BACKGROUND:Macrophages seem to play an important role in the development of glomerulosclerosis. In both human and experimental animal models of focal glomerulosclerosis (FSGS), infiltration of macrophages in the mesangium has been considered key in the development of FSGS. METHODS:In the present study, we evaluated the effect of vasoactive agents on the migration of monocytes across a filter in a modified Boyden chamber as well as across a cultured glomerular endothelial cell layer (in vitro model of glomerular mesangium). Both light as well as scanning electron microscopic studies were performed. We evaluated the effect of vasoactive agents including histamine, prostaglandin (PG) E2, angiotensin II, endothelin-1, platelet-activating factor, and interleukin-1 (IL) on the migration of monocytes/macrophages across an endothelial cell layer as well as a gelatin-coated filter. In addition, we evaluated the effect of cyclic adenosine 3',5' cyclic monophosphate (cAMP) and PGE2 on vasoactive-induced migration of monocytes. RESULTS:Histamine increased (P < 0.003) the migration of monocytes across the filter. This effect of histamine was dose-dependent. Histamine at concentrations of 10(-8) to 10(-5) mol/L induced optimal migration across the filter (control, 16.6 +/- 1.1 vs histamine, 10(-8) mol/L, 40.9 +/- 0.9 monocytes/high power field). Cimetidine, an H2 receptor blocker, attenuated (P < 0.001) the effect of histamine on the migration of monocytes. PGE2 inhibited the migration of monocytes in a dose-dependent manner. Histamine increased (P < 0.001) the passage of monocytes across the glomerular endothelial cell layer (control, 1012 +/- 37 vs 1711 +/- 163 cpm/well). Histamine also increased the migration of murine macrophages across the glomerular endothelial cell layer. PGE2 inhibited the migration of monocytes across the endothelial cell layer under basal as well as histamine-stimulated states. Dibutyryl cyclic (DBc) AMP also attenuated the migration of monocytes under basal as well as histamine-stimulated states. Both PGE2 and DBcAMP also attenuated the IL-1 beta-stimulated migration of monocytes. Angiotensin II, endothelin-1, and platelet-activating factor did not modulate the migration of monocytes. CONCLUSIONS:Vasoactive agents directly modulate the transmigration of monocytes. The present in vitro study provides a basis for a hypothesis that vasoactive agents may also be modulating the migration of monocytes across the glomerular endothelial cell layer (into the mesangium).

BACKGROUND:Systolic blood pressure is well known to increase significantly with age and is strongly correlated with stroke and coronary artery disease. We and other investigators have reported a low prevalence of hypertension in subgroups of patients with HIV infection. In the present study, we examined an ambulatory population of patients with HIV infection to determine whether in the outpatient setting they may lack an age-related increase in systolic blood pressure.METHODS:In an ambulatory outpatient practice, medical records of 178 consecutive patients with HIV infection and those of 200 control subjects were examined. Systolic and diastolic blood pressure and other clinical and laboratory variables were recorded. Scatter plots were generated to compare age with systolic blood pressure. Spearman rank correlation analysis was carried out to determine the relationship between systolic blood pressure and age and other variables.RESULTS:Patients ranged in age from 13 to 69 years. There was only a very slight increase (which did not achieve statistical significance) in systolic blood pressure with aging in the patients with HIV infection, in contrast to the control population, in which an age-related increase in systolic blood pressure was seen that was comparable to published Framingham data. Mean systolic blood pressure for the group as a whole was 118.2 +/- 1.1 mm Hg. Mean serum albumin was 4.2 +/- 0.04 g/dL and was only slightly diminished in older patients. Mean serum cholesterol was 176.8 +/- 3.4 mg/dL and this bore no relationship to aging. More advanced stages of HIV infection also did not correlate with the lack of age-associated systolic hypertension.CONCLUSION:The present population of ambulatory patients infected with HIV seem to lack an age-related increase in systolic blood pressure; this may be caused by such variables as autonomic dysfunction or factors that may attenuate the development of atherosclerosis.

