The Effect of Medical Cooperation in the CKD Patients: 10-Year Multicenter Cohort Study.

INTRODUCTION: While chronic kidney disease (CKD) is one of the most important contributors to mortality from non-communicable diseases, the number of nephrologists is limited worldwide. Medical cooperation is a system of cooperation between primary care physicians and nephrological institutions, consisting of nephrologists and multidisciplinary care teams. Although it has been reported that multidisciplinary care teams contribute to the prevention of worsening renal functions and cardiovascular events, there are few studies on the effect of a medical cooperation system. METHODS: We aimed to evaluate the effect of medical cooperation on all-cause mortality and renal prognosis in patients with CKD. One hundred and sixty-eight patients who visited the one hundred and sixty-three clinics and seven general hospitals of Okayama city were recruited between December 2009 and September 2016, and one hundred twenty-three patients were classified into a medical cooperation group. The outcome was defined as the incidence of all-cause mortality, or renal composite outcome (end-stage renal disease or 50% eGFR decline). We evaluated the effects on renal composite outcome and pre-ESRD mortality while incorporating the competing risk for the alternate outcome into a Fine-Gray subdistribution hazard model. RESULTS: The medical cooperation group had more patients with glomerulonephritis (35.0% vs. 2.2%) and less nephrosclerosis (35.0% vs. 64.5%) than the primary care group. Throughout the follow-up period of 5.59 ± 2.78 years, 23 participants (13.7%) died, 41 participants (24.4%) reached 50% decline in eGFR, and 37 participants (22.0%) developed end-stage renal disease (ESRD). All-cause mortality was significantly reduced by medical cooperation (sHR 0.297, 95% CI 0.105-0.835, p = 0.021). However, there was a significant association between medical cooperation and CKD progression (sHR 3.069, 95% CI 1.225-7.687, p = 0.017). CONCLUSION: We evaluated mortality and ESRD using a CKD cohort with a long-term observation period and concluded that medical cooperation might be expected to influence the quality of medical care in the patients with CKD.

Health economic evaluation of peritoneal dialysis based on cost-effectiveness in Japan: a preliminary study.

BACKGROUND: In Japan, the medical expenditures associated with dialysis have garnered considerable interest; however, a cost-effectiveness evaluation of peritoneal dialysis (PD) is yet to be evaluated. In particular, the health economics of the "PD first" concept, which can be advantageous for clinical practice and healthcare systems, must be evaluated. METHODS: This multicenter study investigated the cost-effectiveness of PD. The major effectiveness indicator was quality-adjusted life year (QALY), with a preference-based utility value based on renal function, and the cost indicator was the amount billed for a medical service at each medical institution for qualifying illnesses. In comparison with hemodialysis (HD), a baseline analysis of PD therapy was conducted using a cost-utility analysis (CUA). Continuous ambulatory PD (CAPD) and automated PD (APD) were compared based on the incremental cost-utility ratio (ICUR) and propensity score (PS) with a limited number of cases. RESULTS: The mean duration since the start of PD was 35.0±14.4 months. The overall CUA for PD (179 patients) was USD 55,019/QALY, which was more cost effective (USD/monthly utility) compared with that for HD for 12-24 months (4,367 vs. 4,852; p<0.05). The CUA reported significantly better results in the glomerulonephritis group than in the other diseases, and the baseline CUA was significantly age sensitive. The utility score was higher in the APD group (mean age, 70.1±3.5 years) than in the CAPD group (mean age, 70.6±4.2 years; 0.987 vs. 0.860; p<0.05, 9 patients). Compared with CAPD, APD had an overall ICUR of USD 126,034/QALY. CONCLUSION: The cost-effectiveness of PD was potentially good in the elderly and in patients on dialysis for <24 months. Therefore, the prevalence of PD may influence the public health insurance system, particularly when applying the "PD first" concept.

Using kidney size for early detection of contrast-induced nephropathy in the emergency department setting.

AIM: We aimed to examine the relationship between kidney size and contrast-induced nephropathy (CIN) in patients who underwent contrast-enhanced computed tomography (CT) in the emergency department. METHODS: This single-center retrospective observational study was undertaken to evaluate risk factors for CIN at Okayama Saiseikai General Hospital (Okayama, Japan) from January 2014 through to December 2016. Contrast-induced nephropathy was defined as an absolute increase in serum creatinine level of ≥0.5 mg/dL or ≥25% over the baseline value within 72 h after contrast-enhanced CT. Independent risk factors for CIN were determined by multiple logistic regression analysis. The thickness of the kidney was evaluated as a predictor of CIN using the area under the receiver operating characteristic curve. We also analyzed CIN as an outcome using the Kaplan-Meier method. RESULTS: The incidence of CIN was 26/262 (9.9%). In the multivariate analysis, CIN was associated with renal thickness (odds ratio = 0.65; 95% confidence interval, 0.53-0.81). No patient underwent renal replacement therapy. CONCLUSION: Renal thickness could be used as a reliable, simple, and easily obtainable marker for identifying CIN in patients undergoing contrast-enhanced CT in the emergency department.

