Kentaro Koike

Low Glomerular Density with Glomerulomegaly in Obesity-Related Glomerulopathy

BACKGROUND AND OBJECTIVES Obesity-related glomerulopathy is a secondary form of glomerular disease that may occur in obese individuals. It is histologically characterized by marked glomerulomegaly closely related to glomerular hyperfiltration. This study examined glomerular density (nonsclerotic glomerular number per renal cortical area of biopsy specimen) in patients with obesity-related glomerulopathy to determine whether any differences in this measure is associated with disease status. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Glomerular density and glomerular volume in renal biopsy samples from patients with obesity-related glomerulopathy were compared with those of kidney transplant donors and patients with IgA nephropathy. Kidneys obtained from persons without renal diseases during autopsy were also analyzed to investigate the effects of obesity on glomerular density and glomerular volume. RESULTS Glomerular density of kidneys from patients with obesity-related glomerulopathy (1.7±0.6/mm(2)) was significantly lower than that in biopsy samples from kidney transplant donors (3.1±1.0/mm(2)) and patients with IgA nephropathy (3.5±1.5/mm(2)). However, an analysis of autopsy cases without renal diseases showed that the glomerular density in overweight (2.9±0.7/mm(2)) or obese (3.1±1.1/mm(2)) persons was similar to that in nonobese (3.1±0.6/mm(2)) individuals. Biopsy specimens of patients with obesity-related glomerulopathy showed marked glomerulomegaly. However, glomerular volume was only modestly increased in the autopsy-examined kidneys from overweight or obese persons without renal diseases. CONCLUSIONS Low glomerular density associated with glomerulomegaly may be a characteristic histologic finding of patients with obesity-related glomerulopathy.

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.

Glomerular Density in Renal Biopsy Specimens Predicts the Long-Term Prognosis of IgA Nephropathy

BACKGROUND AND OBJECTIVES An early histopathologic predictor of the renal prognosis, before the occurrence of advanced glomerular sclerosis/interstitial fibrosis and/or apparent renal dysfunction, remains to be established in IgA nephropathy (IgAN). This study aimed to determine whether the glomerular density (GD; nonsclerotic glomerular number per renal cortical area) of biopsy specimens obtained at an early stage of IgAN could predict the long-term renal outcome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The predictive value of the factors at biopsy, including the GD, on the renal outcome was retrospectively analyzed for 98 patients who had IgAN with an estimated GFR of > or =60 ml/min per 1.73 m(2) at biopsy (87 ml/min per 1.73 m(2) on average). RESULTS The individual value of GD in biopsy ranged from 1.2 to 8.1/mm(2) (i.e., approximately a seven-fold variation), and the GD showed a close inverse correlation with mean glomerular volume. Among the various clinicopathologic factors involved, both a cellular/fibrocellular crescent and the GD were found to be significant predictors of progression in multivariate analyses. A low GD in the biopsy specimens was frequently associated with a steeper slope of the renal function and a synergistically enhanced risk for progression with the presence of cellular/fibrocellular crescent. The renal function, proteinuria, degrees of glomerulosclerosis, and interstitial fibrosis at biopsy were not independent predictors of the prognosis in these patients. CONCLUSIONS A strong predictive relationship of low GD with progression observed in this study suggests that GD may serve as an early histopathologic marker of long-term renal prognosis in IgAN.

Blockade of sphingosine 1-phosphate receptor 2 signaling attenuates streptozotocin-induced apoptosis of pancreatic β-cells

