Plasma D-asparagine and the D/L-serine ratio reflect chronic kidney diseases in children regardless of physique.

Biomarkers that accurately reflect renal function are essential in management of chronic kidney diseases (CKD). However, in children, age/physique and medication often alter established renal biomarkers. We studied whether amino acid enantiomers in body fluids correlate with renal function and whether they are influenced by physique or steroid medication during development. We conducted a prospective study of children 2 to 18 years old with and without CKD. We analyzed associations of serine/asparagine enantiomers in body fluids with major biochemical parameters as well as physique. To study consequences of kidney dysfunction and steroids on serine/asparagine enantiomers, we generated juvenile mice with uninephrectomy, ischemic reperfusion injury, or dexamethasone treatment. We obtained samples from 27 children, of which 12 had CKD due to congenital (n = 7) and perinatal (n = 5) causes. Plasma D-asparagine and the D/L-serine ratio had robust, positive linear associations with serum creatinine and cystatin C, and detected CKD with high sensitivity and specificity, uninfluenced by body size or biochemical parameters. In the animal study, kidney dysfunction increased plasma D-asparagine and the D/L-serine ratio, but dexamethasone treatment did not. Thus, plasma D-asparagine and the D/L-serine ratio can be useful markers for renal function in children.

Hydrogen-rich water reduced oxidative stress and renal fibrosis in rats with unilateral ureteral obstruction.

BACKGROUND: Congenital obstructive nephropathy (CKD) is commonly implicated in the pathophysiology of chronic kidney disease occurring in the pediatric and adolescent age groups and the release of reactive oxygen species contribute to the worsening of renal fibrosis. Molecular hydrogen (H2) protects against tissue injury by reducing oxidative stress. We evaluated the efficacy of oral H2-rich water (HW) intake in preventing unilateral ureteral obstruction (UUO)-induced renal injury in rats. METHODS: Male Sprague-Dawley UUO or control rats were administered with distilled water (DW) or HW for 2 weeks post-surgery. Histopathological and immunohistochemical analyses of kidney samples were performed. RESULTS: Histological changes were not apparent in the sham-operated kidneys. However, UUO kidneys were found to have widened interstitial spaces and tubular dilatation. Compared with the UUO + DW group, HW administration attenuated tubulointerstitial injury and reduced interstitial fibrotic area, causing a substantial decline in the frequency of α-SMA-, ED-1-, and TGF-ß1-positive cells in the UUO + HW group. The decrease in the klotho mRNA expression in the UUO + HW group was less pronounced than that in the UUO + DW group. CONCLUSION: Oral HW intake reduced oxidative stress and prevented interstitial fibrosis in UUO kidneys, potentially involving klotho in the underlying mechanism. IMPACT: Oral intake of hydrogen-rich water (HW) can reduce oxidative stress and suppress interstitial fibrosis in unilateral ureteral obstruction-induced renal injury in rats. This mechanism possibly involves klotho, which is known for its antiaging roles. The association between molecular hydrogen and klotho in renal fibrosis is well known; this is the first report on the association in a unilateral ureteral obstruction model. Drinking HW is a safe and convenient treatment for oxidative stress-induced pathologies, without side effects. As a prospect for future research, oral HW intake to treat oxidative stress may improve renal fibrosis in congenital obstructive nephropathy.

Risk Factors Associated with Poor Computer-based Testing (CBT) Scores - Comparing Students' Performance "Without/With COVID-19" and Backgrounds.

Objective: The present study compared students' CBT scores during the 2-year period before ("without COVID-19") and 2-year period during ("with COVID-19") the COVID-19 pandemic, and analyzed factors associated with poor results. Materials: A total of 530 students (368 males and 162 females), who had taken CBT within the period between 2018 and 2021. Methods: Analysis was performed based on the questionnaire results, and the students' performance was compared between "without/with COVID-19" to identify the causes of poor CBT scores. Results: The overall mean IRT score was 515.5±85.4. The without and with COVID-19 groups' scores were 495.7±85.9 and 534.4±80.8, respectively (p<0.01). Among all students, 43 (8.1%) had IRT scores lower than 400 as poor CBT scores; 27 (10.4%) without and 16 (5.9%) with COVID-19, revealing a decrease in the latter. The multivariate analysis of the risk of students having poor CBT scores showed that students with poor performance during the third year (odds ratio:7.02), starting preparation for CBT late (2.19), and not taking any practice examination (4.58) are more likely to have poor CBT results. Conclusions: Due to the COVID-19 pandemic, students spent more time on online home study, and this may have consequently improved their CBT scores. Such learning performance is desirable for medical students, but they have lost the opportunity to gain valuable experiences that they could have acquired through extracurricular activities, such as club activities. In this respect, we cannot simply be pleased by the improvement in students' CBT scores.

