Kotaro Haruhara

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.

Angiotensin receptor-binding molecule in leukocytes in association with the systemic and leukocyte inflammatory profile

BACKGROUND AND AIMS The components of the renin-angiotensin system in leukocytes is involved in the pathophysiology of non-communicable diseases (NCDs), including hypertension, atherosclerosis and chronic kidney disease. Angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP) is an AT1R-specific binding protein, and is able to inhibit the pathological activation of AT1R signaling in certain animal models of NCDs. The aim of the present study was to investigate the expression and regulation of ATRAP in leukocytes. METHODS Human leukocyte ATRAP mRNA was measured with droplet digital polymerase chain reaction system, and analyzed in relation to the clinical variables. We also examined the leukocyte cytokines mRNA in bone-marrow ATRAP-deficient and wild-type chimeric mice after injection of low-dose lipopolysaccharide. RESULTS The ATRAP mRNA was abundantly expressed in leukocytes, predominantly granulocytes and monocytes, of healthy subjects. In 86 outpatients with NCDs, leukocyte ATRAP mRNA levels correlated positively with granulocyte and monocyte counts and serum C-reactive protein levels. These positive relationships remained significant even after adjustment. Furthermore, the leukocyte ATRAP mRNA was significantly associated with the interleukin-1β, tumor necrosis factor-α and monocyte chemotactic protein-1 mRNA levels in leukocytes of NCDs patients. In addition, the leukocyte interleukin-1β mRNA level was significantly upregulated in bone marrow ATRAP-deficient chimeric mice in comparison to wild-type chimeric mice after injection of lipopolysaccharide. CONCLUSIONS These results suggest that leukocyte ATRAP is an emerging marker capable of reflecting the systemic and leukocyte inflammatory profile, and plays a role as an anti-inflammatory factor in the pathophysiology of NCDs.

Circadian blood pressure abnormalities in patients with primary nephrotic syndrome.

ABSTRACT Background: Only a few studies have evaluated the abnormalities of ambulatory blood pressure (ABP) in patients with nephrotic syndrome (NS). Methods: The 24-h ABPs were measured in primary NS patients with acute onset of disease and analyzed in relation to the clinical variables. Results: Our subjects comprised 21 patients: 17 with minimal change disease and 4 with focal segmental glomerulosclerosis. Of these patients, 8 (38%) had daytime hypertension, 13 (62%) had nighttime hypertension, and 13 (62%) were non-dippers (nighttime-to-daytime ratio of ABP: NDR > 0.9). The serum sodium level was correlated with the average 24-h ABP and NDR, after adjustment for other clinical variables, such as the increase in body weight, serum albumin level, and urinary protein excretion. The data from repeated ABP measurements, before and after the achievement of remission, showed a marked decrease in the average 24-h ABP after remission. Furthermore, change in the serum sodium level was significantly correlated with the change in NDR. Conclusion: These results suggest that alteration in renal handling of sodium and water, which might be reflected in serum sodium level, is involved in the abnormality of circadian blood pressure in primary NS patients.

Ambulatory blood pressure and tubulointerstitial injury in patients with IgA nephropathy

Background Few studies have been conducted to assess the ambulatory blood pressure (ABP) in IgA nephropathy (IgAN) patients. This study aimed to determine the relationships between ABP and renal histopathological findings assessed using the Oxford classification (OC) and the Japanese classification (JC), which have recently established histopathological criteria for IgAN. Methods This cross-sectional study included biopsy-diagnosed IgAN patients, in whom both a renal biopsy and ABP measurement were performed. The histopathological findings were assessed using the OC and the JC and were analyzed in relation to the ABP. Results A total of 111 IgAN patients were included. The score of interstitial fibrosis and tubular atrophy (T score) using the OC was a significantly associated factor with both the daytime and nighttime ABP values. In contrast, the other histopathological scores, including mesangial hypercellularity, endocapillary hypercellularity and segmental glomerulosclerosis, did not show significant associations with the ABP. The histological grade (H-grade) using the JC, which was based on the sum of injured glomeruli, was associated with the daytime ABP, but not with the nighttime ABP. The associations between the T score using the OC (%) and the daytime and nighttime ABP values were independent of age, gender, renal function, proteinuria and the use of antihypertensive medications, whereas the H-grade using the JC (%) did not show significant associations after adjusting for these clinical parameters. Conclusions These results suggest that the T score using the OC is the most relevant renal histopathological parameter associated with abnormalities of circadian blood pressure in IgAN patients.

