Trajectory of GFR Decline and Fluctuation in Albuminuria Leading to End-Stage Kidney Disease in Patients With Biopsy-Confirmed Diabetic Kidney Disease.

Introduction: Data on longitudinal trajectory of kidney function decline and fluctuation in albuminuria leading to end-stage kidney disease (ESKD) is sparse in patients with type 2 diabetes. Methods: Using data from an observational study of patients with type 2 diabetes and biopsy-confirmed diabetic kidney disease (DKD), generalized additive mixed models (GAMMs) were performed to quantify patterns of longitudinal trajectory of estimated glomerular filtration rate (eGFR) decline to ESKD associated with repeated measures of urine albumin-to-creatinine ratio (ACR). Results: Over a median follow-up period of 3.3 years, 155 of 319 patients progressed to ESKD. Among these patients, 91.6% exhibited a curvilinear pattern in their eGFR trajectory. The median coefficient of variation for ACR, representing the variability in ACR measurements, was 48.9 (interquartile range: 36.9, 68.2). The median compound annual growth rate (CAGR) for ACR, reflecting the variation in ACR progression over time, was 43.6% (interquartile range: 0.0, 102.5); and 84.5% of patients developed nephrotic-range albuminuria, with a majority remaining nephrotic and subsequently progressing to ESKD. There was a positive association between the instantaneous speed of eGFR decline and ACR. Conclusion: The observed curvilinear pattern in eGFR trajectory, high variability in ACR progression over time, and positive correlation between the speed of eGFR decline and ACR highlight the complex dynamics of disease progression and emphasize close monitoring of ACR fluctuation over time in patients with DKD.

Synergistic deterioration of prognosis associated with decreased grip strength and hyporesponse to erythropoiesis-stimulating agents in patients undergoing hemodialysis.

INTRODUCTION: We examined the combined effect of erythropoietin (EPO) hyporesponsiveness and low handgrip strength (HGS) on the prognosis of patients undergoing hemodialysis (HD). METHODS: We recruited patients with chronic kidney disease (CKD) Stage 5, who were undergoing HD at our dialysis clinic between January 2015 and March 2015 (n = 182). Patients of ≥20 years of age and who had been undergoing HD for ≧3 months at enrollment were eligible for inclusion. Seven patients treated with epoetin-ß pegol were excluded. First, the erythropoietin resistance index (ERI) and HGS were measured. The patients were stratified by the ERI of 9.44 (U/kg/week/g/dL), and by the HGS of 28 kg for men and 18 kg for women. We then observed death and cardiovascular disease (CVD), composite endpoint (deaths or CVD) for a median of 2 years. RESULTS: A total of 175 patients (male, n = 122; female, n = 53; age, 34-92 years) were included in the analysis. During the observation period of 24 months, 57 events (14 deaths and 43 CVD) were observed. High ERI and low HGS were associated with a high incidence of endpoints compared to low ERI and high HGS. Among the four groups classified by ERI and HGS values, the highest risk group was the high ERI/low HGS group (HR: 4.20 95% CI 2.12-8.33). CONCLUSIONS: EPO hyporesponsiveness combined with low HGS were found to be significant predictors of a poor outcome, and the synergistic effects of the two factors had stronger predictive ability than either single factor.

Association of Thyrotropin Concentration with Chronic Kidney Disease in a Japanese General Population Cohort.