Antithyroid drug-associated MPO-ANCA-positive tubulointerstitial nephritis in a type 2 diabetes patient: a case report.

A 54-year-old man diagnosed with type 2 diabetes and hyperthyroidism was prescribed propylthiouracil (PTU) after the patient developed hepatic dysfunction on thiamazole. At 50 mg/day of PTU, he was stable with thyroid-stimulating hormone receptor and thyrotropic antibody titers remaining stable. After four years of taking PTU, he was referred to the Department of Nephrology due to a rapid increase in his serum creatinine (Cr) level. He showed impaired renal function (Cr 2.26 mg/dL; estimated glomerular filtration rate (eGFR), 25 mL/min). In addition, urinary ß2-microglobulin (ß2 MG) was increased to 71,980 µg/L and was positive for myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibody (ANCA) (33.9 U/mL). Gallium scintigraphy demonstrated a remarkable accumulation in both kidneys. The patient was diagnosed with tubulointerstitial nephritis based on a renal biopsy, the results of which suggested that it might have been induced by PTU. He was treated with prednisolone (PSL) at 30 mg/day. As a result, within two weeks, Cr, eGFR, and urinary ß2 MG levels were progressively improved to 1.72 mg/dL, 34 mL/min, and 22,020 µg/L, respectively. Therefore, we tapered off the PSL with a dose of 5 mg/day after approximately one year. There have been no exacerbated renal function parameters. Although there are many reports on patients developing MPO-ANCA-positive crescentic glomerulonephritis after the administration of PTU, we report on a relatively rare case in which interstitial nephritis occurred after the administration of PTU.

Cost-Effectiveness of Maintenance Hemodialysis in Japan.

The cost-effectiveness according to primary disease or dialysis duration has never been analyzed with respect to maintenance hemodialysis (MHD). Study candidates were > 20 years of age and had received hemodialysis for at least 6 months. Hemodialysis patients were prospectively observed for 36 months, and patient utility was assessed based on the Euro-QOL 5-dimensions (EQ-5D), from which the quality adjusted life years (QALYs) were estimated. Medical costs were calculated based on medical service fees. The cost-effectiveness defined as the incremental cost utility ratio (ICUR) was analyzed from a social perspective. A total of 29 patients (mean age; 59.9 ± 13.1 years) undergoing 437 dialysis sessions were analyzed. Utility based upon the EQ-5D score was 0.75 ± 0.21, and the estimated total medical cost for one year of MHD treatment was 4.52 ± 0.88 US$10 000. ICUR was 6.88 ± 4.47 US$10 000/QALY on average, and when comparing ICUR based on the causes of kidney failure, the value for diabetic nephropathy was found to be higher than that for glomerulonephritis (8.17 ± 6.28 vs. 6.82 ± 4.07). ICUR after 36 months observation increased mainly in the patients below 65 years of age (All; P < 0.05, <65; P < 0.01, 65≤; not significant). MHD is a treatment that could improve the socioeconomic state of elderly patients with end-stage kidney disease (ESKD), but the ICUR for diabetic nephropathy was higher than that for glomerulonephritis.

Survey of the effects of a column for adsorption of ß2-microglobulin in patients with dialysis-related amyloidosis in Japan.

Dialysis-related amyloidosis is a serious complication of long-term hemodialysis. Its pathogenic mechanism involves accumulation of ß2-microglobulin in the blood, which then forms amyloid fibrils and is deposited in tissues, leading to inflammation and activation of osteoclasts. Lixelle, a direct hemoperfusion column for adsorption of ß2-microglobulin, has been available since 1996 to treat dialysis-related amyloidosis in Japan. However, previous studies showing the therapeutic efficacy of Lixelle were conducted in small numbers of patients with specific dialysis methods. Here, we report the results of a nationwide questionnaire survey on the therapeutic effects of Lixelle. Questionnaires to patients and their attending physicians on changes in symptoms of dialysis-related amyloidosis by Lixelle treatment were sent to 928 institutions that had used Lixelle, and fully completed questionnaires were returned from 345 patients at 138 institutions. The patients included 161 males and 184 females 62.9 ± 7.7 years age, who had undergone dialysis for 25.9 ± 6.2 years and Lixelle treatment for 3.5 ± 2.7 years. Based on self-evaluation by patients, worsening of symptoms was inhibited in 84.9-96.5% of patients. Of the patients, 91.3% felt that worsening of their overall symptoms had been inhibited, while attending physicians evaluated the treatment as effective or partially effective for 72.8% of patients. Our survey showed that Lixelle treatment improved symptoms or prevented the progression of dialysis-related amyloidosis in most patients.

