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The results of this study suggest that hypophosphatemia, hypocalcemia, hypokalemia, and hypoalbuminemia may predict more serious illness in patients hospitalized with bacterial pneumonia. The development of hypophosphatemia after hospitalization appears [...]

Angiotensin II (ANG II) and endothelin-1 (ET-1) may both play significant roles in causing mesangial expansion and glomerulosclerosis after renal injury by enhancing mesangial cell (MC) proliferation and by increasing MC uptake of macromolecules. Heparin has been demonstrated to significantly ameliorate the development of glomerulosclerosis in animal models of progressive renal injury, although the mechanism is unknown. We undertook the present study to examine in an in vitro system the mechanism by which heparin might modulate the effects of ANG II and ET-1 on MC proliferation and MC uptake of immunoglobulin G (IgG) complexes. Heparin was found to suppress MC uptake of IgG complexes in a concentration-related manner. Whereas ANG II significantly enhanced (P < .01) uptake of IgG complexes, this increase was significantly antagonized (P < .01) by coincubation of MC with heparin at therapeutic concentration (1 U/ml). ET-1 also was found to significantly increase MC uptake of IgG complexes (P < .02), and this increase also was significantly antagonized by coincubation with heparin (P < .02). Heparin was found to inhibit surface binding of IgG to MC in a concentration-related manner (55% reduction at 1 U/ml). MC [3H]thymidine incorporation was significantly enhanced by both ANG II (P < .01) and ET-1 (P < .001) and these mitogenic effects were significantly attenuated by coincubation of cells with heparin (P < .01 and P < .001, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Substantial in vivo evidence suggests a significant role for glomerular capillary pressure in the pathogenesis of progressive glomerulosclerosis. One presently available in vitro system allows one to study cells while undergoing stretch. However, no comparable system is available to allow one to study in an in vitro system how direct application of pressure to glomerular mesangial cells might result in the development of glomerulosclerosis. We constructed a pressure chamber in which mesangial cells could be subjected to an applied pressure by means of a roller pump and adjustable outlet valve. Mesangial cells were grown either under control conditions or under an applied pressure of 40 to 50 mm Hg corresponding to physiologic intraglomerular pressure. Application of pressure significantly decreased mesangial cell number in prolonged culture though no discernable effect on cell proliferation could be detected after only short-term exposure. Long-term exposure to increased pressure significantly enhanced mesangial cell [3H] proline incorporation, a marker for synthesis of the matrix component collagen, an event considered to be a precursor to the development of glomerulosclerosis. Mesangial cell matrix synthesis was significantly greater for cells subjected to 50 to 60 mm Hg pressure compared to 40 to 50 mm Hg pressure. Secretory products from macrophages subjected to 40 to 50 mm Hg of applied pressure were found to significantly enhance mesangial cell proliferation compared to secretory products from macrophages grown under normal pressure. The enhancement of mesangial cell matrix synthesis by pressure could not be attributed to any change in partial pressure of oxygen in the media nor pH. These data suggest that the direct application of pressure to mesangial cells may result in the development of glomerulosclerosis by increasing mesangial cell matrix synthesis. These in vitro data support a role for glomerular capillary pressure in the pathogenesis of progressive glomerulosclerosis.

Human immunodeficiency virus infection is associated with the development of focal segmental glomerulosclerosis (FSGS). The majority of these patients with renal disease, however, are also cocaine abusers, but it is unknown what role cocaine may play in the development of focal segmental glomerulosclerosis. We undertook the present study to determine in vitro whether cocaine can modulate mesangial cell (MC) proliferation, a process believed to be a precursor to the development of glomerulosclerosis, either directly or indirectly via interaction with macrophages (M phi). Cocaine alone was not found to alter significantly either MC number or MC [3H]thymidine incorporation. However, when MC were incubated with secretory products collected from M phi preincubated with standard medium or medium containing cocaine, MC proliferation was found to be significantly enhanced with secretory products from M phi preincubated with cocaine in both serum-free (P < .001) and serum-stimulated conditions (P < .001). The effect of cocaine was found to be concentration-related. Pretreatment of macrophage secretory products from cocaine-treated M phi with neutralizing antibodies to transforming growth factor-beta significantly augmented the mitogenic effect of cocaine macrophage secretory products, and neutralizing antibodies to interleukin-6 significantly attenuated this effect. Direct incubation of MC with transforming growth factor-beta and interleukin-6 caused significant suppression and augmentation of MC proliferation, respectively. These data suggest that cocaine can modulate MC proliferation via interaction with M phi and that interleukin-6 and transforming growth factor-beta participate in this modulating effect. These results support a potential role for cocaine in the development of focal segmental glomerulosclerosis in patients with human immunodeficiency virus infection.