Adult survivors of childhood-onset steroid-dependent and steroid-resistant nephrotic syndrome treated with cyclosporine: a long-term single-center experience.

BACKGROUND: Although evidence has confirmed that cyclosporine (CS) is efficacious against childhood-onset steroid-dependent and steroid-resistant nephrotic syndrome (SD/SRNS), some patients may continue to relapse during adulthood. However, predictive factors for adult active disease and kidney complications, such as chronic kidney disease (CKD) and hypertension, in this cohort remain unknown. METHODS: We conducted a retrospective study on the long-term outcomes of 81 young adults with childhood-onset SD/SRNS treated with CS. The primary endpoint was the probability of active disease into adulthood. The secondary endpoint was the probability of developing kidney complications. RESULTS: At the last follow-up (median age, 23.2 years; median disease duration, 15.8 years), 44 adult patients (54%) continued to have active disease, whereas 16 patients developed CKD or hypertension, respectively. The proportion of patients developing kidney complications was similar between the active disease and long-term remission groups. Young age at NS onset and history of relapse during the initial CS (median, 31 months) were independent predictive factors for active disease. Acute kidney injury at NS onset, focal segmental glomerulosclerosis, and irreversible CS nephrotoxicity were identified as risk factors for the development of CKD, whereas older age was identified as a risk factor for the development of CKD and hypertension. CONCLUSIONS: More than 50% of adult survivors treated with CS continued to have active disease, and each 20% developed CKD or hypertension. A long-term follow-up is necessary for patients with SD/SRNS to identify the development of kidney complications later in adulthood that can be attributed to prior disease and CS treatment in childhood, irrespective of disease activity. A higher resolution version of the Graphical abstract is available as Supplementary information.

Efficacy of rituximab and risk factors for poor prognosis in patients with childhood-onset steroid-resistant nephrotic syndrome: a multicenter study.

BACKGROUND: The efficacy of rituximab in steroid-resistant nephrotic syndrome (SRNS) is controversial. We previously reported that rituximab in combination with methylprednisolone pulse therapy (MPT) and immunosuppressants was associated with favorable outcomes. We determined risk factors for poor response following rituximab treatment, which remains unknown. METHODS: This retrospective study included 45 patients with childhood-onset SRNS treated with rituximab across four pediatric kidney facilities. Treatment effects were categorized as complete remission (CR), partial remission (PR), and no remission (NR) at one year after rituximab treatment. The primary outcome was the rate of CR, PR, and NR. Risk factors for non-CR were calculated with multivariate logistic regression. Adverse events and the relationship between disease status at one year and long-term prognosis were also evaluated. RESULTS: The rates of CR, PR, and NR at one year were 69%, 24%, and 7%, respectively. The median time from rituximab administration to CR was 90 days. The median follow-up period after rituximab administration was 7.4 years. In multivariate analysis, significant risk factors for poor response were the pathologic finding of focal segmental glomerular sclerosis and a long interval between SRNS diagnosis and rituximab administration. The rates of CR were 90.3% and 21.4% in patients receiving rituximab within and after 6 months following SRNS diagnosis, respectively (p < 0.001). Five patients developed chronic kidney disease stage G5, including 2 of the 11 patients with PR and all 3 patients with NR, whereas none of the 31 patients with CR developed chronic kidney disease stage G5. CONCLUSION: Early administration of rituximab in combination with MPT and immunosuppressants might achieve favorable outcomes in patients with SRNS.

Predictive factors of long-term disease remission after rituximab administration in patients with childhood-onset complicated steroid-dependent nephrotic syndrome: a single-center retrospective study.

