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Background/Aims: Angiotensin-converting enzyme (ACE) inhibitors have cardioprotective properties and functional calcium-sensing receptors express in cardiac myocytes. Methods: Rats were made uremic by 5/6 nephrectomy and treated as follows: uremic rats were fed on a regular diet (UC), uremic + enalapril (E), uremic + calcimimetic agent R-568 (R-568), and uremic + enalapril + R-568 (E+R-568). A group of normal rats served as controls (NC). Results: Blood pressure (BP) and left ventricle mass were elevated significantly in the UC and R-568 groups compared with those in the NC group, but were indistinguishable from normal controls in the E and E+R-568 groups. Cardiac fibrosis was significantly increased in the UC group compared with that in the NC group. This increase was significantly attenuated in the R-568 and E groups, and the attenuation was further enhanced in the E+R-568 group. Factors associated with cardiac hypertrophy such as proliferating cell nuclear antigen, cyclin D1, and cyclin D2, as well as factors associated with cardiac fibrosis such as type I collagen, fibronectin, and transforming growth factor-β1 were significantly increased in the UC group compared with those in the NC group. Monotherapy with R-568 or E attenuated this increase and the combination further attenuated these measures. Conclusions: Calcimimetics can suppress the progression of uremic cardiomyopathy and this effect is amplified when BP is controlled via renin-angiotensin system blockade.

To clarify the degree of parathyroid dysfunction in end-stage renal failure, sigmoidal relationship between serum Ca2+ and intact-PTH was evaluated in vivo in 47 hemodialysis (HD) patients including 12 diabetics. Patients were divided into 3 groups, 9 who had been just introduced to HD (0 years), 31 who were on maintenance HD for 2.5 to 16.2 years without significant secondary hyperparathyroidism (2nd HPT), and 7 who suffered from severe 2nd HPT for 8.5 to 15.3 years on HD. Additional 4 patients who were treated with HD or hemodiafiltration because of acute hepatic failure with normal renal function were selected for control. Sigmoidal curve (SC) in patients with non-diabetics on 0 years on HD was significantly deviated to upper and right direction. Similarly, the set point of calcium (SP) in non-diabetics was deviated to the right (higher calcium level). These abnormalities were more pronounced as the length of HD duration increased. However, these parathyroid dysfunction was not obvious in diabetic patients. In severe 2nd HPT, SC and SP were remarkably deranged. Mean SP in these patients was 1.22 mmol/l, and 1.26 mmol/l in 3 patients who required parathyroidectomy after the study. These results indicate that the earlier treatment to prevent 2nd HPT would be necessary from conservative stage of renal failure in non-diabetic population.

Oxidative stress and resultant accumulation of advanced glycation end products (AGEs) are closely related to the development of cardiovascular disease, which is the major cause of death among end-stage renal disease patients. Several markers of oxidative stress, such as malondialdehyde, oxidized low-density lipoprotein, AGEs and 8-hydroxyde-oxyguanosine, are significantly elevated in circulating blood and/or tissue levels. Vitamin E is one of the scavengers opposed to oxidative stress and has been bonded to the dialyzer membrane surface to suppress oxidative stress related to hemodialysis itself. Vitamin E-coated dialyzers are widely used in Japan and several favorable clinical effects have been reported. Improved biocompatibility leads to decreased activation of circulating blood cells and these are related to reduced doses of heparin, improvement of anemia, and dose reduction in erythropoiesis-stimulating agents. Improvement of the cytokine network and immunological system is also suggested. It is expected that regression of atherosclerosis and slowed vascular calcification might occur parallel with reduction of oxidative stress by vitamin E-coated dialyzer. An improvement of endothelial function and dialysis hypotension during dialysis has also been reported. In small studies in Japan, improvement of nutritional state, insulin resistance and quality of life have been suggested. Although a larger scale control study will be needed, hemodialysis with vitamin E-coated membrane might become another powerful treatment modality other than hemodiafiltration.

Background Studies regarding aspirin metabolism can be important in patients with renal failure who have an increased risk of cardiovascular diseases. We undertook this study to assess the aspirin esterase (AE) status in end-stage renal disease (ESRD) patients. Methods A total of 42 patients on long-term haemodialysis (HD) with a mean dialysis course of 6.1 y were recruited. Results Serum AE levels were 44% lower and cholinesterase (ChE) levels were 22% lower in ESRD patients before dialysis as compared with control subjects ( P = 0.0001). A very strong correlation was found between AE and ChE levels. AE levels increased on average 28% after dialysis with adjustments for age, gender, total cholesterol, triglyceride and high-density lipoprotein cholesterol ( P = 0.002). In addition, ChE levels were significantly increased (48%) after dialysis ( P = 0.0001). Changes in AE activity were significantly and positively correlated with those of ChE ( r = 0.427, P = 0.005). When we adjusted for several confounders, we found that the changes in AE activity operated by dialysis are significant independently of age, gender, aspirin (ASA) intake, cholesterol, triglycerides, high-density lipoprotein cholesterol and ChE. Conclusions We report that serum AE activity is significantly lower in ESRD and that treatment by HD results in an increase of activity. We confirm that AE is associated with lipid parameters and ChE. Our results show variations in ASA catabolism between the dialysis sessions, suggesting an oscillating pattern in ASA disposal in these patients. The mechanisms for reduced AE activity in uraemia and the effects of HD need further investigation.

