Go Kanzaki

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.

New insights on glomerular hyperfiltration: a Japanese autopsy study

It has been suggested that low nephron number contributes to glomerular hypertension and hyperperfusion injury in progressive chronic kidney disease (CKD). The incidence of CKD in Japan is among the highest in the world, but the reasons remain unclear. We estimated total nephron (glomerular) number (NglomTOTAL) as well as numbers of nonsclerosed (NglomNSG) and globally sclerosed glomeruli (NglomGSG), and the mean volume of nonsclerosed glomeruli (VglomNSG) in Japanese normotensive, hypertensive, and CKD subjects and investigated associations between these parameters and estimated glomerular filtration rate (eGFR). Autopsy kidneys from age-matched Japanese men (9 normotensives, 9 hypertensives, 9 CKD) had nephron number and VglomNSG estimated using disector/fractionator stereology. Subject eGFR, single-nephron eGFR (SNeGFR), and the ratio SNeGFR/VglomNSG were calculated. NglomNSG in Japanese with hypertension (392,108 ± 87,605; P < 0.001) and CKD (268,043 ± 106,968; P < 0.001) was less than in normotensives (640,399 ± 160,016). eGFR was directly correlated with NglomNSG (r = 0.70, P < 0.001) and inversely correlated with VglomNSG (r = -0.53, P < 0.01). SNeGFR was higher in hypertensives than normotensives (P = 0.03), but was similar in normotensives and CKD, while the ratio SNeGFR/VglomNSG was similar in normotensives and hypertensives but markedly reduced in CKD. Nephron number in Japanese with hypertension or CKD was low. This results in a higher SNeGFR in hypertensives compared with normotensive and CKD subjects, but lowered SNeGFR/VglomNSG in CKD subjects, suggesting that changes in GFR are accommodated by glomerular hypertrophy rather than glomerular hypertension. These findings suggest glomerular hypertrophy is a dominant factor in maintenance of GFR under conditions of low nephron number.

Distribution of glomerular density in different cortical zones of the human kidney

Our studies have demonstrated that a low glomerular density in renal biopsies is a plausible predictor of a worse renal outcome in patients with primary glomerular diseases. However, there remains a concern regarding the diversity that may exist in the distribution of glomerular density within the same kidney. This study therefore aimed to determine the differences in the glomerular density between anatomically different cortical zones of the human kidney. A total of 89 autopsy kidneys were analyzed to accurately measure the glomerular density in different parts of the renal cortex. As a whole, compared to the glomerular density in the superficial cortex (3.0 ± 0.7/mm2), the average glomerular density in the juxtamedullary cortex (2.2 ± 0.6/mm2) was approximately two‐thirds. The glomerular density showed maximal 3.5‐fold variations between individuals and was inversely correlated with the mean glomerular volume in both cortical areas. A low glomerular density of the superficial cortex was predominantly associated with the increase of global glomerulosclerosis. On the other hand, a low glomerular density of the juxtamedullary cortex was predominantly associated with an increase in the kidney weight. Thus, there are significant zonal differences in the distribution of the glomerular density in human kidneys independent of the potential variations observed between individuals.

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.

Caspase-3-Independent Internucleosomal DNA Fragmentation in Ischemic Acute Kidney Injury

Background/Aims: Renal tubular cell death in ischemia-reperfusion does not follow the classical apoptosis or necrosis phenotype. We characterized the morphological and biochemical features of injured tubular epithelial cells in ischemic acute kidney injury (AKI). Methods: Ischemic AKI was induced in rats by 60 min of ischemia followed by 24 h of reperfusion. Light and electron microscopic TUNEL (LM-TUNEL and EM-TUNEL), gel electrophoresis of extracted DNA, and caspase-3 involvement were examined during the development of death. Results: Damaged tubular epithelial cells with condensed and LM-TUNEL-positive (+) nuclei were prominent at 12 and 18 h after reperfusion with DNA ‘ladder’ pattern on gel electrophoresis. EM-TUNEL+ cells were characterized by nuclei with condensed and clumping chromatin, whereas the cytoplasm showed irreversible necrosis. The protein levels and activity of caspase-3 did not increase in kidneys after reperfusion. In addition, caspase inhibitor (ZVAD-fmk) failed to inhibit DNA fragmentation and prevent tubular epithelial cell death in ischemic AKI. Conclusion: Caspase-3-independent internucleosomal DNA fragmentation occurs in injured tubular epithelial cells undergoing irreversible necrosis in ischemic AKI. The manner of this cell death may be identical to the cell death termed apoptotic necrosis, aponecrosis, or necrapoptosis. Ischemia-reperfusion injury activates caspase-3-independent endonuclease, which in turn induces irreversible damage of tubular epithelial cells, and may contribute to the initiation and development of AKI.

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.

