Glomerular basement membrane ultrastructural changes in a patient with COQ2 glomerulopathy: A case report.

Primary coenzyme Q10 deficiency-1, caused by COQ2 disease-causing variants, is an autosomal recessive disorder, and genetic testing is the gold standard for diagnosing this condition. A Chinese boy with steroid-resistant nephrotic syndrome, focal segmental glomerulosclerosis, and progressive kidney insufficiency was included in the study. Electron microscopy revealed the glomerular basement membrane with irregular thickness and lamellation with diffuse effacement of foot processes in the podocytes, and swollen mitochondria with abnormal cristae in the podocytes. Coenzyme Q10 supplementation started about 3 weeks after the onset of mild kidney dysfunction did not improve the proband's kidney outcome. Proband-only whole-exome sequencing and Sanger sequencing revealed two heteroallelic COQ2 variants: a maternally inherited novel variant c.1013G > A[p.(Gly338Glu)] in exon 6 and a variant of unknown origin c.1159C > T[p.(Arg387*)] in exon 7. Subsequent long-read sequencing demonstrated these two variants were located on different alleles. Our report extends the phenotypic and genotypic spectrum of COQ2 glomerulopathy.

Are children with IgA nephropathy different from adult patients?

BACKGROUND: Previously, several studies have indicated that pediatric IgA nephropathy (IgAN) might be different from adult IgAN, and treatment strategies might be also different between pediatric IgAN and adult IgAN. METHODS: We analyzed two prospective cohorts established by pediatric and adult nephrologists, respectively. A comprehensive analysis was performed investigating the difference in clinical and pathological characteristics, treatment, and prognosis between children and adults with IgAN. RESULTS: A total of 1015 children and 1911 adults with IgAN were eligible for analysis. More frequent gross hematuria (88% vs. 20%, p < 0.0001) and higher proteinuria (1.8 vs. 1.3 g/d, p < 0.0001) were seen in children compared to adults. In comparison, the estimated glomerular filtration rate (eGFR) was lower in adults (80.4 vs. 163 ml/min/1.73 m2, p < 0.0001). Hypertension was more prevalent in adult patients. Pathologically, a higher proportion of M1 was revealed (62% vs. 39%, p < 0.0001) in children than in adults. S1 (62% vs. 28%, p < 0.0001) and T1-2 (34% vs. 8%, p < 0.0001) were more frequent in adults. Adjusted by proteinuria, eGFR, and hypertension, children were more likely to be treated with glucocorticoids than adults (87% vs. 45%, p < 0.0001). After propensity score matching, in IgAN with proteinuria > 1 g/d, children treated with steroids were 1.87 (95% CI 1.16-3.02, p = 0.01) times more likely to reach complete remission of proteinuria compared with adults treated with steroids. CONCLUSIONS: Children present significantly differently from adults with IgAN in clinical and pathological manifestations and disease progression. Steroid response might be better in children.

Histologic and Clinical Factors Associated with Kidney Outcomes in IgA Vasculitis Nephritis.

