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Background Prognosis of nephrotic syndrome has been evaluated based on pathological diagnosis, whereas its clinical course is monitored using objective items and the treatment strategy is largely the same. We examined whether the entire natural history of nephrotic syndrome could be evaluated using objective common clinical items. Methods Machine learning clustering was performed on 205 cases from the Japan Nephrotic Syndrome Cohort Study, whose clinical parameters, serum creatinine, serum albumin, dipstick hematuria, and proteinuria were traceable after kidney biopsy at 5 measured points up to 2 years. The clinical patterns of time-series data were learned using long short-term memory (LSTM)-encoder–decoder architecture, an unsupervised machine learning classifier. Clinical clusters were defined as Gaussian mixture distributions in a two-dimensional scatter plot based on the highest log-likelihood. Results Time-series data of nephrotic syndrome were classified into four clusters. Patients in the fourth cluster showed the increase in serum creatinine in the later part of the follow-up period. Patients in both the third and fourth clusters were initially high in both hematuria and proteinuria, whereas a lack of decline in the urinary protein level preceded the worsening of kidney function in fourth cluster. The original diseases of fourth cluster included all the disease studied in this cohort. Conclusions Four kinds of clinical courses were identified in nephrotic syndrome. This classified clinical course may help objectively grasp the actual condition or treatment resistance of individual patients with nephrotic syndrome.

Background A dose of 0.5–1 mg/kg/day of prednisolone (PSL) is administered for the initial treatment of minimal change disease (MCD). However, little is known about the optimal PSL dose for the initial treatment of MCD. Methods We conducted a retrospective multicenter cohort study of treatment-naive adult patients with MCD diagnosed by renal biopsy from 1981 to 2015 in whom PSL monotherapy was performed as the initial treatment. The exposure of interest was an initial median PSL dose of Results Ninety-one patients met the inclusion criteria. During a median follow-up of 2.98 years, 87 (95.6%) patients achieved complete remission, and 47.1% relapsed after remission. There was no significant difference in the remission rate between the groups at 4 weeks of follow-up (66.7 vs. 82.6%). The median time to remission in Group L was comparable to that in Group H (17.0 vs. 14.0 days). A multivariable Cox hazard model revealed that the initial PSL dose was not a significant predictor of remission. The cumulative steroid doses at 6 months, 1 year, and 2 years after treatment initiation were significantly lower in Group L than in Group H. Conclusion The initial PSL dose was not associated with time to remission, remission rate, time to relapse, or relapse rate. Therefore, a low initial steroid dose may be sufficient to achieve remission.

Previous studies reported conflicting results regarding an association between serum albumin concentration and the cumulative incidence of remission of proteinuria in adult patients with minimal change disease (MCD). The present study aimed to clarify the clinical impact of serum albumin concentration and the cumulative incidence of remission and relapse of proteinuria in 108 adult patients with MCD at 40 hospitals in Japan, who were enrolled in a 5-year prospective cohort study of primary nephrotic syndrome, the Japan Nephrotic Syndrome Cohort Study (JNSCS). The association between serum albumin concentration before initiation of immunosuppressive treatment (IST) and the cumulative incidence of remission and relapse were assessed using multivariable-adjusted Cox proportional hazards models. Remission defined as urinary protein 2: 1.43 [1.08, 1.90]), whereas they were not associated with relapse. A multivariable-adjusted model showed that patients with high eGFR level (≥ 60 mL/min/1.73 m2) and low albumin concentration (≤ 1.5 g/dL) achieved significantly early remission, whereas those with low eGFR (2) and high albumin concentration (> 1.5 g/dL) showed significantly slow remission. In conclusion, lower serum albumin concentration and higher eGFR were associated with earlier remission in MCD, but not with relapse.

Background Despite recent advances in immunosuppressive therapy for patients with primary nephrotic syndrome, its effectiveness and safety have not been fully studied in recent nationwide real-world clinical data in Japan. Methods A 5-year cohort study, the Japan Nephrotic Syndrome Cohort Study, enrolled 374 patients with primary nephrotic syndrome in 55 hospitals in Japan, including 155, 148, 38, and 33 patients with minimal change disease (MCD), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), and other glomerulonephritides, respectively. The incidence rates of remission and relapse of proteinuria, 50% and 100% increases in serum creatinine, end-stage kidney disease (ESKD), all-cause mortality, and other major adverse outcomes were compared among glomerulonephritides using the Log-rank test. Incidence of hospitalization for infection, the most common cause of mortality, was compared using a multivariable-adjusted Cox proportional hazard model. Results Immunosuppressive therapy was administered in 339 (90.6%) patients. The cumulative probabilities of complete remission within 3 years of the baseline visit was ≥ 0.75 in patients with MCD, MN, and FSGS (0.95, 0.77, and 0.79, respectively). Diabetes was the most common adverse events associated with immunosuppressive therapy (incidence rate, 71.0 per 1000 person-years). All-cause mortality (15.6 per 1000 person-years), mainly infection-related mortality (47.8%), was more common than ESKD (8.9 per 1000 person-years), especially in patients with MCD and MN. MCD was significantly associated with hospitalization for infection than MN. Conclusions Patients with MCD and MN had a higher mortality, especially infection-related mortality, than ESKD. Nephrologists should pay more attention to infections in patients with primary nephrotic syndrome.

This retrospective cohort study examined the roles of inflammation in acute kidney injury (AKI). Serum albumin and C-reactive protein (CRP) were used as markers of inflammation. Adults who underwent non–cardiac surgery from 2007 to 2011 were included. Exclusion criteria were urological surgery, obstetric surgery, missing data, and pre-operative dialysis. Subjects were followed until the end of 2015 or loss to follow-up. Associations between pre–operative albumin or CRP and post-operative AKI or association between AKI and mortality were examined by logistic or Cox regression, respectively. Mediation analyses were performed using albumin and CRP as mediators. Among 4,538 subjects, 272 developed AKI. Pre-operative albumin was independently associated with AKI (odds ratio [95% confidence interval (CI)]: 0.63 [0.48–0.83]). During a median follow-up of 4.5 years, 649 died. AKI was significantly associated with mortality (hazard ratio [HR] [95% CI]: 1.58 [1.22–2.04]). Further adjustment for pre-operative albumin and CRP attenuated the association (HR [95% CI]: 1.28 [0.99–1.67]). The proportions explained by mediating effects of lnCRP and albumin were 29.3% and 39.2% and mediation effects were statistically significant. In conclusion, inflammation is a predictor of AKI and a mediator of mortality after AKI. Interventions targeting inflammation might improve outcomes of AKI.

Minimal change disease (MCD) is characterized by a nephrotic syndrome usually steroid-sensitive and a high incidence of relapse of proteinuria. Previous cohort studies have reported conflicting results regarding the association between the time to remission and incidence of relapse.This multicenter prospective cohort study included 102 adult patients with steroid-sensitive MCD or focal segmental glomerulosclerosis from a 5-year cohort study of primary nephrotic syndrome, the Japan Nephrotic Syndrome Cohort Study, who achieved remission of proteinuria within 2 months of immunosuppressive therapy (IST). The association between the time to remission of proteinuria after immunosuppressive therapy and incidence of relapse was assessed using Cox proportional hazards models adjusted for clinically relevant factors.Remission was observed at 3-7, 8-14, 15-21, 22-28, and 30-56 days after initiation of immunosuppressive therapy in 17 (16.7%), 37 (36.3%), 21 (20.6%), 13 (12.7%), and 14 (13.7%) patients, respectively. During a median observation period of 2.3 years after the end of the 2nd month after initiation of immunosuppressive therapy, 46 (45.1%) patients relapsed. The time to remission was associated with the incidence of relapse in an inverse U-shaped pattern (multivariable-adjusted hazard ratios [95% confidence intervals] of the time to remission of 3-7, 8-14, 15-21, 22-28, 30-56 days: 1.00 [reference], 1.76 [0.56, 5.51], 6.06 [1.85, 19.80], 5.46 [1.44, 20.64], and 2.19 [0.52, 9.30], respectively).The time to remission was identified as a significant predictor of relapse in steroid-sensitive patients.