A novel de novo truncating TRIM8 variant associated with childhood-onset focal segmental glomerulosclerosis without epileptic encephalopathy: a case report.

BACKGROUND: Heterozygous truncating variants in the Tripartite motif containing 8 (TRIM8) gene have been reported to cause epileptic encephalopathy, both with and without proteinuria. A recent study showed a lack of TRIM8 protein expression, with suppressor of cytokine signaling 1 (SOCS1) overexpression, in podocytes and tubules from a patient with a TRIM8 variant, who presented with epileptic encephalopathy and focal segmental glomerulosclerosis (FSGS). To date, no patients with TRIM8 variants who presented with nephrotic syndrome but without neurological manifestations have been described. CASE PRESENTATION: An 8-year-old girl presented with nephrotic syndrome, without epilepsy or developmental delay. Her kidney biopsy specimens showed FSGS and cystic dilatations of the distal tubules. Whole-exome sequencing identified a novel de novo heterozygous variant in the C-terminal encoding portion of TRIM8 (c.1461C > A), resulting in a premature stop codon (p.Tyr487*). Reverse transcription-polymerase chain reaction using peripheral blood mononuclear cells identified the mRNA sequence of the mutant allele, which confirmed an escape from nonsense-mediated mRNA decay. Immunofluorescence studies showed a lack of TRIM8 expression in glomerular and tubular cells and cystic dilatation of distal tubules. Immunohistochemical studies showed overexpression of SOCS1 in glomerular and tubular cells. CONCLUSIONS: We reported a patient with FSGS, associated with a de novo heterozygous TRIM8 variant, without any neurological manifestations. Our results expanded the clinical phenotypic spectrum of TRIM8 variants.

Baseline characteristics and long-term outcomes of steroid-resistant nephrotic syndrome in children: impact of initial kidney histology.

BACKGROUND: Although many pediatric nephrologists consider focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) as separate clinical entities, whether the initial histology could affect clinical courses in children with steroid-resistant nephrotic syndrome (SRNS) suspected of having an immune-based etiology remains unknown, especially for long-term outcomes. METHODS: We retrospectively reviewed long-term outcomes (> 3 years; median follow-up, 9.1 years) of 21 children with initial SRNS (FSGS, N = 9; MCD, N = 12) who achieved complete remission with immunosuppressive agents, including cyclosporine. RESULTS: At NS onset, incidence of acute kidney injury (67% vs. 8%, P < 0.05) and proportion of patients with non-selective proteinuria (56% vs. 0%, P < 0.01) were significantly higher in the FSGS group than the MCD group. Furthermore, median days until complete remission after treatment was significantly longer in the FSGS group than the MCD group (116 days vs. 45 days, P < 0.001). Although subsequent biopsy histology of the 12 patients in the MCD group was still identical in all MCD, three of nine patients in the FSGS group were reclassified from FSGS to MCD at second biopsy. At last visit, all patients maintained complete remission, and none developed chronic kidney disease. CONCLUSIONS: Initial presentation in the FSGS group was characterized by more severe clinical manifestations than the MCD group. If complete remission is achieved, FSGS and MCD in children with immune-mediated SRNS may constitute a single disease spectrum because the long-term outcomes are favorable, irrespective of initial histology.

Preventive Effect of Tonsillectomy on Recurrence of Henoch-Schönlein Purpura Nephritis after Intravenous Methylprednisolone Pulse Therapy.

Henoch-Schönlein purpura (HSP) is regarded as a benign and self-limiting vasculitis characterized by purpura, arthritis, and gastrointestinal symptoms; however, about one third of the patients develop HSP nephritis (HSPN), the most serious long-term complication. Since 2013, we have proposed that tonsillectomy in addition to intravenous methylprednisolone pulse therapy (IVMP) be performed in all patients with HSPN, similar to immunoglobulin A nephropathy (IgAN) patients because both diseases are considered to a share common pathogenesis. Herein, we retrospectively reviewed the clinical courses of 71 Japanese children with HSPN (34 boys; median age at diagnosis, 6.7 years; median follow-up period, 5.6 years) who had received initial treatment with IVMP (15-20 mg/kg; on 3 consecutive days/week for 3 weeks) followed by oral prednisolone (initially 1 mg/kg; tapered off within 12 months) and achieved clinical remission (i.e., disappearance of both proteinuria and hematuria). The patients were divided into two groups: 31 patients receiving tonsillectomy after IVMP between 2013 and 2017 (tonsillectomy group) and 40 patients receiving IVMP monotherapy between 2003 and 2012 (IVMP group). For the 2 years after IVMP therapy, the rate of HSPN recurrence (i.e., persistent proteinuria combined with hematuria requiring additional treatments) after clinical remission was significantly lower in the tonsillectomy group than the IVMP group (0% vs. 19%, P < 0.05). Despite the short follow-up period in the tonsillectomy group, this study provides the evidence that tonsillectomy may be beneficial for preventing recurrence of HSPN from clinical remission with IVMP therapy in Japanese children.