Heterogeneous distribution of glomerular size in adult kidneys with normal renal function: Letter to the Editor

To the Editor: Renal glomeruli consist of a nephron and play a central role in maintaining the filtration function of the kidneys. The number of human glomeruli is determined by late gestation and does not increase after birth. Thus, in accordance with the increased filtration demand of whole kidneys after birth, the glomeruli adapt by increasing their size. In fact, human glomeruli increase in size during growth from children to adults, and such adaptation is supposed to be proportional to the increase in body size. However, there may be significant variation in the increase in glomerular volume (GV) during the normal growth process among individuals. Factors that determine such differences in GV among individuals are total nephron number, race, age, sex, and body size. It has been suggested that excessive enlargement of glomeruli represents one of the structural components of glomerular hypertension, a factor that may be related to the development of glomerulosclerosis and subsequent loss of renal function. The glomerular number may differ depending on the cortical areas located within the same kidney. Compared to the superficial cortex (S-cortex), in general, the number of glomeruli in the juxtamedullary cortex (J-cortex) is low. This is likely due to different developmental programs suitable for each location. Indeed, in our previous autopsy study, glomerular density (glomerular number per unit cortical area) in the J-cortex was significantly lower than that in the S-cortex in most cases analyzed. In addition, glomeruli in the J-cortex are continuously exposed to a relatively heavy pressure load, whereas glomeruli in the S-cortex are more prone to ischemic stress. However, to date, only a few studies have reported on the clinically identifiable factors that may also affect GV in each anatomical location. Here, we investigated the differences in GV among anatomically different cortical zones of the human kidneys. As a subanalysis of our previous study, adult Japanese autopsy kidneys (n1⁄4 89, mean age of 65 years) without any evidence of impaired renal function (defined as an estimated glomerular filtration rate [eGFR] <60mL/min/1.73m) or persistent urinary abnormalities were used. Details of the autopsies and methods were previously described. Briefly, approximately 50 glomeruli were randomly selected in each cortical area within the specimens, and glomerular area (GA) was defined as the area described by the outer capillary loops of the tuft determined using a computed imaging analyzer. The mean GV was calculated from the measured GA: GV1⁄4 (GA) b/ d, where b is a dimensionless shape coefficient (b1⁄41.38 for spheres) and d is a size distribution coefficient that is used to adjust for variation in glomerular size. The analysis used d1⁄41.01, as in previous studies. The relationship between the GV of each cortical zone and the clinicopathological findings of these autopsy specimens was analysed. Overall, the mean GV of the S-cortex and J-cortex was 2.69 1.01 10mm and 3.05 0.81 10mm, respectively. The mean GV showed maximal 7and 4-fold variation among individuals in the Sand J-cortex, respectively. Multivariate regression analyses were performed to evaluate the factors closely related to GV. The covariates included in the multivariate analyses were patient age, eGFR, body mass index (BMI), hypertension, rate of glomerulosclerosis, and the non-sclerotic glomerular density in each cortex. The nonsclerotic glomerular density and rate of glomerulosclerosis were identified as independent factors associated with GV in the S-cortex (b1⁄4 0.363, P1⁄4 0.011 and b1⁄4 0.315, P1⁄4 0.023, respectively). In contrast, hypertension was the only factor associated with GV in the J-cortex (b1⁄4 0.395, P1⁄40.006). In 62 cases (70%), GV was significantly larger in the J-cortex than in the S-cortex. Of note, GV was larger in the S-cortex than in the J-cortex in 27 cases (30%). To gain insight into this observation, the autopsies were categorized according to which cortex dominated in GV size. Compared to the J-cortex-dominant group, the S-cortex-dominant group had a higher BMI and body surface area (BSA), a lower non-sclerotic glomerular density, and a higher rate of glomerulosclerosis in both cortical areas. The glomerular density values did not differ significantly among the groups when globally sclerotic glomeruli were included in the calculation (Table 1). To further evaluate the factors associated with S-cortex dominance in GV, we performed univariate and multivariate logistic analyses. In univariate analyses, BMI (R1⁄4 0.363, P< 0.001), kidney weight (R1⁄4 0.242, P1⁄4 0.022), global glomerulosclerosis in both cortical areas (S-cortex R1⁄4 0.270, P1⁄4 0.011 J-cortex R1⁄4 0.328, P1⁄40.002), and non-sclerotic glomerular density in the S-cortex (R1⁄4 0.227, P1⁄40.033) were identified as significant factors associated with S-cortex dominance in GV. All of these factors that were significant in the univariate analyses were included in multivariate analyses, and global glomerulosclerosis in the J-cortex and BMI were identified as factors independently associated with S-cortex dominance in GV (P1⁄40.010, odds ratio (OR)1⁄4 1.195 and P1⁄4 0.005, OR1⁄4 1.196, respectively).