BACKGROUND: Despite the fact that rituximab (RTX)-associated adverse events may be relatively frequent in younger patients, recent studies have reported RTX as a suitable first-line steroid-sparing agent for maintaining remission in children with steroid-dependent nephrotic syndrome (SDNS). However, the impact of age at RTX initiation on the long-term outcome remains unknown in this cohort. METHODS: We retrospectively reviewed the clinical course of 61 patients with complicated SDNS who received a single dose of RTX (375 mg/m2) followed by maintenance immunosuppressive agents (IS) from January 2008 to March 2021. In patients who achieved > 12 months of prednisolone-free remission, IS tapering within 6 months was tried to achieve. The primary endpoint was the probability of achieving long-term treatment-free remission at the last follow-up. RESULTS: After RTX initiation, 52 patients (85.2%) relapsed after a median of 665 days, and 44 patients (72.1%) received additional RTX doses (total, 226 infusions). At the last follow-up (median observation period, 8.3 years; median age, 18.3 years), 16 patients (26.2%) achieved long-term remission. Multivariate analysis showed that older age at RTX initiation was the independent predictive factor for achieving long-term remission (odds ratio, 1.25; p < 0.05). The proportion of those who achieved long-term remission was significantly higher in patients aged ≥ 13.5 years than in those aged < 13.5 years at RTX initiation (52.6 vs 14.3%, p < 0.05). Persistent severe hypogammaglobulinemia did not develop in older children (≥ 13.5 years) at RTX initiation. CONCLUSION: For older children with complicated SDNS, RTX appeared to be a suitable disease-modifying therapy without persistent adverse events.

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.

Clinical, pathological, and genetic characteristics of cases with asymptomatic proteinuria not manifesting nephrotic syndrome at onset: a single-center retrospective study.

BACKGROUND: Cases with asymptomatic proteinuria (ASP) not manifesting nephrotic syndrome often pathologically show focal segmental glomerulosclerosis (FSGS). However, characteristics of those cases had not been intensively studied so far. METHODS: We retrospectively reviewed clinical, pathological, and genetic characteristics of 37 children (median age, 9.3 years) who underwent renal biopsy for persistent isolated proteinuria (urine protein-to-creatinine ratio: UP/C, > 0.2 g/g) between 2003 and 2019. Targeted next-generation sequencing (NGS) was utilized for all patients with FSGS, excluding those with secondary FSGS. RESULTS: At biopsy, all patients with FSGS (N = 14) had UP/C ≥ 0.5 g/g and the median UP/C was significantly higher in those with FSGS than those with minor glomerular abnormalities (MGA) (N = 23) (1.49 vs. 0.53 g/g, P < 0.001). Causative variants were found in seven patients with FSGS (TRPC6, WT1, ACTN4, and INF2 in 3, 2, 1, and 1 patient, respectively): all gene variants were in genes manifesting autosomal dominant inheritance mode. The proportion of the perihilar variant was significantly higher in the genetic FSGS patients than in the non-genetic FSGS patients (4/7 vs. 0/7, P < 0.05). Kaplan-Meier analysis showed that the renal survival rate after ASP diagnosis was significantly lower in the genetic FSGS patients than in the non-genetic FSGS and the MGA patients (P < 0.001). CONCLUSIONS: UP/C was a simple and useful predictive parameter for the diagnosis of FSGS. APS without nephrotic syndrome at onset may be associated with autosomal dominant causes of FSGS, especially in those with the perihilar variant.

Predictors of Treatment Response and Long-Term Outcomes in Young Children with Steroid-Dependent Nephrotic Syndrome Treated with High-Dose Mizoribine as First-Line Steroid-Sparing Agent.

Mizoribine may be a safe and effective treatment for children with steroid-dependent nephrotic syndrome (SDNS). However, predictors of treatment response and long-term outcomes after mizoribine discontinuation remain unknown. We retrospectively reviewed the clinical course of 22 children aged ≤ 10 years (median age, 5.3 years) with SDNS who received high-dose mizoribine as the initial steroid-sparing agent (SSA). Mizoribine was administered at a single daily dose of 10 mg/kg (maximum, 300 mg/day) after breakfast. The dose was adjusted to maintain 2-h post-dose mizoribine levels of > 3 µg/mL and was tapered off after 12 months of steroid-free remission. Patients who regressed to SDNS were switched from mizoribine to other SSAs. The primary endpoint was probability of survival without regression to SDNS after mizoribine initiation. Ten patients were able to discontinue SDNS (response group), whereas twelve were switched from mizoribine to other SSAs (non-response group) during a median observation period of 6.0 years after mizoribine. The steroid-dependent dose prior to mizoribine was significantly lower in the response group than in the non-response group (p < 0.05). The Kaplan-Meier analysis revealed that the probability of regression-free survival was significant higher in patients with steroid-dependent dose of < 0.25 mg/kg/day than in those with steroid-dependent dose of ≥ 0.25 mg/kg/day (p < 0.05). During a median follow-up of 5.5 years after mizoribine discontinuation, all but one patient did not develop SDNS. High-dose mizoribine may be an attractive treatment option as initial SSA in young children with low steroid-dependent dose for improved long-term outcomes.

