The Efficacy of Ramelteon to Prevent Postoperative Delirium After General Anesthesia in the Elderly: A Double-Blind, Randomized, Placebo-Controlled Trial.

OBJECTIVE: Postoperative delirium is common and serious in elderly patients. Several drugs have been proposed as potential prophylactic agents for postoperative delirium. Studies on melatonin receptor agonists showed heterogeneity in age, cognitive function, anesthesia, surgery, interventions, methodologies for assessing outcomes, and results. Our objective was to examine the effect of ramelteon to prevent postoperative delirium in elderly patients, including those with dementia. DESIGN: A stratified, double-blind, randomized, placebo-controlled trial (UMIN000028436, jRCTs031180054). SETTING: Tertiary medical center. PARTICIPANTS: Patients aged older than or equal to 65 years undergoing elective surgery under general anesthesia. INTERVENTION: Ramelteon (8 mg orally) or placebo (lactose) for six nights (the preoperative night and five consecutive nights from postoperative day 1 to 5) at around 9 P.M. MEASUREMENTS: Patients were screened for postoperative delirium using the Confusion Assessment Method for the Intensive Care Unit twice daily until the sixth postoperative day. Patients with positive results were referred to a consultant psychiatrist to establish the diagnosis of delirium. RESULTS: A total of 108 patients were randomly assigned to receive ramelteon (n = 55) or placebo (n = 53). Most of the patients' characteristics were reasonably well-balanced between the two groups. The stratified log-rank test showed no significant difference in preventing postoperative delirium between ramelteon and placebo (χ2 = 0.30, degrees of freedom = 1, p = 0.60). The Cox proportional hazard ratio for ramelteon compared to placebo was 1.40 (95% confidence interval: 0.40-4.85, χ2 for likelihood ratio test = 0.29, degrees of freedom = 1, p = 0.60). CONCLUSION: There was no significant difference in the incidence of postoperative delirium between ramelteon and placebo after general anesthesia in elderly patients.

Nephron Number and Time to Remission in Steroid-Sensitive Minimal Change Disease.

RATIONALE & OBJECTIVE: The response to corticosteroid therapy may differ among patients with minimal change disease (MCD). Previous studies have suggested that glomerular hypertrophy or low areal glomerular density in biopsy specimens, which may be related to fewer nephrons, is associated with such a difference. We examined the associations between nephron number and the therapeutic response to corticosteroids in patients with MCD. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 75 adult patients with a histologic diagnosis of MCD. EXPOSURE: Nephron number per kidney estimated based on the combination of unenhanced computed tomography and nonsclerotic volumetric glomerular density in kidney biopsy specimens. OUTCOMES: Complete remission and relapse following corticosteroid therapy. ANALYTICAL APPROACH: Multivariable Cox proportional hazard analyses of associations between factors, including nephron number, and outcomes. RESULTS: Mean age of patients was 45.9 years and 60.0% were men. Patients had an estimated glomerular filtration rate of 64.6 mL/min/1.73 m2 and proteinuria of 8.7 g/d. The estimated total number of nonsclerotic glomeruli ranged from 1.07 to 18.77 ×105 per kidney among all patients. There were no significant differences in total amounts or selectivity of urinary protein excretion at biopsy among the tertile groups categorized by nephron number. All patients responded to corticosteroid therapy, but those with fewer nephrons had a delayed achievement of complete remission. Multivariable Cox proportional hazard analyses identified nephron number as a significant independent explanatory variable for the achievement of complete remission, with a hazard ratio of 1.10 (95% CI, 1.02-1.19)/100,000 nephrons per kidney. Nephron number in these patients was not associated with achievement of partial remission or relapse following complete remission. LIMITATION: Retrospective design and sampling bias of needle biopsy. CONCLUSIONS: A small nephron number in patients with MCD is associated with longer time to complete remission.

Kidney Disease Associated With Anorexia Nervosa: A Case Series With Kidney Biopsies.

