Ongoing impacts of childhood-onset glomerular diseases during young adulthood.

BACKGROUND: Childhood-onset glomerular disease often requires ongoing treatment and follow-up into adulthood. However, few studies have analyzed the associated impact and distress experienced by patients with this condition during the transition from childhood to adolescence and adulthood. METHODS: At three facilities, we recruited patients who developed idiopathic nephrotic syndrome or IgA nephropathy during childhood and were at least 18 years old at the time of study entry. Among them, a questionnaire-based survey was administered to patients who consented to participate, and the results were analyzed in conjunction with clinical information. RESULTS: Data from a total of 38 patients were analyzed. Of these patients, 15 had idiopathic nephrotic syndrome and 23 had IgA nephropathy. The age of transition from pediatrics to the adult medicine department was correlated with the number of recurrences. Many patients also reported being significantly affected by exercise restrictions and physical decline associated with their diseases and medications. Various impacts, including distress, affected decision-making regarding higher education, with patients engaging in higher education at a significantly higher rate compared with the regional average (66.7% vs. 46.9%, p = 0.028). CONCLUSION: We analyzed the impact of childhood-onset glomerular disease and distress during the transition period from pediatric to adult care. This study highlighted the significant impact of medications and exercise restrictions on patients' decisions regarding higher education. Future prospective studies will be needed to examine patients' distress in more detail and establish management approaches to enhance patient quality of life.

A neonate with multiple hand flexor tendon ruptures due to methicillin-susceptible Staphylococcus aureus sepsis: a case report.

BACKGROUND: Neonatal pyogenic tenosynovitis is a highly emergent soft tissue infection. We report a case of a neonate with pyogenic tendinopathy and tendon rupture diagnosed by ultrasonography (US). He subsequently developed pyogenic arthritis and osteomyelitis during antimicrobial therapy. CASE PRESENTATION: A 7-day-old boy was admitted to our hospital with redness and swelling of the right index finger. US on admission showed rupture of the flexor tendon of the right index finger with inactivity. The day after admission, he developed pyogenic arthritis of the right elbow and, subsequently, pyogenic osteomyelitis. Staphylococcus aureus was identified through bacterial culture, and the patient was treated with intravenous antibiotics for 6 weeks. However, after discharge from our hospital, rupture of the flexor tendon of the left thumb was confirmed. A two-stage flexor tendinoplasty was completed at the age of 2 years and 1 month for the flexor tendon rupture on his right index finger. CONCLUSIONS: In addition to blood culture, ultrasonographic evaluation should be performed in neonates with erythematous and swollen joints to identify the focus of infection as soon as possible. Moreover, repeated regular US examination is important in the follow-up of bone and soft tissue infections.

Cyclosporine therapy could be considered for membranoproliferative glomerulonephritis with immunoglobulin A deposits: a case report.

BACKGROUND: Membranoproliferative glomerulonephritis (MPGN), a rare glomerulonephritis that causes nephrotic syndrome in children, is often difficult to treat. Typical immunofluorescence findings include strong C3 staining in a granular pattern along the glomerular capillary wall and negative IgA staining. IgA-dominant MPGN without hypocomplementemia has been reported. Herein, we report a rare case of MPGN with hypocomplementemia and predominant IgA subclass 2 deposits. CASE PRESENTATION: An 11-year-old girl showed proteinuria on a school urinalysis screening and presented with upper eyelid edema. The urinalysis showed elevated urinary protein levels and hematuria. Laboratory examinations revealed the following: serum albumin, 1.3 g/dL; serum creatinine, 0.54 mg/dL; and C3c, 67 mg/dL (normal range: 73-138 mg/dL). The physical and laboratory findings did not suggest autoimmune diseases. A renal biopsy was then performed. Specimen examination under a light microscope showed mesangial cell proliferation, increased mesangial matrix with lobulation, and some double contours of the glomerular basement membrane in almost all glomeruli, which are characteristic findings of MPGN. Immunofluorescent studies showed IgA deposits not only in the mesangial regions but also along the capillary walls, which were more strongly stained than C3. IgA subclass staining showed a stronger immunoreactivity for IgA2 than IgA1. Electron microscopic studies showed electron-dense deposits in the subendothelial, subepithelial, and paramesangial regions. Based on these findings, the patient was diagnosed with IgA-dominant MPGN. Accordingly, she was treated with three courses of methylprednisolone pulse therapy (MPT), followed by prednisolone, mizoribine, and lisinopril. Although hypocomplementemia improved after three courses of MPT, nephrotic-range proteinuria and hypoalbuminemia remained; therefore, two courses of MPT were additionally administered, and the immunosuppressant was changed from mizoribine to cyclosporine (CsA). Finally, the urinary protein level decreased, and a subsequent renal biopsy, two years later, showed improvement in the lesions. CONCLUSIONS: We report an atypical case of MPGN with IgA2 dominant deposits along the glomerular capillary wall and in the mesangial region. The case was refractory to standard therapy but sensitive to CsA, which resulted in remission. Our findings suggest that CsA may be useful as an immunosuppressant to treat refractory MPGN.

