Mizoribine ameliorates the tubulointerstitial fibrosis of obstructive nephropathy.

Mizoribine has been shown to possess an immunosuppressive action that inhibits the proliferation of lymphocytes selectively by interfering with inosine monophosphate dehydrogenase. Recent studies have demonstrated that mizoribine improves renal tubulointerstitial fibrosis in the rat model of unilateral ureteral obstruction (UUO) by inhibiting the infiltration of macrophages. We, therefore, examined the dose dependency of the suppressive effect of mizoribine on the infiltration of interstitial macrophages and T lymphocytes and the interstitial volume in UUO-treated kidneys. Furthermore, we investigated the expression of osteopontin (OPN), known to be a chemoattractant protein for macrophages, in the renal cortex. In rats with UUO, the interstitial volume was markedly expanded, and macrophage and T lymphocyte infiltration in the interstitium and the expression of OPN in the cortical tubules were greatly increased. Treatment with mizoribine ameliorated the increase in interstitial volume induced by UUO. Interstitial infiltration of macrophages and T lymphocytes was dose dependently suppressed by mizoribine, and the decreased macrophage infiltration was correlated with inhibition of tubular OPN expression. These results suggest that mizoribine has a beneficial effect on several steps contributing to the progression of tubulointerstitial fibrosis caused by obstruction of the ureter.

Genetically modified bone marrow-derived vehicle cells site specifically deliver an anti-inflammatory cytokine to inflamed interstitium of obstructive nephropathy.

In this study, we used genetically modified bone marrow-derived CD11b(+)CD18(+) vehicle cells to deliver IL-1 receptor antagonist (IL-1ra) for treatment of inflamed renal interstitium in an animal model of unilateral ureteral obstruction (UUO). Vehicle cells that expressed the ICAM-1 ligands, CD11b and CD18, were obtained from bone marrow cells of DBA/2j mice and adenovirally transduced with the IL-1ra gene or glucocerebrosidase (GC) gene ex vivo. In kidneys treated to develop UUO, levels of ICAM-1, IL-1 beta, and IL-1R expression increased within 3 days compared with contralateral untreated kidneys in the same mice. Similarly, the macrophage infiltration in the cortical interstitium increased after 3 days in UUO kidneys, but not untreated kidneys. After UUO developed, DBA/2j mice were injected i.v. with either IL-1ra(+) vehicle cells (IL-1ra-treated mice) or GC(+) vehicle cells (GC-treated mice) at 24 h after UUO. Six days after the injection of these vehicle cells, marked increase of CD11b(+) IL-1ra(+) vehicle cells was observed in the ICAM-1-positive interstitium of UUO kidneys from IL-1ra-treated mice. In contrast, no CD11b(+) IL-1ra(+) cells appeared in ICAM-1-negative contralateral kidneys from these mice. Furthermore, the infiltration of macrophages (p < 0.001), expression of ICAM-1 (p < 0.005), and presence of alpha-smooth muscle actin (p = 0.005) in the interstitium of UUO kidneys were significantly decreased in IL-1ra-treated mice compared with GC-treated mice. These findings suggest that IL-1 may contribute to the development of renal interstitial injury and that our method can deliver a functioning gene encoding an antiinflammatory cytokine gene specifically at that site by interacting with local adhesion molecules.

Adrenomedullin amidation enzyme activities in hypertensive patients.

Adrenomedullin (AM) is a potent vasodilating peptide secreted from the vasculature of various organs. It is biologically active when its C-terminus is amidated. Recently, an RIA method was developed for measurement of the active form of AM, or mature AM. We here employed this method to investigate the significance of amidation of AM in controlling cardiovascular function. Thirty-six patients under hemodialysis were recruited and divided into hypertensive (n = 25; 157/86 mmHg) and normotensive (n= 11; 116/66 mmHg) groups. Mature AM, immature AM and blood pressure were monitored during hemodialysis in all patients. There was a significant reduction in blood pressure during hemodialysis in both groups, although after hemodialysis blood pressure was still higher in hypertensives than in normotensives (139 +/-14.8/76 +/- 2.5 mmHg vs. 110 +/- 5.1/66.7 +/- 3.1 mmHg). Mature AM before hemodialysis were lower in hypertensives than normotensives and it decreased in both groups. Although mature AM decreased more in normotensives than in hypertensives (-27 +/- 8% vs. -17 +/- 5%), at the end point, its level was still higher in normotensives. The ratio of mature AM/immature AM decreased only in normotensives (-11.4 8.7%), whereas it remained stable in hypertensives (0.2 +/- 5.6%). Both groups showed similar changes in ANP, endothelin, catecholamines, cGMP, and NOx. The low level in mature AM level in hypertensives may have contributed to the higher blood pressure in this group. The attenuation of AM amidation in normotensives indicates that an unspecified amidative enzyme of AM was regulated in order to normalize blood pressure.

