Post-renal Biopsy Retroperitoneal Haematoma Accompanied by Decreased Coagulation Factor XIII Levels in Immunoglobulin A Nephropathy.

Post-biopsy bleeding is the primary complication of renal biopsy. Retroperitoneal haematoma is a rare but severe bleeding complication; it commonly occurs among patients who have risk factors or vascular lesions. The bleeding risks in patients with immunoglobulin A (IgA) nephropathy (IgAN) have been discussed in the literature, but clinical data are lacking. Here, we report a case of a post-biopsy retroperitoneal haematoma accompanied by decreased coagulation factor XIII (FXIII) in a patient with IgAN. A 14-year-old male patient with haematuria and proteinuria but no bleeding or family history of bleeding underwent pre-renal biopsy evaluation that showed no coagulation abnormalities. He underwent percutaneous renal biopsy, and the histopathological diagnosis was IgAN. Five days after the biopsy, he presented with delayed bleeding from a retroperitoneal haematoma. During the workup for undiagnosed haemorrhagic diatheses, a mildly decreased FXIII level was discovered. This result suggested the possibility of bleeding complications associated with decreased FXIII. Some bleeding diatheses, including FXIII deficiency, cannot be evaluated in routine pre-biopsy coagulation tests. Mild FXIII deficiency can increase the risk of post-biopsy bleeding complications. Therefore, physicians should consider unevaluated haemorrhagic diatheses when a patient presents with major bleeding complications or delayed bleeding following renal biopsy without any known risk factors or vascular lesions.

Recurrent transient severe hypocalcaemia in two siblings with type 1 Bartter syndrome.

Type 1 Bartter syndrome causes hypokalaemia and metabolic alkalosis owing to mutation in the SLC12A1 gene. Meanwhile, hypocalcaemia is rare in Bartter syndrome, except in type 5 Bartter syndrome. Herein, we describe two siblings with type 1 Bartter syndrome with recurrent transient severe hypocalcaemia. They each visited our hospital several times with chief complaints of numbness in the limbs, shortness of breath and tetany after stresses such as exercise or fever. Severe hypocalcaemia was also observed with a serum calcium level of approximately 6.0 mg/dL at each visit. The clinical symptoms and abnormalities in laboratory findings quickly improved with rest and intravenous treatment. In a steady state, no severe hypocalcaemia was evident, but serum intact parathyroid hormone (PTH) levels were high. In recent years, a large-scale study has revealed that type 1 and type 2 Bartter syndrome have high PTH values. In addition, there are reports that these patients develop hypocalcaemia due to PTH resistance. Therefore, our patient was also in a PTH-resistant state, and hypocalcaemia was thought to be exacerbated by physical stress. It is not well known that Bartter syndrome patients other than those with type 5 suffer from hypocalcaemia. And hypocalcaemia was not detected in normal examinations under steady-state conditions. Therefore, in patients with type 1 and type 2 Bartter syndrome, severe hypocalcaemia may occur, but may go unnoticed. When following up these patients, the attending physician must keep in mind that such patients are in a PTH-resistant state and that physical stress can cause severe hypocalcaemia.

A multi-institutional study found a possible role of anti-nephrin antibodies in post-transplant focal segmental glomerulosclerosis recurrence.

Possible roles of anti-nephrin antibodies in post-transplant recurrent focal segmental glomerulosclerosis (FSGS) have been reported recently. To confirm these preliminary results, we performed a multi-institutional study of 22 Japanese pediatric kidney transplant recipients with FSGS including eight genetic FSGS and 14 non-genetic (presumed primary) FSGS. Eleven of the 14 non-genetic FSGS patients had post-transplant recurrent FSGS. Median (interquartile range) plasma levels of anti-nephrin antibodies in post-transplant recurrent FSGS measured using ELISA were markedly high at 899 (831, 1292) U/mL (cutoff 231 U/mL) before transplantation or during recurrence. Graft biopsies during recurrence showed punctate IgG deposition co-localized with nephrin that had altered localization with increased nephrin tyrosine phosphorylation and Src homology and collagen homology A expressions. Graft biopsies after remission showed no signals for IgG and a normal expression pattern of nephrin. Anti-nephrin antibody levels decreased to 155 (53, 367) U/mL in five patients with samples available after remission. In patients with genetic FSGS as in those with non-genetic FSGS without recurrence, anti-nephrin antibody levels were comparable to those of 30 control individuals, and graft biopsies had no signals for IgG and a normal expression pattern of nephrin. Thus, our results suggest that circulating anti-nephrin antibodies are a possible candidate for circulating factors involved in the pathogenesis of post-transplant recurrent FSGS and that this may be mediated by nephrin phosphorylation. Larger studies including other ethnicities are required to confirm this finding.