IntroductionThis study was conducted to investigate the incidence and time trend of lower limb amputation (LLA) among people with and without diabetes.Research design and methodsThis retrospective population-based cohort study was based on the national claims data in Japan, comprising a total population of 150 million. Data of all individuals who had LLA from April 2013 to March 2018 were obtained. We analysed the sex-adjusted and age-adjusted annual LLA rate (every fiscal year) in people with and without diabetes for major and minor amputation. To test for time trend, Poisson regression models were fitted.ResultsIn the 5-year period, 30 187 major and 29 299 minor LLAs were performed in Japan. The sex-adjusted and age-adjusted incidence of major and minor LLAs was 9.5 (people with diabetes, 21.8 vs people without diabetes, 2.3, per 100 000 person-years) and 14.9 (people with diabetes, 28.4 vs people without diabetes, 1.9, per 100 000 person-years) times higher, respectively, in people with diabetes compared with those without. A significant decline in the annual major amputation rate was observed (pConclusionsThis is the first report of the national statistics of LLAs in Japan. The incidence of major and minor LLAs was 10 and 15 times higher, respectively, in people with diabetes compared with those without. A significant decline in the major amputation rate was observed, and the annual minor amputation rate remained stable during the observation period. This information can help to create an effective national healthcare strategy for preventing limb amputations, which affect the quality of life of patients with diabetes and add to the national healthcare expenditure.

IntroductionThere are fewer reports about whether the presence of hematuria affects the progression of chronic kidney disease in patients with diabetic nephropathy. We analyzed whether microscopic hematuria in diabetic nephropathy is a risk factor for end-stage kidney disease (ESKD).Research design and methodsThe present study was a retrospective cohort study of patients with biopsy-proven diabetic nephropathy. We recruited 397 patients with diabetic nephropathy, which was confirmed by renal biopsy between June 1981 and December 2014 and followed them until October 2018 or death. Patients with microscopic hematuria before renal biopsy were defined as the hematuria group (n=91), and the remainder as the no-hematuria group (n=306). The main outcome was the occurrence of ESKD, which was defined by the requirement of permanent renal replacement therapies.ResultsThe systolic and diastolic blood pressure, serum creatinine and proteinuria were significantly higher, and the estimated glomerular filtration rate was significantly lower in the hematuria group compared with the no-hematuria group. Pathological evaluations revealed that glomerular, tubulointerstitial and vascular lesions in the hematuria group were significantly more severe. During a median of 10.1 years, 44 and 52 patients developed ESKD in the hematuria group and the no-hematuria group, respectively. Survival analyses showed that the incidence of ESKD was significantly higher in the hematuria group compared with the no-hematuria group (log-rank, pConclusionsMicroscopic hematuria is a risk factor for ESKD in diabetic nephropathy, independent of proteinuria and renal pathology.

Aims Diabetic nephropathy, a pathologically diagnosed microvascular complication of diabetes, is a strong risk factor for cardiovascular events, which mainly involve arteries larger than those affected in diabetic nephropathy. However, the association between diabetic nephropathy pathological findings and cardiovascular events has not been well studied. We aimed to investigate whether the pathological findings in diabetic nephropathy are closely associated with cardiovascular event development. Methods This retrospective cohort study analysed 377 people with type 2 diabetes and biopsy-proven diabetic nephropathy, with a median follow-up of 5.9 years (interquartile range 2.0 to 13.5). We investigated how cardiovascular events were impacted by two vascular diabetic nephropathy lesions, namely arteriolar hyalinosis and arterial intimal thickening, and by glomerular and interstitial lesions. Results Of the 377 people with diabetic nephropathy, 331 (88%) and 295 (78%) had arteriolar hyalinosis and arterial intimal thickening, respectively. During the entire follow-up period, those with arteriolar hyalinosis had higher cardiovascular event rates in the crude Kaplan-Meier analysis than those without these lesions (P = 0.005, log-rank test). When fully adjusted for clinically relevant confounders, arteriolar hyalinosis independently predicted cardiovascular events [hazard ratio (HR) 1.99; 95% confidence interval (CI) 1.12, 3.86], but we did not find any relationship between arterial intimal thickening and cardiovascular events (HR 0.89; 95% CI 0.60, 1.37). Additionally, neither glomerular nor interstitial lesions were independently associated with cardiovascular events in the fully adjusted model. Conclusions Arteriolar hyalinosis, but not intimal thickening of large arteries, was strongly associated with cardiovascular events in people with diabetic nephropathy.

The aim of the present study was to clarify the prevalence of immunosuppressive drug use and outcomes in elderly and non-elderly patients with primary membranous nephropathy (MN) in nationwide real-world practice in Japan. Between 2009 and 2010, 374 patients with primary nephrotic syndrome were enrolled in the cohort study (The Japan Nephrotic Syndrome Cohort Study, JNSCS), including 126 adult patients with MN. Their clinical characteristics were compared with those of nephrotic patients with primary MN registered in a large nationwide registry (The Japan Renal Biopsy Registry, J-RBR). Outcomes and predictors in the elderly (≥ 65 years) and non-elderly groups were identified. Similar clinical characteristics were observed in JNSCS patients and J-RBR patients (n = 1808). At the early stage of 1 month, 84.1% of patients were treated with immunosuppressive therapies. No significant differences were observed in therapies between age groups. However, elderly patients achieved complete remission (CR) more frequently than non-elderly patients, particularly those treated with therapies that included corticosteroids. No significant differences were noted in serum creatinine (sCr) elevations at 50 or 100%, end-stage kidney disease, or all-cause mortality between age groups. Corticosteroids were identified as an independent predictor of CR (HR 2.749, 95%CI 1.593–4.745, p = 0.000) in the multivariate Cox’s model. sCr levels, hemoglobin levels, immunosuppressants, clinical remission, and relapse after CR were independent predictors of sCr × 1.5 or × 2.0. Early immunosuppressive therapy including corticosteroids for primary MN showed better remission rates in elderly patients in a nationwide cohort study.

Aims/Introduction Although patient self‐efficacy is known to affect adherence to therapy, no available tool measures self‐efficacy of insulin therapy administration while addressing the entire therapeutic process and management. In light of this, we developed the ‘Insulin Therapy Self‐efficacy Scale (ITSS).’ Materials and Methods Development of the ITSS involved three phases: (i) item generation and creation of a questionnaire draft; (ii) testing and correcting the items through interviews with patients; and (iii) a multicenter, single‐arm study to validate the questionnaire. Results A factor analysis and Cronbach's α both confirmed good internal consistency in the patients’ confidence regarding the following four factors: the insulin injection procedure, insulin titration, glycemic control and ability to cope with hypoglycemia. Reproducibility was confirmed using weighted κ statistics and intraclass correlations. Good concurrent validity was confirmed with two other questionnaires. The ITSS score was also found to correlate with several patient characteristics and clinical parameters, as well as with a better adherence to injected insulin therapy 6 months later, suggesting the predictive validity of this scale. Conclusions The ITSS is a reliable and valid tool for assessing and quantifying patients’ self‐efficacy. The ITSS estimation of self‐efficacy can predict a patient's glycemic control and future adherence to insulin therapy. These characteristics will ensure the usefulness of the ITSS in ensuring a successful therapeutic process for patients and physicians.

Little is known about the association between intra-operative fluid balance (IFB) and post-operative acute kidney injury (AKI) in non-cardiac surgery. This is a retrospective cohort study. Adults who underwent non-cardiac surgery under general anesthesia from 2007 to 2011 at Nara Medical University Hospital were included. Those with obstetric or urological surgery, missing data, or pre-operative dialysis were excluded. Exposure of interest was IFB, defined as (amount of fluid administration − urine output − amount of bleeding)/body weight. Outcome variable was post-operative AKI within 1 week after surgery. Data were analyzed using logistic regression models and restricted cubic spline (RCS) analysis. Among 5168 subjects, AKI was observed in 309 (6.0%). Higher IFB (per 1 standard deviation) was independently associated with post-operative AKI after adjustment for potential confounders (odds ratio [95% confidence interval] of 1.18 [1.06–1.31]). The RCS curve showed an increase in expected probability of AKI associated with increase in IFB above 40 mL/kg. Subgroup analyses indicated higher IFB was especially associated with AKI among those with lower serum albumin, higher C-reactive protein, or positive proteinuria. The association was similar across intra-operative urine output or amount of bleeding (p for interaction 0.34 and 0.47, respectively), suggesting the association was not due to intra-operative oliguria or large amount of bleeding necessitating volume resuscitation. Higher IFB was independently associated with increase in post-operative AKI. Excessive fluid administration might have caused renal congestion and subsequent AKI. Avoiding fluid overload might be important in prevention of AKI.

