Mitsuhiro Yoshimura

A multicenter randomized controlled trial of tonsillectomy combined with steroid pulse therapy in patients with immunoglobulin A nephropathy

Background The study aim was, for the first time, to conduct a multicenter randomized controlled trial to evaluate the effect of tonsillectomy in patients with IgA nephropathy (IgAN). Methods Patients with biopsy-proven IgAN, proteinuria and low serum creatinine were randomly allocated to receive tonsillectomy combined with steroid pulses (Group A; n = 33) or steroid pulses alone (Group B; n = 39). The primary end points were urinary protein excretion and the disappearance of proteinuria and/or hematuria. Results During 12 months from baseline, the percentage decrease in urinary protein excretion was significantly larger in Group A than that in Group B (P < 0.05). However, the frequency of the disappearance of proteinuria, hematuria, or both (clinical remission) at 12 months was not statistically different between the groups. Logistic regression analyses revealed the assigned treatment was a significant, independent factor contributing to the disappearance of proteinuria (odds ratio 2.98, 95% CI 1.01–8.83, P = 0.049), but did not identify an independent factor in achieving the disappearance of hematuria or clinical remission. Conclusions The results indicate tonsillectomy combined with steroid pulse therapy has no beneficial effect over steroid pulses alone to attenuate hematuria and to increase the incidence of clinical remission. Although the antiproteinuric effect was significantly greater in combined therapy, the difference was marginal, and its impact on the renal functional outcome remains to be clarified.

A histologic classification of IgA nephropathy for predicting long-term prognosis: emphasis on end-stage renal disease

BACKGROUND A multicenter case-control study on IgA nephropathy (IgAN) was conducted to develop an evidence-based clinicopathologic classification of IgAN for predicting long-term renal outcome. METHODS Two hundred and eighty-seven patients including those with isolated hematuria or very mild proteinuria were enrolled. During a median follow-up of 9.3 years after biopsy, 49 patients (17%) progressed to end stage renal disease (ESRD). The associations between pathological variables and the need for chronic dialysis was examined by multivariate logistic regression analysis separately in patients who required dialysis earlier than 5 years (Early Progressors) and those who required dialysis within 5 to 10 years (Late Progressors) after biopsy. RESULTS Independent pathological variables predicting progression to ESRD were global sclerosis, segmental sclerosis and fibrous crescents for Early Progressors, and global sclerosis and cellular/fibrocellular crescents for Late Progressors. Four histological grades, HG 1, HG 2, HG 3 and HG 4, were established corresponding to <25%, 25-49%, 50-74% and =75% of glomeruli exhibiting cellular or fibrocellular crescents, global sclerosis, segmental sclerosis or fibrous crescents. Eleven (7%) patients in HG 1, 12 (16%) in HG 2, 13 (31%) in HG 3 and 13 (68%) in HG 4 progressed to ESRD. Multivariate logistic analysis revealed that the risk of progression to ESRD was significantly higher in HG 2, 3 and 4 than in HG 1 (odds ratio, 2.4, 5.7 and 27.6 vs. 1.0). CONCLUSIONS Our evidence-based histologic classification can identify the magnitude of the risk of progression to ESRD and is useful for predicting long-term renal outcome in IgAN.

Long-term Outcomes of Japanese Type 2 Diabetic Patients With Biopsy-Proven Diabetic Nephropathy

OBJECTIVE We evaluated the structural-functional relationships and the prognostic factors for renal events, cardiovascular events, and all-cause mortality in type 2 diabetic patients with biopsy-proven diabetic nephropathy. RESEARCH DESIGN AND METHODS Japanese type 2 diabetic patients with biopsy-proven diabetic nephropathy (n = 260) were enrolled. Patients were stratified by albuminuria (proteinuria) and estimated glomerular filtration rate (eGFR) at the time of renal biopsy. The outcomes were the first occurrence of renal events (requirement of dialysis or a 50% decline in eGFR from baseline), cardiovascular events (cardiovascular death, nonfatal myocardial infarction, coronary interventions, or nonfatal stroke), and all-cause mortality. RESULTS The factors associated with albuminuria (proteinuria) regardless of eGFR were hematuria, diabetic retinopathy, low hemoglobin, and glomerular lesions. The factors associated with low eGFR regardless of albuminuria (proteinuria) were age and diffuse, nodular, tubulointerstitial, and vascular lesions. The glomerular, tubulointerstitial, and vascular lesions in patients with normoalbuminuria (normal proteinuria) and low eGFR were more advanced compared to those in patients with normoalbuminuria (normal proteinuria) and maintained eGFR. In addition, compared to patients with micro-/macroalbuminuria (mild/severe proteinuria) and low eGFR, their tubulointerstitial and vascular lesions were similar or more advanced in contrast to glomerular lesions. The mean follow-up period was 8.1 years. There were 118 renal events, 62 cardiovascular events, and 45 deaths. The pathological determinants were glomerular lesions, interstitial fibrosis and tubular atrophy (IFTA), and arteriosclerosis for renal events, arteriosclerosis for cardiovascular events, and IFTA for all-cause mortality. The major clinical determinant for renal events and all-cause mortality was macroalbuminuria (severe proteinuria). CONCLUSIONS Our study suggests that the characteristic pathological lesions as well as macroalbuminuria (severe proteinuria) were closely related to the long-term outcomes of biopsy-proven diabetic nephropathy in type 2 diabetes.