STUDY OBJECTIVES This study was undertaken to evaluate the laboratory abnormalities observed in patients with bacterial pneumonia as predictors of the severity of illness. DESIGN Retrospective analysis. SETTING Tertiary care hospital. PATIENTS AND PARTICIPANTS We studied 302 consecutive patients who were admitted to the Long Island Jewish Medical Center from January through December 1993 and treated for bacterial pneumonia. The patients were subdivided into two groups based on their serum phosphorus level either on hospital admission or 4 days before the onset of pneumonia, if this was acquired in-hospital. Hypophosphatemia (group 1) was defined as serum phosphorus level of < or = 2.4 mg/dL and normophosphatemia > 2.4 mg/dL (group 2). Three hundred randomly selected hospitalized patients treated for conditions other than pneumonia comprised the control group (group 3). MEASUREMENTS Groups 1 and 2 were compared with respect to laboratory data, mortality rate, and duration of hospitalization. The laboratory data of patients in group 3 were compared with those treated for bacterial pneumonia (groups 1 and 2). Stepwise multivariate logistic regression analysis was employed to identify the variables that best predicted the onset of pneumonia. RESULTS In groups 1 and 2, a greater (p < 0.0001) number of patients (135 of 302 patients with pneumonia, 44.7%) developed hypophosphatemia compared with patients in group 3 (31 of 300 control subjects, 10.3%). Patients with pneumonia (groups 1 and 2) had higher levels (p < 0.01) of bicarbonate compared with control subjects. Moreover, patients with pneumonia demonstrated lower levels (p < 0.01) of calcium, phosphorus, albumin, cholesterol, and alanine aminotransferase compared with control patients (group 3). Among patients with pneumonia, those with hypophosphatemia (group 1) had significantly lower levels (p < 0.05) of potassium, calcium, and albumin compared to those subjects with normophosphatemia (group 2). Furthermore, hypophosphatemic subjects manifested higher levels of glucose (p < 0.01) and creatine phosphokinase (p < 0.05) compared to their normophosphatemic counterparts. In addition, hypophosphatemic patients experienced a longer duration of hospital stay (hypophosphatemia, 24.6 +/- 2.0 days, vs normophosphatemia, 14.1 +/- 1.0, p < 0.001) and higher (p < 0.001) mortality compared to normophosphatemic subjects. The incidence of nosocomial pneumonia was higher (p < 0.0001) in hypophosphatemic patients compared to those with normophosphatemia. CONCLUSION We conclude that hypophosphatemia, hypocalcemia, hypokalemia, and hypoalbuminemia may be predictors of the severity of illness in patients admitted to the hospital with bacterial pneumonia.

We report the case of a patient with acquired immunodeficiency syndrome (AIDS) who developed nephrotic syndrome and progressive renal failure mimicking human immunodeficiency virus (HIV)-associated focal segmental glomerulosclerosis (FSGS) who required initiation of hemodialysis and was found on renal biopsy to have membranous nephropathy. Hepatitis B and C serologies were negative. Although she required hemodialysis, she was treated with prednisone and experienced a progressive decline in her serum creatinine from 10.1 mg/dL to 1.9 mg/dL, which permitted the discontinuation of hemodialysis. After she abruptly discontinued prednisone, her creatinine level increased to 4.8 mg/dL, and she experienced marked worsening of her nephrotic syndrome. Resumption of prednisone resulted in normalization of serum creatinine and reduction in urine protein excretion. No adverse effects of prednisone occurred during this time. She remains off of hemodialysis for 1 year with a serum creatinine level of 1.0 mg/dL and urine protein excretion of 0.4 g/d. Although most patients with HIV infection, nephrotic-range proteinuria, and renal failure have FSGS, a minority may have membranous nephropathy. Although typically not a steroid-responsive lesion in the setting of advanced renal failure, membranous nephropathy may be a highly steroid-responsive lesion in the HIV-infected patient, and treatment may help avert the need for dialysis in a patient population that generally has a poor outcome on dialysis.

