Glucocorticoid effects on bone strength in children with renal diseases.

AIM: Glucocorticoids (GC) are essential medicines for idiopathic steroid-sensitive nephrotic syndrome (ISSNS) and IgA nephropathy (IgAN), with good clinical results. However, they cause bone fragility. The aim of this study was to elucidate GC effects on bone strength assessed as bone mineral density (BMD) and bone quality, using bone turnover markers (BTM), in children with ISSNS or IgAN. METHODS: Eleven children with ISSNS and 13 with IgAN were included. All the patients received GC treatment according to each protocol. The BMD and BTM-serum alkaline phosphatase (S-ALP), tartrate-resistant acid phosphatase 5b (S-TRACP-5b), and undercarboxylated osteocalcin (S-ucOC)-were measured from the initiation of steroid treatment (STx) to the end of STx in both groups. RESULTS: In ISSNS, S-ALP and S-ucOC levels were decreased significantly at 1 month. BMD and S-TRACP-5b levels showed no significant change through this observation period. In IgAN, BMD and S-ALP levels were decreased significantly at 1 and 3 months, respectively, and recovered to baseline at 10 months after the initiation of GC dosage reduction. S-TRACP-5b levels were decreased significantly at 3 months and remained lower than at baseline through the observation period. In both groups, S-ucOC levels did not directly reflect bone strength. CONCLUSION: This study clarified the following three points regarding GC effects on bone strength in children with ISSNS or IgAN: first, S-ALP is a more sensitive bone quality marker than S-TRACP-5b; second, BMD loss was observed only when both S-ALP and S-TRACP-5b levels decreased, and third, S-ucOC levels do not directly reflect bone strength.

Efficacy of plasma exchange with a high dose of acyclovir for disseminated varicella infection.

In individuals treated with immunosuppressive therapies, the varicella-zoster virus (VZV) infection can become disseminated and lead to a life-threatening condition. There is currently no established treatment strategy for this life-threatening condition. Here, we describe a case where plasma exchange (PE) with a high dose of acyclovir (ACV) ameliorated the severe effects, including VZV-hemophagocytic lymphohistiocytosis (VZV-HLH) and disseminated intravascular coagulation (DIC), in a 9-year-old girl with steroid-dependent nephrotic syndrome. This 9-year-old girl experienced frequent relapse steroid-dependent nephrotic syndrome. She had been treated with steroids, tacrolimus, mizoribine, and rituximab. She had not previously received a varicella vaccine. She was admitted with only one vesicular rash. At admission, a serum test revealed 1.6 × 106 copies/mL of VZV DNA. The patient rapidly developed VZV-HLH and DIC. A combination of a high dose of ACV, immunoglobulin, and steroid pulse therapy could not improve these severe complications. Therefore, PE was applied. PE with a high dose of ACV successfully reduced serum VZV DNA from 7.5 × 106 to 2.8 × 104 copies/mL. This reduction in the VZV DNA copy number suggested that the combination of PE and a high dose of ACV was effective in treating a disseminated VZV infection. To the best of our knowledge, this is the first report showing that PE with a high dose of ACV ameliorated the severe complications of disseminated VZV by reducing the VZV DNA copy number.

Prevention of recurrent febrile urinary tract infection in infants: Ultrasonography-oriented approach is more practical than a top-down approach.

BACKGROUND: We previously reported that the top-down approach (TDA) for infants with febrile urinary tract infections (fUTI) could prevent recurrent fUTI (r-fUTI) but produced a high number of false-positives on acute-phase 99m Tc dimercaptosuccinic acid (DMSA) renal scintigraphy. Therefore we compared the ultrasonography-oriented approach (USOA) with TDA from the viewpoint of prevention of r-fUTI. METHODS: The TDA was applied between July 2010 and February 2014 and the USOA was applied between March 2014 and April 2017 in infants with first fUTI. In the USOA group, voiding cystourethrography (VCUG) was performed in the case of abnormality on acute-phase renal bladder ultrasonography (RBUS) or on chronic- phase DMSA, which were performed in all cases. The frequency of r-fUTI was compared between the TDA group and USOA group retrospectively. RESULTS: Seventy-four infants (52 male) and 79 infants (60 male) received TDA or USOA, respectively. No significant differences were found between the TDA and USOA groups in male : female ratio, age in months at initial onset of fUTI, observation period, or number of cases of r-fUTI (TDA group, n = 4; USOA group, n = 5). Seventy-four DMSA scintigraphy and 25 VCUG were carried out in the USOA group, and 111 DMSA scintigraphy and 34 VCUG in the TDA group. CONCLUSIONS: Both USOA and TDA were valid for prevention of r-fUTI, but USOA was superior to TDA with regard to the reduced number of patients undergoing VCUG and DMSA.