Oxidative stress and resultant accumulation of advanced glycation end products (AGEs) are closely related to the development of cardiovascular disease, which is the major cause of death among end-stage renal disease patients. Several markers of oxidative stress, such as malondialdehyde, oxidized low-density lipoprotein, AGEs and 8-hydroxyde-oxyguanosine, are significantly elevated in circulating blood and/or tissue levels. Vitamin E is one of the scavengers opposed to oxidative stress and has been bonded to the dialyzer membrane surface to suppress oxidative stress related to hemodialysis itself. Vitamin E-coated dialyzers are widely used in Japan and several favorable clinical effects have been reported. Improved biocompatibility leads to decreased activation of circulating blood cells and these are related to reduced doses of heparin, improvement of anemia, and dose reduction in erythropoiesis-stimulating agents. Improvement of the cytokine network and immunological system is also suggested. It is expected that regression of atherosclerosis and slowed vascular calcification might occur parallel with reduction of oxidative stress by vitamin E-coated dialyzer. An improvement of endothelial function and dialysis hypotension during dialysis has also been reported. In small studies in Japan, improvement of nutritional state, insulin resistance and quality of life have been suggested. Although a larger scale control study will be needed, hemodialysis with vitamin E-coated membrane might become another powerful treatment modality other than hemodiafiltration.

Background/Aims: Fibroblast growth factor 23 (FGF23) has been shown to suppress parathyroid hormone (PTH) secretion. α-Klotho has been demonstrated to function as a fibroblast growth factor receptor (FGFR) cofactor for FGF23. Thus, both α-Klotho and FGFR may play roles in PTH synthesis and/or secretion. Functions of α-Klotho and FGFR in secondary hyperparathyroidism (SHPT) remain to be studied. The present studies explore the role of α-Klotho and FGFR in SHPT. Methods: Hyperplastic parathyroid glands (n = 44) were obtained from patients with SHPT. Results: Immunohistochemical study showed that both α-Klotho and FGFR1c expression in hyperplastic glands was significantly decreased compared with that in normal glands (Klotho p < 0.01, and FGFR1c p < 0.05). A significant positive correlation was observed between α-Klotho and FGFR1c (r2 = 0.375, p < 0.01) indicating a cooperative system. Both α-Klotho (r2 = 0.235, p < 0.05) and FGFR1c (r2 = 0.181, p < 0.05) correlated positively with the calcium-sensing receptor (CaR), which plays an important role in the development of SHPT. In addition, expression of α-Klotho correlated negatively with parathyroid cell proliferation, as confirmed by Ki67 staining (r2 = 0.148, p < 0.05). Conclusion: Decreased expression of α-Klotho and FGFR1c in parallel with CaR expression and parathyroid cell growth may be involved in the pathogenesis of SHPT.

Medial layer vascular calcification is common in patients with end-stage kidney disease. Inorganic phosphate has been shown to accelerate the transformation of vascular smooth muscle cells (VSMCs) into osteoblast-like cells, which is thought to be a major process of medial layer calcification. Although elastin degradation is associated with medial layer calcification, the linkage between elastin degradation and the transformation of VSMCs remains to be clarified. We investigated the involvement of elastin degradation in the transformation of VSMCs. Rat VSMCs were isolated and cultured with a normal- (NP, 1.0 mM) or high- (HP, 2.5 mM) phosphate medium. An elastin-derived peptide, alpha-elastin (500 microg/ml), was also added to the normal- (NP + E) or high- (HP + E) phosphate medium. After a culture period of 2 weeks, von Kossa staining revealed mineralization in the HP group, which was accelerated by alpha-elastin, whereas alpha-elastin did not affect the mineralization at a normal phosphate concentration. The gene expression of osteoblastic differentiation factors, i.e., Runx2 or osteocalcin (OC), in VSMCs was significantly increased in the HP (Runx2 P0.05, OC P0.05) and HP + E (OC P0.05) groups compared with the NP and NP + E groups. Both gene and protein expressions of tissue-nonspecific alkaline phosphatase (TNAP) were significantly increased in the HP group compared with the NP and NP + E groups (P0.01, respectively). This increment was augmented in the HP + E group (P0.01). These results suggest that elastin degradation would accelerate or stabilize the process of VSMC transformation, which is induced by high phosphate through the upregulation of TNAP.

