Morphologic features of extrahepatic manifestations of hepatitis C virus infection.

Cirrhosis and hepatocellular carcinoma are the prototypic complications of chronic hepatitis C virus infection in the liver. However, hepatitis C virus also affects a variety of other organs that may lead to significant morbidity and mortality. Extrahepatic manifestations of hepatitis C infection include a multitude of disease processes affecting the small vessels, skin, kidneys, salivary gland, eyes, thyroid, and immunologic system. The majority of these conditions are thought to be immune mediated. The most documented of these entities is mixed cryoglobulinemia. Morphologically, immune complex depositions can be identified in small vessels and glomerular capillary walls, leading to leukoclastic vasculitis in the skin and membranoproliferative glomerulonephritis in the kidney. Other HCV-associated entities include porphyria cutanea tarda, lichen planus, necrolytic acral erythema, membranous glomerulonephritis, diabetic nephropathy, B-cell non-Hodgkin lymphomas, insulin resistance, sialadenitis, sicca syndrome, and autoimmune thyroiditis. This paper highlights the histomorphologic features of these processes, which are typically characterized by chronic inflammation, immune complex deposition, and immunoproliferative disease in the affected organ.

Identifying risk factors in renal allografts before transplant: machine-measured renal resistance and posttransplant allograft survival.

Enhancement of renal allograft function and survival in an era where expanded criteria donors are increasingly used requires validated selection criteria. The goal of this retrospective study was to evaluate the significance of pretransplant donor and allograft parameters to identify risk factors that can be used in a model to predict 1-year allograft outcomes. Donor demographic factors, donor type, and allograft parameters such as biopsy results and machine-measured renal resistance were correlated with 1-year graft outcome. The Kaplan-Meier method was used to estimate graft survival using the categorical predictors of donor type, donor age, and machine measured renal resistance at 1.5, 3, and 5 hours. The log-rank test was used to test the difference in survival curves between cohorts. The Cox regression analysis was used to estimate hazard ratios for machine-measured renal resistance, donor age, donor terminal creatinine level, donor's estimated glomerular filtration rate, cold ischemia time, and percent glomerulosclerosis. The data show that machine-measured renal resistance at 3 and 5 hours has a statistically significant inverse relationship to 1-year graft survival. All other risk factors had no correlation with 1-year graft survival. The machine-measured renal resistance at 3 hours is the earliest significant predictor of 1-year allograft outcome.

Paraneoplastic glomerulopathy secondary to retroperitoneal sarcoma: a case report.

Glomerulopathy is a rare form of paraneoplastic disease. We present the second reported case of paraneoplastic glomerulopathy due to a retroperitoneal sarcoma. The patient presented with generalized edema and nephrotic syndrome. CT scan showed two large retroperitoneal masses. One large retroperitoneal mass was resected. Post-operatively, she developed kidney failure and biopsy showed minimal change disease. With steroid therapy, patient's symptoms went into remission. We hypothesize that minimal change paraneoplastic glomerulopathy developed due to damage from cytokines released from a T-cell mediated response to the malignancy.

Later-onset Fabry disease: an adult variant presenting with the cramp-fasciculation syndrome.

BACKGROUND: Classic Fabry disease, an X-linked recessive lysosomal storage disease due to the deficient activity of alpha-galactosidase A, typically presents in early childhood with acroparesthesias, angiokeratomas, hypohidrosis, and corneal dystrophy. The neuropathic pain presumably results from glycosphingolipid accumulation in the vascular endothelium and in small-caliber nerve fibers, and is treatable by enzyme replacement therapy. Later-onset variants with residual alpha-galactosidase A activity lack vascular endothelial involvement and classic symptoms, which lead to the development of cardiac and/or renal disease after the fourth decade of life. OBJECTIVE: To expand the later-onset Fabry phenotype to include cramp-fasciculation syndrome without small-fiber neuropathy. METHODS: A 34-year-old man who presented with chronic exercise-induced pain, fasciculations, and cramps of the feet and legs, and his similarly affected mother, were evaluated. Clinical, biochemical, and molecular studies were performed. RESULTS: Clinical evaluation suggested the diagnosis of Fabry disease, which was confirmed by reduced plasma and leukocyte alpha-galactosidase A activities (8.8% and 13.4% of normal, respectively) due to a missense A143T mutation. His mother was heterozygous for the A143T mutation. CONCLUSION: The presentation of cramps and fasciculations without apparent small-fiber neuropathy expands the phenotype of later-onset Fabry disease.

