W. Robert Anderson

Value of liver biopsy in the evaluation and management of chronic liver disease in renal transplant recipients

PURPOSE Liver disease is a frequent complication in renal transplant recipients. To understand the nature and progression of hepatic disease in these patients, we performed percutaneous biopsies in 77 subjects who had chronic liver dysfunction in the posttransplant period. The purpose of the present investigation is to delineate the morphologic spectrum of chronic liver disease in the renal allograft recipients and to characterize the clinical and histologic progression of each of the different morphologic forms. PATIENTS AND METHODS Between 1971 and 1990, 915 patients received renal transplants at the Hennepin County Medical Center, Minneapolis, Minnesota. One hundred nineteen (13%) of them had abnormal liver function that persisted for longer than 6 months. Percutaneous liver biopsies were performed in 77 of these patients, but adequate tissue for histologic evaluation was available in only 72. After the biopsy, the clinical and histologic course of each subject was monitored in relation to the baseline hepatic morphology. To assess the predictive value of serum enzymes in diagnosing the histologic lesions, the level of serum enzymes at the time of the biopsy was correlated with the morphologic diagnosis. In addition, several clinical, biochemical, etiologic, and histologic variables were screened for their association with histologic progression to liver cirrhosis. RESULTS The morphologic diagnosis in the 72 specimens evaluated at baseline was as follows: fat metamorphosis in 8 (11%), chronic persistent hepatitis in 20 (28%), early chronic active hepatitis in 20 (28%), advanced chronic active hepatitis in 15 (21%), and hemosiderosis in 9 (12%). There was no statistical correlation between the serum enzyme levels and the histologic diagnosis. During a mean follow-up of 5.7 +/- 3.9 years, clinical progression to hepatic failure and death occurred in 35% of patients with early chronic active hepatitis, 55% with hemosiderosis, and 60% with advanced chronic active hepatitis. None of the patients with the morphologic diagnosis of fat metamorphosis or chronic persistent hepatitis died as a consequence of hepatic failure. Follow-up liver specimens were obtained in 34 (47%) of the original 72 subjects after a mean interval of 4.5 +/- 4.3 years. Of the 15 patients with the initial diagnosis of early chronic active hepatitis, 9 (60%) showed morphologic transition to advanced chronic active hepatitis, and in 1 of the 5 patients with hemosiderosis (20%), the lesion had resolved after successive phlebotomies. During the follow-up, 60% with early chronic active hepatitis (9 of 14), 66% with hemosiderosis (2 of 3), and 100% with advanced chronic active hepatitis (4 of 4) showed histologic progression to liver cirrhosis. On the contrary, no morphologic alterations were observed in the follow-up specimens of patients with fat metamorphosis or chronic persistent hepatitis. Of the different variables screened for their association with histologic progression, older age at transplant, female sex, and morphologic diagnosis of advanced chronic active hepatitis were found to be significant. CONCLUSION Histologic diagnosis can be a useful marker in predicting the course of chronic liver disease after renal transplantation. Liver biopsy should be incorporated into the evaluation and management of chronic liver disease in renal transplant recipients.

Morphine amplifies HIV-1 expression in chronically infected promonocytes cocultured with human brain cells

Previous studies have shown that morphine promotes the replication of human immunodeficiency virus (HIV)-1 in peripheral blood mononuclear cell cocultures. In the present study, we tested the hypothesis that morphine would amplify HIV-1 expression in the chronically infected promonocytic clone U1 when cocultured with lipopolysaccharide-stimulated human fetal brain cells. Marked upregulation of HIV-1 expression was observed in these cocultures (quantified by measurement of HIV-1 p24 antigen levels in supernatants), and treatment of brain cells with morphine resulted in a bell-shaped dose-dependent enhancement of viral expression. The mechanism of morphines amplifying effect appears to be opioid receptor-mediated and to involve enhanced production of tumor necrosis factor-alpha by microglial cells.