A multicenter cooperative study was designed to evaluate the efficacy and safety of FR-860 as an anticoagulant in hemodialysis. Sixty-five stable maintenance hemodialysis patients were enrolled into the study from fourteen institutions in Japan. 4 cases were excluded from the efficacy analysis because of protocol deviation (a violation of the concomitant drugs). The period of the study was fixed at two weeks. Dosage requirements were 15.0-20.0 anti-Xa units/kg as a bolus and 7.5-10.0 anti-Xa units/kg/hr for continuous hourly administration. Total dosage of FR-860 (F) was 2, 505±127 anti-Xa units compared to that of a conventional heparin (CH) dose of 6, 124 ±190 units. No difference in the residual blood in the extracorporeal circuit was observed between the F and CH groups. The hemostatic time at the puncture site after the completion of dialysis was significantly shortened in the F group (7.9±0.7 min) in comparison with the CH group (11.4±1.1 min; p

A patient with acquired hemophilia complicated with chronic renal failure and lung tuberculosis was successfully treated by consecutive plasma exchange (PE). A 71-year-old man with serious bleeding tendency showed low coagulation factor levels and a high titer of factor VIII (FVIII) inhibitor, and he was diagnosed with acquired hemophilia. Because of the complication of active lung tuberculosis, instead of immunosuppressive therapy, he undertook a series of PE with fresh frozen plasma replacement for 3 months. After the start of PE, his bleeding symptoms and activated partial thromboplastin time (APTT) improved gradually according to the decrease in FVIII inhibitor levels. These results suggest that PE is an effective therapeutic tool for refractory acquired hemophilia.

Vascular calcification is frequently observed and is closely associated with cardiovascular mortality in patients with chronic kidney disease (CKD). Vascular calcification is largely divided into two types. One is atherosclerotic intimal layer calcification and the other is medial layer calcification (Monckeberg's calcification). The latter is more common in patients with CKD than in general population. Evidence is growing that vascular calcification is a regulated active process as well as a passive process resulting from elevated serum phosphate (P) and an increase in the calcium phosphate (Ca x P) product leading to oversaturated plasma. Proving the active process, in vitro studies have demonstrated that the transformation of vascular smooth muscle cells (VSMCs) into osteoblast-like cells is a crucial mechanism in the progression of vascular calcification. Reduction of the activity of systemic and local inhibitors has also been recognized to be important. The link between vitamin D and vascular calcification is complex. Experimental and clinical researches have revealed that both vitamin D excess and vitamin D deficiency have been shown to be associated with vascular calcification in uremic milieu. On the other hand, although there are some biases, recent large observational studies have demonstrated that vitamin D has beneficial effects on the mortality of patients with CKD independent of serum Ca, P, and parathyroid hormone levels, likely due to its activation of the vitamin D receptor in vasculature and cardiac myocytes. Further prospective studies are necessary to evaluate the direct effect of vitamin D on vascular calcification in order to improve the cardiovascular health of patients with CKD.

The purpose of this crossover comparison study is to elucidate the differences between the effects of a novel calcitriol analog, 22-oxacalcitriol, and calcitriol on parathyroid hormone (PTH) and bone mineral metabolism in hemodialysis patients with secondary hyperparathyroidism (SHPT). Twenty-three patients with moderate to severe SHPT were included in a random 2 x 2 crossover trial with two vitamin D analogs (12 weeks for each treatment). Two patients withdrew during the run-in period for personal reasons. Serum electrolyte, bone metabolic marker, intact PTH (iPTH) and whole PTH (wPTH) levels were measured periodically. The primary endpoint measure was a decrease in serum iPTH level, and the secondary outcome measures included changes in serum calcium (Ca), phosphate (P), and metabolic bone marker levels. Both treatments decreased iPTH and wPTH levels by similar degrees. Serum Ca, P, and Ca x P product levels at the end of each treatment were comparable and the frequencies of hypercalcemia and hyperphosphatemia were also similar during each treatment period. 22-Oxacalcitriol significantly decreased the levels of bone metabolic markers, namely, bone-specific alkaline phosphate, intact osteocalcin, pyridinoline, and cross-linked N-telopeptide of type I collagen, after a 12-week treatment. In contrast, calcitriol did not change any of the levels of bone metabolic markers. The present study showed that 22-oxacalcitriol is equally effective for PTH suppression, and Ca and P metabolism. In addition, 22-oxacalcitriol might have putative actions on bone remodeling independent of its PTH suppression. Further study is necessary to confirm the effects of 22-oxacalcitriol on bone metabolism in SHPT.