Non-enhanced magnetic resonance imaging versus renal scintigraphy in acute pyelonephritis.

The utility of non-enhanced magnetic resonance imaging (MRI) has not been examined extensively for diagnosing acute pyelonephritis (APN) in children. The aims of this study were to compare non-enhanced MRI with technetium-99 m dimercaptosuccinic acid (99m Tc-DMSA) renal scintigraphy in detecting APN. Six boys and one girl with temperature ≥38°C and positive urine culture received both non-enhanced MRI with whole body diffusion-weighted imaging (DWI) and 99m Tc-DMSA scintigraphy ≤7 days from the fever onset. The sensitivity and specificity of MRI in detecting APN lesions diagnosed on 99m Tc-DMSA scintigraphy were 80% and 100%, respectively. Non-enhanced MRI in children with suspected APN ≤7 days from fever onset might be a suitable replacement for 99m Tc-DMSA scintigraphy for the detection of APN.

Top-down approach is possible strategy for predicting breakthrough fUTIs and renal scars in infants.

BACKGROUND: Acute-phase technetium-99 m dimercaptosuccinic acid (DMSA) scintigraphy is recommended for initial imaging in children with febrile urinary tract infection (fUTI). Recently, the importance of identifying patients at risk of recurrent fUTI (r-fUTI) has been emphasized. To clarify the effectiveness of DMSA scintigraphy for predicting r-fUTI in infants, we investigated the relationship between defects on DMSA scintigraphy and r-fUTI. METHODS: Seventy-nine consecutive infants (male: female, 60:19) with fUTI were enrolled in this study. DMSA scintigraphy was performed in the acute phase, and patients with defect underwent voiding cystourethrography and chronic-phase (6 months later) DMSA scintigraphy. Patients were followed on continuous antibiotic prophylaxis (CAP). RESULTS: Defects on acute-phase DMSA scintigraphy were observed in 32 children (40.5%) of 79. The mean follow-up observation period was 17.0 ± 10.1 months. Four patients had r-fUTI (5%). Two of them had defects on DMSA scintigraphy in both the acute phase and chronic phase, and had bilateral vesicoureteral reflux (VUR) grade IV. Two others had r-fUTI without defects on DMSA and did not have VUR. Twelve patients had defect on chronic-phase DMSA scintigraphy and four of them had no VUR. CONCLUSIONS: The top-down approach is a possible method for predicting r-fUTI in infants and does not miss clinically significant VUR. Also, given that the prevalence of r-fUTI was 5% regardless of the presence of defects on acute-phase DMSA, then, in conjunction with genital hygiene and CAP, acute-phase DMSA might be unnecessary if chronic-phase DMSA is performed for all patients to detect renal scar.

Apolipoprotein C-I Levels Are Associated with the Urinary Protein/Urinary Creatinine Ratio in Pediatric Idiopathic Steroid-Sensitive Nephrotic Syndrome: A Case Control Study.

Humoral factors may cause idiopathic steroid-sensitive nephrotic syndrome (ISSNS). In the present study, we analyzed serum proteins using mass spectrometry (MS) to identify proteins associated with the pathophysiology of pediatric ISSNS. We collected serial serum samples from 33 children during each ISSNS phase; Phase A1 is the acute phase prior to steroid treatment (STx), Phase A2 represents the remission period with STx, and Phase A3 represents the remission period after completion of STx. Children with normal urinalyses (Group B) and children with a nephrotic syndrome other than ISSNS (Group C) served as controls. No significant differences in urinary protein/urinary creatinine (UP/UCr) ratios were observed between the children with phase A1 ISSNS and Group C. We used surface-enhanced laser desorption/ionization time of flight MS for sample analysis. Four ion peaks with a mass-to-charge ratio (m/z) of 6,444, 6,626, 8,695, and 8,915 were significantly elevated during ISSNS Phase A1 compared to Phase A2, Phase A3, and Group C. The intensity of an m/z of 6,626 significantly correlated with the UP/UCr ratio and an m/z of 6,626 was identified as apolipoprotein C-I (Apo C-I). Apo C-I levels correlate with the UP/UCr ratio in pediatric ISSNS. Our findings provide new insights into the pathophysiology of ISSNS.

Surges in proteinuria are associated with plasma GL-3 elevations in a young patient with classic Fabry disease.

