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Familial juvenile hyperuricemic nephropathy (FJHN) is a rare autosomal dominant disease caused by mutations in the uromodulin (UMOD) gene. It is characterized by the development of gout, tubulointerstitial nephropathy, and end-stage renal disease. Here we report a case of FJHN that was diagnosed in early childhood in a boy with a novel gene mutation. At the age of 4 years, the patient was admitted with a diagnosis of purpura nephritis. He was discharged following symptom alleviation. However, hyperuricemia (7–9 mg/dL) and mild renal dysfunction [creatinine-estimated glomerular filtration rate (eGFR): 80–90 mL/min/1.73 m(2)] persisted after discharge. FJHN was suspected on the basis of a maternal family history of hyperuricemia, renal dysfunction, and dialysis. Direct sequence analysis performed at the age of 5 years revealed a novel missense mutation (c766T > G), p.Cys256Gly, in exon 3. Urate-lowering therapy was started, which provided good uric acid control (6.0 mg/dL). At the age of 8 years, persistent renal dysfunction was observed (eGFR: 80–90 mL/min/1.73 m(2)). Interestingly, cases of FJHN with c744C > G (p.Cys248Trp) mutations also exhibit a high incidence of juvenile onset, and identical disulfide bridges are considered responsible for the accumulation of mutant UMOD in the endoplasmic reticulum. Pediatricians should consider UMOD mutation analysis for families with autosomal dominant tubulointerstitial kidney disease (ADTKD) and a bland urinary sediment, even if hyperuricemia is mild. Also, sex and genotype are very important prognostic factors for ADTKD caused by UMOD mutations.

Infection-related glomerulonephritis (IRGN) was previously thought to be due mostly to Streptococcus species, but is now known to be caused by a variety of other pathogens. Nephritis-associated plasmin receptor (NAPlr) was originally isolated from group A streptococci as the protein responsible for acute poststreptococcal glomerulonephritis, and was shown to be identical to streptococcal glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Here, we describe a 7-year-old boy diagnosed with Mycoplasma pneumoniae IRGN presenting with acute nephritic syndrome. Laboratory data revealed a significant increase in serum anti-M. pneumoniae antibody titer. Renal biopsy revealed diffuse global endocapillary proliferation and cellular crescents in 5/43 glomeruli examined. Although antistreptolysin O antibody titer and serum complement C3 level were within the respective normal ranges, glomeruli showed positive staining for NAPlr and upregulation of plasmin activity. In addition, positive staining for NAPlr in the glomeruli was abolished by preabsorption of anti-NAPlr antibody with recombinant M. pneumoniae GAPDH. Western blotting analysis revealed anti-NAPlr antibody reactivity with a band at around the predicted size of GAPDH in the protein isolate of M. pneumoniae (37 kDa). Furthermore, immobilized M. pneumoniae GAPDH bound to anti-NAPlr antibody as well as plasmin in vitro. These data suggest that M. pneumoniae GAPDH has a function similar to streptococcal GAPDH (NAPlr) and may induce plasmin-related glomerular damage in M. pneumoniae IRGN. NAPlr could be a marker of glomerulonephritis related to infection not only by streptococci but also by &M. pneumoniae.

The association of long-term acute kidney injury (AKI) risk with angiotensin-converting enzyme (ACE) inhibitor use in neonates/infants is poorly understood. We examined this association to identify potential AKI risk factors. We retrospectively evaluated 119 children aged

BackgroundAcute kidney injury (AKI) remains a frequent complication in children undergoing hematopoietic stem cell transplantation (HSCT) and an independent risk factor of the patient’s survival and a prognostic factor of progression to chronic kidney disease (CKD). However, the causes of these complications are diverse, usually overlapping, and less well understood.MethodsThis retrospective analysis was performed in 43 patients (28 boys, 15 girls; median age, 5.5 years) undergoing HSCT between April 2006 and March 2019. The main outcome was the development of AKI defined according to the Pediatric Risk, Injury, Failure, Loss, End-stage Renal Disease (pRIFLE) criteria as ≥ 25% decrease in estimated creatinine clearance. The secondary outcome was the development of CKD after a 2-year follow-up.ResultsAKI developed in 21 patients (49%) within 100 days after HSCT. After adjusting for possible confounders, posttransplant AKI was associated with matched unrelated donor (MUD) (HR, 6.26;P = 0.042), but not total body irradiation (TBI). Of 37 patients who were able to follow-up for 2 years, 7 patients died, but none had reached CKD during the 2 years after transplantation.ConclusionsPosttransplant AKI was strongly associated with HSCT from MUD. Although the incidence of AKI was high in our cohort, that of posttransplant CKD was lower than reported previously in adults. TBI dose reduced, GVHD minimized, and infection prevented are required to avoid late renal dysfunction after HSCT in children since their combinations may contribute to the occurrence of AKI.

Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disease (LSD) caused by a deficiency of the iduronate-2-sulfatase (IDS) that catabolizes glycosaminoglycans (GAGs). Abnormal accumulations of GAGs in somatic cells lead to various manifestations including central nervous system (CNS) disease. Enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT) are the currently available therapy for MPS II, but both therapies fail to improve CNS manifestations. We previously showed that hematopoietic stem cell targeted gene therapy (HSC-GT) with lethal irradiation improved CNS involvement in a murine model of MPS II which lacks the gene coding for IDS. However, the strong preconditioning, with lethal irradiation, would cause a high rate of morbidity and mortality. Therefore, we tested milder preconditioning procedures with either low dose irradiation or low dose irradiation plus an anti c-kit monoclonal antibody (ACK2) to assess CNS effects in mice with MPS II after HSC-GT. Mice from all the HSC-GT groups displayed super-physiological levels of IDS enzyme activity and robust reduction of abnormally accumulated GAGs to the wild type mice levels in peripheral organs. However, only the mice treated with lethal irradiation showed significant cognitive function improvement as well as IDS elevation and GAG reduction in the brain. These results suggest that an efficient engraftment of genetically modified cells for HSC-GT requires strong preconditioning to ameliorate CNS involvement in cases with MPS II.

Alport syndrome (AS) is a progressive hereditary renal disease that is characterized by sensorineural hearing loss and ocular abnormalities. It is divided into three modes of inheritance, namely, X-linked Alport syndrome (XLAS), autosomal recessive AS (ARAS), and autosomal dominant AS (ADAS). XLAS is caused by pathogenic variants in COL4A5, while ADAS and ARAS are caused by those in COL4A3/COL4A4. Diagnosis is conventionally made pathologically, but recent advances in comprehensive genetic analysis have enabled genetic testing to be performed for the diagnosis of AS as first-line diagnosis. Because of these advances, substantial information about the genetics of AS has been obtained and the genetic background of this disease has been revealed, including genotype-phenotype correlations and mechanisms of onset in some male XLAS cases that lead to milder phenotypes of late-onset end-stage renal disease (ESRD). There is currently no radical therapy for AS and treatment is only performed to delay progression to ESRD using nephron-protective drugs. Angiotensin-converting enzyme inhibitors can remarkably delay the development of ESRD. Recently, some new drugs for this disease have entered clinical trials or been developed in laboratories. In this article, we review the diagnostic strategy, genotype-phenotype correlation, mechanisms of onset of milder phenotypes, and treatment of AS, among others.

Background: Data are limited regarding risk factors for acute kidney injury (AKI) following cardiac surgery in children with congenital heart disease (CHD). This observational study was performed to examine temporal trends in AKI incidence according to the Pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease (pRIFLE) criteria, identify independent risk factors for AKI after cardiac surgery, and examine associations between AKI and long-term mortality. Methods: We retrospectively evaluated 418 patients (259 males, 159 females; median age, 5 months) who underwent cardiac surgery for CHD between April 2007 and August 2013. Patients were followed up for 2 years. AKI was defined according to the pRIFLE criteria as ≥25% decrease in estimated creatinine clearance. Results: AKI developed postoperatively in 104 cases (24.9%). Approximately 80% belonged to the “Risk” category according to the pRIFLE criteria, and only 21 cases (5%) required renal replacement therapy (peritoneal dialysis in all cases). Multivariate analysis revealed 3 independent risk factors for onset of AKI: young age (Conclusions: Postoperative AKI was strongly associated with young age, high RACHS-1 category, and prolonged CPB time. In addition, mortality rate was higher in patients who survived after recovery from AKI than in those without AKI, even among the lower pRIFLE categories.