484 Background: Gastric outlet obstruction (GOO) is a late complication of advanced and metastatic malignant tumors. Self-expanding metal stent (SEMS) placement is a safe and effective palliative treatment for patients with GOO. In general, the median survival time after SEMS placement for GOO is approximately 90 days, and advanced chemotherapeutic treatment could further improve prognosis. Methods: This retrospective study aimed to analyze the efficacy of chemotherapy after SEMS placement on improvement of oral intake and survival time. Eight patients with symptomatic malignant GOO were treated by SEMS placement in our hospital. Surgical bypass could not be performed due to severe advanced malignant tumors. Patients were classified into two groups depending on whether they received chemotherapy after SEMS placement. Group A included five patients who were treated with palliative therapy alone (median age: 72 years; cases 1, 2, 3, and 4 with advanced gastric cancer, and case 5 with advanced pancreatic carcinoma). Group B included three patients who were treated with palliative therapy, followed by chemotherapy (median age: 68 years; case 6 with advanced pancreatic cancer treated with gemcitabine chemotherapy; case 7 with advanced gastric carcinoma treated with TS-1 and paclitaxel chemotherapy; and case 8 with duodenal stenosis due to advanced colonic carcinoma treated with irinotecan and cetuximab chemotherapy after SEMS placement). We estimated the gastric outlet obstruction scoring system (GOOSS ; no oral intake: 0; only liquids: 1; soft solids: 2; low-residue or full diet: 3) and survival time as the main outcomes. Results: SEMS placement using endoscopy was successful in all cases. No complications occurred after the procedure. Performance status did not change after SEMS placement. GOOSS improved from 0 to 1 in group A and from 0 to 2 in group B. Median survival time was 68 days in group A and 188 days in group B. We considered chemotherapy after SEMS contributed lifetime. Conclusions: Our study findings indicate that SEMS placement is a safe and effective method for managing malignant GOO and that chemotherapy after SEMS placement can improve diet intake and prognosis.

487 Background: FOLFIRINOX therapy has contributed to the overall survival extension of unresectable advanced pancreatic cancer. This regimen is however associated with significant toxicity. And doing the treatment, while careful to toxicity at our institution. We investigated the tolerability of FOLFIRINOX for the treatment of unresectable advanced pancreatic cancer in clinical practice. Methods: We conducted a retrospective analysis of patients with unresectable advanced pancreatic cancer who received FOLFIRINOX between November 2012 and August 2014. FOLFIRINOX is as follows: irinotecan at 150 mg/m2; oxaliplatin at 85 mg/m2; 5-fluorouracil (5FU) at 400mg/m2 bolus, 2,400mg/m2 continuous infusion. Patients' characteristics, objective response, survival and toxicities were collected. Response were evaluated with RECIST version 1.1 and toxicities with NCI-CTCAE version 4.0. Results: 13 patients were includes (8 males and 5 females). Treatment eligibility criteria in our institution were Performance Status 0 or 1, and UGT1A1 polymorphisms were excluded. Median age was 58.6 years (41-74). Clinical stage IVa/IVb was 3/10. The mean number therapy was 7.7 (3-15) cycles. The toxicity of all grade was 100% and grade 3 was 80%. The non-hematological toxicities included nausea in 8 patients (61.5%) and anorexia in 9 (69.2%). The hematological toxicities included neutropenia in 12 patients (92.3%), of which 11 (84.6%) presented a grade 3/4 neutropenia. In patients who developed grade 3 neutropenia, the treatment of FOLFIRINOX could be continued once every three weeks (triweekly) without reducing the dose. Response rate was 38.5% (CR: 0, PR: 5, SD: 6, PD: 2) and disease control rate was 84.6%. Time to treatment failure was 175 days. Relative dose intensity was 95.0% for oxaliplatin, 88.9% for irinotecan, 81.9% for 5FU (bolus), and 95.6% for 5FU (continuous). Conclusions: In clinical practice, it is expected that FOLFIRINOX is an effective, well-tolerated regimen by reducing the dose or determining the appropriate dosing interval.

The remarkable effect of plasma exchange (PE) was observed on thrombocytopenia in a patient with antiphospholipid syndrome (APS) associated with systemic lupus erythematosus. Three times PE led to recovery from severe thrombocytopenia refractory to treatment with corticosteroid, anticoagulant, and antiplatelet drugs accompanied by a decrease in the serum cardiolipin beta2 glycoprotein I antibody level. This result suggests that PE is a valuable therapeutic tool for refractory thrombocytopenia in APS.