BACKGROUND: Nephritis is a common manifestation of IgA vasculitis and is morphologically indistinguishable from IgA nephropathy. While MEST-C scores are predictive of kidney outcomes in IgA nephropathy, their value in IgA vasculitis nephritis has not been investigated in large multiethnic cohorts. METHODS: Biopsies from 262 children and 99 adults with IgA vasculitis nephritis ( N =361) from 23 centers in North America, Europe, and Asia were independently scored by three pathologists. MEST-C scores were assessed for correlation with eGFR/proteinuria at biopsy. Because most patients ( N =309, 86%) received immunosuppression, risk factors for outcomes were evaluated in this group using latent class mixed models to identify classes of eGFR trajectories over a median follow-up of 2.7 years (interquartile range, 1.2-5.1). Clinical and histologic parameters associated with each class were determined using logistic regression. RESULTS: M, E, T, and C scores were correlated with either eGFR or proteinuria at biopsy. Two classes were identified by latent class mixed model, one with initial improvement in eGFR followed by a late decline (class 1, N =91) and another with stable eGFR (class 2, N =218). Class 1 was associated with a higher risk of an established kidney outcome (time to ≥30% decline in eGFR or kidney failure; hazard ratio, 5.84; 95% confidence interval, 2.37 to 14.4). Among MEST-C scores, only E1 was associated with class 1 by multivariable analysis. Other factors associated with class 1 were age 18 years and younger, male sex, lower eGFR at biopsy, and extrarenal noncutaneous disease. Fibrous crescents without active changes were associated with class 2. CONCLUSIONS: Kidney outcome in patients with biopsied IgA vasculitis nephritis treated with immunosuppression was determined by clinical risk factors and endocapillary hypercellularity (E1) and fibrous crescents, which are features that are not part of the International Study of Diseases of Children classification.

Urinary epidermal growth factor predicts complete remission of proteinuria in Chinese children with IgA nephropathy.

BACKGROUND: This study investigated the association between urinary epidermal growth factor (EGF) and complete remission (CR) of proteinuria in children with IgA nephropathy (IgAN). METHODS: We included 108 patients from the Registry of IgA Nephropathy in Chinese Children. The urinary EGF at the baseline and follow-up were measured and normalized by urine creatinine (expressed as uEGF/Cr). The person-specific uEGF/Cr slopes were estimated using linear mixed-effects models for the subset of patients with longitudinal data of uEGF/Cr. Cox models were used to analyze the associations of baseline uEGF/Cr and uEGF/Cr slope with CR of proteinuria. RESULTS: Patients with high baseline uEGF/Cr were more likely to achieve CR of proteinuria (adjusted HR 2.24, 95% CI: 1.05-4.79). The addition of high baseline uEGF/Cr on the traditional parameters significantly improved the model fit for predicting CR of proteinuria. In the subset of patients with longitudinal data of uEGF/Cr, high uEGF/Cr slope was associated with a higher likelihood of CR of proteinuria (adjusted HR 4.03, 95% CI: 1.02-15.88). CONCLUSIONS: Urinary EGF may be a useful noninvasive biomarker for predicting and monitoring CR of proteinuria in children with IgAN. IMPACT: High levels of baseline uEGF/Cr (>21.45 ng/mg) could serve as an independent predictor for CR of proteinuria. The addition of baseline uEGF/Cr on the traditional clinical pathological parameters significantly improved the fitting ability for the prediction of CR of proteinuria. Longitudinal data of uEGF/Cr were also independently associated with CR of proteinuria. Our study provides evidence that urinary EGF may be a useful noninvasive biomarker in the prediction of CR of proteinuria as well as monitoring therapeutic response, thus guiding treatment strategies in clinical practice for children with IgAN.

Spectrum of Mutations in Pediatric Non-glomerular Chronic Kidney Disease Stages 2-5.