Infection-related glomerulonephritis (IRGN) was previously thought to be due mostly to

Null variants in LAMB2 cause Pierson syndrome (PS), a severe congenital nephrotic syndrome with ocular and neurological defects. Patients' kidney specimens show complete negativity for laminin β2 expression on glomerular basement membrane (GBM). In contrast, missense variants outside the laminin N-terminal (LN) domain in LAMB2 lead to milder phenotypes. However, we experienced cases not showing these typical genotype–phenotype correlations. In this paper, we report six PS patients: four with mild phenotypes and two with severe phenotypes. We conducted molecular studies including protein expression and transcript analyses. The results revealed that three of the four cases with milder phenotypes had missense variants located outside the LN domain and one of the two severe PS cases had a homozygous missense variant located in the LN domain; these variant positions could explain their phenotypes. However, one mild case possessed a splicing site variant (c.3797 + 5G>A) that should be associated with a severe phenotype. Upon transcript analysis, this variant generated some differently sized transcripts, including completely normal transcript, which could have conferred the milder phenotype. In one severe case, we detected the single-nucleotide substitution of c.4616G>A located outside the LN domain, which should be associated with a milder phenotype. However, we detected aberrant splicing caused by the creation of a novel splice site by this single-base substitution. These are novel mechanisms leading to an atypical genotype–phenotype correlation. In addition, all four cases with milder phenotypes showed laminin β2 expression on GBM. We identified novel mechanisms leading to atypical genotype–phenotype correlation in PS.

Despite conventional diuretic therapy, volume overload persists in many patients with decompensated heart failure. Adverse effects of diuretics are common, including worsening kidney function and electrolyte disturbance. Furthermore, decreased kidney function also affects the response to diuretics and is associated with an increased risk of mortality. A 10-year-old boy with congestive heart failure (CHF) complicated by advanced chronic kidney disease (CKD) presented with oliguria and generalized edema. He was being treated with furosemide and spironolactone, and these doses were increased to 3 mg/kg/day after admission. Although edema decreased temporarily, the symptoms worsened and furosemide resistance developed 2 months later. Tolvaptan (0.1 mg/kg/day) was started, resulting in a gradual increase in the plasma sodium level and adequate decongestion of the volume overload state. Cardiac function also improved. The use of tolvaptan should be considered in pediatric cases of conventional diuretic-resistant CHF, even when complicated by advanced CKD.

Despite conventional diuretic therapy, volume overload persists in many patients with decompensated heart failure. Adverse effects of diuretics are common, including worsening kidney function and electrolyte disturbance. Furthermore, decreased kidney function also affects the response to diuretics and is associated with an increased risk of mortality. A 10-year-old boy with congestive heart failure (CHF) complicated by advanced chronic kidney disease (CKD) presented with oliguria and generalized edema. He was being treated with furosemide and spironolactone, and these doses were increased to 3 mg/kg/day after admission. Although edema decreased temporarily, the symptoms worsened and furosemide resistance developed 2 months later. Tolvaptan (0.1 mg/kg/day) was started, resulting in a gradual increase in the plasma sodium level and adequate decongestion of the volume overload state. Cardiac function also improved. The use of tolvaptan should be considered in pediatric cases of conventional diuretic-resistant CHF, even when complicated by advanced CKD.

Sphingosylphosphorylcholine (SPC) increased intracellular Ca(2+) concentration ([Ca(2+)]i) and nitric oxide (NO) production in endothelial cells in situ on bovine aortic valves, and induced endothelium-dependent relaxation of bovine coronary arteries precontracted with U-46619. The SPC-induced vasorelaxation was inhibited by N(omega)-monomethyl-L-arginine, an inhibitor of both constitutive and inducible NO synthase (NOS), but not by 1-(2-trifluoromethylphenyl) imidazole, an inhibitor of inducible NOS (iNOS). Immunoblotting revealed that endothelial constitutive NOS, but not iNOS, was present in endothelial cells in situ on the bovine aortic valves. We propose that SPC activates [Ca(2+)]i levels and NO production of endothelial cells in situ, thereby causing an endothelium-dependent vasorelaxation.

This study investigates the role of sphingosylphosphorylcholine (SPC) in the mechanisms underlying cerebral vasospasm after subarachnoid hemorrhage (SAH). The levels of SPC were measured in cerebrospinal fluid (CSF) of patients with SAH and also in an experimental canine model. CSF samples were collected from 11 patients with SAH, and from dogs that had received an injection of SPC into the cisterna magna to examine SPC kinetics in the CSF. SPC was assayed using solid-phase extraction and triple quadrupole mass spectrometry. The SPC concentrations in SAH patients on days 3, 8, and 14 after the onset of SAH were significantly higher than those in normal CSF. In the canine model, rapid dilution of SPC in CSF was observed. In combination with data from previous studies, these results suggest that SPC is involved in the development of cerebral vasospasm. Rapid dilution of SPC in CSF suggests that SPC is released into CSF at higher concentrations than those measured in the present study.

