Plasma osteoprotegerin, arterial stiffness, and mortality in normoalbuminemic Japanese hemodialysis patients.

UNLABELLED: A high circulating osteoprotegerin (OPG) level may be a risk factor for vascular calcification and mortality in hemodialysis patients. OPG and pulse wave velocity (PWV) were measured at baseline in 151 normoalbuminemic, long-term (>3 years) Japanese hemodialysis patients who were prospectively followed for 6 years. In long-term normoalbuminemic Japanese hemodialysis patients, OPG levels were strongly linked with both arterial stiffness and worse outcome. INTRODUCTION: A high circulating OPG level is reported to be a risk factor for vascular calcification and mortality in Western chronic kidney disease (CKD) patients but it is not known if this is true for Japanese CKD patients, where a different risk profile may operate. METHODS: OPG and PWV were measured at baseline in 151 normoalbuminemic, long-term (>3 years) Japanese hemodialysis patients (median age 62 years) who were prospectively followed for 6 years. RESULTS: OPG levels were associated in multivariate analysis with age, dialysis vintage, history of cardiovascular disease (CVD) and parathyroid hormone levels. C-reactive protein levels did not correlate with OPG. Patients with clinical history of CVD had significantly higher OPG levels and OPG levels were positively correlated to PWV, an index of arterial stiffness. These associations were independent of age, sex, dialysis vintage, and diabetes. During the follow-up period, 40 deaths, including 25 cardiovascular deaths, were recorded. In crude analysis, each unit of increase in OPG was associated with increased all-cause (hazard ratios 1.14, 95% confidence interval 1.08-1.20) and CVD mortality (1.14 [1.07-1.21]), which persisted after adjustment for age, sex, dialysis vintage, diabetes, and baseline CVD (1.12 [1.05-1.19] and 1.11 [1.02-1.19], all-cause and CVD mortality, respectively). CONCLUSIONS: In long-term normoalbuminemic Japanese hemodialysis patients, with low prevalence of inflammation, OPG levels were strongly linked with both arterial stiffness and worse outcome.

Endogenous estrogen may prevent bone loss in postmenopausal hemodialysis patients throughout life.

SUMMARY: Postmenopausal hemodialysis patients are at risk of complications related to renal mineral and bone disorder, and postmenopausal osteoporosis. In 112 postmenopausal hemodialysis patients, free estrogen index was positively correlated with bone mineral density (BMD) Z-score and the annual percent change of BMD in multiple regression analysis. Endogenous estrogen may prevent bone loss in postmenopausal hemodialysis patients throughout life. INTRODUCTION: Women on dialysis are not only at risk of developing mineral and bone disorder, but also suffer from postmenopausal osteoporosis. We assessed the effect of sex hormones on bone metabolism in postmenopausal hemodialysis patients. METHODS: We enrolled 112 postmenopausal hemodialysis patients with a mean age of 68.4 ± 10.4 years. We measured the serum levels of estradiol, testosterone, sex hormone-binding globulin (SHBG), and intact parathyroid hormone (intact-PTH), as well as bone metabolism parameters and radial bone mineral density (BMD). The free estrogen index (FEI) was calculated from the estradiol and SHBG values. After conventional dialysis was performed for 12 months, BMD was measured again and the annual percent change was calculated. Estradiol and SHBG were also measured in 25 postmenopausal women without chronic kidney disease. RESULTS: Estradiol levels were higher in the hemodialysis patients than in the postmenopausal women without chronic kidney disease. In patients with relatively normal bone turnover (intact-PTH: from 150 to 300 pg/ml), the FEI showed a positive correlation with the BMD Z-score. The annual percent change of BMD showed a positive correlation with the FEI according to multiple regression analysis. CONCLUSIONS: Endogenous estrogen may prevent bone loss in postmenopausal hemodialysis patients throughout life.

Renal histology before and after effective enzyme replacement therapy in a patient with classical Fabry's disease.

