Podocyte density as a predictor of long-term kidney outcome in obesity-related glomerulopathy.

Glomerulomegaly and focal segmental glomerulosclerosis are histopathological hallmarks of obesity-related glomerulopathy (ORG). Podocyte injury and subsequent depletion are regarded as key processes in the development of these glomerular lesions in patients with ORG, but their impact on long-term kidney outcome is undetermined. Here, we correlated clinicopathological findings and podocyte depletion retrospectively in patients with ORG. Relative (podocyte density) and absolute (podocyte number per glomerulus) measures of podocyte depletion were estimated using model-based stereology in 46 patients with ORG. The combined endpoint of kidney outcomes was defined as a 30% decline in estimated glomerular filtration rate (eGFR) or kidney failure. Patients with lower podocyte density were predominantly male and had larger body surface area, greater proteinuria, fewer non-sclerotic glomeruli, larger glomeruli and higher single-nephron eGFR. During a median follow-up of 4.1 years, 18 (39%) patients reached endpoint. Kidney survival in patients with lower podocyte density was significantly worse than in patients with higher podocyte density. However, there was no difference in kidney survival between patient groups based on podocyte number per glomerulus. Cox hazard analysis showed that podocyte density, but not podocyte number per glomerulus, was associated with the kidney outcomes after adjustment for clinicopathological confounders. Thus, our study demonstrates that a relative depletion of podocytes better predicts long-term kidney outcomes than does absolute depletion of podocytes. Hence, the findings implicate mismatch between glomerular enlargement and podocyte number as a crucial determinant of disease progression in ORG.

Estimating baseline creatinine levels based on the kidney parenchymal volume.

BACKGROUND: Acute kidney injury (AKI) diagnosis often lacks a baseline serum creatinine (Cr) value. Our study aimed to create a regression equation linking kidney morphology to function in kidney donors and chronic kidney disease patients. We also sought to estimate baseline Cr in minimal change disease (MCD) patients, a common AKI-predisposing condition. METHODS: We analyzed 119 participants (mean age 60 years, 50% male, 40% donors) with CT scans, dividing them into derivation and validation groups. An equation based on kidney parenchymal volume (PV) was developed in the derivation group and validated in the validation group. We estimated baseline Cr in 43 MCD patients (mean age 45 years, 61% male) using the PV-based equation and compared with their 6 month post-MCD onset Cr values. RESULTS: In the derivation group, the equation for the estimated glomerular filtration rate (eGFR) was: eGFR (mL/min/1.73m2) = 0.375 × PV (cm3) + (- 0.395) × age (years) + (- 2.93) × male sex + (- 13.3) × hypertension + (- 14.0) × diabetes + (- 0.210) × height (cm) + 82.0 (intercept). In the validation group, the eGFR and estimated Cr values correlated well with the measured values (r = 0.46, p = 0.01; r = 0.51, p = 0.004, respectively). In the MCD group, the baseline Cr values were significantly correlated with the estimated baseline Cr values (r = 0.52, p < 0.001), effectively diagnosing AKI (kappa = 0.76, p < 0.001). CONCLUSIONS: The PV-based regression equation established in this study holds promise for estimating baseline Cr values and diagnosing AKI in patients with MCD. Further validation in diverse AKI populations is warranted.

Clinical characteristics of secondary bladder cancer developing after low-/high-dose-rate brachytherapy to treat localized prostate cancer.

BACKGROUND: To explore correlations between the clinical attributes of secondary bladder cancer and brachytherapy, we retrospectively reviewed our institutional database on patients with localized prostate cancer who underwent low-dose-rate brachytherapy (LDR-BT) or high-dose-rate brachytherapy (HDR-BT) with or without external beam radiation therapy (EBRT) or radical prostatectomy (RP). METHODS: From October 2003 to December 2014, 2551 patients with localized prostate cancer were treated at our institution. Of these, data on 2163 were available (LDR-BT alone: n = 953; LDR-TB with EBRT: n = 181; HDR-BT with EBRT: n = 283; RP without EBRT: n = 746). The times of secondary bladder cancer development subsequent to radical treatment, and their clinical characteristics, were studied. RESULTS: Age-adjusted Cox's regression analyses indicated that brachytherapy did not significantly impact the incidence of secondary bladder cancer. However, the pathological characteristics of such cancer differed between patients treated via brachytherapy and RP without EBRT; invasive bladder cancer was more common in such patients. CONCLUSION: The risk for secondary bladder cancer was not significantly increased after brachytherapy compared to non-irradiation therapy. However, brachytherapy patients exhibited a higher incidence of invasive bladder cancer. Therefore, meticulous follow-up is crucial for early detection and treatment of bladder cancer in such patients.

