Hepatocyte growth factor ameliorates methylglyoxal-induced peritoneal inflammation and fibrosis in mouse model.

BACKGROUND: Peritoneal dialysis (PD) is essential for patients with end-stage renal disease. Peritoneal fibrosis (PF) is a complex inflammatory, fibrogenic process. No effective treatments are available to prevent these processes. Hepatocyte growth factor (HGF) possesses anti-inflammatory and anti-fibrotic properties. The aim of this study was to analyze whether HGF suppresses MGO-induced peritoneal inflammation and fibrosis in a mouse model. METHODS: PF was induced by intraperitoneal (IP) injections of MGO for 14 days. C57/BL/6 mice were divided into three groups: Sham group (only vehicle); Sham + MGO group (PF induced by MGO); and HGF + MGO group (PF mice treated with recombinant human-HGF). PF was assessed from tissue samples by Masson's trichrome staining. Inflammation and fibrosis-associated factors were assessed by immunohistochemistry and quantitative real-time PCR. RESULTS: MGO-injected mice showed significant thickening of the submesothelial compact zone with PF. Treatment with HGF significantly reduced PM thickness and suppressed the expression of collagen I and III and α-SMA. Expression of profibrotic and proinflammatory cytokines (TGF-ß, TNF-α, IL-1ß) was reduced by HGF treatment. The number of macrophages, and M1 and M2 macrophage-related markers, such as CD86, CD206, and CD163, was reduced in HGF + MGO mice. CONCLUSION: HGF attenuates MGO-induced PF in mice. Furthermore, HGF treatment reduces myofibroblast and macrophage infiltration, and attenuates the upregulated expression of proinflammatory and profibrotic genes in peritoneal tissues. HGF might be an effective approach to prevent the development of PF in patients undergoing PD.

Effect of Cinacalcet on the Redox Status of Albumin in Secondary Hyperparathyroidism Patients Receiving Hemodialysis.

Chronic kidney disease (CKD) patients with secondary hyperparathyroidism (SHPT) have an increased risk of cardiovascular disease (CVD). Cinacalcet is a calcimimetic that permits impaired endothelial functions to be recovered via inhibiting parathyroid hormone (PTH) production in SHPT patients. However, the underlying mechanism for its action remains unknown. The purpose of this study was to examine the effect of cinacalcet on the redox state of human serum albumin (HSA), a reliable marker for assessing endothelial oxidative damage in SHPT patients who were receiving hemodialysis. Cinacalcet was administered to six SHPT patients for a period of 8 weeks. After 4 weeks of treatment, cinacalcet significantly decreased the oxidized albumin ratio which is a ratio of reduced and oxidized forms of HSA via increasing reduced form of HSA. Moreover, the radical scavenging abilities of HSA that was isolated from SHPT patients were increased by cinacalcet, suggesting the recovery of the impaired vascular anti-oxidant ability. Interestingly, the oxidized albumin ratio in SHPT patients was significantly higher than that in hemodialysis patients. In addition, the changes of intact PTH levels were significantly correlated with the oxidized albumin ratio. It therefore appears that PTH may induce oxidative stress in SHPT patients. In fact, an active analogue of PTH increased the production of reactive oxygen species in human endothelial cells. Thus, cinacalcet exhibits anti-oxidative activity through its pharmacological action. Additionally, cinacalcet itself showed radical scavenging activity. In conclusion, cinacalcet improves the redox status of HSA by inhibiting PTH production and partially by its radical scavenging action.

Efficacy of vasopressin V2 receptor antagonist tolvaptan in treatment of hepatic edema.

AIM: Tolvaptan, an oral active vasopressin V2 receptor antagonist, is widely used for hepatic edema in Japan, but its clinical benefits have yet to be fully clarified. The present study evaluated the efficacy of tolvaptan in hepatic edema. METHODS: The efficacy and treatment regimen of tolvaptan were evaluated in 150 patients with hepatic edema by analyzing the initial (day 14) and long-term (day 90) responses to the drug and their predictive factors. All patients were divided into good (Child-Pugh classification B, and absent of advanced hepatocellular carcinoma) and poor hepatic condition groups, and the response rates were compared between the two groups. RESULTS: The initial response rate was 62%, and the long-term response rate was 47%. The assessment of predictive factors for response to tolvaptan showed that serum creatinine and C-reactive protein levels were important predictors of initial response, and that hepatic conditions, such as the Child-Pugh score or presence of hepatocellular carcinoma, as well as initial response, were significant predictors of long-term response. In addition, both the initial and long-term response rates and the cumulative survival rate were found to be higher in the good hepatic condition group than in the poor hepatic condition group, respectively (71% vs. 57%, P = 0.113; 62% vs. 39%, P = 0.009; log-rank test, P < 0.001). CONCLUSION: These results suggest that tolvaptan may provide high response rates when used early in the course of hepatic edema, or when both hepatic and renal functions are still retained, leading to an improved disease prognosis.