A 38-year-old man underwent renal biopsy because of proteinuria. It revealed swelling and vacuolation of glomerular epithelial cells, as well as myelin-like structures characteristic of Fabry's disease. Detection of decreased plasma activity of alpha-galactosidase A confirmed the diagnosis. Enzyme replacement therapy was provided with recombinant agalsidase-beta, resulting in improvement of his symptoms. When renal biopsy was repeated, specific staining for globotriaosylceramide showed that renal deposits were decreased by enzyme therapy.

Oral mizoribine pulse therapy for steroid-dependent focal segmental glomerulosclerosis.

A 24-year-old woman with focal segmental glomerulosclerosis was referred to our hospital for treatment of nephrotic syndrome. Though she experienced partial remission following treatment with prednisone and cyclosporine, she had a relapse of nephrotic syndrome when her prednisone was tapered off to 30 mg/day. The prednisone could not be tapered to less than 30 mg/day due to repeated relapses. After introduction of oral mizoribine (MZR) pulse therapy, the patient's prednisone was tapered to 15 mg/day and she had no signs of relapse for more than 1 year. This case suggests that oral MZR pulse therapy is a good therapeutic option for patients with steroid-dependent nephrotic syndrome.

Beneficial effect of low-density lipoprotein apheresis (LDL-A) on refractory nephrotic syndrome (NS) due to focal glomerulosclerosis (FGS).

AIMS: Hypercholesterolemia is one of the factors which deteriorate renal function in NS especially due to FGS. LDL-A is a potential option for treating NS due to FGS accompanied by hypercholesterolemia and resistant to conventional drug therapy with steroids and/or cyclosporine A (CsA). As reported by Muso et al. [2001], LDL-A combined with drug therapy yields more rapid relief from NS and better prognosis than drug therapy alone. However, very limited data are available on outcome at several years after treatment. The aim of this study was to clarify long-term outcome of NS patients treated with LDL-A and to evaluate the effectiveness of this treatment. PATIENTS AND METHODS: To clarify the long-term outcome of LDL-A, we conducted a retrospective survey on outcome up to 5 years. From 36 hospitals in Japan, 41 patients with NS whose short-term outcomes with LDL-A were reported from 1999-2004 were collected and analyzed. RESULTS: In all, 29 and 15 patients with outcomes determined at 2 and 5 years after treatment, respectively, were obtained. At 2 and 5 years after treatment, 62 and 87% of patients, respectively, were classified into complete or Type 1 incomplete remission. The strength of correlations between outcome and several factors including parameters of renal function measured before and after treatment and treatment condition revealed that early administration of LDL-A after the onset of NS provided a good long-term outcome. The data also suggest that more drastic decrease of LDL favored a better prognosis. CONCLUSIONS: In NS due to FGS treated with LDL-A, long-term outcome was as good as short-term outcome. Early administration of LDL-A after the onset of NS provided a good long-term outcome. To obtain more precise findings regarding the effects of this treatment, a large-scale prospective study will be needed.

Ultrastructural localization of vascular cell adhesion molecule-1 in proliferative and crescentic glomerulonephritis.

Recent studies have demonstrated an important role of vascular cell adhesion molecule-1 (VCAM-1) in the pathogenesis of nephritis. In the present study, renal biopsy specimens from patients with proliferative and crescentic glomerulonephritis were subjected to immunoelectron microscopy using an anti-VCAM-1 monoclonal antibody. In control normal kidney tissue, VCAM-1 expression was restricted to the free surface of parietal epithelial cells. In diseased glomeruli, VCAM-1 was expressed on the free surface of parietal and visceral epithelial cells, on the luminal surface of capillary endothelial cells, on infiltrating monocyte/macrophage-like cells, on mesangial cells, and in the matrix of the expanded mesangium. There was also VCAM-1 expression on almost all cell types in the crescents, including macrophage-like cells, fibroblast-like cells, and epithelial cells. Some cells also showed VCAM-1 positivity in the rough endoplasmic reticulum and the perinuclear space. Both the glomerular capillary lumen and urinary spaces of Bowman's capsule contained positive reaction products, which were often associated with exocytosis by the surrounding cells. VCAM-1 was predominantly expressed on the basal and lateral surfaces of a few proximal tubules, but it could not be localized ultrastructurally. These findings suggest that production and secretion of VCAM-1 by both infiltrating monocyte/macrophages and resident glomerular cells may be related to the pathogenesis of proliferative and crescentic glomerulonephritis.

