Pediatric Bilateral Hypoplastic Kidney Complicated With C1q Nephropathy: A Case Report.

Progressive kidney dysfunction is often observed in children with bilateral hypoplastic kidneys. While glomerulopathy can exacerbate hypoplastic kidney progression, only IgA nephropathy and post-streptococcal acute glomerulonephritis have been noted in such cases. Herein, we present a case of a four-year-old female patient with bilateral hypoplastic kidney, kidney dysfunction, and significant proteinuria (urinary protein/creatinine ratio > 1 g/gCr), prompting referral owing to persistent hematuria since two years of age. Enalapril was initiated; however, urinary findings exhibited no improvement despite stable symptoms and kidney function. Subsequently, a kidney biopsy was performed at six years of age, and C1q nephropathy was diagnosed. Given the presence of only mild mesangial proliferation, steroids were not administered; enalapril treatment was continued. By seven years of age, the patient's hematuria had resolved, and proteinuria levels had decreased. On the latest follow-up at 12 years of age, kidney function was preserved with only mild proteinuria. This case report highlights the favorable prognosis of asymptomatic C1q nephropathy characterized by mild mesangial proliferation, even in patients with hypoplastic kidneys, renal dysfunction, and significant proteinuria. It emphasizes the significance of timely pathological evaluation for guiding appropriate interventions in such patients.

Mother-child correlation of kidney function: data from the Yamanashi Adjunct Study of Japan Environment and Children's Study (JECS).

BACKGROUND: Individual variation in kidney function can be affected by both congenital and acquired factors, and kidney function in children is possibly correlated with that in their mothers. However, the mother-child correlation in kidney function remains directly unconfirmed. METHODS: We conducted a cross-sectional study of 655 healthy pairs of 7- or 8-year-old children and their mothers as an adjunct study of a nationwide epidemiological study (Japan Environment and Children's Study). RESULTS: Both serum creatinine level (all children, r = 0.324, p < 0.001; girls, r = 0.365, p < 0.001; boys, r = 0.278, p < 0.001) and estimated glomerular filtration rate (eGFR) (r = 0.274, p < 0.001; r = 0.352, p < 0.001; r = 0.195, p < 0.001, respectively) in children were weakly associated with their maternal values. In the single linear regression analyses, maternal values of serum creatinine and eGFR were significantly associated with the children's values. Moreover, several body composition values in children, such as weight-SDS, fat (%), and predicted muscle weight, were also significantly associated with kidney function values in children. In the multiple linear regression analysis for serum creatinine levels in children, in which weight-SDS and predicted muscle weight in children were selected as adjustment factors, maternal serum creatinine level showed a significant positive association (B = 0.214, p < 0.001 in the adjusted model). Moreover, in the multiple linear regression analysis for eGFR value in children, in which fat (%) and predicted muscle weight in children were selected as adjustment factors, maternal eGFR values showed a significant positive association (B = 0.319, p < 0.001). CONCLUSIONS: We directly confirmed mother-child correlations in both serum creatinine levels and eGFR values, particularly in girls. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information.

Epidemiology conduction of paediatric rheumatic diseases based on the registry database of the Pediatric Rheumatology Association of Japan.

OBJECTIVES: Although epidemiological surveys of paediatric rheumatic diseases in Japan have been conducted, they were single surveys with no continuity. This is the first report of the Pediatric Rheumatology Association of Japan registry database, which was established to continuously collect data for paediatric rheumatic diseases. METHODS: Pediatric Rheumatology International Collaborate Unit Registry version 2 (PRICUREv2) is a registry database established by the Pediatric Rheumatology Association of Japan. The registry data were analysed for the age of onset, time to diagnosis, sex differences, seasonality, and other factors. RESULTS: Our data showed the same trend regarding rates of paediatric rheumatic diseases reported in Japan and other countries. The age of onset was lower in juvenile idiopathic arthritis (JIA) and juvenile dermatomyositis and higher in systemic lupus erythematosus and Sjögren's syndrome. The time to diagnosis was relatively short in JIA and systemic lupus erythematosus but longer in juvenile dermatomyositis and Sjögren's syndrome. Rheumatoid factor-positive polyarticular JIA showed a seasonality cluster with regard to onset. CONCLUSION: PRICUREv2 aided the retrieval and evaluation of current epidemiological information on patients with paediatric rheumatic diseases. It is expected that the data collection will be continued and will be useful for expanding research in Japan.