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 outcomes after early treatment with rituximab for Japanese children with cyclosporine- and steroid-resistant nephrotic syndrome.

BACKGROUND: Although rituximab (RTX) may be effective treatment in children with nephrotic syndrome who are resistant to cyclosporine A and steroid (CsA-SRNS), long-term outcomes after B cell depleting therapy remain unclear. CASE-DIAGNOSIS/TREATMENT: We retrospectively reviewed the clinical courses (median follow-up, 5.1 years) of six CsA-SRNS children (three boys; median age at RTX, 4.2 years) unresponsive to oral cyclosporine combined with ≥ 2 courses of intravenous methylprednisolone pulses, who received RTX within 6 months after disease onset (median 11 weeks). After initial RTX treatment (median two doses of 375 mg/m2) followed by retreatment with intravenous methylprednisolone pulses and/or high-dose prednisolone, all patients achieved complete remission at a median of 158 days. Although 17 relapses occurred in five patients during follow-up, all but one patient became steroid sensitive. Severe neutropenia and hypogammaglobulinemia developed in two and four patients, respectively. However, no life-threatening infections were identified in the cohort. At last visit (median age, 11.3 years), all patients maintained complete remission without renal insufficiency. CONCLUSIONS: Although late-onset adverse events should be considered, particularly for young patients, early RTX treatment may have positive outcomes in children with CsA-SRNS in the long term.

Positive effects of single-daily high-dose mizoribine therapy after cyclophosphamide in young children with steroid-dependent nephrotic syndrome.

BACKGROUND: Mizoribine (MZR) therapy after cyclophosphamide (CPM) therapy may be an attractive option in patients with steroid-dependent nephrotic syndrome (SDNS) for the purpose of maintaining remission. This is because CPM is administered only once due to its severe side effects such as gonadal toxicity. However, the long-term prognosis after the treatment regimen remains unknown. METHODS: We retrospectively analyzed the clinical course (median follow-up, 5.9 years) of 54 young children with SDNS (43 boys; age < 10 years) who had undergone 12-week CPM therapy. The patients were classified into two groups: group A, undergoing MZR therapy for > 12 months for maintaining remission after CPM therapy (N = 36), and group B, undergoing CPM monotherapy (N = 18). RESULTS: For 2 years after CPM therapy, 21 of the 36 group A patients were in sustained remission, whereas only 4 of the 18 group B patients had maintained remission (58% vs. 22%, p < 0.05). Furthermore, the rate of regression to SDNS after CPM was significantly lower in group A than in group B (6% vs. 39%, p < 0.05). At the last follow-up (mean age, 10.9 years), 27 of the 36 group A patients (75%) had not received any steroid-sparing agent after the treatment regimen. CONCLUSIONS: Single daily high-dose MZR therapy after CPM therapy may have positive outcomes in young children with SDNS in the long term.

Rapidly Progressive Nephronophthisis in a 2-Year-Old Boy with a Homozygous SDCCAG8 Mutation.

Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease that is characterized by primary ciliary dysfunction (ciliopathy) and progresses to end-stage kidney disease (ESKD) during the second decade of life (juvenile and adolescent NPHP) or before the age of 3 years (infantile NPHP). Here we describe the case of an infant with NPHP who carries a homozygous mutation in SDCCAG8 (also called NPHP10 or BBS16) that encodes SDCCAG8 (serologically defined colon cancer antigen 8). SDCCAG8 is localized at the centrioles of both renal epithelial cells and retinal photoreceptor cells. A mutation in SDCCAG8 is also associated with Bardet-Biedl syndrome (BBS), characterized by NPHP, obesity, polydactyly, and rod-cone dystrophy. A 2-year-old boy was referred to our hospital due to kidney dysfunction of unknown etiology; the patient presented with delayed development and opsoclonus but did not exhibit the clinical characteristics of BBS. Histological findings such as dilatation of tubules and irregular thickness of tubular basement membrane confirmed the diagnosis of NPHP. Four months after referral, the patient's renal function was rapidly deteriorated, and emergency peritoneal dialysis was initiated. Next-generation sequencing (NGS) was performed, showing that the patient carries a homozygous four-base-pair deletion in SDCCAG8 (c.849_852delTTTG, p.Cys283Ter). The patient's parents were also found to be heterozygous for this loss-of-function mutation. To the best of our knowledge, the present patient is the first case of biopsy-proven infantile NPHP with a homozygous SDCCAG8 mutation. We conclude that NGS is extremely useful in the identification of SDCCAG8-related NPHP as a cause of sudden-onset ESKD during infancy.