BACKGROUND: Previous studies have indicated an association between hypothyroidism and kidney dysfunction; however, few studies have investigated whether thyroid dysfunction is a risk factor for chronic kidney disease (CKD) development. And their result is not consistent. OBJECTIVES: We evaluated the association of thyroid dysfunction with CKD prevalence and development by a multivariate logistic regression analysis. METHOD: In cross-sectional and longitudinal studies, 16,390 subjects and 7,609 subjects, respectively, who underwent annual health check-ups were analyzed. We categorized the subjects into the following 4 groups based on their serum thyrotropin (TSH) -concentrations: below-normal (TSH < 0.54 mU/L), lower-normal -(0.54-2.40 mU/L), higher-normal (2.41-4.26 mU/L) and above-normal (> 4.26 mU/L). Subjects with eGFR <60 mL/min/1.73 m2 were determined to have CKD. RESULTS: The cross-sectional study revealed a positive correlation between TSH concentration and CKD -prevalence. Compared with the lower-normal TSH group, the ORs and 95% CIs of CKD prevalence were 0.61 (0.45-0.82, p = 0.001) for the below-normal group, 1.49 (1.33-1.67, p < 0.001) for the higher-normal group, and 1.90 (1.57-2.30, p < 0.001) for the above-normal group. The longitudinal study revealed that the risk of CKD development within 3 years was significantly higher in the above-normal TSH group than in the lower-normal TSH group (OR 1.58, 95% CI 1.02-2.45, p = 0.04). CONCLUSIONS: Our data indicate that higher TSH concentrations are positively correlated with CKD prevalence and that a high TSH concentration is a risk factor for CKD development.

A new pathological scoring system by the Japanese classification to predict renal outcome in diabetic nephropathy.

BACKGROUND AND OBJECTIVES: The impact of the newly proposed pathological classification by the Japan Renal Pathology Society (JRPS) on renal outcome is unclear. So we evaluated that impact and created a new pathological scoring to predict outcome using this classification. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A multicenter cohort of 493 biopsy-proven Japanese patients with diabetic nephropathy (DN) were analyzed. The association between each pathological factor-Tervaert' and JRPS classifications-and renal outcome (dialysis initiation or 50% eGFR decline) was estimated by adjusted Cox regression. The overall pathological risk score (J-score) was calculated, whereupon its predictive ability for 10-year risk of renal outcome was evaluated. RESULTS: The J-scores of diffuse lesion classes 2 or 3, GBM doubling class 3, presence of mesangiolysis, polar vasculosis, and arteriolar hyalinosis were, respectively, 1, 2, 4, 1, and 2. The scores of IFTA classes 1, 2, and 3 were, respectively, 3, 4, and 4, and those of interstitial inflammation classes 1, 2, and 3 were 5, 5, and 4 (J-score range, 0-19). Renal survival curves, when dividing into four J-score grades (0-5, 6-10, 11-15, and 16-19), were significantly different from each other (p<0.01, log-rank test). After adjusting clinical factors, the J-score was a significant predictor of renal outcome. Ability to predict 10-year renal outcome was improved when the J-score was added to the basic model: c-statistics from 0.661 to 0.685; category-free net reclassification improvement, 0.154 (-0.040, 0.349, p = 0.12); and integrated discrimination improvement, 0.015 (0.003, 0.028, p = 0.02). CONCLUSIONS: Mesangiolysis, polar vasculosis, and doubling of GBM-features of the JRPS system-were significantly associated with renal outcome. Prediction of DN patients' renal outcome was better with the J-score than without it.

Uric Acid Is a Strong Risk Marker for Developing Hypertension From Prehypertension: A 5-Year Japanese Cohort Study.

Prehypertension frequently progresses to hypertension, a condition associated with high morbidity and mortality from cardiovascular diseases and stroke. However, the risk factors for developing hypertension from prehypertension remain poorly understood. We conducted a retrospective cohort study using the data from 3584 prehypertensive Japanese adults (52.1±11.0 years, 2081 men) found to be prehypertensive in 2004 and reexamined in 2009. We calculated the cumulative incidences of hypertension over 5 years, examined risk factors, and calculated odds ratios (ORs) for developing hypertension after adjustments for age, sex, body mass index, smoking and drinking habits, baseline systolic and diastolic blood pressure, pulse rate, diabetes mellitus, dyslipidemia, chronic kidney disease, and serum uric acid levels. The additional analysis evaluated whether serum uric acid (hyperuricemia) constituted an independent risk factor for developing hypertension. The cumulative incidence of hypertension from prehypertension over 5 years was 25.3%. There were no significant differences between women and men (24.4% versus 26.0%; P=0.28). The cumulative incidence of hypertension in subjects with hyperuricemia (n=726) was significantly higher than those without hyperuricemia (n=2858; 30.7% versus 24.0%; P<0.001). After multivariable adjustments, the risk factors for developing hypertension from prehypertension were age (OR, 1.023; P<0.001), female sex (OR, 1.595; P<0.001), higher body mass index (OR, 1.051; P<0.001), higher baseline systolic (OR, 1.072; P<0.001) and diastolic blood pressure (OR, 1.085; P<0.001), and higher serum uric acid (OR, 1.149; P<0.001). Increased serum uric acid is a strong risk marker for developing hypertension from prehypertension. Further studies are needed to determine whether treatment of hyperuricemia in prehypertensive subjects could impede the onset of hypertension.