A Case of Hepatic Glomerulosclerosis with Monoclonal IgA1-κ Deposits

Glomerular immunoglobulin A (IgA) deposition is a common finding in hepatic glomerulosclerosis; thus, this disease is also called hepatic IgA nephropathy. However, only a small number of patients with hepatic IgA nephropathy have active glomerular lesions, so functional decline is slow in most cases. In this report, we describe a 60-year-old man who developed nephrotic syndrome and progressive renal impairment during follow-up for alcoholic liver cirrhosis. A renal biopsy showed a membranoproliferative glomerulonephritis-like pattern; diffuse double-contours of the glomerular basement membrane and focal active glomerular lesions with moderate-to-severe endocapillary proliferation and fibrocellular crescents. Immunofluorescence findings revealed granular staining for monoclonal IgA1-κ and C3 on the peripheral capillary walls. Laboratory examinations did not reveal any definitive evidence of myeloproliferative disorders. Therefore, this case may represent a previously unrecognized etiology of renal injury in relation to liver cirrhosis that is characterized by monoclonal IgA1-κ deposits and proliferative glomerulonephritis.

Volume Ratio of Glomerular Tufts to Bowman Capsules and Renal Outcomes in Nephrosclerosis

BACKGROUND The concomitant appearance of glomerular collapse and enlargement is characteristic of the histological findings in nephrosclerosis. However, no previous study quantitatively examined the clinicopathological significance of this feature in patients with biopsy-proven nephrosclerosis. METHODS Renal biopsy specimens and follow-up data from nephrosclerosis patients with estimated glomerular filtration rates >30 ml/min/1.73 m2 at diagnosis were retrospectively reviewed. Mean volumes for glomerular tufts (GV) and Bowman capsules (BV) were separately calculated, based on the measurement of all areas of glomerular tufts and Bowman capsules in a cross-section of biopsy specimens. The G/B ratio was defined as the ratio of GV to BV. The doubling of serum creatinine levels (DSC) and the initiation of renal replacement therapies (end-stage renal disease (ESRD)) were examined as renal outcome indices. RESULTS A total of 67 patients with biopsy-proven nephrosclerosis were included. Clinicopathological findings at biopsy, other than GV, were comparable among all patients, irrespective of G/B ratio. Overall, 25 patients (37%) developed DSC and 9 (13%) developed ESRD during the median observation periods of 7.8 and 8.5 years, respectively. Renal survival curve analyses indicated a significantly worse prognosis for patients with a low G/B ratio, as compared with those with a high G/B ratio. Cox hazard analyses for DSC identified low G/B ratio as a significant predictor, but not low GV or BV. CONCLUSIONS These results suggest that the quantitative evaluation of G/B ratio may detect subtle abnormalities in the glomerulus, indicating the subsequent renal outcomes of nephrosclerosis patients.

Bowman Capsule Volume and Related Factors in Adults With Normal Renal Function

Introduction Alterations in glomerular filtration can considerably influence the dynamics and functions of the Bowman capsule. Despite the potentially important role in maintaining normal renal functions, few studies have focused on Bowman capsule volume in normal human kidneys. Methods We analyzed specimens from biopsies performed 1 hour after kidney transplantation from living donors without apparent renal disease. The measurements of all cross-sectional areas of the Bowman capsules and glomerular capillaries were used to estimate the mean Bowman capsule volume (BV) and glomerular capillary volume (GV) in each subject. The G/B ratio was defined as the ratio of GV to BV. The morphometric findings were examined in relation to the clinical findings in donors just before kidney transplantation. Results We analyzed 37 adults with a mean creatinine clearance of 111 ml/min. The mean BV and GV of these subjects were 6.10 ± 2.46 × 106 μm3 and 3.83 ± 1.52 × 106 μm3, respectively. Both the BV and GV varied up to 6-fold and were significantly higher in elderly, obese, or hypertensive subjects in comparison to nonelderly, nonobese, or normotensive subjects, whereas the renal function of each subgroup was similar. The G/B ratio (0.63 ± 0.05) was unaffected, and BV and GV were strongly correlated regardless of these clinical factors (r = 0.980 [95% confidence interval = 0.961−0.990], P < 0.001). Conclusion In the normal adult kidney, there may be an optimal BV to GV ratio for maintaining effective filtration in a variety of clinical situations, including advanced age, obesity, and hypertension.