Single low-dose rituximab for the treatment of steroid-resistant nephrotic syndrome with acute kidney injury.

The efficacy of rituximab for kidney disease, such as frequent relapsing nephrotic syndrome, has been reported recently. Herein, we report a case of a patient with acute kidney injury that was steroid-resistant nephrotic syndrome who responded to a single administration of low-dose rituximab. An 86-year-old Japanese woman with hypertension presented with severe peripheral edema within several days after onset. Due to the patient's age, renal biopsy was not performed, nephrotic syndrome was diagnosed and prednisolone was administered at 40 mg/day on the day after admission. However, anuria developed and hemodialysis was inevitably initiated on the 5th hospital day. The renal function did not recover, and the general condition gradually became aggravated. On the 50th hospital day, 100 mg rituximab was administered, which led to immediate depletion of CD20-positive cells. The urine volume gradually increased from 2-3 weeks after the rituximab administration, and the renal function recovered slightly. After 5 weeks, it became possible to wean the patient from dialysis, which had been applied for 3 months. Rituximab might be an option for the treatment of acute kidney injury due to steroid-resistant nephrotic syndrome.

Calcitonin gene-related peptide released by capsaicin suppresses myoelectrical activity of gastric smooth muscle.

BACKGROUND: It is widely accepted that the inhibition of gastric motor activity as well as the maintenance of gastric mucosal blood flow and mucous secretion are important for the homeostasis of the gastric mucosa. The present study was performed to ascertain whether or not capsaicin, which can protect the stomach from noxious stimuli, affects gastric motor activity. METHODS: Male Sprague-Dawley rats were anesthetized with urethane, and the stomach was cannulated by two catheters from esophageal and duodenal sides. A biopolar electrode was fixed to the serosal surface of the antrum and myoelectrical activity was recorded during the instillation of a small volume of solutions. RESULTS: The myoelectrical activity of rat gastric smooth muscle was increased at intragastric pressures of >2 cmH(2)O. Replacement of intragastric physiological saline with 1.6 mmol/L capsaicin solution significantly suppressed this myoelectrical activity by 50%. Intragastric capsaicin administration caused a significant release of substance P (SP) and calcitonin gene-related peptide (CGRP). The maximum released levels of CGRP in the gastric perfusates were 100-fold those of SP. The myoelectrical activity observed at an intragastric pressure of 2 cmH(2)O was avoided by continuous infusion of CGRP (0.1-3.0 nmol/kg per min) into the gastric artery in a dose-dependent manner, but not by that of SP (1.0 nmol/kg per min). Continuous CGRP-(8-37) infusion into the gastric artery completely blocked the reduction by intragastric capsaicin of myoelectrical activity. CONCLUSION: These results suggest that the suppression of the myoelectrical activity of gastric smooth muscle by capsaicin is attributable to the endogenous CGRP released.

Mild irritant prevents ethanol-induced gastric mucosal microcirculatory disturbances through actions of calcitonin gene-related peptide and PGI2 in rats.

Pretreatment with a mild irritant such as 1 M NaCl prevented ethanol-induced mucosal injury, which was abolished by indomethacin, suggesting involvement of endogenous PGs. With the use of intravital microscopy, we investigated the mechanism in microcirculation whereby a mild irritant prevents ethanol-induced mucosal injury. Microcirculation of the basal part of gastric mucosa in anesthetized rats was observed through a window with transillumination. Diameters of arterioles, collecting venules, and venules were measured with an electric microscaler. One molar NaCl alone caused dilation of arterioles and constrictions of collecting venules and venules, which were inhibited by indomethacin. Ethanol (50%) applied to mucosa constricted collecting venules and venules but dilated arterioles. Constriction of collecting venules resulted in mucosal congestion. Pretreatment with 1 M NaCl inhibited ethanol-induced constrictions of collecting venules and venules, and administration of indomethacin or a calcitonin gene-related peptide (CGRP) antagonist, CGRP-(8-37), abolished elimination of constrictions. Topical application (1 nM-10 microM) of PGE2 or beraprost sodium (a PGI2 analog) to microvasculature markedly and dose-dependently dilated arterioles, whereas that of PGE2, but not beraprost, slightly constricted collecting venules. Pretreatment of microvasculature with a nonvasoactive concentration of PGE2 (100 nM) or beraprost (1 nM) completely inhibited ethanol-induced constriction of collecting venules. The inhibitory effect of beraprost but not of PGE2 was abolished by CGRP-(8-37). Present results suggest that the mechanism whereby 1 M NaCl prevents ethanol-induced injury is elimination of constrictions of collecting venules and venules by CGRP whose release may be enhanced by PGI2 but not by PGE2.