Effect of lipoproteins on mesangial cell proliferation.

BACKGROUND: Triglyceride (TG)-rich lipoproteins have been reported to promote atherosclerosis, but little is known about their role in kidney disease or about their effects on mesangial cells. Accordingly, the purpose of this study was to investigate which lipoproteins could influence mesangial cell proliferation in vitro. We assessed the effect of various lipoproteins [very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low density lipoprotein (LDL), oxidized LDL, and high-density lipoprotein (HDL)] on the proliferation of cultured human mesangial cells and also assessed the influence of these lipoproteins on cytokine production. METHODS: We investigated the effect of various lipoproteins on cultured human mesangial cells using 3H-thymidine incorporation and cell counting assays and investigated the levels of several cytokines [interleukin (IL)-6, platelet-derived growth factor (PDGF), transforming growth factor (TGF)-beta, and tumor necrosis factor-alpha] in mesangial cell culture supernatants after stimulation by the lipoproteins. RESULTS: Not only LDL but also TG-rich lipoproteins (VLDL and IDL) promoted the proliferation of mesangial cells up to certain concentrations, but cell growth was actually decreased at higher concentrations. Oxidized LDL caused a concentration-dependent decrease of 3H-thymidine incorporation, and HDL had no proliferative effect at any concentration. Exposure to VLDL, IDL, LDL, or a high concentration of HDL enhanced the secretion of IL-6, PDGF-AB, and TGF-beta by mesangial cells, whereas TNF-alpha secretion was stimulated by oxidized LDL. CONCLUSIONS: TG-rich lipoproteins, LDL, and oxidized LDL may be involved in mesangial cell proliferation and injury in patients with mesangial proliferative glomerulonephritis.

Apolipoprotein E polymorphism and renal disease.

BACKGROUND: Lipid abnormalities are frequently found in end-stage renal disease (ESRD), and abnormal lipid metabolism may contribute to the progression of renal disease. Previous investigators have reported that apolipoprotein E (apoE) has an important role in lipoprotein metabolism and that the process of lipoprotein catabolism varies according to the apoE phenotype. In addition, the relative frequency of the apoE alleles is different among the races. In this study, we investigated the allele frequency of apoE phenotypes and evaluated the impact of apoE polymorphism on lipid profile in Japanese patients with renal disease. METHODS: ApoE phenotypes were determined using isoelectric focusing and Western blotting in 592 Japanese patients with renal disease [86 out of 107 patients with glomerulonephritis had proteinuria of not less than 0.25 g per 24 hr and 485 with ESRD; 448 were on hemodialysis (HD), and 37 were on continuous ambulatory peritoneal dialysis (CAPD)]. The allele frequency and apoE phenotype distribution were estimated by the gene-counting method. Serum lipid parameters related to lipid metabolism were measured after at least a 12-hour fast. RESULTS: The allele frequency of the three major apoE phenotypes (apoE2, apoE3, and apoE4) in 107 glomerulonephritis patients (epsilon 2; 0.037, epsilon 3; 0.860, epsilon 4; 0.103) was almost identical to that in the normal control population (epsilon 2; 0.036, epsilon 3; 0.848, epsilon 4; 0.115). However, 86 glomerulonephritis patients with proteinuria had higher allele frequency of apoE2 (epsilon 2; 0.052, P < 0.01) and apoE4 (epsilon 4; 0.140, P < 0.001) and lower allele frequency of apoE3 (epsilon 3; 0.808, P < 0.001) than the controls. Furthermore, ESRD patients had higher allele frequency of apoE2 (epsilon 2; 0.058, P < 0.01) and lower allele frequency of apoE4 (epsilon 4; 0.091, P < 0.05) than the controls. Higher prevalence of nephrotic syndrome was found in proteinuric glomerulonephritis patients with apoE2. The impact of apoE polymorphism on serum lipid profile in patients with glomerulonephritis, HD, and CAPD was different from that generally expected. CONCLUSIONS: The higher frequency of apoE2 in ESRD patients suggests that apoE2 is a possible genetic predisposition to ESRD in a Japanese population. The impact of apoE2 and apoE4 on lipid profile in patients with renal disease was unique and different from that in the normal population.

