Urinary NGAL, IGFBP-7, and TIMP-2: novel biomarkers to predict contrast medium-induced acute kidney injury in children.

BACKGROUND: Serum creatinine (SCr) is unreliable in detecting acute changes in kidney function. Early recognition of contrast-induced acute kidney injury (CI-AKI) can provide better opportunities for preventive interventions. Therefore, the purpose of this study is to examine the value of the combined detection of urinary neutrophil gelatinase-associated lipocalin (NGAL), insulin-like growth factor binding protein-7 (IGFBP-7), and tissue inhibitor of metalloproteinase-2 (TIMP-2) in the early diagnosis of children with CI-AKI. METHODS: A prospective, single-center clinical trial was performed and included 172 children aged 0-18 years. The dynamic changes of urinary NGAL, IGFBP-7, and TIMP-2 levels in children with intravascular injection of contrast medium were investigated to determine whether they can diagnose CI-AKI early. RESULTS: CI-AKI occurred in 20 of 137 enrolled patients, and the incidence was 14.59%. In the CI-AKI group, urinary levels of NGAL, IGFBP-7, TIMP-2, and [IGFBP-7]*[TIMP-2] were significantly increased 2 h after angiography and remained at high levels at 6 h. Using a cutoff value of 36.274 ng/mL, the specificity was 70.0%, and the sensitivity was 68.4% for the prediction of CI-AKI, which was excellent for urinary NGAL. When both urinary IGFBP-7 and TIMP-2 were used together, urinary [IGFBP-7]*[TIMP-2] at 0.417(ng/mL)2/1000 was regarded as the cutoff value. The specificity was 80.0%, and the sensitivity was 81.2%. CONCLUSIONS: NGAL, IGFBP-7, and TIMP-2 concentrations in the urine of children after receiving injections of contrast medium increased faster than SCr and had good clinical value for the early diagnosis of CI-AKI in children. The combination of IGFBP-7 and TIMP-2 was better than either analyte alone.

[Comparison of therapeutic effects of prednisone combined with mycophenolate mofetil versus cyclosporin A in children with steroid-resistant nephrotic syndrome].

OBJECTIVE: To compare the therapeutic effects of prednisone combined with mycophenolate mofetil (MMF) versus cyclosporin A (CsA) in children with steroid-resistant nephrotic syndrome (SRNS). METHODS: The clinical data of 164 SRNS children who were treated with prednisone combined with MMF or CsA between January 2004 and December 2013 were collected, and the clinical effect of prednisone combined with MMF (MMF group, 112 children) or CsA (CsA group, 52 children) was analyzed retrospectively. RESULTS: At 1 month after treatment, the CsA group had a significantly higher remission rate than the MMF group (67.3% vs 42.9%; P<0.05). At 3 months after treatment, the CsA group also had a significantly higher remission rate than the MMF group (78.8% vs 63.3%; P<0.05). The 24-hour urinary protein excretion in both groups changed significantly with time (P<0.05) and differed significantly between the two groups (P<0.05). There were no serious adverse events in the two groups. CONCLUSIONS: Prednisone combined with MMF or CsA is effective and safe for the treatment of SRNS in children, and within 3 months of treatment, CsA has a better effect than MMF.

Mycophenolate mofetil therapy for steroid-resistant IgA nephropathy with the nephrotic syndrome in children.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) presents as nephrotic syndrome (NS) relatively rarely, and the current treatment experience of IgAN patients with NS is mostly with adults. The objective of our study was to investigate the efficacy of corticosteroids and mycophenolate mofetil (MMF) in treating childhood immunoglobulin A nephropathy (IgAN) with nephrotic syndrome. METHODS: A total of 58 children (39 boys and 19 girls) diagnosed with nephrotic syndrome and primary IgAN were enrolled in the study. All the patients were administered prednisone 2 mg/kg per day for 8 weeks. Steroid-resistant patients were treated with the combined use of MMF (dose of 20 ~ 30 mg/kg per day) and prednisone for 6-12 months. The prednisone dose was reduced stepwise during the combined treatment. RESULTS: Of the 58 children, 14 were steroid-sensitive (M, S, and T variants of the Oxford classification were 0 in most children), and 44 cases who presented serious pathological damage to the kidney were steroid-resistant. The estimated glomerular filtration rate (eGFR) of the steroid-resistant children (86.69 ± 26.85 ml/min/1.73 m(2)) was significantly lower (P < 0.05) than that of the steroid-sensitive children (106.89 ± 26.94 ml/min/1.73 m(2)). After 4 months of combined MMF treatment in 33 steroid-resistant children, complete remission of proteinuria was found in 21 cases, partial remission of proteinuria in 6 cases, and no response was found in 6 cases. Except for the T variant, other variants of the Oxford classification, including M, E, and S morphological variables, was not significantly different among patients complete remission, those with partial remission, and those with no response. The eGFR of children with complete remission of proteinuria (100.04 ± 18.47 ml/min/1.73 m(2)), that of those with partial remission (92.24 ± 27.63 ml/min/1.73 m(2)), and that of those with no response (72.17 ± 27.55 ml/min/1.73 m(2)) were significantly different (P < 0.05). CONCLUSION: Corticosteroid therapy showed satisfactory efficacy in IgAN children with nephrotic syndrome and slight pathological damage. The effect of MMF was good for steroid-resistant IgAN children, but poor for those with tubular atrophy/interstitial fibrosis and renal function impairment.