RATIONALE & OBJECTIVE: Anorexia nervosa is often intractable and induces various physical disorders, including kidney disease and mineral disorders, occasionally progressing to kidney failure. No consensus-based clinical practice guidelines have been established for patients with anorexia nervosa referred to a nephrologist. STUDY DESIGN: Patients with anorexia nervosa-associated kidney disease diagnosed were analyzed retrospectively. Kidney outcomes were defined as doubling of serum creatinine level and/or progression to end-stage kidney disease. SETTING & PARTICIPANTS: Patients with a history of anorexia nervosa with kidney disease, including electrolyte abnormalities, who were referred to our hospital between 1992 and 2017 were included. RESULTS: 14 female patients were included. The time from anorexia nervosa onset to the initial visit with a nephrologist was 17.8 years. At the first visit, median body mass index was 13.4 kg/m2, median serum creatinine level was 1.9 mg/dL, and median serum potassium level was 2.7 mmol/L. All patients showed hypokalemia and addictive vomiting or diuretic/laxative abuse. During the median observation period of 3.1 years, kidney outcomes occurred in 9 patients, and 2 died due to their anorexia nervosa. 4 patients underwent kidney biopsy. The kidney biopsy findings of these patients included hypertrophy of the juxtaglomerular apparatus, advanced glomerular collapse, and interstitial fibrosis, consistent with ischemic kidney injury and hypokalemic nephropathy. LIMITATIONS: The sample size was small, and kidney function was assessed based on serum creatinine levels in patients with anorexia nervosa with low muscle mass. CONCLUSIONS: Most patients with anorexia nervosa referred to nephrologists had kidney disease at the time of the first visit. Improving kidney outcomes of patients with anorexia nervosa may require earlier collaboration between psychiatrists and nephrologists.

Time-averaged proteinuria during follow-up and renal prognosis in patients with biopsy-proven benign nephrosclerosis.

BACKGROUND: Heavy proteinuria at diagnostic renal biopsy has been reported as an independent risk factor for deteriorating renal function in benign nephrosclerosis (BNS). However, studies investigating the relationship between the amount of proteinuria during follow-up and long-term renal prognosis in BNS are limited. This study aimed to assess the relationship between time-averaged proteinuria (TAP) and renal prognosis in BNS. METHODS: The study participants included 98 patients with biopsy-proven BNS (average age 52 ± 13 years, estimated glomerular filtration rate (eGFR) 53 ± 25 ml/min/1.73 m2, urine protein excretion at baseline 1.34 ± 1.30 g/gCr) from the Jikei University Hospital. Multivariate analysis was used to investigate the effects of TAP and other clinicopathological findings on the risk for renal outcome in biopsy-proven BNS (a 30% decline in eGFR from baseline or end-stage renal disease). Proteinuria was measured every 6 months and the mean value was used as an indicator of TAP. RESULTS: The average observation period was 56 ± 43 months. In the unadjusted model, higher levels of TAP and urinary protein at baseline, glomerulosclerosis, and tubulointerstitial damage were associated with renal prognosis. The adjusted model demonstrated a significant association between TAP and renal outcomes (hazard ratio 5.45, 95% confidence interval 3.02-10.7), which was independent of higher baseline proteinuria, glomerulosclerosis, and tubulointerstitial damage. CONCLUSIONS: TAP is an independent risk factor for renal prognosis in patients with BNS, indicating the significance of urinary protein excretion during follow-up for the progression of BNS. Clinicians should understand the importance of follow-up evaluation for proteinuria in patients with BNS.

Remission of proteinuria under therapeutic intervention and the renal outcomes in Japanese patients with lupus nephritis class III and IV.

AbstractsBackground: Recent studies have identified the significance of proteinuria levels after initial induction therapies on the renal outcomes in patients with proliferative lupus nephritis, but the issue has not been evaluated in Japanese patients.Methods: Based on the ISN/RPS classification, only patients diagnosed with lupus nephritis class III or IV were included. The remission of proteinuria 12 months after diagnosis, as well as the clinicopathological features at diagnosis, on renal outcomes was examined retrospectively. Renal progression was defined as a 50% decrease in the estimated glomerular filtration rate or the development of end-stage renal disease.Results: This study included 82 Japanese patients with a median follow-up period of seven years. Although all patients received intensive induction therapy, 15 patients (18%) showed progression. Proteinuric remission 12 months after diagnosis predicted a good renal outcome by multivariate analysis. A receiver-operating characteristic analysis of 38 patients whose quantitative urinary protein excretion levels at 12 months were available for analysis showed that a cut-off value of 0.8 g/day predicted renal progression most effectively. Neither the renal function nor proteinuria level at diagnosis were associated with the renal outcomes.Conclusion: In Japanese patients with lupus nephritis class III or IV, proteinuria levels after 12 months under intensive therapy predicted renal outcomes more accurately than did factors identified at diagnosis.

Anesthesia for a long-term anorexic patient with end-stage liver cirrhosis†:†A Case Report.