Arterial spin labeling perfusion imaging in an infant with anti-N-methyl-D-aspartate receptor encephalitis: A case report.

BACKGROUND: Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is an autoimmune encephalitis characterized by complex neuropsychiatric syndromes and the presence of cerebrospinal fluid (CSF) antibodies against NMDAR. The characteristics of anti-NMDAR encephalitis in children, particularly infants, are unclear due to difficulties in neurologic assessment such as psychiatric symptoms. Additionally, subtle or non-specific findings of conventional magnetic resonance imaging (MRI) make early diagnosis even more difficult. Herein, we present the first case of infant anti-NMDAR encephalitis in which perfusion imaging demonstrated marked abnormalities and the absence of conventional MRI findings. CASE PRESENTATION: The patient was an 11-month-old boy who was admitted because of seizure and prolonged fever. He presented with involuntary movements of the mouth and tongue. Brain MRI showed no morphological abnormalities, but three-dimensional arterial spin labeling (ASL) perfusion imaging showed reduced blood flow in the left temporal and frontal regions and the right cerebellum. After that, a positive anti-NMDAR antibody test result was received. Despite treatment with IVIG and methylprednisolone, the involuntary movements and autonomic dysfunction gradually became more prominent. After rituximab administration, the clinical symptoms improved slightly, and follow-up MRI revealed diffuse brain atrophy and improvement in the balance of brain perfusion. CONCLUSIONS: To the best of our knowledge, this is the first case report of infantile anti-NMDAR encephalitis in which cerebral blood flow was evaluated using three-dimensional ASL perfusion imaging. Indeed, our case, which showed abnormalities only in ASL perfusion imaging, suggests that CBF assessment could aid in the early diagnosis of anti-NMDAR encephalitis in infants.

Strong Association of the HLA-DR/DQ Locus with Childhood Steroid-Sensitive Nephrotic Syndrome in the Japanese Population.

Background Nephrotic syndrome is the most common cause of chronic glomerular disease in children. Most of these patients develop steroid-sensitive nephrotic syndrome (SSNS), but the loci conferring susceptibility to childhood SSNS are mainly unknown.Methods We conducted a genome-wide association study (GWAS) in the Japanese population; 224 patients with childhood SSNS and 419 adult healthy controls were genotyped using the Affymetrix Japonica Array in the discovery stage. Imputation for six HLA genes (HLA-A, -C, -B, -DRB1, -DQB1, and -DPB1) was conducted on the basis of Japanese-specific references. We performed genotyping for HLA-DRB1/-DQB1 using a sequence-specific oligonucleotide-probing method on a Luminex platform. Whole-genome imputation was conducted using a phased reference panel of 2049 healthy Japanese individuals. Replication was performed in an independent Japanese sample set including 216 patients and 719 healthy controls. We genotyped candidate single-nucleotide polymorphisms using the DigiTag2 assay.Results The most significant association was detected in the HLA-DR/DQ region and replicated (rs4642516 [minor allele G], combined Pallelic=7.84×10-23; odds ratio [OR], 0.33; 95% confidence interval [95% CI], 0.26 to 0.41; rs3134996 [minor allele A], combined Pallelic=1.72×10-25; OR, 0.29; 95% CI, 0.23 to 0.37). HLA-DRB1*08:02 (Pc=1.82×10-9; OR, 2.62; 95% CI, 1.94 to 3.54) and HLA-DQB1*06:04 (Pc=2.09×10-12; OR, 0.10; 95% CI, 0.05 to 0.21) were considered primary HLA alleles associated with childhood SSNS. HLA-DRB1*08:02-DQB1*03:02 (Pc=7.01×10-11; OR, 3.60; 95% CI, 2.46 to 5.29) was identified as the most significant genetic susceptibility factor.Conclusions The most significant association with childhood SSNS was detected in the HLA-DR/DQ region. Further HLA allele/haplotype analyses should enhance our understanding of molecular mechanisms underlying SSNS.