Renal hypodysplasia and cystic kidney diseases, the common non-glomerular causes of pediatric chronic kidney disease (CKD), are usually diagnosed by their clinical and imaging characteristics. The high degree of phenotypic heterogeneity, in both conditions, makes the correct final diagnosis dependent on genetic testing. It is not clear, however, whether the frequencies of damaged alleles vary among different ethnicities in children with non-glomerular CKD, and this will influence the strategy used for genetic testing. In this study, 69 unrelated children (40 boys, 29 girls) of predominantly Han Chinese ethnicity with stage 2-5 non-glomerular CKD caused by suspected renal hypodysplasia or cystic kidney diseases were enrolled and assessed by molecular analysis using proband-only targeted exome sequencing and array-comparative genomic hybridization. Targeted exome sequencing discovered genetic etiologies in 33 patients (47.8%) covering 10 distinct genetic disorders. The clinical diagnoses in 13/48 patients (27.1%) with suspected renal hypodysplasia were confirmed, and two patients were reclassified carrying mutations in nephronophthisis (NPHP) genes. The clinical diagnoses in 16/20 patients (80%) with suspected cystic kidney diseases were confirmed, and one patient was reclassified as carrying a deletion in the hepatocyte nuclear factor-1-beta gene (HNF1B). The diagnosis of one patient with unknown non-glomerular disease was elucidated. No copy number variations were identified in the 20 patients with negative targeted exome sequencing results. NPHP genes were the most common disease-causing genes in the patients with disease onsets above 6 years of age (14/45, 31.1%). The children with stage 2 and 3 CKD at onset were found to carry causative mutations in paired box gene 2 (PAX2) and HNF1B gene (11/24, 45.8%), whereas those with stage 4 and 5 CKD mostly carried causative mutations in NPHP genes (19/45, 42.2%). The causative genes were not suspected by the kidney imaging patterns at disease onset. Thus, our data show that in Chinese children with non-glomerular renal dysfunction caused by renal hypodysplasia and cystic kidney diseases, the common causative genes vary with age and CKD stage at disease onset. These findings have the potential to improve management and genetic counseling of these diseases in clinical practice.

Factors predicting the recovery from acute kidney injury in children with primary nephrotic syndrome.

BACKGROUND: The prognosis of acute kidney injury (AKI) varies in children with nephrotic syndrome (NS), data on factors predicting the recovery and recurrence of AKI in children with NS are limited. This study aimed to explore the possible factors predicting the recovery from and recurrence of AKI in children with primary NS. METHODS: Children with primary NS complicated with AKI from 1993 to 2017 in a single centre were reviewed retrospectively. The clinical pictures and possible factors predicting the recovery from and recurrence of AKI in children with primary NS were investigated. RESULTS: Sixty-eight episodes of AKI in 59 children with NS were analysed: 88.2% of AKI recovered within 3 months, and 2.9% of AKI did not recover after 3 months. Survival analysis revealed that leucocyturia is significantly related to the AKI recovery time (P = 0.001), and children with leucocyturia [22 (4, 79) days] recovered significantly slower than did children without leucocyturia [12.0 (2, 39) days]. Renal tubular and interstitial injury were prominent in children with leucocyturia, and 11.9% of children with index AKI experienced the recurrence of AKI. CONCLUSIONS: Most episodes of AKI that occurred in children with NS recovered completely. Leucocyturia is a significant factor predicting the recovery time of AKI.

LAMB2 novel variant c.2885-9 C>A affects RNA splicing in a minigene assay.

BACKGROUND: Both Pierson syndrome (PS) and isolated nephrotic syndrome can be caused by LAMB2 biallelic pathogenic variants. Only 15 causative splicing variants in the LAMB2 gene have been reported. However, the pathogenicity of most of these variants has not been verified, which may lead to incorrect interpretation of the functional consequence of these variants. METHODS: Using high-throughput DNA sequencing and Sanger sequencing, we detected variants in a female with clinically suspected PS. A minigene splicing assay was performed to assess the effect of LAMB2 intron 20 c.2885-9C>A on RNA splicing. We also performed the immunohistochemical analysis of laminin beta-2 in kidney tissues. RESULTS: Two novel LAMB2 heteroallelic variants were found: a paternally inherited variant c.2885-9C>A in intron 20 and a maternally inherited variant c. 3658C>T (p. (Gln1220Ter)). In vitro minigene assay showed that the variant c.2885-9C>A caused erroneous integration of a 7 bp sequence into intron 20. Immunohistochemical analysis revealed the absence of glomerular expression of laminin beta-2, the protein encoded by LAMB2. CONCLUSION: We demonstrated the impact of a novel LAMB2 intronic variant on RNA splicing using the minigene assay firstly. Our results extend the mutational spectrum of LAMB2.

Spectrum of thrombotic complications and their outcomes in Chinese children with primary nephrotic syndrome.