Screening for gastroenterological malignancies in new and maintenance dialysis patients.

To screen for gastroenterological malignancies in dialysis patients, we used the fecal occult blood test, examined the upper and lower gastrointestinal tract, and used abdominal ultrasonography in 178 patients starting dialysis (171 on hemodialysis and 7 on continuous ambulatory peritoneal dialysis (CAPD)) and 34 patients on maintenance dialysis (27 on hemodialysis and 7 on CAPD). Screening disclosed ten cancers (one esophageal cancer, three gastric cancers, four colorectal cancers, and two hepatocellular carcinomas) in 9 of the patients starting dialysis. Six cancers (one esophageal, three gastric, one colorectal, and one renal) were detected in 5 of the patients on maintenance dialysis. Since an increased incidence of malignancy has been reported in dialysis patients, gastroenterological screening appears to be worthwhile.

Tenascin expression may reflect the activity and chronicity of human IgA nephropathy.

BACKGROUND: Tenascin is a large oligomeric glycoprotein component of the extracellular matrix that increases rapidly after inflammation or injury, suggesting that it may be an indicator of renal disease activity. Histological activity and chronicity indices are currently used to evaluate the activity and chronicity of IgA nephrophathy. PATIENTS AND METHODS: We investigated whether tenascin staining could be an indicator of activity or chronicity in patients with IgA nephropathy using immunohistochemical and in situ polymerase chain reaction methods. Immunostaining for tenascin was done on 58 renal specimens, (51 from IgA nephropathy patients and 7 from normal kidneys), and the in situ polymerase chain reaction was performed on 24 renal specimens (21 from IgA nephropathy patients and 3 from normal kidneys). RESULTS: Tenascin expression in the glomeruli was correlated with tenascin expression in the tubulointerstitium (protein; r = 0.386, p = 0.0063, mRNA; r = 0.510, p = 0.0225). Tenascin protein staining in the glomeruli was correlated with the chronicity index (r = 0.506, p = 0.0003), and glomerular tenascin mRNA positivity was correlated with the activity index (r = 0.449, p = 0.0448). CONCLUSION: Tenascin expression was similar in the glomeruli and tubulointerstitium, but glomerular staining more closely reflected the pathological state. Tenascin protein expression may be an indicator of chronicity and tenascin mRNA expression may be an indicator of disease activity in IgA nephropathy.

Expression of macrophage migration inhibitory factor in patients with myeloperoxidase anti-neutrophil cytoplasmic antibody-associated glomerulonephritis.