The lack of high-quality clinical evidences hindered broad consensus on optimal therapies for primary nephrotic syndromes. The aim of the present study was to compare prevalence of immunosuppressive drug use in patients with primary nephrotic syndrome across 6 regions in Japan. Between 2009 and 2010, 380 patients with primary nephrotic syndrome in 56 hospitals were enrolled in a prospective cohort study [Japan Nephrotic Syndrome Cohort Study (JNSCS)], including 141, 151, and 38 adult patients with minimal change disease (MCD), membranous nephropathy (MN), and focal segmental glomerulosclerosis (FSGS), respectively. Their clinical characteristics were compared with those of patients registered in a large nationwide registry of kidney biopsies [Japan Renal Biopsy Registry (J-RBR)]. The regional prevalence of use of each immunosuppressive drug was assessed among adult MCD, MN, and FSGS patients who underwent immunosuppressive therapy in the JNSCS (n = 139, 127, and 34, respectively). Predictors of its use were identified using multivariable-adjusted logistic regression models. The clinical characteristics of JNSCS patients were comparable to those of J-RBR patients, suggesting that the JNSCS included the representatives in the J-RBR. The secondary major immunosuppressive drugs were intravenous methylprednisolone [n = 33 (24.6%), 24 (19.7%), and 9 (28.1%) in MCD, MN, and FSGS, respectively] and cyclosporine [n = 25 (18.7%), 62 (50.8%), and 16 (50.0%), respectively]. The region was identified as a significant predictor of use of intravenous methylprednisolone in MCD and MN patients. Use of intravenous methylprednisolone for MCD and MN differed geographically in Japan. Its efficacy should be further evaluated in a well-designed trial.

Key Points Question Is the Simple Postoperative AKI Risk (SPARK) index, which was developed to predict postoperative acute kidney injury in noncardiac surgery, useful in a different population? Findings In a cohort study of 5135 adults in Japan, the incidence of postoperative acute kidney injury increased as scores on the SPARK index increased. However, the model’s discriminative and calibration powers were suboptimal owing to overestimated probability among those with especially high risk of developing acute kidney injury. Meaning These findings suggest that it is difficult to precisely predict the probability of acute kidney injury preoperatively in noncardiac surgery, which includes various surgical procedures and participants with various medical backgrounds., This cohort study externally validates the Simple Postoperative Acute Kidney Injury Risk (SPARK) index for prediction of acute kidney injury among patients undergoing noncardiac surgery., Importance The Simple Postoperative AKI Risk (SPARK) index is a prediction model for postoperative acute kidney injury (PO-AKI) in patients undergoing noncardiac surgery. External validation has not been performed. Objective To externally validate the SPARK index. Design, Setting, and Participants This single-center retrospective cohort study included adults who underwent noncardiac surgery under general anesthesia from 2007 to 2011. Those with obstetric or urological surgery, estimated glomerular filtration rate (eGFR) of less than 15 mL/min/1.73 m2, preoperative dialysis, or an expected surgical duration of less than 1 hour were excluded. The study was conducted at Nara Medical University Hospital. Data analysis was conducted from January to July 2021. Exposures Risk factors for AKI included in SPARK index. Main Outcomes And Measures PO-AKI, defined as an increase in serum creatinine of at least 0.3 mg/dL within 48 hours or 150% compared with preoperative baseline value or urine output of less than 0.5 mL/kg/h for at least 6 hours within 1 week after surgery, and critical AKI, defined as either AKI stage 2 or greater and/or any AKI connected to postoperative death or requiring kidney replacement therapy before discharge. The discrimination and calibration of the SPARK index were examined with area under the receiver operating characteristic curves (AUC) and calibration plots, respectively. Results Among 5135 participants (2410 [46.9%] men), 303 (5.9%) developed PO-AKI, and 137 (2.7%) developed critical AKI. Compared with the SPARK cohort, participants in our cohort were older (median [IQR] age, 56 [44-66] years vs 63 [50-73] years), had lower baseline eGFR (median [IQR], 82.1 [71.4-95.1] mL/min/1.73 m2 vs 78.2 [65.6-92.2] mL/min/1.73 m2), and had a higher prevalence of comorbidities (eg, diabetes: 3956 of 51 041 [7.8%] vs 802 [15.6%]). The incidence of PO-AKI and critical AKI increased as the scores on the SPARK index increased. For example, 10 of 593 participants (1.7%) in SPARK class A, indicating lowest risk, experienced PO-AKI, while 53 of 332 (16.0%) in SPARK class D, indicating highest risk, experienced PO-AKI. However, AUCs for PO-AKI and critical AKI were 0.67 (95% CI, 0.63-0.70) and 0.62 (95% CI, 0.57-0.67), respectively, and the calibration was poor (PO-AKI: y = 0.24x + 3.28; R2 = 0.86; critical AKI: y = 0.20x + 2.08; R2 = 0.51). Older age, diabetes, expected surgical duration, emergency surgery, renin-angiotensin-aldosterone system blockade use, and hyponatremia were not associated with PO-AKI in our cohort, resulting in overestimation of the predicted probability of AKI in our cohort. Conclusions and Relevance In this study, the incidence of PO-AKI increased as the scores on the SPARK index increased. However, the predicted probability might not be accurate in cohorts with older patients with more comorbidities.

Aims/Introduction To compare the treatment satisfaction of four classes of oral hypoglycemic agents (OHAs): dipeptidyl peptidase-4 (DPP-4) inhibitors, α-glucosidase inhibitors (αGI), biguanides (BG) and sulfonylureas (SU), which are common initial treatments for type 2 diabetes mellitus patients in Japan, and to identify the best oral hypoglycemic agent in terms of treatment satisfaction. Materials and Methods In this 12-week, randomized, controlled, open-label study, Japanese outpatients with type 2 diabetes mellitus who were naive to pharmacological treatment were randomly assigned a DPP-4 inhibitor, a BG., an αGI or a SU. The primary end-point was the Oral Hypoglycemic Agent Questionnaire (OHA-Q) total and subscale scores (treatment convenience, somatic symptoms and satisfaction) at week 4. Adherence, glycated hemoglobin (HbA1c) level and safety were also evaluated. Results The DPP-4 inhibitor group scored highest in the OHA-Q total and all subscale scores at week 4. The total score was significantly higher in the DPP-4 inhibitor group than in the BG or αGI groups (P = 0.0084 and 0.0147, respectively). The mean total score at week 12 was also highest in the DPP-4 inhibitor group, with a significant difference compared with the αGI group (P = 0.0293). The mean HbA1c decreased from baseline to week 12 in all groups. The DPP-4 inhibitor group had the highest adherence at weeks 4 and 12. A total of 11 patients reported adverse events, including one hypoglycemic event in the SU group. Conclusions The DPP-4 inhibitor was the most preferable option in terms of treatment satisfaction.

Background Little is known about the association between pre-operative proteinuria and post-operative acute kidney injury (AKI) in noncardiac surgery. Methods This is a retrospective cohort study. Adults who underwent noncardiac surgery under general anesthesia from 2007 to 2011 at Nara Medical University Hospital were included. Those with obstetric or urological surgery, missing data for analyses or pre-operative dialysis were excluded. Exposure of interest was pre-operative proteinuria, defined as (+) or more by dipstick test. The outcome variable was post-operative AKI, defined by Kidney Disease: Improving Global Outcomes criteria, within 1 week after surgery. Multivariable logistic regression analyses were performed. Results Among 5168 subjects, 309 (6.0%) developed AKI. Pre-operative proteinuria was independently associated with post-operative AKI, with an odds ratio (OR) [95% confidence interval (CI)] of 1.80 (1.30–2.51). A sensitivity analysis restricted to elective surgery yielded a similar result. As proteinuria increased, the association with AKI became stronger [OR (95% CI) 1.14 (0.75–1.73), 1.24 (0.79–1.95), 2.75 (1.74–4.35) and 3.95 (1.62–9.62) for urinary protein (+/−), (+), (2+) and (3+), respectively]. Subgroup analyses showed proteinuria was especially associated with post-operative AKI among subjects with renin–angiotensin system inhibitors, other anti-hypertensives, hypoalbuminemia or impaired renal function (P for interaction = 0.05, 0.003, 0.09 or 0.02, respectively). Conclusions In noncardiac surgery, pre-operative proteinuria was independently associated with post-operative AKI. Subjects with proteinuria should be managed with caution to avoid AKI peri-operatively.