Renal disease in the elderly and the very elderly Japanese: analysis of the Japan Renal Biopsy Registry (J-RBR).

BACKGROUND AND OBJECTIVES: Data regarding renal disease in the elderly (age ≥65 years old) and very elderly (age ≥80 years old) Japanese are extremely limited. The aim of this study was to examine the causes of renal disease and their clinical presentations in elderly patients who underwent renal biopsy. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: From July 2007 to November 2011, all of the elderly native renal biopsy patients who had been registered in the Japan Renal Biopsy Registry (J-RBR; 2802 including 1596 males and 1206 females) were identified. Their data were compared with a control group of 7416 patients who ranged in age from 20 to 64 years old and were registered on the J-RBR over the same period. In addition, the clinical and pathological classifications of 276 very elderly patients were also analyzed. RESULTS: The indications for biopsy were nephrotic syndrome (NS) in 36.2 and 50.7 % of the elderly and the very elderly patients, chronic nephritic syndrome in 31.8 and 17.4 %, and acute kidney injury including rapidly progressive glomerulonephritis in 18.6 and 22.5 %, respectively. Primary glomerular disease was the most frequent diagnosis, followed by MPO-ANCA-positive nephritis, IgA nephropathy (IgAN), and diabetic nephropathy. In primary GN including IgAN, membranous nephropathy (MN) was the most frequent histological type, followed by IgAN and minor glomerular abnormalities. A comparison with the control group showed that MN, MPO-ANCA-positive nephritis, and amyloid nephropathy were more common in the elderly (P < 0.001), and IgAN was less common (P < 0.001). As for nephrotic syndrome in the elderly, MN was the most common histological type, followed by minimal change NS, diabetic nephropathy, amyloid nephropathy, and focal segmental glomerulosclerosis. There was a significant discrepancy between the urinary protein/creatinine ratio and daily proteinuria after the 7th decade of life. CONCLUSIONS: Renal biopsy is a valuable diagnostic tool, even in elderly and very elderly Japanese patients. In the future, modified clinical guidelines for elderly renal disease should be developed.

Application of peritoneal dialysis in elderly patients by classifying the age into young-old, old, and oldest-old.

BACKGROUND: A greater number of end-stage renal disease patients are receiving peritoneal dialysis (PD) or hemodialysis (HD) in Japan. However, medical concerns with advancing age have been raised in PD utilization for elderly patients. The objective of this study was to address the indications for PD in elderly patients in terms of medical concerns such as nutrition state, residual renal function, dialysis efficiency, peritonitis, cardiovascular disease (CVD) complications, and technique survival. METHODS: In a retrospective, two-center study, we evaluated 247 patients who newly started PD from 2002 to 2008. All patients were divided into four groups: young (<64 years, n = 99), young-old (65-74 years, n = 55), old (75-84 years, n = 62) and oldest-old (≥85 years, n = 31). Serum albumin, hemoglobin, ß(2)-microglobulin, cardio-thoracic ratio, 24-hour urine collection and spent dialysate volume was collected at the initiation of PD and after 1, 2, 3, and 4 years. PD withdrawal, occurrence of CVD complications, peritonitis and death were recorded. RESULTS: Nephrosclerosis as a primary disease increased with advancing age (p = 0.001). At baseline, gender, body weight, serum creatinine, hemoglobin and cardio-thoracic ratio were significantly different among the four groups. No significant decrease was shown in urine output with advancing age. The spent dialysate volume was significantly lower (mean 3.8 liters/day) in the oldest-old group compared with the other groups (p = 0.001). However, a smaller volume of PD fluid in the oldest-old group was not accompanied by a significantly higher serum ß(2)-microgloblin level compared with the other groups and there was no reason of PD withdrawal for underdialysis in the old and oldest-old groups. Neither the incidence of CVD complications nor that of peritonitis was increased with advancing age. There was no significant difference in technique survival rate excluding death between each group. These findings suggest that there are no medical concerns to avoid PD therapy in elderly end-stage renal disease patients.

Effluent free radicals are associated with residual renal function and predict technique failure in peritoneal dialysis patients.

