Cerebral ischemia as a causative mechanism for rapid progression of brain atrophy in chronic hemodialysis patients.

BACKGROUND: It has been found that brain atrophy develops more rapidly in patients with end-stage renal failure after initiation of dialysis therapy. The present study was designed to analyze the relationship between brain atrophy and asymptomatic ischemic brain lesions. PATIENTS AND METHODS: Magnetic resonance imaging (MRI) was performed for the evaluation of brain atrophy and ischemic lesions. Brain atrophy was assessed by the ventricular-brain ratio (VBR), calculated as the ratio of the ventricular area to the whole brain area on the maximum MRI slice. The severity of periventricular hyperintensity (PVH) and the number of lacunae were also regarded as ischemic brain lesions. Fifty-five patients undergoing maintenance hemodialysis (HD) without clinically overt neurological signs and symptoms, with a mean age of 52 +/- 11 (SD) years and a mean HD duration of 7 +/- 6 (SD) years were subjected. VBR and its relationship to ischemic brain lesion data were compared to those in 35 non-HD patients (controls), with a mean age of 42 +/- 14 (SD) years. RESULTS: The VBR, the number of lacunae and the severity of PVH tended to increase with age in HD. The VBRs at all age groups were significantly higher in HD than in controls (7.0 vs 3.7% at the 4th decade, p < 0.05; 8.4 vs 5. 9% at the 5th decade, p < 0.05; 9.6 vs 5.4% at the 6th decade, p < 0.05; and 11.6 vs 6.3% at the 7th decade, p < 0.05). HD patients had significantly higher number of lacunae and had more advanced PVH than did controls. Both the number of lacunae and the severity of PVH were significantly correlated to VBR in HD. CONCLUSION: In conclusion, the rapid progression of brain atrophy was related to the asymptomatic ischemic brain lesions in our HD patients. Such data indicated that cerebral ischemia might be a causative mechanism of brain atrophy in chronic hemodialysis patients.

Inhibitory effects of antihypertensive drugs on mesangial cell proliferation after anti-thymocyte serum (ATS)-induced mesangiolysis in spontaneously hypertensive rats.

The effects of antihypertensive drugs on mesangial cell proliferation were studied in spontaneously hypertensive rats (SHR) with anti-thymocyte serum (ATS)-induced glomerulo-nephritis. Rats were treated with either enalapril (Group 1), nifedipine (Group 2), or reserpine + hydrochlorothiazide + hydralazine (Group 3), or were untreated (Group 4). The animals were sacrificed 2, 4 and 7 days after ATS injection and the glomerular cell number and degree of mesangial area expansion were examined. A marked, similar decrease in glomerular nuclear cell number (NC) due to severe mesangiolysis was observed in all of the groups on day 2. Thereafter, an increase in NC reflecting mesangial cell proliferation after mesangiolysis occurred in Group 4 on days 4 and 7. In Group 1 and 2, the NC was significantly smaller than that in Group 4 on days 4 and 7, indicating suppression of mesangial cell proliferation. In Group 3, however, the number of NCs did not differ from that in Group 4 on days 4 and 7, indicating a lack of such suppression by conventional antihypertensive drugs. The degree of mesangial area expansion (MS) showed the same pattern as mesangial cell proliferation. That is, the rapid increases in MS seen in Group 4 on days 4 and 7 were apparently suppressed in Groups 1 and 2, but not in Group 3. Our in vivo observations that both an angiotensin converting enzyme (ACE) inhibitor and a calcium channel blocker suppress mesangial cell proliferation and mesangial area expansion suggest that these agents have practical implications in the treatment of mesangial proliferative glomerular diseases through the suppression of excess mesangial cell proliferation.

Effects of endothelin and angiotensin II on renal hemodynamics in experimental mesangial proliferative nephritis.

The renal hemodynamic response to pressor substances in the diseased kidney has been suggested to be different from that in the normal kidney. The aim of this study was to investigate the effects of endothelin and angiotensin II on renal hemodynamics in experimental nephritis induced by the administration of antithymocyte serum in Wistar rats. This model showed mesangiolytic lesions in the glomeruli on day 2 and hypercellular lesions on day 8. Prior to the injection of either endothelin or angiotensin II, the glomerular filtration rate and renal plasma flow were significantly lower in model rats on day 2 or day 8 than in the control rats. The basal glomerular filtration rate and renal plasma flow on day 8 were negatively correlated with the mesangium cell number. The injection of endothelin (0.5 ng/kg BW) led to a decrease in both renal plasma flow and glomerular filtration rate in rats on day 8 which was significantly greater than that in the control rats. Similarly, angiotensin II infusion (0.2 micrograms/kg BW) reduced both renal plasma flow and glomerular filtration rate in the rats on day 8 and the reductions were significantly greater than those in the control rats. In conclusion, renal hemodynamics in rats with mesangial proliferation of the kidney were more sensitive to both endothelin and angiotensin II than those in the normal kidney.

Glomerular matrix accumulation is linked to inhibition of the plasmin protease system.