Placental growth factor (PlGF) contributes to atherogenesis through vascular inflammation and plaque destabilization. High levels of PlGF may be associated with mortality and cardiovascular disease, but the relationship between PlGF level and adverse outcomes in patients with CKD is unclear. We conducted a prospective cohort study of 1351 consecutive participants with CKD enrolled in the Novel Assessment of Risk management for Atherosclerotic diseases in CKD (NARA-CKD) study between April 1, 2004, and December 31, 2011. During a median follow-up of 3 years, 199 participants died and 383 had cardiovascular events, defined as atherosclerotic disease or heart failure requiring hospitalization. In adjusted analyses, mortality and cardiovascular risk increased in each successive quartile of serum PlGF level; hazard ratios (HRs) (95% confidence intervals [95% CIs]) for mortality and cardiovascular risk, respectively, were 1.59 (0.83 to 3.16) and 1.55 (0.92 to 2.66) for the second quartile, 2.97 (1.67 to 5.59) and 3.39 (2.20 to 5.41) for the third quartile, and 3.87 (2.24 to 7.08) and 8.42 (5.54 to 13.3) for the fourth quartile. The composite end point of mortality and cardiovascular events occurred during the study period in 76.4% of patients in both the highest PlGF quartile (≥19.6 pg/ml) and the lowest eGFR tertile (

Paroxysmal nocturnal hemoglobinuria is a rare clonal hematopoietic stem cell disorder characterized by intravascular hemolysis, hemoglobinuria, and inflammatory thrombotic state. Intravascular hemolysis in paroxysmal nocturnal hemoglobinuria (PNH) can lead to acute and chronic renal injury through hemoglobin-mediated toxicity. A 32-year-old pregnant woman with myelodysplastic syndrome was admitted to our hospital with severe preeclampsia. Shortly after an urgent caesarean section, she became obtunded and showed signs of acute kidney injury (AKI) with anuria, severe intravascular hemolysis, and hypermagnesemia. She was diagnosed with PNH with a positive Ham test and flow cytometry analysis. Renal magnetic resonance imaging revealed decreased signal intensity in the renal cortex due to hemosiderin deposition. Hemodialysis, plasma exchange, and administration of corticosteroids ameliorated her clinical condition and renal function. This case illustrates that careful management is required to prevent postpartum AKI in pregnant women with PNH.

It is important to establish glycemic markers which reflect accurate glycemic status in advanced chronic kidney disease (CKD) patients; however, adequate glycemic markers have not been established. We evaluated the accuracy of glycemic markers in non-dialysis CKD patients.139 non-dialysis CKD patients with diabetes were enrolled. The patients were divided into three groups as follows: group 1 (G1), patients with an estimated glomerular filtration rate (eGFR)= 60 mL/min/1.73 m2; group 2 (G2), 30 ≤ eGFR60; and group 3 (G3), eGFR30. The patients were also classified by serum albumin: patients with serum albumin= 3.5 g/dL as group S1 (S1) and serum albumin3.5 as group S2 (S2).Glycated hemoglobin (A1C) was positively correlated with random PG in G1 and G2; however, no significant correlation was observed in G3. Whereas glycated albumin (GA) was correlated with random PG in S1, there was no significant correlation in S2. To clarify the significance of A1C and GA, the relationships among A1C, GA, and various clinical parameters were examined. GA was correlated with serum albumin and the urinary albumin-creatinine ratio, whereas A1C was significantly correlated with hemoglobin, the dose of recombinant human erythropoietin, and eGFR.A1C was affected by eGFR, and GA was influenced by hypoalbuminemia; therefore, it is necessary to choose adequate glycemic markers according to the CKD stage and serum albumin level. GA is a superior glycemic marker in patients with eGFR30 mL/min/1.73 m2 and serum albumin= 3.5 g/dL.

Recently, plasma globotriaosylsphingosine (lyso-Gb3) has attracted attention as a biomarker of Fabry disease. However, we found a subset of Fabry disease patients who did not show any increase in the plasma lyso-Gb3 concentration, although other patients exhibited apparent enhancement of it. This subset predominantly exhibited the clinical phenotype of later-onset Fabry disease, and gene analysis revealed that the patients harbored the M296I mutation common to Japanese Fabry patients. This amino acid substitution is predicted to cause a small conformational change on the surface of the α-galactosidase A molecule, resulting in residual enzyme activity. Plasma lyso-Gb3 is a good biomarker of Fabry disease but care should be taken when it is used for a definitive diagnosis.

Technique failure remains a frequent cause of peritoneal dialysis (PD) withdrawal. Many post-commencement predictors of PD technique failure have been identified, while predialysis predictors have remained unclear. The aim of this study was to identify predialysis indices for technique failure in PD patients. We recruited 206 consecutive PD patients who were treated at Nara Medical University Hospital between 1 April 1997 and 31 December 2012. Forty-eight patients were excluded because of transition from hemodialysis (HD) or withdrawal from PD within 3 months, leaving 158 patients for analysis. Clinical characteristics and laboratory data from within 3 months preceding PD commencement were analyzed. The primary outcome was the composite of time to combined use of HD, transition to HD, and all-cause mortality within 2 years after PD commencement. During the study period, the primary outcome was observed in 50 patients. Using multivariate analysis, greater age (odds ratios (ORs) [95%CI], 3.08 [1.72-5.61]), anemia (ORs [95%CI], 2.12 [1.08-4.43]), overweight/obesity (ORs [95%CI], 2.09 [1.16-3.72]), and hypocalcemia (ORs [95%CI], 1.86 [1.04-3.35]) were independently associated with technique failure. Adding corrected calcium to the model incorporating age, body mass index, and hemoglobin significantly increased the c-statistic from 0.678 to 0.755 (P = 0.048) relative to the model incorporating age alone. The integrated discrimination improvement was 0.085 (95% CI 0.036-0.134, P 0.001) and the continuous net reclassification improvement was 0.395 (95% CI 0.066-0.724, P = 0.02). In conclusion, the combination of predialysis indices comprising age, overweight/obesity, anemia, and corrected calcium could provide a significant predictive value for technique failure of PD.

Background Depletion of glomerular podocytes is an important feature of progressive diabetic nephropathy. Although the most plausible explanation for this podocyte depletion is detachment from the glomerular basement membrane after cellular apoptosis, the mechanism is unclear. Fibroblast-specific protein 1 (FSP1; encoded by the S100A4 gene) is a member of the S100 family of calcium-binding proteins and is constitutively expressed in the cytoplasm of tissue fibroblasts or epithelial cells converted into fibroblasts by means of epithelial-mesenchymal transition. Study Design Retrospective cross-sectional analysis. Settings & Participants 109 patients with type 2 diabetes mellitus, of whom 43 (39%) underwent kidney biopsy. Predictor Clinical stage (4 categories) and histological grade (5 categories) of diabetic nephropathy. Outcome FSP1 expression in podocytes in urine and glomeruli in kidney biopsy specimens. Measurements Immunohistochemistry, real-time polymerase chain reaction, and in situ hybridization. Results 38 of 109 patients (35%) were normoalbuminuric, 16 (15%) had microalbuminuria, 8 (7%) had macroalbuminuria, and 47 (43%) had decreased kidney function. Approximately 95% of podocytes in urine sediment were not apoptotic, and 86% expressed FSP1. The number of FSP1-positive podocytes in urine sediment was significantly larger in patients with macroalbuminuria than in those with normoalbuminuria ( P = 0.03). Intraglomerular expression of FSP1 occurred almost exclusively in podocytes from patients with diabetes, and the number of FSP1-positive podocytes was larger in glomeruli showing diffuse mesangiopathy than in those showing focal mesangiopathy ( P = 0.01). The number also was larger in glomeruli with nodular lesions than in those without nodular lesions ( P Limitations Nonrepresentative study population. Conclusions These results suggest that the appearance of FSP1 in podocytes of patients with diabetes is associated with more severe clinical and pathological findings of diabetic nephropathy, perhaps because of induction of podocyte detachment through epithelial-mesenchymal transition–like phenomena.