OBJECTIVE: Residual renal function (RRF) is associated with low oxidative stress in peritoneal dialysis (PD). In the present study, we investigated the relationship between the impact of oxidative stress on RRF and patient outcomes during PD. METHODS: Levels of free radicals (FRs) in effluent from the overnight dwell in 45 outpatients were determined by electron spin resonance spectrometry. The FR levels, clinical parameters, and the level of 8-hydroxy-2'-deoxyguanosine were evaluated at study start. The effects of effluent FR level on technique and patient survival were analyzed in a prospective cohort followed for 24 months. RESULTS: Levels of effluent FRs showed significant negative correlations with daily urine volume and residual renal Kt/V, and positive correlations with plasma ß(2)-microglobulin and effluent 8-hydroxy-2'-deoxyguanosine. A highly significant difference in technique survival (p < 0.05), but not patient survival, was observed for patients grouped by effluent FR quartile. The effluent FR level was independently associated with technique failure after adjusting for patient age, history of cardiovascular disease, and presence of diabetes mellitus (p < 0.001). The level of effluent FRs was associated with death-censored technique failure in both univariate (p < 0.001) and multivariate (p < 0.01) hazard models. Compared with patients remaining on PD, those withdrawn from the modality had significantly higher levels of effluent FRs (p < 0.005). CONCLUSIONS: Elevated effluent FRs are associated with RRF and technique failure in stable PD patients. These findings highlight the importance of oxidative stress as an unfavorable prognostic factor in PD and emphasize that steps should be taken to minimize oxidative stress in these patients.

Darbepoetin alfa (KRN321) is safe and effective when administered subcutaneously once every 2 or 4 weeks to patients on peritoneal dialysis in Japan.

BACKGROUND: Darbepoetin alfa (KRN321) is a recombinant protein that stimulates erythropoiesis by the same mechanism as endogenous erythropoietin. Due to its longer half-life and greater biological activity than recombinant human erythropoietin (rHuEPO), KRN321 maintains an effective hemoglobin (Hb) level at extended dose intervals compared with rHuEPO. The efficacy and safety of KRN321 administered subcutaneously to patients on peritoneal dialysis (PD) were tested. METHODS: In a multicenter, open-label, single-arm study, KRN321 was administered subcutaneously to patients on PD for 26-28 weeks. Ninety-six patients initially were given a 60 µg subcutaneous dose once every 2 weeks until a target of Hb (11.0-13.0 g/dL) was achieved. Thereafter, their dose was every 2 or 4 weeks. RESULTS: After the target of Hb was reached in most subjects (96.9%), it was maintained with KRN321 administered every 2 or 4 weeks. On completion of (or withdrawal from) study, 65 subjects (67.7%) maintained the target Hb. Although a number of adverse event related to hypertension occurred, their incidence did not appear to be related to Hb or its rate of increase. These events could be controlled adequately by interrupting or reducing the dose, and/or treatment with antihypertensives. CONCLUSIONS: The efficacy and safety of KRN321 when administered subcutaneously for 28 weeks to PD patients were confirmed. It was suggested that the quality of life of patients can be improved by treatment with KRN321 due to the reduced frequency of administration.