Long-term renal tubular damage in intrauterine growth-restricted rats.

BACKGROUND: Intrauterine growth restriction (IUGR) has been shown to be associated with increased risk of renal disease or hypertension in later life. Glomerular dysfunction, however, has mainly been reported, and limited information is available to link IUGR with renal tubular damage. The aim of this study was therefore to investigate urinary markers of tubular damage in a rat model of IUGR induced by bilateral uterine artery ligation. METHODS: Pregnant Sprague-Dawley rats underwent bilateral uterine artery ligation, while the control group underwent sham surgery. RESULTS: Birthweight was reduced, and urinary ß2-microglobulin (ß2-MG)-, cystatin C (Cys-C)-, and calbindin-to-creatinine ratios were significantly higher at weeks 4 and 8 in the IUGR group compared with the control group. These urinary markers were not significantly different at week 16 between the two groups. Increased excretion of urinary ß2-MG, Cys-C, and calbindin was observed in IUGR rats at ≥8 weeks of age. CONCLUSION: Children born with IUGR are at increased risk for renal tubular damage.

Evaluation of Urinary Aquaporin 2 and Plasma Copeptin as Biomarkers of Effectiveness of Desmopressin Acetate for the Treatment of Monosymptomatic Nocturnal Enuresis.

PURPOSE: Desmopressin is a synthetic V2 specific analogue of antidiuretic hormone (arginine vasopressin) that is widely used as first line treatment for monosymptomatic nocturnal enuresis. However, no biomarkers to predict desmopressin effectiveness have yet been established. Because arginine vasopressin is unstable, we prospectively measured the major urine concentration factor aquaporin 2 and serum copeptin (as a surrogate marker for vasopressin) in patients with monosymptomatic nocturnal enuresis, and evaluated whether they are useful for predicting desmopressin treatment outcome. MATERIALS AND METHODS: The study included 32 children 6 to 11 years old with monosymptomatic nocturnal enuresis and nocturnal polyuria. Exclusion criteria were daytime urinary symptoms and underlying diseases causing nocturnal enuresis. Subjects were treated with 120 µg or 240 µg desmopressin oral disintegrating tablet and were divided into responders (at 120 or 240 µg) and nonresponders (at 240 µg). Day/night ratios of plasma copeptin and urinary aquaporin 2 were measured during desmopressin treatment. RESULTS: There was no significant difference in baseline day/night ratio of urinary aquaporin 2 between desmopressin responders and nonresponders. After 8 weeks of treatment there was a significant correlation between day/night ratio of aquaporin 2 and percentage of wet nights. In responders (but not nonresponders) there was a significant difference in the change in aquaporin 2 day/night ratio from before treatment to complete remission (p = 0.0004). For plasma copeptin the baseline day/night ratio for responders at 120 µg was significantly lower than in the 240 µg nonresponder group (p = 0.02). CONCLUSIONS: Urinary aquaporin 2 appears to be a biomarker of desmopressin treatment effectiveness during therapy, while plasma copeptin levels before treatment are predictive of desmopressin response.

Impaired nephrogenesis in neonatal rats with oxygen-induced retinopathy.

BACKGROUND: Preterm neonates are born while nephrogenesis is ongoing, and are commonly exposed to factors in a hyperoxic environment that can impair renal development. Oxidative stress has also been implicated in the development of retinopathy of prematurity (ROP). The rat model of oxygen-induced retinopathy (OIR) is the most clinically relevant model of ROP because its biologic features closely resemble those of ROP in preterm infants. We investigated impaired renal development in a rat model of OIR. METHODS: Newborn Sprague-Dawley rats were maintained in either a normoxic (room air, 21% O2 ; control group) or a controlled hyperoxic (80% O2 ; OIR group) environment from birth to postnatal day (P) 12. All pups were then raised in room air from P12 to P19. RESULTS: The hyperoxic environment led to significantly higher urinary excretion of 8-hydroxy-2'-deoxyguanosine, a marker of oxidative DNA damage, and a reduction in nephrogenic zone width at P5 in OIR pups. Additionally, glomerular count was significantly reduced by 20% in the OIR group, and avascular and neovascular changes in the retina were observed only in the OIR group at P19. Messenger RNA levels of vascular endothelial growth factor-A (VEGF-A) and platelet-derived growth factor-ß, essential angiogenic cytokines for glomerulogenesis, in the renal cortex were significantly lower at P5 and significantly higher at P19 in the OIR group compared with controls. CONCLUSION: Renal impairment was caused by exposure to a hyperoxic environment during nephrogenesis, and the pathology of the impaired nephrogenesis in this OIR model reflects the characteristics of ROP observed in preterm infants.