A 50-year-old woman was admitted for active rheumatoid arthritis (RA). She was found to have RA 1 year prior to this admission. Past history was unremarkable and she had no family history for rheumatic diseases. As nonsteroidal anti-inflammatory drug (NSAID) and methotrexate were not effective, etanercept was started (25 mg, twice a week). Mild elevation of alanine transaminase (ALT) and aspartate transaminase (AST) was found as an outpatient, and it was considered to be NSAID-induced liver injury. Two weeks after the first dose of etanercept, she developed progressive elevation of AST and ALT with right upper quadrant tenderness and hepatomegaly. Etanercept was discontinued and liver biopsy was performed, which demonstrated portal-area-dominant lymphoplasmacytic inflammatory cell infiltration. She was diagnosed as autoimmune hepatitis (AIH). Glucocorticoid was started with normalized liver function and stable joint symptoms. AIH was thought to be acutely aggravated by the administration of etanercept.

Corticosteroids are frequently used to treat patients with active IgA nephropathy (IgAN); however, there have been few reports describing factors that are predictive of the response to corticosteroid treatment. The purpose of this study is to determine the extent to which fibroblast-specific protein 1-positive (FSP1(+)) cells are predictive of corticosteroid responsiveness in patients with IgAN.Fifty biopsy-proven IgAN patients who received corticosteroid therapy were enrolled and followed for 7.1 +/- 3.0 years. FSP1(+) cells were identified using an anti-FSP1 antibody.Twelve patients showed progression of renal impairment or no reduction of urinary protein (non-responders) after steroid therapy. In the remaining 38 patients, renal function was stable during follow-up, and their urinary protein declined to1.0 g/day (responders). Serum creatinine, estimated GFR, severity of mesangial proliferation, percent glomerulosclerosis/total glomeruli, extent of interstitial damage and FSP1(+) cell number were all significantly higher in non-responders than in responders. Cox regression analysis using two covariates with every possible combination of factors indicated that FSP1(+) cell number was the strongest and most significant predictor of corticosteroid responsiveness. When IgAN patients had32.6 FSP1(+) cells/HPF at diagnosis, they were the more likely to show steroid resistance.FSP1(+) cell number can serve as an excellent predictor of corticosteroid responsiveness in patients with IgAN.

Background Fractalkine (Fkn) is a chemokine that affects cells expressing its receptor, CX3CR1, including CD16-positive (CD16 + ) monocytes/macrophages (CD16 + Mos). The relationship of levels of glomerular Fkn expression and infiltration by CD16 + Mos with the severity and diversity of glomerular lesions in human lupus nephritis is not known. Study Design Retrospective cross-sectional analysis of variables observed in biopsy specimens. Settings & Participants 88 patients with systemic lupus erythematosus. Predictor Histological class and severity of lupus nephritis according to the International Society of Nephrology/Renal Pathology Society and clinicopathologic factors. Outcomes Outcome variables are assays related to the degree of glomerular Fkn expression and CD16 + Mo infiltration. Measurements Immunohistological grading of Fkn staining, number of CD16 + Mos, and messenger RNA levels of Fkn and CD16 in glomeruli. Results Patients with proliferative lupus nephritis (class III and IV glomeruli) showed significantly greater glomerular Fkn expression and CD16 + Mo counts than those with other classes. Infiltrating CD16 + Mos within glomeruli expressed CX3CR1. Moreover, glomerular Fkn expression significantly correlated with the histopathologic activity index and CD16 + Mo counts, and CD16 + Mo counts significantly correlated with serum levels of blood urea nitrogen, complement (CH 50 ), and anti-DNA antibody; estimated glomerular filtration rate; and urinary protein excretion. Glucocorticoid therapy had a tendency to decrease both glomerular Fkn expression and CD16 + Mo counts. Limitations Only frozen biopsy specimens (from 49 patients) were analyzed for the evaluation of glomerular Fkn expression. Conclusion Disease activity and proliferative glomerular lupus nephritis lesions are associated with the glomerular Fkn expression and CD16 + Mo accumulation.

Background: Placental growth factor (PlGF), a member of the vascular endothelial growth factor (VEGF) family, has recently emerged as a predictor of survival and cardiovascular risk. Along with others, we have shown an independent association between PlGF and cardiovascular events in CKD patients, but not much is known about patients receiving dialysis. Methods: We studied 205 dialysis patients undergoing cardiac catheterization at the Nara Medical University between April 1, 2004, and December 31, 2012. Serum levels of PlGF and VEGF were measured with ELISA in all the patients. Results: During a median follow-up of 20 months, 121 participants died from any cause or experienced a cardiovascular event. In the fully adjusted analysis, having an above-median PlGF or VEGF level was associated with a hazards ratio for adverse outcomes of 2.55 (1.72-3.83) and 1.39 (0.95-2.04), respectively. Using a multimarker strategy in a model with age, serum albumin, history of coronary artery disease, brain natriuretic peptide and PlGF, patients with 2, 3 and 4 positive markers had a 3.82-, 5.77- and 6.59-fold higher risk of mortality or a cardiovascular event, respectively, compared to those with no positive markers. The model with PlGF had a significantly higher c-statistic, integrated discrimination improvement index and category-free net reclassification improvement index than the model without PlGF. Conclusion: PlGF is independently associated with mortality and cardiovascular events, but the association between VEGF and adverse events was attenuated with covariate adjustment. The addition of PlGF to models with established clinical predictors provides additional useful prognostic information in patients receiving dialysis.

To evaluate the subclinical articular involvement in patients with primary Sjögren's syndrome (pSS) using musculoskeletal ultrasound (MSUS), and to correlate the findings with laboratory results and clinical manifestations.Forty-eight consecutive patients with pSS were enrolled. The bilateral metacarpophalangeal, proximal interphalangeal, and interphalangeal joints were examined using MSUS, and the synovial hypertrophy and power Doppler signal were recorded for each joint using semi-quantitative scores (0 = normal, 1 = mild change compared with undamaged joint, 2 = moderate change, and 3 = severe change).Mild or moderate synovial hypertrophy was found in 151 (15.7%) and 2 (0.2%) out of 960 hand joints, respectively, and power Doppler signals were present in 19 (2.0%) of the 960 joints. While anti-centromere antibody (ACA) was found in 10 patients (20.8%), none of the patients with MSUS-confirmed synovitis was positive for ACA. No other autoantibodies, laboratory tests, or clinical manifestations correlated with MSUS-confirmed synovitis.MSUS is useful for detecting subclinical synovitis in pSS patients. MSUS showed that ACA-positive pSS patients had a low prevalence of synovitis.

We report a case of hypokalemic nephropathy associated with primary Sjögren's syndrome (SS). The patient presented with profound and persistent hypokalemia secondary to distal renal tubular acidosis (RTA). A renal biopsy exhibited tubular degeneration, marked interstitial fibrosis and intense macrophage infiltration. Hypokalemia has been reported to induce macrophage infiltration in experimental animal models but not in humans. This is the first report of intense tubulointerstitial macrophage infiltration in a patient with hypokalemic nephropathy associated with SS.