Hemorrhagic stroke and ischemic heart disease continue to be key problems in patients with end stage renal failure. Reduced serum paraoxonase (PON-1) activity has been described in these patients, which could contribute to the accelerated development of atherosclerosis. We hypothesized that retention of uremic toxins and or "middle molecules" including advanced glycation (AGE) free adducts and peptides could play a mechanistic role in decreasing PON-1 activity.We enrolled 22 ESRD patients undergoing hemodialysis in whom paired pre- and post-dialysis samples were studied along with 30 age-matched control subjects.ESRD patients showed a 76% decrease in PON-1 activity. As expected, ESRD patients had an increase in lipoperoxides and advanced oxidation protein products (AOPP). Our patients had a 3-fold increase in serum AGEs and a striking 10-fold increase in low molecular weight (10 kDa) AGEs. Post-dialysis samples in all patients displayed an increase in PON-1 activity, which ranged from 4 to 40% of the predialysis value. HDL-cholesterol, apoAI, free cholesterol (as a LCAT surrogate), HDL-subclasses and TG did not change significantly after dialysis. Changes in PON-1 activity display a good correlation (r=0.66, p0.001) with rates in which creatinine and urea are cleared. Clearance of low molecular weight AGEs after hemodialysis explains 79% of the changes in PON-1 activity and are hence a much better predictor than creatinine changes (r=0.89, p0.00). In vitro incubation of paraoxonase with serum ultrafiltrates show a time and concentration dependent inhibition of PON-1 by the ultrafiltrates, an inhibition that is up to 3 times higher (from 8 to 24%) when chronic renal failure patients are the source of the ultrafiltrate.We showed that HD results in a significant, consistent increase in the activity of the antioxidant enzyme PON-1. The effect, correlates with the effectiveness of dialysis to clear creatinine and urea, and with the clearance of AGE adducts of low molecular weight. This effect was replicated in vitro, showing time and dose dependency. Our results suggest that another cause for the observed lower PON-1 concentrations in CRF are the retention of low-middle molecules and demonstrate a positive effect of hemodialysis in the delicate oxidant-antioxidant state of these patients, that should be weighted against other pro-oxidant effects that have also been shown to occur previously. If the hypothesis that AGEs are the main culprits is proved in further research, this opens a putative therapeutic avenue for AGE blockers in ESRD.

A 55-year-old man was admitted complaining of hemosputa, fever and dyspnea. The chest radiographs and computed tomography showed a diffuse alveolar filling pattern; suggesting alveolar hemorrhage. Laboratory data demonstrated renal dysfunction with hematuria and proteinuria and serum MPO-ANCA was also elevated. Respiratory failure progressed rapidly within two days. Steroid pulse therapy and plasmapheresis was performed. Thereafter, symptoms and chest radiograph findings improved dramatically. However proteinuria persisted as steroid administration was tapered. Renal biopsy demonstrated gromeluronephritis and interstitial lymphocyte infiltration. After administering a second course of steroid semi-pulse therapy, her proteinuria improved. C-reactive protein and MPO-ANCA decreased to normal levels after the initial steroid therapy, but serum amyloid A protein (SAA) gradually elevated. The second course of steroid pulse therapy normalized SAA, and proteinuria improved. Based on these findings, SAA seems to be a more sensitive marker for steroid tapering than either CRP or MPO-ANCA.

The mechanism through which calcimimetic compounds suppress parathyroid cell growth has not been fully elucidated. We investigated the effect of the calcimimetic compound (NPS R-568:R568) on the parathyroid cell growth in vitro. Whole parathyroid glands of subtotally nephrectomized rats fed high phosphorus diet for 8 weeks were used in this study. Fresh rat parathyroid glands were incubated in a media (phosphorus concentration is 1.0 mM and calcium is 1.25 mM) with R-568 (10-4 M) or calcitriol (10-7 M) or vehicle for 6 hours. Medium PTH level was significantly decreased in both R568-treated group and calcitriol-treated group compared with either vehicle-treated group, or no-treated group. While TUNEL-positive cells were similar in calcitriol-treated group compared with both vehicle-treated and no-treated groups, they were significantly increased in R568-treated group compared with other three groups. These results suggest that calcimimetic compounds, NPS R-568 reduces PTH secretion and induces apoptosis of hyperfunctional parathyroid cell in vitro.

Management of 2nd HPT in ESRD patients consists of administration of vitamin D (VD) and phosphate control. VD possesses not only suppressive effect on parathyroid hormone (PTH) secretion via increase in serum calcium, but also shows direct suppressive action on transcription of PTH mRNA and parathyroid cell growth, especially in high dose intermittent administratin (pulse therapy). However, hypercalcemia, a major side effect of VD pulse therapy, have limited the effective usage of VD, especially in patients with severe hyperparathyroidism. Several new VD analogs have been developed that specifically target parathyroid cells while having less calcemic action, and currently approved for clinical use.

Phosphate (P) homeostasis has long been considered to be closely linked with calcium metabolism regulated by calcium-regulating hormones, such as PTH and 1,25-dihydroxyvitamin D(3). The regulation of P is controlled mainly by three factors, absorption in the intestine, redistribution among intracellular, extracellular, and osseous compartments, and reabsorption in the kidney. Renal P reabsorption in the proximal tubule is a key process through sodium-dependent P cotransport, which is regulated mainly by dietary phosphate intake and PTH. Recently, it has been suggested that some putative P-regulating factors might play an important role in the pathogenesis of hypophosphatemic disorders, including TIO, ADHR, and XLH. This review focuses primarily on P regulatory mechanism and some candidates for putative humoral P-regulating factors.