[Clinical characteristics of children with an initial onset of IgA nephropathy with nephrotic syndrome].

OBJECTIVE: To study the clinical characteristics of children with an initial onset of IgA nephropathy with nephrotic syndrome and compare them with children with primary nephrotic syndrome, in order to provide a theoretical basis for the differential diagnosis of the two diseases. METHODS: Fifty children diagnosed with an initial onset of IgA nephropathy with nephrotic syndrome were included in this study. Seventy-two children diagnosed with an initial onset of primary nephrotic syndrome served as the control group. The clinical and laboratory examination characteristics were compared between the two groups. RESULTS: The IgA nephropathy group had significantly higher incidence rates of gross haematuria, microscopic haematuria, hypertension, acute kidney injury, low serum high-density lipoprotein cholesterol, anemia, low serum complement C4, steroid resistance, and nephritis-type nephrotic syndrome and a significantly lower incidence of elevated serum IgE compared with the control group (P<0.05). There were significant differences in serum creatinine, serum uric acid, serum total cholesterol, serum high-density lipoprotein cholesterol, serum IgE, serum complement C4, and hemoglobin levels between the IgA nephropathy and the control groups (P<0.05). The thresholds of serum IgE (<131.2 IU/mL) and high-density lipoprotein cholesterol (<1.35 mmol/L) were reference parameters in the differential diagnosis of IgA nephropathy with nephrotic syndrome and primary nephrotic syndrome. CONCLUSIONS: Children with IgA nephropathy presenting nephrotic syndrome manifest mainly as nephritis type and steroid-resistant type in the clinical classification. Cinical manifestations accompanied by serum levels of high-density lipoprotein cholesterol and IgE are helpful for differential diagnosis of IgA nephropathy presenting nephrotic syndrome and primary nephrotic syndrome.

[Significance of trace deposition of immunoglobulin M in glomerular mesangium in children with minimal change nephrotic syndrome].

OBJECTIVE: To study the significance of trace immunoglobulin M (IgM) deposits in glomerular mesangium in children with minimal change primary nephrotic syndrome (PNS). METHODS: One hundred and six children who were clinically diagnosed with PNS and pathologically diagnosed with minimal change disease (MCD) and trace deposition of IgM in renal tissues were enrolled as subjects. Eighty-one PNS children with MCD but no deposition of immune complexes were used as the control group. The clinical characteristics and efficacies of glucocorticoids and immunosuppressants were retrospectively analyzed in the two groups. All patients were given full-dose prednisone by oral administration, and patients with glucocorticoid resistance or frequent relapses were additionally given immunosuppressants. RESULTS: The incidence of glucocorticoid resistance in the IgM deposit group was significantly higher than that in the control group (27.2% vs 12.3%; P<0.05). The incidence of frequent relapses in the IgM deposit group was also significantly higher than that in the control group (48.1% vs 10.4%; P<0.05). The complete remission rate for glucocorticoid-resistant patients treated with prednisone combined with mycophenolate mofetil (MMF) was 68% and 62% respectively in the IgM deposit and control groups (P>0.05). The relapse frequency in patients with frequent relapses was significantly reduced in both groups after treatment with prednisone and MMF in combination (P<0.05). CONCLUSIONS: Trace deposition of IgM in renal tissues may be an important factor for glucocorticoid resistance and frequent relapses in PNS children with MCD. Prednisone combined with MMF may be a better choice in the treatment of patients with glucocorticoid resistance or frequent relapses.

Clinical and pathological features of acute kidney injury in children.

