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.

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.

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.

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.

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.

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.