Kazue Ueki

Revised classification of lupus nephritis is valuable in predicting renal outcome with an indication of the proportion of glomeruli affected by chronic lesions

OBJECTIVES To determine if the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification of lupus nephritis (LN) is helpful in predicting renal outcome. METHODS A total of 92 patients with LN who underwent renal biopsy in our hospital were re-classified according to the ISN/RPS 2003 criteria. RESULTS The mean patient age was 36.8 yrs and the median observation period was 65 months. The relative frequency for each class was as follows: Class I (minimal mesangial LN) 0%, Class II (mesangial proliferative LN) 13%, Class III (focal LN) 17%, Class IV (diffuse LN) 60% and Class V (membranous LN) 10%. Within Class IV, diffuse segmental (Class IV-S) was 25% and diffuse global (Class IV-G) 75%. During the observation period, renal function was more likely to deteriorate in Class IV-G cases than in Class IV-S cases. Importantly, when Class IV-G was subdivided into cases involving active lesion alone [IV-G (A)] or chronic lesion [IV-G (A/C)], the majority of cases in IV-G (A) was nephrotic, but responded well to therapy. In contrast, renal function declined only in IV-G (A/C) cases. Patients with Class IV-G (A/C) had persistent proteinuria in spite of intensified therapies. Moreover, the higher proportion of chronic lesions was related with the deterioration of renal function. CONCLUSIONS This study showed that in Class IV-G cases, renal outcome differed in the presence of chronicity. Chronicity could be a critical factor in predicting outcome. Thus, the revised classification of LN is clinically valuable in identifying different renal outcomes among patients with diffuse LN.

Increased levels of serum sulfite in patients with acute pneumonia.

Sulfite, a common air pollutant, is toxic for humans, causing hypersensitivity or chronic airway diseases. We previously reported that sulfite is actively produced from neutrophils by stimulation with bacterial endotoxin, lipopolysaccharide (LPS). We also found that the serum sulfite concentration is increased in a rat model of sepsis induced by systemic injection of LPS. However, information on sulfite metabolism in human inflammatory conditions is limited. In the current study, the serum concentration of sulfite was determined in 25 patients with acute pneumonia. Serum sulfite concentration in pneumonia patients was significantly higher than that in control subjects (3.75 ± 0.88 vs. 1.23 ± 0.48 &mgr;M, respectively, P < 0.05). Among 20 patients, serum sulfite was serially determined before and after antibiotic therapy. The levels of serum sulfite were significantly reduced during the recovery phase compared with those during the acute phase (1.34 ± 0.56 vs. 3.65 ± 0.92 &mgr;M, respectively, P < 0.05). Moreover, neutrophils obtained from three patients during the acute phase of pneumonia spontaneously produced higher amounts of sulfite in vitro than those obtained after recovery. There was a close positive correlation (r = 0.71, P < 0.05) between serum sulfite and C-reactive protein (CRP) in patients with pneumonia. Taken together, the current findings suggest that serum sulfite increases during systemic inflammation in humans. Activated neutrophils might be responsible, at least in part, for the up-regulation of sulfite. Given various biological effects reported previously, sulfite may act as a mediator in inflammation.

SULFITE IS RELEASED BY HUMAN NEUTROPHILS IN RESPONSE TO STIMULATION WITH LIPOPOLYSACCHARIDE

Exposure to sulfite, a well‐known air pollutant, induces inflammatory reactions characterized by neutrophil infiltration into the airways. Using a simple and sensitive assay for sulfite concentration in biological fluids, we demonstrate herein that human neutrophils released significant amounts of sulfite (1.0 nmol/h/107 cells) in response to lipopolysaccharide (LPS), a major component of bacterial endotoxin. A large proportion of the sulfite release by neutrophils was dependent on inorganic sulfate contained in culture media, suggesting production via the sulfate reducing pathway in this response. We also show that glucocorticoids and FK506 completely inhibit LPS‐mediated sulfite release by neutrophils. Given the well‐known antimicrobial activities of sulfite, our results suggest that sulfite acts as a neutrophil mediator of host defense. A putative role of sulfite as an endogenous biological mediator is further underscored by the observation that in vivo administration of LPS is associated with a marked increase in the serum concentration of sulfite in Wistar rats. Inhibition of sulfite release by immunosuppressive agents may contribute to increased susceptibility to bacterial infection commonly associated with the administration of these drugs. J. Leukoc. Biol. 64: 595–599; 1998.

Integrin-mediated signal transduction in cells lacking focal adhesion kinase p125FAK.