AIM AND METHODS: To investigate the relationship between macrophage migration inhibitory factor and clinical or pathological findings in patients with myeloperoxidase anti-neutrophil cytoplasmic antibody MPO-ANCA-associated glomerulonephritis characterized by idiopathic necrotizing crescentic glomerulonephritis, renal biopsy specimens from 16 patients with MPO-ANCA-associated glomerulonephritis and 15 controls were stained using an enzyme antibody method to detect macrophage migration inhibitory factor and macrophages infiltrating the glomeruli. The relationship of this factor with various clinical parameters and with cellular crescents was determined. RESULTS: Macrophage migration inhibitory factor was detected in 11 out of 16 patients with MPO-ANCA-associated glomerulonephritis, but was not found in any of the controls. In the positive patients, the blood MPO-ANCA level was significantly higher than in the negative patients. Both cellular crescents and the number of macrophages infiltrating the glomeruli were significantly increased in the patients positive for macrophage migration inhibitory factor. CONCLUSION: Thus, macrophage migration inhibitory factor may be closely related to cellular crescent formation and disease activity in patients with MPO-ANCA-associated glomerulonephritis.

Myeloperoxidase antineutrophil cytoplasmic antibody-positive necrotizing crescentic glomerulonephritis and membranous glomerulonephropathy.

In September 1997, a 68-year-old woman was found to have proteinuria and renal dysfunction. In December 1997, renal biopsy revealed necrotizing crescentic glomerulonephritis and membranous glomerulonephropathy. We diagnosed myeloperoxidase antineutrophil cytoplasmic antibody-positive necrotizing crescentic glomerulonephritis and membranous glomerulonephropathy because of the presence of necrotizing cellular crescents and spike lesions in the subepithelial region of the glomerular basement membrane. After steroid therapy, the antibody level and the incidence of cellular crescents showed a decrease. This is a rare case of myeloperoxidase antineutrophil cytoplasmic antibody-positive necrotizing crescentic glomerulonephritis associated with membranous glomerulonephropathy.

Clinicopathological study of myeloperoxidase anti-neutrophil cytoplasmic antibody-associated glomerulonephritis.

AIMS: To investigate the potential prognostic factors for myeloperoxidase anti-neutrophil cytoplasmic antibody- (MPO-ANCA) associated glomerulonephritis. MATERIALS: The clinical and pathological findings were reviewed in 17 patients with this type of glomerulonephritis. METHODS: The relationship between the outcome and various clinical and pathological factors were assessed. The relationship between the blood MPO-ANCA level and cellular crescent formation was also investigated. RESULTS: Patients who died had a significantly lower serum albumin and creatinine clearance than those who survived, but there were no differences of age, blood MPO-ANCA, urinary protein, and serum creatinine levels or cellular crescent formation between the two groups. There was a close relationship between blood MPO-ANCA levels and cellular crescent formation. CONCLUSIONS: Hypoalbuminemia and renal dysfunction may be indicators of a poor prognosis in MPO-ANCA-associated glomerulonephritis. Patients with high blood levels of this antibody and increased cellular crescent formation appear to have active disease, but these factors are not statistically associated with a fatal outcome. Therefore, aggressive treatment may be indicated in patients with active disease initially.

A case of CREST syndrome and myeloperoxidase-specific anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis.

We report the first case of myeloperoxidase-specific anti-neutrophil cytoplasmic autoantibody (MPO-ANCA)-associated glomerulonephritis in a patient with CREST syndrome. A 74-year-old Japanese man with CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia) developed rapidly progressive renal failure without elevation of blood pressure. Renal biopsy revealed glomerular sclerosis and fibrous crescents. The MPO-ANCA titer was elevated to 145 EU/ml. When patients with collagen diseases develop rapidly progressive glomerulonephritis, the possibility of MPO-ANCA-associated glomerulonephritis should be kept in mind.

Glomerular localization of interleukin-6 suppressed by steroid mini-pulse therapy in an IgA nephropathy patient.

A 16-year-old female with IgA nephropathy harboring histologically active lesions was treated with steroid mini-pulse therapy. Immunohistochemical examination revealed a diffuse distribution of interleukin-6 (IL-6) in the renal biopsy tissue. After treatment, her clinical factors and renal function improved, and renal biopsy showed reduced histological lesions and disappearance of the IL-6 distribution. Immunohistological studies of cytokines, such as IL-6, may be useful for evaluating the therapeutic effects in IgA nephropathy.

