reluctance to use it early after the onset of obvious signs, symptoms, and laboratory findings indicative of renal disease with or without involvement of other organs. Although all such patients may not benefit from the information provided by a proper biopsy, we will illustrate some of the characteristic histologic details found in specific circumstances in our experience where the biopsy has been particularly helpful in reaching a diagnosis, in assessing prognosis, and in choosing therapy.

Morphometric analysis of glomerular basement membranes (GBM) in thin basement membrane disease (TBMD).

We measured the thickness of glomerular basement membrane in 46 patients with thin basement membrane disease (TBMD), (age range 15-50 years, almost equal M:F ratio), and compared with that in a control group of 5 patients (age range 5-38 years) with normal glomerular morphology. The measurements of glomerular basement membrane taken from electron micrographs (magnification x 12,500) were analyzed using an interactive image analysis system assembled around an INTEL 10 microcomputer, with a high resolution touch sensitive screen as the interactive peripheral. Calculation was done by printing on an electron micrograph a grating replica (21,600 lines/cm), with the same magnification as the electron micrographs of the glomeruli and calibrating the arithmetic (AM) and harmonic (HM) mean for each case. Comparing the results of TBMD cases (AM 129-202 nm; HM 128-213 nm) with those of the control group consisting of 5 cases of "minimal change nephrotic syndrome" (AM 287-317 nm; HM 300-333 nm) it was found that GBM in TBMD is remarkably thin. The thinning was caused mainly by the decreased width of the lamina densa (TBMD group: 71.4-147.0 nm; HM 72.4-154.4 nm in comparison with the control group: AM 174.4-235.5 nm; HM 184.2-249.6 nm). This finding allows us to differentiate thin basement membrane disease from other glomerulopathies presenting primarily with isolated or recurrent hematuria.

Comparative value of urinalysis, urine cytology and urine sIL2R in the assessment of renal disease in patients with systemic lupus erythematosus (SLE).

Serial immunological testing has been recently proposed for monitoring patients with lupus nephritis as routine serological tests have shown sub-optimal correlation with clinical status. To assess the value of urine cytology and urine sIL2R in the evaluation of patients with SLE, in particular those with lupus nephritis, we conducted a prospective double-blind study of 31 patients with SLE, during an 18-month period. A comparison of routine urinalysis with urine cytology and urine sIL2R was performed in 84 samples: 15 from patients without a history of renal involvement and 69 from patients with a history of renal involvement. A high urine cytology score (> or = 6), particularly in the presence of lymphoblasts, plasma cells or monocytes, was significantly associated with lupus nephritis in relapse. Urine sIL2R levels were significantly elevated during all SLE relapses, unrelated to the presence of renal involvement. Fifteen urine specimens were obtained at the time of a kidney biopsy: 9 with active lesions and 6 with inactive renal disease. UC score was 2.0 +/- 1.89 for those with absent activity, 8.4 +/- 3.4 for mild activity and 11.0 +/- 2.4 for moderate/severe activity (p < 0.001 between active vs inactive disease). No urinalysis parameter alone permitted distinguishing the degree of renal disease activity. In the subgroup of patients with renal disease urinalysis was overall less accurate than urine cytology or urinary sIL2R levels for predicting renal disease activity defined by biopsy. Urine cytology and urine sIL2R proved to be reliable measures of lupus activity.