Case Report: Guanfacine and methylphenidate improved chronic lower back pain in autosomal dominant polycystic kidney disease with comorbid attention deficit hyperactivity disorder and autism spectrum disorder.

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited renal disease characterized by the bilateral development of multiple cysts in the kidneys. Pain management is a clinically important issue, especially because approximately 60% of patients with ADPKD experience chronic pain related to hemorrhage from renal cysts, which significantly reduces their daily life. The cystic fibrosis transmembrane conductance regulator, the molecule responsible for cyst formation in ADPKD, is also the cause of cystic fibrosis. Since attention deficit hyperactivity disorder (ADHD) is known to occur frequently in conjunction with cystic fibrosis, ADPKD may be associated with ADHD. However, to our knowledge, no study has investigated 1) ADHD or autism spectrum disorder (ASD) as comorbidities with ADPKD, 2) the effects of ADHD medications on chronic pain in ADPKD, or 3) cerebral blood flow corresponding to guanfacine (GF) or methylphenidate (MP) treatment for chronic pain. We report the case of a 15-year-old girl with ADPKD, who had chronic back pain associated with ADPKD and had to withdraw from high school because the pain interfered with her daily life. Although she took antihypertensive medications to prevent bleeding, they did not provide adequate blood pressure control. The patient was referred to a child psychiatrist and diagnosed with ASD; however, the pain did not improve. Subsequently, she was referred to our pain center. The diagnosis of ADHD was confirmed and treatment with ADHD medications was initiated. Monotherapy with MP, atomoxetine, and GF resulted in hypertension and hypotension as side effects; however, a combination of MP 18 mg and GF 4 mg provided pain relief and moderate blood pressure control, and the patient was able to go on to college. During the course of treatment, there was an improvement in the distribution of cerebral blood flow in the prefrontal and insular cortices. Confirmation of an ADHD diagnosis comorbid with ASD enabled the use of ADHD medications. The combination of MP and GF improved chronic back pain and high blood pressure due to ADPKD and cerebral blood flow. Screening for ADHD is important in the treatment of ADPKD.

Precise clinicopathologic findings for application of genetic testing in pediatric kidney transplant recipients with focal segmental glomerulosclerosis/steroid-resistant nephrotic syndrome.

BACKGROUND: Establishing a molecular genetic diagnosis of focal segmental glomerulosclerosis (FSGS)/steroid-resistant nephrotic syndrome (SRNS) can be useful for predicting post-transplant recurrence. Monogenic causes are reportedly present in approximately 20-30% of patients with FSGS/SRNS. However, the characteristics of patients who are likely to have a monogenic cause remain to be determined. METHODS: Pediatric recipients with SRNS and/or biopsy-proven FSGS who underwent their first kidney transplantation at our center between 1999 and 2019 were analyzed. Patients with secondary FSGS/SRNS were excluded. The recipients were divided into three groups: familial/syndromic, presumed primary, and undetermined FSGS/SRNS. Patients who met all of the following criteria were categorized as having presumed primary FSGS/SRNS: (i) nephrotic syndrome, (ii) complete or partial remission with initial steroid therapy and/or additional immunosuppressive therapies, and (iii) diffuse foot process effacement on electron microscopy in the native kidney biopsy. All patients underwent genetic testing using next-generation sequencing. RESULTS: Twenty-four patients from 23 families were analyzed in this study. Pathogenic or likely pathogenic variants in FSGS/SRNS-related genes were identified in four of four families, zero of eight families, and 10 of 11 families with familial/syndromic, presumed primary, and undetermined FSGS/SRNS, respectively. Post-transplant recurrence only occurred in patients with presumed primary FSGS/SRNS. CONCLUSIONS: Our systematic approach based on precise clinicopathological findings including nephrotic syndrome, treatment responses, and diffuse foot process effacement might be useful to differentiate pediatric kidney transplant recipients with FSGS/SRNS who are likely to have a monogenic cause from patients who are not, and to predict post-transplant recurrence. A higher resolution version of the Graphical abstract is available as Supplementary information.

A case of right hypodysplastic kidney and ectopic ureter associated with bicornuate uterus in a prepubertal girl.