Influences of Helicobacter pylori on serum pepsinogen concentrations in dialysis patients.

BACKGROUND: Patients with impaired renal function have been known to have elevated concentrations of serum pepsinogens, which are raised by Helicobacter pylori infection of the stomach. The present study was performed to examine the effect of H. pylori infection on serum pepsinogen concentrations in dialysis patients. METHODS: Forty nine patients on dialysis and 48 subjects with no known kidney disease were examined for upper gastroduodenal endoscopy, H. pylori infection and serum concentrations of pepsinogen I and II. The status of H. pylori infection was evaluated from results of a urease test, histology and culture of biopsy specimens of the gastric mucosa. Serum pepsinogen levels were measured by radioimmunoassay. RESULTS: Serum concentrations of pepsinogen I and II were elevated in the dialysis patients in comparison with those in the controls (277.4+/-24.2 vs 52.6+/-4.0 pg/ml, P<0.01 for pepsinogen I, and 30.2+/-2.9 vs 14.9+/-1.3 pg/ml, P<0.01 for pepsinogen II). In both the dialysis patients and controls, those with H. pylori infection had significantly higher concentrations of serum pepsinogen I and II and a lower ratio of pepsinogen I to pepsinogen II than those without infection. Among the controls, 15 of 25 subjects with atrophic gastritis had a pepsinogen I/pepsinogen II ratio < or = 3.0, while only two out of 17 patients on dialysis fell into this range. CONCLUSIONS: We conclude that H. pylori status should be taken into account when serum pepsinogen concentrations are evaluated in dialysis patients.

[Hyperhomocysteinemia in CAPD patients: peritoneal transport of total homocysteine at peritoneal equilibration test and daily elimination of total homocysteine].

Peritoneal equilibration tests (PET) were performed in patients on continuous ambulatory and automated peritoneal dialysis (CAPD, APD) to evaluate the peritoneal transport capabilities for total homocysteine (tHcy) and other amino acids. Forty-five patients (24 males, 21 females, 50.6 +/- 12.8 years old) maintained on PD for 43.4 +/- 30.3 months participated in the study. PET revealed a markedly lower dialysate to plasma (D/P) ratio of tHcy at 4 hours (0.148 +/- 0.047) than those of other amino acids. A significant positive correlation between the D/P ratio of tHcy and the D/P ratio of creatinine was found, as well as between the D/P ratio of tHcy and the D/P ratio of albumin. The most significant positive correlation was found between dialysate and plasma levels of tHcy at 4 hours. There was no difference in the D/P ratio of tHcy between patients with D/P ratios of creatinine higher than the sample median of 0.68 and with D/P ratios of creatinine below 0.68, while the D/P ratios of other amino acids except threonine in the former patients tended to be higher than those of the latter patients. The D/P ratio of tHcy in patients with serum levels of albumin higher than 4.0 g/dl was significantly higher than that in patients with a ratio less than the sample median of 3.9 g/dl, whereas there were no significant differences in the D/P ratios of other amino acids. These observations suggest that the dialysate level of tHcy is primarily affected by the plasma level of tHcy, and that protein-bound Hcy mainly regulates the D/P ratio of tHcy. Daily peritoneal elimination of tHcy in 20 PD patients was 40.6 +/- 28.4 micromol. A significant positive correlation between the elimination of tHcy and plasma level of tHcy was also found. Daily elimination of tHcy in 7 patients with APD tended to be lower than that in 13 patients with CAPD. These findings indicate that the daily peritoneal elimination of tHcy does not compensate for the daily amount of tHcy metabolized in normal kidney, and that other therapies, such as folic acid administration, are required to improve hyperhomocysteinemia in patients on PD.

Eradication of Helicobacter pylori restores elevation of serum gastrin concentrations in patients with end-stage renal disease.

