Structural modeling for Oxford histological classifications of immunoglobulin A nephropathy.

In immunoglobulin A nephropathy (IgAN), Cox regression analysis can select independent prognostic variables for renal functional decline (RFD). However, the correlation of the selected histological variables with clinical and/or treatment variables is unknown, thereby making histology-based treatment decisions unreliable. We prospectively followed 946 Japanese patients with IgAN for a median of 66 mo. and applied structural equation modeling (SEM) to identify direct and indirect effects of histological variables on RFD as a regression line of estimated glomerular filtration rate (eGFR) via clinical variables including amount of proteinuria, eGFR, mean arterial pressure (MAP) at biopsy, and treatment variables such as steroid therapy with/without tonsillectomy (ST) and renin-angiotensin system blocker (RASB). Multi-layered correlations between the variables and RFD were identified by multivariate linear regression analysis and the model's goodness of fit was confirmed. Only tubular atrophy/interstitial fibrosis (T) had an accelerative direct effect on RFD, while endocapillary hypercellularity and active crescent (C) had an attenuating indirect effect via ST. Segmental sclerosis (S) had an attenuating indirect effect via eGFR and mesangial hypercellularity (M) had accelerative indirect effect for RFD via proteinuria. Moreover, M and C had accelerative indirect effect via proteinuria, which can be controlled by ST. However, both T and S had additional indirect accelerative effects via eGFR or MAP at biopsy, which cannot be controlled by ST. SEM identified a systemic path links between histological variables and RFD via dependent clinical and/or treatment variables. These findings lead to clinically applicable novel methodologies that can contribute to predict treatment outcomes using the Oxford classifications.

An equation to estimate the renal cortex volume in chronic kidney disease patients.

BACKGROUND: The renal cortex volume is associated with the kidney function and chronic kidney disease (CKD) risk factors, and it may also be a prognostic factor. We aimed to create an equation to estimate the renal cortex volume of CKD patients in day-to-day clinical practice. METHODS: The subjects included 116 ethnic Japanese CKD patients who were ≥ 18 years of age. The renal size (length, width and thickness) was measured by ultrasound. The body height, weight, year of age, sex, birth weight, gestational age, diabetes status, hypertension status, family history of CKD and dialysis and estimated glomerular filtration rate (eGFR) were collected as expected dependent variables. We made models for the equation regarding the renal cortex volume measured by non-contrast magnetic resonance imaging as a true renal cortex volume. Stepwise multiple linear regression analyses were performed with the log-transformation of dependent and independent variables. The accuracy of the models was compared using the leave one out cross-validation method. RESULTS: The estimated volume of the renal cortex (cm3) = 0.012 × renal length (cm)0.92 × width (cm)0.53 × body weight (kg)0.40 × body height (cm)0.67 × eGFR (ml/min/1.73 m2)0.22 × 1.12 if diabetes. The adjusted R 2 value and the accuracy within 30 and 50% were 0.73, 0.94 and 0.99, respectively. CONCLUSIONS: This study provided a new method for estimating the renal cortex volume in day-to-day clinical practice.

Determinants of renal shape in chronic kidney disease patients.

BACKGROUND: The determinants of renal shape are not well established. The purpose of this study was to investigate the relationship between the renal shape, as measured by ultrasound, and the clinical characteristics in chronic kidney disease (CKD) patients. METHODS: The study included 121 CKD patients who had undergone kidney biopsy. The renal shape was defined by: (1) the renal shape index: renal length/(renal width + renal thickness) and (2) the renal width/length. IgA nephritis patients (excluding patients with diabetes), comprised the largest subgroup (n = 49) and were analyzed separately. RESULTS: The correlation analyses and two-sample Student's t test results showed that age, eGFR, BMI, cortex volume fraction measured by MRI (cortex volume/renal volume), percentage of global sclerosis, weight, sex, hypertension and diabetes were significantly correlated with the renal shape in both kidneys. In a stepwise multiple linear regression analysis, old age and high BMI were independently associated with plump kidney. As for the left renal shape index, low cortex volume fraction was also independently associated with plump kidney. In the IgA nephritis patient subgroup, the cortex volume fraction was the most significant factor contributing to the left renal shape index (r = 0.50, p < 0.01) and the width/length (r = -0.47, p < 0.01). CONCLUSION: Age and BMI were stronger determinants of renal shape than renal function in CKD patients. The left renal cortex volume fraction was also an independent determinant and a more important factor in IgA nephritis patients.