Received August 2, 2010; revised manuscript received August 31, 2010; accepted September 7, 2010; released online November 28, 2010 Time for primary review: 7 days First Department of Internal Medicine, Nara Medical University, Kashihara (K.O., T.I., S.O., M.H., Y.A., S.U., Y. Sakaguchi, Y. Saito); Department of Molecular Anatomy, Hamamatsu University School of Medicine, Hamamatsu (K.O., N.Z., Y. Sugiura, M.S.); Division of Cardiology, Gifu University Graduate School of Medicine, Gifu (G.T.); and Department of Analytical Biochemistry, Meiji Pharmaceutical University, Tokyo (H.S.), Japan Mailing address: Mitsutoshi Setou, MD, PhD, Department of Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan. E-mail: setou@hama-med.ac.jp ISSN-1346-9843 doi: 10.1253/circj.CJ-10-0767 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp Using Imaging Mass Spectrometry to Accurately Diagnose Fabry’s Disease

We studied vascular endothelial growth factor (VEGF) mRNA synthesis by peripheral blood mononuclear cells (PBMCs) in 30 patients with acute myocardial infarction (AMI) and 20 healthy individuals. PBMCs were isolated from all patients on days 3 and 14 after the onset of aMI, and from all of control individuals. To prepare samples containing identical amounts of GAPDH cDNA, competitive PCR was performed by co-amplifying serial dilutions of GAPDH mutant templates. Next, to measure VEGF cDNA quantitatively in the samples containing identical amounts of GAPDH, we also used competitive PCR by co-amplifying mutant templates of VEGF. The serum VEGF concentrations on day 14 in patients with aMI were measured by an ELISA method. Higher levels of VEGF mRNA in PBMCs were present on day 14 than either on day 3 or in the control group. Serum VEGF concentrations correlated with the VEGF mRNA levels of PBMCs on day 14. Peak serum CK levels correlated well with VEGF mRNA levels of PBMCs on day 14. The present findings suggest that PBMCs may be one of the candidates responsible for elevated circulatory VEGF protein following aMI. In addition, VEGF mRNA may be overexpressed in PBMCs in response to cardiac muscle damage.

Systemic lupus erythematosus (SLE) is an immune complex-mediated disease and organ damage is caused by the deposition of immune complex. Receptors which recognize the Fc portion of immunoglobulin G (FcgammaR) play a key role in the phagocytosis of immune complexes. As the gene encoding for FcgammaR of class IIa (FcgammaRIIa) has two allelic forms, H131 and R131, which differ in their affinity to IgG2, this polymorphism might have implications in handling immune complex. We studied the distribution of the FcgammaRIIa polymorphism in 90 Japanese patients with SLE. We also examined the association between FcgammaRIIa polymorphism and the disease activity of SLE and the histopathological findings of lupus nephritis. FcgammaRIIa polymorphism was determined by PCR and dot blot analysis. The allelic frequency of H131 in patients with SLE was significantly lower (H131/R131 = 0.44/0.56) than that of normal controls (H131/R131 = 0.62/0.38; P0.05). No significant association was observed between FcgammaRIIa polymorphism and the clinical parameters for the activity of SLE. There was no association between FcgammaRIIa polymorphism and the histological findings in lupus nephritis. The difference in the distribution of FcgammaRIIa alleles between patients with SLE and normal subjects indicates that this polymorphism is a candidate of susceptibility gene for SLE in Japanese.

We measured the plasma levels of adrenomedullin (AM), a novel vasodilating peptide, in 89 patients with various forms of systemic inflammatory response syndrome (SIRS) and 13 healthy volunteers serving as controls. Plasma levels of AM in SIRS (burns: 20.5 +/- 3. 2 fmol/ml [mean +/- SEM]; pancreatitis: 13.8 +/- 3.8 fmol/ml; trauma: 14.9 +/- 2.5 fmol/ml; traumatic shock: 41.1 +/- 7.8 fmol/ml; severe sepsis: 59.9 +/- 11.2 fmol/ml; septic shock: 193.5 +/- 30.1 fmol/ml) were significantly increased over those of controls (5.1 +/- 0.2 fmol/ml). The patients with traumatic shock or septic shock especially had higher levels of plasma AM than those with trauma or severe sepsis, respectively. These data showed that in patients with SIRS, plasma AM levels increased in proportion to the severity of illness. Subsequently, we measured the plasma levels of mediators such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-8, plasminogen activator inhibitor (PAI)-1, and thrombomodulin (TM) in patients with traumatic shock and septic shock. A significant correlation was observed between plasma AM and TNF-alpha levels in patients with septic shock, suggesting an important role for AM as well as of TNF-alpha in the pathophysiology of inflammation. Plasma AM and IL-8 levels correlated positively with Acute Physiology and Chronic Health Evaluation (APACHE) II score, peak multiple organ failure (MOF) score during the first month and prognosis in patients with septic shock, as did plasma IL-6 levels in patients with traumatic shock. The plasma AM level might serve as a useful marker for evaluating the severity of disease and as an early predictor of subsequent organ failure and outcome in septic shock.

In this study, we measured plasma and urinary adrenomedullin (AM) concentrations in 47 patients with IgA nephropathy. Controls were 39 healthy volunteers. Plasma and urinary AM values were measured by specific radioimmunoassay. The plasma AM concentrations were higher, and the urinary AM levels were lower in patients with IgA nephropathy than in healthy volunteers. Plasma AM concentrations showed a positive correlation with serum creatinine and blood urea nitrogen, whereas urinary AM levels correlated negatively with serum creatinine and blood urea nitrogen. The plasma AM concentrations showed a positive correlation with fractional excretions of sodium and potassium. Renal biopsy specimens of patients without renal failure were scored for activity (percentage of glomeruli demonstrating cellular crescent formation, degree of mesangial proliferation and interstitial infiltration; total score = 9). Urinary AM levels were shown to be lower in the group with a high activity (score 3–9) as compared with the group with a low activity (score 0–2) based on renal biopsy. Thus, urinary levels of AM are affected by the degree of the activity in IgA nephropathy, and AM may participate in the pathophysiology of IgA nephropathy.

SUMMARY We measured levels of IL-6 mRNA in PBMC obtained from patients with chronic renal failure, using polymerase chain reaction (PCR), PBMC were isolated from 45 patients on haemodialysis (HD) at the start of HD. PBMC were also isolated from 35 patients on HD at the end of HD, 23 patients on continuous ambulatory peritoneal dialysis (CAPD), 24 undialysed patients with chronic renal failure (CRF), and 19 healthy controls. Total RNA was extracted from PBMC with RNA zol and reverse transcribed into cDNA. To prepare samples containing identical amounts of β-actin cDNA, we performed competitive PCR by co-amplifying serial dilutions of mutant templates containing a single point mutation which generated a unique Eco RI site. Next, to measure IL-6 cDNA semiquantitatively in the samples containing identical amounts of β-actin (100 pg), we performed PCR amplification using 2 fg of the IL-6 mutant template containing a unique Eco RI site. Higher levels of IL-6 mRNA in the PBMC were observed in the HD patients than in the CAPD patients and healthy controls. The levels of IL-6 mRNA in the PBMC at the end of HD were not significantly higher than those at the start of HD. These results suggest that the dialysis session itself did not significantly affect IL-6 mRNA levels in the PBMC, but that chronic stimulation by maintenance HD may be associated with higher levels of IL-6 mRNA observed in HD patients.

Background Low-dose aspirin is widely recommended for patients at high risk for cardiovascular disease (CVD); however, it remains uncertain whether long-term treatment adversely affects renal function in patients with diabetes. We investigated whether long-term low-dose aspirin affects renal dysfunction in patients with diabetes. Methods We conducted a randomized controlled trial (RCT), the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial, to evaluate low-dose aspirin as primary prevention for CVD in patients with type 2 diabetes. We followed the patients with negative urine dipstick albumin of the JPAD trial in a cohort study after the RCT period was completed. Patients were randomly allocated to receive aspirin (81 mg or 100 mg daily, aspirin group) or no aspirin (no aspirin group). After the RCT, the treating physician decided whether to administer aspirin. We evaluated the incidence of positive urine dipstick albumin and annual changes in estimated glomerular filtration rate (eGFR). Results Positive urine dipstick albumin developed in 297 patients in the aspirin group (n = 1,075) and 270 patients in the no aspirin group (n = 1,098) during follow-up (median, 8.5 years). Intention-to-treat analysis showed low-dose aspirin did not increase the incidence of positive urine dipstick albumin (hazard ratio [HR], 1.17; 95% confidence interval [CI], 0.995–1.38). On-treatment analysis yielded similar results (HR, 1.08; 95% CI, 0.92–1.28). Multivariable analysis showed the incidence of positive urine dipstick albumin was higher among the elderly and those with elevated serum creatinine, high hemoglobin A1c, or high blood pressure; however, low-dose aspirin did not increase the risk of positive urine dipstick albumin. There were no significant differences in annual changes in eGFR between the groups (aspirin, −0.8 ± 2.9; no aspirin, −0.9 ± 2.5 ml/min/1.73m2/year). Conclusion Long-term low-dose aspirin does not affect eGFR and positive urine dipstick albumin in patients with type 2 diabetes.