BACKGROUND: Thromboembolism is a life-threatening, limb-threatening or organ-threatening complication that occurs in patients with primary nephrotic syndrome (NS). There are few studies on the spectrum, complications and outcomes of thrombosis in children with NS. This study aimed to determine the spectrum of thrombosis and its relationship with the nephrotic state, treatment and outcomes in children and adolescents with primary NS. METHODS: The medical records of subjects aged 1-18 years with NS complicated with thromboembolism treated at our centre within the last 26 years were retrieved. Data on the status of NS, site, symptoms and signs, laboratory investigations, diagnosis, treatment, complications and outcomes of thrombosis were collected and reviewed retrospectively. A severe complication was defined as a condition associated with thrombosis requiring a special diagnostic modality to confirm or a specific treatment such as surgical intervention. The outcome of thrombosis was defined as the status of thrombosis, as determined by imaging methods and the functional status with respect to the anatomic sites of thrombosis at the last follow-up. The permanent dysfunction of an organ or limb related to thrombosis was defined as a sequela. RESULTS: We observed thrombosis in 1.4% (27/1995) of subjects with NS during the study period. There were 27 subjects with thrombosis, including 21 males and 6 females. Thrombosis was observed in 51.9% (14/27) of the study participants with steroid resistant NS. Most episodes of thrombosis occurred during the active stage of NS; however, 7.4% of thrombosis cases occurred during the remission of proteinuria. Renal vein thrombosis (33.3%) and pulmonary embolism (25.9%) were the most common types of thrombosis. Among the 17 subjects biopsied, minimal change disease and membranous nephropathy were the two most common findings. Six (22.2%) subjects experienced severe complications or sequelae; 1 had persistent intracranial hypertension, 1 had intestinal perforation, 1 had hypoxemia and pulmonary hypertension, 1 had lameness, 1 had epilepsy, and 1 had an askew mouth due to facial paralysis. In 19 (70.4%) subjects, the symptoms resolved completely or improved without severe complications or sequelae. CONCLUSIONS: Thrombosis mostly occurred in males of school age during the active stage of NS. Renal vein thrombosis and pulmonary embolism were the most common types of thrombosis. In most patients with thrombosis, the symptoms improved completely without complications with standard anticoagulation therapy. However, 22.2% had severe complications or sequelae requiring an advanced diagnostic modality and aggressive treatment.

Value of electron microscopy in the pathological diagnosis of native kidney biopsies in children.

BACKGROUND: Pediatric native kidney diseases are common worldwide. The pathological diagnosis of kidney lesions is crucial for clinical treatment and prognosis. The aim of the current study was therefore to evaluate the value of electron microscopy (EM) to the final diagnosis of native kidney biopsies in children. METHODS: A retrospective evaluation of 855 pediatric kidney biopsies obtained from the Department of Pediatrics in Peking University First Hospital between November 2010 and December 2017 was performed to assess the contribution of EM to the final diagnosis. RESULTS: The role of EM in the final diagnosis was determined to be crucial in 300 cases (35.1%), important in 280 cases (32.7%), and auxiliary in 275 cases (32.2%). EM is considered most valuable in a large percentage of glomerular diseases, mainly including minimal change disease, early-stage membranous nephropathy, postinfectious glomerulonephritis, Alport syndrome, thin basement membrane nephropathy, and thrombotic microangiopathy. EM also provided helpful diagnostic information in cases of focal segmental glomerulosclerosis, lupus nephritis, IgA nephropathy, and IgA vasculitis (Henoch-Schonlein purpura nephritis). Additionally, EM was crucial in 90.0% of cases of subtle pathological changes observed with light microscopy (LM) and immunofluorescence (IF) and in 69.3% of the IF-negative specimens. Patients with nephrotic syndrome or hematuria also benefit from ultrastructural examination. CONCLUSIONS: The present study demonstrated the crucial or important role of EM in the diagnosis of a majority of native kidney biopsies in children. The application of EM should be integrated together with LM and IF as a routine method of assessing pediatric kidney specimens. Graphical abstract.