PKD1-Dependent Renal Cystogenesis in Human Induced Pluripotent Stem Cell-Derived Ureteric Bud/Collecting Duct Organoids.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease leading to renal failure, wherein multiple cysts form in renal tubules and collecting ducts derived from distinct precursors: the nephron progenitor and ureteric bud (UB), respectively. Recent progress in induced pluripotent stem cell (iPSC) biology has enabled cyst formation in nephron progenitor-derived human kidney organoids in which PKD1 or PKD2, the major causative genes for ADPKD, are deleted. However, cysts have not been generated in UB organoids, despite the prevalence of collecting duct cysts in patients with ADPKD. METHODS: CRISPR-Cas9 technology deleted PKD1 in human iPSCs and the cells induced to differentiate along pathways leading to formation of either nephron progenitor or UB organoids. Cyst formation was investigated in both types of kidney organoid derived from PKD1-deleted iPSCs and in UB organoids generated from iPSCs from a patient with ADPKD who had a missense mutation. RESULTS: Cysts formed in UB organoids with homozygous PKD1 mutations upon cAMP stimulation and, to a lesser extent, in heterozygous mutant organoids. Furthermore, UB organoids generated from iPSCs from a patient with ADPKD who had a heterozygous missense mutation developed cysts upon cAMP stimulation. CONCLUSIONS: Cysts form in PKD1 mutant UB organoids as well as in iPSCs derived from a patient with ADPKD. The organoids provide a robust model of the genesis of ADPKD.

Homozygous splicing mutation in NUP133 causes Galloway-Mowat syndrome.

OBJECTIVE: Galloway-Mowat syndrome (GAMOS) is a neural and renal disorder, characterized by microcephaly, brain anomalies, and early onset nephrotic syndrome. Biallelic mutations in WDR73 and the 4 subunit genes of the KEOPS complex are reported to cause GAMOS. Furthermore, an identical homozygous NUP107 (nucleoporin 107kDa) mutation was identified in 4 GAMOS-like families, although biallelic NUP107 mutations were originally identified in steroid-resistant nephrotic syndrome. NUP107 and NUP133 (nucleoporin 133kDa) are interacting subunits of the nuclear pore complex in the nuclear envelope during interphase, and these proteins are also involved in centrosome positioning and spindle assembly during mitosis. METHODS: Linkage analysis and whole exome sequencing were performed in a previously reported GAMOS family with brain atrophy and steroid-resistant nephrotic syndrome. RESULTS: We identified a homozygous NUP133 mutation, c.3335-11T>A, which results in the insertion of 9bp of intronic sequence between exons 25 and 26 in the mutant transcript. NUP133 and NUP107 interaction was impaired by the NUP133 mutation based on an immunoprecipitation assay. Importantly, focal cortical dysplasia type IIa was recognized in the brain of an autopsied patient and focal segmental glomerulosclerosis was confirmed in the kidneys of the 3 examined patients. A nup133-knockdown zebrafish model exhibited microcephaly, fewer neuronal cells, underdeveloped glomeruli, and fusion of the foot processes of the podocytes, which mimicked human GAMOS features. nup133 morphants could be rescued by human wild-type NUP133 mRNA but not by mutant mRNA. INTERPRETATION: These data indicate that the biallelic NUP133 loss-of-function mutation causes GAMOS. Ann Neurol 2018;84:814-828.

