Familial focal segmental glomerulosclerosis with Alport-like glomerular basement changes caused by paired box protein 2 gene variant.

Paired box protein 2 (PAX2) gene variant causes renal coloboma syndrome (MIM#120330). Further, they are associated with focal segmental glomerulosclerosis and characterized by basement membrane changes similar to Alport syndrome.Herein, we report an 8-year-old boy who presented with proteinuria and decreased renal function. His paternal uncle has focal segmental glomerulosclerosis and renal failure, and his paternal grandmother has renal failure and is receiving peritoneal dialysis. Further, his father has stage 2 chronic kidney disease. At 3 years of age, his serum creatinine-estimated glomerular filtration rate was 40-50 mL/min/1.73 m2. At 8 years of age, his renal function further decreased and he had proteinuria (urinary protein/Cr 3.39 g/g Cr). Renal histopathology showed oligonephronia and focal segmental glomerulosclerosis. A partial basket-weave pattern, similar to Alport syndrome, was also observed on a transmission electron microscope, and low-vacuum scanning electron microscopy revealed coarse meshwork changes in the glomerular basement membrane. Genetic analysis revealed a PAX2 heterozygous variant (NM_003987.4:c.959C  >  G), a nonsense variant in which the serine at position 320 changes to a stop codon, in our patient and his father. PAX2 is a transcription factor that is important for the podocyte variant. However, podocytes with PAX2 gene variants may cause abnormal basement membrane production and repair, thereby resulting in Alport-like changes.

Clinical and histological features in pediatric and adolescent/young adult patients with renal disease: a cross-sectional analysis of the Japan Renal Biopsy Registry (J-RBR).

BACKGROUND: Only a few studies have investigated epidemiological and clinicopathological information regarding pediatric and adolescent and young adult (AYA) patients with renal disease. The purpose of this study was to clarify the differences and relationship of clinicopathological findings between pediatric and AYA patients using the Japan Renal Biopsy Registry (J-RBR). METHODS: This cross-sectional study analyzed data from patients registered in the J-RBR between 2007 and 2017. Clinicopathological findings at diagnosis were analyzed for 3,463 pediatric (age < 15 years) and 6,532 AYA (age 15-30 years) patients. RESULTS: Although chronic nephritic syndrome was the most common clinical diagnosis at age > 5 years, nephrotic syndrome was the most frequent diagnosis at age < 4 years. The most common pathological diagnosis as classified by pathogenesis in pediatric patients was primary glomerular disease (except IgA nephropathy), whereas IgA nephropathy was increased in AYA patients. Mesangial proliferative glomerulonephritis was the most common pathological diagnosis as classified by histopathology in both pediatric and AYA patients. Minor glomerular abnormalities were the most frequent histopathologic diagnoses of nephrotic syndrome in childhood, but their frequency decreased with age. CONCLUSION: To the best of our knowledge, this is the first report of clinicopathological features of pediatric and AYA patients in a large nationwide registry of renal biopsy. There were differences of clinical, pathological and histopathologic findings between pediatric and AYA patients.

Successful Treatment of Cyst Infection in an Infant With Autosomal Dominant Polycystic Kidney Disease Using Trimethoprim/Sulfamethoxazole.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disease causing renal cysts. Reports on kidney cyst infection in children are rare despite cyst infections being important complications of ADPKD. Here, we report a case of a child without any medical history who had a urinary tract infection with sepsis at 7 months. Leukocyturia persisted despite antibiotic therapy because the infection was treatment-resistant. Initial ultrasound and contrast computed tomography were inconclusive because cysts could not be detected clearly, and a family history of renal cysts was not determined. Subsequently, history of paternal renal cysts, thick walls in infectious cystic lesions on diffusion-weighted magnetic resonance imaging (MRI), and multiple small lesions with high signals on T2-weighted imaging in both kidneys became apparent. Upon diagnosis of ADPKD with cyst infection, antibiotic therapy was switched from cefotaxime to trimethoprim/sulfamethoxazole to achieve better cyst penetration, which successfully resolved the infection. In this patient, MRI was effective for clear visualization and diagnosis of infectious lesions and small cysts in undiagnosed ADPKD with cyst infection. Administering antibiotics with better cyst penetration is important. Trimethoprim/sulfamethoxazole is an option for use in children. This is the first case report that describes ADPKD with cyst infection in an infant in detail.