We have previously shown that integrin‐dependent tyrosine phosphorylation of p130Cas (Cas) could be induced in a mouse fibroblast cell line that does not express focal adhesion kinase p125FAK (FAK). By analyzing FAK‐deficient (FAK−/−) cells transiently expressing Cas mutant proteins, we demonstrate here that the Src homology 3 (SH3) domain of Cas is indispensable for adhesion‐mediated Cas phosphorylation in this mutant cell line. While the FAK directly binds to Cas‐SH3, our findings imply that SH3‐binding molecule(s) other than FAK might regulate Cas phosphorylation, at least in FAK−/− cells. In this regard, we observed that FAK−/− cells expressed cell adhesion kinase β (CAKβ), a protein tyrosine kinase of the FAK subfamily. CAKβ expressed by FAK−/− cells was associated in vivo with Cas in a Cas‐SH3‐dependent manner. Moreover, integrin stimulation induces tyrosine phosphorylation of CAKβ in FAK−/− cells. Thus, our results suggest that CAKβ contributes to integrin‐mediated signal transduction in place of FAK in FAK‐deficient cells.

Adult Still's disease as a paraneoplastic manifestation of breast cancer

We treated a patient who developed symptoms and findings indistinguishable from those of adult Stills disease as a manifestation of metastatic breast cancer 7 years after treatment for a stage 1 tumor. Although clinical features fulfilled diagnostic criteria for adult Stills disease, examination of a bone marrow biopsy specimen indicated that the apparent adult Stills disease was a paraneoplastic manifestation associated with diffuse marrow infiltration by breast cancer. The fever and polyarthralgia resolved with administration of prednisolone, and antiestrogen therapy with tamoxifen citrate was also started.We treated a patient who developed symptoms and findings indistinguishable from those of adult Stills disease as a manifestation of metastatic breast cancer 7 years after treatment for a stage 1 tumor. Although clinical features fulfilled diagnostic criteria for adult Stills disease, examination of a bone marrow biopsy specimen indicated that the apparent adult Stills disease was a paraneoplastic manifestation associated with diffuse marrow infiltration by breast cancer. The fever and polyarthralgia resolved with administration of prednisolone, and antiestrogen therapy with tamoxifen citrate was also started.

Fluvastatin Reduces Renal Fibroblast Proliferation and Production of Type III Collagen: Therapeutic Implications for Tubulointerstitial Fibrosis

Background: Accumulating evidence suggests that hydroxymethylglutaryl-CoA reductase inhibitors have many biological effects beyond reducing cholesterol synthesis. In a mouse model of renal interstitial fibrosis induced by unilateral ureteral obstruction, fluvastatin, one of the lipophilic hydroxymethylglutaryl-CoA reductase inhibitors, was shown to ameliorate fibrosis. Methods: In the present study, we examined the direct effects of fluvastatin on proliferation, matrix and growth factor production by rat kidney fibroblasts (NRK-49F cells). Results: Treatment with fluvastatin reduced proliferation of NRK-49F cells in a dose-dependent manner. The addition of mevalonate or geranylgeranyl pyrophosphate but not farnesyl pyrophosphate to the culture medium almost completely abolished the effect of fluvastatin. Moreover, fluvastatin treatment decreased the expression of activated Rho in NRK-49F cells suggesting that fluvastatin may decrease cell growth through blocking the activation of Rho. The majority of fluvastatin-treated cells were arrested at the G1 phase, associated with down-regulation of cyclin A and up-regulation of cyclin-dependent kinase inhibitor p27kip1, indicating that cell cycle modulation is an important mechanism. Fluvastatin significantly decreased messenger RNA expression of type III collagen and connective tissue growth factor. Conclusions: Taken together, it is suggested that fluvastatin may prevent tubulointerstitial fibrosis in a variety of progressive renal diseases by inhibiting proliferation of interstitial fibroblasts and their matrix synthesis.

Widespread crystalline inclusions affecting podocytes, tubular cells and interstitial histiocytes in the myeloma kidney

Numerous crystalline inclusions were observed in glomerular and tubular epithelial cells in a 46-year-old female patient with multiple myeloma and renal dysfunction. On light microscopy, epithelial cells were filled with homogenous materials and were remarkably swollen. Infiltrations of histiocytes with expanded cytoplasm were also seen in the interstitium of the kidney and bone marrow. On electron microscopy, cytoplasmic inclusions had crystalline structure showing rhomboid and oval shapes. Immunofluorescence study revealed that these cells were positive for IgG-kappa. The combination chemotherapy followed by autologous stem cell transplantation led to a partial resolution of her renal dysfunction, continued by a slight reduction in the number of crystalline-containing podocytes at the second renal biopsy. Crystal inclusions in the kidney are rarely found and cause renal impairment in multiple myeloma.