Congenital anomalies of the kidney and urinary tract (CAKUT) are frequently associated with Mullerian anomalies. This can be explained by the fact that Mullerian duct elongation depends on the preformed Wolffian duct during embryogenesis. While CAKUT such as unilateral renal agenesis and multicystic dysplastic kidney are commonly identified prenatally by routine ultrasound, the diagnosis of Mullerian anomalies is often delayed, increasing the risk of complications such as endometriosis or pelvic inflammatory disease. Herein, we report a case of a premenarchal girl who had initially been diagnosed with right multicystic dysplastic kidney. She presented with continuous urinary incontinence at 4 years old and further evaluation by contrast-enhanced computed tomography, cystoscopy, colposcopy, ureterography, and hysterosalpingography led to the final diagnosis of right hypodysplastic kidney and ectopic ureter associated with bicornuate uterus. A strong family history of uterine malformations prompted the examination of the uterus. Genetic testing was suggested but the family declined. She is planned to be referred to a gynecologist at puberty for further assessment. The recognition and screening rate of concurrent Mullerian anomalies in CAKUT patients varies between institutions. Screening for Mullerian anomalies in prediagnosed CAKUT girls may enable to provide timely counseling and to prevent gynecological complications.

Urinary extracellular vesicles signature for diagnosis of kidney disease.

Congenital disorders characterized by the quantitative and qualitative reduction in the number of functional nephrons are the primary cause of chronic kidney disease (CKD) in children. We aimed to describe the alteration of urinary extracellular vesicles (uEVs) associated with decreased renal function during childhood. By nanoparticle tracking analysis and quantitative proteomics, we identified differentially expressed proteins in uEVs in bilateral renal hypoplasia, which is characterized by a congenitally reduced number of nephrons. This expression signature of uEVs reflected decreased renal function in CKD patients by congenital anomalies of the kidney and urinary tract or ciliopathy. As a proof-of-concept, we constructed a prototype ELISA system that enabled the isolation of uEVs and quantitation of expression of molecules representing the signature. The system identified decreased renal function even in its early stage. The uEVs signature could pave the way for non-invasive methods that can complement existing testing methods for diagnosing kidney diseases.

A case of early onset cystinuria in a 4-month-old girl.

Cystinuria is an autosomal recessive disorder characterized by a decrease in the reabsorption of cystine and dibasic amino acids (lysine, ornithine, and arginine) in the renal proximal tubule. It presents with recurrent urolithiasis. Cystinuria accounts for 6-8% of all pediatric urolithiasis. The age of onset is typically 10-30 years. Here, we report a case of early-onset cystinuria. A 4-month-old girl presented with hematuria. We noticed multiple renal calculi in ultrasonography and abdominal computerized tomography scans. The diagnosis was cystinuria with urinary calculus analysis and urinary amino acid analysis. The patient was treated with urine alkalinization and cystine chelating drugs. Gene analysis showed a P482L heterozygous mutation from her mother, and an A70V heterozygous mutation from her father, in the SLC7A9 gene. This gene encodes a putative subunit of the neutral and basic amino acid transport protein, BAT1. Although cystinuria is an autosomal recessive disease, there have been previous reports of P482L heterozygous mutations greatly suppressing cystine reabsorption and causing cystinuria symptoms. Therefore, the highly influential P482L mutation of the SLC7A9 gene may have contributed to the onset of this autosomal recessive disease at an extremely young age.

Response to steroid and immunosuppressive therapies may predict post-transplant recurrence of steroid-resistant nephrotic syndrome.

BACKGROUND: Recurrence of SRNS is a major challenge in KT. Several clinical factors, including initial steroid sensitivity, have been associated with increased post-transplant SRNS recurrence risk. However, conflicting data have been reported, possibly due to the heterogeneous pathophysiology of SRNS and the lack of genetic testing of SRNS patients. Furthermore, the response to immunosuppressive therapies has not been evaluated. METHODS: Seventy patients aged 1-15 years at SRNS onset who underwent KT between 2002 and 2018 were enrolled. Patients with secondary, familial, syndromic, and genetic forms of SRNS and those who were not treated with steroid were excluded. This study aimed to assess the risk factors for post-transplant recurrence, including treatment responses to initial steroid therapy and additional therapies with immunosuppressive agents, rituximab, plasmapheresis, and/or LDL-A. RESULTS: Data from 36 kidney transplant recipients were analyzed. Twenty-two (61%) patients experienced post-transplant SRNS recurrence, while 14 patients did not. The proportion of patients who achieved complete or partial remission with initial steroid therapy and/or additional therapies with immunosuppressive agents, rituximab, plasmapheresis, and/or LDL-A was significantly higher in the SRNS recurrence group (19/22, 86%) than in the group without SRNS recurrence (6/14, 43%; p = .01). CONCLUSION: This study suggests that the response to steroid treatment, other immunosuppressive agents, rituximab, plasmapheresis, and/or LDL-A may predict post-transplant SRNS recurrence.