Low-vacuum scanning electron microscopy may allow early diagnosis of human renal transplant antibody-mediated rejection.

Antibody-mediated rejection (ABMR) is an important cause of both short- and long-term injury to renal allografts. Transplant glomerulopathy (TG) is strongly associated with ABMR and reduced graft survival. Ultrastructural changes in early-stage ABMR include TG as a duplication of the glomerular basement membrane (GBM), which can be observed only by transmission electron microscopy (TEM). Low-vacuum scanning electron microscopy (LVSEM) is a new technique that allows comparatively inexpensive, rapid, and convenient observations with high magnification. We analyzed human renal transplants using LVSEM and evaluated the ultrastructural changes representing TG in ABMR. GBM duplication was more clearly visible in the LVSEM images than in the light microscopy (LM) images. In the ABMR group, the cg score of the Banff classification was higher in 54% (7/13) of specimens for LVSEM images than for LM images. And 4 specimens exhibited duplication of the GBM analyzed by LVSEM, but not by LM. In addition, three-dimensional ultrastructural changes, such as coarse meshwork structures of GBM, were observed in ABMR specimens. The ABMR group also exhibited ultrastructural changes in the peritubular capillary basement membranes. In conclusion, analyses of renal transplant tissues using LVSEM allows the identification of GBM duplication and ultrastructural changes of basement membranes at the electron microscopic level, and is useful for early-stage diagnosis of ABMR.

Morphological diagnosis of Alport syndrome and thin basement membrane nephropathy by low vacuum scanning electron microscopy.

Alport syndrome (AS) and thin basement membrane nephropathy (TBMN) are genetic disorders caused by mutations of the type IV collagen genes COL4A3, COL4A4, and/or COL4A5. We here aimed to investigate the three-dimensional ultrastructure of the glomerular basement membrane (GBM) in order to introduce a novel method of diagnosing AS and TBMN. The subjects were 4 patients with AS and 6 patients with TBMN. Conventional renal biopsy paraffin sections from AS and TBMN patients were stained with periodic acid methenamine silver (PAM) and observed directly under low vacuum scanning electron microscopy (LVSEM). The PAM-positive GBMs were clearly visible under LVSEM through the overlying cellular components. The GBMs showed characteristic coarse meshwork appearances in AS, and thin and sheet-like appearances in TBMN. At the cut side view of the capillary wall, the GBMs in AS appeared as fibrous inclusions between a podocyte and an endothelial cell, while the GBMs in TBMN showed thin linear appearances. These different findings of GBMs between AS and TBMN were easily observed under LVSEM. Thus, we conclude that three-dimensional morphological evaluation by LVSEM using conventional renal biopsy paraffin sections will likely be useful for the diagnosis of AS and TBMN, including for retrospective investigations.

Fluctuating liver functions in siblings with MPV17 mutations and possible improvement associated with dietary and pharmaceutical treatments targeting respiratory chain complex II.

BACKGROUND/AIMS: To describe the clinical and biological findings of two Japanese siblings with novel MPV17 gene mutations (c.451insC/c.509C > T) manifesting hepatic mitochondrial DNA depletion syndrome. METHODS: We observed these brothers and sought to determine the efficacy of treatment targeting respiratory chain complex II for the younger brother. RESULTS: A 3-month-old boy had presented with profound liver dysfunction, failure to thrive, and watery diarrhea. Although he was then placed on a carbohydrate-rich diet, his liver function thereafter fluctuated greatly in association with viral infections, and rapidly deteriorated to liver failure. He underwent liver transplantation at 17 months of age but died at 22 months of age. The younger brother, aged 47 months at the time of this writing, presented with liver dysfunction from 8 months of age. His transaminase levels also fluctuated considerably fluctuations in association with viral infections. At 31 months of age, treatment with succinate and ubiquinone was initiated together with a lipid-rich diet using ketone milk. Thereafter, his transaminase levels normalized and never fluctuated, and the liver histology improved. CONCLUSIONS: These cases suggested that the clinical courses of patients with MPV17 mutations are greatly influenced by viral infections and that dietary and pharmaceutical treatments targeting the mitochondrial respiratory chain complex II may be beneficial in the clinical management of MPV17 mutant patients.