UNLABELLED: Fabry disease is an X-linked glycosphingolipidosis caused by deficient synthesis of the enzyme α-galactosidase A, which results in accumulations of globotriaosylceramide (GL-3) in systemic tissues. Nephropathy is a dominant feature of Fabry disease. It still remains unclear how the nephropathy progresses. Recombinant agalsidase replacement therapy is currently the only approved, specific therapy for Fabry disease. The optimal dose of replacement enzyme also still remains unclear. The worldwide shortage of agalsidase-ß in 2009 forced dose reduction of administration. It showed that the proteinuria emerged like surges, followed by temporary plasma GL-3 elevations in the early stages of classic Fabry disease. Additionally, it also showed that 1 mg/kg of agalsidase-ß every other week could clear the GL-3 accumulations from podocytes and was required to maintain negative proteinuria and normal plasma GL-3 levels. CONCLUSION: This observation of a young patient with classic Fabry disease about 5 years reveals that the long-term, low-dose agalsidase-ß caused proteinuria surges, but not persistent proteinuria, followed by temporary plasma GL-3 elevations, and agalsidase-ß at 1 mg/kg every other week could clear accumulated GL-3 from podocytes and was required to maintain normal urinalysis and plasma GL-3 levels.

Renal-limited necrotizing granulomatous vasculitis in a pediatric patient.

A 10-year-old girl presented with mild proteinuria and hypertension. Laboratory data indicated slightly elevated serum creatinine (0.67 mg/dL) and elevated serum IgG (2111 mg/dL). On renal arteriography mild stenosis over the entire length of the right renal artery and irregular stenosis of the interlobar arteries in the right kidney were seen. She was diagnosed with renovascular hypertension, and received conventional anti-hypertensive therapy, but did not respond to them. The right kidney had atrophy and dysfunction on technetium-99m-labeled dimercaptosuccinic acid renal scintigraphy, and was therefore resected. Histopathology of the kidney indicated severe necrotizing granulomatous vasculitis affecting the arteries from the renal hilus to the interlobar area. After nephrectomy plus steroid pulse therapy, blood pressure and urinary protein returned to normal. To our knowledge, this is the first report of necrotizing granulomatous vasculitis limited to the medium-sized renal arteries.

A case of post-pneumococcal acute glomerulonephritis with glomerular depositions of nephritis-associated plasmin receptor.

We report the case of a 12-year-old girl who was referred to our hospital with anuria associated with pneumonia. On admission, the patient's blood test results revealed severe renal failure, hypoproteinemia, and hypocomplementemia. Her urinalysis results revealed hematuria, proteinuria, and a positive titer for Streptococcus pneumoniae. S. pneumoniae was also detected in her sputum and blood cultures. The patient was diagnosed with post-pneumococcal acute glomerulonephritis (AGN) with acute renal failure. A renal biopsy demonstrated the infiltration of neutrophils and mononuclear cells into capillary loops. Immunofluorescence studies showed dominant-positive deposition of C3c along the capillary loops and nephritis-associated plasmin receptor (NAPlr) depositions in the mesangial area and capillary loops. Electron microscopy revealed dense deposits in the glomerular basement membrane without a hump in the subepithelial area. These findings were consistent with endocapillary proliferative glomerulonephritis. AGN associated with pneumococcal infection is very rare. This case suggests that NAPlr is the causative antigen not only of post-streptococcal AGN, but also of post-pneumococcal AGN. To our knowledge, this is the first report that shows a relationship between post-pneumococcal AGN and NAPlr depositions in the glomeruli.

Apolipoprotein AII levels are associated with the UP/UCr levels in idiopathic steroid-sensitive nephrotic syndrome.

BACKGROUND: Various humoral factors have been proposed as causal agents of idiopathic steroid-sensitive nephrotic syndrome (ISSNS), resulting in varying data. We used mass spectrometry (MS) to analyze serum proteins in a search for proteins that might be involved in ISSNS pathophysiology. METHODS: Serial serum samples were obtained from 33 children with ISSNS. Samples were collected during Phase A1 [the acute phase prior to steroid treatment (STx)], Phase A2 (remission with STx), and Phase A3 (remission without any medication). We also included age- and sex-matched two control groups comprising children with normal urinalysis (Group B) and children with a nephrotic syndrome other than ISSNS (Group C). The urinary protein/urinary creatinine (UP/UCr) ratios were not statistically different between Phase A1 and Group C. Samples were analyzed using surface-enhanced laser desorption/ionization time of flight MS. RESULTS: A total of 207 peptide ion peaks were detected in the range of m/z 2000-10000. Four peptide ions (m/z 6444, 6626, 8695, and 8915) were detected at significant elevation during Phase A1 compared with Phase A2, Phase A3, and Group C. The intensities of m/z 6444 and 8695 were higher in Phase A3 than in Group B. There were significant correlations between the intensities of m/z 6626, 8695, and 8915 and UP/UCr levels. The m/z 8695 was identified as apolipoprotein AII. CONCLUSIONS: Apolipoprotein AII was detected as a protein associated with the UP/UCr levels in pediatric ISSNS. Our findings present an interesting starting point for further investigation into the pathophysiology of ISSNS.