Expression of p53 in virally infected tubular cells in renal transplant patients with polyomavirus nephropathy.

Polyomavirus (PV) infection is associated with ureteral stenosis, hemorrhagic cystitis, and interstitial nephritis in renal transplant patients. The 3 PVs detected in human beings-BK virus, JC virus, and simian virus 40-each encode highly homologous forms of a large T antigen, a transcriptional and replicational regulatory protein. We describe immunohistochemical findings in 5 renal transplant patients who developed PV nephropathy (PVN) and a sixth patient with both PVN and PV infection of the bladder mucosa. Polyomavirus infection was confirmed by immunohistochemical detection of T antigen in kidney and bladder biopsies. We report on the expression of p53 specific to virally infected cells in all biopsies positive for T antigen. Examination of posttransplant biopsies obtained from these 6 patients before they were diagnosed with PVN revealed no expression of T antigen or p53. Accumulation of p53 in PV-infected cells may occur in response to binding of p53 by T antigen, resulting in stabilization of p53. These results provide the first evidence for intracellular actions of PV T antigen in the context of nonneoplastic diseases.

Autoimmune disease complicating antiviral therapy for hepatitis C virus infection.

OBJECTIVE: To review autoimmune disease complicating therapy with type I interferons (IFNs), specifically in the setting of hepatitis C virus (HCV) infection. METHODS: This study describes 13 reported cases of drug-induced systemic lupus erythematosus (SLE) associated with IFN therapy for the period reported during 1990-2002 by searching MEDLINE. In addition, 2 additional patients are presented, 1 with SLE and 1 with an antineutrophil cytoplasmic antibody (ANCA)-positive nephritis, with long-term follow-up. RESULTS: Of 13 cases of SLE-like syndromes caused by IFN, 2 occurred in patients being treated for HCV infection. Two occurred in patients with rheumatoid arthritis (RA); 1 had Sjogren's syndrome (SS), and 1 laryngeal papillomatosis. The rest were receiving IFN for hematologic malignancies. Symptoms developed between 2 weeks and 7 years after initiation of therapy. Most developed fever and arthralgias/arthritis. Other findings included serositis manifested by tachycardia, dyspnea and pleural effusions, headaches, and hair loss. All had a positive antinuclear antibody (ANA), and the majority had double stranded (ds) DNA antibodies. Two additional patients with chronic HCV infection developed autoimmune disease after combination treatment with IFN-alpha and ribavirin. In each patient, autoimmune disease manifested as severe joint pains, myalgias, fever, rash, and proteinuria. Skin and renal biopsy specimens showed vasculitis and crescentic glomerulonephritis (GN) in the first case, and typical histologic findings of lupus nephritis in the second; clinical and laboratory features were consistent with Wegener's granulomatosis and SLE, respectively. Although both patients had mixed polyclonal cryoglobulins, they were HCV RNA and HCVAb negative. Both received corticosteroids, with gradual clinical and biochemical improvement and without recurrence of viremia. CONCLUSIONS: Autoimmune disorders occur in 4% to 19% of patients receiving IFN-alpha, though SLE-like syndromes are only seen in 0.15% to 0.7%. Clinical and laboratory features of SLE in this setting resemble idiopathic disease, with a generally good outcome after discontinuance of the drug. RELEVANCE: Type I IFNs may cause autoimmune disease such as SLE. As the armamentarium of drugs expands to include other biologics, such as the tumor necrosis factor (TNF)-alpha-inhibiting drugs, the development of autoimmune diseases induced by these drugs is an important consideration for diagnosis and appropriate treatment. Semin Arthritis Rheum 32:163-173.

Renal transplant patient with polyoma virus bladder infection and subsequent polyoma virus nephropathy.

Polyoma virus nephropathy (PVN) is a significant cause of renal allograft dysfunction in transplant patients. A 58-year-old male received a cadaveric renal transplant and 12 weeks later presented with fever, diarrhea, and dysuria. He was diagnosed with a polyoma virus infection of the bladder by a transurethral bladder biopsy. One year post-transplant, he presented with renal allograft dysfunction and was diagnosed by biopsy with PVN of the non-native kidney. The diagnosis of a polyoma virus infection was confirmed by immunoreactivity to the polyoma T-antigen. We suggest that polyoma virus infection of the bladder be included in the differential diagnosis of urinary dysfunction in post-transplant patients, as such infections might be an under-recognized comorbidity in individuals with PVN.