Associations between nephron number and podometrics in human kidneys.

Podocyte loss and resultant nephron loss are common processes in the development of glomerulosclerosis and chronic kidney disease. While the cortical distribution of glomerulosclerosis is known to be non-uniform, the relationship between the numbers of non-sclerotic glomeruli (NSG), podometrics and zonal differences in podometrics remain incompletely understood. To help define this, we studied autopsy kidneys from 50 adults with median age 68 years and median eGFR 73.5 mL/min/1.73m2 without apparent glomerular disease in a cross-sectional analysis. The number of NSG per kidney was estimated using the physical dissector/fractionator combination, while podometrics were estimated using model-based stereology. The number of NSG per kidney was directly correlated with podocyte number per tuft and podocyte density. Each additional 100,000 NSG per kidney was associated with 26 more podocytes per glomerulus and 16 podocytes per 106 µm3 increase in podocyte density. These associations were independent of clinical factors and cortical zone. While podocyte number per glomerulus was similar in the three zones, superficial glomeruli were the smallest and had the highest podocyte density but smallest podocytes. Increasing age and hypertension were associated with lower podocyte number, with age mostly affecting superficial glomeruli, and hypertension mostly affecting juxtamedullary glomeruli. Thus, in this first study to report a direct correlation between the number of NSG and podometrics, we suggest that podocyte number is decreasing in NSG of individuals losing nephrons. However, another possible interpretation may be that more nephrons might protect against further podocyte loss.

Tubulointerstitial nephritis: a biopsy case series of 139 Japanese patients.

BACKGROUND: Tubulointerstitial nephritis (TIN) is an important cause of acute kidney injury (AKI) and advanced CKD. Only a limited number of studies have reported etiology-based differences in the clinical and/or histopathological properties and kidney outcomes of the biopsy-proven TIN. METHODS: Patients with biopsy-proven TIN identified from 2005 to 2016 in five hospitals were categorized based on the etiologies and were retrospectively analyzed in relation to the clinicopathological findings and kidney outcomes. RESULTS: Among 4815 biopsy cases screened, 153 Japanese TIN patients were identified, of whom 139 patients with ≥ 6 months of follow-up data (median 58 years old, 45.3% female, median 31.5 months follow-up) were further analyzed. TIN was drug-induced in 32.4%, autoimmune-related in 24.5%, of unknown etiology in 27.3% and other disease-related in 15.8%. Non-steroidal anti-inflammatory drugs and antibiotics were major causative drugs in drug-induced TIN, and IgG4-related disease, Sjögren's syndrome and sarcoidosis were common in autoimmune-related TIN. Among etiology groups, drug-induced TIN showed advanced AKI with elevated serum creatinine (sCr) and increased C-reactive protein levels at the diagnosis. TIN patients with autoimmune diseases showed less-severe AKI, but were more frequently treated with corticosteroids than others. Tubulointerstitial injury expansion in biopsy specimens was comparable among the groups. Complete or partial kidney function recovery at 6 months was more frequent in drug-induced and autoimmune-related TIN than in others. sCr levels at 6 months were similar among the groups. CONCLUSIONS: This largest case series study of the biopsy-proven TIN in Japan provides detailed information regarding both etiology-based clinicopathological properties and kidney outcomes.

Podometrics in Japanese Living Donor Kidneys: Associations with Nephron Number, Age, and Hypertension.