Detection of Splicing Abnormalities and Genotype-Phenotype Correlation in X-linked Alport Syndrome.

BACKGROUND: X-linked Alport syndrome (XLAS) is a progressive hereditary nephropathy caused by mutations in the COL4A5 gene. Genotype-phenotype correlation in male XLAS is relatively well established; relative to truncating mutations, nontruncating mutations exhibit milder phenotypes. However, transcript comparison between XLAS cases with splicing abnormalities that result in a premature stop codon and those with nontruncating splicing abnormalities has not been reported, mainly because transcript analysis is not routinely conducted in patients with XLAS. METHODS: We examined transcript expression for all patients with suspected splicing abnormalities who were treated at one hospital between January of 2006 and July of 2017. Additionally, we recruited 46 males from 29 families with splicing abnormalities to examine genotype-phenotype correlation in patients with truncating (n=21, from 14 families) and nontruncating (n=25, from 15 families) mutations at the transcript level. RESULTS: We detected 41 XLAS families with abnormal splicing patterns and described novel XLAS atypical splicing patterns (n=14) other than exon skipping caused by point mutations in the splice consensus sequence. The median age for developing ESRD was 20 years (95% confidence interval, 14 to 23 years) among patients with truncating mutations and 29 years (95% confidence interval, 25 to 40 years) among patients with nontruncating mutations (P=0.001). CONCLUSIONS: We report unpredictable atypical splicing in the COL4A5 gene in male patients with XLAS and reveal that renal prognosis differs significantly for patients with truncating versus nontruncating splicing abnormalities. Our results suggest that splicing modulation should be explored as a therapy for XLAS with truncating mutations.

Urinary fibrin/fibrinogen degradation products measured using an anti-fibrinogen antibody predict orthostatic proteinuria.

BACKGROUND: The aim of this study was to assess the diagnostic value of urinary fibrin/fibrinogen degradation products (uFDP) measured using an anti-fibrinogen antibody in patients with orthostatic proteinuria (OP), and their use in differentiating between OP and glomerulonephritis (GN). METHODS: uFDP were measured using first urine in the morning (supine) and non-first urine during a hospital visit (upright) and then normalized to urine creatinine (uFDP/Cr, ng/mgCr). We compared (i) OP patients (n = 16); (ii) those in remission from nephrotic syndrome (NS, n = 14) and from GN (IgA nephropathy [IgAN], n = 14; Henoch-Schönlein purpura nephritis [HSPN], n = 12); and (iii) those with active GN (IgAN, n = 12; HSPN, n = 19). RESULTS: The uFDP/Cr ratio increased from supine to upright urine in patients with OP (P < 0.001), but decreased in one case. uFDP were excreted in supine urine in 94% of OP patients, with no excretion in NS remission patients or in 92% of GN remission patients (P < 0.001 for both). uFDP/Cr in supine urine was similar between the OP and active GN patients (P = 0.40), whereas proteinuria in supine urine was in the normal range in all OP patients, but was significantly higher in upright urine in the OP patients (P < 0.001). In upright urine, urinary protein/creatinine ratio was significantly lower in patients with OP than in those with active GN (P = 0.005). A uFDP/Cr ratio cut-off of 1,108 ng/mgCr in upright urine correctly differentiated OP from active GN, with a sensitivity of 87.5% and a specificity of 100%. CONCLUSION: Comparison of uFDP levels in supine/upright urine can be reliable for diagnosing OP and for differentiating it from active GN.

A pediatric case with peripheral facial nerve palsy caused by a granulomatous lesion associated with cat scratch disease.

BACKGROUND: Cat scratch disease is a common infectious disorder caused by Bartonella henselae that is transmitted primarily by kittens. It typically exhibits a benign and self-limiting course of subacute regional lymphadenopathy and fever lasting two to eight weeks. The most severe complication of cat scratch disease is involvement of the nervous system, such as encephalitis, meningitis, and polyneuritis. Peripheral facial nerve palsy associated with Bartonella infection is rare; few reported pediatric and adult cases exist and the precise pathogenesis is unknown. CASE REPORT: A previously healthy 7-year-old boy presented with fever, cervical lymphadenopathy, and peripheral facial nerve palsy associated with serologically confirmed cat scratch disease. The stapedius muscle reflex was absent on the left side and brain magnetic resonance imaging revealed a mass lesion at the left internal auditory meatus. The patient's symptoms and imaging findings were gradually resolved after the antibiotics and corticosteroids treatment. CONCLUSIONS: The suspected granulomatous lesion was considered to have resulted from the host's immune reaction to Bartonella infection and impaired the facial nerve. This is the first case report providing direct evidence of peripheral facial nerve palsy caused by a suspected granulomatous lesion associated with cat scratch disease and its treatment course.