Phenotypic spectrum and antialbuminuric response to angiotensin converting enzyme inhibitor and angiotensin receptor blocker therapy in pediatric Dent disease.

BACKGROUND: To characterize the phenotypic spectrum and assess the antialbuminuric response to angiotensin converting enzyme (ACE) inhibitor and/or angiotensin receptor blocker (ARB) therapy in a cohort of children with Dent disease. METHODS: The patients' clinical findings, renal biopsy results, genetic and follow-up data were analyzed retrospectively. Mutations in CLCN5 or OCRL were detected by next-generation sequencing or Sanger sequencing. RESULTS: Of 31 Dent disease boys, 24 carried CLCN5 and 7 carried OCRL mutations. Low molecular weight proteinuria and albuminuria were detected in all cases. Nephrotic-range proteinuria and severe albuminuria were identified in 52% and 62% of cases, respectively; by 7 years of age, 6 patients had hematuria and nephrotic-range proteinuria, and 7 patients had hematuria and moderate to severe albuminuria. In addition to disease-related renal features, patients with Dent-1 disease also presented with congenital cataract (1/9) and developmental delay (2/7). Seventeen of 31 patients underwent renal biopsy. Glomerular changes included mild glomerular lesions, mesangial proliferative glomerulonephritis and focal segmental glomerular sclerosis. Thirteen of the 31 patients had follow-up records and received ACE inhibitor and/or ARB treatment for more than 3 months. After a median 1.7 (range 0.3-8.5) years of treatment, a reduction in the urinary microalbumin-to-creatinine ratio was observed in 54% of children. CONCLUSIONS: Hematuria with nephrotic-range proteinuria or moderate to severe albuminuria was common in Dent disease patients. Extrarenal manifestations were observed in Dent-1 patients, which extends the phenotypic spectrum. In addition, ACE inhibitors and ARBs are well tolerated, and they are partially effective in controlling albuminuria.

Interpretation of Autosomal Recessive Kidney Diseases With "Presumed Homozygous" Pathogenic Variants Should Consider Technical Pitfalls.

Background: A false interpretation of homozygosity for pathogenic variants causing autosomal recessive disorders can lead to improper genetic counseling. The aim of this study was to demonstrate the underlying etiologies of presumed homozygous disease-causing variants harbored in six unrelated children with five different genetic renal diseases when the same variant was identified in a heterozygous state in only one of the two parents from each family using direct sequencing. Methods: Peripheral blood genomic DNA samples were extracted. Six short tandem repeats were used to verify the biological relationships between the probands and their parents. Quantitative PCR was performed to detect mutant exons with deletions. Single nucleotide polymorphism analysis and genotyping with polymorphic microsatellite markers were performed to identify uniparental disomy (UPD). Results: Each proband and his/her parents had biological relationships. Patients 2, 4, and 6 were characterized by large deletions encompassing a missense/small deletion in DGKE, NPHP1, and NPHS1, respectively. Patients 1 and 5 were caused by segmental UPD in NPHS2 and SMARCAL1, respectively. In patient 6, maternal UPD, mosaicism in paternal sperm or de novo variant in NPHP1 could not be ruled out. Conclusions: When a variant analysis report shows that a patient of non-consanguineous parents has a pathogenic presumed homozygous variant, we should remember the need to assess real homozygosity for the variant, and a segregation analysis of the variants within the parental DNAs and comprehensive molecular tests to evaluate the potential molecular etiologies, such as a point variant and an overlapping exon deletion, UPD, germline mosaicism and de novo variant, are crucial.

OFD1 mutation induced renal failure and polycystic kidney disease in a pair of childhood male twins in China.