Utility of non-enhanced magnetic resonance imaging to detect acute pyelonephritis.

It has been established that enhanced computed tomography (CT) and (99m) Tc-dimercaptosuccinic acid renal scintigraphy ((99m) Tc-DMSA scintigraphy) used in conjunction with single-photon emission CT is a useful tool for the diagnosis of acute pyelonephritis (APN). The utility of non-enhanced magnetic resonance imaging (MRI), however, has not been investigated extensively for the diagnosis of APN or renal abscess in children. We describe the case of a 23-month-old boy with suspected APN who received non-enhanced MRI. Whole body diffusion-weighted imaging (DWI) was used, and a background body-signal suppression sequence was applied. High-intensity focal lesions were identified on DWI and low-intensity lesions on the apparent diffusion coefficient map in the acute phase. This case suggested that non-enhanced MRI could be a useful tool for the diagnosis of APN in children, because it can avoid the risks of not only radiation exposure but also nephrogenic systemic fibrosis associated with gadolinium-based contrast agents, especially in infants.

Cytokine dynamics in a 14-year-old girl with tubulointerstitial nephritis and uveitis syndrome.

Tubulointerstitial nephritis and uveitis (TINU) syndrome, which was first described in 1975, has been reported in more than 130 patients, mostly in adolescent or young women. Although data concerning the etiologic background of this inflammatory disease are limited, several humoral factors, including cytokines, have been reported in association with the disease. Here, we report a case of TINU in a 14-year-old girl, whose renal and ophthalmological improvement was associated with the decrease of serum levels of tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and interleukin-8 (IL-8). This suggests the presence of T-cell-mediated immunity in this unique syndrome.

Elevated serum interleukin-7 level in idiopathic steroid-sensitive nephrotic syndrome.

BACKGROUND: Several cytokines have a pathological association with idiopathic steroid-sensitive nephrotic syndrome (ISSNS) in inducing proteinuria or regulating T cells. Because interleukin (IL)-7 plays important roles in regulating T-cell proliferation and sustaining naïve or memory T cells, IL-7 is one of the candidate cytokines in the pathogenesis of ISSNS. Very little is known, however, about the association of IL-7 with ISSNS. To clarify the IL-7 dynamics in children with ISSNS, serum IL-7 level was investigated, from the nephrotic phase before steroid treatment (STx; group A1) to the remission phase with STx (group A2) and without STx (group A3). METHODS: Eighteen children with ISSNS were included in the present study. A total of 25 paired samples were analyzed for groups A1 and A2, and a total of 10 paired samples for groups A1, A2, and A3 due to recurrence. Two control groups (with normal urinalysis, group B; or with nephrotic syndrome other than ISSNS, group C), matched for age and gender, were also included. Serum cytokine level was measured on bead-based assay. RESULTS: Each serum IL-7 level in groups A1 and A3 was higher than each serum IL-7 level of groups C and B, respectively. The group A2 serum IL-7 level was higher than that of group A1. There was no statistical significance of serum IL-7 level between group A1 and group A3. CONCLUSION: Serum IL-7 level was elevated in children with ISSNS regardless of the status of the disease. This brings us one step closer to a better understanding of the pathophysiology of ISSNS in children.

Foot process effacement with normal urinalysis in classic fabry disease.

Fabry disease is an X-linked glycosphingolipidosis caused by deficient synthesis of the enzyme α-galactosidase A, which results in glycosphingolipidosis, predominantly globotriaosylceramide, progressively accumulating in systemic tissue. A dominant complication of Fabry disease is nephropathy. The average age for the development of clinical nephropathy is 27 years in male patients, with up to half of all patients developing end-stage renal failure by their 50s. A recent study revealed podocytes play important roles in antiproteinuria. Podocyte injury leads to foot process effacement and proteinuria. The foot process effacement induces podocyte depletion from the glomerular wall, glomerulosclerosis, and results in end-stage renal failure. We report on a 13-year-old boy with classic Fabry disease, who developed foot process effacement and podocyte depletion even before proteinuria appeared. At the time, his only symptom of Fabry disease was acroparesthesia. He was administered Agalsidase ß (1 mg/kg/dose div) every other week and 14 months after treatment, his renal function remained normal. This is the first report of a patient with classic Fabry disease, with only acroparesthesia, who had normal urinalysis but manifested foot process effacement and podocyte depletion. Podocytes are highly differentiated cells with a limited capacity for cell division and replacement. The large individual variation and often progressive nature of this disease raises concerns about the appropriate timing for initiating enzyme replacement therapy (ERT). Recent data have shown a limited effect of ERT on progressive organ damage. In our case, ERT was initiated before proteinuria appeared, with good outcome.

