Kazumasa Hamano

Enhanced Expression of Plasminogen Activator Inhibitor 1 in Patients with Nephrotic Syndrome

Hypercoagulability is present in patients with nephrotic syndrome. However, alterations in coagulation and fibrinolysis reflected in the glomeruli and urine are not fully understood. We examined plasma and urine concentrations of tissue-type plasminogen activator (tPA) and type 1 plasminogen activator inhibitor (PAI-1) in 33 patients with nephrotic syndrome (nephrotic group). We compared these concentrations with the concentrations in 30 nonnephrotic patients with chronic glomerulonephritis (nonnephrotic group) and with the concentrations in 30 healthy volunteers (control group). We also examined fibrin/fibrinogen degradation products in serum and urine and plasma D-dimers. The expression of tPA and PAI-1 was examined in isolated glomeruli using RT-PCR methods. Deposition of fibrinogen/fibrin-related antigen was observed by direct immunofluorescence. The incidence of fibrinogen/fibrin-related antigen deposition in the nephrotic group was significantly higher than that in the nonnephrotic group. The concentrations of fibrin/fibrinogen degradation products in serum and urine and of plasma D-dimers were significantly elevated in the nephrotic group as compared with the nonnephrotic and control groups. The plasma concentrations of tPA in the nephrotic group were significantly higher than those in the control group. The urinary excretion of tPA in the nephrotic group was also significantly higher than in the nonnephrotic and control groups. The urinary excretion of PAI-1 in the nephrotic group was higher than that in the control group. The ratio of PAI-1 mRNA to tPA mRNA in glomeruli was increased in the nephrotic group as compared with the nonnephrotic group. These results indicate that the fibrinolytic activity is increased in patients with nephrotic syndrome despite urinary losses of tPA. However, a relatively enhanced expression of PAI-1 may be involved in the intraglomerular fibrinogen/fibrin-related antigen deposition seen in nephrotic syndrome.

Association of Interleukin-1 Receptor Antagonist Gene Polymorphism with IgA Nephropathy

It is evident that cytokines play an important role in the pathogenesis as well as disease progression of IgA nephropathy (IgAN). Several gene polymorphisms of the pertinent cytokines have an influence on the level of cytokine production. Interleukin-1 receptor antagonist (IL-1ra) gene polymorphism has been found to affect disease susceptibility and activity in several inflammatory diseases. In the present study, we analyzed polymorphism of the variable number tandem repeat (VNTR) of IL-1ra in patients diagnosed as having IgAN (n = 106) and normal controls (n = 74). The allele frequency of IL-1ra polymorphism in IgAN patients was not statistically different from that of the control group. There was no significant difference in the carriage rate of the two-repeat allele (IL1RN*2) between IgAN patients and the control group (8.5 vs. 6.8%). The carriage rate of IL1RN*2 was significantly higher in IgAN patients with severe proteinuria (≧1.6 g/day) or increased serum creatinine level (≧2.0 mg/dl; p < 0.05). Furthermore, the carriage rate of IL1RN*2 was significantly higher in patients with severe mesangial cell proliferation (p < 0.01). Our results suggest that IL-1ra polymorphisms are not associated with the development of IgAN in Japanese patients but the presence of IL1RN*2 may be associated with increased disease activity.

Expression of Bcl-2 and Bax in Hypokalemic Nephropathy in Rats

Objectives: Potassium depletion results in hyperplasia of renal tubular and interstitial cells in humans and animals, and potassium repletion induces rapid regression of hyperplasia. Apoptosis participates importantly in this reduction of cell number, although we have observed tubular and interstitial apoptosis in rats during potassium depletion as well. Methods: To investigate mechanisms of apoptosis in this model, we assessed expression of Bcl-2 and Bax, using immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR). Results: Cell proliferation identifiable by labeling with 5-bromo 2′-deoxyuridine was prominent in tubular and interstitial cells of the cortex and outer medulla (OM) 7 days after potassium depletion. Simultaneously present apoptotic cells identified by light microscopy, electron microscopy, and nick end labeling were located mainly in the OM. Seven days after potassium repletion, apoptotic cells increased again but proliferating cells decreased. Bcl-2 protein distributed in the tubules of the OM was significantly decreased in potassium-depleted and potassium-repleted rats compared with control rats, while immunoreactivity for Bax protein tended to increase above control levels in potassium-depleted rats. RT-PCR for bcl-2 and bax demonstrated a significant decrease in levels of bcl-2 mRNA in potassium-depleted and potassium-repleted rats relative to those in controls. Expression of bax mRNA in potassium-depleted and potassium-repleted rats tended to increase, while ratios of bcl-2 mRNA to bax mRNA significantly decreased. Conclusions: These results suggest that apoptosis is associated with progression and regression of cellular proliferation in hypokalemic nephropathy, and a decrease in Bcl-2 may be involved in promoting this apoptotic process.