Reduced INF2 expression in nephrotic syndrome is possibly related to clinical severity of steroid resistance in children.

AIM: Mutations of the inverted formin 2 gene (INF2), which encodes a member of the formin family, cause autosomal dominant focal segmental glomerulosclerosis (FSGS) and Charcot-Marie-Tooth (CMT) disease-associated FSGS. However, their role in idiopathic FSGS remains unclear. This study investigated INF2 localization in the normal adult kidney and its expression in children with idiopathic nephrotic syndrome. METHODS: We generated a rabbit polyclonal antibody against the conjugated peptide from human INF2 and studied the glomerular expression of INF2 and synaptopodin using normal human adult kidney tissues and tissues from children with glomerular diseases such as minimal change disease (MCD), FSGS, IgA nephropathy (IgAN), non-IgA mesangial proliferative glomerulonephritis (non-IgAN), and Henoch-Schönlein purpura nephritis (HSPN). RESULTS: The anti-INF2 antibody detected an approximately 140-kD fragment isolated from adult mature glomeruli by western blotting. Immunohistochemically, INF2 was detected in podocytes and renal arteries. Among 56 patients, INF2 in glomeruli was expressed at a similar level in patients with MCD, IgAN, non-IgAN, or HSPN and controls. In FSGS patients, INF2 expression in glomeruli was either decreased or absent. There was a relationship between decreased INF2 expression and the clinical severity of steroid resistant nephrotic syndrome (SRNS). CONCLUSION: We propose that examination of INF2 expression may help to differentiate MCD from FSGS and evaluate the clinical severity of SRNS in children.

A case of secondary pseudohypoaldosteronism that presented as poor weight gain.

Key clinical message: Pseudohypoaldosteronism (PHA) carries a good prognosis if treated early and appropriately, but some cases can have life-threatening events. We underscored the need to consider secondary PHA as one of the differential diagnoses of hyponatremia and hyperkalemia in infancy. Abstract: Pseudohypoaldosteronism (PHA) type 1 has two classifications; the primary type, caused by genetic abnormalities that develop during neonatal and infancy periods, and the secondary type, caused by urinary tract malformation and urinary tract infection. Secondary PHA, if treated early and appropriately, has a good prognosis; however, some cases can present life-threatening events. Therefore, early diagnosis is crucial. We present a case of early infancy secondary PHA presented with marked hyponatremia and poor weight gain. The patient's growth and development improved with secondary PHA treatment. Here, were demonstrated the value of prompt action against infection and electrolyte imbalance and the importance of imaging for diagnosis, and underscore the need to consider secondary PHA as a differential diagnoses of hyponatremia and hyperkalemia in infancy. However further studies, including basic research, to elucidate the diseases pathology is warranted.

Renal arteriovenous fistula discovered ~2 years after renal biopsy: A case report.

Key Clinical Message: Although percutaneous renal biopsy is considered safe, this invasive procedure has complications such as renal arteriovenous fistula (RAVF). Even if complications such as RAVFs are not observed early after renal biopsy, considering the possibility of delayed renal hemorrhage, follow-up with ultrasound after renal biopsy even in asymptomatic cases could be important. Abstract: Although percutaneous renal biopsy is considered safe, this invasive procedure can lead to complications such as renal arteriovenous fistula (RAVF). RAVF occurs when some arteries and veins communicate in the absence of capillaries in the renal hilum or renal parenchyma. It was previously thought to be relatively rare; however, with advances in imaging diagnostics, it is sometimes found asymptomatically. In addition, renal biopsy is the most common cause of acquired RAVF. In this case, RAVF was discovered 2 years after renal biopsy. Late-onset RAVF is scarce. This case highlights that even if complications such as RAVFs are not observed early after renal biopsy, considering the possibility of delayed RAVF, follow-up with ultrasound could be important.

