We studied the clinicopathological findings of the patients with C1q nephropathy. Among a total of 277 series of first renal biopsies, seven cases met the diagnostic criteria of C1q nephropathy. In five cases, renal biopsies were performed because of asymptomatic urine abnormalities. The age of onset ranged from 5 to 13 years (8.7 years on average). All cases showed histologic features of mesangial proliferative glomerulonephritis. On electron microscopy, five cases showed electron-dense deposits in the capillary loop as well as in the mesangial area. Treatment with corticosteroid was performed in three cases. After the follow-up period of 4 to 17 years (8.0 years on average), one patient showed microscopic hematuria, and other patients showed normal urinary findings. Our data indicate that most of C1q nephropathy cases are found with asymptomatic urine abnormalities detected by school urinary screening program, and that these cases may have a better clinical course.

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In 2009, we published the new guide named “Manual of Urinary Screening of Elementary and Junior High School Children in Aichi Prefecture.” One of the most important characteristics of the manual is the induction of the ideas for specialized medical institutions of pediatric kidney disease. In total, we fixed eight institutions on specialized medical institutions of pediatric kidney disease in Aichi prefecture. During 2010 and 2011, 76 patients were introduced to these institutions under our criteria. Chronic glomerulonephritis was diagnosed in two-thirds of these patients. A renal biopsy was performed in half these patients, in which approximately 90% were required pharmacotherapy. We figure that our new urinary screening program for school children is beneficial to supply sufficient treatment for pediatric patients with moderate to severe kidney disease.

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We often use immunosuppressive drugs to treat frequently relapsing nephrotic syndrome (FRNS) to avoid the side effects of corticosteroids. Calcineurin inhibitors, especially cyclosporine A (CsA), are commonly used, however, nephrotoxicity is the main adverse effect of CsA. Recently, endoplasmic reticulum stress (ER stress) has been shown to be one of the activators of apoptosis. Here we review the mechanism of ER stress and the unfolded protein response (UPR). There are three major UPR pathways activated via protein sensors located in the ER membrane, including activating transcription factor-6 (ATF6), inositol-requiring 1α (IRE1α), and protein kinase RNA-like ER kinase (PERK). We then discuss in vivo studies that examined the mechanisms, especially through ER stress, which are induced renal cell apoptosis by CsA. Finally, we show our data of ER stress related molecules obtained by real time PCR in renal biopsy tissues from FRNS children before and after 2 year of CsA treatment. The results suggest that CsA induces UPR due to ER stress. ER stress may be a mechanism of CsA-induced nephrotoxicity, and could be a therapeutic target in humans.

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Ureteric branching is a major determinant of nephron number. We showed that inhibited ureteric branching is a mechanism for low nephron number by maternal nutrient restriction. Signaling molecules important in kidney development was also suppressed at an earlier stage of kidney development, suggesting a role in the inhibition of ureteric branching. Caspase-3, a well-known enzyme mediating apoptosis, was suppressed by maternal nutrient restriction contrary to what expected. Caspase-3 was reported to enhance ureteric branching, and we found that its mechanism was to promote ureteric bud cell migration stimulated by Wnt11 via inhibition of β catenin and activation of ROCK1. Low nephron number by maternal protein restriction is known to be transmitted to the next generation, suggesting the presence of an epigenetic mechanism. We examined the effect of maternal undernutrition on DNA methylation profiles in rat embryonic kidney. Methylated genes by maternal nutrient restriction included PI3K, β catenin, activin A receptor, HB-EGF, integrin β4, HGF, Akt2, BMP4 TGF-β1, MMP9, PKA, ILK, and others, most of which are critical for ureteric branching. In conclusion, ureteric branching is important as a mechanism for the reduced nephron number by maternal nutrient restriction and may also be responsible for its transgenerational transmission.

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Ossifying renal tumor of infancy (ORTI) is a rare renal tumor, and the pathogenesis of this condition has not been well established. We present a 4-month-old boy with ORTI, who presented with intermittent gross hematuria for 2 months. CT scan showed a partially calcified soft-tissue mass that was located in the lower pole of the left kidney and extended into the renal sinus. The mass size was about 1.5 cm × 1.5 cm. After 6 months, CT scan showed the mass of same size and the enlarged calcification. After much discussion, left radical nephrectomy was performed. Pathological examination led to a diagnosis of ORTI. ORTI should be considered in the differential diagnosis for infants with gross hematuria and a calcified mass in the renal sinus.

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Here we report the case of a 6-month-old boy with infantile nephrotic syndrome caused by a mutation in the NPHS2 gene. He was admitted to our hospital with palpebral edema. The urinalysis and blood test showed the presence of a high level of protein uria (4+) with hypoalbuminemia (albumin, 1.2 g/dl), which led to the diagnosis of nephrotic syndrome. Although the patient was initiated on prednisolone therapy, he did not achieve remission even after administration of the maximum dose of prednisolone. A kidney biopsy was performed on the 33rd day after initiation of the therapy. Light microscopy findings of the biopsy revealed mesangial cell proliferation and glomerular sclerosis in one third of the glomeruli. Immunofluorescence was negative. Electron microscopic findings of the biopsy revealed effacement of the podocyte foot processes. Genetic testing revealed a missense mutation in the exon4 of the NPHS2 gene (homozygous mutation, p.R168C). Moreover, the same heterozygous mutation was noted in both the parents. Because the condition was difficult to treat with immunosuppressive therapy, single-sided nephrectomy was performed. The NPHS2 gene encodes podocin, a protein expressed in podocyte slit diaphragm. This gene is usually mutated in steroid resistant nephrotic syndrome (SRNS) or focal segmental glomerular sclerosis (FSGS). Although the NPHS2 gene mutations are major cause of FSGS in Europe and America, these mutations are rare in japan, and to the best of our knowledge, only 3 cases have been reported to date. Genetic testing of children with symptoms of this disease may help avoid unnecessary immunosuppressive therapy.

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A 1-month-old boy was diagnosed with infant acute lymphoblastic leukemia. At age 6 months, he underwent CBSCT after achieving remission with induction chemotherapy. Cyclosporin (CsA) was tapered because acute graft versus host disease (GVHD) showed amelioration. He was discharged 101 days after CBSCT without evidence of chronic GVHD. At age 9 months, he developed nephrotic syndrome and prednisolone therapy was started. However, proteinuria persisted for more than four weeks. Steroid resistant nephrotic syndrome was diagnosed. Three steroid pulse therapy courses were administered after the diagnosis. Percutaneous renal biopsy then revealed minimal change disease. Subsequently, mizoribine was introduced and the CsA dosage was increased. Two further steroid pulse therapy courses were administered. However, complete remission was not achieved. Many immunosuppressant drug types were administered, raising concern about recurrence of the original hematologic malignancy. Since the primary disease was B-cell lymphoblastic leukemia, rituximab was administered four times. Proteinuria disappeared and he was discharged at age 1 year and 3 months. To date, he has remained in complete remission. This is a rare case report of nephrotic syndrome developing in a child after CBSCT.

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[in Japanese]

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