BACKGROUND: Oral-facial-digital syndrome type 1 (OFD1) is a rare ciliopathy mainly with an X-linked dominant pattern of inheritance, which is caused by mutations in the OFD1 gene. The OFD1 protein is located within the centrosomes and basal bodies of the primary cilia. It is reported that approximately 15%-50% cases of OFD1 progress to end-stage renal disease (ESRD) following development of polycystic kidney diseases (PKD). Here we report a pair of childhood male twins who presented only renal failure and PKD caused by an OFD1 mutation in China. CASE SUMMARY: A pair of 14-year male twins were hospitalized with a complaint of abnormal renal function for nine days. They both complained of ankle pain for 3 mo vs 2 wk, respectively. They denied fever, abdominal pain, daytime or nighttime enuresis, urgency, dysuria, or gross hematuria. Laboratory tests at a local hospital showed renal failure (serum creatinine 485 µmol/L vs 442 µmol/L, blood urea nitrogen 14.7 mol/L vs 14.5 mol/L) and anemia (hemoglobin 88 g/L vs 98 g/L). The twins are monozygotic. There was no abnormal birth, past medical, or family history. Clinical data were analyzed and genetic analysis on PKD was carried out in the twins by next-generation sequencing. The results showed that the twins presented low-molecular-weight proteinuria, hyposthenuria, anemia, renal failure, and renal polycystic changes. Genetic tests showed that the twins both carried a hemizygous mutation in exon 19 c.2524G>A (p. G842R) of the OFD1 gene. Their mother heterozygously carried the same mutation as the twins but was without any phenotypes while their father was normal. CONCLUSION: We have reported a pair of childhood male twins with an OFD1 mutation who presented ESRD and PKD but without any other phenotypes of OFD1 in China.

Diverse phenotypes in children with PAX2-related disorder.

BACKGROUND: The aim of this study was to analyze the diverse phenotypes of children with PAX2-related disorder so as to improve our understanding of this disease. METHODS: The clinical data of ten children with PAX2 mutations, detected by targeted region capture sequencing or whole-exome sequencing, were retrospectively analyzed. Family members of index cases were verified by Sanger sequencing and family segregation analysis was performed. RESULTS: The age of first symptom of 10 unrelated children (six girls and four boys) was 6.4 (ranged from postnatal day to 14.8) years old. Proteinuria, abnormal renal function, and structure were found in all patients. Renal hypoplasia and renal cysts were found in 10 of 10 and five of 10 cases, respectively. Three patients progressed to chronic kidney disease stage 5 and the onset age of end-stage renal disease was 9.8-16.4 years old. PAX2-related ocular abnormalities were found in five of seven cases and three patients were observed to have more than one ocular findings involved. In addition to diverse renal and ocular findings, new phenotypes including congenital ventricular septal defect, skeletal deformity (fourth metatarsal microsomia), ovarian teratoma, and relatively rare extrarenal manifestations such as growth retardation, gout, and microcephaly were also found. Three novel mutations were reported for the first time. De novo mutations occurred in all patients who were carried out segregation analysis. Patients with the same mutation had different manifestations. PAX2-related disorder showed remarkable clinical variability and phenotypic heterogeneity. CONCLUSION: We firstly reported skeletal deformity (fourth metatarsal microsomia), ovarian teratoma, and congenital ventricular septal defect as new phenotypes of PAX2-related disorder which enlarged the phenotypic spectrum. Gout was firstly reported as the onset symptom of PAX2-related disorder. The diagnosis of PAX2-related disorder should be considered without family history due to a much higher percentage of De novo mutations.