Three Pediatric Patients with Congenital Nephrogenic Diabetes Insipidus due to AVPR2 Nonsense Mutations and Different Clinical Manifestations: A Case Report.

Congenital nephrogenic diabetes insipidus (CNDI), a rare hereditary disorder, is characterized by the inability of the kidneys to concentrate urine in response to the antidiuretic hormone arginine vasopressin (AVP); as a result, large volumes of unconcentrated urine are excreted. In addition to the clinical manifestations of CNDI, such as dehydration and electrolyte disturbances (hypernatremia and hyperchloremia), developmental delay can result without prompt treatment. In approximately 90% of cases, CNDI is an X-linked disease caused by mutations in the arginine vasopressin receptor 2 (AVPR2) gene. In approximately 9% of cases, CNDI is an autosomal recessive disease caused by mutations in the water channel protein aquaporin 2 (AQP2), and 1% of cases are autosomal dominant. We report a case of CNDI caused by a novel AVPR2 nonsense mutation, c.520C>T (p.Q174X), and cases of siblings in another family who had a different AVPR2 nonsense mutation, c.852G>A (p.W284X). Both cases responded well to treatment with hydrochlorothiazide and spironolactone. If CNDI is suspected, especially in carriers and neonates, aggressive genetic testing and early treatment may alleviate growth disorders and prevent irreversible central nervous system disorders and developmental delay.

Relationship between the Mediterranean Diet Score in Pregnancy and the Incidence of Asthma at 4 Years of Age: The Japan Environment and Children's Study.

Several scoring methods for the Mediterranean diet, which is considered as a healthy diet, are available, but studies that have compared more than one of these scores are rare. In addition, the applicability of Mediterranean diet scoring has not been sufficiently examined outside of Mediterranean regions. We collected data on the Mediterranean diet during pregnancy and the incidence of type 1 allergies in offspring from the Japan Environment and Children's Study. Using multiple Mediterranean diet scoring methods, we analyzed the effect of adherence to the Mediterranean diet in pregnancy on the allergies of the offspring. Overall, 46,532 pairs of mothers and children were analyzed. In Japan, a high adherence to the Mediterranean diet during pregnancy was associated with a lower incidence of asthma in the offspring (odds ratio: 0.896, 95% confidence interval: 0.835, 0.962). Furthermore, we found that the selection of the Mediterranean diet scoring method and the setting of the reference value significantly altered the results. Our findings suggest that an appropriate selection of scoring methods and a reference value for food items are important to analyze the effects of adherence to the Mediterranean diet inside and outside of Mediterranean regions.

Elective Cesarean Section during Preterm Prevents Pulmonary Hypoplasia Development in Potter Sequence.

Potter syndrome, first reported in 1946 by Edith Potter, refers to fatal cases of bilateral renal aplasia with pulmonary hypoplasia, peculiar facial features, and limb deformities. Presently, patients with oligohydramnios showing similar pathological manifestations due to oligohydramnios caused by conditions other than bilateral renal aplasia have been reported, and are known as the Potter sequence. There are limited studies and unclear guidelines on the safest delivery time and detailed postpartum management for patients with the Potter sequence. We experienced a case of Potter sequence, in which the patient was born by elective cesarean section at gestational age (GA) of 34 weeks. Fetal ultrasound at GA of 26 weeks 4 days showed oligohydramnios, multilocular cystic lesions in the left kidney, and an absent right kidney. Prenatal fetal MRI at GA of 33 weeks and 3 days showed pulmonary hypoplasia, and the ratio of fetal lung volume (FLV) to fetal body weight (FBW) was 0.0135 ml/g. We suspected that the fetal lung could not grow because of persistent oligohydramnios, which leads to a further decline in the ratio of FLV to FBW during pregnancy. We performed a cesarean section at GA of 34 weeks to prevent the exacerbation of the imbalance between lung volume and physique. We struggled to keep her condition stabilized with strict management of her respiratory condition, dialysis, and nutrition. She was discharged from the hospital at 169 days of age. Elective caesarean section in the term of premature birth prevented the progression of pulmonary hypoplasia and made it possible to save her life. Potter sequence is still relatively unknown, and it is necessary for more studies to be conducted in the future.