Initial treatment with pulse methylprednisolone followed by short-term prednisolone and tonsillectomy for childhood IgA nephropathy.

BACKGROUND: Although a combination therapy, comprising 2-year high-dose oral prednisolone (PSL), is effective for treating childhood immunoglobulin A nephropathy (IgAN), severe adverse effects and residual proteinuria occur in some patients after the therapy. METHODS: To clarify the efficacy of intravenous pulse methylprednisolone (IVMP; 15-20 mg/kg; maximum 600 mg/day; for 3 consecutive days/week for 3 weeks) followed by short-term reduced-dose PSL (initially 1 mg/kg; maximum 30 mg on alternate days; tapered off within approximately 12 months) and tonsillectomy as an initial treatment, we retrospectively reviewed the clinical courses of 54 consecutive children with IgAN (32 boys; mean age at onset, 12.2 years; follow-up period of > 2 years) after initiating the treatment. According to the Japanese pediatric IgAN guidelines, we divided the 54 patients into the following two groups: group 1, comprising 24 patients with severe IgAN, and group 2, comprising 30 patients with mild IgAN. RESULTS: After the treatment, proteinuria disappeared in all patients at a median of 1.6 months (group 1, 2.8 months; group 2, 0.4 months) and hematuria disappeared in 47 patients (87%) at a median of 13.2 months (group 1, 15.9 months; group 2, 13.2 months). During the follow-up period (median 5 years), no severe adverse effects were observed in any patient. At the last visit, although two patients (4%) had mild proteinuria, none developed hypertension or renal insufficiency. CONCLUSIONS: As an initial treatment, IVMP followed by short-term PSL and tonsillectomy appears to be effective for treating childhood IgAN.

Predictors of relapse and long-term outcome in children with steroid-dependent nephrotic syndrome after rituximab treatment.

BACKGROUND: In patients with complicated steroid-dependent nephrotic syndrome (SDNS), rituximab (RTX) followed by immunosuppressive agent (IS) can maintain remission without the use of prednisolone (PSL). However, available data on the predictive factors for relapse and the long-term outcome after this protocol are few. METHODS: We retrospectively analyzed 43 SDNS patients who were followed-up for a long time (>2 years, mean 5.4 years) after a single dose of RTX (375 mg/m2) from September 2007. After RTX, PSL was tapered off within 6 months; monotherapy with IS, such as cyclosporine or mycophenolate mofetil, was continued to prevent post-RTX relapse. For patients who achieved >12 months of PSL-free remission, IS was also tapered off. RESULTS: Thirty-nine patients (91 %) could discontinue PSL without relapses at a median of 154 days after the initial RTX. The first relapse of NS occurred in 39 patients (91 %) at a median of 586 days; additional RTX doses were administered in 28 patients (65 %). Kaplan-Meier analysis showed that shorter CD19 cell depletion (<150 days) and younger age at RTX initiation (<12.5 years) were significantly associated with high risk for first relapse after RTX (log rank p < 0.05). In multivariate analysis, mycophenolate mofetil therapy as maintenance IS after RTX was the only predicted risk factor for first relapse (hazard ratio 2.75; p = 0.027). At the last follow-up, IS was still used in 33 patients (77 %); treatment-free remission (>12 months) was achieved in only five patients (12 %). CONCLUSIONS: The introduction of RTX may not be necessarily associated with improved long-term outcome.

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.

Late-onset adverse events after a single dose of rituximab in children with complicated steroid-dependent nephrotic syndrome.