OBJECTIVE: Based on the diagnostic and staging criteria of acute kidney injury (AKI), we analyze the clinical and pathological characteristics of children at different stages of AKI and explored their clinical significances. METHODS: 165 children with AKI were divided into stage 1, stage 2, and stage 3 groups. Clinical and pathologic characteristics of AKI children were analyzed. RESULTS: The three groups of patients showed significant differences in age, etiology, pathological damage, and the median recovery time of serum creatinine. Of the 165 patients, the incidence and duration of hematuria showed significant differences among the three groups, and the stage 1 group showed longer duration of proteinuria. CONCLUSION: The patients were largely in stage 1 and 3. The children with AKI in stage 1 were largely school-age children and acute glomerulonephritis (AGN) was the main etiology. The AKI children in stage 3 were mainly infants, of which the etiology was mainly drugs and septicemia. The pathological type was mainly acute tubulointerstitial nephritis, and the renal function recovery was slow.

Association of the clinicopathological characteristics and proteinuria remission of pediatric IgAV with nephrotic-range proteinuria: A retrospective cohort study.

Background: IgA vasculitis (IgAV) combined with nephrotic-range proteinuria is uncommon, and nephrotic-range proteinuria is considered a risk factor for poor prognosis in children with IgAV. There are few clinical studies with large samples. Methods: Children with IgAV and nephrotic-range proteinuria who were hospitalized at the Department of Nephrology, Rheumatology and Immunology, Hunan Children's Hospital, from March 2008 to January 2020 were retrospectively studied; the patients were aged ≤18 years and were followed up for ≥12 months. We analyzed clinical characteristics, pathological changes, treatment responses, and their relationships in patients with IgAV combined with nephrotic-range proteinuria. Results: Two hundred seventy-seven children with an average age at onset of IgAV with nephritis (IgAVN) of 8.0 years (interquartile range (IQR), 6.0-10.0) were enrolled; 65.7% were aged 6-10 years. The male-to-female ratio was 1.35:1. All children had both nephrotic-range proteinuria and hematuria, 49 (17.7%) had hypoalbuminemia, and 9 (3.2%) had estimated glomerular filtration rate < 90 (mL/min/1.73 m2). All included children were followed up for at least 1 year. At 3, 6, and 12 months of follow-up, the remission rates of proteinuria in children with IgAV combined with nephrotic-range proteinuria were 27.8%, 62.1%, and 83.0%, respectively, and the remission rates of hematuria were 1.4%, 8.7%, and 35.7%, respectively. In addition, children with age at onset of IgAV with nephrotic-range proteinuria ≥10 years, who were female, who had proteinuria ≥100 mg/kg/24 h, and who had a pathological grade III or above had lower remission rates of hematuria and proteinuria (P < 0.05). Multivariate factor analysis was performed by logistic regression and showed age at onset of IgAVN ≥ 10 years and crescents to be risk factors for nonremission of proteinuria at 12 months of follow-up (P < 0.05). Conclusions: Age at onset of IgAVN, sex, proteinuria level, pathological grade, and crescents significantly affect proteinuria remission in children with IgAV combined with nephrotic-range proteinuria.

Risk assessment and prediction model of renal damage in childhood immunoglobulin A vasculitis.

Objectives: To explore the risk factors for renal damage in childhood immunoglobulin A vasculitis (IgAV) within 6 months and construct a clinical model for individual risk prediction. Methods: We retrospectively analyzed the clinical data of 1,007 children in our hospital and 287 children in other hospitals who were diagnosed with IgAV. Approximately 70% of the cases in our hospital were randomly selected using statistical product service soltions (SPSS) software for modeling. The remaining 30% of the cases were selected for internal verification, and the other hospital's cases were reviewed for external verification. A clinical prediction model for renal damage in children with IgAV was constructed by analyzing the modeling data through single-factor and multiple-factor logistic regression analyses. Then, we assessed and verified the degree of discrimination, calibration and clinical usefulness of the model. Finally, the prediction model was rendered in the form of a nomogram. Results: Age, persistent cutaneous purpura, erythrocyte distribution width, complement C3, immunoglobulin G and triglycerides were independent influencing factors of renal damage in IgAV. Based on these factors, the area under the curve (AUC) for the prediction model was 0.772; the calibration curve did not significantly deviate from the ideal curve; and the clinical decision curve was higher than two extreme lines when the prediction probability was ~15-82%. When the internal and external verification datasets were applied to the prediction model, the AUC was 0.729 and 0.750, respectively, and the Z test was compared with the modeling AUC, P > 0.05. The calibration curves fluctuated around the ideal curve, and the clinical decision curve was higher than two extreme lines when the prediction probability was 25~84% and 14~73%, respectively. Conclusion: The prediction model has a good degree of discrimination, calibration and clinical usefulness. Either the internal or external verification has better clinical efficacy, indicating that the model has repeatability and portability. Clinical trial registration: www.chictr.org.cn, identifier ChiCTR2000033435.