TGF-beta plays a pivotal role in the pathological accumulation of extracellular matrix in experimental glomerulonephritis. Increased TGF-beta expression leads to increased synthesis and deposition of extracellular matrix components while administration of anti-serum to TGF-beta suppresses the major manifestations of the disease. We hypothesized that TGF-beta might also enhance matrix accumulation by decreasing matrix turnover via effects on protease/protease inhibitor balance. Plasmin is a potent protease capable of degrading a variety of matrix molecules. Plasmin generation from plasminogen is regulated by plasminogen activator(s) (PA) and plasminogen activator inhibitor(s) (PAI). In this study PA activity was markedly reduced and PAI-1 synthesis dramatically increased when TGF-beta was added to normal glomeruli. Diseased glomeruli also showed decreased PA activity, increased PAI-1 synthesis and increased PAI-1 deposition into matrix. Administration of anti-TGF-beta serum to glomerulonephritic rats blocked the expected increase in glomerular PAI-1 deposition. Thus changes in the PA/PAI balance favoring accumulation of matrix are induced by TGF-beta in normal glomeruli and are present in nephritic glomeruli when endogenous TGF-beta production is high. Our findings implicate the plasmin protease system in tissue repair following acute glomerular injury and suggest another mechanism by which TGF-beta enhances the matrix accumulation characteristic of many glomerular diseases.

'Radioresistant' CD4-CD8- intrathymic T cell precursors differentiate into mature CD4+CD8- and CD4-CD8+ T cells. Development of 'radioresistant' CD4-CD8- intrathymic T cell precursors.

Using lectin (PNA) and monoclonal antibodies for Pgp-1, IL-2R, H-2k, CD3, and F23.1 (T cell receptor V beta 8), we characterized the 'radioresistant' CD4-CD8- double negative thymocytes at an early stage after 800 rad irradiation. Most of the CD4-CD8- cells on day 8 after irradiation expressed a high level of Thy-1, H-2k, and PNA, while a small proportion of these cells were CD3+ and/or F23.1+. The appearance of Pgp-1 and IL-2R on the 'radioresistant' double negative precursors was also sequentially examined from day 5 to day 9 after irradiation. The double negative thymocytes at day 5 expressed the highest level of Pgp-1 antigens and these cells gradually decreased in number from day 7 to day 9. By contrast, IL-2R was transiently expressed on the double negative cells on the day 7 and 8 after irradiation. These results indicate that progression of thymocyte development occurred within the CD4-CD8- thymocytes after irradiation. We further examined the homing ability of the double negative 'radioresistant' intrathymic T cell precursors to the periphery by intrathymic cell transplantation method. The double negative thymocytes proliferate and differentiate into CD4+CD8+ cells and CD4+CD8- cells but few CD4-CD8+ cells in the thymus, while only CD4-CD8+ cells were detected in the peripheral lymphoid organs 14 days after intrathymic transplantation of the double negative cells in the H-2 compatible Thy-1 congenic mice. These results suggest that the 'radioresistant' intrathymic precursors differentiate and mature in the thymus and migrate to the periphery.

A new T cell subset expressing B220 and CD4 in lpr mice: defects in the response to mitogens and in the production of IL-2.

Autoimmune-prone mice homozygous for the lpr gene develop prominent lymphadenopathy composed mainly of Thy-1+ CD8- CD4- B220+ cells. Expression patterns of B220 vs CD4 on lymph node cells from lpr mice were analysed using two-colour flow microfluorometry. B220+CD4+ cells, which were hardly seen in lymph nodes of B6-+/+ mice, increased significantly in B6-lpr mice with ageing. Functional analysis of purified B220+ CD4+ cells from lpr mice revealed that these cells scarcely responded to T cell mitogens with or without rIL-2. Furthermore, B220+ CD4+ cells were defective in IL-2 production when cultured with Con A. On the other hand, B220-CD4+ cells from B6-lpr mice showed an ability to respond to T cell mitogens similar to that of B220- CD4+ cells from B6-+/+ mice. These results indicate that an unusual T cell subset expressing both B220 and CD4 in lpr mice is functionally defective, but the intrinsic ability of B220-CD4+ cells is almost intact as compared with the counterpart in normal mice.

"Radioresistant" intrathymic T cell precursors express T cell receptor C gamma 4- and C delta-specific gene messages.

We have studied the expression and sequences of T cell receptor gamma and delta chain gene messages in intrathymic T cell precursors of mice irradiated with 600 rads. On day 7 after irradiation a high level of expression of gamma and delta chain messages was detected in thymocytes which were composed of a relatively high proportion of CD3+CD4-CD8- thymocytes. During further development of the precursors from day 7 to day 14 after irradiation, gamma and delta chain messages fell to low levels and alpha and beta mRNA levels increased. Nucleotide sequence analysis of 14 gamma and 10 delta chain complementary DNA (cDNA) in the thymocytes on day 7 revealed that there were 7 functional gamma chain transcripts composed of V gamma 2-J gamma 2-C gamma 2 or V gamma 1-J gamma 4-C gamma 4 gene segments, and only 1 functional delta chain transcript composed of the V delta M23-D delta 1-D delta 2-J delta 1-C delta gene segments. The repertoire of gamma chain and delta chain genes used in "radioresistant" intrathymic T cell precursors of adult mice appears to be limited.