Th2 cells predominate in idiopathic steroid-sensitive nephrotic syndrome.

BACKGROUND: Various studies reported a higher incidence of allergic disorders, with an overreactivity of type 2 helper T-cell (Th2) immune mechanisms, in children with idiopathic steroid-sensitive nephrotic syndrome (ISSNS). However, Th2 predominance in ISSNS has not been definitively identified. To determine whether Th2 was predominant in children with ISSNS, we used paired samples to measure the type 1 helper T-cell (Th1)/Th2 ratios and serum cytokine levels secreted by Th1 and Th2. METHODS: We measured the Th1/Th2 ratios and levels of Th1- or Th2-secreted cytokines in paired samples. Fourteen children met the inclusion criteria: (1) ISSNS; (2) selectivity index < 0.1; (3) sera obtained in at least two disease phases; (4) no infection; (5) no immunosuppressants. Two control groups (group B, normal urinalysis; group C, nephrotic syndrome other than ISSNS) were included for cytokine level comparisons. Th1 and Th2 numbers were counted by three-color flow cytometry. Cytokine levels were measured by bead-based assay. RESULTS: The Th1/Th2 ratio was lower in group A-1 [nephrotic-phase before steroid treatment (STx)] than in groups A-2 (remission-phase with STx) and A-3 (remission-phase without STx). Th2-secreted interleukin-5 (IL-5) levels were higher in group A-1 than in groups A-2 and A-3. There were no differences in IL-5 levels between groups A-1 and C and between groups A-3 and B. CONCLUSION: Our results suggest that Th2 played a predominant role both in the Th1/Th2 ratio and in the serum IL-5 level in children with ISSNS in the nephrotic phase.

Cytokine profiles of seventeen cytokines, growth factors and chemokines in cord blood and its relation to perinatal clinical findings.

Few papers have investigated the cytokine profiles of multiple cytokines in cord blood. We obtained cord blood samples from 224 infants admitted to our neonatal intensive care unit. Cytokine profiles of 17 cytokines were investigated using cytometric bead array technology. We found a wide variety of cytokines of various levels which ranged from 0.59pg/ml (in Interleukin (IL)-4) to 222.0pg/ml (in macrophage inflammatory protein-1beta. Pro-inflammatory cytokines were highly correlated with each other and with granulocyte-colony stimulating factor and IL-8. On the contrary, IL-5, IL-13, and IL-17 did not show any significant correlation with other cytokines. Several maternal factors were strongly related to several cytokines in cord blood. IL-6, IL-8 and monocyte chemotactic protein-1 were closely related to certain neonatal diseases in preterm neonates. Some cytokines may be regulated independently of each other, while others appear to work as a network affecting physiological and pathological conditions in the fetus.

Refractory kaposiform hemangioendothelioma that expressed vascular endothelial growth factor receptor (VEGFR)-2 and VEGFR-3: a case report.

This report describes the case of a 10-month-old boy who was diagnosed to have kaposiform hemangioendothelioma (KHE) with Kasabach-Merritt syndrome (KMS), which is a rare pediatric vascular tumor with a high mortality rate. Although both KHE with KMS were resistant to various therapies, such as oral prednisolone, sclerotherapy, and chemotherapy, repeated radiation therapy with methylprednisolone pulse therapy did reduce the volume of KHE and improved the symptoms of KMS. Unfortunately, a regrowth of KHE with KMS was observed 4 months after the cessation of treatment and the patient thereafter died from an intracranial hemorrhage and Pneumocystis carinii pneumonia, which is a complication related to repetitive radiation and steroid therapy. A histopathologic examination of autopsy specimens confirmed a diagnosis of KHE and immunohistologic staining was positive for vascular endothelial growth factor receptor (VEGFR)-2 and VEGFR-3. These findings may provide the rationale to further investigate the role of VEGFRs in the pathogenesis of KHE and also to elucidate its prognostic value, along with the application of inhibitors for VEGFRs for the treatment of refractory KHE.