Henoch-Schönlein Purpura /IgA Vasculitis Complicated by Coronary Artery Aneurysm: A Case Report and Literature Review.

Henoch-Schönlein purpura (HSP)/ IgA vasculitis (IgAV) is the most common form of systemic vasculitis in children and often involves the skin, gastrointestinal tract, joints, and kidneys, though cardiac involvement rarely occurs. We report on a 6-year-old male child with HSP/IgAV who had renal and cardiac involvement at the initial stage of the disease and in whom we found an extremely rare coronary artery aneurysm. After administration of glucocorticoid combined with mycophenolate mofetil, the renal involvement improved, but the coronary artery aneurysm remained. Pursuant to this case, we retrieved information on other cases of HSP/IgAV complicated with cardiac involvement from the PubMed database, and excluded cases of cardiac involvement accompanied by Kawasaki disease, polyarteritis nodosa, rheumatic fever, Takayasu arteritis, systemic lupus erythematosus, poststreptococcal glomerulonephritis, or sepsis. We then analyzed gender, age, cardiac involvement, renal involvement, treatment, and prognoses. To date, 24 cases of HSP/IgAV complicated with cardiac involvement have been reported. Among them, there were 22 male and 2 female patients, with the onset age ranging from 3 to 71 years old. A total of 10 children (including the child we examined) and 14 adults were identified, and 17 patients (70.8%) had HSP/IgAV complicated with renal involvement. The majority of patients were treated with glucocorticoid and/or immunosuppressants or biological agents, 4 patients died (16.7%), 8 patients were completely relieved (33.3%), and 3 patients had unknown prognoses. This article suggests that HSP/IgAV complicated with cardiac involvement may result in a poor prognosis and early treatment may therefore be essential. Our case revealed that glucocorticoid does not prevent the occurrence of renal and cardiac involvement in HSP/IgAV patients. If HSP/IgAV is complicated with coronary artery dilation, the therapeutic effect of glucocorticoid combined with immunosuppressants is not satisfactory, and early administration of biological agents or IVIG may be an effective therapeutic regimen.

Mycophenolate mofetil therapy for children with steroid-resistant nephrotic syndrome.

Treating children with steroid-resistant nephrotic syndrome (SRNS) has been a clinical challenge for pediatricians. We recruited 24 children (18 boys and six girls) with steroid-resistant idiopathic nephrotic syndrome (SRINS) who were <2 years. All patients were administered prednisone 2 mg/kg per day prior to mycophenolate mofetil (MMF). By the end of the eighth week, MMF was initiated at 25-30 mg/kg daily for 6- 12 months. Prednisone dose was reduced stepwise. Biochemical assays were performed every 2 months. Complete remission was achieved in 15 patients, partial remission in six, and no response to MMF was noted in three. With MMF treatment, the levels of urinary protein and serum cholesterol decreased and that of serum albumin increased in a time-dependant manner. We demonstrated the MMF could reduce proteinuria in SRINS children <2 years. Our study suggests that MMF therapy might be an effective strategy for treating SRINS in children <2 years.

[Relationship between integrin-linked kinase expression and renal glomerular damage in children with Henoch-Schnlein purpura nephritis].

OBJECTIVE: Recent studies have shown that integrin linked kinase (ILK) plays an important role in the pathogenesis and development of some kidney diseases. This study aimed to investigate the relationship between ILK and renal glomerular damage in children with Henoch schonlein purpura nephritis (HSPN). METHODS: One hundred and eighty eight HSPN children (aged 3 to 17 years) were assigned to five groups according to the classification of the International Study of Kidney Disease in Children (ISKDC): grade < or = IIa (n = 62), grade IIb (n = 42), grade IIIa (n = 29), grade IIIb (n = 40) and grade > or = IV (n = 15). Fifteen children with basement membrane nephropathy served as the control group. ILK expression on glomeruli was ascertained by immunohistochemical staining. The relationships of ILK expression on glomeruli with glomerular histopathologic lesions and urinary protein excretions were examined. RESULTS: The positive areas of ILK expression on glomeruli in the control, grade < or = IIa, grade IIb, grade IIIa, grade IIIb and grade > or = IV groups were (3.35 + or - 1.01)%, (4.88 + or - 1.13)%, (9.64 + or - 1.36)%, (11.27 + or - 1.68)%, (17.42 + or -3.0)% and (20.62 + or - 2.32%), respectively. There were significant differences in the ILK expression between groups (p<0.01). ILK expression on glomeruli increased with increased urinary protein excretions. There were significant differences in the ILK expression in children with different urinary protein excretions (p<0.01). CONCLUSIONS: ILK might be involved in the process of renal glomerular histopathologic damage and the production of proteinuria in children with HSPN.