Background Immunoglobulin (Ig) A nephropathy (IgAN) is characterized by mesangial deposits of IgA1 and C3, often with co-deposits of IgG. We attempted to clarify the clinical significance of mesangial IgG deposition in patients with IgAN. Methods We retrospectively reviewed 57 patients who were diagnosed with IgAN on the basis of pathological examination of renal biopsy specimens obtained between October 2006 and December 2010. Subjects were divided into two groups: IgA+IgG deposition (IgA-IgG) group (n = 29) and IgA deposition alone (IgA) group (n = 28). The study outcome was complete remission (CR), defined as negative proteinuria by dipstick urinalysis and urinary erythrocytes of less than 1–4/high-power field. Results Proteinuria was greater in the IgA-IgG group than the IgA group (1.1 ± 0.8 vs. 0.7 ± 0.6 g/day, Mann–Whitney U test, P = 0.042). Capillary wall IgA deposits were noted more frequently in the IgA-IgG group than the IgA group (59 vs. 11 %, Fisher’s exact test, P = 0.014). During the median follow-up period of 33.3 months (range 6–55 months) in the 57 patients, we observed CR in 24 cases (42.1 %). After the start of treatment, urinary abnormalities disappeared earlier in the IgA group than in the IgA-IgG group (log rank test, P = 0.012). Cox’s regression model showed that IgG deposition reduced the hazard ratio for CR (hazard ratio 0.35; 95 % confidence interval 0.14–0.82, P = 0.014). Therefore, IgG deposition is a risk factor for persistent urinary abnormalities. Conclusion Mesangial IgG deposition is associated with more severe clinical features in patients with IgAN.

Patients with chronic renal disease (CKD)almost always develop secondary hyperparathyroidism (SHPT) due to hypocalcemia, phosphate retention, and abnormalities in vitamin D (VD) metabolism. Concomitant decreases in VD receptor and calcium sensing receptor in the parathyroid glands render them more resistant to the action of VD and calcium, and accelerate parathyroid cell growth. Several types of bone diseases are known to occur in CKD patients. Excessive secretion of parathyroid hormone (PTH) due to SHPT causes high-turnover bone disease, called osteitis fibrosa. Among low-turnover bone disease (LTBD), osteomalacia which is characterized by calcification defect is often complicated with VD deficiency and/or aluminum accumulation. Recently, frequency of adynamic bone disease caused by PTH suppression, another type of LTBD, is increasing probably due to calcium salts as phosphate binder with or without VD treatment.

Hyperphosphatemia, vitamin D deficiency, and resulted hypocalcemia have been regarded as classical pathogeneses of secondary hyperparathyroidism. These factors have been treated by the administration of phosphorus binder and vitamin D derivatives. However, these therapies have not brought about a successful result for the prevention and treatment of secondary hyperparathyroidism. The reason could be mainly attributed to the hypercalcemia that results from the administration of calcium salts as a phosphorus binder and the calcemic action of vitamin D. To prevent hypercalcemia, non-calcium containing phosphorus binder (sevelamer hydrochloride) and vitamin D analogues, which suppress PTH secretion with minimum calcemic action, have been developed. These new vitamin D analogues include 19-nor-1-alpha, 25-dihydroxyvitamin D2 (paricalcitol), 1-alpha-hydroxyvitamin D2 (doxercalciferol), 22oxa-calcitriol (maxacalcitol) and F6-calcitriol (falecalcitriol). Furthermore, calcimimetics that stimulate calcium-sensing receptor of parathyroid cells as calcium and suppress PTH secretion are now under clinical trial. Percutaneous direct injection therapy of vitamin D, vitamin D analogue or calcimimetics into parathyroid gland has also been reported. The combination of these new strategies is expected to effectively and safely suppresses secondary hyperparathyroidism that has been resistant to conventional medical treatments.

Classic pathogeneses of secondary hyperparathyroidism (2HPT), hyperphosphatemia, vitamin D deficiency, and hypocalcemia, have been treated by the administration of phosphorus binders and vitamin D derivatives. However, these therapies have not brought about a successful result. The main reason could be attributed to hypercalcemia resulting from the administration of calcium salts as a phosphorus binder and the calcemic action of vitamin D. To prevent hypercalcemia, non-calcium-containing phosphorus binders and vitamin D analogues, which suppress parathyroid hormone (PTH) secretion with minimum calcemic action, have been developed. Furthermore, calcimimetics that stimulate the calcium-sensing receptor of parathyroid cells and suppress PTH secretion are now under clinical trial. Direct injection therapy of vitamin D analogues or calcimimetics into the parathyroid gland also has been reported. These new strategies are expected to effectively and safely suppress 2HPT, which has been resistant to conventional medical treatments. Am J Kidney Dis 41(S1):S100-S103. © 2003 by the National Kidney Foundation, Inc.