Population pharmacokinetics and dosage optimization of tacrolimus in pediatric patients with nephrotic syndrome
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OBJECTIVES: The aims of this study were to investigate the population pharmacokinetic (PPK) characteristics of tacrolimus in Chinese children with nephrotic syndrome and to apply it in clinical practice. MATERIALS AND METHODS: A total of 137 concentrations from 61 patients were collected from routine therapeutic drug monitoring data between 2011 and 2018. Population modeling was performed with the nonlinear mixed-effects model (NONMEM) program, using a one-compartment model with first-order absorption and elimination. The mean population estimate values of clearance (CL/F) and volume of distribution (V/F) were determined. Common demographic and clinical variables were tested for their influence on these parameters. External validation was conducted, and Monte Carlo simulation, based on the final model, was carried out to determine optimal dosage regimen. RESULTS: Age and body weight were the covariates that displayed a significant influence on CL/F and V/F according to the final regression model. Goodness-of-fit plots, bootstrap outcomes, and external validation confirmed the relatively good stability and prediction capability of the model. The interindividual variability of CL/F was 31.10%, and the residual variability was 0.91 ng/mL. Mean prediction error (MPE, %) and Mean absolute prediction error (MAPE, %) were 10.3% and 16.6%, respectively. Monte Carlo simulation based on the final model was carried out to determine optimal dosage regimen. CONCLUSION: A PPK model of tacrolimus in children with nephrotic syndrome was developed. Age and bodyweight could partly explain the interindividual variability in the CL/F and V/F of tacrolimus. The final model could be used to accurately predict tacrolimus individual pharmacokinetic parameters and assist in dosage optimization.
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What is the impact of human leukocyte antigen mismatching on graft survival and mortality in renal transplantation? A meta-analysis of 23 cohort studies involving 486,608 recipients.

BACKGROUND: The magnitude effects of human leukocyte antigen (HLA) mismatching on post-transplant outcomes of kidney transplantation remain controversial. We aim to quantitatively assess the associations of HLA mismatching with graft survival and mortality in adult kidney transplantation. METHODS: We searched PubMed, EMBASE and the Cochrane Library from their inception to December, 2016. Priori clinical outcomes were overall graft failure, death-censored graft failure and all-cause mortality. RESULTS: A total of 23 cohort studies covering 486,608 recipients were selected. HLA per mismatch was significant associated with increased risks of overall graft failure (hazard ratio (HR), 1.06; 95% confidence interval (CI), 1.05-1.07), death-censored graft failure (HR: 1.09; 95% CI 1.06-1.12) and all-cause mortality (HR: 1.04; 95% CI: 1.02-1.07). Besides, HLA-DR mismatches were significant associated with worse overall graft survival (HR: 1.12, 95% CI: 1.05-1.21). For HLA-A locus, the association was insignificant (HR: 1.06; 95% CI: 0.98-1.14). We observed no significant association between HLA-B locus and overall graft failure (HR: 1.01; 95% CI: 0.90-1.15). In subgroup analyses, we found recipient sample size and ethnicity maybe the potential sources of heterogeneity. CONCLUSIONS: HLA mismatching was still a critical prognostic factor that affects graft and recipient survival. HLA-DR mismatching has a substantial impact on recipient's graft survival. HLA-A mismatching has minor but insignificant impact on graft survival outcomes.

Mutations in TTC21B cause different phenotypes in two childhood cases in China.

AIM: The TTC21B gene is now known as causative of nephronophthisis-related ciliopathies (NPHP-RC). We reported two Chinese paediatric cases with end-stage renal disease and other phenotypes caused by the TTC21B gene mutations. METHODS: The clinical features of Chinese paediatric cases with NPHP-RC were summarized. Mutation analysis of the TTC21B gene was performed using next-generation sequencing. RESULTS: The two cases both had nephrotic proteinuria, renal failure, hypertension and abnormal liver function (or hepatic fibrosis). One case also presented situs inversus and short phalanges. They developed end-stage renal disease (ESRD) at 1 year old and 8 years old, respectively, when renal pathology both showed focal segmental glomerular sclerosis (FSGS) with tubulointerstitial lesions including interstitial fibrosis and atrophic tubules. Three novel disease-causing TTC21B mutations were identified. One case carried homozygous mutation c.2211 + 3A > G, while the other case carried compound heterozygous mutations c.1552 T > C (p.C518R) and c.1456dupA (p.R486KfsX22). CONCLUSION: Mutations in TTC21B cause a range of ciliopathy phenotypes in humans. We identified 3 novel TTC21B mutations in two Chinese paediatric cases that both presented end-stage renal disease and other different features. This is the first TTC21B mutations ever reported in China.