Recent advancements in intensive care have increased the number of severe anorexia nervosa patients presenting for surgery. We provided anesthesia to a patient who had a 22-year history of anorexia with life-threatening cirrhosis. Although surgery should be avoided in patients with end-stage cirrhosis, she was in the best preoperative optimized condition compared to her condition over the past few years. Potential complications are heart failure easily caused by deterioration of cirrhosis, lethal arrhythmias related to electrolyte disturbances and increased myocardial sensitivity to drugs, and refeeding syndrome in the postoperative period. The several rare events that we experienced are worth reporting. J. Med. Invest. 66 : 337-339, August, 2019.

Spot urine protein/creatinine ratio as a reliable estimate of 24-hour proteinuria in patients with immunoglobulin A nephropathy, but not membranous nephropathy.

BACKGROUND: Proteinuria is known to be associated with both kidney function deterioration and cardiovascular diseases. While proteinuria estimation from 24-h urine samples has traditionally been considered as the standard method for assessment of the degree of urinary protein excretion, sample collection is associated with several technical problems such as inaccurate collection and the potential spread of drug-resistant pathogens. Therefore, the spot urine protein/creatinine ratio (PCR) assessment is currently recommended as an alternative. While the utility of PCR has been validated, studies on the association between spot urine PCR and 24-h proteinuria (24HP) in patients with chronic glomerular nephritis (CGN) and nephrotic syndrome (NS) are limited. This study aimed to evaluate whether an estimated result from a spot urine PCR could sufficiently approximate the daily urine protein excretion amount from a 24-h urine sample in patients with immunoglobulin A nephropathy (IgAN), minimal change disease (MCD), and membranous nephropathy- nephrotic syndrome (MN-NS). METHODS: The study participants included 161 patients with IgAN, MCD, or MGN-NS at the Jikei University Kashiwa Hospital and Kanagawa Prefecture Shiomidai Hospital. The correlation between spot urine PCR and a 24-h urine protein was investigated using linear regression analysis with Spearman's correlation (r) coefficient and intraclass correlation coefficient (ICC). RESULTS: While high correlation coefficients (r = 0.86, P < 0.001) and substantial agreement (ICC: 0.806, P < 0.001) were observed in patients with IgAN, similar correlations were not observed in patients with MCD or MN-NS. In the patients with MCD, r was 0.53 (P < 0.001), which signified a slight correlation, and in the patients with MN-NS, r was 0.289 (P = 0.17), which was not statistically significant. CONCLUSIONS: This study revealed that spot urine PCR is a reliable estimate of 24HP value in patients with IgAN. In contrast, there is a considerable difference between the daily urine protein excretion amount based on a 24-h urine sample and that which is calculated from spot urine PCR in patients with NS.

Biopsy-based estimation of total nephron number in Japanese living kidney donors.

BACKGROUND: Increasing evidence suggests that individuals with low nephron number have an increased lifetime risk of renal insufficiency, thereby emphasizing the importance of evaluating total nephron number in each individual. In recent years, new methods have been described for estimating human total nephron number using a combination of image analysis and renal biopsy, though the reproducibility and accuracy of these methods remain uncertain. This study estimated total nephron number in healthy Japanese subjects using such a method. METHODS: Implantation biopsies from 44 living kidney donors were analyzed. Using pre-donation contrast CT angiograms, transplantation donor kidneys were three-dimensionally reconstructed, and total renal cortical volume was estimated. Total nephron number was estimated based on glomerular density in biopsy specimens and total renal cortical volume. The obtained results were analyzed in relation to clinical variables and compared with those of a previously reported Japanese autopsy study. RESULTS: The estimated non-sclerotic and total numbers of glomeruli in this cohort were 650,000 ± 220,000 and 710,000 ± 220,000 (mean ± SD) per kidney. Non-sclerotic glomerular number ranged from 280,000 to 1,220,000 per kidney (4.4-fold) and correlated directly with eGFR (r = 0.328, p = 0.030) and inversely with age (r = - 0.355, p = 0.018). CONCLUSION: The estimated total nephron number obtained in the present study was 25% less than that reported in American living kidney donors obtained using the same procedure and similar to that obtained in a previous Japanese autopsy study using the disector/fractionator method. These results confirm the feasibility of a combined CT angiography and biopsy-based method to estimate total nephron number in humans.

Clinical and Pathological Characteristics of Elderly Japanese Patients with IgA Vasculitis with Nephritis: A Case Series.