Hyperimmunoglobulin E syndrome associated with nephrotic syndrome.

A 21-year-old man was admitted to Kure National Hospital with nephrotic syndrome in September 1996. He had suffered from an intractable pruritic skin rash and recurrent subcutaneous abscesses caused by the hyperimmunoglobulin E syndrome since the age of 18 months. Renal biopsy gave a diagnosis of membranoproliferative glomerulonephritis. Steroid therapy decreased urinary protein loss and hypoproteinemia, and his pruritic skin rash was improved. Patients with hyperimmunoglobulin E syndrome have a defective immune response, especially to Staphylococcus aureus infection. Continuous antigen stimulation may have caused this patient's renal histological damage as in immune complex glomerulonephritis.

Nonasthmatic case of Churg-Strauss syndrome with rapidly progressive glomerulonephritis.

A 61-year-old man developed mononeuritis multiplex accompanied by eosinophilia in 1993. Approximately 3 years later, acute renal dysfunction, a subendocardial tumor, and a high peripheral anti-neutrophil cytoplasmic antibody titer were also detected. Renal biopsy revealed glomerular crescents and interstitial infiltration of eosinophils, so allergic granulomatosis and angiitis was diagnosed. These clinical abnormalities regressed with steroid therapy. He had no history of asthma. This was therefore considered to be an atypical form of Churg-Strauss syndrome with rapidly progressive glomerulonephritis.

Myeloperoxidase-antineutrophil cytoplasmic antibody-associated glomerulonephritis with membranous nephropathy in remission.

A 47-year-old woman developed pulmonary hemorrhage and an increase in proteinuria during remission of membranous nephropathy. Renal biopsy revealed crescentic glomerulonephritis. She also had a high perinuclear antineutrophil cytoplasmic antibody level, so a diagnosis of myeloperoxidase-antineutrophil cytoplasmic antibody-associated glomerulonephritis was made. After immunosuppressive therapy was started, the pulmonary hemorrhage resolved and her proteinuria decreased. Renal biopsy was repeated after treatment and showed histological improvement. This case suggests that there may be a relationship between membranous nephropathy and myeloperoxidase-antineutrophil cytoplasmic antibody-associated glomerulonephritis.

Stimulation of interleukin-1 beta production may be involved in unresponsiveness to erythropoietin therapy.

Recombinant human erythropoietin (rHuEPO) can dramatically improve anemia in dialysis patients, but about 20% of patients show a poor response to this agent. It has been reported that cytokines, including interleukin (IL)-1 beta, may inhibit the maturation of erythrocytes. To investigate the mechanisms of unresponsiveness to rHuEPO, we isolated peripheral blood mononuclear cells from 12 patients on continuous ambulatory peritoneal dialysis who were receiving maintenance rHuEPO therapy for renal anemia. Cells were cultured with rHuEPO and IL-1 beta production was assessed. In the six patients who did not respond to rHuEPO therapy, there was a marked increase in IL-1 beta during culture with rHuEPO. In contrast, the addition of rHuEPO to cultures of cells from the six responding patients caused little increase in IL-1 beta, and there was a significant difference between the two groups. Induction of IL-1 beta by rHuEPO may be one cause of persistent anemia in dialysis patients.

Direct infusion of ascites into the blood circuit during hemodiafiltration in uremic patients with cirrhosis.

Two chronic dialysis patients with massive ascites caused by cirrhosis were treated by infusion of their ascites directly into the blood circuit. This stabilized their hemodynamics during dialysis, facilitating the control of weight gain and ascites, and thus markedly improving their general condition. Long-term use of this therapy was able to prevent the accumulation of ascitic fluid. Interestingly, fever occurred when this therapy was performed with hemodialysis, but not with hemofiltration or hemodiafiltration, suggesting that a pyrogen in the ascites was removed by filtration.