Paratubular basement membrane insudative lesions predict renal prognosis in patients with type 2 diabetes and biopsy-proven diabetic nephropathy.

AIMS: Glomerular insudative lesions are a pathological hallmark of diabetic nephropathy (DN). However, paratubular basement membrane insudative lesions (PTBMIL) have not attracted much attention, and the association between such lesions and the renal prognosis remains unclear. METHODS: Among 142 patients with biopsy-proven DN and type 2 diabetes encountered from 1998 to 2011, 136 patients were enrolled in this study. Patients were classified into 3 groups (Group 1: mild, Group 2: moderate, Group 3: severe) according to the extent of cortical and medullary PTBMIL. The endpoint was a decline of the estimated glomerular filtration rate (eGFR) by ≥ 40% from baseline or commencement of dialysis for end-stage renal disease. The Cox proportional hazard model was employed to calculate hazard ratios (HRs) and 95% confidence interval (CIs) for the death-censored endpoint. RESULTS: During a median follow-up period of 1.8 years (IQR: 0.9-3.5), the endpoint occurred in 104 patients. Baseline mean eGFR was 43.9 ± 22.8 ml/min/1.73 m2, and 125 patients (92%) had overt proteinuria. After adjusting for known indicators of DN progression, the HR for the endpoint was 2.32 (95% CI: 1.20-4.51) in PTBMIL Group 2 and 3.12 (1.48-6.58) in PTBMIL Group 3 versus PTBMIL Group 1. Furthermore, adding the PTBMIL Group to a multivariate model including known promoters of DN progression improved prediction of the endpoint (c-index increased by 0.02 [95% CI: 0.00-0.04]). CONCLUSIONS: PTBMIL may be useful for predicting the renal prognosis of patients with biopsy-proven DN, but further investigation of these lesions in various stages of DN is needed.

Nodular lesions in diabetic nephropathy: Collagen staining and renal prognosis.

AIMS: Nodular lesions are one of the most characteristic pathological changes of advanced diabetic nephropathy (DN). Previous studies have demonstrated that the pattern of both routine and collagen staining of nodular lesions changes during their development. However, the association between such changes of staining and the renal prognosis remains unclear. METHODS: Among 252 patients with biopsy-proven DN, 67 met the selection criteria and were enrolled to investigate this relationship. In all patients, nodular lesions were stained with periodic acid Schiff, periodic acid methenamine silver, and Masson trichrome stains, and immunostaining was done for type I, III, IV, V, and VI collagen. The endpoint was commencement of dialysis due to end-stage renal disease. RESULTS: At least one mesangiolytic nodular lesion (MNL) that showed faint staining for PAS and PAM was found in 61% of the patients. MNLs were negative for type IV collagen staining, unlike the strong positivity of non-MNLs, while type V and VI collagen staining were strongly positive in all nodular lesions. Cox proportional hazards regression analysis revealed that the hazard ratio (HR) for the endpoint was significantly higher in patients with at least one MNL than in patients with no MNLs after adjustment for known promoters of renal progression (HR: 2.94; 95% confidence interval: 1.24-7.07). CONCLUSIONS: MNLs may reflect characteristic differences of collagen production and could be a useful prognostic indicator in patients with nodular lesions. Further investigation of the mechanism underlying these differences of collagen production could contribute to finding new therapeutic targets for DN.