[A case of renal Fanconi syndrome due to Bence Jones' protein K-type multiple myeloma].

A 60-year-old man, who had been treated for chronic kidney disease and chronic hepatitis B infection, was referred to our hospital following presentation with thoracic bone pain and exacerbation of proteinuria and hematu- ria. On admission, laboratory test results showed evidence of hypophosphatemia, glucosuria and elevated levels of both urinary NAG and 62MG.The patient was diagnosed with Fanconi syndrome based on findings indicating the presence of pan-aminoaciduria, elevated urinary excretion of uric acid and an increased phosphorus reabsorption rate. Furthermore, bone scintigraphy showed increased multiple symmetric uptake of radiotracer in both sides of the ribs, leading to the diagnosis"of hypoposphatemia-related osteomalacia with renal Fanconi syndrome. Urinary immunoelectrophoresis indicated the presence of K Bence Jones' protein (BJP). A bone marrow biopsy examina- tion showed that the plasma-to-cell ratio was less than 10%. However, the patient had over lg/day of proteinuria and suppression of serum IgM (18mg/dL) and was, therefore, diagnosed with multiple myeloma based on SWOG criteria. Light microscopic examination showed evidence of glomerulosclerosis, intimal thickness of interlobular arteries and acidophilic granular deposits in the cytoplasm of the proximal epithelial tubular cells. Immunofluores- cence indicated positive anti-K staining in these regions. Electron microscopic examination of the proximal tubular epithelial cells revealed the presence of numerous diamond-shaped and oval crystals, thought to be the K light chain of BJP. In general, cast nephropathy, light chain deposition disease (LCDD) and AL amyloidosis are recog- nized renal injuries caused by myeloma. However, there have been few clinical reports of Fanconi syndrome with multiple myeloma, such as the case study we have described here. In addition, histological examination of a biopsy sample provided further evidence of K BJP in the proximal epithelial tubular cells.

A case of latent heterozygous Fabry disease in a female living kidney donor candidate.

A 52-year-old woman had been found to have hematuria at her annual checkup 5 years in a row. She hoped to donate her kidney to her husband, so we performed a percutaneous kidney biopsy at our department. It was difficult for us to detect apparent abnormalities under a light microscopic examination, and she was determined to meet the eligibility criteria for living kidney transplantation. However, the sample for electron microscopy was not evaluated before kidney donation. She subsequently underwent living kidney transplantation as a donor. A 1-h biopsy revealed swelling and obvious vacuolation of the glomerular podocytes, which were characteristic of Fabry disease. Her medical history and examinations were reviewed. No findings or episodes were observed. Pre-donation electronmicroscopy revealed numerous zebra bodies in the podocytes. A definite diagnosis of heterozygous Fabry disease was made based on the GLA gene mutation despite the normal range of leukocyte α-Gal A activity. Based on the pathological deposition of GL-3, chaperone therapy was initiated to suppress the progression of organ damage. In this case, we could not confirm a diagnosis of Fabry disease despite performing a renal biopsy prior to kidney donation. Kidney donor candidates may sometimes have factors that cannot be assumed based on medical or family history. Thus, it is important to perform a renal biopsy before kidney donation when necessary, and to always conduct a detailed evaluation including electron microscopy.

Insulin-like growth factor binding protein-1 levels are increased in patients with IgA nephropathy.

The mechanisms underlying the pathogenesis of immunoglobulin A (IgA) nephropathy (IgAN) are not well understood. In this study, we examined gene expression profiles in kidneys obtained from mice with high serum IgA levels (HIGA mice), which exhibit features of human IgAN. Female inbred HIGA, established from the ddY line, were used in these experiments. Serum IgA levels, renal IgA deposition, mesangial proliferation, and glomerulosclerosis were increased in 32-week-old HIGA mice in comparison to ddY animals. By microarray analysis, five genes were observed to be increased by more than 2.5-fold in 32-week-old HIGA in comparison to 16-week-old HIGA; these same five genes were decreased more than 2.5-fold in 32-week-old ddY in comparison to 16-week-old ddY mice. Of these five genes, insulin-like growth factor (IGF) binding protein (IGFBP)-1 exhibited differential expression between these mouse lines, as confirmed by quantitative RT-PCR. In addition, serum IGFBP-1 levels were significantly higher in patients with IgAN than in healthy controls. In patients with IgAN, these levels correlated with measures of renal function, such as estimated glomerular filtration rate (eGFR), but not with sex, age, serum IgA, C3 levels, or IGF-1 levels. Pathologically, serum IGFBP-1 levels were significantly associated with the severity of renal injury, as assessed by mesangial cell proliferation and interstitial fibrosis. These results suggest that increased IGFBP-1 levels are associated with the severity of renal pathology in patients with IgAN.