Serum soluble transferrin receptor (sTfR) has been reported to be higher in patients with iron deficiency or with elevated erythropoiesis. In the present study, serum sTfR was measured in various anemic diseases and their clinical significance was examined in a multi-institutional joint study. Serum sTfRs in patients with the following anemic diseases were markedly higher than those in normal healthy adults: non-treated iron deficiency anemia (IDA) (9.13 +/- 7.04 mg/l, n = 52, p < 0.0001), anemia of chronic disorders (ACD) (3.45 +/- 1.38 mg/l, n = 20, p < 0.0001), hemolytic anemia (HA) (5.57 +/- 3.26 mg/l, n = 17, p < 0.0001), and myelodysplastic syndrome (MDS) (4.03 +/- 2.83 mg/l, n = 20, p < 0.0001). There were significant differences between IDA and ACD (p < 0.0001), between aplastic anemia (AA) (1.58 +/- 1.26 mg/l, n = 16) and MDS (p < 0.001), and between AA and MDS with refractory anemia (MDS-RA) (4.16 +/- 3.40 mg/l, n = 9) (p < 0.02). In patients with chronic renal failure (CRF), serum sTfR levels and serum sTfR/log serum ferritin ratios (sTfR/F index) were compared in the two classified groups according to Muirhead's criteria, as IDA and non-IDA groups with or without recombinant human erythropoietin (rHuEPO) treatment. Significantly high levels of both serum sTfR (p < 0.0001) and the sTfR/F index (p < 0.0001) were observed in IDA without rHuEPO treatment. Especially in CRF with rHuEPO treatment, the sTfR/F index showed marked elevation in the IDA group (p < 0.0001) compared with serum sTfR (p < 0.001), indicating more diagnostic efficacy of the sTfR/F index for CRF with IDA. In conclusion, the serum sTfR concentration is a useful diagnostic tool for discrimination between IDA and ACD, and between AA and MDS-RA, and for the detection of iron deficiency in CRF patients in the Japanese population.

Changes in mineral metabolism associated with progressive renal failure bring about disturbances of bone metabolism. Metabolic bone disease induced by chronic renal failure has been called renal bone disease or renal osteodystrophy. Some therapeutic interventions to this abnormal mineral metabolism also contribute to the development of bone disorder.

Dialytic performance and biocompatibility of a newly developed cellulose triacetate (CTA) membrane with a microgradient porous structure, produced without using polyvinylpyrrolidone (PVP) and liquid paraffin, were compared with those of a conventional polysulfone (PS) membrane dialyzer. In vitro and clinical results demonstrated no significant difference in the dialytic performance and biocompatibility of the two dialyzers, but the CTA dialyzer lost less albumin during dialysis than the PS. These results suggest that a CTA membrane dialyzer with a porous microgradient structure attained comparable performance and biocompatibility to PS, and the risk of albumin loss was suppressed by the new CTA membrane.

Background. Although elevation of blood pressure is considered to be the main adverse effect under rHuEpo therapy in haemodialysis patients, the precise mechanism remains obscure. The direct effect of rHuEpo on endothelial cells (EC) has been suggested as one of contributing factors of rHuEpo-induced hypertension. Methods. EC were incubated with various concentrations of rHuEpo (0, 1000, 5000, 10 000 mU/ml) for up to 7 days, and cell numbers, DNA and protein synthesis by EC and supernatant concentrations of immunoreactive endothelin-1 (ET) were determined by haemocytometer, 3 H-thymidine and 3 H-leucine incorporation, and RIA, respectively. The effect of rHuEpo on EC proliferation was confirmed by anti-rHuEpo rabbit antiserum. The effect of cycloheximide or actinomycin D was also examined on the increase in ET production by rHuEpo. Results. rHuEpo dose-dependently stimulated the proliferation of cultured EC, and this proliferative effect was inhibited by anti-rHuEpo rabbit antiserum. DNA and protein syntheses by EC were also increased by rHuEpo. The supernatant concentrations of ET cultured with rHuEpo at 5000 mU/ml or more showed significantly greater values than those without rHuEpo and the increase in ET in the supernatants of media containing 5000 mU/ml rHuEpo was inhibited by incubation with 0.2 μg/ml actinomycin D or 10 μg/ml cycloheximide. Further, rHuEpo increased DNA synthesis by EC which had been cultured in E-BM medium containing 0.5 or 2% FBS for 3h and which were recultured in E-BM medium containing 5% FBS for 15 h. Conclusions. rHuEpo directly stimulates EC proliferation as a competence factor, and it also accelerates endothelin-1 production in association with stimulation of DNA and protein syntheses by EC.

To clarify the effects of correction of anemia with recombinant human erythropoietin (r-HuEPO) on the hemostatic defects in uremia, hemostatic parameters were examined in 18 hemodialysis patients with renal anemia. Anemia improved significantly 12 weeks after r-HuEPO therapy (stage II) compared to pretreatment (stage I) and 6 weeks discontinuation (stage III) periods. Platelet count did not change among the three stages, however, mean platelet volume increased significantly at stage II in comparison with stage I. Ivy bleeding time (BT) significantly shortened at stage II and prolonged again at stage III. Although there were no significant changes in platelet aggregation, plasma TxB2, 6-keto-PGF1 alpha, F.VIII:C and F.VIII:Ag levels throughout the study, platelet adhesion and von Willebrand factor (vWf):Ag significantly increased at stages II and III. Augmentations in these parameters were more remarkable in BT-shortened patients (n = 12) than in the BT-unchanged group. These results indicate that correction of anemia with r-HuEPO brought about improvement in uremic hemostatic defect via the increase in red cell volume and vWf:Ag, and new production of platelets, reflected by the improvement in platelet adhesion.