Five Sequential Evaluations of Renal Histology in a Patient with Light Chain Deposition Disease.

A 58-year-old man was referred to our institution for an evaluation of nephrotic range proteinuria. Renal biopsy showed a marked expansion of the mesangial matrix and thickening of glomerular basement membrane (GBM) in periodic acid-silver methenamine (PAM). Immunofluorescence (IF) revealed strong staining for the monoclonal kappa light chain. EM demonstrated massive subendothelial and mesangial dense deposits. As a result, light chain deposition disease (LCDD) was diagnosed. Melphalan and prednisolone (MP) therapy was started, which was continued for 10 years with minimal complications. Serial evaluations of renal histology revealed the resolution of nodular lesions and the glomeruli became nearly normal. MP therapy can therefore be an effective therapeutic option for LCDD if it is continued over the long term.

Impact of individual components and their combinations within a family history of hypertension on the incidence of hypertension: Toranomon hospital health management center study 22.

Although a family history (FH) of hypertension is a risk factor for the development of hypertension, only a few studies have investigated in detail the impact of individual components of an FH on incident hypertension. We investigated the impact of individual components and their combinations on the presence or development of hypertension considering obesity, smoking habits, physical activity, and other metabolic parameters.Studied were 12,222 Japanese individuals without hypertension (n = 9,766) and with hypertension (n = 2,456) at the baseline examination. The presence or incidence of hypertension during 5 years after a baseline examination was assessed by the presence of systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg or a self-reported history of clinician-diagnosed hypertension. In this prospective study, the odds ratio for incident hypertension was 1.39 (95% confidence interval [CI], 1.22, 1.59) for individuals with any FH of hypertension compared with those without such an FH. Individuals with an FH of hypertension in both parents and one or more grandparents had an odds ratio of 3.05 (95% CI 1.74, 5.36) for hypertension compared with those without an FH of hypertension. FH was associated with incident hypertension independently of other modifiable risk factors such as obesity, smoking, physical inactivity, hyperglycemia, hyperuricemia, and hypertriglyceridemia.A parental history of hypertension was an essential component within an FH for incident hypertension. FH of hypertension over two generations with both parents affected was the most important risk factor for incident hypertension. Although an FH is not a modifiable risk factor, modifying other risk factors could contribute to reducing the risk of hypertension even among individuals with a family history of hypertension.

Assessment of kidney dysfunction with cystatin C- and creatinine-based estimated glomerular filtration rate and predicting type 2 diabetes: Toranomon Hospital Health Management Center Study 21.

OBJECTIVE: Whether early stages of kidney dysfunction assessed by the estimated glomerular filtration rate from cystatin C measurements (eGFRCysC) rather than from creatinine measurements (eGFRCr) would more precisely reflect the risk of developing type 2 diabetes (T2D) has not been clarified. We compared the risk of developing T2D associated with renal dysfunction indicated by eGFRCysC or eGFRCr measurements. METHODS: Studied were 2131 Japanese individuals without diabetes. Hazard ratios (HRs) for the development of T2D over 3-5 y were calculated across categories of eGFRCysC and eGFRCr, respectively. RESULTS: Reduced levels of eGFRCysC were associated with a step-wise increase in the cumulative incidence rate of T2D (p=0.007). In comparison with the eGFRCysC >85th percentile group (≥ 117.4 ml/min/1.73 m(2)), the lowest group, which was the eGFRCysC <15th percentile group (<86.2 ml/min/1.73 m(2)), had an adjusted HR of 2.30 (95% CI 1.13, 4.68) for T2D. Compared with the eGFRCr >85th percentile group, the lowest eGFRCr group (<15th percentile) had an HR of 1.19 (0.63, 2.24) for T2D. However, individuals with eGFRCr <60 ml/min/1.73 m(2) had a significantly increased risk of T2D. Clustering of both low eGFRCysC and low eGFRCr further elevated the HR for T2D compared with the presence of either. CONCLUSIONS: Although eGFRCr in ranges indicating chronic kidney disease reflected an elevated risk of developing diabetes, earlier stages of kidney dysfunction indicated by reduced eGFRCysC, which could not be captured by reduced eGFRCr, would be a marker for an elevated risk of developing T2D.