It is evident that cytokines play an important role in the pathogenesis as well as disease progression of IgA nephropathy (IgAN). Several gene polymorphisms of the pertinent cytokines have an influence on the level of cytokine production. Interleukin-1 receptor antagonist (IL-1ra) gene polymorphism has been found to affect disease susceptibility and activity in several inflammatory diseases. In the present study, we analyzed polymorphism of the variable number tandem repeat (VNTR) of IL-1ra in patients diagnosed as having IgAN (n = 106) and normal controls (n = 74). The allele frequency of IL-1ra polymorphism in IgAN patients was not statistically different from that of the control group. There was no significant difference in the carriage rate of the two-repeat allele (IL1RN*2) between IgAN patients and the control group (8.5 vs. 6.8%). The carriage rate of IL1RN*2 was significantly higher in IgAN patients with severe proteinuria (≧1.6 g/day) or increased serum creatinine level (≧2.0 mg/dl; p < 0.05). Furthermore, the carriage rate of IL1RN*2 was significantly higher in patients with severe mesangial cell proliferation (p < 0.01). Our results suggest that IL-1ra polymorphisms are not associated with the development of IgAN in Japanese patients but the presence of IL1RN*2 may be associated with increased disease activity.

Background/Aims: Insulin resistance and hyperinsulinemia has been reported in patients with chronic renal failure. However, usefulness and validation of new indices for assessment to insulin sensitivity and pancreatic beta-cell function were unknown. Methods: We evaluated insulin sensitivity and pancreatic beta-cell function in 61 normal glucose tolerant (NGT) and 60 diabetic (DM) subjects; both groups were subdivided as normal renal function (NRF; Ccr ≥ 70 ml/min) and impaired renal function (IRF; Ccr 0–180). Results: There was no evidence of insulin resistance in NGT-IRF group. No differences in both insulinogenic index and first-phase insulin secretion index between NGT-NRF and NGT-IRF, but these were significantly decreased in DM-NRF and DM-IRF. There were inverse linear correlations between the insulin sensitivity index and insulin-AUC0–180 in patients with NGT and DM, respectively. These correlations were similarly robust in NRF subjects and IRF subjects. Conclusions: New indices for assessment of insulin sensitivity and pancreatic beta-cell function calculated from plasma glucose and plasma insulin concentrations after OGTT are applicable for clinical use even in patients with renal dysfunction.

Fibroblast-specific protein 1 (FSP1)–expressing cells accumulate in damaged kidneys, but whether urinary FSP1 could serve as a biomarker of active renal injury is unknown. We measured urinary FSP1 in 147 patients with various types of glomerular disease using ELISA. Patients with crescentic GN, with or without antinuclear cytoplasmic antibody–associated GN, exhibited elevated levels of urinary FSP1. This assay had a sensitivity of 91.7% and a specificity of 90.2% for crescentic GN in this sample of patients. Moreover, we found that urinary FSP1 became undetectable after successful treatment, suggesting the possible use of FSP1 levels to monitor disease activity over time. Urinary FSP1 levels correlated positively with the number of FSP1-positive glomerular cells, predominantly podocytes and cellular crescents, the likely source of urinary FSP1. Even in patients without crescent formation, patients with high levels of urinary FSP1 had large numbers of FSP1-positive podocytes. Taken together, these data suggest the potential use of urinary FSP1 to screen for active and ongoing glomerular damage, such as the formation of cellular crescents.

OBJECTIVE Type 2 diabetes accompanied by renal damage is a strong risk factor for atherosclerotic events. The purpose of this study was to investigate the efficacy of low-dose aspirin therapy on primary prevention of atherosclerotic events in patients with type 2 diabetes and coexisting renal dysfunction. RESEARCH DESIGN AND METHODS The Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) trial was a prospective, randomized, open-label trial conducted throughout Japan that enrolled 2,539 type 2 diabetic patients without a history of atherosclerotic diseases. Patients were assigned to the aspirin group (81 mg/day or 100 mg/day) or the nonaspirin group and followed for a median of 4.37 years. The primary end points were atherosclerotic events of fatal and nonfatal ischemic heart disease, stroke, and peripheral arterial disease. RESULTS The analysis included 2,523 patients who had serum creatinine measured. In 1,373 patients with baseline estimated glomerular filtration rate (eGFR) 60–89 mL/min/1.73 m2, the incidence of primary end points was significantly lower in the aspirin group than in the nonaspirin group (aspirin, 30/661; nonaspirin, 55/712; hazard ratio 0.57 [95% CI 0.36–0.88]; P = 0.011). Low-dose aspirin therapy did not reduce primary end points in patients with eGFR ≥90 mL/min/1.73 m2 (aspirin, 9/248; nonaspirin, 11/270; 0.94 [0.38–2.3]) or those with eGFR

Backgrounds/Aims: We previously reported that fibroblast-specific protein 1 (FSP1) is a marker of epithelial-mesenchymal transition (EMT) in tubulointerstitial fibrosis. The EMT-like changes observed in podocytes are reportedly associated with podocyte detachment which may cause focal glomerulosclerosis. Methods: In cross-sectional studies, we analyzed podocyte expression of FSP1 immunohistochemically using renal biopsy specimens from 31 patients with focal segmental glomerulosclerosis (FSGS) and 39 patients with minimal change disease (MCD). We also semiquantitatively analyzed glomerular expression of FSP1 mRNA using laser capture microdissection and real-time PCR. Results: We found that FSP1 was localized to podocytes in both FSGS and MCD patients; however, the number of FSP1+ podocytes per glomerular profile was significantly higher in patients with FSGS than in those with MCD, and there was a corresponding difference in the levels of FSP1 mRNA. FSP1+ podocyte counts per glomerular profile in FSGS patients correlated significantly with the prevalence of glomerulosclerosis and the extent of interstitial type-I collagen-positive areas. Conclusion: Taken together, these data suggest that podocyte expression of FSP1 could shed light on the potential linkage between EMT-like changes, detachment of podocytes from the glomerular basal membrane and the pathophysiology underlying FSGS.

Background— Renal dysfunction is commonly accompanied by a worsening of atherosclerosis; however, the underlying molecular mechanism is not fully understood. We examined the role played by soluble fms-like tyrosine kinase-1 (sFlt-1), an endogenous antagonist of the proatherogenic cytokine placental growth factor (PlGF), in the worsening of atherosclerosis in patients with renal dysfunction and in an animal model of renal failure. Methods and Results— In this study, 329 patients who received cardiac catheterization and 76 patients who underwent renal biopsy were enrolled. Both plasma sFlt-1 levels and renal sFlt-1 mRNA expression were positively correlated with estimated glomerular filtration rate ( P P Conclusions— The present study demonstrates that a reduction in the circulating levels of sFlt-1 is associated with the worsening of atherosclerosis that accompanies renal dysfunction.

Our objective was to investigate the plasma levels of brain and atrial natriuretic peptides (BNP and ANP, respectively) in patients with septic shock/severe sepsis and to study the association of BNP and ANP levels with hemodynamic parameters, severity of the disease, and prognosis of those patients. This is a prospective case series study of 22 patients with septic shock, 11 patients with severe sepsis, and 20 healthy volunteers at the Department of Emergency and Critical Care Medicine, Nara Medical University Hospital, Japan. Blood collection was performed on admission and on days 1, 2, and 4. Plasma BNP and ANP levels were measured by radioimmunoassay. Right atrial pressure, mean pulmonary arterial pressure, pulmonary arterial wedge pressure, and left ventricular stroke work index were determined using a thermodilution catheter. Acute Physiological and Chronic Health Evaluation II scores were calculated. Plasma levels of BNP and ANP were markedly elevated in patients with septic shock/severe sepsis compared with controls (BNP, 7 +/- 0.3 pg mL; ANP, 13 +/- 1 pg mL). In patients with septic shock, both BNP and ANP peaked on day 2 (BNP, 987 +/- 160 pg mL; ANP, 103 +/- 17 pg mL). Plasma levels of BNP on day 2 in patients with septic shock significantly correlated with right atrial pressure (r = 0.744, P < 0.01), mean pulmonary arterial pressure (r = 0.670, P < 0.01), pulmonary arterial wedge pressure (r = 0.709, P < 0.01), left ventricular stroke work index (r = -0.552, P < 0.05), Acute Physiological and Chronic Health Evaluation II score (r = 0.581, P < 0.01), and poor prognosis (P < 0.05). The optimal cutoff point for predicting mortality in patients with septic shock was a BNP level of 650 pg mL on day 2, in which sensitivity and specificity were 92% and 80%, respectively. Increased plasma levels of BNP may reflect not only the severity of myocardial depression but also the disease severity and could be of prognostic value in patients with septic shock.