Value of the Oxford classification of IgA nephropathy in children with Henoch-Schönlein purpura nephritis.

BACKGROUND: The widely used International Study of Kidney Disease in Children (ISKDC) classification for Henoch-Schönlein purpura nephritis (HSPN) does not completely correlate with the clinical presentation and long-term prognosis of this disease. Primary IgA nephropathy (IgAN) and HSPN share common features; thus, the Oxford classification of IgAN might be useful in predicting the long-term outcomes of HSPN. However, its value has not been confirmed in children with HSPN. METHODS: We selected children with HSPN diagnosed between 2003 and 2015, and reclassified their renal biopsies according to the Oxford classification scoring system. The primary outcome was impaired renal function, and remission of proteinuria and clinical remission were secondary outcomes. RESULTS: We included 104 patients (58 males, 46 females) with a median age of 10 (4-17) years. Mesangial hypercellularity (M1) was strongly associated with proteinuria, and tubular atrophy/interstitial fibrosis (T1&2) and C2 (with crescents in > 25% of glomeruli) were associated with reduced estimated glomerular filtration rate (eGFR) at the time of biopsy. Patients with M1, endocapillary proliferation (E1), segmental glomerulosclerosis (S1), and crescents (C1&2) were more likely to have been treated with high-dose methylprednisolone. At univariate time-dependent analyses, S1 was strongly associated with the primary outcome (p = 0.025), whereas T1&2 was significantly negatively associated with proteinuria remission (p = 0.035) and clinical remission (p = 0.038). CONCLUSIONS: Our findings suggest that the Oxford classification is valid for children with HSPN. S and T lesions, which are ignored in the ISKDC classification, can be used to assess renal outcomes of HSPN, and such assessments are not affected by currently available treatments. The value of M, E and C lesions in predicting response to therapy and renal outcome warrants further study.

Long-term treatment by ACE inhibitors and angiotensin receptor blockers in children with Alport syndrome.

BACKGROUND: The aim of this study was to analyze the long-term efficacy and safety of angiotensin-converting enzyme inhibitor (ACEi) and ACEi + angiotensin receptor blocker (ARB) treatments in a cohort of children with Alport syndrome (AS). METHODS: This was a respective review of 79 Chinese children with AS who received ACEi alone or combined ACEi + ARB therapy. RESULTS: The mean age of the pediatric patients with AS at onset of treatment was 8.6 ± 4.1 (range 1.5-16.3) years. The mean duration of follow-up was 2.5 ± 1.8 (range 0.5-7.8) years. For analysis, we separated the children into three groups according to proteinuria level before treatment, namely, <25, 25-50, and ≥50 mg/kg/day, respectively; after 1 year of treatment the proteinuria had decreased from 11.0 to 9.7 mg/kg/day, from 34.6 to 15.2 mg/kg/day, and from 73.0 to 50.0 mg/kg/day in each group, respectively. Proteinuria decreased significantly during the first 2 years of treatment and was stable from the third to fifth years of treatment. There was no statistically significant difference in the antiproteinuric effect of the ACEi and ACEi + ARB treatments in patients with severe or less severe mutations after 1 year of therapy. Five children stopped the ACEi + ARB treatment due to a decline in creatinine clearance. CONCLUSION: Our findings demonstrate that early and long-term ACEi and ARB treatments in children with AS is efficient and well tolerated. The antiproteinuric effect of ACEi and ARB is of equal value in children with severe and less severe mutations in the COL4An gene.