Objective This case series aimed to identify the clinical and pathological characteristics of elderly patients (≥60 years) with biopsy-proven IgA vasculitis with nephritis (IgAVN). Methods The clinical and pathological presentation and treatment outcomes were compared between two groups. Patients Patients with IgAVN who were ≥19 years old at the time of their renal biopsy were divided into elderly (≥60 years) and adult (19-59 years) groups. Results Of the 23 patients in our study, 13 were elderly. In the elderly group, the median age at the diagnosis was 68 years (range, 60-85 years), with a median follow-up period of 15 months (range, 3-80 months). Twelve elderly patients had comorbidities, including hypertension, diabetes mellitus, chronic kidney disease, cardiovascular disease, and malignancies. A decrease in the estimated glomerular filtration rate, as well as massive proteinuria and rapidly progressive nephritic syndrome, were more frequent in the elderly group than in the adult group. Furthermore, renal pathological changes, including cellular or fibrocellular crescents, interstitial fibrosis, tubular atrophy, and arteriosclerosis, were more severe among elderly patients than adult patients. All elderly patients were treated with glucocorticoids and had no incidence of end-stage renal disease at the final follow-up; in addition, nine elderly patients had reduced proteinuria with a preserved renal function. Adverse events, including infection, diabetes mellitus, and vascular disorders, were identified in nine patients. Three elderly patients died from severe infections. Conclusion IgAVN in elderly patients is characterized by severe renal involvement. Elderly patients are at higher risk than adults for treatment-related adverse events.

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.

A grading system that predicts the risk of dialysis induction in IgA nephropathy patients based on the combination of the clinical and histological severity.

Histological classification is essential in the clinical management of immunoglobulin A nephropathy (IgAN). However, there are limitations in predicting the prognosis of IgAN based on histological information alone, which suggests the need for better prognostic models. Therefore, we defined a prognostic model by combining the grade of clinical severity with the histological grading system by the following processes. We included 270 patients and explored the clinical variables associated with progression to end-stage renal disease (ESRD). Then, we created a predictive clinical grading system and defined the risk grades for dialysis induction by a combination of the clinical grade (CG) and the histological grade (HG). A logistic regression analysis revealed that the 24-h urinary protein excretion (UPE) and the estimated glomerular filtration rate (eGFR) were significant independent variables. We selected UPE of 0.5 g/day and eGFR of 60 ml/min/1.73 m2 as the threshold values for the classification of CG. The risk of progression to ESRD of patients with CG II and III was significantly higher than that of patients with CG I. The patients were then re-classified into nine compartments based on the combination of CG and HG. Furthermore, the nine compartments were grouped into four risk groups. The risk of ESRD in the moderate, high, and super-high-risk groups was significantly higher than that in the low-risk group. Herein, we are giving a detailed description of our grading system for IgA nephropathy that predicted the risk of dialysis based on the combination of CG and HG.

Distribution of nephrologists and regional variation in the clinical severity of IgA nephropathy at biopsy diagnosis in Japan: a cross-sectional study.

OBJECTIVES: The clinical severity of IgA nephropathy (IgAN) at the time of biopsy diagnosis differs significantly among cases. One possible determinant of any such difference is the time taken for referral from the primary care physician to a nephrologist, but the definitive cause remains unclear. This study examined the contribution of the number of nephrologists per regional population as a potential social factor influencing the clinical severity at diagnosis among patients with IgAN in Japan, which has an ethnically homogeneous population. DESIGN: A cross-sectional study. SETTING AND PARTICIPANTS: Patients were registered in the Japan Renal Biopsy Registry (J-RBR), a nationwide multicentre registry, and 6426 patients diagnosed with IgAN were analysed. The facilities registered to the J-RBR were divided into 10 regions and the clinical features of IgAN at biopsy diagnosis, including renal function and level of proteinuria, were examined. MAIN OUTCOME MEASURES: Renal prognosis risk at the time of biopsy diagnosis defined by Kidney Disease Improving Global Outcomes guideline 2012. RESULTS: Among the regions, there were significant differences in the estimated glomerular filtration rate (67.5-91.4 mL/min/1.73 m2), urinary protein excretion rate (0.93-1.93 g/day) and renal prognosis risk group distribution at diagnosis. The severity of all clinical parameters was inversely correlated with the number of nephrologists per regional population, which showed an up to 2.7-fold difference among regions. A generalised linear mixed model revealed that a low number of nephrologists per regional population were significantly associated with fulfilment of clinical criteria indicating a very-high-risk renal prognosis (ß=-0.484, 95% CI -0.959 to -0.010). CONCLUSIONS: Among Japanese patients with IgAN, significant regional differences were detected in clinical severity at the time of diagnosis. Social factors, such as an uneven distribution of nephrologists across regions, may influence the timing of biopsy and determine such differences.