7501 T > A mitochondrial DNA variant in a patient with glomerulosclerosis.

The presence of granular swollen epithelial cells (GSECs) in tubular cells was recently reported to be a specific change associated with mitochondrial cytopathy. However, at present, GSEC is not routinely evaluated. We, in this study, present a case of glomerulosclerosis, in which the presence of GSECs should provide us one clue to understand the pathogenesis of its progressive decline of renal function. A 54-year-old Japanese female, who had been diagnosed with Graves' disease, was referred for the examination and treatment of her proteinuria (5.4 g/gCre at the first visit to our hospital). A kidney biopsy showed 28.6% of the glomeruli to be globally sclerosed and 10.7% of the glomeruli to have completely collapsed. However, according to a light microscopic analysis, all other glomeruli showed an almost normal appearance, except for some slight enlargement. Almost 30% of the interstitium was damaged by fibrosis. Characteristically, GSECs were observed in the medulla collecting ducts. Although she had no symptoms of either myopathy or encephalopathy, no history of stroke-like episodes or difficulty in hearing, her serum concentrations of lactate and pyruvate were both elevated. Therefore, mitochondrial DNA sequencing was performed to assess the etiopathogenesis of her nephropathy. Consequently, a homoplasmic 7501 T > A replacement, which has not been previously reported in patients with renal diseases, was detected. This case suggests that the routine evaluation of GSECs can provide important clues to assess the etiopathogenesis of cryptogenic glomerulosclerosis.

Predicting the outcome of chronic kidney disease by the estimated nephron number: the rationale and design of PRONEP, a prospective, multicenter, observational cohort study.

BACKGROUND: The nephron number is thought to be associated with the outcome of chronic kidney disease (CKD). If the nephron number can be estimated in the clinical setting, it could become a strong tool to predict renal outcome. This study was designed to estimate the nephron number in CKD patients and to establish a method to predict the outcome by using the estimated nephron number. METHODS/DESIGN: The hypothesis of this study is that the estimated nephron number can predict the outcome of a CKD patient. This will be a multicenter, prospective (minimum 3 and maximum 5 years follow-up) study. The subjects will comprise CKD patients aged over 14 years who have undergone a kidney biopsy. From January 2011 to March 2013, we will recruit 600 CKD patients from 10 hospitals belonging to the National Hospital Organization of Japan. The primary parameter for assessment is the composite of total mortality, renal death, cerebro-cardiovascular events, and a 50% reduction in the eGFR. The secondary parameter is the rate of eGFR decline per year. The nephron number will be estimated by the glomerular density in biopsy specimens and the renal cortex volume. This study includes one sub-cohort study to establish the equation to calculate the renal cortex volume. Enrollment will be performed at the time of the kidney biopsy, and the data will consist of a medical interview, ultrasound for measurement of the kidney size, blood or urine test, and the pathological findings of the kidney biopsy. Patients will continue to have medical consultations and receive examinations and/or treatment as usual. The data from the patients will be collected once a year after the kidney biopsy until March 2016. All data using this study are easily obtained in routine clinical practice. DISCUSSION: This study includes the first trials to estimate the renal cortex volume and nephron number in the general clinical setting. Furthermore, this is the first prospective study to examine whether the nephron number predicts the outcome of CKD patients. The results from this study should provide powerful new tools for nephrologists in routine clinical practice. TRIAL REGISTRATION: UMIN-Clinical Trial Registration, UMIN000004784.

Association between the rate of low-birth weight newborns and the incidence of end-stage renal disease in 47 prefectures in Japan.