2008 Japanese Society for Dialysis Therapy: guidelines for renal anemia in chronic kidney disease.

The Japanese Society for Dialysis Therapy (JSDT) guideline committee, chaired by Dr Y. Tsubakihara, presents the Japanese guidelines entitled "Guidelines for Renal Anemia in Chronic Kidney Disease." These guidelines replace the "2004 JSDT Guidelines for Renal Anemia in Chronic Hemodialysis Patients," and contain new, additional guidelines for peritoneal dialysis (PD), non-dialysis (ND), and pediatric chronic kidney disease (CKD) patients. Chapter 1 presents reference values for diagnosing anemia that are based on the most recent epidemiological data from the general Japanese population. In both men and women, hemoglobin (Hb) levels decrease along with an increase in age and the level for diagnosing anemia has been set at <13.5 g/dL in males and <11.5 g/dL in females. However, the guidelines explicitly state that the target Hb level in erythropoiesis stimulating agent (ESA) therapy is different to the anemia reference level. In addition, in defining renal anemia, the guidelines emphasize that the reduced production of erythropoietin (EPO) that is associated with renal disorders is the primary cause of renal anemia, and that renal anemia refers to a condition in which there is no increased production of EPO and serum EPO levels remain within the reference range for healthy individuals without anemia, irrespective of the glomerular filtration rate (GFR). In other words, renal anemia is clearly identified as an "endocrine disease." It is believed that defining renal anemia in this way will be extremely beneficial for ND patients exhibiting renal anemia despite having a high GFR. We have also emphasized that renal anemia may be treated not only with ESA therapy but also with appropriate iron supplementation and the improvement of anemia associated with chronic disease, which is associated with inflammation, and inadequate dialysis, another major cause of renal anemia. In Chapter 2, which discusses the target Hb levels in ESA therapy, the guidelines establish different target levels for hemodialysis (HD) patients than for PD and ND patients, for two reasons: (i) In Japanese HD patients, Hb levels following hemodialysis rise considerably above their previous levels because of ultrafiltration-induced hemoconcentration; and (ii) as noted in the 2004 guidelines, although 10 to 11 g/dL was optimal for long-term prognosis if the Hb level prior to the hemodialysis session in an HD patient had been established at the target level, it has been reported that, based on data accumulated on Japanese PD and ND patients, in patients without serious cardiovascular disease, higher levels have a cardiac or renal function protective effect, without any safety issues. Accordingly, the guidelines establish a target Hb level in PD and ND patients of 11 g/dL or more, and recommend 13 g/dL as the criterion for dose reduction/withdrawal. However, with the results of, for example, the CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) study in mind, the guidelines establish an upper limit of 12 g/dL for patients with serious cardiovascular disease or patients for whom the attending physician determines high Hb levels would not be appropriate. Chapter 3 discusses the criteria for iron supplementation. The guidelines establish reference levels for iron supplementation in Japan that are lower than those established in the Western guidelines. This is because of concerns about long-term toxicity if the results of short-term studies conducted by Western manufacturers, in which an ESA cost-savings effect has been positioned as a primary endpoint, are too readily accepted. In other words, if the serum ferritin is <100 ng/mL and the transferrin saturation rate (TSAT) is <20%, then the criteria for iron supplementation will be met; if only one of these criteria is met, then iron supplementation should be considered unnecessary. Although there is a dearth of supporting evidence for these criteria, there are patients that have been surviving on hemodialysis in Japan for more than 40 years, and since there are approximately 20 000 patients who have been receiving hemodialysis for more than 20 years, which is a situation that is different from that in many other countries. As there are concerns about adverse reactions due to the overuse of iron preparations as well, we therefore adopted the expert opinion that evidence obtained from studies in which an ESA cost-savings effect had been positioned as the primary endpoint should not be accepted unquestioningly. In Chapter 4, which discusses ESA dosing regimens, and Chapter 5, which discusses poor response to ESAs, we gave priority to the usual doses that are listed in the package inserts of the ESAs that can be used in Japan. However, if the maximum dose of darbepoetin alfa that can currently be used in HD and PD patients were to be used, then the majority of poor responders would be rescued. Blood transfusions are discussed in Chapter 6. Blood transfusions are attributed to the difficulty of managing renal anemia not only in HD patients, but also in end-stage ND patients who respond poorly to ESAs. It is believed that the number of patients requiring transfusions could be reduced further if there were novel long-acting ESAs that could be used for ND patients. Chapter 7 discusses adverse reactions to ESA therapy. Of particular concern is the emergence and exacerbation of hypertension associated with rapid hematopoiesis due to ESA therapy. The treatment of renal anemia in pediatric CKD patients is discussed in Chapter 8; it is fundamentally the same as that in adults.

Microinflammation is a common risk factor for progression of nephropathy and atherosclerosis in Japanese patients with type 2 diabetes.

AIM: This study aimed to evaluate the change of serum levels of proinflammatory molecules in patients with type 2 diabetes and clarify the involvement of these molecules in diabetic nephropathy and atherosclerosis. METHODS: Sixty-six Japanese type 2 diabetic patients (T2DM) and 39 healthy control subjects were enrolled. We assessed clinical parameters, urinary albumin excretion rate (AER), brachial-ankle pulse wave velocity (baPWV), intima media thickness (IMT) and serum levels of proinflammatory molecules. RESULTS: Serum levels of IL-6, IP-10 and MCP-1 were significantly higher in T2DM than in control subjects. In T2DM, serum levels of high-sensitivity (hs) CRP, IP-10, hsTNF-alpha, VCAM-1 and E-selectin were positively correlated with AER. Serum levels of IP-10, hsTNF-alpha and VCAM-1 were positively correlated with baPWV. Serum levels of hsCRP, IL-6, IP-10 and hsTNF-alpha were positively correlated with IMT. Multiple linear regression analysis revealed that serum levels of hsTNF-alpha were independently associated with AER (beta=0.235, P=0.038) and serum levels of IP-10 were independently associated with baPWV (beta=0.209, P=0.047) and IMT (beta=0.303, P=0.032). CONCLUSION: Our results suggest that low-grade inflammation, microinflammation, may be a common risk factor for diabetic nephropathy and atherosclerosis in Japanese type 2 diabetic patients.

Serum cytokeratin 18 M30 antigen level and its correlation with nutritional parameters in middle-aged Japanese males with nonalcoholic fatty liver disease (NAFLD).