[Case of multiple nodular lesions of bilateral kidneys with IgG4-related systemic disease].

A 59-year-old woman was admitted to our hospital because of a pancreatic mass lesion. Serum gamma-globulin and IgG4 levels were elevated to 2.2 g/dL and 1,310 mg/dL, respectively. Computed tomography examination revealed multiple low-density areas without enhancement by contrast in the pancreatic body and bilateral kidneys. Endoscopic retrograde cholangiopancreatography images demonstrated diffuse narrowing of the main pancreatic duct with an irregular wall from the body to the tail of the pancreas. Positron emission tomography examination revealed intense 18F-fluorodeoxyglucose uptake by the pancreas and kidneys. Accordingly, the patient was diagnosed as having IgG4-related autoimmune pancreatitis. In addition, the findings of a renal tissue specimen obtained by biopsy demonstrated IgG4-positive plasma cell infiltration in both abnormal mass lesions and normal regions by imaging, leading to the final diagnosis of IgG4-related sclerotic disease. The patient was treated with prednisolone (30 mg/day), and the size of the pancreatic and renal lesions markedly decreased four weeks later. We report here a rare case of IgG4-related autoimmune pancreatitis with multiple renal lesions, which were confirmed by renal biopsy.

Correlation of serum levels of complement C4a desArg with pathologically estimated severity of glomerular lesions and mesangial hypercellularity scores in patients with IgA nephropathy.

The aim of the present study was to explore serum biomarkers for the pathology of IgA nephropathy using serum proteomics. The subjects were 57 patients with IgA nephropathy who were divided into two groups (group 1, n=25; group 2, n=32) and 14 healthy controls. Serum protein profiles were analyzed using the ProteinChip surface-enhanced laser desorption ionization (SELDI) system. Associations between signal intensities of proteins and histological findings in patients with IgA nephropathy were studied in group 1. Serum levels of a candidate biomarker protein (complement component C4a desArg) for IgA nephropathy were determined by enzyme linked-immunosorbent assay (ELISA) in group 2 and the relationships of these levels with histological findings were evaluated. There were significant differences in 93 protein signals between patients in group 1 and controls. Among these signals, 3 proteins at 8592, 8757 and 8806 m/z were significantly correlated with the severity of glomerular lesions. The protein at 8592 m/z was identified as C4a desArg and the signal intensity of 8592 m/z was strongly correlated with serum C4a levels, including C4a desArg, determined by ELISA. In addition, the serum levels of C4a (mainly C4a desArg) were significantly higher in patients in group 2 compared to controls and were correlated with the severity of glomerular lesions and with mesangial hypercellularity scores. In conclusion, the serum levels of complement C4a desArg are significantly higher in patients with IgA nephropathy compared to healthy controls and are significantly correlated with the severity of glomerular lesions and mesangial hypercellularity scores. Thus, serum C4a desArg is a potential biomarker for the severity of histological findings in patients with IgA nephropathy.

High serum thioredoxin levels are reduced after tonsillectomy in patients with IgA nephropathy.

OBJECTIVE: The role of oxidative stress in IgA nephropathy (IgAN), the most common type of primary glomerulonephritis, is unknown. We evaluated the clinical significance of serum levels of oxidative stress markers, thioredoxin (TRX) and manganese superoxide dismutase (MnSOD), in patients with IgAN. METHODS: Forty-eight patients with histologically confirmed IgAN and 14 healthy subjects were enrolled in this study. Serum samples from 14 IgAN patients were obtained after tonsillectomy, a procedure hypothesized to be an effective treatment for IgAN. RESULTS: Serum TRX levels were significantly higher in patients with IgAN than in healthy subjects (mean [ng/mL]; 49.5 vs.14.4, p<0.001). Serum TRX levels are positively correlated with blood urea nitrogen, serum uric acid and proteinuria, and negatively with estimated glomerular filtration rate (eGFR). In addition, serum TRX levels gradually increased as the severity of renal histology increased. High levels of serum TRX were significantly decreased after tonsillectomy in patients with IgAN (mean [ng/mL]; 55.5 to 41.1, p=0.02). In contrast, serum MnSOD levels did not differ between IgAN patients and healthy subjects, and these levels did not change after tonsillectomy in IgAN patients. CONCLUSION: Serum TRX is associated with IgAN, and tonsillectomy may decrease oxidative stress in IgAN patients, leading to clinical improvement.