Fibrocytes are involved in the pathogenesis of human chronic kidney disease

The presence of chronic kidney disease in humans is associated with a risk of kidney function loss as well as the development of cardiovascular disease. Fibrocytes have been shown to contribute to organ fibrosis. In this study, the presence of fibrocytes was investigated immunohistochemically in kidney biopsy specimens from 100 patients with chronic kidney disease. In addition, 6 patients with thin basement membrane disease were studied as a disease control. In patients with chronic kidney disease, the infiltration of fibrocytes was observed mainly in the interstitium. The number of interstitial fibrocytes in patients with chronic kidney disease was higher than that in patients with thin basement membrane disease. The number of infiltrated fibrocytes in the interstitium correlated well with the severity of tubulointerstitial lesions, such as interstitial fibrosis, in patients with chronic kidney disease. In addition, there were significant correlations between the number of interstitial fibrocytes and the number of CD68-positive macrophages in the interstitium as well as urinary monocyte chemoattractant protein-1/CCL2 levels. In particular, there was an inverse correlation between the number of interstitial fibrocytes and kidney function at the time of biopsy. Finally, the numbers of interstitial fibrocytes and macrophages as well as urinary CCL2 levels were significantly decreased during convalescence induced by glucocorticoid therapy. These results suggest that fibrocytes may be involved in the pathogenesis of chronic kidney disease through the interaction with macrophages as well as CCL2.

Intraglomerular Expression of MHC Class II and Ki-67 Antigens and Serum γ-lnterferon Levels in IgA Nephropathy

In order to clarify intraglomerular cellular activation and cytokine involvement in IgA nephropathy, the glomerular expression of MHC class II antigens (HLA-DR and DQ) and cellular proliferative nucle

Significance of IgA deposits on the glomerular capillary walls in IgA nephropathy.

Based on immunofluorescence findings, 232 patients with IgA nephropathy were classified into two groups; one consisted of 88 patients (38%) with IgA deposits in the glomerular capillary walls together with the mesangial deposits (capillary type), and the other consisted of 144 patients (62%) with deposits confined to the mesangium (mesangial type). Electron microscopic findings revealed dense deposits on the capillary walls (subepithelial, 50%; intramembranous, 65%; and subendothelial, 24%) in 37 of 46 patients with capillary type and six of 47 with mesangial type (P less than .001). Crescent formation observed in greater than or equal to 10% of glomeruli was more frequently found in patients with the capillary type (30/88, 34%) than those with the mesangial type (9/144, 6%) (P less than .01), especially higher in those with subepithelial deposits (15/26, 57%). The capillary type patients showed heavier proteinuria (1.7 +/- 0.2 g/d) than the mesangial type patients (0.6 +/- 0.1 g/d) (P less than .05). Thirteen of the 14 patients in an acute exacerbation phase, manifested by an abrupt increase in urinary protein and development of macroscopic hematuria, showed capillary type IgA deposits. The ratio of patients with normal renal function in the fifth year after apparent onset was lower in the capillary type (74.0%) than in the mesangial type patients (96.9%) (P less than .05). These findings suggest that capillary IgA deposition is closely related to clinical and histologic activities of IgA nephropathy and is considered to be an important factor responsible for the progression of the disease, possibly through crescent formation.

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

BackgroundThe 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/DesignThe 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.DiscussionThis 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 registrationUMIN-Clinical Trial Registration, UMIN000004784.

Overestimation of the risk of progression to end-stage renal disease in the poor prognosis’ group according to the 2002 Japanese histological classification for immunoglobulin A nephropathy

BackgroundThe current (2012) histological classification of immunoglobulin A nephropathy was established using a case–control study of 287 patients. However, the risk of progression to end-stage renal disease (ESRD) has not been validated for the previous (2002) classification. This study aimed to determine whether the previous classification could identify the risk of long-term renal outcome through re-analysis of the 2012 cohort.MethodsOn the basis of the 2002 classification, namely ‘good prognosis’, ‘relatively good prognosis’, ‘relatively poor prognosis’, and ‘poor prognosis’, we examined the clinical data at the time of biopsy, the correlation between the 2002 classification and long-term renal outcomes, and a patient-by-patient correlation between the 2002 and 2012 classification systems. This was performed by analyzing samples from the 287 patients used to establish the 2012 classification.ResultsThe rate of decline of estimated glomerular filtration rate was greater and the odds ratio of progression to ESRD was higher in the ‘poor prognosis’ group. In contrast, the odds ratio for renal death was comparable between the groups described as ‘relatively poor prognosis’ and ‘relatively good prognosis’ in the 2002 classification. Many patients in the 2002 classification were classified with a lower histological grade in the current classification, but none were classified with a higher grade.ConclusionsThe 2002 classification could also identify the risk of progression to ESRD. However, it was overestimated for patients in the ‘poor prognosis’ group in the 2002 classification, as that group included patients with milder histological damage.

Hemodialysis Patients Born With a Low Birth Weight Should Have a Different Time Course of Kidney Diseases Than Those Born With a Normal Birth Weight

Low birth weight (LBW) is thought to be one of the risk factors for the progression of kidney diseases. This study hypothesized that the onset age of kidney disease, the rate of progression of kidney disease, or the age at the time of hemodialysis (HD) induction among HD patients that were born with LBW is different from those without a history of LBW. A questionnaire survey in nine dialysis units in Japan was performed and 427 answer sheets were collected. There were statistically significant differences in the present age, the age of kidney disease onset, and the age of HD induction between LBW group and normal birth weight group (NBW). An analysis limited to participants whose underlying disease was diabetic nephropathy revealed that the duration from the onset of nephropathy to HD induction was much shorter in HD patients with a history of LBW than those with a NBW history. In addition, the Pearsons correlation coefficient between the birth weight and the period from onset of diabetic nephropathy to HD induction was 0.283. Although these results might partly support the primary hypothesis, the necessity to perform other clinical studies is also emphasized.