Vesicoureteral Reflux Causes Interstitial Inflammation in Pediatric Kidney Allograft: A Clinicopathological Analysis of 1-Year Protocol Biopsies.

INTRODUCTION: At present, there is limited evidence of the histological impact of vesicoureteral reflux (VUR) on pediatric kidney allografts. In this study, we aimed to investigate the relationship between VUR diagnosed by voiding cystourethrography (VCUG) and 1-year protocol biopsy results. METHODS: One hundred thirty-eight pediatric kidney transplantations were performed in Toho University Omori Medical Center between 2009 and 2019. We included 87 pediatric transplant recipients who were evaluated for VUR by VCUG prior to or at the time of the 1-year protocol biopsy and underwent a 1-year protocol biopsy after transplantation. We evaluated the clinicopathological findings of the VUR and non-VUR groups, and histological scores were evaluated using the Banff score. Tamm-Horsfall protein (THP) within the interstitium was identified by light microscopy. RESULTS: Of the 87 transplant recipients, 18 cases (20.7%) were diagnosed with VUR by VCUG. The clinical background and findings were not significantly different between the VUR and non-VUR groups. The pathological findings revealed a significantly higher Banff total interstitial inflammation (ti) score in the VUR group than in the non-VUR group. Multivariate analysis indicated a significant relationship between the Banff ti score and THP within the interstitium, and VUR. The 3-year protocol biopsy results (n = 68) revealed a significantly higher Banff interstitial fibrosis (ci) score in the VUR group than in the non-VUR group. CONCLUSION: VUR caused interstitial fibrosis in the 1-year pediatric protocol biopsies, and interstitial inflammation at the 1-year protocol biopsy may affect interstitial fibrosis at the 3-year protocol biopsy.

ABO-incompatible pediatric kidney transplantation without antibody removal.

BACKGROUND: Because of the severe shortage of suitable deceased donors, ABO-incompatible living donor kidney transplantation (ABOi LDKT) is performed even in pediatric recipients in Japan. We performed pediatric ABOi LDKT using rituximab without anti-A/B antibody removal. METHODS: Thirteen pediatric recipients (mean age 7.4, range 3.4-15.7, four females) whose baseline anti-A/B IgG titers were ≤ × 64 underwent ABOi LDKT without antibody removal and splenectomy between July 2013 and April 2017 at Toho University. Mycophenolate mofetil (MMF) was initiated on day - 10. Rituximab (100 mg) was administered twice. Basiliximab and triple maintenance immunosuppression (calcineurin inhibitor, MMF, and steroids) were administered. Protocol biopsy was performed at 3 months and 1 year after transplantation. We retrospectively compared the clinical outcomes between these recipients and 37 children (mean age 9.0, range 2.6-18.9, 15 female) who underwent ABO-compatible (ABOc) LDKT during the same period. RESULTS: The mean follow-up periods of ABOi and ABOc groups were 31.9 ± 13.5 and 28.8 ± 14.4 months, respectively. In the ABOi group, no clinical acute rejection (AR) was noted and subclinical AR was observed in four patients without evidence of acute antibody-mediated rejection. In the ABOc group, clinical and subclinical AR developed in 3 and 10 patients, respectively. No significant difference was identified for the mean eGFR between the ABOi and ABOc groups (98.3 ± 48.8 vs. 86.9 ± 39.4, P = 0.452 at 3 months; 78.2 ± 21.2 vs. 79.7 ± 21.3, at 1 year, P = 0.830). Death-censored graft survival at follow-up was 100% in the ABOi group and 94.6% in the ABOc group. Patient survival during the follow-up period in both the groups was 100%. Late-onset neutropenia (LON) requiring granulocyte colony-stimulating factor occurred more frequently in the ABOi group than in the ABOc group (4 vs. 0 patients) (P < 0.001). CONCLUSIONS: Pre- and post-transplantation antibody removal is not a prerequisite for successful pediatric ABOi LDKT, at least in patients with a low anti-A/B IgG antibody titer. However, LON caused by rituximab should be monitored.

Donor-Recipient Body Weight Mismatch May Affect Glomerular Basement Membrane Thinning in Electron Microscopic Examination of 1-Hour Renal Allograft Biopsy Specimens.