Parathyroidectomy markedly reduces oxidative stress in a patient with primary hyperparathyroidism.

Parathyroidectomy for hyperparathyroidism has been associated with a survival benefit, but the mechanisms remain unclear. We are reporting on an 88-year-old female patient who had high serum calcium and intact parathyroid hormone levels associated with an enlarged parathyroid gland. A parathyroidectomy was performed due to a diagnosis of primary hyperparathyroidism. After the surgery, there was a marked decrease in the oxidative stress markers, such as the ratios of oxidized to unoxidized albumin and advanced oxidation protein products. These results suggest that parathyroidectomy reduces oxidative stress in patients with primary hyperparathyroidism, which may in part explain the reduced risk for cardiovascular and all-cause mortality after parathyroidectomy.

Vitamin D receptor activator reduces oxidative stress in hemodialysis patients with secondary hyperparathyroidism.

Treatment with a vitamin D receptor activator (VDRA) has survival benefits probably related to its effects beyond the traditional role in mineral metabolism. We hypothesized that VDRA reduces oxidative stress in hemodialysis (HD) patients. To test this hypothesis, we investigated the effect of VDRA on the oxidative status of albumin in HD patients with secondary hyperparathyroidism. Eleven HD patients with secondary hyperparathyroidism were treated with calcitriol at an intravenous dose of 1.5 µg/week for four weeks. Serum intact parathyroid hormone, calcium and phosphorus were monitored and we measured the amount of oxidized albumin and albumin hydroperoxides form before and after calcitriol treatment. The ratio of oxidized to un-oxidized albumin was determined as a representative marker of oxidative stress. The radical scavenging activity of albumin was also evaluated. After four weeks of calcitriol therapy, there were no significant changes in serum intact parathyroid hormone, calcium, or phosphorus levels; however, the ratio of oxidized to un-oxidized albumin was markedly decreased and serum thiol content was significantly increased after calcitriol treatment. Furthermore, the radical scavenging activity of albumin was greater after calcitriol treatment compared with that of untreated albumin. Our data suggest that intravenous calcitriol treatment reduces oxidative stress and strengthens antioxidant defenses by inhibiting albumin oxidation in HD patients with secondary hyperparathyroidism.

Clinical significance of alanine aminotransferase levels and the effect of ursodeoxycholic acid in hemodialysis patients with chronic hepatitis C.

BACKGROUND: The natural history of hepatitis C virus (HCV) carriers and the effect of ursodeoxycholic acid (UDCA) have not been fully elucidated among hemodialysis (HD) patients. METHODS: Eighty-four anti-HCV antibody- and HCV RNA-positive and 154 anti-HCV antibody-negative HD patients who were retrospectively observed for at least 3 years were analyzed. We investigated the factors associated with thrombocytopenia (< 1.3 x 10(5)/microL) and decreased platelet count (PLT) (more than 20% decrease during the follow-up period), which were considered to be indicators of hepatic fibrosis. In addition, another 16 HD patients with HCV who received 300 mg/day UDCA orally for at least 6 months were investigated. Changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT) and PLT were assessed. RESULTS: After the 60.3-months mean follow-up period, HCV infection was independently associated with both thrombocytopenia [odds ratio (OR) 2.589] and decreased PLT (OR 2.339) in 238 HD patients. In 84 HD patients with HCV, the average ALT levels (> or = 15 IU/L) during the follow-up period was associated with thrombocytopenia (OR 3.882) and decreased PLT (OR 4.470). In addition, ALT, AST and GGT significantly decreased at 6 months after starting UDCA, but PLT did not change in 16 HD patients with HCV. CONCLUSIONS: These results indicate that HCV infection is a risk for thrombocytopenia which should be associated with hepatic fibrosis in HD patients. In addition, the clinical course of ALT levels predicts the progression of thrombocytopenia, and UDCA may effectively lower ALT levels in HD patients with HCV.