because the nodular lesion is at an advanced stage of Introduction parathyroid hyperplasia. In order to elucidate the relationship of CaR and 2In uraemic secondary hyperparathyroidism (2-HPT), HPT more precisely, the expression of CaR mRNA a normal serum calcium (Ca) does not adequately and protein was studied in surgically resected parasuppress excessive parathyroid hormone (PTH) prothyroid glands of six patients with severe 2-HPT (intact duction and secretion [1]. This result suggests an PTH>800 pg/ml ) on haemodialysis. Light microscopy abnormal Ca-sensing mechanism in 2-HPT. The sensitshowed that all glands included hypertrophic and ivity of the parathyroid to extracellular Ca has been hyperplastic lesions with or without nodular change. evaluated by the sigmoidal curve between serum intact Immunohistological examination demonstrated the PTH and Ca concentrations [2]. Although there is decreased expression of CaR protein in all hyperplastic controversy that the set-point Ca concentration calcuparathyroid glands tissues, in particular in nodular lated from this curve precisely reflects the sensitivity hyperplastic lesions compared with diffuse lesions. In of the parathyroid cell for Ca [3–5], the depressed addition, the expression of CaR mRNA by quantitative sensitivity for Ca has been clearly shown in vitro and RT–PCR and Northern blotting analyses showed a by the common experience in severe 2-HPT that high PTH develops despite the unphysiological hypercalcaemore profound reduction in large nodular hyperplastic mia. The mechanism for this abnormality has been parathyroid glands compared to that in small hyperplpartially explained by decreased plasma-activated vitastic parathyroid glands. The finding that the expresamin D, an increased parathyroid cellular mass, or a sion of parathyroid gland CaR mRNA and protein reduced vitamin D receptor in the parathyroid gland. decreases particularly in large nodular hyperplastic However, the precise mechanism is not yet fully glands is consistent with the results of two previous understood. reports. We next evaluated the correlation between resected gland weight and the expression of CaR mRNA, which Ca-sensing receptor in 2-HPT was classified into four grades by mRNA density. A significant inverse correlation was observed between Since the discovery of the Ca-sensing receptor (CaR) the weight and CaR mRNA of resected parathyroid in bovine [6 ] and human parathyroid [7], much attenglands. tion has been directed at the relationship between CaR Parathyroid cells in nodular hyperplasia generally and abnormal sensitivity for Ca in 2-HPT. Kifor et al. show a greater proliferative change compared with first reported the decreased expression of CaR protein those in diffuse hyperplasia [11]. Therefore, the relation in parathyroid tissue [8]. This finding was also supbetween proliferative activity and CaR protein expresported by CaR mRNA levels [9]. sion in the parathyroid cell was examined. Proliferation These two reports together demonstrate that the was determined by proliferative cellular nuclear antigen downregulation of CaR is more remarkable in nodular (PCNA) staining. CaR protein was strongly expressed hyperplastic lesions of the parathyroid compared with in parathyroid tissue where the PCNA staining was that in diffuse lesions and that the same downregulation scarce. In contrast, CaR expression was rare in tissue is observed in the hyperplastic tissue of primary hyperwhere the PCNA was strongly stained. These results parathyroidism. Since hyperplastic parathyroid glands suggest that the proliferative potential of parathyroid display less sensitivity to Ca [10], it appears to be tissue inversely correlates with CaR expression and reasonable that CaR expression and the sensitivity for sensitivity for Ca. Ca are suppressed more in nodular hyperplastic glands, The relation between cell proliferation and expression of CaR is similar to that between cell proliferation Correspondence and offprint requests to: Tadao Akizawa, 1-30 Fujigaoka, Aoba-ku, Yokohama, 227, Japan. and vitamin D receptor density [12]. Expression of

Several lines of evidence suggest that beta 2-microglobulin (beta 2M) accumulation in long-term hemodialysis (HD) patients results in so-called dialysis-associated amyloidosis (DAA), which is clinically manifested by carpal tunnel syndrome, osteoarthropathy, and the other organ involvements. For the purpose of preventing the beta 2M accumulation, the efficiency of beta 2M removal during (HPM), hemofiltration (HF), HD, and charcoal hemodiafiltration (HDF) with high-performance membranes (HPM), hemofiltration (HF), HD, and charcoal hemoperfusion was evaluated. Among 27 patients treated with these methods, significant beta 2M removal was noted in HDF with HPM and HD with polyacrylonitril (PAN) membrane. However, treatment of HDF with HPM for more than 6 months caused no remarkable improvement in clinical symptoms of patients, and serum beta 2M levels decreased in only two out of 15 patients. These results imply that beta 2M might be most effectively removed by HDF with HPM and HD with PAN membrane, but further long-term studies will be necessary to conclude whether these procedures could become successful therapeutic regimen for DAA.