Sphingosine 1-phosphate (S1P) is a potent sphingolipid mediator that acts through five cognate G protein-coupled receptors (S1P(1)-S1P(5)) and regulates many critical biological processes. Recent studies indicated that S1P at nanomolar concentrations significantly reduces cytokine-induced apoptosis of pancreatic beta-cells in which genes for S1P(1)-S1P(4) are co-expressed. However, the S1P receptor subtype(s) involved in this effect remains to be clarified. In this study, we investigated the potential role of S1P(2) in streptozotocin (STZ)-induced apoptosis of pancreatic beta-cells and progression of diabetes. S1P(2)-deficient (S1P(2)(-/-)) mice displayed a greater survive ability, lower blood glucose levels, and smaller numbers of TUNEL-positive apoptotic beta-cells to administration of a high dose of STZ than wild-type (WT) mice. S1P(2)(-/-) mice showed higher insulin/glucose ratios (an index of relative insulin deficiency) and larger insulin-positive islet areas to administration of a low dose of STZ than WT mice. Moreover, administration of JTE-013, a S1P(2)-specific antagonist, to WT mice ameliorated STZ-induced blood glucose elevation and reduced the incidence of diabetes. Our findings indicate that blockade of S1P(2) signaling attenuates STZ-induced apoptosis of pancreatic beta-cells and decreases the incidence of diabetes.

Glomerular Density-Associated Changes in Clinicopathological Features of Minimal Change Nephrotic Syndrome in Adults

Background: Differences in nephron number and/or glomerular size between individuals, in relation to intrauterine growth retardation or low birth weight, have been suggested to affect the clinical course of minimal change nephrotic syndrome (MCNS) in children. However, no previous study has investigated the potential influences of these histological variables on the clinical course of adult patients with MCNS. Methods: The glomerular density (GD; the number of non-sclerotic glomeruli per renal cortical area) and the glomerular volume (GV) were evaluated using renal biopsy specimens from adult patients with a histological diagnosis of MCNS (n = 50). Relationships between these variables and clinicopathological features, including the initial response to corticosteroid therapy, were analyzed. Results: Both the GD (1.5–6.5/mm2) and the GV (1.2–4.4 × 106 µm3) showed about 4-fold variations, and a close inverse correlation was observed between these two variables. Notably, the MCNS patients with a low GD showed a trend towards having similar clinicopathological characteristics as patients with a histological diagnosis of focal segmental glomerular sclerosis, as compared to the MCNS patients with a high GD. In addition, during the initial treatment with corticosteroids, the number of patients achieving complete remission was significantly lower in the MCNS patients with a low GD than that in the MCNS patients with a high GD. Conclusion: These results suggest that the GD in renal biopsies may be an important determinant of the glomerular size variability, and can therefore influence the clinical phenotype, such as the response to corticosteroid therapy, in adult patients with MCNS.

Factors associated with a vicious cycle involving a low nephron number, hypertension and chronic kidney disease.

It has been reported that there is substantial variation in the nephron number between individuals. Previous studies using autopsy kidneys have demonstrated that a low nephron number, in relation to a low birth weight, may result in hypertension (HTN) and/or chronic kidney disease (CKD). However, recent studies have revealed that the association between a low nephron number and HTN is not a universal finding. This observation indicates that a low nephron number is unlikely to be the sole factor contributing to an elevated blood pressure. In addition to the nephron number, various genetic and congenital factors may contribute to increased susceptibility to HTN and/or CKD in a complex manner. Acquired factors, including aging, obesity and related metabolic abnormalities, and various causes of renal injury, may additionally promote further nephron loss. Such a vicious cycle may induce HTN and/or CKD via the common mechanisms of renal hemodynamic maladaptation.

Clinicopathological assessment of the nephron number

Recent studies have demonstrated much larger variability in the total number of nephrons in normal populations than previously suspected. In addition, it has been suggested that individuals with a low nephron number may have an increased lifetime risk of hypertension or renal insufficiency, emphasizing the importance of evaluating the nephron number in each individual. In view of the fact that all previous reports of the nephron number were based on analyses of autopsy kidneys, the identification of surrogate markers detectable in living subjects is needed in order to enhance understanding of the clinical significance of this parameter. In this review, we summarize the clinicopathological factors and findings indicating a reduction in the nephron number, focusing particularly on those found at the time of a preserved renal function.