Prognostic Value of Tubulointerstitial Lesions, Urinary N-Acetyl-ß-d-Glucosaminidase, and Urinary ß2-Microglobulin in Patients with Type 2 Diabetes and Biopsy-Proven Diabetic Nephropathy.

BACKGROUND AND OBJECTIVES: Some biomarkers of renal tubular injury are reported to be useful for predicting renal prognosis in the early stage of diabetic nephropathy (DN). Our study compared predictions of the renal prognosis by such biomarkers and by histologic tubulointerstitial damage. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Among 210 patients with type 2 diabetes and biopsy-proven DN managed from 1985 to 2011, 149 patients with urinary N-acetyl-ß-d-glucosaminidase (NAG) and urinary ß2-microglobulin (ß2-MG) data at the time of renal biopsy were enrolled. The primary outcome was a decline in eGFR of ≥50% from baseline or commencement of dialysis for ESRD. RESULTS: The median follow-up period was 2.3 years (interquartile range, 1.1-5.3), and the primary outcome was noted in 94 patients. Mean eGFR was 46.3±23.2 ml/min per 1.73 m(2), and 132 patients (89%) had overt proteinuria at baseline. Cox proportional hazards analysis revealed that the association of urinary NAG and ß2-MG with the outcome was attenuated after adjustment for known promoters of progression (+1 SD for log NAG: hazard ratio [HR], 1.14; 95% confidence interval [95% CI], 0.84 to 1.55; +1 SD for log ß2-MG: HR, 1.23; 95% CI, 0.94 to 1.62). In contrast, the interstitial fibrosis and tubular atrophy (IFTA) score was still significantly correlated with the outcome after adjustment for the same covariates (+1 for IFTA score: HR, 2.31; 95% CI, 1.56 to 3.43). Moreover, adding the IFTA score to a model containing known progression indicators improved prediction of the outcome (increase of concordance index by 0.02; 95% CI, 0.00 to 0.05; category-free net reclassification improvement by 0.54; 95% CI, 0.03 to 1.05; and relative integrated discrimination improvement by 0.07; 95% CI, -0.08 to 0.22). CONCLUSIONS: Adding urinary NAG and ß2-MG excretion to known promoters of progression did not improve prognostication, whereas adding the IFTA score did. The IFTA score may be superior to these tubulointerstitial markers for predicting the renal prognosis in advanced DN.

A pathological scoring system to predict renal outcome in diabetic nephropathy.

BACKGROUND: With the association between diabetic nephropathy (DN) and renal outcome being increasingly clear, we aimed at creating a new DN pathological scoring system that could predict the renal outcome. METHODS: We studied 205 patients with DN confirmed by renal biopsy, sometime between March 1985 and January 2010, who met the inclusion criteria. Renal biopsy included clinical parameters and Tervaert classifications. Hazard ratios (HRs) for death-censored end-stage renal disease (ESRD) were estimated by adjusted Cox proportional-hazards regression. The overall pathological risk score (D-score) was calculated by summing the products of beta coefficient and bootstrap-inclusion fractions, its predictive utility evaluated by Kaplan-Meier methods and c-statistics for a 10-year risk of ESRD. RESULTS: The D-scores of glomerular classes 1, 2A, 2B, 3, and 4 were, respectively, 0, 3, 4, 6, and 6. Those of interstitial fibrosis and tubular atrophy classes 0, 1, 2, and 3 were 0, 7, 9, and 11, and those of interstitial inflammation classes 0, 1, and 2 were 0, 3, and 4, respectively. The D-score of hyalinosis class 2 was 3 and that of arteriosclerosis class 2 was 1. So, a patient's D-score could be 0-25. HRs for ESRD in patients with D-score ≤14, 15-18, 19-21, and 22-25 were, respectively, 1.00 (reference) 16.21 (95% confidence interval (CI), 1.86-140.90), 19.78 (95% CI, 2.15-182.40), and 45.46 (95% CI, 4.63-446.68) after adjusting for clinical factors. The c-statistics suggested a better predictive ability for a 10-year renal death with models that included the D-score. CONCLUSION: Prediction of DN patients' renal outcome was better with the D-score than without it. Patients with a D-score ≤14 had excellent renal prognosis.

