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It was reported previously that dietary fish oil supplementation retarded the progression of renal disease in patients with IgA nephropathy in a multicenter, placebo-controlled, randomized, 2-yr clinical trial. The aim of this study was to determine the long-term influence of fish oil treatment on renal progression in observations on the study cohort of 106 patients extending beyond the 2-yr trial. Renal function was assessed by serial serum creatinine and 24-h urine protein measurements. Vital, end-stage renal disease (ESRD), and BP status and treatment beyond completion of the 2-yr trial were determined. As in the trial, the primary end point was an increase of 50% or more in the serum creatinine, and the secondary end point was ESRD. After a mean follow-up of 6.4 yr, 46 patients-17 in the fish oil group versus 29 in the placebo group-reached the primary end point (P = 0.002), and 27 patients-eight in the fish oil group versus 19 in the placebo group-developed ESRD (P = 0.009). At the end of the 2-yr trial, 75 patients (45 fish oil, 30 placebo) remained at risk for the primary end point. This is also when the double-blind part of the trial ended, allowing physicians to stop supplements, switch original placebo-assigned patients to fish oil, and continue fish oil in original fish oil-assigned patients. A significantly greater number of nonsupplemented placebo patients developed the primary end point (P = 0.02) and ESRD (P = 0.003) compared with long-term supplemented fish oil patients. Conversely, more fish oil-supplemented patients had stable renal function than nonsupplemented patients (P = 0.02). By intention, BP control, primarily treated with angiotensin-converting enzyme inhibition, was equal in the fish oil and placebo groups. Proteinuria was modestly reduced in both groups. It is concluded that early and prolonged treatment with fish oil slows renal progression for high-risk patients with IgA nephropathy.

Tissue factor (TF), the cellular initiator of the protease blood coagulation cascade, has been shown to be expressed in a variety of solid tumors, particularly those of epithelial origin. However, the mechanisms that mediate TF expression in tumors, as well as the clinical implications of this expression, remain largely unknown. In this study, we examined the cytological distribution of TF in normal human breast tissue and breast carcinomas. Epithelial cells exhibited TF immunoreactivity with little obvious correlation with malignant progression from in situ lesions to invasive cancer. However, there was a strong correlation between progression to invasive cancer and the expression of TF antigen in cellular components of the stroma. TF-positive cells were particularly abundant in close proximity to infiltrating tumor cells and included both macrophages and myofibroblasts, as determined by double-immunofluorescent staining for TF and cell type-specific marker proteins. Double-immunofluorescent staining for TF and transforming growth factor beta (TGF-beta) revealed TGF-beta immunoreactivity both in tumor cells and in the extracellular matrix surrounding TF-positive stromal cells. To test the role of carcinoma cell-derived growth factors in the regulation of stromal cell TF activity, we examined the ability of conditioned media (CM) from breast carcinoma cell lines to stimulate TF activity in myofibroblast-like cells in vitro. Extracts from myofibroblasts exposed to CM displayed strong TF procoagulant activity. However, extracts from cells exposed to unconditioned media or CM pretreated with anti-TGF-beta antibodies did not. The induction of TF activity was also observed upon treatment of indicator cells with recombinant TGF-beta isoforms. Collectively, these data indicate that the recruitment and/or activation of TF-expressing stromal cells is an early event in progression to invasive breast cancer and likely occurs, in part, as a paracrine response to tumor cell-derived members of the TGF-beta family of growth factors.

To investigate the frequency of membranous nephropathy associated with nonsteroidal anti-inflammatory drug (NSAID) use and identify associated clinical characteristics.Retrospective chart review.A large group practice that staffs 2 large teaching hospitals.All patients diagnosed as having stage I or early stage II membranous nephropathy by renal biopsy between January 1975 and May 1995.Nephrotic syndrome was said to be associated with NSAID use if patients developed nephrotic syndrome while taking an NSAID and if other causes of membranous nephropathy were excluded and a rapid remission of the nephrotic syndrome followed withdrawal of the drug.Of 125 patients identified with early membranous nephropathy, 29 were taking NSAIDs at the time symptoms of nephrotic syndrome developed. Thirteen of these patients met the criteria for NSAID-associated membranous nephropathy. None of these patients had any evidence of renal insufficiency or significant proteinuria after follow-up periods ranging from 5 months to 13 years. In addition to diclofenac and fenoprofen, which have previously been implicated, ibuprofen, nabumetone, naproxen, and tolmetin were found to be associated.Nephrotic syndrome due to membranous nephropathy should be recognized as an idiosyncratic drug reaction to many NSAIDS. Because withdrawal of the drug may result in prompt and complete recovery of normal renal function, a history of NSAID intake should be sought in patients with membranous nephropathy.

The gene PKD I, which is mutated in type I autosomal dominant polycystic kidney disease (ADPKD 1), encodes a large protein of novel structure and unknown function and distribution that has been named polycystin. To gain better insight into polycystin function, we raised a panel of antisera against synthetic peptide antigens derived from the unique portion of the predicted polycystin sequence. Antisera were used to immunolocalize the protein in a variety of normal human fetal, childhood, and adult tissues as well as kidney and liver tissue from individuals with ADPKD 1, the genetically distinct ADPKD 2, and acquired renal cystic disease (ARCD). Subcellular localization studies were carried out on human cultured cell lines of renal epithelial origin. In normal tissues, polycystin expression was noted in renal tubular epithelial cells from 20 weeks gestation to 4 years postpartum, and in hepatocytes and biliary epithelium up to 4 years, but not in adult kidney or liver. Expression also was present in fetal and childhood pancreas, myocardium, bowel, and adrenal medulla. In cell lines of renal epithelial origin, immunofluorescence and immunoelectron-microscopical studies showed localization of polycystin epitopes to the peripheral cytoplasm. Kidney and liver from four unrelated adults with known ADPKD 1 showed strong staining, which was not seen in kidney and liver from one adult with ADPKD 2 or in kidney from three patients with ARCD. We conclude that polycystin is expressed in renal tubular epithelial cells as well as a variety of other cell types during development and growth but is absent or weakly expressed in adult kidney and liver. Overexpression of polycystin epitopes within affected tissue may be a specific feature of some or all cases of ADPKD 1.

Among 28 autopsied patients with aortoenteric fistulas, the mean age was 67 years (range, 19 to 91 years) and 23 (82%) were men. The most common causes were aortobifemoral bypass grafts (16 cases [57%]) and gastrointestinal carcinomas (6 cases [21%]). Fistulas developed at proximal anastomosis sites in 15 of 16 patients with grafts and were associated with radiation injury in 3 of 6 patients with carcinomas. Aortoenteric fistulas involved the duodenum in 16 (57%), esophagus in 9 (32%), and other gastrointestinal sites in 3 patients (11%). They involved the abdominal aorta in 20 cases (71%) and descending thoracic aorta in 8 cases (29%). Exsanguination from aortoenteric fistulas was the cause of death in 23 cases (82%). Major risk factors for aortoenteric fistulas are aortic bypass grafts and gastrointestinal carcinomas.