Identification of a novel COL4A5 mutation in the proband initially diagnosed as IgAN from a Chinese family with X-linked Alport syndrome.

Alport syndrome (AS) is a hereditary progressive nephropathy characterized by hematuria, ultrastructural lesions of the glomerular basement membrane, ocular lesions and sensorineural hearing loss. Germline mutations of COL4A5 are associated with X-linked AS with an extreme phenotypic heterogeneity. Here, we investigated a Chinese family with Alport syndrome. The proband was a 9-year-old boy with hematuria and proteinuria. Based on the test results of renal biopsy and immunofluorescence, the proband was initially diagnosed as IgA nephropathy and the treatment was recommended accordingly. Meanwhile, we found that the treatment outcome was poor. Therefore, for proper clinical diagnosis and appropriate treatment, targeted exome-based next-generation sequencing has been undertaken. We identified a novel hemizygous single nucleotide deletion c.1902delA in COL4A5 gene. Segregation analysis identified that this novel mutation is co-segregated among the affected family members but absent in unaffected family members. The clinical diagnosis of the proband was revised as AS accompanied by IgA nephropathy, which has been rarely reported. Our findings demonstrated the significance of the application of Genetic screening, expanded the mutation spectrum of COL4A5 associated AS patients with atypical renal phenotypes and provided a good lesson to be learned from our detour during the diagnosis.

[Clinical features of the nephrotic syndrome associated with ichthyosis vulgaris and analysis of related gene mutation].

OBJECTIVE: To study clinical features of 3 children who presented with nephrotic syndrome (NS) associated with ichthyosis vulgaris (IV), and to detect relationship between NS associated with IV in patients and FLG gene or NPHS2 gene. METHOD: Clinical and kidney pathological data of the 3 patients were analyzed and progress of pathologic damage in the patient kidney was observed through repeated percutaneous renal biopsy. Using polymerase chain reaction-single strand conformation polymorphism and DNA sequencing, the diversity of the expression of NPHS2 gene in the 3 patients were analyzed, and FLG gene in the 3 patients and parts of their family members with IV was detected. RESULT: (1) The age of the 3 patients (patient 1 was a girl and patients 2 and 3 were boys) suffering from NS was 3 years and 8 months, 2 years and 6 months, and 5 years and 3 months, respectively. The age of onset of IV was 1 year and 6 months, 10 months, and 2 years and 6 months, respectively. All the 3 patients were resistant to steroid therapy. Despite multi-immunosuppressive therapy, no clinical response was achieved. The patients were followed up for 1.5 to 4.0 years. The patients displayed continuous proteinuria, renal function was normal, but their heights were lower than other children at the same age. (2) The older brother of patient 1 died of uremia. The other patients' family members did not have kidney disease. (3) Renal histopathology showed that the patients 1 and 2 had mild mesangial proliferative glomerulonephritis (MsPGN) and the patient 3 had minimal change disease (MCD). One and a half years after the first renal biopsy, the patients 1 and 2 underwent repeated renal biopsy. Renal histopathology showed that the 2 patients' disease developed to medium MsPGN. (4) None of the 3 patients had NPHS2 gene mutation. All the three patients had R501X and 2282del4 which are the common gene mutation type of the FLG, and all the patients were heterozygote. With the detection of the FLG gene of the part of the patients of the three families, the second patient's grandfather had the R501X homozygote mutation and the others were the R501X heterozygote mutation and 2282del4 heterozygote mutation. CONCLUSION: The 3 cases of NS associated with IV had no response to steroid and multi-immunosuppressive therapy, the renal damage observed by histopathology progressed fast. The children with NS associated with IV displayed R501X heterozygote mutation and 2282del4 heterozygote mutation of FLG gene, which suggested that the absence of response to steroid and multi-immunosuppressive therapy may be related to the FLG gene.