Showing papers by "Charles E. Alpers published in 2006"

Lung cancer induced in mice by the envelope protein of jaagsiekte sheep retrovirus (JSRV) closely resembles lung cancer in sheep infected with JSRV

Abstract: Jaagsiekte sheep retrovirus (JSRV) causes a lethal lung cancer in sheep and goats. Expression of the JSRV envelope (Env) protein in mouse lung, by using a replication-defective adeno-associated virus type 6 (AAV6) vector, induces tumors resembling those seen in sheep. However, the mouse and sheep tumors have not been carefully compared to determine if Env expression alone in mice can account for the disease features observed in sheep, or whether additional aspects of virus replication in sheep are important, such as oncogene activation following retrovirus integration into the host cell genome. We have generated mouse monoclonal antibodies (Mab) against JSRV Env and have used these to study mouse and sheep lung tumor histology. These Mab detect Env expression in tumors in sheep infected with JSRV from around the world with high sensitivity and specificity. Mouse and sheep tumors consisted mainly of well-differentiated adenomatous foci with little histological evidence of anaplasia, but at long times after vector exposure some mouse tumors did have a more malignant appearance typical of adenocarcinoma. In addition to epithelial cell tumors, lungs of three of 29 sheep examined contained fibroblastic cell masses that expressed Env and appeared to be separate neoplasms. The Mab also stained nasal adenocarcinoma tissue from one United States sheep, which we show was due to expression of Env from ovine enzootic nasal tumor virus (ENTV), a virus closely related to JSRV. Systemic administration of the AAV6 vector encoding JSRV Env to mice produced numerous hepatocellular tumors, and some hemangiomas and hemangiosarcomas, showing that the Env protein can induce tumors in multiple cell types. Lung cancers induced by JSRV infection in sheep and by JSRV Env expression in mice have similar histologic features and are primarily characterized by adenomatous proliferation of peripheral lung epithelial cells. Thus it is unnecessary to invoke a role for insertional mutagenesis, gene activation, viral replication, or expression of other viral gene products in sheep lung tumorigenesis, although these processes may play a role in other clinically less important sequelae of JSRV infection such as metastasis observed with variable frequency in sheep.

A clinicopathologic study of thrombotic microangiopathy in the setting of IgA nephropathy.

Abstract: Background IgA nephropathy is the most common glomerulonephritis in the world. Thrombotic microangiopathy occurs in a number of clinical settings, including but not limited to thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, malignant hypertension, anti-phospholipid antibody syndrome and radiation nephropathy. Renovascular complications, such as thrombotic microangiopathy, in the setting of IgA nephropathy may be overlooked and their significance as a concomitant histologic finding is unclear. Methods We conducted a clinicopathologic study to understand the possible relationship between IgA nephropathy and a concurrent thrombotic microangiopathy injury process. We identified 10 patients with an established diagnosis of IgA nephropathy and concurrent findings of thrombotic microangiopathy based on their renal biopsies. Results Six patients presented with malignant hypertension, while three others had severe hypertension (> or = 100 mmHg, diastolic). Five patients had nephrotic-range proteinuria. Seven patients had occasional arteriolar thrombi identified by light microscopy and prominent glomerular subendothelial space widening by electron microscopy, while three patients demonstrated only ultrastructural features of thrombotic microangiopathy. Other possible etiologic causes of thrombotic microangiopathy were not identified with the available clinical information. Conclusion Our study suggests that a thrombotic microangiopathy injury, when present, is usually found in advanced stages of IgA nephropathy and can be associated with severe proteinuria. Although other possible causes of thrombotic microangiopathy, such as anti-phospholipid antibody syndrome, were excluded in only two patients, the thrombotic microangiopathy injury process may be a cause or a consequence of the severe hypertension encountered in most of the patients which, in turn, may be a consequence of the disease progression of IgA nephropathy.

Giant Cell Tubulitis with Tubular Basement Membrane Immune Deposits: A Report of Two Cases after Cardiac Valve Replacement Surgery

Abstract: This paper presents two elderly patients who had normal baseline renal function and had stenotic valvular lesions secondary to rheumatic fever and underwent aortic valve replacements with mechanical valves. Both patients developed acute renal failure after cardiac valve replacement procedures. The renal biopsies revealed acute granulomatous tubulointerstitial nephritis. The unique histologic features were tubular basement membrane (TBM) immune complex deposition detected by both immunofluorescence and electron microscopy and prominent multinucleated giant cells surrounding intact TBM. The temporal relationship to the surgical procedure and the subsequent recovery of the patients' renal functions upon therapy suggested that the renal failure may have been due to an allergic drug reaction from the perioperative exposure to unknown agents, such as prophylactic antibiotics and furosemide. The literature on TBM immune complex deposition was reviewed, and the pathophysiologic mechanisms that may account for the similarities between the clinicopathologic features of these two cases were examined. These two cases expand the histopathologic spectrum of previously described cases of putative drug-induced acute tubulointerstitial nephritis.

Renal Anatomy and Basic Concepts and Methods in Renal Pathology

Abstract: Each kidney weighs approximately 150 g in adults, with ranges of 125 to 175 g for men and 115 to 155 g for women; both together represent 0.4% of the total body weight. Each kidney is supplied by a single renal artery originating from the abdominal aorta; the main renal artery branches to form anterior and posterior divisions at the hilus and divides further, its branches penetrating the renal substance proper as interlobar arteries, which course between lobes. Interlobar arteries extend to the corticomedullary junction and give rise to arcuate arteries, which arch between cortex and medulla and course roughly perpendicular to interlobar arteries. Interlobular arteries, branches of arcuate arteries, run perpendicular to the arcuate arteries and extend through the cortex toward the capsule (Fig. 1.1). Afferent arterioles branch from the interlobular arteries and give rise to glomerular capillaries (Fig. 1.2). A glomerulus represents a spherical bag of capillary loops arranged in several lobules (Fig. 1.3); the capillaries merge to exit the glomerulus as efferent arterioles, which, in most nephrons, branch to form another vascular bed, peritubular or interstitial capillaries, which surround tubules. Efferent arterioles from juxtamedullary glomeruli extend into the medulla as vasa recta, which supply the outer and inner medulla. The vasa recta and peritubular capillaries collect, forming into interlobular veins; the veins follow the arteries in distribution, size, and course, and leave the kidneys as renal veins, which empty into the inferior vena cava.