Emergence of Panton-Valentine leukocidin-positive ST59 methicillin-susceptible Staphylococcus aureus with high cytolytic peptide expression in association with community-acquired pediatric osteomyelitis complicated by pulmonary embolism.

A 15-year-old boy, who had had a furuncle on his femur, developed femoral pyomyositis and osteomyelitis complicated by septic pulmonary embolism. Panton-Valentine leukocidin-positive (PVL(+)) ST59 methicillin-susceptible Staphylococcus aureus (MSSA) was isolated from pus and blood. Chemotherapy was started with cefazolin, followed by combination therapy with meropenem/vancomycin with surgery. The MSSA (strain KS1) was positive for increased levels of cytolytic peptide (psmα and hld) and staphylococcal enterotoxin B (SEB), and manifested IS1216V-mediated multidrug resistance (to erythromycin, clindamycin, kanamycin, streptomycin, and chloramphenicol), similar to a genome-analyzed reference strain (PM1) of ST59/SCCmecV(5C2&5) community-associated methicillin-resistant S. aureus (Taiwan CA-MRSA), but unlike another reference strain (M013) of Taiwan CA-MRSA in terms of resistance. The data suggest that CA-MSSA KS1, characterized by PVL, increased levels of cytolytic peptide, SEB, and multidrug resistance, is a possible ancestral strain of Taiwan CA-MRSA and causes the unique association of osteomyelitis and septic pulmonary embolism, requiring complicated management.

Pediatric case of crescentic post-streptococcal glomerulonephritis with myeloperoxidase anti-neutrophil cytoplasmic antibody.

Post-streptococcal glomerulonephritis (PSGN) generally has a good renal prognosis, and immunosuppressive therapies are not needed. However, a few patients present with severe acute kidney injury and extensive crescent formations. The etiology of such patients is not well known, and involvement of anti-neutrophil cytoplasmic antibodies is rarely reported. A 9-year-old girl with rapidly progressive nephritic syndrome was diagnosed with PSGN. A biopsy showed diffuse crescentic glomerulonephritis with immunoglobulin G and C3 deposits; moreover, humps were observed on electron microscopy. After she was administered methylprednisolone pulse therapy and intravenous cyclophosphamide, followed by prednisolone and azathioprine therapy, her urinary abnormalities improved and renal function normalized. However, the myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) titers gradually increased. We speculated that PSGN may be augmented by increased MPO-ANCA levels. Therefore, the patient is currently being treated with losartan, enalapril, azathioprine, and prednisolone. Although the MPO-ANCA titer remains high, urinary findings show mild proteinuria and her renal function has been norma for 18 months since onset. A progressive clinical course and severe histological findings may indicate the involvement of ANCA in deterioration of condition in patients with PSGN. Furthermore, in such cases immunosuppressive therapies should be considered even in pediatric PSGN.

Methylprednisolone pulse therapy and intravenous cyclophosphamide therapy combined with cocktail therapy in severe pediatric Henoch-Schönlein purpura nephritis patient.