Cytokeratin (CK) 18 M30 antigen has been proposed as a diagnostic marker of nonalcoholic fatty liver disease (NAFLD). We studied serum CK18 M30 antigen level and examined the correlations among CK18 and biological data, dietary intake, and plasma fatty acid composition in middle-aged Japanese males with (NAFLD; n=42) and without NAFLD (control; n=35). NAFLD was diagnosed if subjects showed fatty liver on abdominal ultrasonography and their alcohol consumption was <20 g/d. They were also confirmed to have negative serological results for tests of autoimmune liver disease and hepatitis B and C. In the NAFLD group, body mass index, waist circumference, serum M30 antigen, alanine transaminase (ALT), cholinesterase, triacylglycerol, LDL-cholesterol, and HbA1c were significantly higher than in the control group. In the fatty acid analysis of plasma phospholipids, significantly higher dihomo-γ-linolenic acid (DGLA), total saturated fatty acids (SFA), and palmitic/linoleic acid ratio as well as lower arachidonic acid/DGLA ratio were observed in the NAFLD group compared with the control group. In the NAFLD group, M30 antigen was correlated positively with serum ALT, plasma DGLA, dietary SFA, and serum TNF-α as determined by partial correlation analysis controlled for BMI. On the basis of multivariate regression analysis using a stepwise method, M30 antigen was significantly associated with ALT and plasma DGLA. Regarding the determinants of NAFLD as revealed by logistic regression analysis, a high odds ratio was observed for plasma DGLA. In conclusion, members of the NAFLD group showed higher levels of serum CK18 M30 antigen and M30 antigen was strongly associated with serum ALT and plasma DGLA. Abnormal fatty acid metabolism may be a factor that causes aggravation of NAFLD.

Differences in corrective mode for divalent ions and parathyroid hormone between standard- and low-calcium dialysate in patients on continuous ambulatory peritoneal dialysis--result of a nationwide survey in Japan.

BACKGROUND: In patients on continuous ambulatory peritoneal dialysis (CAPD), dialysate calcium concentration has a strong influence on correction of serum calcium, phosphorus, and parathyroid hormone (PTH); however, the optimal concentration of Ca in PD solution is still uncertain. The aim of the survey reported here was to evaluate the prevalence of patients treated with standard- [SCD (approximately 3.25 - 4.0 mEq/L)] or low-calcium [LCD (approximately 1.8 - 2.5 mEq/L)] dialysate and differences in the clinical effects for correction of abnormalities in divalent ions and PTH. MATERIALS AND METHODS: We used a questionnaire to survey 333 peritoneal dialysis facilities nationwide in Japan. Then, we analyzed serum Ca, P, and PTH levels and the prescription rates for CaCO(3) as a P binder and for vitamin D (VitD) analogs. RESULTS: The 2384 CAPD patients enrolled in this analysis had a mean age of 60.5 +/- 14.2 years and a mean duration of CAPD of 44.1 +/- 39.2 months. The prevalences of SCD, LCD, and combination of SCD and LCD were, respectively, 49%, 50%, and 1% at initiation, and 40%, 38%, and 22% at the time of the survey. In 735 and 876 patients respectively, LCD and SCD had been prescribed from initiation to the time of the survey. In these two groups, we observed no difference in initiation and current serum levels of Ca and P. But prescription rates for CaCO(3) and VitD analogs were higher in the LCD group than in the SCD group, and PTH levels were higher in the LCD group than in the SCD group. CONCLUSIONS: A beneficial effect of LCD was revealed in the increased doses of CaCO(3) and VitD analogs seen in that group without the occurrence of hypercalcemia; however, PTH levels in that group were not maintained within an acceptable range. The survey suggests that more serious attention should be paid to the Ca concentration in peritoneal dialysate so as to lessen mineral and PTH disorders in CAPD.

Darbepoetin alfa (KRN321) administered intravenously once monthly maintains hemoglobin levels in peritoneal dialysis patients.

Darbepoetin alfa (KRN321) is a novel molecule that stimulates erythropoiesis by the same mechanism as endogenous erythropoietin. Due to its longer half-life and greater biological activity than recombinant human erythropoietin (rHuEPO), KRN321 maintains an effective hemoglobin (Hb) level at extended dose intervals compared with rHuEPO. This multicenter, open-label, single-arm study of 72 patients with end stage renal failure on peritoneal dialysis (PD) evaluated the efficacy and safety of KRN321 administered intravenously with the dosing intervals extended to monthly. PD patients that were either rHuEPO-naïve or rHuEPO-receiving were enrolled. In rHuEPO-naïve patients, the initial dose of KRN321 was 40 mug weekly by intravenous administration. For rHuEPO-receiving patients, an initial regimen of fortnightly intravenous administration was given and the initial dose was based on the dose of rHuEPO used before switching to KRN321. After starting the study medication, the Hb concentration was maintained between 10.0 g/dL and 13.0 g/dL. In those patients whose Hb concentrations showed a stable time-course, the dosing intervals of KRN321 were extended. The results suggest that it may be feasible to reduce the frequency of treatment to a monthly schedule, with an associated adjustment of dose, in most patients. Adverse events were observed in 67 of the 72 patients (93.1%, 267 events). Most of all the adverse events were reported in patients with chronic renal failure receiving conventional rHuEPO. No safety problems specific to KRN321 were noted. These results suggest that KRN321 could reduce of frequency of hospital visits for PD patients receiving erythropoietic therapy for renal anemia.