BACKGROUND: An ecological study is a useful epidemiologic tool for public health surveillance and establishment of a new hypothesis. Here, we used an ecological study to analyze the association between birth weight and end-stage renal disease (ESRD). METHODS: We performed ecological regression analysis by using data obtained from the national database of Japan. The data include regional incidence of ESRD beginning maintenance dialysis therapy, regional rate of low-birth weight (LBW) newborn babies of all newborn babies, the average birth weight of newborns, the body mass index (BMI) score, the prevalence of diabetes mellitus, and the amount of payment for drugs, in the 47 prefectures of Japan. RESULTS: The mean regional rates of LBW newborn babies from 1999 to 2008 statistically correlated with the mean incidences of ESRD during the same time periods in each prefecture. The correlation coefficients between the yearly rate of LBW newborns and the yearly incidence of ESRD in each prefecture became higher after statistically considering the effects of the cost per resident for prescriptions of angiotensin II receptor blocker and angiotensin converting enzyme inhibitor. Furthermore, the final model predicting the regional incidence of ESRD by a stepwise multiple regression analysis consisted of the average BMI score and the rate of LBW newborns in each prefecture. CONCLUSION: Although this study cannot explain the reason for this unexpected correlation between the regional rate of LBW babies and the regional incidence of ESRD at the same time points, the statistically significant correlations shown in this study should be taken into consideration.

[Status of board-certified nephrologists of the Japanese Society of Nephrology among 47 prefectures].

To improve chronic kidney disease (CKD) outcomes, board-certified nephrologists of the Japanese Society of Nephrology (certified nephrologists) are anticipated to play an important role in community medicine and establish an effective cooperative relationship with primary care physicians. We analyzed the present status of certified nephrologists in each prefecture of Japan based on national data. As a result, in 2008, the maximum number of certified nephrologists per population among the 47 prefectures was 5.3 times higher than the minimum number. The rate of increase was not high in prefectures with a small number of certified nephrologists per population, which indicates that the disparities among the prefectures will persist in the future. To analyze how certified nephrologists participate in the community medicine of the 47 prefectures of Japan, we performed an ecological regression study. At first, it was shown that the number of certified nephrologists per resident population according to prefectures in 2007 had no significant correlation with the annual amount paid for angiotensin converting enzyme inhibitor (ACEI), angiotensin II receptor blocker (ARB), calcium channel-blocker (CCB), or erythropoiesis stimulating agent (ESA) per resident. Furthermore, to determine what parameters had a significant correlation with the incidence of dialysis in each prefecture, simple linear regression analysis was first performed. As a result, parameters with a significant correlation were the average age of the inhabitants, and the annual amounts paid for ARB, ARB plus ACEI, CCB, and ESA per resident. Furthermore, multiple regression analysis revealed that there were two variables included in the final model which could explain the low incidence of dialysis in each prefecture. One was the annual amount of ESA used for predialysis CKD patients, and the other was the number of certified nephrologists per population. Based on these findings, although our ecological study cannot identify causation, we predict that certified nephrologists can effectively prevent the progression of CKD, and an increase in certified nephrologists will decrease the incidence of dialysis.

Left ventricular hypertrophy was infrequent in patients starting dialysis after undergoing a strict blood pressure control in the pre-dialytic period.

OBJECTIVE: We retrospectively investigated the factors influencing the left ventricular hypertrophy (LVH) occurrence in patients with chronic renal failure (CRF). METHODS AND PATIENTS: Blood pressure and echocardiographyically determined LVH were assessed in 110 patients on the basis of availability of monthly follow-up data obtained during the period of 2 years before the start of dialysis. When the patients showed the left ventricular mass index of not less than 125 g/m2, they were diagnosed as having LVH. Mean casual blood pressure distribution was classified into 5 groups: Group 1; <93 mmHg, Group 2; 93-100 mmHg, Group 3; 100-106 mmHg, Group 4; 106-114 mmHg and Group 5; >114 mmHg. RESULTS: LVH frequencies were 31.8, 72.7, 72.7, 81.8 and 95.5 (%) in Groups 1-5, respectively. Logistic regression showed that the factors influencing the progression of LVH were the duration of hypertension (per 1 year relative risk) (RR) 1.13, 95% confidential interval (CI) (1.01-1.26), treatment with angiotensin-converting enzyme inhibitors (ACE-1) (RR: 0.20, 95%CI: 0.04-0.99), pulse pressure (RR: 1.06, 95%CI: 1.00-1.11) and mean blood pressure (MBP). The RR of developing LVH increased progressively as MBP increased: Compared with LVH frequency in Group 1, RR of Group 2 was 4.38 (95%CI: 1.05-18.19), that of Group 3 was 5.50 (95%CI: 1.08-28.02), that of Group 4 was 5.66 (95%CI: 1.22-26.15), and that of Group 5 was 19.13 (95%CI: 1.75-209.4). CONCLUSION: Strict blood pressure control and ACE-I treatment could prevent LVH in patients with CRF.