BACKGROUND: Although an association between body weight mismatch and impaired graft function has been reported, few histologic studies have evaluated this issue, especially using electric microscopic analysis. During routine observations, we have noted a thin glomerular basement membrane (GBM) in the 1-hour biopsy specimen in cases with an overweight recipient and a lightweight donor. Therefore, we hypothesized that donor-recipient body weight mismatch affects the GBM thickness in the 1-hour biopsy specimen. The aim of the present study was to clarify the effect of donor-recipient body weight mismatch on the GBM thickness of the 1-hour biopsy specimen measured using electron microscopy. METHODS: We used an electron microscope to measure the GBM thickness of specimens at 1-hour post-transplantation (n = 24) and at 1 year post-transplantation (n = 17). The GBM thickness of cases with donor-recipient body weight mismatch was compared with those without mismatch. In accordance with a previous study, we defined a donor/recipient body weight ratio of less than 0.9 as donor-recipient body weight mismatch and a ratio of more than 0.9 as no mismatch. RESULTS: At 1-hour post-transplantation, the mean GBM was significantly thinner in the mismatch group than in the nonmismatch group. However, at 1-year post-transplantation, the mean GBM thickness did not significantly differ between the 2 groups. CONCLUSIONS: The GBM thickness at 1-hour post-transplantation is thinner in cases with donor-recipient body weight mismatch than in cases without mismatch. This implies that donor-recipient body weight mismatch may have to be considered when assessing donor-derived thin GBM disease using the 1-hour biopsy specimen.

Can Lipofuscin Deposition on Renal Allograft Tubular Epithelium Be a Surrogate Marker for Kidney Allograft Aging?

BACKGROUND: Lipofuscin is an indicator of aging. We examined the clinicopathologic significance of lipofuscin deposition in the renal tubules of renal allografts. METHOD: We analyzed allograft biopsy specimens from living kidney transplantations from January to December 2015. For controls, we analyzed native kidney biopsy specimens obtained from January 2015 to December 2016. We identified granules with a yellow-to-tan shade in renal tubules as lipofuscin. RESULTS: The donor age at transplantation was significantly older in lipofuscin deposition biopsy specimens than in those without, whereas the time after transplantation age was not different between the 2 groups with renal allografts. In native kidney biopsies, age at biopsy was significantly older in lipofuscin deposition biopsy specimens than in those without. We compared "massive lipofuscin deposition," defined as lipofuscin deposition on both sides of 3 or more renal tubules, and donor-age matched control allograft biopsies without lipofuscin deposition. Comparing these 2 groups, recipient age at transplantation was significantly older in the massive lipofuscin deposition group. CONCLUSION: Lipofuscin deposition on tubular epithelium is not a surrogate marker of aging of kidneys allografts, although lipofuscin deposition was significantly greater in older tissues from native kidneys. The older age of recipients may be associated with massive lipofuscin deposition in renal allografts.

Vasa recta hyalinosis reflects severe arteriolopathy in renal allografts.

AIM: We examined the clinicopathologic significance of hyalinosis in the vasa recta in the medulla of allograft kidney biopsies. METHOD: We analyzed biopsy specimens from January 2010 to December 2015, obtained from both the cortex and medulla (including the vasa recta) ≥ 1 year after living-donor kidney transplantation. We excluded biopsy specimens from recipients who had undergone transplantation due to diabetic nephropathy or who had diabetes mellitus after transplantation. We evaluated hyaline arteriolopathy in the cortex using the aah score determined by the Banff 2007 classification. RESULT: Among 381 biopsy specimens obtained from 248 transplant recipients ≥ 1 year after transplantation, 36 specimens obtained from 34 recipients showed vasa recta hyalinosis (VRH) in the medulla. Among these 36 specimens, 17 had a score of aah3, 16 had a score of aah2, and 3 had a score of aah1. The incidence of VRH was 1.9% at ≥ 1 to < 4 years, 7.1% at ≥ 4 to < 8 years, and 50.0% at ≥ 8 years. The aah scores and the proportion of hyalinosis in the arteriolar media among all muscular arterioles in the cortex were significantly higher in the VRH group at ≥ 8 years in the late-phase biopsy (P < 0.01). The graft survival was worse in the VRH group (P = 0.024), although there was no significant difference in the graft survival between the ≥ aah2 and < aah2 groups at ≥ 8 years in the late-phase biopsy (P = 0.159). CONCLUSION: VRH in renal allografts reflects severe arteriolopathy of the cortex. VRH in the late-phase biopsy may be a prognostic factor for graft survival.