BACKGROUND: Podocyte depletion, low nephron number, aging, and hypertension are associated with glomerulosclerosis and CKD. However, the relationship between podometrics and nephron number has not previously been examined. METHODS: To investigate podometrics and nephron number in healthy Japanese individuals, a population characterized by a relatively low nephron number, we immunostained single paraffin sections from 30 Japanese living-kidney donors (median age, 57 years) with podocyte-specific markers and analyzed images obtained with confocal microscopy. We used model-based stereology to estimate podometrics, and a combined enhanced-computed tomography/biopsy-specimen stereology method to estimate nephron number. RESULTS: The median number of nonsclerotic nephrons per kidney was 659,000 (interquartile range [IQR], 564,000-825,000). The median podocyte number and podocyte density were 518 (IQR, 428-601) per tuft and 219 (IQR, 180-253) per 106µm3, respectively; these values are similar to those previously reported for other races. Total podocyte number per kidney (obtained by multiplying the individual number of nonsclerotic glomeruli by podocyte number per glomerulus) was 376 million (IQR, 259-449 million) and ranged 7.4-fold between donors. On average, these healthy kidneys lost 5.63 million podocytes per kidney per year, with most of this loss associated with glomerular loss resulting from global glomerulosclerosis, rather than podocyte loss from healthy glomeruli. Hypertension was associated with lower podocyte density and larger podocyte volume, independent of age. CONCLUSIONS: Estimation of the number of nephrons, podocytes, and other podometric parameters in individual kidneys provides new insights into the relationships between these parameters, age, and hypertension in the kidney. This approach might be of considerable value in evaluating the kidney in health and disease.

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.

Elite Male Lacrosse Players' Match Activity Profile.

Match demands in international men's lacrosse have yet to be explored. Therefore, this investigation quantified positional match demands of international men's lacrosse. This study quantified activity profiles of 50 lacrosse players [attack (AT): 11, midfield (MD): 22, defense (DF): 17] on Japan's national team, using a global positioning system (GPS), players' acceleration, and a heart rate (HR) apparatus to investigate their movement and physiological load. The study revealed that in thirteen international matches, distance, walk distance, jog distance, low-intensity acceleration, and low-intensity deceleration for the AT and DF groups was significantly greater than for the MD group, but the MD group's average speed and sprint distance were the highest. Multiple comparison tests showed that measurements for the AT and DF groups were significantly greater than the MD group for distance, low-intensity acceleration, medium-intensity decelerations, and low-intensity deceleration. This data can become the physical data for helping coaches with strength and conditioning training at the international level. For MD players, anaerobic power and load condition (long rest, high intensity) should be emphasized. In addition, coaches can decide on tactics and a running-quantity target for the next game by acquiring continuous activity data.

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.

Fractional excretion of total protein predicts renal prognosis in Japanese patients with primary membranous nephropathy.

Background: Primary membranous nephropathy (pMN) is one of the most common types of glomerulonephritis, with a third of patients progressing to renal insufficiency. Various prognostic factors have been reported, of which urinary protein and renal function are the most critical parameters. Fractional excretion of total protein (FETP) indicates protein leakage that accounts for creatinine kinetics and serum protein levels. In this study, we investigated the association between FETP and renal prognosis in pMN. Methods: We retrospectively identified 150 patients with pMN. FETP was calculated as follows: (serum creatinine × urine protein)/(serum protein × urine creatinine) %. We divided the patients into three groups according to FETP values and compared the clinicopathological findings. The primary outcome was an estimated glomerular filtration rate (eGFR) decrease of ≥30% from the baseline level. Results: FETP was associated with urinary protein and renal function, Ehrenreich and Churg stage, and global glomerulosclerosis. The primary outcome was observed in 38 patients (25.3%), and the frequency of the primary outcome was higher in the high FETP group (P = .001). FETP is higher than protein-creatinine ratio (PCR) in the area under the curve. In the multivariate analysis adjusted for age, eGFR, PCR and treatment, FETP was significantly associated with primary outcome (adjusted hazard ratio, 8.19; P = .019). Conclusions: FETP is a valuable indicator that can reflect the pathophysiology and is more useful than PCR as a predictor of renal prognosis in patients with Japanese pMN.

Does age impact clinical outcomes of radical nephroureterectomy in the elderly?-results from a multicenter retrospective study.

Background: Few studies have addressed the efficacy of nephroureterectomy for managing upper tract urothelial carcinoma (UTUC) in very elderly patients (those aged 85 years and older). We aimed to elucidate the association between age and clinical outcomes in patients with UTUC who underwent radical nephroureterectomy. Methods: We retrospectively analyzed data from 847 patients who underwent nephroureterectomy for UTUC. These patients were classified into four age brackets: young (≤64 years, n=177), intermediate (65-74 years, n=300), elderly (75-84 years, n=312), and very elderly (≥85 years, n=58). We applied logistic regression models to ascertain predictors of postoperative complications. Cox's proportional hazards models were used to evaluate key prognostic factors affecting non-urothelial tract recurrence-free survival (NUTRFS), cancer-specific survival (CSS), and overall survival (OS). Results: In all, 56 patients reported postoperative complications. An Eastern Cooperative Oncology Group performance status ≥2 was identified as a significant predictor for postoperative complications whereas age did not show a noteworthy correlation. Kaplan-Meier survival analyses indicated that very elderly patients had notably poorer OS than younger groups. Nevertheless, the differences in NUTRFS and CSS across the age brackets were not statistically significant. In multivariable analyses, very elderly age was a substantial independent determinant of OS but not NUTRFS or CSS. Conclusions: The therapeutic benefits of surgical procedures are relatively consistent across age groups. This underscores the potential of considering surgical treatment for UTUC in patients aged 85 and above, provided they are deemed fit to withstand the surgical rigors and associated invasiveness.