Central retinal vein occlusion and cerebellar infarction complicating systemic lupus erythematosus: a case report

Abstract We treated a 17-year-old woman who had systemic lupus erythematosus (SLE) complicated by central retinal vein occlusion (CRVO) and bilateral cerebellar infarction in the absence of demonstrable antiphospholipid antibodies. General fatigue, diffuse polyarthralgia, malar rash, and fever had developed during the 2 weeks preceding admission. The patient was diagnosed with SLE based on the presence of pleuritis, oral ulceration, pancytopenia, and antinuclear antibodies. Despite intravenous pulse therapy with methylprednisolone, blindness developed in the left eye and bilateral cerebellar infarcts were evident on magnetic resonance images. Fluorescein angiography revealed extensive retinal venous thrombosis leading to widespread retinal vein leakage, and a diagnosis of CRVO.

Gene polymorphism and clinical manifestations in Japanese patients with IgA nephropathy

To investigate the influence of genetic polymorphism on clinical manifestations of IgA nephropathy (IgAN), we studied the gene polymorphism of angiotensin-I converting enzyme (ACE), angiotensinogen (Ang), angiotensin II type 1 receptor (AngT1R), and interleukin-1 receptor antagonist (IL-1Ra) in Japanese patients with IgAN. A total of 85 patients (29 males and 56 females) with IgAN and 100 healthy controls were enrolled in this study. All patients gave informed consent to participate in this study. The average follow-up period in this study was 5.5 years. Gene polymorphism was determined by the polymerase chain reaction (PCR) method. Twenty four-hour urinary protein excretion and serum creatinine were measured by routine chemical methods. Renal biopsy specimens were examined before treatment in all patients to evaluate the degree of mesangial proliferation. There were no differences in either the genotype or allele frequency of the D/I polymorphism between the patients with IgAN and normal controls (D allele frequency; 39 and 40%, respectively). In patients with worsening renal function versus those without progression in follow-up period, ACE genotype frequencies were 20, 40 and 40% versus 17, 46 and 37%, for DD, DI, and II genotypes, respectively. The levels of urinary protein excretion were not different among these three genotypes. Furthermore, there were no significant associations between ACE polymorphism and histological findings in patients with IgAN. The deviation of Ang M235T and Ang T174M gene polymorphism in patients with IgAN did not differ from those of normal controls (36, 47 and 17% vs 34, 50, and 16% for MM, MT, and TT genotypes, respectively, in Ang M235T polymorphism, 6, 11 and 83% vs 4, 15 and 81%, respectively, for TT, TM, and MM genotypes, respectively, in Ang T174M polymorphism). The frequency in patients who excreted over 1 g/day proteinuria was 10, 23 and 28% for MM, MT, and TT genotypes, respectively, in Ang M235T polymorphism (P < 0.05). There were no significant associations between Ang T174M polymorphism and the clinical features of IgAN. There were no differences in the genotype frequencies of the AngT1R polymorphism between the patients with IgAN and normal controls (81, 17 and 2% vs 88, 12 and 0% for AA, AC, and CC genotypes, respectively). AngT1R polymorphism was not associated with the levels of urinary protein excretion, the degree of mesangial proliferation, and deterioration of renal function. The allele frequency of the IL-1Ra polymorphism was not different between IgA nephropathy and normal controls (94, 4 and 2% vs 96, 3 and 1% for 4-, 2-, and 1repeat allele, respectively), but the degree of mesangial proliferation was severe in patients with two-repeat allele in IL-1Ra polymorphism (56, 11 and 33% vs 10, 45 and 45% for severe, moderate, and mild mesangial proliferation, respectively, in patients with two-repeat allele vs those without two-repeat allele in IL-1Ra polymorphism). IL-1Ra polymorphism was not associated with the levels of urinary protein excretion and deterioration of renal function. Ang M235T and IL-1Ra polymorphism may influence the progression of renal function in Japanese patients with IgAN. ACE, Ang T174M, and AngT1R polymorphism are not associated with the clinical manifestations of IgA nephropathy. Gene polymorphism and clinical manifestations in Japanese patients with IgA nephropathy