A novel de novo truncating TRIM8 variant associated with childhood-onset focal segmental glomerulosclerosis without epileptic encephalopathy: a case report.

BACKGROUND: Heterozygous truncating variants in the Tripartite motif containing 8 (TRIM8) gene have been reported to cause epileptic encephalopathy, both with and without proteinuria. A recent study showed a lack of TRIM8 protein expression, with suppressor of cytokine signaling 1 (SOCS1) overexpression, in podocytes and tubules from a patient with a TRIM8 variant, who presented with epileptic encephalopathy and focal segmental glomerulosclerosis (FSGS). To date, no patients with TRIM8 variants who presented with nephrotic syndrome but without neurological manifestations have been described. CASE PRESENTATION: An 8-year-old girl presented with nephrotic syndrome, without epilepsy or developmental delay. Her kidney biopsy specimens showed FSGS and cystic dilatations of the distal tubules. Whole-exome sequencing identified a novel de novo heterozygous variant in the C-terminal encoding portion of TRIM8 (c.1461C > A), resulting in a premature stop codon (p.Tyr487*). Reverse transcription-polymerase chain reaction using peripheral blood mononuclear cells identified the mRNA sequence of the mutant allele, which confirmed an escape from nonsense-mediated mRNA decay. Immunofluorescence studies showed a lack of TRIM8 expression in glomerular and tubular cells and cystic dilatation of distal tubules. Immunohistochemical studies showed overexpression of SOCS1 in glomerular and tubular cells. CONCLUSIONS: We reported a patient with FSGS, associated with a de novo heterozygous TRIM8 variant, without any neurological manifestations. Our results expanded the clinical phenotypic spectrum of TRIM8 variants.

An infant with X-linked anhidrotic ectodermal dysplasia with immunodeficiency presenting with Pneumocystis pneumonia: A case report.

Pneumocystis jirovecii pneumonia associated with primary immunodeficiency should be considered in infants with slowly progressing cyanosis, even without fever or respiratory symptoms. Genetic counseling is crucial for incontinentia pigmenti families in advance of pregnancy because lethal infections can occur before the diagnosis of X-linked anhidrotic ectodermal dysplasia with immunodeficiency.

Cancer After Pediatric Kidney Transplantation: A Long-term Single-center Experience in Japan.

BACKGROUND: The cancer incidence, types, and risk factors after pediatric kidney transplantation (KT) have been reported in the United States, Canada, Europe, Australia, and New Zealand. However, no information is available about cancer in pediatric KT recipients in Asian countries. METHODS: Children aged <20 y who underwent initial KT from 1983 to 2016 were analyzed. We compared the cancer incidence with that in the general Japanese population using standardized incidence ratio and examined posttransplant cancer risk using Cox proportional hazards models. RESULTS: A total of 356 children (median age, 11.7 y; interquartile range, 5.0-17.6) received KT with a follow-up period of 4466 person-years. The median age of cancer onset was 18.5 y (interquartile range, 8.0-32.3), and 13 cancers occurred in 12 patients (3.4%). Two patients died from cancer. The most common cancers were posttransplant lymphoproliferative disorders (PTLDs) (38.5%). The median time to PTLD and non-PTLD diagnosis after KT was 0.6 and 16.4 y, respectively. There was no occurrence of skin cancer. The posttransplant cancer incidence was 9.9 times higher than that in the general age-matched population (standardized incidence ratio = 9.9; 95% confidence interval, 4.80-18.39). The cumulative cancer incidence was 5.3% in 20 y after KT, which is lower than that reported in previous studies. We could not identify any risk factors for all cancer after KT in all patients, whereas subgroup analysis in 264 patients with available data of recipient Epstein-Barr virus serological status showed that recipient Epstein-Barr virus-negative serology was an independent risk factor for cancer development. CONCLUSIONS: The incidence of cancer is higher in Japanese pediatric KT recipients than in the general population. The cumulative incidence of cancer after KT was lower in our population than that previously reported. This may be because there was no skin cancer observed in the Japanese pediatric KT recipients in our study.

A case of 17q12 deletion syndrome that presented antenatally with markedly enlarged kidneys and clinically mimicked autosomal recessive polycystic kidney disease.