Role of elevated serum uric acid levels at the onset of overt nephropathy in the risk for renal function decline in patients with type 2 diabetes.

AIMS/INTRODUCTION: Despite the use of intensive therapies, declining renal function is often observed during the overt nephropathy stage of type 2 diabetes. We aimed at investigating the role of serum uric acid (SUA) levels at the onset of overt nephropathy in the risk of renal function decline in type 2 diabetes patients. MATERIALS AND METHODS: The present cohort study included 290 type 2 diabetes patients who were followed from the onset of overt nephropathy. The relationship between SUA and declining renal function was assessed using Cox regression models after adjusting for known risk factors. RESULTS: Over a median 4.8-year follow-up period, 85 patients (4.9/100 person-years) showed serum creatinine (Cr) doubling with a total cumulative incidence of 71.9% at 20 years of follow up. The highest SUA tertile resulted in significantly a higher incidence (7.7/100 person-years) and cumulative incidence at 20 years (85.7%) than the middle (3.9/100 person-years, 54.2%) and lowest (3.0/100 person-years, 55.5%) tertiles. The univariate Cox hazard model resulted in significant risks for Cr doubling related to female sex, short diabetes duration, smoking and elevated levels of low-density lipoprotein cholesterol (LDL-c), glycated hemoglobin and SUA tertiles. SUA tertiles remained statistically significant in the multivariate model (highest vs lowest hazard ratio 2.68, 95% confidence interval 1.48-5.00, P = 0.0009). CONCLUSIONS: Elevated SUA levels within the normal range (men >6.3 mg/dL, women >5.1) at the onset of overt nephropathy resulted in an increased risk for declining renal function in type 2 diabetes patients.

Clinical and pathological predictors of estimated GFR decline in patients with type 2 diabetes and overt proteinuric diabetic nephropathy.

BACKGROUND: The effect of clinical and pathological parameters on the estimated glomerular filtration rate (eGFR) decline has not been investigated in patients with type 2 diabetes and overt proteinuric biopsy-proven diabetic nephropathy. METHODS: Among 198 patients with type 2 diabetes who underwent renal biopsy and were confirmed to have pure diabetic nephropathy according to the recent classification, 128 patients with overt proteinuria were enrolled. Receiver operating characteristic, net reclassification improvement (NRI) and integrated discrimination improvement (IDI) analyses were performed using models adjusted for various clinical and pathological covariates to determine the best predictors of rapid eGFR decline [defined as >14.9%/year (median eGFR decline)]. RESULTS: A model that incorporated proteinuria showed the largest area under the curve (AUC) among clinical models, which suggested that proteinuria was the best clinical predictor. Although a model incorporating interstitial fibrosis and tubular atrophy (IFTA) score did not display a significantly larger AUC than the model with proteinuria (0.843 vs 0.812, respectively, p = 0.47), a model with both IFTA score and proteinuria had a significantly larger AUC than the model with proteinuria alone (0.875 vs 0.812, respectively, p = 0.014). Similarly, the addition of IFTA score resulted in a significantly greater net reclassification improvement and integrated discrimination improvement than the model with proteinuria alone [NRI: 0.78 (95% CI: 0.43-1.13; p < 0.001), IDI: 0.13 (95% CI: 0.07-0.19; p < 0.001)]. CONCLUSIONS: Our results suggest that not only proteinuria but also tubulointerstitial lesions should be assessed to predict rapid eGFR decline in patients with type 2 diabetes who have overt proteinuria and biopsy-proven diabetic nephropathy.

Clinical implications of linear immunofluorescent staining for immunoglobulin G in patients with diabetic nephropathy.