A 49-year-old woman with a history of chronic hepatitis C virus infection and Hashimoto disease was admitted to our hospital because of proteinuria, hematuria, purpura, and edema in the lower extremities. Laboratory data on admission revealed proteinuria (0.2 g/day), microscopic hematuria (3+) with RBC casts, renal dysfunction(serum creatinine 1.4 mg/dl), positive anti nuclear antigen (x640, speckled type), hypocoplementemia, mixed cryoglobulinemia (type III), and hepatitis C virus infection (AST 45 IU/l, ALT 33 IU/l). MPO-ANCA level was found to be high (356 EU). In renal biopsy, most glomeruli showed crescentic formation with the weak deposition of IgG, IgM, and C3 in the mesangial area and along the capillary wall. She was diagnosed as having systemic vasculitis associated with MPO ANCA. Methylprednisolone pulse therapy followed by oral prednisolone (40 mg/day) effectively normalized MPO ANCA level. It has been reported that ANCA is found in patients with HCV-associated mixed cryoglobulinemia. Therefore, in chronic hepatitis C patients with systemic vasculitis, we should consider the possibility of ANCA-related microscopic polyangiitis and make a correct diagnosis by renal biopsy.

Background. Insulin resistance and hyperinsulinaemia have been reported among patients with chronic renal failure. However, little is known concerning insulin sensitivity among patients with hypertensive kidney disease (HKD), especially in those with moderate or severe renal dysfunction. Methods. We examined and compared 30 patients with HKD, 30 normotensive patients with chronic kidney disease (CKD-NT), 30 normal controls and 30 patients with hypertension and normal renal function (HTN). Moderate and severe renal dysfunction were defined according to the K/DOQI definitions (estimated glomerular filtration rates between 15 and 59 ml/min per 1.73 m 2 ). The homeostasis model assessment of insulin resistance (HOMA-R) and three surrogate indexes based on 75 g oral glucose tolerance test results were used to determine insulin sensitivity. Results. A trend to higher HOMA-R values in the HTN and HKD groups than in the other groups was noted, but the difference was not statistically significant. The insulin sensitivity index (ISI) proposed by Stumvoll et al. was significantly lower in the HTN, HKD and CKD-NT groups than in controls and was significantly lower in HKD than in the HTN and CKD-NT groups. The insulin sensitivity index proposed by Gutt et al. was significantly lower in HKD than in the control and HTN groups and showed a trend to being lower in HKD than in CKD-NT. The same patterns prevailed in the oral glucose ISI. We assumed that subjects whose ISI values decreased below the mean value minus 2-SD in the control group manifest apparent insulin resistance. According to this criterion, � 40% of HKD subjects were in an insulinresistant state: only

A 74-year-old man was admitted because of appetite loss in November 1999. A gastric ulcer was diagnosed, and a H2 blocker was given. He had had appetite loss since July 1997 and had experienced epigastric discomfort since October of 1997. On admission, hepatic and pancreatic lymph node swelling was detected by ultrasonography of the abdomen. Physical examination revealed a palpable mass in the middle region of the upper abdomen as well as gynecomastia. Laboratory findings showed high serum levels of hCG (11,700 mIU/ml) and high urinary levels of hCG (1,600 mIU/ml). Upper gastrointestinal endoscopy showed a gastric cancer of Borrmann type 3 in the posterior wall of the middle body. A biopsy revealed a moderately differentiated adenocarcinoma. hCG immunoreactivity was not seen in the cancer tissue. A contrast-enhanced CT scan of the abdomen revealed multiple lymph node swelling in the hepatic and pancreatic lymph nodes. There was a low-density area suggesting liver metastases. No other primary carcinomas were not detected. We believe that the gynecomastia was due to the hCG-producing tumor. The patient died 2 months after diagnosis.

We evaluated the significance of urinary IL-6 levels in the prediction of long-term renal outcome in patients with IgA nephropathy (IgAN). Fifty-nine patients with biopsy-proven IgAN were enrolled in this study. All patients had a creatinine clearance (Ccr) greater than 80 ml/min and normal serum creatinine concentration (Scr) on enrollment and were followed for 8.07 ± 1.72 years. Twenty- four-hour urine samples were obtained and urinary IL-6 was measured by ELISA. Fifteen patients exhibited a worsening of renal function (progressor). Renal function of the remaining 44 patients was stable during follow-up (non-progressor). The urinary IL-6 levels of progressors on enrollment were significantly higher than those of non-progressors (3.8 ± 3.8 and 1.8 ± 1.5 ng/day, respectively, p = 0.0138). We calculated the risk ratio for the progression to renal failure. Patients with a urinary IL-6 level greater than 2.5 ng/day at diagnosis had a 7.8-fold higher risk for the progression of the disease (95% CI 1.31–46.47, p = 0.024) compared with those whose urinary IL-6 level was less than 1.0 ng/day. In conclusion, urinary IL-6 levels could be used as a predictor of long-term renal outcome in patients with IgAN. Patients with a urinary IL-6 level greater than 2.5 ng/day at diagnosis may have a worse prognosis.

We describe a 76-year-old Japanese woman with primary systemic amyloidosis who presented with angina pectoris associated with ST-segment and T-wave abnormalities resulting from intramyocardial coronary artery amyloidosis. The patient was admitted to our hospital because of dyspnea and pretibial edema 7 years after the diagnosis of variant angina. A diagnosis of primary systemic amyloidosis (AL amyloid protein) was made after examination of gastric and endomyocardial biopsy specimens. The patient died of progressive, uncontrolled heart failure 3 months later. An autopsy study demonstrated only mild-to-moderate atherosclerosis in the epicardial coronary arteries. However, histological examination of the heart revealed diffuse stenoses and obstructions in the intramural coronary arteries by amyloid deposits. This patient had small-vessel coronary disease with ST-segment changes and angina caused by cardiac amyloidosis. A correct diagnosis of ischemic heart disease due to primary amyloidosis is important for estimation of the prognosis and for appropriate management.

Plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator (tPA) are the major regulators of plasmin generation. Glomerular PAI-1/tPA balance is involved in extracellular matrix turnover, as well as fibrin deposition in glomeruli. Renal biopsy specimens were obtained from 80 patients with either primary or secondary glomerulonephritis (10 patients, minimal change nephrotic syndrome; 6 patients, focal segmental glomerulosclerosis [FSGS]; 10 patients, membranous nephropathy [MN]; 24 patients, mesangial proliferative glomerulonephritis; 15 patients, lupus nephritis; 14 patients, diabetic nephropathy; and 1 patient, membranoproliferative glomerulonephritis). We quantified glomerular PAI-1 and tPA messenger RNA (mRNA) by competitive polymerase chain reaction. We also determined PAI-1 mRNA localization by in situ hybridization. Glomerular PAI-1 mRNA levels in patients with FSGS and MN were significantly greater than those of controls. There was a sixfold increase in PAI-1-tPA mRNA ratio in patients with MN compared with the control group. In addition, glomerular PAI-1 mRNA level correlated with level of proteinuria. Conversely, there was no difference in tPA mRNA levels among types of glomerulonephritis. These results suggest that suppressed glomerular fibrinolytic and proteolytic activity may be associated with the pathogenesis of glomerulonephritis, especially in FSGS and MN.