Cytomegalovirus as a potential trigger for systemic lupus erythematosus: a case report.

BACKGROUND: The role of cytomegalovirus infection in triggering systemic lupus erythematosus remains a subject of debate. Here, we present a case of childhood systemic lupus erythematosus with concomitant cytomegalovirus infection, which sheds light on the relationship between these conditions and their treatment in pediatric patients. CASE PRESENTATION: A 12-year-old Japanese girl with no history of systemic illness was diagnosed with systemic lupus erythematosus and concomitant primary cytomegalovirus infection. Her anti-cytomegalovirus immunoglobulin G antibodies were elevated during diagnosis and treatment. Further, the patient's cytomegalovirus pp65 antigenemia level was slightly elevated (1 cell per 5 × 10(4) cells). Treatment included the administration of ganciclovir, prednisolone, methylprednisolone, and cyclophosphamide, none of which prompted adverse effects. The patient was in good condition at the most recent follow-up. CONCLUSION: Ganciclovir treatment is not completely safe, and there are no clinical guidelines regarding its use in patients with systemic lupus erythematosus triggered by cytomegalovirus infection. Our experience with this case suggests that the decision to administer ganciclovir treatment in pediatric cases should be guided by a variety of factors in addition to the cytomegalovirus antigenemia level. These factors include lymphopenia, renal biopsy results, and cytomegalovirus DNA levels detected by polymerase chain reaction. The details of our patient's presentation and treatment should prove illustrative to other clinicians who face similar cases.

Evaluation of kidney dysfunction and angiotensinogen as an early novel biomarker of intrauterine growth restricted offspring rats.

BACKGROUND: Few studies have addressed the growing concerns of chronic kidney diseases in children with intrauterine growth restriction (IUGR). Therefore, the purpose of this study was to evaluate long-term kidney dysfunction and determine if urinary angiotensinogen (AGT) was suitable as a novel early biomarker for kidney dysfunction in IUGR offspring. METHODS: Pregnant rats underwent bilateral uterine artery ligation, and as a control group, sham surgeries were performed. RESULTS: The birth weight was reduced, the urinary AGT to creatinine ratio was significantly higher at week 20, and urinary protein levels were significantly higher at week 32 in IUGR rats than in control rats. On the other hand, the histological findings at week 32 revealed long-term kidney dysfunction, more severe glomerulosclerosis, and greater glomerular diameters in IUGR rats. Moreover, AGT mRNA expression and immunohistological staining were significantly increased in IUGR rats; this suggests that the intrarenal renin-angiotensin system (RAS) contributes to renal dysfunction of IUGR offspring. CONCLUSION: Urinary AGT elevation prior to urinary protein levels suggests that AGT is an early biomarker. At week 32, kidney dysfunction was severe in IUGR rats and intrarenal RAS appeared to be one of the causes.

Optimal urinary protein-to-creatinine ratio as a renal biopsy criterion in children with asymptomatic proteinuria.

BACKGROUND: This retrospective case series aimed at exploring the optimal urinary protein-to-creatinine ratio (uP/uCr) cut-off value to determine the need for renal biopsy in pediatric patients with isolated asymptomatic proteinuria (ASP). METHODS: Data from 32 patients (16 boys, 16 girls) with persistent isolated ASP treated between January 2001 and September 2010 were analyzed. The uP/uCr cut-off value at which a renal biopsy is indicated was determined using the minimum p-value approach. An "optimal" cut-off value was selected to distinguish significant and non-significant glomerular changes. RESULTS: The minimum p-value approach using the χ2-test resulted in a peak uP/uCr of 0.5 g/g x Cr, which was then used to divide the patients into a low-proteinuria group and a high-proteinuria group. The proportion of significant glomerular changes was marginally higher (p = 0.097) in the high-proteinuria group than in the low-proteinuria group after adjustment for multiple tests. In addition, the number of patients with severe proteinuria at the most recent followup was higher in the high-proteinuria group than in the low-proteinuria group. CONCLUSION: The use of a uP/uCr >= 0.5 g/g x Cr may be a reasonable criterion for renal biopsy aimed at distinguishing renal outcomes in patients with persistent isolated ASP.