Perioperative renal function change and oncological outcomes of radical nephroureterectomy in patients with upper tract urothelial carcinoma: A multicenter retrospective study.

BACKGROUND: The effect of radical nephroureterectomy (RNUx) on postoperative renal function in patients diagnosed with upper tract urothelial carcinoma (UTUC) has not been thoroughly explored. METHODS: We conducted a retrospective analysis including 785 patients who underwent RNUx for UTUC. We assessed the preoperative and postoperative estimated glomerular filtration rates (eGFRs) and factors related to the decline in eGFR. Additionally, we examined the effect of comorbidities (diabetes or hypertension) on the postoperative eGFR at 1 year. Cox proportional hazard models were employed to investigate the clinical effect of RNUx on oncological outcomes, including non-urothelial tract recurrence-free survival (NUTRFS), cancer-specific survival (CSS), and overall survival (OS). RESULTS: The median preoperative and postoperative eGFR levels were 54.7 and 40.6 ml/min/1.73 m2 respectively. The proportions of patients with preoperative and postoperative eGFR ≥60 mL/min/1.73 m2 were 35.9% and 5.1%, respectively. The median decline in the eGFR after surgery was 26.8%. Patients with preoperative eGFR <60 ml/min/1.73 m2 demonstrated significantly lower odds of a postoperative decline in eGFR of 25% or more. The effect of comorbidities on postoperative eGFR at 1 year was significant (P = 0.048). The 3-year NUTRFS, CSS, and OS rates were 72.9%, 85.2%, and 81.5%, respectively. Preoperative chronic kidney disease was an independent factor associated with inferior NUTRFS, CSS, and OS. CONCLUSION: Different degrees of impairment of renal function occur among UTUC patients. Only 5.1% of patients retain a postoperative eGFR ≥60 ml/min/1.73 m2. Preoperative renal impairment was linked to reduced odds of postoperative eGFR decrease and associated with survival. In addition, the presence of comorbidities had a significant effect on the decline in eGFR. These findings emphasize the importance of developing evidence-based perioperative treatment strategies for UTUC patients with impaired renal function.

Non-dipping pulse rate and chronic changes of the kidney in patients with chronic kidney disease.

Introduction: An insufficient decrease in nocturnal pulse rate (PR), non-dipping PR, reflects autonomic imbalance and is associated with cardiovascular events and all-cause mortality. We aimed to investigate the clinical and microanatomical structural findings associated with the non-dipping PR status in patients with chronic kidney disease (CKD). Methods: This cross-sectional study included 135 patients who underwent ambulatory blood pressure monitoring and kidney biopsy concurrently at our institution between 2016 and 2019. Non-dipping PR status was defined as (daytime PR-nighttime PR)/daytime PR <0.1. We compared clinical parameters and microstructural changes in the kidney between patients with and without non-dipping PR, including 24 h proteinuria, glomerular volume, and Mayo Clinic/Renal Pathology Society Chronicity Score. Results: The median age was 51 years (interquartile range: 35-63), 54% of which were male, and the median estimated glomerular filtration rate was 53.0 (30.0-75.0) mL/min/1.73 m2. Non-dipping PR status was observed in 39 patients. Patients with non-dipping PR were older and had worse kidney function, higher blood pressure, greater prevalence of dyslipidemia, lower hemoglobin levels, and a larger amount of urinary protein excretion than patients with dipping PR. Patients with non-dipping PR had more severe glomerulosclerosis, interstitial fibrosis, tubular atrophy, and arteriosclerosis. In the multivariable analysis, the severe chronic changes of the kidney were associated with non-dipping PR status after adjusting for age, sex, and other clinical parameters (odds ratio = 20.8; 95% confidence interval, 2.82-153; P = 0.003). Conclusion: This study is the first to indicate that non-dipping PR is significantly associated with chronic microanatomical changes in the kidneys of patients with CKD.