Henoch-Schönlein purpura (HSP) is a common self-limited vasculitis in children. The long-term prognosis depends on renal involvement. In severe Henoch-Schönlein purpura nephritis (HSPN) patients, >50 % have crescent formation and nephrotic syndrome that are important predicted outcomes. Therefore, for such patients, an aggressive immunosuppressive therapy is needed to prevent the progression. However, there is no consensus for an appropriate therapeutic regimen for severe pediatric HSPN patients. In this paper, we have reported on a 6-year-old boy who presented with HSPN with nephrotic syndrome and severe histopathological abnormalities; he was diagnosed with International Study of Kidney Disease in Children (ISKDC) grade IVb. Despite treatment with methylprednisolone pulse therapy, followed by oral prednisolone and dipyridamole; the nephrotic syndrome persisted. Subsequently, intravenous cyclophosphamide therapy (IVCY) (500-1,000 mg m-2 once a month for 7 months; total 6,000 mg m-2) was administered, followed by azathioprine and enarapril. Within 7 months of disease onset, complete remission was achieved. After 22 months of the initial renal biopsy, the second biopsy was performed to confirm treatment efficacy. Histopathological findings improved, and ISKDC grade IIIa was diagnosed. Even after 5 years of HSPN onset, complete remission and normal renal function is maintained. Although our evidence is restricted to single patient, we have shown that MPT and IVCY combined with cocktail therapy may be an effective treatment for severe pediatric HSPN.

Early treatment with methylprednisolone pulse therapy combined with tonsillectomy for heavy proteinuric henoch-schönlein purpura nephritis in children.

BACKGROUND: There is no clear consensus as to which patients with Henoch-Schönlein purpura nephritis (HSPN) at risk of a poor outcome should be treated and what therapeutic regimen should be used. METHODS: Nine children with heavy proteinuric HSPN received prompt initiation of methylprednisolone pulse therapy (MPT) combined with tonsillectomy in a prospective study. RESULTS: At presentation, the mean values for the patients' urine protein excretion (early-morning urinary protein/creatinine ratio), serum IgA, activity index (AI), and chronicity index (CI) were 5.0 ± 5.6 g/g Cr, 135.6 ± 56.5 mg/dl, 4.0 ± 0.7, and 1.7 ± 1.3, respectively. At the second biopsy, conducted approximately 24 months after initiation of therapy, the patients' serum albumin had significantly increased (4.4 ± 0.2, p < 0.01), and the serum IgA and AI had significantly decreased (88.1 ± 30.8 mg/dl, p < 0.05; 2.0 ± 1.2, p < 0.01, respectively), whereas the CI remained unchanged. Proteinuria disappeared within 24 months in all but 1 patient, and hematuria disappeared within 38 months in all patients. No patient showed renal impairment or experienced a recurrence and/or exacerbation of HSP/HSPN. CONCLUSIONS: Early treatment with MPT combined with tonsillectomy is effective in ameliorating the histopathological progression and improving the clinical course of children with heavy proteinuric HSPN.

Localization of nephritis-associated plasmin receptor in acute poststreptococcal glomerulonephritis.

The nephritis-associated plasmin receptor is a recently identified nephritogenic antigen associated with acute poststreptococcal glomerulonephritis and proposed to play a pathogenic role, but its precise glomerular localization in acute poststreptococcal glomerulonephritis has not been elucidated. We therefore analyzed renal biopsy sections from 10 acute poststreptococcal glomerulonephritis patients by using immunofluorescence staining with anti-nephritis-associated plasmin receptor antibody and various markers of glomerular components. Nephritis-associated plasmin receptor was detected in the glomeruli of all patients, and double staining for nephritis-associated plasmin receptor and collagen IV showed nephritis-associated plasmin receptor to be predominantly on the inner side of the glomerular tufts. Nephritis-associated plasmin receptor-positive areas within glomerular tufts were further characterized with markers for neutrophils, mesangial cells, endothelial cells, and macrophages. In 6 of the patients, nephritis-associated plasmin receptor staining was seen mainly in neutrophils and to a lesser degree in mesangial and endothelial cells. In the other 4 patients, nephritis-associated plasmin receptor staining was seen mainly in mesangial cells and to a lesser degree in neutrophils and endothelial cells. In all patients, macrophages showed little staining. Elevated plasmin activity in glomerular neutrophils was identified by combining in situ zymography staining for plasmin activity and immunofluorescence staining for neutrophils. The glomerular localizations of nephritis-associated plasmin receptor and another nephritogenic antigen, streptococcal pyrogenic exotoxin B, were compared by double immunofluorescence staining and found to be similar. These findings indicate the nephritogenic potential of nephritis-associated plasmin receptor and offer valuable information with respect to the pathogenic mechanism of acute poststreptococcal glomerulonephritis.