Extracorporeal membrane oxygenation for the management of respiratory failure due to ANCA-associated vasculitis.

We present here two patients whose near fatal respiratory distress was caused by pulmonary hemorrhage, and who were treated successfully by extracorporeal membrane oxygenation (ECMO). The underlying disease was antineutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis. They were initially treated with methylprednisolone pulse therapy along with cyclophosphamide. However, their respiratory failure progressed with a low PaO2/FiO2 ratio (<100 mmHg) despite mechanical ventilation, and ECMO was initiated. After several days, the pulmonary hemorrhage subsided, and the patients were weaned successfully from ECMO. We suggest that ECMO may be used to manage life-threatening pulmonary hemorrhage in patients suffering from ANCA-associated systemic vasculitis.We present here two patients whose near fatal respiratory distress was caused by pulmonary hemorrhage, and who were treated successfully by extracorporeal membrane oxygenation (ECMO). The underlying disease was anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis. They were initially treated with methylprednisolone pulse therapy along with cyclophosphamide. However, their respiratory failure progressed with a low PaO2/FiO2 ratio (< 100 mmHg) despite mechanical ventilation, and ECMO was initiated. After several days, the pulmonary hemorrhage subsided, and the patients were weaned successfully from ECMO. We suggest that ECMO may be used to manage life-threatening pulmonary hemorrhage in patients suffering from ANCA-associated systemic vasculitis.

Treatment of adult Still's disease with dexamethasone, an alternative to prednisolone.

We successfully treated three cases of adult Stills disease (ASD) with dexamethasone. High dose prednisolone, which was initially used to treat these patients, failed to remit the disease in all cases. Although they were resistant to prednisolone, all these patients had remarkable improvements in clinical and laboratory findings after switching to an equivalent dose of dexamethasone. We propose using dexamethasone as an alternative for treating ASD before adding immunosuppressants or disease modifying anti-rheumatic drugs (DMARD), when prednisolone therapy does not suppress disease activity sufficiently.We successfully treated three cases of adult Stills disease (ASD) with dexamethasone. High dose prednisolone, which was initially used to treat these patients, failed to remit the disease in all cases. Although they were resistant to prednisolone, all these patients had remarkable improvements in clinical and laboratory findings after switching to an equivalent dose of dexamethasone. We propose using dexamethasone as an alternative for treating ASD before adding immunosuppressants or disease modifying anti-rheumatic drugs (DMARD), when prednisolone therapy does not suppress disease activity sufficiently.

Comparison of the efficacy of an oral calcitriol pulse or intravenous 22-oxacalcitriol therapies in chronic hemodialysis patients.

Background1,25-dihydroxy-22-ovavitamin D3 (22-oxacalcitriol, OCT) was recently introduced commercially as an analogue of 1,25 (OH)2 vitamin D3, but one which has less pronounced calcemic activity.MethodsTo examine the efficacy and tolerability of OCT, 46 hemodialysis patients with secondary hyperparathyroidism were randomly assigned to receive either intravenous OCT or oral calcitriol pulse therapies. The patients were monitored for serum calcium, phosphate, intact parathyroid hormone (PTH), and bone alkaline phosphatase (BAP) for 24 weeks. The efficacy of intravenous OCT was also examined in 24 additional patients who were refractory to oral calcitriol pulse therapy.ResultsIn the randomized trial, intact PTH levels were significantly suppressed within 4 weeks after the initiation of each therapy, and this effect was well maintained thereafter in both treatment groups. While intact PTH was significantly lower at 4 weeks in the calcitriol pulse group than in the OCT group (P = 0.02), no statistical differences were observed during later treatment periods. BAP was reduced equally by each treatment. At 4 weeks (P = 0.02) and thereafter (P = 0.06), serum calcium was higher among calcitriol-treated patients than among those who received OCT treatment. Eight of 24 patients who were refractory to oral calcitriol pulse therapy responded to intravenous OCT. The patients who responded tended to have lower serum intact PTH and phosphorus levels and smaller parathyroid glands at the start of OCT treatment than nonresponders.ConclusionsOCT is as effective as oral calcitriol pulse therapy in suppressing intact PTH and BAP in chronic hemodialysis patients. It was confirmed that OCT exhibits less calcemic activity than calcitriol. Moreover, under certain conditions, switching to OCT may help in the treatment of hyperparathyroidism, which is refractory to conventional oral calcitriol pulse therapy.