Interlobular hyaline arteriopathy reflects severe arteriolopathy in renal allografts.

AIM: The present study was performed to examine the clinicopathological significance of hyaline deposits in the smooth muscle of the interlobular artery (interlobular hyaline arteriopathy [IHA]) in renal allografts. METHODS: Tissue specimens that included the interlobular artery from biopsies performed from January 2012 to December 2015, as well as specimens from biopsies performed ≥1 year after living kidney transplantation were analyzed. Biopsies of recipients with new-onset diabetes mellitus after transplantation were excluded, as well as those of recipients who had undergone transplantation because of diabetic nephropathy. Arteriolopathy was evaluated using the aah score determined by the Banff 2007 classification. RESULTS: In total, 51 specimens with IHA lesions were identified among 381 biopsies obtained from 243 recipients performed ≥1 year after kidney transplantation. Among these 51 biopsies, 18 specimens had a score of aah3, 29 had a score of aah2, and four had a score of aah1. The incidence of IHA lesions was 3.6% at ≥1 to <4 years, 18.5% at ≥4 to <8 years, and 54.1% at ≥8 years. Older kidney grafts exhibited more IHA lesions. Among the biopsy specimens obtained ≥8 years after transplantation, no significant differences in the recipient or donor age, duration after transplantation, or prevalence of hypertension were observed between the IHA and non-IHA groups. The aah scores were significantly higher in the IHA group ≥8 years after transplantation as determined by the mean score test (P < 0.01). CONCLUSION: IHA in renal allografts is associated with severe arteriolopathy.

Focal Segmental Glomerulosclerosis Secondary to Juxtaglomerular Cell Tumor during Pregnancy: A Case Report.

Juxtaglomerular cell tumor is a rare renal neoplasm. Secondary hypertension with juxtaglomerular cell tumor can be seen in females in their 20s and 30s. We present a case of juxtaglomerular cell tumor during pregnancy. A 32-year-old female was hospitalized for refractory hypertension and nephrotic syndrome in the 23rd gestational week. One year before admission, she had been diagnosed with hypertension; plasma renin activity at that time had been 2.3 ng/ml/h. Her blood pressure was uncontrolled during pregnancy, and proteinuria was detected in the 12th gestational week despite the administration of antihypertensive medications. Laboratory data showed proteinuria, hypokalemia, and hypoalbuminemia. In the 25th gestational week, she underwent surgical termination of the pregnancy because of congestive heart failure and acute renal injury. After the termination of the pregnancy and the delivery of a viable fetus, her hypertension and nephrotic syndrome were found to persist with a high plasma renin activity (13 ng/ml/h). Ultrasonography showed a 5.5-cm left renal cystic mass with a partially solid component at the lower renal pole. The left kidney with the renal mass was excised by laparoscopic nephrectomy. Plasma renin activity normalized the next day, with a decrease in blood pressure to 120-130/80-90 mm Hg; however, proteinuria remained at ≥3.5 g/day. On the basis of histopathological findings, the patient was diagnosed with a juxtaglomerular cell tumor and focal segmental glomerulosclerosis. Juxtaglomerular cell tumor is a rare renin-secreting tumor associated with refractory hypertension in young females and is a possible cause of hypertension during pregnancy.

Effluent markers related to epithelial mesenchymal transition with adjusted values for effluent cancer antigen 125 in peritoneal dialysis patients.

Objectives. Epithelial mesenchymal transition (EMT) is important for peritoneal deterioration. We evaluated the association between peritoneal solute transport rate (PSTR) and effluent markers related to EMT with adjusted values for effluent cancer antigen 125 (CA125). Methods. One hundred five incident peritoneal dialysis (PD) patients on PD for 25 (12-68) months with biocompatible solutions were included in the study. Fast peritoneal equilibration test was used to evaluate PSTR. Effluent hepatocyte growth factor (HGF), bone morphogenic protein-7 (BMP-7), vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), and CA125 at 4 h were measured. Results. Patients with dialysate/plasma creatinine ≧0.82 showed significantly higher effluent HGF (240 versus 133 pg/mL, P < .001), VEGF, IL-6, and IL6/CA125 levels than the others but no significant differences in effluent HGF/CA125, BMP-7, and BMP7/CA125 were observed. Conclusion. Increase in the effluent HGF levels as a compensatory mechanism is a marker of peritoneal deterioration, but controversy remains regarding adjusted value for CA125.