Role of kinin and prostaglandin in cutaneous thermal nociception.

Involvements of kinin and prostaglandin and their interaction in noxious thermal stimuli were investigated in noninflamed and inflamed rats. The nociceptive response was evaluated from the escape latency of foot withdrawal to the thermal stimuli with a beam of light. The escape latency in kininogens-deficient Brown Norway (B/N-) Katholiek rats was significantly longer than that in the normal strain, B/N-Kitasato rats. The latency in B/N-Kitasato rat was prolonged by administration of a bradykinin (BK) B2 receptor antagonist, FR173657 (30 mg/kg, p.o.), whereas it was shortened by pretreatment with a kininase II inhibitor, captopril (10 mg/kg, i.p.). Both agents did not affect the latency in B/N-Katholiek rats. In normal Sprague-Dawley (SD) rat, administration of indomethacin did not change the escape latency against the thermal stimuli. In contrast, administration of indomethacin or a relatively cyclooxygenase-1-selective inhibitor, mofezolac (10 mg/kg, p.o.) significantly reduced numbers of writhing reaction in mice induced by acetic acid solution. Injection of lipopolysaccharide (1 mg/kg, i.v.) resulted in shortening escape latency at 8 h after the injection in B/N-Kitasato rats. This hyperalgesia could be reversed by pretreatment of the rats with indomethacin, a cyclooxygenase-2-selective inhibitor JTE-522 (10 mg/kg, p.o.), or FR173657, but not with mofezolac. The hyperalgesia was not seen in B/N-Katholiek rats. These results indicate that kinin has major participation in peripheral skin thermal nociception under noninflamed condition, although cyclooxygenases may have little participation. Prostaglandins produced by cyclooxygenase-2 could coordinate with BK to elicit hyperalgesia during inflammation induced by lipopolysaccharide.

Suppressed angiogenesis in kininogen-deficiencies.

We investigated whether the kinin-generating system enhanced angiogenesis in chronic and proliferative granuloma and in tumor-surrounding stroma. In rat sponge implants, angiogenesis was gradually developed in normal Brown Norway Kitasato rats (BN-Ki). The development of angiogenesis was significantly suppressed in kininogen-deficient Brown Norway Katholiek rats (BN-Ka). The angiogenesis enhanced by basic fibroblast growth factor was also significantly less marked in BN-Ka than in BN-Ki. Naturally occurring angiogenesis was significantly suppressed by B(1) or B(2) antagonist. mRNA of vascular endothelial growth factor was more highly expressed in the granulation tissues in BN-Ki than in BN-Ka. Daily topical injections of aprotinin, but not of soy bean trypsin inhibitor, suppressed angiogenesis. Daily topical injections of low-molecular weight kininogen enhanced angiogenesis in BN-Ka. Topical injections of serum from BN-Ki, but not from BN-Ka, also facilitated angiogenesis in BN-Ka. FR190997, a nonpeptide mimic of bradykinin, promoted angiogenesis markedly, with concomitant increases in vascular endothelial growth factor mRNA. Angiogenesis in the granulation tissues around the implanted Millipore chambers containing Walker-256 cells was markedly more suppressed in BN-Ka than in BN-Ki. Our results suggest that endogenous kinin generated from the tissue kallikrein-kinin system enhances angiogenesis in chronic and proliferative granuloma and in the stroma surrounding a tumor. Thus, the agents for the kinin-generating system and/or kinin receptor signaling may become useful tools for controlling angiogenesis.