How to improve survival in geriatric peritoneal dialysis patients.

BACKGROUND: Recently, more elderly patients who are independent or able to live at home with the support of family are opting for continuous ambulatory peritoneal dialysis (CAPD). At the end of 2005, the annual statistical survey conducted by the Japanese Society for Dialysis Therapy indicated that the mean age of patients at initiation of dialysis treatment is 66.2 years. Only 3.6% of the overall end-stage renal disease population were treated with CAPD, and this small number of elderly patients was treated with CAPD despite the many merits of peritoneal dialysis (PD) for the elderly. In the present study, we reviewed our experience with patients 65 years of age and older at the start of PD and the results from two multicenter studies on PD treatment in elderly patients in Japan. PATIENTS AND METHODS: Study 1: Of 313 PD patients at Okayama Saiseikai General Hospital between January 1991 and June 2006, 166 patients 65 years of age and older were studied. The characteristics of these elderly PD patients were reviewed to determine which elderly patients can continue PD for more than 5 years, and what the causes of death and the effects of icodextrin were in elderly PD patients. Study 2: A multicenter study of 421 patients introduced to PD from April 2000 to December 2004 in Japan was carried out by the Japanese Society for Elderly Patients on Peritoneal Dialysis to retrospectively analyze patient survival and technique survival and to find factors that have the potential to influence prognosis in these patients. Study 3: A review of the PD management and nursing-care insurance system (long-term care insurance) targeted patients 65 years of age and older who were initiated onto PD from January 2000 to June 2002 at 82 centers in Japan. The review found 765 patients under the age of 65 years (62.6%), and 458 patients 65 years of age and over (37.4%). Data on 409 elderly PD patients from 73 centers were analyzed. RESULTS: Study 1: In 166 elderly patients, 27 (16.3%; 18 women, 9 men) continued PD for more than 5 years at our hospital. The original disease was chronic glomerulonephritis in 21 patients, diabetic nephropathy in 2 patients, nephrosclerosis in 2 patients, and polycystic kidney disease in 2 patients. The causes of death in the elderly PD patients at our hospital were heart failure (20.3%), cerebrovascular disease (17.7%), myocardial infarction (15.2%), debilitation (12.7%), peritonitis (7.6%), and pneumonia (3.8%). We observed significant differences in ultrafiltration, body weight, sodium, chloride, red blood cells, and hematocrit after using icodextrin in 14 elderly PD patients. Also, use of icodextrin in the daytime helps the family supporting an elderly member on PD by reducing the number of exchanges. Study 2: The average age of 421 patients in 37 hospitals throughout Japan was 76.4 years. Women accounted for 41% of all patients. The average modified (exclusive of factors of aging) Charlson comorbidity index (CCI) was 3.7. The modified CCI was an important factor not only in patient survival but also in technique survival. Patient survival was significantly different for the three modified CCI groups (CCI<3, 3

Pharmacokinetics of arundic acid, an astrocyte modulating agent, in acute ischemic stroke.

Arundic acid is an astrocyte modulating agent that improves neurological outcome in experimental acute stroke models. The pharmacokinetics of arundic acid in patients with acute ischemic stroke was investigated in a randomized, double-blind study. Six groups of 8 to 9 patients each received 2, 4, 6, 8, 10, or 12 mg/kg/h of arundic acid for a daily 1-hour infusion until completion of 7 doses. Maximum plasma concentrations of arundic acid increased with increasing dose; however, the systemic exposure was less than dose proportional at higher doses. The mean terminal half-life was approximately 2 to 3 hours. There was no excessive accumulation in plasma. Although systemic exposure in elderly patients was 30% greater than that in younger patients, the plasma concentration returned to nearly or below the limit of quantification prior to next administration. The pharmacokinetics of arundic acid in acute stroke patients assessed in this study were similar to that in healthy adults.

[Survey on the current status of delivered informed consent for renal replacement therapy among patients with end-stage renal disease].

We conducted a survey on the adequacy of delivered informed consent (IC) among patients with end-stage renal disease (ESRD) regarding the information provided on renal replacement therapies (RRT): Hemodialysis (HD), peritoneal dialysis (PD), and renal transplantation (RTx). A self-assessment style of questionnaire entitled "Informed consent for the selection of dialysis therapy modality" was prepared for evaluation, and the adequacy of IC was scored by 5 grades ranging from "excellent" to "bad". The questionnaire was sent to all the JSDT registered facilities (n=3484), and 480 centers replied (13.8%). Among these, 407 centers had patients introduced onto some form of RRT modality in the last 12 months. As to the adequacy of delivered IC for each modality, "excellent and good" status was reported as follows: 80.8% in HD, 49.8% in PD, and 32.5% in RTx, respectively. The major reason for "poor and bad" IC adequacy in PD and RTx, was "not available in the facility". By analyzing the facilities stratified by the clinical experiences of each modality in the past, poorly delivered IC for PD and RTx was revealed in centers lacking experience. Delivered information about RRT to ESRD patients may be biased in Japan. The findings of this study suggested that a lack of medical experience of the modality contributes to insufficient IC.