Patients with chronic renal interstitital diseases often develop glomerular lesions (focal segmental glomerular sclerosis). Because mesangial expansion (enhanced mesangial cell (MC) growth and matrix accumulation) has been demonstrated to precede the development of focal segmental glomerulosclerosis, we studied the effect of the interaction between bacteria such as Escherichia coli and macrophages on MC proliferation and matrix synthesis. We determined the effect of control media (CM), E. coli supernatant (ESP), serum-free macrophage supernatant (MSP), and E. coli-treated macrophage supernatants (HB101-MSP, H10-MSP) on the proliferation of MCs and synthesis of laminin (a component of mesangial matrix). ESP did not alter MC growth, whereas E. coli MSP increased the mean MC number by 5- to 6-fold when compared to cells treated with CM. Both HB101-MSP and H10-MSP stimulated greater (p < 0.05) incorporation of [3H]thymidine when compared with MSP (HB101-MSP 3.1 +/- 0.4, H10-MSP 2.7 +/- 0.3 vs. MSP 1.6 +/- 0.2 x 10(6) cpm/micrograms protein). When MC proliferation was judged by incorporation of bromodeoxyuridine, both HB101-MSP- and H10-MSP-treated cells showed a greater (p < 0.01) number of proliferating cells compared with cells treated with either MSP or CM. MC treated with H10-MSP grew in a specific pattern and showed a tendency to form hillocks (foci of cell proliferation and matrix aggregation). Both HB101-MSP and H10-MSP enhanced (p < 0.01) synthesis of laminin compared with CM. HB101-MSP-induced enhanced laminin synthesis was attenuated when MCs were treated with anti-transforming growth factor (TGF)-beta antibodies. HB101-MSP also increased mRNA expression of TGF-beta by MCs. These results indicate that E. coli-macrophage interaction has the potential to cause mesangial expansion.

Increased pressure, as may occur with hypertension, may alter cellular function by inducing repetitive mechanical strain. However, increased pressure itself may directly alter cellular function independent of stretching of cells. We undertook the present study to determine whether increased applied pressure could alter uptake of IgG complexes by macrophages. Increased pressure was applied to confluent macrophages grown on plastic culture plates using a pressure chamber apparatus kept inside the incubator at 37 degrees C and pressure regulated using a rotator pump and adjustable outlet valve. Macrophages that were subjected to increased pressure were found to have a significantly greater uptake of IgG complexes in a dose-dependent manner. The effect of increased pressure could be abrogated by carrying out experiments in calcium-free medium while this exerted no effect on uptake by macrophages under control conditions. Increased uptake of IgG complexes by macrophages subjected to increased applied pressure could also be attenuated by incubation with the calcium channel blockers amlodipine and cinnarizine. To determine whether the effect of increased pressure was related to the plastic substrate on which the cells are grown, cells were also seeded onto type I collagen gels and uptake of IgG complexes was measured. Uptake by macrophages on the type I collagen substrate was significantly enhanced with increased applied pressure compared to control (p < 0.01). These studies demonstrate that exposure of macrophages to increased pressure enhances their uptake of IgG complexes via a mechanism that appears to involve an increase in intracellular calcium. This effect might play a role in some of the consequences of systemic arterial and glomerular capillary hypertension.

Uptake of immunoglobulin G (IgG) complexes by macrophages (M phi) may play an important role in disease states characterized by increased levels of circulating immune complexes. In sites such as the glomerular mesangium M phi may be subjected to repetitive mechanical strain, although in vitro studies of M phi endocytosis are typically carried out with cells grown on rigid surfaces. We undertook the present study to determine whether repetitive mechanical strain could modulate M phi endocytosis of IgG complexes. IgG complex uptake was significantly diminished in M phi that were subjected to repetitive mechanical strain using parameters corresponding to peak and minimal intraglomerular pressures compared with control, and uptake varied according to the amount of mechanical strain applied. There was no significant difference in surface binding of IgG between M phi subjected to strain and those not. Mechanical strain did not significantly influence the rate of IgG complex degradation. Inhibition of nitric oxide synthase and guanylate cyclase activity did not alter the effect of mechanical strain, although this effect was potentiated by 3-isobutyl-1-methylxanthine (IBMX). Angiotensin II, which has been shown to reduce adenosine 3',5'-cyclic monophosphate (cAMP) production in M phi, significantly attenuated the suppressive effect of mechanical strain on IgG complex uptake as well as another inhibitor of cAMP generation, indomethacin. Enzyme immunoassay demonstrated significantly enhanced levels of cAMP in M phi that were subjected to mechanical strain compared with control, an effect that was potentiated by IBMX and attenuated by angiotensin II and indomethacin. These results demonstrate that repetitive mechanical strain significantly reduces IgG complex uptake by M phi, most likely by enhancing cAMP synthesis. Such an effect might play a significant role in macromolecule handling by M phi in sites in which they are subjected to repetitive mechanical deformation such as the glomerular mesangium.