In order to explore the role of Helicobacter pylori (H. pylori) infection in hypergastrinemia in patients on dialysis, the changes in serum gastrin concentration were examined before and after eradication treatment for H. pylori. Twenty-seven patients on dialysis were treated for the eradication of H. pylori. Fasting serum gastrin concentrations were measured by a radioimmunoassay which detects gastrin 17. Ammonia and pH levels of the gastric juice were also measured. The serum gastrin concentrations were significantly decreased following eradication of H. pylori, and the mean value reached the normal range. The restoration of hypergastrinemia was associated with marked reductions of gastric juice ammonia and pH levels. In contrast, patients in whom H. pylori was not eradicated showed no changes in these parameters. In conclusion, the elevation of the fasting serum gastrin 17 concentration seen in dialysis patients appeared to be attributable to H. pylori infection in the stomach.

[Effects of folic acid supplementation on hyperhomocysteinemia in CAPD patients: effects on unsaturated fatty acids].

Hyperhomocysteinemia has been recognized as one of the risk factors for atherosclerosis and premature vascular disease. Patients on dialysis and end-stage renal disease also manifest high plasma concentrations of homocysteine. We performed this study to evaluate the effects of folic acid supplementation on hyperhomocysteinemia in CAPD patients. Twenty-three CAPD patients (8 males, 15 females, 49.1 +/- 14.2-years-old) dialyzed for 22.7 +/- 19.2 months participated in the study. Daily 5-mg doses of folic acid supplementation for 4 weeks significantly reduced plasma concentrations of total homocysteine (p < 0.01) and serine (p < 0.001). This observation suggests that the reduction of plasma concentrations of total homocysteine results from activation of homocysteine remethylation to methionine. On the other hand, folic acid supplementation also revealed significant correlations between changes in serum concentrations of both dihomo-gamma-linolenic acid and arachidonic acid and changes in plasma concentrations of total homocysteine (r = -0.517, p < 0.05, r = -0.451, p < 0.05, respectively). In addition, serum concentrations of both dihomo-gamma-linolenic acid and arachidonic acid in 11 CAPD patients with hyperhomocysteinemia (> or = 35 micromol/litter) were significantly lower than those of 12 CAPD patients with normohomocysteinemia (< 35 micromol/litter) (p < 0.05, p < 0.05, respectively). Serum concentrations of both dihomo-gamma-linolenic acid and arachidonic acid in CAPD patients with hyperhomocysteinemia increased significantly (p < 0.01, p < 0.05, respectively) and reached similar levels of CAPD patients with normohomocysteinemia, while plasma concentrations of total homocysteine decreased after folic acid supplementation. These findings suggest that correction of hyperhomocysteinemia in patients on dialysis produces an increase in unsaturated fatty acids.

Changes in phenytoin concentrations in blood and cerebrospinal fluid caused by direct hemoperfusion in a patient intoxicated with phenytoin.

We performed direct hemoperfusion (DHP) 5 times on a patient with consciousness disorder and phenytoin intoxication. We then measured the phenytoin concentrations in her cerebrospinal fluid (CSF) and blood at various times. After the first DHP session, consciousness began to improve, and it normalized after the fourth DHP session when the blood concentration of phenytoin had decreased from 54.0 microg/ml to 16.5 microg/ml. The average plasma phenytoin elimination rate of DHP was 18.0% over 120-180 min. The concentration of phenytoin in the CSF decreased as that in the blood was lowered by DHP. The average reduction rate of phenytoin in the CSF after a DHP session was 23.7%, which was similar to the rate of elimination from the blood. The CSF/blood phenytoin ratio was 0.17, and no marked changes were detected before or after a DHP session.

Massive uncomplicated vascular immune complex deposits in the kidney of a patient with systemic lupus erythematosus.

The case of a patient with systemic lupus erythematosus (SLE) is reported which was accompanied by renal dysfunction and massive vascular immune deposits in the kidney without active glomerular lesions. The renal biopsy showed arterioles and small arteries with circumferential periodic acid-Schiff (PAS) and Masson trichrome-positive homogenous material in the subendothelial area in the absence of thrombotic, necrotizing or inflammatory lesions. Immunofluorescence and electron microscopy examination demonstrated immune deposits in the vascular walls. Glomeruli showed only minor abnormalities with a trend to collapse. There was no improvement in renal dysfunction over a 4-year period until the patient's death, despite steroid therapy producing a decrease in disease activity. The autopsy showed similar vascular changes to those seen in the biopsy, however; glomeruli were either sclerotic or showed a trend to collapse. Massive uncomplicated vascular immune complex deposition without active glomerular lesions is rare. The present case indicates that this type of lupus vasculopathy may be a prognostic factor for the loss of renal function in SLE mediated by hemodynamic glomerular injury.