Synergistic protective effects of mizoribine and angiotensin II receptor blockade on cyclosporine A nephropathy in rats.

BACKGROUND: Chronic cyclosporine A (CsA) nephrotoxicity is manifested by renal dysfunction, progressive histopathological kidney lesions characterized by afferent arteriolopathy, and tubulointerstitial fibrosis. In addition to the direct toxic effect of CsA, many other etiological factors such as angiotensin II, transforming growth factor (TGF)-ß, and macrophage infiltration are involved in this pathogenesis. This study investigated the hypothesis that concomitant administration of mizoribine (MZR) and angiotensin II receptor blockade (ARB) may prevent CsA nephrotoxicity in rats. METHODS: Sprague-Dawley male rats were divided into the following seven groups: group 1, treated with CsA; group 2, treated with CsA + MZR; group 3, treated with CsA + valsartan (Val); group 4, treated with CsA + MZR + Val; group 5, treated with MZR; group 6, treated with Val; and group 7, controls (n = 5 each). Renal histopathology and the effect of CsA-induced nephrotoxicity on inflammatory mediators were evaluated. RESULTS: Results of this study demonstrated that ARB administration significantly decreased arteriolopathy and that in comparison with monotherapy, concomitant administration of MZR and ARB further decreased arteriolopathy, fibrosis, macrophage infiltration, and TGF-ß1 mRNA expression associated with CsA nephrotoxicity. CONCLUSION: These findings indicate that MZR and ARB combination treatment provides synergistic protective effects against chronic CsA nephrotoxicity.

The synergistic effect of mizoribine and a direct renin inhibitor, aliskiren, on unilateral ureteral obstruction induced renal fibrosis in rats.

PURPOSE: Renal fibrosis, the major histopathological change in various renal disorders, is closely related to renal dysfunction. Unilateral ureteral obstruction is a well established model of experimental renal disease that results in tubulointerstitial fibrosis. Previous studies showed that aliskiren and mizoribine ameliorated unilateral ureteral obstruction induced renal fibrosis. However, to our knowledge the protective effect of combination therapy with aliskiren and mizoribine against renal fibrosis is unknown. We investigated the synergistic effects of aliskiren and mizoribine combination therapy on unilateral ureteral obstruction induced fibrosis in rats. MATERIALS AND METHODS: Male Sprague Dawley® rats underwent unilateral ureteral obstruction followed by aliskiren and/or mizoribine treatment. Kidney samples were fixed for histopathology and immunohistochemistry of myofibroblasts (α-SMA) and macrophages (ED-1). Real-time quantitative reverse transcription-polymerase chain reaction was performed to measure α-SMA, TGF-ß1, osteopontin, MCP-1 and renin expression. RESULTS: After unilateral ureteral obstruction the tubular dilatation, interstitial volume and α-SMA expression scores were significantly decreased by combination therapy compared with monotherapy with aliskiren or mizoribine. Combination therapy caused a significant decrease in the number of ED-1 positive cells and in TGF-ß1 gene expression compared with monotherapy with either drug (each p <0.05). Combination therapy also decreased OPN and MCP-1 gene expression (p <0.05). CONCLUSIONS: Aliskiren and mizoribine combination therapy provides increased renal protection against renal fibrosis and unilateral ureteral obstruction induced inflammation.

Uncertainty in management of childhood-onset idiopathic nephrotic syndrome: is the long-term prognosis really favorable?

Despite the recent establishment of clinical practice guidelines, many areas in the management of childhood idiopathic nephrotic syndrome (INS) remain uncertain. In this edition of Pediatric Nephrology Samuel et al. report significant differences between Canadian pediatric nephrologists' practice and guideline recommendations, including initial duration of glucocorticoid treatment, choice of glucocorticoid-sparing agents in cases of frequently relapsing or steroid-dependent INS, and biopsy timing. Although evidence is emerging that the incidence of subsequent relapse can be reduced with longer initial glucocorticoid therapy, even with this new regimen relapse occurs in more than half of the children with steroid-sensitive INS. Cyclosporine (CsA) as a glucocorticoid-sparing agent for children with frequently relapsing or steroid-dependent INS is believed to provide protection from steroid toxicity and significantly improve the quality of life. However, recent follow-up studies of the post-CsA era have revealed a high incidence of INS relapse in adulthood in patients treated with CsA in childhood, and CsA use itself is a significant predictor of recurrent relapses. Therefore, pediatric nephrologists must recognize the potential of adverse effects that may appear later in life because of prolonged immunosuppressive therapy in childhood.