AIMS: The kidneys of patients with diabetes mellitus usually exhibit a characteristic pattern of linear immunofluorescent staining for immunoglobulin G (IgG) along the glomerular and tubular basement membranes. However, the association between linear IgG staining and the renal prognosis remains unclear. METHODS: Among 223 patients with diabetes who underwent renal biopsy from 1985 to 2010 and were confirmed to have pure diabetic nephropathy according to the classification of Tervaert et al., 165 patients (glomerular classes I to III) were enrolled in this study. Immunofluorescent staining was classified into three categories according to its intensity (0=none, 1=weakly positive, and 2=positive). Cox proportional hazards regression analysis was used to calculate the hazard ratio (HR) and 95% confidence interval (CI) for death-censored renal death, with each regression analysis employing four levels of multivariate adjustment. RESULTS: After adjustment for important clinical factors at the time of renal biopsy, the HR for death-censored renal death in patients with an IgG staining score of 1 or 2 was, respectively, 3.01 (95% CI: 1.05-8.68) and 4.68 (1.67-13.1) compared with patients who had a staining score of 0. Even after adjustment for clinical variables and pathological findings, the HR for IgG score of 1 or 2 was higher than that for an IgG score of 0, and it was, respectively, 2.22 (0.71-7.00) and 3.76 (1.27-11.2). CONCLUSIONS: More intense linear IgG staining is associated with a higher HR for renal death, which suggests that linear immunofluorescent staining for IgG may be a prognostic indicator in patients with diabetic nephropathy.

Renal prognosis a long time after renal biopsy on patients with diabetic nephropathy.

BACKGROUND: A new classification of diabetic nephropathy was reported by Tervaert et al., but the association between pathological findings and the clinical outcomes remains unclear. METHODS: Among 310 patients with diabetes mellitus who underwent renal biopsy from March 1985 to January 2010 and were confirmed to have diabetic nephropathy according to the Tervaert's classification, 205 patients were enrolled in this study. Cox proportional hazard regression analysis was used to calculate the hazard ratio (HR) and 95% confidence interval (CI) for death-censored renal death. Each regression analysis employed two levels of multivariate adjustment. RESULTS: After adjustment for age, gender, estimated glomerular filtration rate, type of diabetes, urinary protein excretion, systolic blood pressure, body mass index, HbA1c, diabetic retinopathy and red blood cells in urinary sediment at the time of renal biopsy, compared with glomerular class IIA, the HRs for death-censored renal death of glomerular classes I, IIB, III and IV were 0.21 (95% CI: 0.04-1.25), 2.12 (0.89-5.04), 4.23 (1.80-9.90), and 3.27 (1.32-8.10), respectively. Also, compared with an interstitial fibrosis and tubular atrophy score 1 group, HRs for score 0 group, score 2 group and score 3 group were 0.08 (0.01-0.57), 2.17 (0.96-4.91), 4.78 (1.96-11.68), respectively. CONCLUSIONS: The progression of glomerular, tubulointerstitial and vascular lesions was associated with higher HRs for renal death. These results suggest the clinical utility of Tervaert's pathological classification.

Variegate porphyria complicated by systemic AA amyloidosis: a case report.

We report a Japanese woman with variegate porphyria accompanied by amyloid A (AA) amyloidosis. Arthropathy involving multiple joints occurred at 35 years old and persisted. C-reactive protein was 4.0 mg/dL, but rheumatoid factor was negative. Radiographs did not reveal any loss or narrowing of the joint spaces. Two years later, blister formation after sun exposure and reddish urine were first noted. At the age of 45 years, she developed abdominal pain, nausea, vomiting and seizures. After administration of phenobarbital, reddish urine was noted and muscular weakness progressed to atonic quadraparesis. Porphyria attack was diagnosed from high urinary levels of ∂ aminolevulinic acid and porphobilinogen. At the age of 47 years, hemodialysis was started. At the age of 49 years, progression of her gastrointestinal event resulted in death. Autopsy showed massive deposits of AA amyloidosis in various organs, including the kidneys and digestive tract. Thus, amyloid deposition may have contributed to both end-stage renal failure and her gastrointestinal symptoms. This is the first report about the coexistence of porphyria and AA amyloidosis. Chronic inflammation related to this patient's seronegative arthropathy, although atypical for porphyria, might have contributed to the development of AA amyloidosis.