Anatomical and Morphological Evaluation of Pacemaker Lead Compression

In recent years, pacemaker lead failure due to compressive damage has been reported with increasing frequency. To document the mechanism of this failure, we evaluated explanted mechanically damaged leads with electrical testing, optical microscopy, and in some cases, scanning electron microscopy (SEM) In addition, we performed an autopsy study to measure the compressive loads on catheters placed percutaneously through the costoclavicular angle, as well as by cephalic cutdown. Of the 49 explanted compression damaged leads with enough clinical data for analysis, all had been placed by percutaneous subclavian puncture. Our autopsy data confirmed the significant increase in pressures generated in the costoclavicular angle for medial percutaneous subclavian catheterization (126 ± 26 mmHg) compared to a more lateral percutaneous subclavian puncture (63 ± 15 mmHg) or a cephalic cutdown (38 ± 13 mmHg) (P < 0.01). In vivo coil compression testing documented loads up to 100 pounds per linear inch of coil and a compressive morphology by SEM identical to that seen in the clinical explants. Pacemaker leads appear to be susceptible to compression damage when placed by subclavian venipuncture. When possible, leads should be placed such that they avoid the tight costoclavicular angle.

Transforming growth factor-β protects human neurons against β-amyloid-induced injury

Deposition of amyloid fibrils in the brain is a histopathologic hallmark of Alzheimer disease (AD) and β-amyloid protein (Aβ), the principal component of amyloid fibrils, has been implicated in the neuropathogenesis of AD. In the present study, we first developed an in vitro model of Aβ-induced neurodegeneration using human fetal brain-cell cultures and then tested the hypothesis that cytokines modulate Aβ-induced neurodegeneration. When brain-cell cultures were exposed to Aβ, marked neuronal loss (60% of neurons by microscopic assessment) and functional impairment (i.e., reduction in uptake of [3H]γ-aminobutryric acid) were observed after 6 d of incubation. Aβ-induced neurodegeneration was dose-dependent with maximal effect at 100 μM. Although interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-α had a nominal effect, both the β1 and β2 isoforms of transforming growth factor-β dose-dependently protected >50% of neurons against Aβ-induced injury. IL-4 also proved to be neuroprotective. Aβ-induced neurodegeneration was accompanied by microglial cell proliferation and enhanced release of IL-1, IL-6, and TNF-α. These findings are consistent with the emerging concept that AD is an inflammatory disease and may lead to new therapeutic strategies aimed at reducing Aβ-induced neurotoxicity.

Radiation-induced renal disease: A clinicopathologic study

Radiation injury to the renal parenchyma is an unusual cause of renal insufficiency. Light, immunofluorescence and electron microscopic studies were performed on the renal tissue from two patients in whom renal insufficiency developed within a year after they received abdominal irradiation. The glomerular lesion in both patients was similar. Mild endothelial cell swelling and basement membrane splitting were noted consistently on light microscopy. The electron microscopic examination revealed marked subendothelial expansion with electron-lucent material associated with deposition of basement membrane-like material adjacent to the endothelial cells. In some capillary loops, the endothelial cell lining appeared to be completely lost. The pathogenesis of radiation-induced renal injury is still uncertain. It is speculated that local activation of the coagulation system with consequent thrombosis of the renal microvasculature may be extremely important.

Correlative Study of Adult Respiratory Distress Syndrome by Light, Scanning, and Transmission Electron Microscopy

The sequential pulmonary changes occurring in the evolution of adult respiratory distress syndrome (ARDS) were studied in 35 patients by correlative light, scanning, and transmission electron microscopy. The causes of ARDS were diverse, the major ones being sepsis or aspiration. Patient survival ranged from 3 to 51 days. The acute stage in patients surviving 2 to 7 days was characterized by an exudative reaction with a predominance of hyaline membranes. This acute stage merged with and was replaced by a subacute reparative stage in patients surviving 7 to 14 days, which in turn was replaced by a chronic fibroproliferative stage complicated by interstitial pulmonary fibrosis and a deranged acinar architecture. Correlation of findings by scanning electron microscopy with those by light and transmission electron microscopy provided an added dimension to understanding of the evolving stages of ARDS and demonstrated that type 2 pneumocytes contributed to the fibroproliferative stage through organization of hyaline membranes and re-epithelialization of alveoli.