Elevated serum interleukin-18 levels might reflect the high risk of hospitalization in patients on peritoneal dialysis.

BACKGROUND: Interleukin (IL)-18 is a potent pro-inflammatory cytokine and plays a central role in atherosclerotic plaque rupture and accelerates atherosclerosis. AIM: The aim of this study was to determine serum IL-18 levels in patients on peritoneal dialysis (PD) and to assess their relationship with hospitalization. METHODS: Forty-three PD patients and 20 healthy individuals were enrolled in this study. We investigated the relationship of the serum concentrations of IL-18 and other well-established atherosclerotic markers, such as asymmetric dimethylarginine (ADMA). Hospitalization data from over a 18-month period were prospectively obtained on all 43 PD patients. Classic factors were entered into a Cox regression model to predict first hospitalization. RESULTS: The serum levels of IL-18 in patients on PD were significantly higher than those of healthy individuals (228.5 +/- 140.3 pg/mL vs 154.8 +/- 44.7 pg/mL, P < 0.05, respectively). Furthermore, serum IL-18 levels showed a positive correlation with duration of PD, serum beta2 microglobulin and serum ADMA levels. Mean serum levels of IL-18 were significantly higher among patients who had experienced at least one hospitalization than those who had not (279.9 +/- 164.3 vs 158.5 +/- 43.9 pg/mL, P = 0.0426). Furthermore, the relative risk for first hospitalization for each increase in IL-18 (pg/mL) levels was associated with a 1.182 (95% confidence interval, 1.012-1.364; P = 0.0071) increase in the risk for future hospitalization events. CONCLUSION: The present study suggests the elevated serum IL-18 levels might increase the risk for future hospitalization in patients on PD.

Serum interleukin-18 levels are associated with nephropathy and atherosclerosis in Japanese patients with type 2 diabetes.

OBJECTIVE: Interleukin (IL)-18 is a proinflammatory cytokine secreted from mononuclear cells. Serum concentration of IL-18 is a strong predictor of death in patients with cardiovascular diseases. Recent studies have shown that microinflammation is involved in the pathogenesis of diabetic nephropathy as well as of cardiovascular diseases. This study aimed to test the hypothesis that the serum level of IL-18 is a common predictor of nephropathy and atherosclerosis in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Eighty-two Japanese patients with type 2 diabetes and 55 age- and sex-matched healthy control subjects were enrolled. Patients with renal dysfunction (creatinine clearance <1 ml/s) were excluded. We assessed clinical parameters and measured serum and urinary IL-18 levels, serum IL-6 levels, carotid intima-media thickness (IMT), and brachial-ankle pulse wave velocity (baPWV) in all patients. Further, we evaluated changes of urinary albumin excretion rate (AER) after 6 months in 76 diabetic patients. RESULTS: Serum and urinary IL-18 levels were significantly elevated in patients with type 2 diabetes as compared with control subjects (serum IL-18 179 +/- 62 vs. 121 +/- 55 pg/ml, P < 0.001; urinary IL-18 97 +/- 159 vs. 47 +/- 54 pg/ml, P = 0.035). Univariate linear regression analysis showed significant positive correlations between serum IL-18 and AER (r [correlation coefficient] = 0.525, P < 0.001), HbA(1c) (r = 0.242, P = 0.029), high-sensitivity C-reactive protein (hs-CRP) (r = 0.240, P = 0.031), and urinary beta-2 microglobulin (r = 0.235, P = 0.036). Serum IL-18 levels also correlated positively with carotid IMT (r = 0.225, P = 0.042) and baPWV (r = 0.232, P = 0.040). We also found a significant correlation between urinary IL-18 and AER (r = 0.309, P = 0.005). Multivariate linear regression analysis showed that AER (standard correlation coefficients [B] = 0.405, P < 0.001) and hs-CRP (B = 0.207, P = 0.033) were independently associated with serum IL-18 levels. AER was also independently associated with urinary IL-18 levels (B = 0.295, P = 0.005). Moreover, serum and urinary IL-18 levels correlated positively with AER after 6 months (r = 0.489, P < 0.001 and r = 0.320, P = 0.005) and changes in AER during the follow-up period (r = 0.268, P = 0.018 and r = 0.234, P = 0.042). CONCLUSIONS: Serum levels of IL-18 might be a predictor of progression of diabetic nephropathy as well as cardiovascular diseases.