Development of a screening score for undiagnosed diabetes and its application in estimating absolute risk of future type 2 diabetes in Japan: Toranomon Hospital Health Management Center Study 10 (TOPICS 10).

OBJECTIVE: The objective of the study was to develop a screening score for undiagnosed diabetes by eliciting information on noninvasive clinical markers and to assess its effectiveness for identifying the presence of diabetes and predicting future diabetes. DESIGN, SETTING, AND PARTICIPANTS: A screening score was cross-sectionally developed for 33 335 Japanese individuals aged 18-88 years without known diabetes who underwent a health examination. We validated its utility and compared it with existing screening tools in an independent population (n = 7477). After initial assessment of the instrument, 7332 nondiabetic individuals were followed up for a mean 4.0 years. RESULTS: Prevalence of undiagnosed diabetes (fasting plasma glucose ≥ 7.0 mmol/L or glycated hemoglobin ≥ 6.5%) was 2.9% (n = 965). Diabetes score included age, sex, family history of diabetes, current smoking habit, body mass index, and hypertension with an area under the receiver-operating characteristics curve of 0.771. Screening with 8 or more points yielded a sensitivity of 72.7% and a specificity of 68.1%. In the validation cohort, the area under the receiver-operating characteristics curve was 0.806. The developed score with 8 or more points had better positive predictive value (9.6%) and positive likelihood ratio (2.52) compared with existing tools (positive predictive value, from 6.9% to 9.4%; positive likelihood ratio, from 1.77 to 2.46) in which each tool's highest combination of sensitivity and specificity was observed. The 4-year cumulative risk of developing diabetes gradually escalated in association with higher screening scores at the initial examination. CONCLUSIONS: Our algorithm could serve as a self-assessment tool for undiagnosed diabetic patients needing timely medical care and as a prognostic tool for individuals without present diabetes who must be closely followed up to prevent future diabetes.

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.

Role of alcohol drinking pattern in type 2 diabetes in Japanese men: the Toranomon Hospital Health Management Center Study 11 (TOPICS 11).

BACKGROUND: Findings of past studies on the effect of drinking patterns on diabetes risk have been inconsistent. OBJECTIVE: We aimed to investigate the role of drinking frequency and usual quantity consumed in the development of type 2 diabetes. DESIGN: Enrolled were 1650 Japanese men without diabetes (diabetes: fasting plasma glucose ≥7.0 mmol/L, glycated hemoglobin ≥6.5%, or self-reported clinician-diagnosed diabetes). Average alcohol consumption and 12 combinations of frequency and usual quantity per drinking occasion were assessed at the baseline examination. The absolute risk and HR for the development of diabetes were calculated. RESULTS: During a mean follow-up period of 10.2 y, 216 individuals developed diabetes. Lifetime abstainers (n = 153) had a relatively low incidence of diabetes (9.1/1000 person-years), similar to moderate consumers (99-160 g ethanol/wk; 9.0/1000 person-years). Increasingly higher quantities of alcohol usually consumed per occasion increased the risk of diabetes regardless of drinking frequency. The lowest incidence rate of diabetes (8.5/1000 person-years) was associated with the consumption of <1 drink (<23 g ethanol) per occasion over ≥6 times/wk. Binge drinking (≥3 drinks per occasion) significantly increased the risk of future diabetes regardless of frequency (HR: 1.79; 95% CI: 1.17, 2.74) compared with <1 drink per occasion. CONCLUSIONS: Among current drinkers, a drinking pattern of <1 drink per occasion regularly over 6 times within a week was associated with the lowest risk of developing diabetes. Usual quantity per drinking occasion was a more important determinant than was weekly drinking frequency in the association between alcohol consumption and risk of diabetes in Japanese men.