Renal histopathological findings in relation to ambulatory blood pressure in chronic kidney disease patients

Recent studies have demonstrated that ambulatory blood pressure monitoring is useful for predicting the long-term renal prognosis and future cardiovascular events in chronic kidney disease patients. Currently, however, information is limited regarding the relationships between individual renal histopathological findings and abnormalities in ambulatory blood pressure. This retrospective cross-sectional study included a total of 138 patients, in whom both renal biopsies and ambulatory blood pressure monitoring were performed during the same admission period. Renal histopathological findings, including global glomerulosclerosis, interstitial fibrosis/tubular atrophy and the presence of arterial lesions and arteriole lesions, were scored and analyzed in relation to the ambulatory blood pressure values. Among these histopathological characteristics, only the severity of interstitial fibrosis/tubular atrophy exhibited a significant association with an increased mean value of daytime and nighttime blood pressure. However, the remaining histopathological features showed only trends or weak relationships with these values. In addition, a moderately advanced grade of interstitial fibrosis/tubular atrophy was found to be significantly associated with both daytime and nighttime hypertension, independent of the kidney function, overt proteinuria and the use of antihypertensive medications, according to multivariate analyses. Furthermore, the night-to-day ratio of the mean blood pressure displayed a significant increasing trend according to the grade of interstitial fibrosis/tubular atrophy. These results suggest that interstitial fibrosis/tubular atrophy is the most relevant renal histopathological parameter associated with abnormalities in ambulatory blood pressure, including nocturnal hypertension, in this population.

Galactosialidosis associated with IgA nephropathy: Morphological study of renal biopsy

Galactosialidosis is an autosomal recessive lysosomal disease associated with a deficiency of β‐galactosidase and neuraminidase. Described herein is the case of a young adult who had been diagnosed with galactosialidosis at 8 years of age. At the age of 30 years, proteinuria and hematuria appeared and the patient underwent a renal biopsy 1 year later. Light microscopy of the kidney sections indicated fine granular contents in the cytoplasm of glomerular endothelial and epithelial cells, arteriolar smooth muscles and proximal tubular epithelial cells on periodic acid silver–methenamin (PAM) stain. Electron microscopy of these cells indicated enlarged, smooth endoplasmic reticulum and lysosomes containing 150 nm‐wide rods with a fine lattice structure at 66 Å periodicity. Moreover, electron‐dense deposits were located in the paramesangial area. Immunofluorescence staining indicated diffuse and global anti‐human IgA and C3‐positive staining as a mesangial pattern. Given these findings this patient was therefore diagnosed with both galactosialidosis and IgA nephropathy. This is the first report to describe light and electron microscopy observations of storage materials in the kidneys in young/adult galactosialidosis.

Factors related to the glomerular size in renal biopsies of chronic kidney disease patients.

BACKGROUND Glomerular enlargement is an important process that preserves the optimal surface area of glomerular capillaries under both physiological and pathological conditions. However, information is limited regarding how the glomerular size is defined, especially in chronic kidney disease (CKD) patients. METHODS A total of 206 renal biopsy specimens obtained from two different patient cohorts with or without a diagnosis of glomerulonephritis (non-GN group and IgAN group) were examined. The mean glomerular volume was estimated from the outer capillary area of individual glomeruli, and the clinicopathological factors at biopsy that were associated with the mean glomerular volume were analyzed in each group. RESULTS The mean glomerular volume showed maximal 5.8 and 7.9-fold variations between individuals in the non-GN and IgAN groups, respectively. In both groups, the body mass index and glomerular density (non-sclerotic glomerular number per renal cortical area of the biopsy) were consistently identified as independent factors that were associated with the mean glomerular volume. In addition, the multivariate analyses using the glomerular density/body mass index ratio showed a more close association with the mean glomerular volume than the analyses using each measure separately. CONCLUSION These results suggest that factors presumably reflecting both body consumption and nephron number have close relationships with the glomerular size, regardless of mechanism(s) underlying the injury. The most relevant factor affecting glomerular size may be a balance between these two measures.