The gene encoding hepatocyte nuclear factor 1ß (HNF1B), a transcription factor involved in the development of the kidney and other organs, is located on chromosome 17q12. Heterozygous deletions of chromosome 17q12, which involve 15 genes including HNF1B, are known as 17q12 deletion syndrome and are a common cause of congenital anomalies of the kidneys and urinary tract (CAKUT) and may also present as a multisystem disorder. Autosomal recessive polycystic kidney disease (ARPKD), on the other hand, is a severe form of polycystic kidney disease caused by mutations in PKHD1 (polycystic kidney and hepatic disease 1). It is important to differentiate between these two diseases because they differ significantly in inheritance patterns, renal prognosis, and extrarenal manifestations. Here we report a case of 17q12 deletion syndrome that clinically mimicked ARPKD in which genetic testing was essential for appropriate genetic counseling and monitoring of possible extrarenal manifestations. The patient presented antenatally with markedly enlarged kidneys and showed bilaterally hyperechoic kidneys with poor corticomedullary differentiation and multiple cysts on ultrasonography. There was no family history of renal disease. ARPKD was clinically suspected and genetic testing was performed to confirm diagnosis, resulting in an unexpected finding of 17q12 deletion including HNF1B. While some research has been done to identify patients that should be tested for HNF1B anomalies, this case illustrates the difficulty of recognizing HNF1B-related disease and the importance of genetic testing in appropriately managing CAKUT cases.

Development of an exon skipping therapy for X-linked Alport syndrome with truncating variants in COL4A5.

Currently, there are no treatments for Alport syndrome, which is the second most commonly inherited kidney disease. Here we report the development of an exon-skipping therapy using an antisense-oligonucleotide (ASO) for severe male X-linked Alport syndrome (XLAS). We targeted truncating variants in exon 21 of the COL4A5 gene and conducted a type IV collagen α3/α4/α5 chain triple helix formation assay, and in vitro and in vivo treatment efficacy evaluation. We show that exon skipping enabled trimer formation, leading to remarkable clinical and pathological improvements including expression of the α5 chain on glomerular and the tubular basement membrane. In addition, the survival period was clearly prolonged in the ASO treated mice group. This data suggests that exon skipping may represent a promising therapeutic approach for treating severe male XLAS cases.

A cellular model of albumin endocytosis uncovers a link between membrane and nuclear proteins.

Cubilin (CUBN) and amnionless (AMN), expressed in kidney and intestine, form a multiligand receptor complex called CUBAM that plays a crucial role in albumin absorption. To date, the mechanism of albumin endocytosis mediated by CUBAM remains to be elucidated. Here, we describe a quantitative assay to evaluate albumin uptake by CUBAM using cells expressing full-length CUBN and elucidate the crucial roles of the C-terminal part of CUBN and the endocytosis signal motifs of AMN in albumin endocytosis. We also demonstrate that nuclear valosin-containing protein-like 2 (NVL2), an interacting protein of AMN, is involved in this process. Although NVL2 was mainly localized in the nucleolus in cells without AMN expression, it was translocated to the extranuclear compartment when coexpressed with AMN. NVL2 knockdown significantly impaired internalization of the CUBN-albumin complex in cultured cells, demonstrating an involvement of NVL2 in endocytic regulation. These findings uncover a link between membrane and nucleolar proteins that is involved in endocytic processes.

Renal hypoplasia can be the cause of membranous nephropathy-like lesions.

BACKGROUND: Renal hypoplasia (RH) is the most common cause of chronic kidney disease in children. In cases of RH, proteinuria is often induced by glomerular hypertrophy and hyperfiltration that is commonly associated with focal segmental glomerulosclerosis. This study reports the first case series of a possible association between RH and membranous nephropathy (MN). METHODS: Of the 168 children with RH who visited our department between 1999 and 2017, five with overt proteinuria (≥ 1 g/gCr) underwent renal biopsy. We retrospectively reviewed the medical charts and analyzed biopsy specimens using light microscopy (LM), immunofluorescence (IF), and electron microscopy. RESULTS: The five children (four boys and one girl) had a median age of 5.5 years at the time of renal biopsy. The median proteinuria was 4.23 g/gCr (range 1.46-14.25), median serum albumin, 2.9 g/dL (range 2.3-3.7), and median estimated glomerular filtration rate, 59.7 mL/min/1.73 m2 (range 36.7-103.6). LM showed segmental spike formation and mesangial hypercellularity and IF study showed segmental granular immunoglobulin G (IgG) staining (IgG1 and IgG3 dominant) along the capillary loops in all five patients. Electron-dense deposits were observed in the subepithelial and mesangial areas. Thus, the pathological studies showed MN-like lesions in all patients. CONCLUSION: Our study suggests that RH can be the cause of MN-like lesions.