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.

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.

A case of infection-related glomerulonephritis with massive eosinophilic infiltration
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Infection-related glomerulonephritis (IRGN) is rarely complicated with eosinophil infiltration into the glomerulus. Here we report a case of eosinophilic proliferative glomerulonephritis related with infection. A 70-year-old man with respiratory symptoms displayed hypereosinophilia, hypocomplementemia, impaired renal function, and nephrotic syndrome. Renal biopsy revealed endocapillary proliferative glomerulonephritis with immunostaining for immunoglobulin G and complement 3, and subepithelial hump-like electron-dense deposits, thus fulfilling the criteria for IRGN. Immunostaining for the nephritis-associated plasmin receptor (NAPlr) in the glomerulus confirmed the diagnosis of IRGN. Of note, eosinophils infiltrated into the glomerular subendothelial spaces, renal tubules, peritubular capillaries, and the interstitium in the kidney as well as in the alveolar walls and pulmonary arteries in the lung. Corticosteroid therapy rapidly improved hypereosinophilia as well as respiratory symptoms and renal function. Urinary protein exertion was decreased, and serum level of complement and albumin was increased. These findings suggest that eosinophil infiltration might play a prominent role in respiratory and renal disorders. Severe endothelial damage of glomeruli and tubulointerstitial nephritis, caused by eosinophil-rich inflammation, might significantly contribute to exacerbation of renal insufficiency.
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Measurement of daily sodium excretion in patients with chronic kidney disease; special reference to the difference between the amount measured from 24 h collected urine sample and the estimated amount from a spot urine.

It is important to grasp a patient's daily sodium intake in the management of chronic kidney disease, as sodium intake is widely recommended at 6 g/day or less. There are multiple equations widely known for estimating the daily sodium excretion from a spot urine sample, but these are aimed at healthy people. There are few reports that validate equations in patients with chronic kidney disease. The purpose of this study is to evaluate whether the amount of measured daily sodium excretion from a sample collected for 24-h urine (24HU) is equal to that of using an equation from a spot urine sample (SU) in patients with chronic kidney disease. One hundred sixty-two patients with chronic kidney disease from Kanagawa Prefecture Shiomidai Hospital, Japan and the Jikei University Kashiwa Hospital, Japan participated in the study. Daily sodium excretion was measured from 24HU and compared with it from SU by using the formula according to Tanaka et al. Sodium excretion by 24HU was 2744 mg/day and estimating daily sodium excretion from SU was 3315 mg/day. The coefficient of determination was 0.17 (p < .001) in multivariate regression analysis. The coefficient of determination was extremely low. Thus, there is a considerable difference between the amount of sodium excretion calculated from a 24HU and that from a SU in patients with chronic kidney disease.

Forced expression of vascular endothelial growth factor-A in podocytes decreases mesangial cell numbers and attenuates endothelial cell differentiation in the mouse glomerulus.

BACKGROUND: Glomerular podocyte-derived vascular endothelial growth factor (VEGF) is indispensable for the migration and proliferation of glomerular endothelial cells. In contrast, podocyte-specific Vegf overexpression leads to the collapse of glomerular tufts; however, the mechanisms underlying this outcome have not yet been reported. METHODS: To further clarify the effects of elevated levels of Vegf expression on glomerular cells, we established a dual transgenic mouse line in which Vegf was exclusively and inducibly expressed in podocytes under the control of the "Tet-on system" (Podocin-rtTA/TetO-Vegf164 mice). RESULTS: Macroscopic and microscopic examination of Podocin-rtTA/TetO-Vegf164 animals following Vegf induction identified the presence of prominent red bloody spots. In addition, the endothelial cell number was increased along with enlargement of the subendothelial spaces. We also observed impaired endothelial fenestrations and aberrant plasmalemmal vesicle-associated protein-1 (PV-1) expression. In contrast, the mesangial cell number markedly decreased, resulting in a glomerular tuft intussusceptive splitting defect. Furthermore, whereas platelet-derived growth factor-B (PDGF-B) expression in the glomerular cells of Podocin-rtTA/TetO-Vegf164 mice was not decreased, phospho-PDGF receptor immunoreactivity in the mesangial cells was significantly decreased when compared to wild-type animals. CONCLUSION: Taken together, the results of this study indicated that the upregulation of podocyte VEGF decreased the number of mesangial cells, likely owing to inhibition of PDGF-B-mediated signaling.

Circadian blood pressure abnormalities in patients with primary nephrotic syndrome.

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.

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.