Effect of Adequate Local Radiation Dose on Oncological Outcomes in Localized Prostate Cancer Patients Treated With Low-dose-rate Brachytherapy.

BACKGROUND/AIM: We retrospectively investigated the effect of a biologically effective dose (BED) of Low-dose rate brachytherapy (LDR-BT) and its possible interaction with androgen deprivation therapy (ADT) during LDR-BT treatment for intermediate-risk prostate cancer (PCa). PATIENTS AND METHODS: A total of 693 patients with localized, intermediate-risk PCa, who underwent LDR-BT with or without supplemental external beam radiotherapy, were included in this study. We stratified patients into two groups according to BED (<180 Gy2, lower BED group; ≥180 Gy2, higher BED group) and evaluated the effect of ADT duration on the oncological outcomes of each group. RESULTS: In total, 431 patients received BED ≥180 Gy2. Significant differences in biochemical recurrence-free survival (BCRFS) and clinical progression-free survival (CPFS) were observed among the non-ADT, ADT ≤3 months, and ADT >3 months subgroups of the lower BED group (p=0.005 and 0.049, respectively). However, no significant differences in BCRFS or CPFS were detected in the higher BED group (p=0.63 and 0.76, respectively). Multivariate analysis of BCR and CP in the lower BED group revealed a significant decreasing trend in the BCRFS (p for trend=0.001) and CPFS rates (p for trend=0.015) as ADT duration increased, which was associated with favorable outcomes. However, no significant trend was observed in the BCRFS or CPFS rate in the higher BED group. CONCLUSION: An adequate local radiation dose provides favorable oncological outcomes and could potentially reduce the need for long-term ADT.

Active flare of IgA nephropathy during long-term therapy with anti-tumor necrosis factor-α antibody drugs for Crohn's disease: three case reports and literature review.

In recent years, increasing numbers of reports have described new onset or active disease flare of IgA nephropathy (IgAN) during administration of TNF-α inhibitor (TNFi) therapy for chronic inflammatory diseases. Crohn's disease (CD) is the most common indication for TNFi therapy in this clinical setting, but the underlying etiology of IgAN in such patients remains unclear. We report our experience with three patients who developed acute worsening of preexisting urinalysis abnormalities and kidney dysfunction approximately 2 to 6 years after TNFi administration for CD. Kidney biopsies at the time of kidney disease flare revealed IgAN in two patients and IgAN complicated by acute tubulointerstitial nephritis in one patient. The CD and IgAN in all three patients were successfully managed with additional corticosteroid therapy and tonsillectomy without discontinuing TNFi therapy. The clinical course of our patients and similar patients described in the literature suggests that TNFi therapy for CD is associated with a relatively high risk for new onset or disease flare of IgAN. This report discusses the possible involvement of Th1/Th2 imbalance on the immunological background of CD or IgAN.

Day-to-Day Blood Pressure Variability and Risk of Incident Chronic Kidney Disease in a General Japanese Population.

Background Several longitudinal studies have reported that higher visit-to-visit blood pressure variability is associated with greater risk for developing chronic kidney disease. However, no population-based studies have investigated the association between day-to-day home blood pressure variability and incident chronic kidney disease. Methods and Results A total of 2342 Japanese community-dwelling residents aged ≥40 years without chronic kidney disease at baseline were followed up by annual health examinations for 10 years. Home blood pressure was measured 3 times every morning for 28 days. Day-to-day coefficients of variation of home systolic blood pressure levels were categorized into quintiles. Chronic kidney disease was defined as an estimated glomerular filtration rate <60 mL/min per 1.73 m2 or the presence of proteinuria. The hazard ratios for developing chronic kidney disease were estimated with a Cox proportional hazards model. During the follow-up period, 772 participants developed chronic kidney disease. Increased coefficients of variation of home systolic blood pressure were associated significantly with higher risk of chronic kidney disease after adjusting for confounders (P for trend <0.001): Individuals in the highest quintile of coefficients of variation had a 1.50-fold (95% CI, 1.17-1.94) greater risk of developing chronic kidney disease than those in the lowest quintile. The combination of higher coefficients of variation and higher mean value of home systolic blood pressure was associated with the multivariable-adjusted risk of developing chronic kidney disease. Conclusions These findings suggest that increased day-to-day blood pressure variability is a significant risk factor for developing chronic kidney disease in a general Japanese population.