We recently reported that sphingosylphosphorylcholine (SPC) is a novel messenger for Rho-kinase–mediated Ca 2+ sensitization of vascular smooth muscle (VSM) contraction. Subcellular localization and kinase activity of Src family protein kinases (SrcPTKs), except for c-Src, is controlled by a reversible S-palmitoylation, an event inhibited by eicosapentaenoic acid (EPA). We examined the possible involvement of SrcPTKs in SPC-induced Ca 2+ sensitization and effects of EPA. We used porcine coronary VSM and rat aortic VSM cells (VSMCs) in primary culture. An SrcPTKs inhibitor, PP1, and EPA inhibited SPC-induced contraction, concentration-dependently, without affecting [Ca 2+ ] i levels and the Ca 2+ -dependent contraction induced by high K + depolarization. A digitized immunocytochemical analysis in VSMCs revealed that SPC induced translocation of Fyn, but not of c-Src, from the cytosol to the cell membrane, an event abolished by EPA. Translocation of Rho-kinase from the cytosol to the cell membrane by SPC was also inhibited by EPA and PP1. The SPC-induced activation of SrcPTKs was blocked by EPA and PP1, but not by Y27632, an Rho-kinase inhibitor. Rho-kinase–dependent phosphorylation of myosin phosphatase induced by SPC was inhibited by EPA, PP1, and Y27632. Translocation and activation of SrcPTKs, including Fyn, play an important role in Ca 2+ sensitization of VSM contractions mediated by a SPC-Rho-kinase pathway.

Although recent investigations have suggested that a Rho-kinase–mediated Ca 2+ sensitization of vascular smooth muscle contraction plays a critical role in the pathogenesis of cerebral and coronary vasospasm, the upstream of this signal transduction has not been elucidated. In addition, the involvement of protein kinase C (PKC) may also be related to cerebral vasospasm. We recently reported that sphingosylphosphorylcholine (SPC), a sphingolipid, induces Rho-kinase–mediated Ca 2+ sensitization in pig coronary arteries. The purpose of this present study was to examine the possible mediation of SPC in Ca 2+ sensitization of the bovine middle cerebral artery (MCA) and the relation to signal transduction pathways mediated by Rho-kinase and PKC. In intact MCA, SPC induced a concentration-dependent (EC 50 =3.0 μmol/L) contraction, without [Ca 2+ ] i elevation. In membrane-permeabilized MCA, SPC induced Ca 2+ sensitization even in the absence of added GTP, which is required for activation of G-proteins coupled to membrane receptors. The SPC-induced Ca 2+ sensitization was blocked by a Rho-kinase inhibitor (Y-27632) and a dominant-negative Rho-kinase, but not by a pseudosubstrate peptide for conventional PKC, which abolished the Ca 2+ -independent contraction induced by phorbol ester. In contrast, phorbol ester–induced Ca 2+ sensitization was resistant to a Rho-kinase inhibitor and a dominant-negative Rho-kinase. In primary cultured vascular smooth muscle cells, SPC induced the translocation of cytosolic Rho-kinase to the cell membrane. We propose that SPC is a novel messenger for Rho-kinase–mediated Ca 2+ sensitization of cerebral arterial smooth muscle and, therefore, may play a pivotal role in the pathogenesis of abnormal contraction of the cerebral artery such as vasospasm. The SPC/Rho-kinase pathway functions independently of the PKC pathway.

Background: Xeroderma pigmentosum (XP) is a rare, autosomal recessive, premalignant condition of the skin, and is reported to be associated with ocular surface disorders such as conjunctival malignancy and pterygium. Herein, we report a case of successful management of pterygium with multi-layer amniotic membrane graft (AMG) in a young XP patient. Case: An 11-year-old Japanese girl, who had been diagnosed as having XP, was referred to us for treatment of her bilateral pterygium. Surgical intervention was attempted for a temporal, presumably fast-growing pterygium in her left eye. Multi-layer amniotic membrane grafting was performed. Observations: The surgery-induced pain and irritation disappeared within a day. The limbal conjunctival autograft survived on the AMG and re-epithelialization over the AMG was completed in 2 weeks. Best corrected visual acuity improved from 20/32 to 20/16 one month postoperatively. During the 1-year follow-up period, no recurrence was noted. Conclusions: The present case exemplifies that AMG as an adjunct to primary pterygium resection is effective even in a young patient with XP. In addition, multi-layer AMG, which we first demonstrated in this report, seems to be useful for protecting bare sclera and extraocular muscles from mechanical injury.