Sequential appearance of thymocyte subpopulations and T cell antigen receptor gene messages in the mouse thymus after sublethal irradiation.

The sequential differentiation patterns of thymocyte were observed with cell surface phenotypes and the expression of T cell antigen receptor in 800 rad irradiated adult mice. Thymus was severely reduced in size and cell number by day 5 after whole body irradiation and rapidly recovered from day 7 to day 14. Surface marker analysis on day 5 after irradiation showed thymocytes with Thy-1low L3T4+/Lyt-2- dominantly existed and suggested that these cells were radioresistant-survived cells. On the other hand, thymocytes on day 7 were composed of a large number of Thy-1high L3T4+/Lyt-2+ blast-like cells and a relatively high proportion of Thy-1high L3T4-/Lyt-2- cells which expressed a large amount of gamma-chain gene messages but scarcely any alpha- and beta-chain gene messages similar to the fetal thymocytes. On day 14, thymocytes were composed mostly of Thy-1high H-2low L3T4+/Lyt-2+ subpopulation which expressed a remarkably low level of gamma-chain gene messages, and high levels of alpha- and beta-chain transcripts analogous to those of normal adult thymus. Taken together, intrathymic radioresistent stem cells for T thymocytes seem to proliferate and differentiate after irradiation with the same pattern as was seen in a fetal thymus development.

Incidence of strokes and its prognosis in patients on maintenance hemodialysis.

The incidences of cerebral hemorrhage (CH), cerebral infarction (CI) and subarachnoid hemorrhage (SAH) were examined retrospectively in patients with chronic renal failure on maintenance hemodialysis, followed for 13 years in our 26 satellite dialysis centers. During 10,364 patient-years of experience (PYE), CH developed in 66, CI in 16, SAH in 3 and unclassified stroke in 5 cases. The incidence was 637 per 10(5) PYE for CH and 154 for CI, the former being approximately 5 times and the latter one third of the incidence of CH or CI in the general population in Japan. Forty-six percent of fatal CH cases died within 24 hours and 73% within 3 days after the onset, while 13% of CI deaths died within 24 hours and 26% within 3 days. These data suggest that factors such as the regular use of heparin as an anticoagulant in hemodialysis patients or other inherent factors in these patients may increase vulnerability to CH and decrease the probability of CI.

Indomethacin-induced sialic acid-mediated changes in surface markers from "cortical type" to "medullary type" in murine thymoma line EL-4.

The effect of indomethacin (INDO), a specific inhibitor of prostaglandin (PG) synthesis, on the expression of markers during thymocyte differentiation such as Thy-1, H-2K, and peanut agglutinin (PNA) receptor was examined by immunofluorescence, using poorly differentiated thymoma, EL-4, as the indicator cells. EL-4 cells grown in the culture medium in the presence of INDO exhibited lower levels of Thy-1 and PNA, and a higher level of H-2K, compared with the EL-4 cells grown in medium without INDO. The decrease in PNA level by INDO was attributed to an increased density of sialic acid bound to PNA receptors on the cell surface, because treatment with neuraminidase (Nase) released more sialic acid from such cells, as compared with control cells, and markedly increased the detectable amounts of PNA receptors. On the other hand, a decrease of Thy-1 or an increase of H-2K may be ascribed to the decrease of Nase-resistant sialic acid on the cell surface, determined by analyses with FITC-LPA, sialic acid-specific lectin, and by metabolic labeling of surface sialic acid. These results suggest that the PG-system modulates the metabolism of sialic acid located on the thymocyte surface and alters the expression of surface markers of thymocytes.

Pharmacokinetics of a new angiotensin I converting enzyme inhibitor (alacepril) after oral dosing in fasting or fed states.

The plasma concentration and urinary excretion of a newly developed angiotensin I converting enzyme inhibitor, alacepril (which is converted to captopril after absorption), were investigated in seven normal healthy subjects. Fifty milligrams of the drug was administered orally either in the fasting or in the fed state. In the fasting state, the time of maximal plasma concentration (tmax) was 1 hour for free captopril, 1.7 hours for protein-conjugated captopril, and 1.6 hours for total captopril. The biologic t1/2 of free, protein-conjugated, and total captopril was 1.9, 4.2, and 5 hours, respectively. In the fed state, neither tmax nor t1/2 changed, except that the tmax of free captopril was prolonged to 1.9 hours (P less than 0.01). Cumulative urinary excretion of free captopril at 8 hours was 35% of the drug administered in the fasting state and that of total captopril at 24 hours was 59%. These data did not differ significantly from those obtained after food intake. The biologic t1/2 of free captopril after alacepril dosing was longer than in previous studies of captopril per se. Because biologic or clinical effects have not been studied, it should be left conjectural whether alacepril is a longer-acting angiotensin I converting enzyme inhibitor. A prolonged effect of the drug can be expected by its administration after a meal.