Effects of new peritoneal dialysis solutions, pyridoxamine and AT1 receptor blocker, on TGF-beta1 and VEGF expression in rat peritoneal mesothelial cells.

BACKGROUND: Transforming growth factor beta1 (TGF-beta1) and vascular endothelial growth factor (VEGF) are involved in peritoneal deterioration in continuous ambulatory peritoneal dialysis. The present study was designed to determine whether new peritoneal dialysis solutions (PDS), pyridoxamine (advanced glycation end products (AGE) inhibitor) or AT1 receptor blocker (ARB), affect the expression of VEGF and TGF-beta1 in rat peritoneal mesothelial cells (RPMC). METHODS: RPMC were stimulated by phosphate-buffered saline (PBS) as control, Dianeal 1.5% (D 1.5%), Dianeal 2.5% (D 2.5%), Dianeal 4.25% (D 4.25%), Dianeal N 1.5% (N 1.5%), Dianeal N 2.5% (N 2.5%) or Extraneal (Ex). In co-incubation experiments, RPMC were stimulated with N 2.5% including pyridoxamine or olmesartan (ARB). VEGF and TGF-beta1 protein and mRNA expression in RPMC were analyzed by ELISA and RT-PCR. RESULTS: Glucose-containing PDS, even N 2.5% diluted twofold with M199 (which contains 1.25% glucose), increased VEGF and TGF-beta1 expression in RPMC (p < 0.05). Ex did not inhibit VEGF expression and did not inhibit TGF- beta1 expression after 24 h in RPMC. Pyridoxamine and ARB significantly reduced N 2.5%-induced VEGF and TGF-beta1 protein and mRNA expression in RPMC (p < 0.01). CONCLUSIONS: Neither new pH-neutral, lactate-buffered, low-GDP, two-chamber bag PDS, nor 7.5% icodextrin PDS alone satisfactorily inhibited VEGF and TGF-beta1 overproduction in RPMC, but ARB or pyridoxamine effectively inhibited glucose-containing PDS (N 2.5%)-induced overproduction.

Membranoproliferative glomerulonephritis in a girl and her mother.

A girl and her mother were diagnosed as having membranoproliferative glomerulonephritis (MPGN) type I. Microscopic hematuria and proteinuria presented at 9 years of age in the mother and at 14 years in the daughter. Both had persistent hypocomplementemia and were treated with steroids. When the mother was 40 years old, proteinuria was still continuing and creatinine clearance was 64.4 ml/min per 1.73 m(2). When the daughter was 15 years old, microscopic hematuria was still continuing. To our knowledge, familial cases of MPGN in two generations have not been reported in Japan.

Expression of ACE and ACE2 in individuals with diabetic kidney disease and healthy controls.

BACKGROUND: Angiotensin-converting enzyme (ACE) 2 (ACE2) is expressed mainly in the heart and kidney and forms angiotensin-1-7 from angiotensin II. ACE2 might act in a counterregulatory manner to ACE. There is little information about renal ACE and ACE2 expression in human diabetic nephropathy. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: Kidney tissue from 20 patients with type 2 diabetes and overt nephropathy and 20 healthy kidney donors. PREDICTOR: Diabetes status. OUTCOMES & MEASUREMENTS: Renal expression of ACE and ACE2 assessed by means of immunohistochemistry and in situ hybridization. Correlation between ACE and ACE2 expression and levels of various biochemical parameters. RESULTS: Decreased ACE2 and increased ACE expression in both the tubulointerstitium and glomeruli resulted in a significant (P < 0.001) increase in ACE/ACE2 ratio in patients with diabetes with overt nephropathy compared with controls, although ACE messenger RNA in the tubulointerstitium did not significantly increase. ACE/ACE2 ratio correlated positively with values for mean blood pressure, fasting blood glucose, serum creatinine, proteinuria, and hemoglobin A(1c) and inversely with estimated glomerular filtration rate (P < 0.001). LIMITATIONS: Inclusion of small number of human renal biopsy specimens with structural distortion of cortical tissue. CONCLUSIONS: The high ACE/ACE2 ratio in kidneys of patients with type 2 diabetes with overt nephropathy may contribute to renal injury.