A case of tubulointerstitial nephritis and uveitis syndrome following drug-induced acute interstitial nephritis.

Distinguishing between late-onset TINU syndrome and drug-induced AIN remains difficult given that patients with TINU syndrome may develop uveitis long after the onset of AIN. Therefore, ophthalmic examination is required not only upon diagnosis but also continuously or when eye symptoms and relapse of urinary findings are observed.

Impaired Height Growth Associated with Vitamin D Deficiency in Young Children from the Japan Environment and Children's Study.

Vitamin D is essential for calcium absorption and bone homeostasis. Although short-stature children were reported to have low vitamin D concentrations, there is no clear evidence of a link between vitamin D and height growth in young children not limited to those with short stature. We collected height and weight data at 2 and 4 years of age, serum vitamin D concentrations at 4 years, and questionnaire results on sun exposure from the Japan Environment and Children's Study (JECS). We then analyzed the relationship between vitamin D deficiency and height growth. We also analyzed the correlation between serum vitamin D concentration and sun exposure. Overall, 3624 participants from JECS were analyzed. We identified cases of subclinical vitamin D deficiency and insufficiency. We further found that definitive vitamin D deficiency (<10 ng/mL) impaired height growth by 0.6 cm per year even in young children not limited to those with short stature. Furthermore, we clarified that children with vitamin D deficiency had reduced outdoor activity, especially during winter. In children with either short or normal stature, definitive vitamin D deficiency was associated with height growth decline, and reduction in outdoor activity, especially during winter, was a risk factor for vitamin D deficiency.

Steroid therapy is effective for IgA nephropathy after liver transplantation in a pediatric patient.

Hepatic IgA nephropathy is a complication of chronic liver disease. IgA nephropathy after liver transplantation is rare, especially in children, and carries a significant risk factor for chronic renal failure and mortality. In cases without viral hepatitis, steroid therapy may be useful for IgA nephropathy associated with liver dysfunction.

A Case of Nephrotic Syndrome that Resolved with Influenza B Infection.

It has been postulated that measles virus infection is associated with remission of idiopathic nephrotic syndrome (INS) in childhood. There are few reports on the correlation of INS remission with other infections. Previously, there have been two case reports suggesting an association between influenza B virus infection and the remission of INS. The patient was an 18-year-old Japanese woman. The onset of steroid-sensitive NS was at 9 years of age, and pathological diagnosis was minimal change nephrotic syndrome (MCNS). Until 10 months prior to visiting our hospital, the patient's NS was in remission. The patient experienced fever, cough, and malaise and she was diagnosed with type B influenza by a local physician 4 days before visiting our hospital. The patient had vomiting and diarrhea 1 day prior to visiting our hospital. Her weight was 54.7 kg (+5.0 kg) and she had pitting edema of both lower legs. Her serum albumin level was 0.9 g/dL, proteinuria level was 8.73 g/gCr, and urine sediments showed 1-4 red blood cells per high-power field. She was diagnosed with relapse of NS. The level of proteinuria decreased to 0.03 g/gCr with rest alone on day 4 of admission, and a complete remission from NS was observed at approximately 2 weeks after the onset of influenza B infection. We report a rare case wherein spontaneous remission of NS occurred within a short period of 2 weeks after influenza B infection. It is clear that some immunity is involved in the pathogenesis of INS, but there are some cases in which infection improves NS and others in which it recurs.

Impact of the 2016 Kumamoto earthquake on patients with nephrogenic diabetes insipidus and preparations for the future.

Patients with nephrogenic diabetes insipidus should establish a support network system by contacting the government to ensure that water can be preferentially obtained in the event of a disaster and create and carry a medical alert card.