Tissue acoustic properties of fresh left ventricular thrombi and visualization by two dimensional echocardiography: Experimental observations

Abstract Although two dimensional echocardiography can detect left ventricular thrombi In certain cardiovascular disease states, there Is theoretical concern that the acoustic Impedance properties of recently formed fresh thrombi may not allow their echocardiographic visualization. If such were the case, false negative studies might occur even with technically adequate echocardiographic examinations. To determine if the tissue acoustic properties of acute thrombi allow their visualization and differentiation from surrounding intracavitary blood and adjacent myocardium with two dimensional echocardiography, an in vivo canine model of acute left ventricular thrombus was studied. In 10 dogs left ventricular thrombus was induced using coronary ligation and subendocardial injection of a sclerosing agent, sodium rlclnoleate. Acoustically distinct left ventricular thrombi were imaged by two dimensional echocardiography within hours (mean ± standard deviation 121 ± 40 minutes, range 45 to 180), and the thrombi could easily be differentiated from surrounding blood and adjacent myocardium. Thrombi with a maximal dimension as small as 0.6 cm at autopsy were highly reflective and could be imaged with echocardiography. Histologic examination of the thrombi showed characteristic features of early thrombosis. In six dogs, echocardiographic imaging revealed two acoustically distinct areas of thrombi. Gross and microscopic examination of the thrombi in these animals confirmed two distinct types of thrombus with differing histologie features. Although technical aspects of the echocardiographic examination or certain biologic features of thrombi such as thrombus size may limit the detection of thrombi by echocardiography in certain situations, our data indicate that the tissue acoustic properties of recently formed thrombi are not a primary limitation to their echocardiographic detection. These findings support the use of two dimensional echocardiography in the investigation of the natural history, prevention and therapy of left ventricular thrombus in patients during the early course of acute myocardial Infarction.

De novo immunotactoid glomerulopathy of the renal allograft : possible association with cytomegalovirus infection

A 59-year-old man with end-stage renal failure from systemic vasculitis developed de novo immunotactoid glomerulopathy of the renal allograft, with clinical evidence of hematuria, proteinuria, and acute renal failure 6 weeks after cadaveric renal transplantation. The morphologic lesion of immunotactoid glomerulopathy and the clinical renal disease resolved during the following 2 weeks. The disease had not recurred in the subsequent 20 months of posttransplant follow-up. During the same period, the patient also developed systemic cytomegalovirus (CMV) infection with viremia, acute hepatitis, and bone marrow suppression. The clinical manifestations of CMV illness and the renal disease have subsided following the withdrawal of immunosuppressive agents and simultaneous treatment with ganciclovir. Although there is no direct proof that CMV infection was responsible for the development of immunotactoid glomerulopathy, the circumstantial evidence in this patient strongly suggests that these two disease were temporally linked. To our knowledge, the association between CMV infection and immunotactoid glomerulopathy has not been documented previously.

Insudative hyalin cap lesions of diabetic glomerulosclerosis

Peripheral hyalin cap lesions of glomerular capillaries are a common finding in diabetic renal disease. Although these have been referred to as exudative in nature, most studies ascribe an insudative process in their pathogenesis. We report a case of diabetic renal disease in which glomeruli demonstrated both late and early developmental stages of peripheral cap lesions in which the presence of plasma constituents was indicative of an insudative process.

Radiation induced renal disease: a clinicopathologic study

Sixteen patients with membranoproliferative glomerulonephritis who required kidney transplantation because of renal failure were evaluated for evidence of recurrence of the original disease by serologic and morphologic studies. Of the 12 patients with transplant tissue available for study, seven showed membranoproliferative glomerulonephritis by light morphology. Four of these seven also had hypocomplementemia, and this hypocomplementemia was characterized by decreased serum CH50, C3 beta1A or C3-C9 but norma serum C1, C4 and C2 by hemolytic assay. Immunofluorescent microscopy demonstrated more intense glomerular deposition of C3 and properdin in the hypocomplementemic patients. Ultrastructural studies demonstrated intramembranous deposits typical of dense deposit disease in one patient who also had marked hypocomplementemia. One patient who had two transplant biopsies and persistent hypocomplementemia showed progression from predominantly mesangial glomerular changes to both capillary wall and mesangial abnormalities. This study has shown a high rate of recurrence of membranoproliferative glomerulonephritis in the transplanted kidneys. A high death rate was noted in persistently hypocomplementemic patients. The serum C profile in hypcomplementemic patients who received translants was similar to that seen before transplantation, but the signficance of this finding remains unknown.