Glomerular Density and Volume in Renal Biopsy Specimens of Children with Proteinuria Relative to Preterm Birth and Gestational Age

BACKGROUND AND OBJECTIVES A low total nephron number, which is associated with low birth weight (LBW), may indicate increased susceptibility to early-onset renal diseases in children. However, few studies have assessed renal biopsy findings in LBW children. We examined the relationship between LBW and glomerular density (GD) and/or glomerular volume (GV) in renal biopsy samples as a surrogate for total nephron number. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Renal biopsy findings of children of LBW were compared with those of age-matched control subjects of normal birth weight (NBW) who were histopathologically diagnosed with FSGS or minimal change nephrotic syndrome (MCNS) from 1995 to 2011. The GD and GV were estimated on the basis of measurements obtained by computerized image analysis. RESULTS A total of 31 subjects (mean age 11 years; eight with low birth weight-FSGS [LBW-FSGS], 10 with normal birth weight-FSGS [NBW-FSGS], and 13 with normal birth weight-minimal change nephrotic syndrome [NBW-MCNS]) were analyzed. The mean birth weight of each group was 777 g (629-1000), 3110 g (2888-3358), and 3120 g (2748-3398), respectively (median [25th-75th percentile]). Age, body mass index, BP, and degrees of globally sclerotic glomeruli at biopsy were comparable between the groups. The GD was lower (LBW-FSGS, 1.4±0.6/mm2; NBW-FSGS, 3.3±1.2/mm2; and NBW-MCNS, 3.6±1.1/mm2; P<0.05) and the GV was greater (LBW-FSGS, 4.1 [3.1-5.1]×106µm3; NBW-FSGS, 1.6 [1.5-2.1]×106µm3; and NBW-MCNS, 1.3 [1.1-1.8]×106µm3 [median, (25th-75th percentile)]; P<0.05) in patients with LBW-FSGS than in the other patient groups. The GD showed close positive correlations with birth weight (r=0.48) and gestational age (r=0.54), independent of renal function and degree of global glomerular sclerosis. CONCLUSIONS A low GD together with marked glomerular enlargement characterizes renal biopsy samples of children born with a LBW at an early stage of gestation.

Glomerular Density in Biopsy-Proven Hypertensive Nephrosclerosis.

BACKGROUND Previous autopsy studies suggested that a reduced nephron number is associated with increased risk of hypertension and chronic kidney disease. However, the significance of the nephron number estimated from a renal biopsy in patients with hypertensive nephrosclerosis (HNS) has not yet been elucidated. METHODS In this cross-sectional study, we examined the clinicopathological findings of biopsy-proven HNS patients with preserved renal function (estimated glomerular filtration rate ≥ 60 ml/min/1.73 m(2)). The glomerular density (GD; the number of glomeruli per total renal cortical area) in biopsy specimens was evaluated as a surrogate of the nephron number. Renal biopsies from kidney transplant donors were used as healthy controls. RESULTS A total of 58 HNS patients were enrolled. The GD value in the HNS patients was low compared with those in the kidney transplant donors (2.0 vs. 3.2 /mm(2)). These differences remained significant when globally sclerotic glomeruli were included in the calculation of the GD. Of note, the GD in HNS patients with overt proteinuria (≥1 g/day) was significantly lower than that of HNS patients with mild proteinuria (<1g/day; 1.8 vs. 2.2/mm(2), P = 0.014). In contrast, other histopathological parameters, including the severity of global glomerulosclerosis, interstitial fibrosis/tubular atrophy and arterial and arteriole lesions were comparable between the 2 HNS subgroups. In addition, the GD was identified as a factor that was associated with the amount of urinary protein excretion at biopsy, independent of other clinicopathological factors. CONCLUSIONS These results suggest that a low GD is a renal histological characteristic of HNS patients, especially those with overt proteinuria.

Glomerulopathy Associated With Moderate Obesity

Introduction Obesity-related glomerulopathy is an established secondary glomerular disease that may occur in obese individuals with a body mass index (BMI) of ≥30 kg/m2. However, patients with moderate obesity (BMI ≤ 30 kg/m2) may also develop this disease. Methods A total of 20 patients with grade 1 obesity (25 ≤ BMI < 30 kg/m2) with persistent proteinuria, without evidence of other renal diseases, were analyzed retrospectively. These patients were compared with 20 patients with grade 2 or higher obesity (BMI ≥ 30 kg/m2) with persistent proteinuria. Biopsies of 31 kidney transplant donors as healthy controls were used to compare histologic parameters. Results Similar to the grade 2 or higher obesity group, the grade 1 obesity group had a male predominance (85%) and showed a high incidence of hypertension (80%). Urinary protein excretion and renal outcome parameters were comparable between the groups. Patients with grade 1 obesity showed typical histologic features of obesity-related glomerulopathy: low glomerular density with glomerulomegaly. The glomerular density and mean glomerular volume in the grade 1 group, the grade 2 or higher group, and the kidney transplant donors with grade 1 obesity were 1.6 ± 0.8 versus 1.4 ± 0.6 versus 3.0 ± 1.1 (per mm2) and 6.1 ± 2.1 versus 6.4 ± 1.6 versus 2.9 ± 0.8 (×106 μm3), respectively. Discussion A glomerulopathy similar to obesity-related glomerulopathy can occur in moderately obese individuals. Renal factor(s), such as low glomerular density, may thus underlie susceptibility to this disease entity as well as BMI.