BACKGROUND: Rituximab (RTX) is regarded as a relatively safe and effective treatment for children with steroid-dependent nephrotic syndrome (SDNS). However, late-onset adverse events after RTX, including neutropenia, hypogammaglobulinemia, and increased risk of infections, have been rarely reported in this cohort. MATERIALS AND METHODS: This was a single-center retrospective analysis of adverse events during B-cell depletion periods after a single dose of RTX (375 mg/m2) in 60 patients with complicated SDNS (total 126 doses). After RTX, maintenance therapy with cyclosporine (CsA) or mycophenolate mofetil (MMF) was continued, and prednisolone was discontinued within 6 months. To detect potential drug toxicity, clinical and laboratory parameters were measured before and 1 week after RTX infusion and every month thereafter during B-cell depletion periods (at least 6 months). A single dose of RTX was added if NS relapsed despite maintenance therapy with MMF or CsA after the re-emergence of CD19+ B cells (> 1% of total lymphocytes) in the peripheral blood. RESULTS: Severe neutropenia (neutrophil count < 500/mm3) was identified in 3 patients and hypogammaglobulinemia (IgG levels < 500 mg/dL) in 9 patients. During B-cell depletion periods (median 5 months; range 1 - 20 months), 2 patients required hospitalization because of bacterial infections. However, no lifethreatening infections were identified in our cohort. CONCLUSION: Although neutropenia and hypogammaglobulinemia should be kept in mind as late-onset adverse events of RTX therapy in patients with complicated SDNS, severe infections during B-cell depletion periods are infrequent when our treatment strategies are implemented.

Effect of insulin-like growth factor-I during the early postnatal period in intrauterine growth-restricted rats.

BACKGROUND: Insulin-like growth factor-I (IGF-I) is essential for perinatal growth and development; low serum IGF-I has been observed during intrauterine growth restriction (IUGR). We investigated the effects of recombinant human (rh) IGF-I in IUGR rats during the early postnatal period. METHODS: Intrauterine growth restriction was induced by bilateral uterine artery ligation in pregnant rats. IUGR pups were divided into two groups injected daily with rhIGF-I (2 mg/kg; IUGR/IGF-I, n = 16) or saline (IUGR/physiologic saline solution (PSS), n = 16) from postnatal day (PND) 7 to 13. Maternal sham-operated pups injected with saline were used as controls (control, n = 16). Serum IGF-I and IGF binding proteins (IGFBP) 3 and 5 were measured on PND25. The expression of Igf-i, IGF-I receptor (Igf-ir), Igfbp3, and 5 mRNA in the liver and brain was measured using real-time polymerase chain reaction on PND25. Immunohistochemical staining of the liver for IGF expression was performed. RESULTS: Mean bodyweight on PND3 and PND25 in the IUGR pups (IUGR/IGF-I and IUGR/PSS) was significantly lower than that of the control pups. Serum IGF-I and hepatic Igf-ir mRNA in the IUGR pups were significantly lower than those in the control pups. In the IUGR/IGF-I group, hepatic Igfbp3 mRNA and liver immunohistochemical staining were increased. In the IUGR/PSS and control pups, there were no significant differences between these two groups in serum IGFBP3 and IGFBP5, hepatic Igf-i and Igfbp-5 mRNA, or brain Igf mRNA. CONCLUSIONS: No benefits on body and brain weight gain but an effective increase in hepatic IGFBP-3 was observed after treatment with 2 mg/kg rhIGF-I during the early postnatal period.

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.

Positive role of rituximab in switching from cyclosporine to mycophenolate mofetil for children with high-dose steroid-dependent nephrotic syndrome.

BACKGROUND: Recent randomized studies indicate that mycophenolate mofetil (MMF) is inferior to cyclosporine (CsA) in preventing relapses of nephrotic syndrome (NS). During the last decade, rituximab (RTX) has emerged as a rescue therapy in patients with complicated, frequently relapsing, or steroid-dependent NS. CASE-DIAGNOSIS/TREATMENT: After introducing RTX in our single center, we analyzed 26 patients with steroid-dependent NS who had relapses while receiving long-term CsA and who were subsequently switched to MMF. MMF was adjusted to maintain a targeted predose mycophenolic acid (MPA) level of 2-5 µg/ml. Moreover, for patients who required MMF and high-dose prednisolone (PSL) to maintain remission, a single infusion of RTX (375 mg/m(2)) was added. The primary endpoint was the probability of achieving PSL-free remission for >1 year. At a mean follow-up of 28.8 ± 9.9 months, 11 of 26 patients (42 %) required RTX treatment, and 22 of those patients (85 %) achieved PSL-free sustained remission. The mean predose MPA levels for patients who achieved PSL-free sustained remission were significantly higher compared with those for patients who did not (3.1 µg/ml vs. 1.7 µg/ml, p < 0.05). CONCLUSIONS: After RTX introduction, most patients were able to switch from CsA to MMF and achieve sustained PSL-free remission.